Guidelines on TaT1 (Non-muscle invasive) Bladder Cancer

Guidelines on TaT 1 (Non-muscle invasive)

Bladder Cancer M. Babjuk, W. Oosterlinck, R. Sylvester, E. Kaasinen, A. Böhle, J. Palou

© European Association of Urology 2009

TABLE OF CONTENTS

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1.

BACKGROUND

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2.

EPIDEMIOLOGY

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3. CLASSIFICATION 3.1 Tumour, Nodes, Metastases classification (TNM) 3.2 Histological grading of non-muscle invasive bladder tumours 3.2.1 WHO/ISUP grading 3.3 Controversial definition of non-muscle invasive (superficial) tumours 3.4 Inter- and intra-observer variability in staging and grading

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4.

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RISK FACTORS

5. DIAGNOSIS 5.1 Symptoms of TaT1 bladder tumours 5.2 Physical examination 5.3 Imaging 5.3.1 Intravenous urography and CT scan 5.3.2 Ultrasonography (US) 5.4 Urinary cytology 5.5 Urine molecular tests 5.6 Cystoscopy 5.7 Transurethral resection of TaT1 bladder tumours 5.8 Bladder and prostatic urethra biopsies 5.9 Fluorescence cystoscopy 5.10 Second resection 5.11 Pathological report 5.12 Recommendations for primary assessment of TaT1 bladder tumours

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6.

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PREDICTING RECURRENCE AND PROGRESSION IN TaT1 TUMOURS

7. ADJUVANT TREATMENT 7.1 Intravesical chemotherapy 7.1.1 One, immediate, post-operative intravesical instillation of chemotherapy 7.1.2 Additional adjuvant intravesical chemotherapy instillations 7.1.3 Optimizing intravesical chemotherapy 7.2 Intravesical BCG immunotherapy 7.2.1 Efficacy of bacillus Calmette-Guérin (BCG) 7.2.2 The optimal BCG schedule 7.2.3 The optimal dose of BCG 7.2.4 BCG toxicity 7.2.5 Indications for BCG 7.3 Treatment of failures of intravesical therapy 7.3.1 Failure of intravesical chemotherapy 7.3.2 Failure of intravesical BCG immunotherapy 7.4 Recommendations for intravesical therapy

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8.

CYSTECTOMY FOR NON-MUSCLE INVASIVE BLADDER CANCER

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9.

FOLLOW-UP OF PATIENTS WITH TaT1 BLADDER TUMOURS 9.1 Recommendations for follow-up cystoscopy

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10.

REFERENCES

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11.

ABBREVIATIONS USED IN THE TEXT

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1. BACKGROUND The first European Association of Urology (EAU) Guidelines on Bladder Cancer were published in 2002 (1). It was later decided to develop separate guidelines for different categories of bladder tumours: • TaT1 papillary tumours (non-muscle invasive bladder cancer) • Upper urinary tract tumours • Carcinoma in situ (CIS) • Muscle invasive bladder tumours. Separate guidelines have been published in European Urology for CIS and upper urinary tract tumours (2-3). This overview represents the updated EAU guidelines on TaT1 (non-muscle invasive) bladder cancer.

2. EPIDEMIOLOGY Bladder carcinoma is the most common malignancy of the urinary tract. In Europe, the highest incidence (given as ASR = age-standardized rate) is reported from its Western (23.6 in males and 5.4 in females) and Southern parts (27.1 in males and 4.1 in females), followed by Northern Europe (16.9 in males and 4.9 in females). The lowest incidence can be observed in Eastern European countries (14.7 in males and 2.2 in females, respectively) (4). Approximately 75-85% of patients with bladder cancer present with disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1).

3. CLASSIFICATION 3.1 Tumour, Nodes, Metastases Classification (TNM) The 2002 TNM classification approved by the Union International Contre le Cancer (UICC) has been widely accepted (Table 1) (5). It differs from the previous versions in the definition of stage T2 and T3 tumours.

Table 1: 2002 TNM classification of urinary bladder cancer T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: ‘flat tumour’ T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscle T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue: T3a Microscopically T3b Macroscopically (extravesical mass) T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate, uterus or vagina T4b Tumour invades pelvic wall or abdominal wall N - Lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node 2 cm or less in greatest dimension N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension N3 Metastasis in a lymph node more than 5 cm in greatest dimension

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M - Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

3.2

Histological grading of non-muscle invasive bladder tumours

In 1998, the new classification of non-invasive urothelial tumours was proposed by the World Health Organization (WHO) and the International Society of Urological Pathology (ISUP) (1998 WHO/ISUP classification) and published by the WHO in 2004 (6,7) (Table 2). Its major contribution is a detailed histological description of the various grades, employing specific cytological and architectural criteria. A website (www. pathology.jhu.edu/bladder) illustrating examples of various grades was developed to improve accuracy further in using the system.

Table 2: WHO grading in 1973 and in 2004 (6,7) 1973 WHO grading Urothelial papilloma Grade 1: well differentiated Grade 2: moderately differentiated Grade 3: poorly differentiated 2004 WHO grading Urothelial papilloma Papillary urothelial neoplasm of low malignant potential (PUNLMP) Low-grade papillary urothelial carcinoma High-grade papillary urothelial carcinoma

3.2.1 WHO/ISUP grading The 2004 WHO grading differentiates between papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade and high-grade urothelial carcinomas. PUNLMP are defined as lesions that do not have cytological features of malignancy but show normal urothelial cells in a papillary configuration. Although they have a negligible risk for progression, they are not completely benign and still have a tendency to recur. The intermediate grade (grade 2), which was the subject of controversy in the 1973 WHO classification, has been eliminated. The use of the 2004 WHO classification is advocated, as this should result in a uniform diagnosis of tumours, which is better classified according to risk potential. However, until the 2004 WHO classification has been validated by more clinical trials, tumours should be graded using both the 1973 and the 2004 WHO classifications (8). The majority of clinical trials published so far on TaT1 bladder tumours have been performed using the 1973 WHO classification, and therefore the following guidelines are based on the 1973 WHO grade classification.

3.3

Controversial definition of non-muscle invasive (superficial) tumours

A papillary tumour confined to the mucosa is classified as stage Ta according to the TNM system. Tumours that have invaded the lamina propria are classified as stage T1. As Ta and T1 tumours can be removed by transurethral resection (TUR), they are grouped under the heading of non-muscle invasive (superficial) bladder cancer for therapeutic purposes. Also included under this heading are flat, high-grade tumours confined to the mucosa, classified as carcinoma in situ (CIS). However, molecular biology techniques and clinical experience have demonstrated the highly malignant, invasive potential of CIS and T1 lesions. Therefore, the terms nonmuscle invasive and superficial bladder cancer are a suboptimal description.

3.4

Inter- and intra-observer variability in staging and grading

Despite well-defined criteria for the diagnosis of urothelial carcinoma, there is significant variability among pathologists defining dysplasia and CIS. There is also important interobserver variability in classifying stage T1 versus Ta tumours and grading tumours (9,10). As a consequence, this working party strongly recommends that the urologist reviews histological findings with the pathologist.

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4. RISK FACTORS Many of the aetiological factors for the development of bladder tumours are known and the urologist should be aware of the types of occupational exposures that may be related to urothelial carcinogens (11). Aromatic amines were the first to be recognized. At-risk groups include workers in the following industries: printing, iron and aluminium processing, industrial painting, gas and tar manufacturing (level of evidence: 3). Another prominent risk factor is cigarette smoking, which triples the risk of developing bladder cancer (12,13) (level of evidence: 3a). Smoking leads to higher mortality from bladder cancer during long-term followup, even though in a multivariate analysis the prognostic effect of smoking was weaker than that of other factors, such as stage, grade, size and multifocality of the tumour (14).

5. DIAGNOSIS 5.1

Symptoms of TaT1 bladder tumours

Haematuria is the most common finding in TaT1 bladder tumours. TaT1 tumours do not cause bladder pain and rarely present with bladder irritation, dysuria or urgency. In patients who do complain of these symptoms, CIS may be suspected.

5.2

Physical examination

Physical examination will not reveal TaT1 bladder tumours.

5.3

Imaging

5.3.1 Intravenous urography and CT scan Large tumours may be seen as filling defects in the bladder. Intravenous urography (IVU) is also used to detect filling defects in the calyces, renal pelvis and ureters, and hydronephrosis, which may indicate the presence of a ureteral tumour. The necessity to perform routine IVP once a bladder tumour has been detected is now questioned because of the low incidence of significant findings obtained with this method (15-17) (level of evidence: 3). The incidence of upper urinary tract tumours is low (1.8%), but increases to 7.5% in tumours located in the trigone (16). The risk of tumour recurrence in the upper urinary tract during follow-up increases in multiple and high-risk tumours (18). In many centres, computed tomography (CT) urography is used as an alternative to conventional IVU (19). Especially in invasive tumours of the upper tract, CT urography gives more information than IVU (level of evidence: 4). However, CT urography has the disadvantage of a much higher radiation exposure than IVU. 5.3.2 Ultrasonography (US) Ultrasonography (US) has been used with increasing frequency as the initial tool to assess the urinary tract. This is not only because it avoids the use of contrast agents, but also because sensitive transducers have improved imaging of the upper urinary tract and bladder. Transabdominal US permits characterization of renal masses, detection of hydronephrosis and visualization of intraluminal filling defects in the bladder. Combined with plain abdominal film, it can be as accurate as IVU in the diagnosis of the cause of haematuria (15,16) (level of evidence: 3).

5.4

Urinary cytology

Examination of a voided urine or bladder-washing specimen for exfoliated cancer cells has high sensitivity in high-grade tumours but low sensitivity in low-grade tumours (level of evidence: 3). It is thus useful when a highgrade malignancy or CIS is present; however, a negative result cannot exclude the presence of a low-grade cancer. Positive urinary cytology may indicate urothelial tumour anywhere in the urinary tract, from the calyx, through the ureters, into the bladder and proximal urethra. Cytological interpretation is user-dependent (20). The evaluation can be hampered by low cellular yield, urinary tract infections, stones or intravesical instillations. In experienced hands however the specificity exceeds 90% (21) (level of evidence: 2b). Cytology should be performed on fresh urine with adequate fixation. Morning urine is not suitable as cytolysis may be often present.

5.5

Urine molecular tests

Many studies have focused on evaluating urinary molecular markers. Several tests based on detection of soluble markers or cell-associated markers are available (21). Most of these tests have a better sensitivity

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for detecting bladder cancer than urinary cytology, but specificity is lower (level of evidence: 2b). It remains unclear whether these tests offer additional information that is useful for decision-making, follow-up, treatment and prognosis of non-muscle invasive bladder tumours (21-24). Moreover, the additional costs of some of these tests should be considered.

5.6

Cystoscopy

The diagnosis of bladder cancer ultimately depends on cystoscopic examination of the bladder and histological evaluation of the resected tissue. In general, cystoscopy is initially performed in the office, using flexible instruments. If a bladder tumour has been visualized in earlier imaging studies, a diagnostic cystoscopy can be omitted since the patient will undergo TUR. A careful description of the finding is necessary. It should include the site, size, number and appearance (papillary or solid) of the tumours as well as a description of mucosal abnormalities. Use of a bladder diagram is recommended.

5.7

Transurethral resection of TaT1 bladder tumours

The goal of the TUR in TaT1 bladder tumours is to make the correct diagnosis and remove all visible lesions. The strategy of resection depends on the size of the lesion. Small tumours (less than 1 cm) can be resected en bloc, where the specimen contains the complete tumour plus a part of the underlying bladder wall. Some experts believe that a deep resection is not necessary in small apparently low grade lesions with a previous history of TaG1 tumour. Larger tumours should be resected separately in fractions, which include the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle and the edges of the resection area. The specimens from different fractions must be referred to the pathologist in separate containers to enable him to make a correct diagnosis. Cauterization has to be avoided as much as possible during the resection to prevent tissue destruction. A complete and correct TUR is essential for the prognosis of the patient (25).

5.8

Bladder and prostatic urethra biopsies

Bladder tumours are often multifocal. Moreover TaT1 tumours can be accompanied by CIS or dysplasia. These lesions may present themselves as velvet-like, reddish areas indistinguishable from inflammation or may be not visible at all. The biopsies from normal-looking mucosa in patients with TaT1 tumours, so called random biopsies (R-biopsies) or selected site mucosal biopsies, are not routinely recommended. The likelihood of detecting CIS, especially in low-risk tumours, is extremely low (less than 2%) and the choice of adjuvant intravesical therapy is not influenced by the biopsy result (26) (level of evidence: 2a). Cold cup biopsies from normal-looking mucosa should be performed when cytology is positive or when exophytic tumour is of non-papillary appearance. When abnormal areas of urothelium are seen, it is advised to take ‘cold cup’ biopsies or biopsies with a resection loop. Material obtained by random or directed biopsies must be sent for pathological assessment in separate containers. The involvement of the prostatic urethra and ducts in male patients with TaT1 bladder tumours has been reported. Although the exact risk is not known, it seems to be higher if tumour is located on the trigone or bladder neck, in the presence of bladder CIS and in multiple tumours (27,28) (level of evidence: 3). In these cases and when cytology is positive, with no evidence of tumour in the bladder, or when abnormalities of prostatic urethra are visible, biopsies of the prostatic urethra are recommended. The biopsy is taken using resection loop from the precolicular area.

5.9

Fluorescence cystoscopy

As a standard procedure, cystoscopy and TUR are performed using white light. However, the use of white light may lead to missing lesions that are present but not visible. Fluorescence cystoscopy is performed using violet light after intravesical instillation of a photosensitizer, usually 5-aminolaevulinic acid (5-ALA) or hexaminolaevulinate (HAL). It has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventional procedures in detecting malignant tumour, particularly CIS (29-31) (level of evidence: 2a). However, false-positivity can be induced by inflammation and recent TUR or intravesical instillation. The benefit of fluorescence-guided TUR for recurrence-free survival was shown in several, small, randomized clinical trials (32-34), but its value remains to be proven in improving the outcome of patients for progression rates or survival. The additional costs of the equipment should be considered.

5.10

Second resection

The significant risk of residual tumour after the initial TUR of TaT1 lesions has been demonstrated (25,35) (level of evidence: 1). Persistent disease after resection of T1 tumours was observed in 33-53% of patients (35-41).

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Moreover, the tumour may be understaged by the initial resection. The likelihood that a TaT1, high-grade tumour has been understaged and is therefore muscle invasive is 10% (36,37). As the treatment of a TaT1, high-grade tumour and a T2 tumour is completely different, correct staging is important. A second TUR should be considered when the initial resection was incomplete, e.g. when multiple and/or large tumours are present, or when the pathologist has reported that the specimen contained no muscle tissue. Furthermore, a second TUR should be performed when a high-grade, non-muscle invasive tumour or a T1 tumour has been detected at the initial TUR. It has been demonstrated that a second TUR can increase recurrence-free survival (39,40) (level of evidence: 2a). There is no consensus about the strategy and timing of a second TUR. Most authors recommend resection at 2-6 weeks after the initial TUR. The procedure should include a resection of the primary tumour site.

5.11

Pathological report

Pathological investigation of the specimen obtained by TUR and biopsies is an essential step in the diagnosis of bladder cancer. The pathological report should specify the grade of the lesion and the depth of tumour invasion into the bladder wall and should give information about whether the lamina propria and muscle are present in the specimen (42). Close cooperation between urologist and pathologist is recommended.

5.12 Recommendations for primary assessment of TaT1 bladder tumours • • • • • • • •

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Renal and bladder ultrasonography, IVU or CT in selected cases (tumours located in the trigone). (Grade of recommendation: B) Cystoscopy with description of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended. (Grade of recommendation: C) Urine analysis Urine cytology TUR in one piece for small tumours (less than 1 cm), including a part from the underlying bladder wall. (Grade of recommendation: B) TUR in fractions (including muscle tissue) for larger tumours. (Grade of recommendation: B) Biopsies of abnormal-looking urothelium, biopsies from normal-looking mucosa when cytology is positive or when exophytic tumour is of non-papillary appearance. (Grade of recommendation: C) Biopsy of the prostatic urethra in the case of bladder neck tumour, when bladder CIS is present or suspected, in the case of positive cytology without evidence of tumour in the bladder or when abnormalities of prostatic urethra are visible. If it was not performed during the initial procedure it can be completed at the time of the second resection. The biopsy is taken using resection loop from the precolicular area (Grade of recommendation: C) If equipment is available, fluorescence-guided biopsy when bladder CIS is suspected (e.g. positive cytology, recurrent tumour with previous history of a high grade lesion) (Grade of recommendation: C) A second TUR at 2-6 weeks after the initial resection when it was incomplete or when a high-grade or T1 tumour was detected. (Grade of recommendation: B) The pathological report should specify the grade, the depth of tumour invasion and whether the lamina propria and muscle are present in the specimen. (Grade of recommendation: C)

6. PREDICTING RECURRENCE AND PROGRESSION IN TaT1 TUMOURS The classic way to categorize patients with TaT1 tumours is to divide them into risk groups based on prognostic factors derived from multivariate analyses. Using such a technique, it was proposed to divide patients into low-risk, intermediate-risk and high-risk groups (43). When using these risk groups, however, no difference is usually made between the risk of recurrence and progression. Although prognostic factors may indicate a high risk for recurrence, the risk of progression may still be low and other tumours may have a high risk of both recurrence and progression. In order to separately predict the short-term and long-term risks of both recurrence and progression in individual patients, the European Organization for Research and Treatment of Cancer (EORTC) developed a scoring system and risk tables (44). The basis for these tables is the EORTC database, which provided

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individual patient data for 2,596 patients diagnosed with TaT1 tumours who were randomized in seven EORTC trials. Patients with CIS only were not included. Seventy eight percent received intravesical treatment, mostly chemotherapy. They did not however have a second TUR or receive maintenance BCG. The scoring system is based on the six most significant clinical and pathological factors: • number of tumours • tumour size • prior recurrence rate • T category • presence of concomitant CIS • tumour grade. Table 3 illustrates the weights applied to various factors for calculating the total scores for recurrence and progression. Table 4 shows the total scores stratified, as in the original article (44), into four categories reflecting various probabilities of recurrence and progression at 1 and 5 years. With combining two of the four categories distinctly in recurrence and progression, the EAU working group suggests to use, as shown in the rightmost column in table 4, a 3-tier system defining low, intermediate and high risk groups for recurrence and progression.

Table 3: Weighting used to calculate recurrence and progression scores Factor Number of tumours Single 2-7 > 8 Tumour diameter < 3 cm > 3 cm Prior recurrence rate Primary < 1 recurrence/year > 1 recurrence/year Category Ta T1 Concomitant CIS No Yes Grade (1973 WHO) G1 G2 G3 Total score CIS = carcinoma in situ

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Recurrence

Progression

0 3 6

0 3 3

0 3

0 3

0 2 4

0 2 2

0 1

0 4

0 1

0 6

0 1 2 0-17

0 0 5 0-23

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Table 4: Probability of recurrence and progression according to total score Recurrence score 0 1-4 5-9 10-17

Probability of recurrence at 1 year % (95% CI) 15 (10-19) 24 (21-26) 38 (35-41) 61 (55-67)

Probability of recurrence at 5 years % (95% CI) 31 (24-37) 46 (42-49) 62 (58-65) 78 (73-84)

Recurrence risk group

Progression score 0 2-6 7-13 14-23

Probability of progression at 1 year % (95% CI) 0.2 (0-0.7) 1 (0.4-1.6) 5 (4-7%) 17 (10-24)

Probability of progression Progression at 5 years risk group % (95% CI) 0.8 (0-1.7) Low risk 6 (5-8) Intermediate risk 17 (14-20) High risk 45 (35-55)

Low risk Intermediate risk High risk

Note: Electronic calculators for Tables 3 and 4 are available at http://www.eortc.be/tools/bladdercalculator/

7. ADJUVANT TREATMENT 7.1

Intravesical chemotherapy

7.1.1 One, immediate, post-operative intravesical instillation of chemotherapy Although a state-of-the-art TUR by itself could eradicate a TaT1 tumour completely, these tumours will recur in a high percentage of cases and progress to muscle invasive bladder cancer in a limited number of cases. The high variability in the 3-month recurrence rate indicates that TUR is incomplete or provokes recurrences in a considerable percentage of patients (25). It is therefore necessary to consider adjuvant therapy in all patients. In a meta-analysis of seven randomized trials (1,476 patients with a median follow-up of 3.4 years), one immediate instillation of chemotherapy after TUR decreased the percentage of patients with recurrence by 12% (from 48.4% to 36.7%) and the odds of recurrence by 39%. The benefit was confirmed in both single and multiple tumours (45) (level of evidence: 1a). The difference of 12% means that in every 100 patients, 12 TURs may be avoided with one postoperative instillation, i.e. that 8.5 patients must be treated to prevent one recurrence. Since the costs of a TUR, anaesthesia and hospitalization in most countries exceed the cost of 8.5 times one instillation, this procedure is considered to be cost-effective. The effect can be explained by the destruction of circulating tumour cells, immediately after TUR, or as an ablative effect (chemoresection) of residual tumour cells at the resection site. The timing of the instillation is crucial. In all studies, the instillation was administered within 24 hours. One study reported that if the first instillation was not given the same day as TUR, there was a twofold increase in the relative risk of recurrence (46) (level of evidence: 2a). There is no single drug that is superior with regards to efficacy. Mitomycin C, epirubicin and doxorubicin have all shown a beneficial effect (45) (level of evidence: 1b). One immediate post-operative instillation of chemotherapy should be given in all patients after TUR of presumably non-muscle invasive bladder cancer. Severe complications have been reported in patients in whom extravasation of the drug occurred (47). Thus, an immediate instillation should be omitted in case of overt or suspected intra- or extra-peritoneal perforation, which is most likely to appear in extensive TUR procedures. Clear instructions should be given to the nursing staff for controlling the free flow of the bladder catheter at the end of the instillation. 7.1.2 Additional adjuvant intravesical chemotherapy instillations The need for further adjuvant intravesical therapy depends on the patient’s prognosis. In patients with a low risk of tumour recurrence (see Table 4), a single immediate instillation reduces the risk of recurrence and may be considered to be the standard treatment in these patients (45) (level of evidence: 1a). No further treatment should be given in these patients prior to a subsequent recurrence. For other patients, however, it remains an incomplete treatment as the likelihood of recurrence and/or progression is considerable. The effect of the immediate instillation of chemotherapy occurs during the first and second year (48,49) (level of evidence: 1b). It has been calculated from the data of five randomized trials (49) that the

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reduction of recurrence lasts for a period of approximately 500 days. The choice between further chemotherapy or immunotherapy largely depends on the risk that needs to be reduced: recurrence or progression. A meta-analysis of EORTC and Medical Research Council data, comparing intravesical chemotherapy to TUR alone, demonstrated that chemotherapy prevents recurrence but not progression (50) (level of evidence: 1a). The efficacy of intravesical chemotherapy in reducing the risk of tumour recurrence was confirmed by two other meta-analyses in primary (51) and recurrent tumours (52). It is still controversial how long and how frequently instillations of intravesical chemotherapy have to be given. From a systematic review of the literature of randomized clinical trials, which compared different schedules of intravesical chemotherapy instillations, one could only conclude that the ideal duration and intensity of the schedule remains undefined because of conflicting data (53). 7.1.3 Optimizing intravesical chemotherapy One randomized trial has demonstrated that adapting the urinary pH, decreasing the urinary excretion and buffering the intravesical solution reduced the recurrence rate (54) (level of evidence: 1b). Another randomized trial documented that concentration was more important than the duration of the treatment (55) (level of evidence: 1b). In view of these data, which need confirmation, it seems advisable to ask the patient not to drink the morning before instillation and to dissolve the drug in a buffered solution at optimal pH.

7.2

Intravesical BCG immunotherapy

7.2.1 Efficacy of Bacillus Calmette-Guérin (BCG) Several meta-analyses have addressed important questions concerning the efficacy of BCG in TaT1 bladder tumours. None of them however are based on individual patient data. Four meta-analyses confirmed that BCG after TUR is superior to TUR alone or TUR and chemotherapy in preventing recurrences of TaT1 tumours (56-59) (level of evidence: 1a). Two meta-analyses demonstrated that BCG therapy prevents, or at least delays, the risk of tumour progression (60,61) (level of evidence: 1a). A meta-analysis carried out by the EORTC evaluated data from 4,863 patients enrolled in 24 randomized trials. A total of 3,967 (81.6%) patients had only papillary tumours and 896 (18.4%) had primary or concomitant CIS. Five different BCG strains were used, and in 20 out of the 24 trials some form of BCG maintenance was used. In four trials only, a 6-week induction course was used. Based on a median follow-up of 2.5 years and a maximum of 15 years, 260 out of 2,658 patients (9.8%) on BCG progressed compared to 304 out of 2,205 (13.8%) in the control groups (TUR alone, TUR plus intravesical chemotherapy, or TUR plus another immunotherapy). This result is a reduction of 27% in the odds of progression with BCG treatment (p = 0.0001). The size of the reduction is similar in patients with TaT1 papillary tumours and in those with CIS (61). However, another two meta-analyses suggested a possible bias in favour of BCG by the inclusion of patients previously treated with intravesical chemotherapy in the studies (62,63). 7.2.2 The optimal BCG schedule For optimal efficacy, BCG must be given in a maintenance schedule (59-61) (level of evidence: 1a). In the EORTC meta-analysis, only patients receiving maintenance BCG benefited. In the four trials where no maintenance was given, no reduction in progression was observed. In the 20 trials in which some form of BCG maintenance was given, a reduction of 37% in the odds of progression was observed (p = 0.00004). The metaanalysis was unable to determine which BCG maintenance schedule was the most effective (61). In their metaanalyses, Böhle et al. concluded that at least 1 year of maintenance BCG was required to show the superiority of BCG over mitomycin C in preventing recurrence or progression (59,60). Although some modifications have been tried, induction BCG instillations are classically given according to the empirical 6-weekly induction schedule introduced by Morales 30 years ago. However, many different maintenance schedules have been used, ranging from a total of 10 instillations given in 18 weeks, to 30 instillations given over 3 years (64). The optimal number of induction instillations and the optimal frequency and duration of maintenance instillations remain unknown. Based on the extent of intravesical immune response, it is suggested that three, consecutive, weekly instillations give a maximum response (65). 7.2.3 The optimal dose of BCG To reduce BCG toxicity, a number of authors have proposed one-third and one-quarter dose instillations of BCG. Comparing one-third dose to full-dose BCG in 500 patients, the Spanish Oncology Group (CUETO) found no overall difference in efficacy. However, there was a suggestion that a full dose of BCG may be more effective in multifocal disease (66,67) (level of evidence: 1b). Although fewer patients reported toxicity with the reduced dose, the incidence of severe systemic toxicity was similar in the standard- and reduced-dose groups. The same Spanish group showed in a prospective randomized trial that one-third of the standard dose of BCG

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may be the minimum effective dose in intermediate-risk tumours. A further reduction to one-sixth dose resulted in a decrease in efficacy for preventing recurrence with no decrease in toxicity (68). 7.2.4 BCG toxicity Assuming that maintenance therapy is necessary for optimal efficacy, the issue of BCG toxicity becomes more relevant. Due to the more pronounced side-effects of BCG compared to intravesical chemotherapy, reluctance still exists about BCG use. Deaths due to BCG sepsis and the high frequency of BCG-induced cystitis have compromised the use of BCG. However, with increased experience in applying BCG, the side-effects now appear to be less prominent. Serious side-effects are encountered in less than 5% of patients and can be effectively treated in virtually all cases (69) (level of evidence: 1b). Major complications can appear after systemic absorption of the drug. Thus, BCG should not be administered during the first 2 weeks after TUR, in patients with haematuria and after traumatic catheterization. 7.2.5 Indications for BCG Although BCG is a very effective treatment, consensus exists that not all patients with non-muscle invasive bladder cancer should be treated with BCG due to the risk of toxicity. Ultimately, the choice of treatment will depend upon the patient’s risk of recurrence and progression. The use of BCG will not alter the natural course of the disease in tumours at low risk of recurrence and progression (see Table 4) and may be considered to be over-treatment for this category. In patients with tumours at high risk of progression, for whom a cystectomy is not carried out, after an immediate instillation of chemotherapy, BCG including a maintenance schedule is indicated. Although patients at intermediate-risk of progression were included in the meta-analyses (59,60), a separate confirmation of the superiority of BCG in these patients is not available. BCG can be offered in this group if chemotherapy is badly tolerated or if the patient continues to have recurrences in spite of repeated chemotherapy instillations. BCG should then be given for at least 1 year.

7.3

Treatment of failures of intravesical therapy

7.3.1 Failure of intravesical chemotherapy Patients with non-muscle invasive recurrences after intravesical chemotherapy can profit from BCG instillations (62). 7.3.2 Failure of intravesical BCG immunotherapy Treatment with BCG is considered to have failed in following situations: a. Whenever muscle invasive tumour is detected during follow-up. b. If high-grade, non-muscle invasive tumour is present at both 3 and 6 months (70). In patients with tumour present at 3 months, an additional BCG course provokes complete response in more than 50% of cases, both in patients with papillary tumours and CIS (70,71). c. Any worsening of the disease under BCG treatment, such as a higher number of recurrences, higher T or higher grade, or appearance of CIS, in spite of an initial response (level of evidence: 3). Patients with a later recurrence after completion of BCG therapy can be treated according to the risk classification (Tables 3 and 4). Changing from BCG to intravesical chemotherapy or device-assisted chemotherapy instillations can yield responses in selected cases with non-muscle invasive BCG failure. However, experience is limited and these strategies are considered experimental. Because of the high risk of development of muscle invasive tumour in these patients (70,72) (level of evidence: 3), immediate cystectomy is strongly advocated upon BCG failure.

7.4

Recommendations for adjuvant therapy

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The type of intravesical therapy is based on the risk groups as shown in Table 4 In patients at low risk of tumour recurrence and progression, one immediate instillation of chemotherapy is strongly recommended as the complete adjuvant treatment. (Grade of recommendation: A) In patients at an intermediate or high risk of recurrence and an intermediate risk of progression, one immediate instillation of chemotherapy should be followed by further instillations of chemotherapy or a minimum of 1 year of BCG. (Grade of recommendation: A) If chemotherapy is given, it is advised to use the drug at its optimal pH and to maintain the concentration of the drug during instillation by reducing fluid intake. The optimal schedule and the duration of the chemotherapy instillations remain unclear, but it should probably be given for 6 to 12 months. (Grade of recommendation: B) In patients at high risk of tumour progression, after an immediate instillation of chemotherapy, intravesical BCG for at least 1 year is indicated. (Grade of recommendation: A)

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Immediate radical cystectomy may be offered to patients at highest risk of tumour progression. In patients with BCG failure, cystectomy is recommended. (Grade of recommendation: C) The absolute risks of recurrence and of progression do not always indicate the risk at which a certain therapy is optimal. The choice of therapy may be considered differently according to what risk is acceptable for the individual patient and the urologist.

8. CYSTECTOMY FOR NON-MUSCLE INVASIVE BLADDER CANCER Many experts consider it is reasonable to propose immediate cystectomy to those patients with non-muscle invasive tumour who are at high risk of progression. According to the risk tables of the EORTC (see Tables 3 and 4) these are: • multiple recurrent high-grade tumours • high-grade T1 tumours • high-grade tumours with concomitant CIS. Cystectomy is advocated in patients with non-muscle invasive BCG failure as mentioned above. Delaying cystectomy in these patients may lead to decreased disease-specific survival (73).

9. FOLLOW-UP OF PATIENTS WITH TaT1 BLADDER TUMOURS Because of the risk of recurrence and progression, patients with TaT1 bladder tumours need be followed; however, the frequency and duration of cystoscopies should reflect the individual patient’s degree of risk. Using risk tables (see Tables 3 and 4), we are able to predict the short-term and long-term risks of both recurrence and progression in individual patients and can adapt the follow-up schedule accordingly (44): a. The prompt detection of muscle invasive and high-grade non-muscle invasive recurrences is critical since a delay in diagnosis and therapy threatens a patient’s life. b. Tumour recurrence in the low-risk group is nearly always low stage and low grade. Small, non-invasive (Ta), low-grade papillary recurrences do not present an immediate danger to the patient and their early detection is not essential for successful therapy (74-81) (level of evidence: 2b). c. The result of the first cystoscopy after TUR at 3 months is a very important prognostic factor for recurrence and for progression (44,72,82,83) (level of evidence: 1a). The first cystoscopy should thus always be performed 3 months after TUR in all patients with TaT1 bladder tumour. Randomized studies investigating the possibility of safely reducing follow-up cystoscopies are lacking. The following recommendations are therefore based only on retrospective experience.

9.1

Recommendations for follow-up cystoscopy

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Patients with tumours at low risk of recurrence and progression should have a cystoscopy at 3 months. If negative, the following cystoscopy is advised at 9 months and consequently yearly for 5 years. (Grade of recommendation: C) Patients with tumours at high risk of progression should have a cystoscopy and urinary cytology at 3 months. If negative, the following cystoscopies and cytologies should be repeated every 3 months for a period of 2 years, every 4 months in the third year, every 6 months thereafter until 5 years, and yearly thereafter. A yearly exploration of the upper tract is recommended. (Grade of recommendation: C) Patients with intermediate-risk of progression (about one-third of all patients) should have an in-between follow-up scheme using cystoscopy and cytology, adapted according to personal and subjective factors. (Grade of recommendation: C)

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Oge O, Erdem E, Atsu N, Ahin A, Ozen H. Proposal for changes in cystoscopic follow-up of patients with low-grade pTa bladder tumor. Eur Urol 2000;37(3):271-4. http://www.ncbi.nlm.nih.gov/pubmed/10720851 Holmäng S, Andius P, Hedelin H, Wester K, Busch C, Johansson SL. Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 2001;165(4);1124-8. http://www.ncbi.nlm.nih.gov/pubmed/11257652 Fujii Y, Kawakami S, Koga F, Nemoto T, Kihara K. Long-term outcome of bladder papillary urothelial neoplasms of low malignant potential. BJU Int 2003;92(6):559-62. http://www.ncbi.nlm.nih.gov/pubmed/14511033 Leblanc B, Duclos AJ, Bénard F, Côté J, Valiquette L, Paquin JM, Mauffette F, Faucher R, Perreault JP.Long-term follow-up of initial Ta grade 1 transitional cell carcinoma of the bladder. J Urol 1999;162(6);1946-50. http://www.ncbi.nlm.nih.gov/pubmed/10569544 Zieger K, Wolf H, Olsen PR, Hojgaard K. Long-term follow-up of non-invasive bladder tumours (stage Ta): recurrence and progression. BJU Int 2000;85(7):824-8. http://www.ncbi.nlm.nih.gov/pubmed/10792160 Borhan A, Reeder JE, O’Connell MJ, Wright KO, Wheeless LL, di Sant’ Agnese PA, McNally ML, Messing EM. Grade progression and regression in recurrent urothelial cancer. J Urol 2003;169(6):2106-9. http://www.ncbi.nlm.nih.gov/pubmed/12771728 Soloway M, Bruck DS, Kim SS. Expectant management of small recurrent, non-invasive papillary bladder tumours. J Urol 2003;170(2 Pt 1):438-41. http://www.ncbi.nlm.nih.gov/pubmed/12853794 Gofrit ON, Pode D, Lazar A, Katz R, Shapiro A. Watchful waiting policy in recurrent Ta G1 bladder tumors. Eur Urol 2006;49(2):303-7. http://www.ncbi.nlm.nih.gov/pubmed/16413659 Holmang S, Johansson SL. Stage Ta-T1 bladder cancer: the relationship between findings at first followup cystoscopy and subsequent recurrence and progression. J Urol 2002;167(4):1634-7. http://www.ncbi.nlm.nih.gov/pubmed/11912378 Mariappan P, Smith G. A surveillance schedule for G1Ta bladder cancer allowing efficient use of check cystoscopy and safe discharge at 5 years based on a 25-year prospective database. J Urol 2005;173(4):1008-11. http://www.ncbi.nlm.nih.gov/pubmed/15758711

LIMITED TEXT UPDATE MARCH 2009

11. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations.

5-ALA ASR BCG CIS CT CUETO EAU EORTC HAL ISUP IVU PUNLMP TNM TUR UICC US WHO

5-aminolaevulinic acid age-standardized rate bacillus Calmette-Guérin carcinoma in situ computed tomography Club Urológico Español de Tratamiento Oncológico (Spanish Oncology Group) European Association of Urology European Organization for Research and Treatment of Cancer hexaminolaevulinic acid International Society of Urological Pathology intravenous urography papillary urothelial neoplasms of low malignant potential tumour, node, metastasis transurethral resection Union International Contre le Cancer ultrasonography World Health Organization

Conflict of interest All members of the Non-Muscle Invasive Bladder Cancer guidelines writing panel have provided disclosure statements of all relationships which they have and which may be perceived as a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

LIMITED TEXT UPDATE MARCH 2009

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Guidelines on

Bladder Cancer Muscle-invasive and Metastatic A. Stenzl, N.C. Cowan, M. De Santis, G. Jakse, M. Kuczyk, A.S. Merseburger, M.J. Ribal, A. Sherif, J.A. Witjes

© European Association of Urology 2009

TABLE OF CONTENTS

PAGE

1

INTRODUCTION

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2

EPIDEMIOLOGY AND RISK FACTORS 2.1 Epidemiology 2.2 Risk factors for bladder cancer 2.3 Conclusions 2.4 Recommendation 2.5 References

5 5 6 7 7 7

3 CLASSIFICATION 3.1 Tumour, Nodes, Metastases Classification (TNM) 3.2 Histological grading of non-muscle-invasive bladder tumours 3.2.1 WHO/ISUP grading 3.3 References 3.4 Pathology 3.4.1 Urologist handling of the specimens 3.4.2 Pathologist handling of the specimens 3.4.3 Pathology of muscle-invasive bladder cancer 3.4.4 Guidelines on assessment of tumour specimens 3.5 References

8 8 9 9 9 9 9 10 10 10 10

4 DIAGNOSIS AND STAGING 4.1 Diagnosis 4.1.1 Symptoms 4.1.2 Physical examination 4.1.3 Imaging 4.1.3.1 Intravenous urography and CT scan 4.1.3.2 Ultrasonography 4.1.4 Urinary cytology and urinary markers 4.1.5 Cystoscopy 4.1.6 Transurethral resection of invasive bladder tumours 4.1.7 Bladder and prostatic urethral biopsy 4.1.8 Fluorescence cystoscopy 4.1.9 Second resection 4.1.10 Concomitant prostate cancer 4.1.11 Recommendations for primary assessment of presumably invasive bladder tumours 4.1.12 References 4.2 Imaging for staging in verified bladder tumours 4.2.1 Local staging of invasive bladder cancer 4.2.1.1 MR imaging for local staging of invasive bladder cancer 4.2.1.2 CT for local staging of invasive bladder cancer 4.2.2 Imaging of nodal involvement 4.2.3 Extravesical urothelial carcinoma 4.2.4 Distant metastases other than lymph nodes 4.2.5 Conclusions 4.2.6 Recommendations for staging 4.3 References

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TREATMENT FAILURE OF NON-MUSCLE INVASIVE BLADDER TUMOURS 5.1 High-risk non-muscle-invasive urothelial carcinoma 5.2 Carcinoma in situ 5.3 Recommendations 5.4 References

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NEOADJUVANT CHEMOTHERAPY 6.1 Conclusions 6.2 Recommendations 6.3 References

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7 RADICAL SURGERY AND URINARY DIVERSION 7.1 Removal of the tumour bearing bladder 7.1.1 Background 7.1.2 Timing and delay of cystectomy 7.1.3 Indications 7.1.4 Technique and extent 7.1.5 Laparoscopic cystectomy 7.2 Urinary diversion after radical cystectomy 7.2.1 Ureterocutaneostomy 7.2.2 Ileal conduit 7.2.3 Continent cutaneous urinary diversion 7.2.4 Ureterocolonic diversion 7.2.5 Orthotopic neobladders 7.3 Morbidity and mortality 7.4 Survival 7.5 Conclusions 7.6 Recommendations 7.6.1 Recommendations for radical surgery 7.6.2 Recommendations for urinary diversion 7.7 References

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NON-RESECTABLE TUMOURS 8.1 Palliative cystectomy for muscle-invasive bladder carcinoma 8.2 Conclusions 8.3 Recommendations 8.4 References

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NEOADJUVANT BLADDER CANCER 9 neoadjuvantRADIOTHERAPY radioactivityINinMUSCLE-INVASIVE muscle-invasive bladder cancer 9.1 Pre-operative radiotherapy 9.1.1 Retrospective studies 9.1.2 Randomized studies 9.2 Conclusions 9.3 Recommendation s 9.4 References

32 32 32 32 33 33 33

10 BLADDER-SPARING TREATMENTS 10.1 Transurethral resection of bladder tumour (TURBT) 10.1.1 Conclusion and recommendation 10.1.2 References 10.2 External beam radiotherapy 10.2.1 Conclusions 10.2.2 Recommendation 10.2.3 References 10.3 Chemotherapy 10.3.1 Conclusion 10.3.2 Recommendation 10.3.3 References 10.4 Multimodality treatment 10.4.1 Conclusions 10.4.2 Recommendations 10.4.3 References

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ADJUVANT CHEMOTHERAPY 11.1 Conclusion 11.2 Recommendation 11.3 References

38 39 39 39

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METASTATIC DISEASE 12.1 Prognostic factors and treatment decisions 12.2 Single-agent chemotherapy 12.3 Standard first-line chemotherapy for ‘fit’ patients 12.4 Carboplatin-containing chemotherapy in ‘fit’ patients 12.5 Non-platinum combination chemotherapy 12.6 Chemotherapy in patients ‘unfit”’ for cisplatin 12.7 Second-line treatment 12.8 Low-volume disease and post-chemotherapy surgery 12.9 Conclusions 12.10 Recommendations 12.11 References

40 40 40 41 41 41 41 41 42 42 42 42

13.

QUALITY OF LIFE 13.1 Conclusions 13.2 Recommendations 13.3 References

47 48 48 48

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FOLLOW-UP 14.1 Conclusions and recommendations according to condition 14.2 General recommendations for follow-up 14.3 References

50 50 51 51

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ABBREVIATIONS USED IN THE TEXT

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1. INTRODUCTION The EAU guideline group for muscle-invasive and metastatic bladder cancer (MiM-BC) have prepared this guideline to help urologists assess the evidence-based management of muscle-invasive and metastatic bladder cancer and to incorporate the guideline recommendations into their clinical practice. Publications concerning muscle-invasive and metastatic bladder cancer are mostly based on retrospective analysis, including some larger multicentre studies and well-designed controlled studies. Only a few randomized studies are available, so that it is difficult to obtain high-level evidence-based data. The recommendations provided in the current guidelines are based on a systemic literature search using Medline, the Cochrane Central Register of Systematic Reviews, and reference lists in publications and review articles. There is clearly a need for continuous re-evaluation of the information presented in the current guideline by an expert panel. It has to be emphasized that the current guideline contains information for the treatment of an individual patient according to a standardized approach. The information should be considered as providing recommendations without legal implications. The level of evidence and grade of recommendation provided in this guideline follow the listings in Table 1. The aim of grading the recommendations is to provide transparency between the underlying evidence and the recommendation given. Table 1: Levels of evidence and grade of guideline recommendations as used by EAU (1) Level Type of evidence 1a Evidence obtained from meta-analysis of randomized trials 1b Evidence obtained from at least one randomized trial 2a Evidence obtained from one well-designed controlled study without randomization 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial B Based on well-conducted clinical studies, but without randomized clinical trials C Made despite the absence of directly applicable clinical studies of good quality

1.1

Reference

1.

Modified from Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [access date February 2009].

2. EPIDEMIOLOGY AND RISK FACTORS 2.1

Epidemiology

In 2006, in Europe, an estimated 104,400 incident cases of bladder cancer were diagnosed, of which 82,800 were diagnosed in men and 21,600 in women. This represents 6.6% of the total cancers in men and 2.1% in women, with an estimated male-to-female ratio of 3.8:1. In men, bladder cancer was the fourth most common cancer. Bladder cancer resulted in 4.1% of total deaths for cancer in men and 1.8% of total deaths in women (1). At the initial diagnosis of bladder cancer, 70% of cases are diagnosed as non-muscle-invasive disease and 30% as muscle-invasive disease. Among patients treated with radical cystectomy because of muscle-invasive disease, 57% had muscle invasion at presentation, while 43% had been initially diagnosed with non-muscle-invasive disease that progressed despite organ-preserving treatment (2). Approximately onethird of patients diagnosed with muscle-invasive bladder cancer have undetected metastasis at the time of treatment of the primary tumour (3), while 25% of patients submitted to radical cystectomy present with lymph node involvement at the time of surgery.

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2.2

Risk factors for bladder cancer

Tobacco smoking. Tobacco smoking is the most well-established risk factor for bladder cancer, causing about 50-65% of male cases and 20-30% of female cases. A casual relationship has been established between an exposure to tobacco and cancer in studies in which chance, bias and confounding can be ruled out with reasonable confidence (4). The alleged carcinogenic constituents of tobacco smoke include arylamines, particularly the potent carcinogen 4-aminobiphenyl, polycyclic aromatic hydrocarbons (PAHs), N-nitroso compounds, heterocyclic amines and various epoxides. The incidence of bladder cancer is directly related to the duration of smoking and number of cigarettes smoked per day (5). There is also a higher risk of bladder cancer in those who start smoking at a young age and for those exposed to environmental tobacco smoke during childhood (6). An immediate decrease in the risk of bladder cancer has been observed in those who quit smoking. This reduction was about 40% within 1 to 4 years of quitting smoking and reached 60% after 25 years of cessation (5). The promotion of cessation of smoking would result in the incidence of bladder cancer decreasing equally in men and women. Occupational exposure to chemicals. Occupational exposure is the second most important risk factor for bladder cancer. Work-related cases account for 20-25% of all bladder cancer cases in several series. The substances involved in chemical exposure have been benzene derivatives and arylamines (2-naphthylamine, 4-ABP, 4,4’-methylenedianiline and o-toluidine). Professions in which this exposure occurs include those that use dyes, rubbers, textiles, paints, leathers and chemicals (7). Because of strict regulations, these chemicals have contributed minimally to the current incidence of bladder cancer in Western countries. In fact, a trend towards a decrease in bladder cancer due to occupational exposure has been reported in a pooled analysis of 11 case-control studies on bladder cancer conducted in European countries between 1976 and 1996 (8). An example of occupational exposure is aromatic amines, which are established carcinogens for urothelium and which can be inactivated by a metabolic acetylation pathway. It has been postulated that patients with slow acetylation capability were more susceptible to bladder cancer than rapid acetylators. NAT1 and NAT-2 are N-acetyltransferase genes located on the short arm of human chromosome 8 and involved in amine inactivation. The presence of an NAT2 slow acetylation genotype has been related to a higher risk of bladder cancer (9). Other risk factors include phenacetin, which was included in 1987 among proven human carcinogens by the International Agency for Research on Cancer (IARC). Some studies have suggested that the risk of bladder cancer due to phenacetin is dose-dependent; however, the data is controversial concerning its metabolite acetaminophen (10). External beam radiation therapy. Increased rates of secondary bladder malignancies have been reported after external beam radiation therapy (EBRT) for gynaecological malignancies with relative risks of 2 to 4 (11). In patients treated for prostate cancer, the incidence of bladder cancer was significantly lower in patients treated with radical prostatectomy than in patients who underwent EBRT (12). Dietary factors. Several dietary factors had been related to bladder cancer, but the results of different studies have been controversial. Currently, there is limited evidence of a causal relationship between bladder cancer and dietary factors. A meta-analysis of 38 articles reporting data on diet and bladder cancer supported the hypothesis that vegetable and fruit intake reduced the risk of bladder cancer (13). Chronic urinary tract infection. Muscle-invasive bladder cancer, particularly invasive squamous cell carcinoma, is directly related to the presence of chronic urinary tract infection. Bladder schistosomiasis has been considered a definitive cause of urinary bladder cancer with an associated five-fold risk. Schistosomiasis is the second most common parasitic infection after malaria, with about 600 million people exposed to infection in Africa, Asia, South America and the Caribbean (14). In the same way as cyclophosphamide, an alkylating agent used for treatment of lymphoproliferative diseases and other non-neoplastic diseases, it has been correlated with posterior development of muscle-invasive bladder cancer with a period of latency of 6-13 years. Acrolein is a metabolite of cyclophosphamide and is responsible for an increase in the incidence of bladder cancer, which is independent of the occurrence of haemorrhagic cystitis related to the same treatment (15, 16). Gender. Finally, differences in bladder cancer incidence by gender have been studied. In a retrospective study of patients submitted to radical cystectomy, it was demonstrated that women are more likely to be diagnosed with primary muscle-invasive disease than men (85% vs 51%) (2). It has been proposed that women are more likely to be older than men when diagnosed with a direct effect on their survival. In addition, delayed diagnosis is more likely in women after haematuria is observed because the differential diagnosis in women includes diseases more prevalent than bladder cancer (17). Differences in the gender prevalence of bladder cancer may also be due to other factors than tobacco and chemical exposure. In a large prospective cohort study, post-menopausal status was associated with

6

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an increase in bladder cancer risk even after adjusting for smoking status. Thus, the differences in oestrogen and androgen levels between men and women could be responsible for some of the difference in gender prevalence of bladder cancer (18).

2.3

Conclusions

• •

The incidence of muscle invasive disease has not changed for a period of 5 years. Active and passive tobacco smoking continues to be the major risk factor while exposure-related incidence is decreasing (Level of evidence: 2a). The estimated male to female ratio was 3.8:1, with women more likely to be diagnosed with primary muscle invasive disease than men. Currently, treatment decisions cannot be based on molecular markers.

• •

2.4

Recommendation

•

The most important primary prevention for muscle-invasive bladder cancer is to eliminate active and passive smoking (Grade of recommendation: B).

2.5

References

1.

Ferlay J, Autier P, Boniol M. Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007;18(3):581-92. http://www.ncbi.nlm.nih.gov/pubmed/17287242 Vaidya A, Soloway MS, Hawke C, Tiguert R, Civantos F. De novo muscle invasive bladder cancer: is there a change in trend?. J Urol 2001;165(1):47-50. http://www.ncbi.nlm.nih.gov/pubmed/11125361 Prout GR Jr, Griffin PP, Shipley WU. Bladder carcinoma as a systemic disease. Cancer 1979;43(6):2532-9. http://www.ncbi.nlm.nih.gov/pubmed/455239 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum 2004;83:1-1438. http://www.ncbi.nlm.nih.gov/pubmed/15285078 Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P, Lopez-Abente G, Tzonou A, ChangClaude J, Bolm-Audorff U, Jöckel KH, Donato F, Serra C, Wahrendorf J, Hours M, T’Mannetje A, Kogevinas M, Boffetta P. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 casecontrol studies. Int J Cancer 2000;86(2):289-94. http://www.ncbi.nlm.nih.gov/pubmed/10738259 Bjerregaard BK, Raaschou-Nielsen O, Sørensen M, Frederiksen K, Christensen J, Tjønneland A, Overvad K, Chapelon FC, Nagel G, Chang-Claude J, Bergmann MM, Boeing H, Trichopoulos D, Trichopoulou A, Oikonomou E, Berrino F, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, Buenode-Mesquita HB, Kiemeney L, Gram IT, Braaten T, Lund E, Gonzalez CA, Berglund G, Allen N, Roddam A, Bingham S, Riboli E. Tobacco smoke and bladder cancer–in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2006;119(10):2412-6. http://www.ncbi.nlm.nih.gov/pubmed/16894557 Pashos CL, Botteman MF, Laskin BL, Redaelli A. Bladder cancer: epidemiology, diagnosis, and management. Cancer Pract 2002;10(6):311-22. http://www.ncbi.nlm.nih.gov/pubmed/15285078 Kogevinas M, T’Mannetje A, Cordier S, Ranft U, González CA, Vineis P, Chang-Claude J, Lynge E, Wahrendorf J, Tzonou A, Jöckel KH, Serra C, Porru S, Hours M, Greiser E, Boffetta P. Occupation and bladder cancer among men in Western Europe. Cancer Causes and Control 2003;14(10):907-14. http://www.ncbi.nlm.nih.gov/pubmed/14750529 García-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW, Tardón A, Serra C, Carrato A, García-Closas R, Lloreta J, Castaño-Vinyals G, Yeager M, Welch R, Chanock S, Chatterjee N, Wacholder S, Samanic C, Torà M, Fernández F, Real FX, Rothman N. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 2005;366(9486):649-59. http://www.ncbi.nlm.nih.gov/pubmed/16112301 Castelao JE, Yuan JM, Gago-Dominguez M, Yu MC, Ross RK.Non-steroidal anti-inflammatory drugs and bladder cancer prevention. Br J Cancer 2000;82(7):1364-9. http://www.ncbi.nlm.nih.gov/pubmed/10755416 Chrouser K, Leibovich B, Bergstralh E, Zincke H, Blute M. Bladder cancer risk following primary and adjuvant external beam radiation for prostate cancer. J Urol 2006;174(1):107-10. http://www.ncbi.nlm.nih.gov/pubmed/15947588

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

UPDATE MARCH 2008

7

12.

13.

14.

15.

16.

17.

18.

Boorjian S, Cowan JE, Konety BR, DuChane J, Tewari A, Carroll PR, Kane CJ; Cancer of the Prostate Strategic Urologic Research Endeavor Investigators. Bladder cancer incidence and risk factors in men with prostate cancer: results from Cancer of the Prostate Strategic Urologic Research Endeavor. J Urol 2007;177(3):883-7. http://www.ncbi.nlm.nih.gov/pubmed/17296367 Steinmaus CM, Nuñez S, Smith AH. Diet and bladder cancer: a meta-analysis of six dietary variables. Am J Epidemiol 2000;151(7):693-702. http://www.ncbi.nlm.nih.gov/pubmed/10752797 [No authors listed.] Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June, 1994. IARC Monogr Eval Carcinog Risks Hum 1994;61:1-241. http://www.ncbi.nlm.nih.gov/pubmed/7715068 Kaldor JM, Day NE, Kittelmann B, Pettersson F, Langmark F, Pedersen D, Prior P, Neal F, Karjalainen S, Bell J et al. Bladder tumours following chemotherapy and radiotherapy for ovarian cancer: a casecontrol study. Int J Cancer 1995;63(1):1-6. http://www.ncbi.nlm.nih.gov/pubmed/7558434 Travis LB, Curtis RE, Glimelius B, Holowaty EJ, Van Leeuwen FE, Lynch CF, Hagenbeek A, Stovall M, Banks PM, Adami J et al. Bladder and kidney cancer following cyclophosphamide therapy for nonHodgkin’s lymphoma. J Natl Cancer Inst 1995;87(7):524-30. http://www.ncbi.nlm.nih.gov/pubmed/7707439 Cárdenas-Turanzas M, Cooksley C, Pettaway CA, Sabichi A, Grossman HB, Elting L. Comparative outcomes of bladder cancer. Obstet Gynecol 2006;108(1):169-75. http://www.ncbi.nlm.nih.gov/pubmed/16816072 McGrath M, Michaud DS, De Vivo I. Hormonal and reproductive factors and the risk of bladder cancer in women. Am J Epidemiol 2006;163(3):236-44. http://www.ncbi.nlm.nih.gov/pubmed/16319290

3. CLASSIFICATION 3.1

Tumour, Nodes, Metastases Classification (TNM)

The 2002 TNM classification approved by the Union International Contre le Cancer (UICC) has been widely accepted (Table 2) (1). It differs from the previous versions in the definition of stage T2 and T3 tumours.

Table 2: 2002 TNM classification of urinary bladder cancer T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: ‘flat tumour’ T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscle T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue T3a Microscopically T3b Macroscopically (extravesical mass) T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate, uterus or vagina T4b Tumour invades pelvic wall or abdominal wall N - Lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node 2 cm or less in greatest dimension N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension N3 Metastasis in a lymph node more than 5 cm in greatest dimension

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M - Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

3.2

Histological grading of non-muscle-invasive bladder tumours

In 1998, the new classification of non-invasive urothelial tumours was proposed by the World Health Organization (WHO) and the International Society of Urological Pathology (ISUP) (1998 WHO/ISUP classification). It was published by the WHO in 2004 (2, 3) (Table 3). Its major contribution is a detailed histological description of the various grades using specific cytological and architectural criteria. A website (www.pathology.jhu.edu/bladder) illustrating examples of various grades was developed to improve accuracy further in using the system. Table 3: WHO grading in 1973 and in 2004 (2, 3) 1973 WHO grading • Urothelial papilloma • Grade 1: well differentiated • Grade 2: moderately differentiated • Grade 3: poorly differentiated 2004 WHO grading • Urothelial papilloma • Papillary urothelial neoplasm of low malignant potential (PUNLMP) • Low-grade papillary urothelial carcinoma • High-grade papillary urothelial carcinoma 3.2.1 WHO/ISUP grading The 2004 WHO grading differentiates between papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade and high-grade urothelial carcinomas. The PUNLMP are defined as lesions that do not have cytological features of malignancy but show normal urothelial cells in a papillary configuration. Although they have a negligible risk for progression, they are not completely benign and still have a tendency to recur. The intermediate grade (grade 2), which was controversial in the 1973 WHO classification, has been eliminated. The use of the 2004 WHO classification is advocated, as this should result in a uniform diagnosis of tumours, which will be better classified according to risk potential. However, until the 2004 WHO classification has been validated by more clinical trials, tumours should be graded using both the 1973 and the 2004 WHO classifications (4). Most clinical trials published so far on bladder tumours have been performed using the 1973 WHO classification and this edition of the guidelines therefore uses the 1973 WHO grade classification.

3.3

References

1.

Sobin DH, Wittekind Ch, eds. In: TNM Classification of Malignant Tumours. 6th edn. New York: WileyLiss, 2002; pp. 199-202. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Am J Surg Pathol 1998;22(12):1435-48. http://www.ncbi.nlm.nih.gov/pubmed/9850170 Sauter G, Algaba F, Amin M, Busch C, Cheville J, Gasser T, Grignon DJ, Hofstadter F, Lopez-Beltran A, Epstein JI. Tumours of the urinary system: non-invasive urothelial neoplasias. In: Eble JN, Sauter G, Epstein Jl, Sesterhenn I, eds. WHO classification of classification of tumors of the urinary system and male genital organs. Lyon: IARCC Press, 2004, pp. 29-34. Lopez-Beltran A, Montironi R. Non-invasive urothelial neoplasms: according to the most recent WHO classification. Eur Urol 2004;46(2):170-6. http://www.ncbi.nlm.nih.gov/pubmed/15245809

2.

3.

4.

3.4

Pathology

3.4.1 Urologist handling of the specimens In transurethral resection (TUR) specimens, the superficial and deep areas of the tumour must be sent to pathology separately. If random biopsies of the flat mucosa have been done, each biopsy of the flat mucosa must also be sent separately.

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In radical cystectomy, bladder fixation must be performed as soon as possible. The pathologist must open the specimen from the urethra to the bladder dome and fix the specimen in formalin. In some circumstances, this procedure can also be performed by the urologist. In a female cystectomy specimen, the length of the urethral segment removed en bloc with the specimen should be checked preferably by the urological surgeon (1). 3.4.2 Pathologist handling of the specimens Handling of specimens should follow the general rules as published by a collaborative group of pathologists and urologists (2). It must be stressed that it can be very difficult to certify the presence of a neoplastic lesion using gross examination of the cystectomy specimen after TUR or chemotherapy, and it is therefore necessary to include the entire retracted or ulcerated area. Of the margins, it is mandatory to study the urethra, ureter, the prostate in men, and radial margins (3). In urethra-sparing cystectomy, the level of urethral dissection, the completeness of the prostate specifically at the apex (in men), and the inclusion of the entire bladder neck and the amount of adjacent urethra (in women) should be documented. 3.4.3 Pathology of muscle-invasive bladder cancer At this stage, there are no cases of papillary urothelial neoplasms of low malignant potential and low-grade carcinoma. All cases are high-grade urothelial carcinomas (grade II or grade III in WHO 1973). For this reason, no more prognostic information can be provided by grading muscle-invasive bladder cancer (4). However, some morphological subtypes can be most important for prognosis and treatment decisions, as in: • Small-cell carcinomas • Urothelial carcinomas with squamous and/or glandular partial differentiation • Spindle cell carcinomas • Some urothelial carcinomas with trophoblastic differentiation. For staging, TNM 2002 is recommended. The pattern of muscular invasion can provide some prognostic information. Most cases show nodular or cordonal growth, but about 44% of cases show an infiltrative pattern. According to some authors (4), the median survival time of a patient with an infiltrative pattern is lower than with other pattern types (p = 0.06). Blood vessel invasion and lymph node infiltration have an independent prognostic significance (5). It seems that the pN category is closely associated with the number of lymph nodes studied by the pathologist. For this reason, some authors have observed that more than nine lymph nodes have to be investigated to reflect pN0 appropriately (6). New prognostic markers are under study (7). Currently, insufficient evidence exists to recommend the standard use of p53 as a prognostic marker in high-risk muscle-invasive disease, since it will not yield sufficient data upon which to base treatment in an individual patient. 3.4.4 GUIDELINES ON ASSESSMENT OF TUMOUR SPECIMENS Mandatory evaluations • Depth of invasion (categories pT2 vs pT3a, pT3b or pT4) • Margins with special attention paid to the radial margin • Histological subtype, if it has clinical implications • Extensive lymph node representation (more that eight) Optional evaluations • Bladder wall blood vessel invasion • Pattern of muscle invasion

3.5

REFERENCES

1. 2.

Stenzl A. Current Concepts for Urinary Diversion in Women. Eur Urol(EAU Update Series 1);2003:91-9. Lopez-Beltran A, Bassi PF, Pavone-Macaluso M, Montironi R, European Society of Uropathology; Uropathology Working Group. Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. A joint proposal of the European Society of Uropathology and the Uropathology Working Group. Vichows Arch 2004;445(2):103-10. http://www.ncbi.nlm.nih.gov/pubmed/15185074 Herr HW. Pathologic evaluation of radical cystectomy specimens. Cancer 2002;95(3):668-9. http://www.ncbi.nlm.nih.gov/pubmed/12209761

3.

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4.

5.

6. 7.

Jimenez RE, Gheiler E, Oskanian P, Tiguert R, Sakr W, Wood DP Jr, Pontes JE, Grignon DJ. Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progressionfree survival. Am J Surg Pathol 2000;24(7):980-7. http://www.ncbi.nlm.nih.gov/pubmed/10895820 Leissner J, Koeppen C, Wolf HK. Prognostic significance of vascular and perineural invasion in urothelial bladder cancer treated with radical cystectomy. J Urol 2003;169:955-60. http://www.ncbi.nlm.nih.gov/pubmed/12576821 Shariat SF, Karam JA, Lerner SP. Molecular markers in bladder cancer. Curr Opin Urol 2008;18(1):1-8. http://www.ncbi.nlm.nih.gov/pubmed/18090481 Tiguert R, Lessard A, So A, Fradet Y. Prognostic markers in muscle invasive bladder cancer. World J Urol 2002;20:190-5. http://www.ncbi.nlm.nih.gov/pubmed/12196903

4. DIAGNOSIS AND STAGING 4.1

Diagnosis

4.1.1 Symptoms Painless haematuria is a common finding. In addition, there is a group of patients who complain of urgency, dysuria, increased frequency and pelvic pain. Pelvic pain and all the symptoms related to urinary tract obstruction are found in more advanced tumours. 4.1.2 Physical examination Physical examination should include rectal and vaginal bimanual palpation. A palpable pelvic mass can be found in patients with locally advanced tumours. In addition, bimanual examination should be carried out before and after TUR to assess whether there is a palpable mass or the tumour fixed to the pelvic wall (1,2). 4.1.3 Imaging 4.1.3.1 Intravenous urography and CT scan Large tumours may be seen as filling defects in the bladder. Intravenous urography (IVU) is also used to detect filling defects in the calices, renal pelvis and ureters, and hydronephrosis, which may indicate the presence of a ureteral tumour. The necessity to perform routine intravenous pyelography once a bladder tumour has been detected is now questioned because of the low incidence of significant findings obtained with this method (3-5) (Level of evidence: 3). The incidence of upper urinary tract tumours is low (1.8%), but increases to 7.5% in tumours located in the trigone (4). In many centres, computed tomography (CT) urography is used as an alternative to conventional IVU (6). CT tomography gives more information than IVU, especially in invasive tumours of the upper tract (Level of evidence: 2a). 4.1.3.2 Ultrasonography Ultrasonography (US) is increasingly used as the initial tool to assess the urinary tract. This is not only because it avoids the use of contrast agents, but also because sensitive transducers have improved imaging of the upper urinary tract and bladder. Transabdominal US permits characterization of renal masses, detection of hydronephrosis and visualization of intraluminal filling defects in the bladder. Combined with plain abdominal film, it can be as accurate as IVU in diagnosing the cause of haematuria (1, 2) (Level of evidence: 3). 4.1.4 Urinary cytology and urinary markers Examination of a voided urine or bladder-washing specimen for exfoliated cancer cells has high sensitivity in high-grade tumours (Level of evidence: 3). It is therefore useful when a high-grade malignancy or carcinoma in situ (CIS) is present. Positive urinary cytology may indicate urothelial tumour anywhere in the urinary tract from the calix, through the ureters, into the bladder and proximal urethra. Cytological interpretation is user-dependent (7). The evaluation can be hampered by low cellular yield, urinary tract infections, stones or intravesical instillations. In experienced hands, however, specificity exceeds 90% (8) (Level of evidence: 2b). Cytology should be performed on fresh urine with adequate fixation. Morning urine is not suitable as cytolysis may be often present. There is no urinary marker registered specifically for the diagnosis of invasive bladder cancer. However, since most invasive tumours are high-grade, the positive predictive value of markers may be higher.

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4.1.5 Cystoscopy The diagnosis of bladder cancer ultimately depends on cystoscopic examination of the bladder and histological evaluation of the resected tissue. In general, cystoscopy is initially performed in the office, using flexible instruments. If a bladder tumour has been visualized in earlier imaging studies, such as 3D ultrasonography, multidetector row CT or MRI a diagnostic cystoscopy can be omitted since the patient will undergo TUR for a histological diagnosis. A careful description of the finding is necessary. It should include the site, size, number and appearance (papillary or solid) of the tumours as well as a description of mucosal abnormalities. Use of a bladder diagram is recommended. 4.1.6 Transurethral resection of invasive bladder tumours The goal of TUR is to make the correct diagnosis, which means including bladder muscle in the resection biopsies. The strategy of resection depends from the size of the lesion. Small tumours (less than 1 cm) can be resected en bloc, where the specimen contains the complete tumour plus a part of the underlying bladder wall including bladder muscle. Larger tumours have to be resected separately in fractions, which include the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle and the edges of the resection area. The specimens from different fractions must be referred to the pathologist in separate containers to enable him to make a correct diagnosis. Cauterization has to be avoided as much as possible during the resection to prevent tissue destruction. 4.1.7 Bladder and prostatic urethral biopsy Bladder tumours are often multifocal. Moreover tumours can be accompanied by CIS or dysplasia. These lesions may present themselves as velvet-like, reddish areas, indistinguishable from inflammation or may be not visible at all. The biopsies from normal-looking mucosa in patients with bladder tumours, so called random biopsies (R-biopsies) or selected site mucosal biopsies, are only recommended if fluorescent areas are seen with photodynamic diagnosis (PDD). Cold cup biopsies from normal-looking mucosa should be performed when cytology is positive, when exophytic tumour is of non-papillary appearance, or when fluorescent areas are seen with PDD. When abnormal areas of urothelium are seen, it is advised to take ‘cold cup’ biopsies or biopsies with a resection loop. Material obtained by random or directed biopsies must be sent for pathological assessment in separate containers. The involvement of the prostatic urethra and ducts in male patients with bladder tumours has been reported. Although the exact risk is not known, it seems to be higher if tumour is located on the trigone or bladder neck, in the presence of bladder CIS and in multiple tumours (9, 10) (Level of evidence: 3). In these cases and when cytology is positive or when abnormalities of prostatic urethra are visible, biopsies of the prostatic urethra are recommended. The biopsy is taken using resection loop from the precolicular area. Special care must be taken with tumours at the bladder neck and trigone in female patients where urethral preservation in subsequent orthotopic neobladder is planned. Tumour bladder neck biopsies are advisable but not mandatory, provided frozen section at the urethral margin is taken at the time of surgery (Level of evidence 4). 4.1.8 Fluorescence cystoscopy As a standard procedure, cystoscopy and TUR are performed using white light. However, the use of white light may lead to missing lesions that are present but not visible. Fluorescence cystoscopy is performed using filtered blue light after intravesical instillation of a photosensitizer, usually (5-ALA) or hexaminolaevulinate (HAL). It has been confirmed that fluorescenceguided biopsy and resection are more sensitive than conventional procedures in detecting malignant tumour, particularly CIS (11-13) (Level of evidence: 2a). However, false-positive results can be induced by inflammation, a recent TUR, or intravesical instillation therapy. 4.1.9 Second resection There is a significant risk of residual tumour after the initial TUR (14, 15) (Level of evidence: 1). Persistent disease was observed in 33-53% of patients (15-21). Moreover, the tumour may be understaged by the initial resection. There is a 10% probability that tumours initially staged as being of a lower stage are in fact muscleinvasive (16, 17). Correct staging is extremely important since it will directly affect the treatment modality. A second TUR should always be performed when the initial resection has been incomplete, e.g. when multiple and/or large tumours are present, or when the pathologist has reported that the specimen contained no muscle tissue. Furthermore, a second TUR should be performed when a high-grade, non-muscle-invasive tumour or a T1 tumour has been detected at the initial TUR. There is no consensus about the strategy and

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timing of a second TUR. Most authors recommend resection at 2-6 weeks after the initial TUR. The procedure should include a resection of the primary tumour site. 4.1.10 Concomitant prostate cancer Ruling out progressive prostate cancer should be considered since 25-46% of patients submitted to cystectomy for bladder cancer (22) appear to have prostate cancer on final pathology. Unless the entire prostate is to be removed during cystectomy, any type of prostate cancer should be excluded. 4.1.11 Recommendations for primary assessment of presumably invasive bladder tumours • Renal and bladder ultrasonography, IVU or CT prior to TUR (Grade of recommendation: B). • Cystoscopy with description of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended (Grade of recommendation: C). • TUR in one piece for small tumours (less than 1 cm), including a part from the underlying bladder muscle wall (Grade of recommendation: B). • TUR in fractions (including muscle tissue) for larger tumours (Grade of recommendation: B). • Biopsies of abnormal-looking urothelium, biopsies from normal-looking mucosa when cytology is positive or when exophytic tumour is of non-papillary appearance or in case of fluorescence if PDD is used (Grade of recommendation: C). • Biopsy of the prostatic urethra in the case of bladder neck tumour, when bladder CIS is present or suspected or when abnormalities of prostatic urethra are visible (Grade of recommendation: C). • Careful inspection with histological evaluation of the bladder neck and urethral margin, either prior to or at the time of cystoscopy in women undergoing a subsequent orthotopic neobladder (Grade of recommendation: C). • A second TUR at 2-6 weeks after the initial resection when it was incomplete or when a high-grade or T1 tumour was detected (Grade of recommendation: B). • The pathological report should specify the grade, the depth of tumour invasion and whether the lamina propria and muscle are present in the specimen (Grade of recommendation: C). 4.1.12 References 1. Fossa SD, Ous S, Berner A. Clinical significance of the ‘palpable mass’ in patients with muscle infiltrating bladder cancer undergoing cystectomy after pre-operative radiotherapy. Br J Urol 1991;67(1):54-60. http://www.ncbi.nlm.nih.gov/pubmed/1993277 2. Wijkstrom H, Norming U, Lagerkvist M, Nilsson B, Naslund I, Wiklund P. Evaluation of clinical staging before cystectomy in transitional cell bladder carcinoma: a long-term follow-up of 276 consecutive patients. Br J Urol 1998;81(5):686-91. http://www.ncbi.nlm.nih.gov/pubmed/9634042 3. Goessl C, Knispel HH, Millar K, Klan R. Is routine excretory urography necessary at first diagnosis of bladder cancer? J Urol 1997;157(2):480-1. http://www.ncbi.nlm.nih.gov/pubmed/8996338 4. Palou J, Rodriguez-Rubio F, Huguet J, Segarra J, Ribal MJ, Alcaraz A, Villavicencio H. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumors. J Urol 2005;174(3):859-61. http://www.ncbi.nlm.nih.gov/pubmed/16093970 5. Holmang S, Hedelin H, Anderstrom C, Holmberg E, Johansson SL. Long-term follow-up of a bladder carcinoma cohort: routine followup urography is not necessary. J Urol 1998;160(1):45-8. http://www.ncbi.nlm.nih.gov/pubmed/9628602 6. Nolte-Ernsting C, Cowan N. Understanding multislice CT urography techniques: many roads lead to Rome. Eur Radiol 2006;16(12):1670-86. http://www.ncbi.nlm.nih.gov/pubmed/16953373 7. Raitanen M-P, Aine R, Rintala E, Kallio J, Rajala P, Juusela H, Tammela TL; FinnBladder Group. Differences between local and review urinary cytology and diagnosis of bladder cancer. An interobserver multicenter analysis. Eur Urol 2002;41(3):284-9. http://www.ncbi.nlm.nih.gov/pubmed/12180229 8. Lokeshwar VB, Habuchi T, Grossman HB, Murphy WM, Hautmann SH, Hemstreet GP 3rd, Bono AV, Getzenberg RH, Goebell P, Schmitz-Dräger BJ, Schalken JA, Fradet Y, Marberger M, Messing E, Droller MJ. Bladder tumor markers beyond cytology: international consensus panel on bladder tumor markers. Urology 2005;66 (6 Suppl 1):35-63. http://www.ncbi.nlm.nih.gov/pubmed/16399415

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Matzkin H, Soloway MS, Hardeman S. Transitional cell carcinoma of the prostate. J Urol 1991;146(5):1207-12. http://www.ncbi.nlm.nih.gov/pubmed/1942262 Mungan MU, Canda AE, Tuzel E, Yorukoglu K, Kirkali Z. Risk factors for mucosal prostatic urethral involvement in superficial transitional cell carcinoma of the bladder. Eur Urol 2005;48(5):760-3. http://www.ncbi.nlm.nih.gov/pubmed/16005563 Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M, Marberger M; Hexvix PCB301/01 Study Group. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol 2004;171(1):135-8. http://www.ncbi.nlm.nih.gov/pubmed/14665861 Jichlinski P, Guillou L, Karlsen SJ, Malmstrom PU, Jocham D, Brennhovd B, Johansson E, Gartner T, Lange N, van den Bergh H, Leisinger HJ. Hexyl aminolevulinate fluorescence cystoscopy: a new diagnostic tool for photodiagnosis of superficial bladder cancer –a multicenter study. J Urol 2003;170(1):226-9. http://www.ncbi.nlm.nih.gov/pubmed/12796694 Hungerhuber E, Stepp H, Kriegmair M, Stief Ch, Hofstetter A, Hartmann A, Knuechel R, Karl A, Tritschler S, Zaak D. Seven years’ experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology 2007;69(2):260-4. http://www.ncbi.nlm.nih.gov/pubmed/17320660 Brausi M, Collette L, Kurth K, van der Meijden A, Oosterlinck W, Witjes JA, Newling D, Bouffioux C, Sylvester R; EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol 2002;41(5):523-31. http://www.ncbi.nlm.nih.gov/pubmed/12074794 Miladi M, Peyromaure M, Zerbib M, Saighi D, Debre B. The value of a second transurethral resection in evaluating patients with bladder tumours. Eur Urol 2003;43(3):241-5. http://www.ncbi.nlm.nih.gov/pubmed/12600426 Jakse G, Algaba F, Malmstrom PU, Oosterlinck W. A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol 2004;45(5):539-46. http://www.ncbi.nlm.nih.gov/pubmed/15082193 Brauers A, Buettner R, Jakse G. Second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? J Urol 2001;165(3):808-10. http://www.ncbi.nlm.nih.gov/pubmed/11176474 Schips L, Augustin H, Zigeuner RE, Gallé G, Habermann H, Trummer H, Pummer K, Hubmer G. Is repeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer? Urology 2002;59(2):220-3. http://www.ncbi.nlm.nih.gov/pubmed/11834389 Grimm MO, Steinhoff Ch, Simon X, Spiegelhalder P, Ackermann R, Vögeli, TA. Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. J Urol 2003;170(2 Pt 1):433-7. http://www.ncbi.nlm.nih.gov/pubmed/12853793 Divrik RT, Yildirim Ü, Zorlu F, Özen H. The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. J Urol 2006;175(5):1641-4. http://www.ncbi.nlm.nih.gov/pubmed/16600720 Jahnson S, Wiklund F, Duchek M, Mestad O, Rintala E, Hellsten S, Malmström PU. Results of secondlook resection after primary resection of T1 tumour of the urinary bladder. Scand J Urol Nephrol 2005;39(3):206-10. http://www.ncbi.nlm.nih.gov/pubmed/16127800 Damiano R, Di Lorenzo G, Cantiello F, De Sio M, Perdona S, D’Armiento M, Autorino R. Clinicopathologic features of prostate adenocarcinoma incidentally discovered at the time of radical cystectomy: an evidence-based analysis. Eur Urol 2007;52(3):648-57. http://www.ncbi.nlm.nih.gov/pubmed/17600614

Imaging for staging in verified bladder tumours

Imaging is indicated only if there is a clinical consequence. The treatment and prognosis for invasive bladder cancer is determined by tumour stage and grade (1). Tumour staging must be accurate for selecting the correct treatment In clinical practice. The use of CT scan and magnetic resonance imaging (MRI) has largely replaced other imaging modalities for staging of invasive bladder cancer. The purpose of imaging for staging invasive bladder cancer is to:

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• Assess the extent of local tumour invasion • Detect tumour spread to lymph nodes • Detect tumour spread to other distant organs, (liver, lung, bones, peritoneum, pleura, kidney, adrenal gland and others). 4.2.1 Local staging of invasive bladder cancer Both CT and MRI may be used for assessment of local invasion (2) but they are unable to detect microscopic invasion of perivesical fat (T3a) (3). The aim of CT and MRI is therefore to detect T3b disease or higher. 4.2.1.1 MRI for local staging of invasive bladder cancer MRI has superior soft tissue contrast resolution compared with CT, but poorer spatial resolution. In studies performed before the availability of multidetector-row CT (MDCT), MRI was reported to be more accurate for local assessment. The accuracy of MRI for primary tumour staging varies from 73% to 96% (mean 85%). These values were 10-33% (mean 19%) higher than those obtained with CT (4). Fast dynamic contrast-enhanced MRI helps to differentiate bladder tumour from surrounding tissues because enhancement of the tumour occurs earlier than the normal bladder wall due to neovascularization (5, 6). Fast dynamic MRI with images acquired at one image per second helps to distinguish tumour from postbiopsy reaction (5). 4.2.1.2 CT for local staging of invasive bladder cancer The advantages of CT include shorter acquisition time, wider coverage in a single breath hold, and lower susceptibility to various patient factors. CT scan is unable to differentiate between stages Ta to T3a, but it is useful clinically for detecting invasion into the perivesical fat (T3b) and adjacent organs. The accuracy of CT in determining extravesical tumour extension varies from 55% to 92% (7) and increases with more advanced disease (8). A study by Kim et al. to determine the accuracy of MDCT for detection and staging of bladder cancer showed that CT had lower sensitivity (89%) and higher specificity (95%) compared to MRI for diagnosis of perivesical invasion, while the cancer detection rate and overall accuracy for perivesical invasion were similar (9). These findings are explained by better visualization of perivesical fat invasion on MRI, but because only mild inflammation around bladder cancers mimics perivesical invasion, this results in overstaging with MRI. 4.2.2 Imaging of nodal involvement The assessment of nodal status based simply on size is limited by the inability of both CT and MRI to identify metastases in normal sized or minimally enlarged nodes. Sensitivities for detection of lymph node metastases are low, ranging from 48% to 87%. Specificities are also lowas nodal enlargement may be due to benign pathology. Overall, the results of CT and MRI for detection of lymph node metastases in a variety of primary pelvic tumours are similar (10-14). Pelvic nodes greater than 8 mm and abdominal nodes greater than 10 mm in maximum short axis diameter (MSAD) should be regarded as enlarged on CT and MRI (15, 17). 4.2.3 Extravesical urothelial carcinoma MDCT urography is the technique of choice for diagnosing upper urinary tract urothelial cancer (18, 19). MDCT urography should be incorporated into the CT staging protocol to rule out extravesical carcinoma. 4.2.4 Distant metastases other than lymph nodes Prior to any treatment aimed at cure, it is essential to evaluate the presence of distant metastases. MDCT and MRI are the diagnostic tools of choice to detect metastases to lung and liver. Metastases to bones or brain at presentation of invasive bladder cancer are rare. Bone scan and additional brain imaging are therefore not routinely indicated unless the patient has specific symptoms or signs to suggest bone or brain metastases (20, 21). MRI is more sensitive and specific for diagnosing bone metastases than bone scintigraphy (22, 23) (Level of evidence: 2b). 4.2.5 Conclusions • Diagnosis of invasive bladder cancer is made by cystoscopy and biopsy. • Imaging is used for formal staging only if it will make a difference to the selection of treatment options. • In all T1 tumours considered for conservative treatment, a second TUR is recommended before deciding on definite treatment (Grade of recommendation: B). • MRI is still the preferred modality if the patient is considered for radical treatment. MDCT due to its higher specificity may be equivalvent to MRI regarding local staging.

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•

CT is recommended if there is suspicion of locally advanced or metastatic disease precluding radical treatment (Level of evidence: 2b-3).

4.2.6 Recommendations for staging • For optimal local staging, either MRI with fast dynamic contrast-enhancement or MDCT with contrast enhancement are recommended for patients considered suitable for radical treatment (Grade of Recommendation: B). • For patients with confirmed muscle-invasive bladder cancer, MDCT of the chest, abdomen and pelvis is the optimal form of staging, including MDCT urography for complete examination of the upper urinary tracts. If MDCT is not available, lesser alternatives are excretory urography and a chest X-ray (Grade of Recommendation: B).

4.3

References

1.

Jewett HJ. Proceedings: Cancer of the bladder. Cancer 1973;32(5):1072-4. http://www.ncbi.nlm.nih.gov/pubmed/4757902 Husband JE, Olliff JF, Williams MP, Heron CW, Cherryman GR. Bladder cancer: staging with CT and MR imaging. Radiology 1989;173(2):435-40. http://www.ncbi.nlm.nih.gov/pubmed/2798874 Paik ML, Scolieri MJ, Brown Sl, Spirnak JP, Resnick MI. Limitations of computerized tomography in staging invasive bladder cancer before radical cystectomy. J Urol 2000;163(6):1693-6. http://www.ncbi.nlm.nih.gov/pubmed/10799162 Barentsz JO, Jager GJ, Witjes JA, Ruijs JH. Primary staging of urinary bladder carcinoma: the role of MR imaging and a comparison with CT. Eur Radiol 1996;6(2):129-33. http://www.ncbi.nlm.nih.gov/pubmed/8797968 Barentsz JO, Jager GJ, van Vierzen PB, Witjes JA, Strijk SP, Peters H, Karssemeijer N, Ruijs SH. Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhanced MR imaging. Radiology 1996;201(1):185-93. http://www.ncbi.nlm.nih.gov/pubmed/8816542 Mallampati GK, Siegelman ES. MR imaging of the bladder. Magn Reson Imaging Clin N Am 2004;12(3):545-55. http://www.ncbi.nlm.nih.gov/pubmed/15271370 Kundra V, Silverman PM. Imaging in oncology from the University of Texas M. D. Anderson Cancer Center. Imaging in the diagnosis, staging, and follow-up of cancer of the urinary bladder. AJR Am J Roentgenol 2003 180(4):1045-54. http://www.ncbi.nlm.nih.gov/pubmed/12646453 Kim B, Semelka RC, Ascher SM, Chalpin DB, Carroll PR, Hricak H. Bladder tumor staging: comparison of contrast-enhanced CT, T1- and T2-weighted MR imaging, dynamic gadoliniumenhanced imaging, and late gadolinium-enhanced imaging. Radiology 1994;193(1):239-45. http://www.ncbi.nlm.nih.gov/pubmed/8090898 Kim JK, Park S-Y, Ahn HJ, Kim CS, Cho KS. Bladder cancer: analysis of multidetector row helical CT enhancement pattern and accuracy in tumor detection and perivesical staging. Radiology 2004;231(3):725-31. http://www.ncbi.nlm.nih.gov/pubmed/15118111 Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Ruijs SJ. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional TI-weighted magnetization-prepared- rapid gradient-echo sequence. AJR Am J Roentgenol 1996;167(6):1503-7. http://www.ncbi.nlm.nih.gov/pubmed/8956585 Yang WT, Lam WW, Yu MY, Cheung TH, Metreweli C. Comparison of dynamic helical CT and dynamic MR imaging in the evaluation of pelvic lymph nodes in cervical carcinoma. AJR Am J Roentgenol 2000;175(3):759-66. http://www.ncbi.nlm.nih.gov/pubmed/10954463 Kim SH, Kim SC, Choi BI, Han MC. Uterine cervical carcinoma: evaluation of pelvic lymph node metastasis with MR imaging. Radiology 1994;190(3):807-11. http://www.ncbi.nlm.nih.gov/pubmed/8115631 Kim SH, Choi BI, Lee HP, Kang SB, Choi YM, Han MC, Kim CW. Uterine cervical carcinoma: comparison of CT and MR findings. Radiology 1990;175(1):45-51. http://www.ncbi.nlm.nih.gov/pubmed/2315503

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22.

23.

Oyen RH, Van Poppel HP, Ameye FE, Van de Voorde WA, Baert AL, Baert LV. Lymph node staging of localized prostatic carcinoma with CT and CT-guided fine-needle aspiration biopsy: prospective study of 285 patients. Radiology 1994;190(2):315-22. http://www.ncbi.nlm.nih.gov/pubmed/8284375 Barentsz JO, Engelbrecht MR, Witjes JA, de la Rosette JJ, van der Graaf M. MR imaging of the male pelvis. Eur Radiol 1999;9(9):1722-36. http://www.ncbi.nlm.nih.gov/pubmed/10602944 Vinnicombe SJ, Norman AR, Nicolson V, Husband JE. Normal pelvic lymph nodes: evaluation with CT after bipedal lymphangiography [published erratum appears in Radiology 1995 Sep;196(3):800]. Radiology 1995;194(2):349-55. http://www.ncbi.nlm.nih.gov/pubmed/7824709 Dorfman RE, Alpern MB, Gross BH, Sandler MA. Upper abdominal lymph nodes: criteria for normal size determined with CT. Radiology 1991;180(2):319-22. http://www.ncbi.nlm.nih.gov/pubmed/2068292 Cowan NC, Turney BW, Taylor NJ, McCarthy CL, Crew JP. Multidetector computed tomography urography (MDCTU) for diagnosing upper urinary tract tumour. BJU Int 2007;99(6):1363-70. http://www.ncbi.nlm.nih.gov/pubmed/17428251 Van Der Molen AJ, Cowan NC, Mueller-Lisse UG, Nolte-Ernsting CC, Takahashi S, Cohan RH; CT Urography Working Group of the European Society of Urogenital Radiology (ESUR). CT urography: definition, indications and techniques. A guideline for clinical practice. Eur Radiol 2008;18(1):4-17. http://www.ncbi.nlm.nih.gov/pubmed/17973110 Braendengen M, Winderen M, Fosså SD. Clinical significance of routine pre-cytectomy bone scans in patients with muscle-invasive bladder cancer. Br J Urol 1996;77(1):36-40. http://www.ncbi.nlm.nih.gov/pubmed/8653315 Brismar J, Gustafson T. Bone scintigraphy in staging bladder carcinoma. Acta Radiol 1988;29(2):2512. http://www.ncbi.nlm.nih.gov/pubmed/2965914 Lauenstein TC, Goehde SC, Herborn CU, Goyen M, Oberhoff C, Debatin JF, Ruehm SG, Barkhausen J. Whole-body MR imaging: evaluation of patients for metastases. Radiology 2004;233(1):139-48. http://www.ncbi.nlm.nih.gov/pubmed/15317952 Schmidt GP, Schoenberg SO, Reiser MF, Baur-Melnyk A. Whole-body MR imaging of bone marrow. Eur J Radiol 2005;55(1):33-40. http://www.ncbi.nlm.nih.gov/pubmed/15950099

5. TREATMENT FAILURE OF NON-MUSCLE INVASIVE BLADDER TUMOURS 5.1

High-risk non-muscle-invasive urothelial carcinoma

The recurrence and progression rate of non-muscle-invasive bladder cancer is strongly associated with tumour grade and invasion into the lamina propria. The progression to T2 tumours varies from 6% to 25% in Ta and from 27% to 48% in T1 tumours of all grades. Inter- and intra-observer varying abilities in grading as well as staging and completeness of TUR are key variables confounding the results of present long-term studies of TUR, with or without intravesical therapy. The understaging error in TaT1 tumours of 35% to 62% presented in large cystectomy series is due to the presence of recurrent tumours of largely unknown pre-cystectomy therapy and the lack of a second TUR (1-3) (Level of evidence: 3). The latter identifies 24% to 49% T2 tumours diagnosed initially as non-muscleinvasive tumours (4, 5) (Level of evidence: 3). However, in spite of these disadvantages, recent meta-analyses have shown that intravesical therapy with Bacillus Calmette-Guerin (BCG) maintenance therapy prevents recurrence (6) and progression (7) - but not significantly overall- or disease specific survival - compared to no therapy, intravesical chemotherapy or a BCG induction course only (7, 8) (Level of evidence: 1). Especially in patients with small tumours (< 3 cm) and without associated CIS, the progression rate is low (20% within 5 years), with approximately 90% of patients keeping their intact bladder during follow-up of up to 10 years (9) (Level of evidence: 2). The EAU guidelines therefore recommend a complete TUR and intravesical therapy in patients with high-grade TaT1-tumours (10) (Grade of recommendation: C). Initial cystectomy can be considered based on tumour multiplicity, size, concomitant in situ cancer and

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urothelial tumour of the prostatic urethra (10) (Grade of recommendation: C). Although the percentage of patients with primary TaT1 tumours and the indication for cystectomy in TaT1 tumours is not specified in large cystectomy series, the 10-year recurrence-free survival is approximately 80% and similar to TUR and BCG maintenance therapy (1, 3, 11, 12) (Level of evidence: 3). In case of recurrent Ta/T1, mostly associated with carcinoma in situ, the understaging at time of cystectomy is 34%, but the 10-year survival is not significantly different for patients with pT1 and pT2 tumours (13) (Level of evidence: 3). This is in contrast to an earlier report indicating a significant worse outcome for patients with previous TUR(s) (14) (Level of evidence: 3). Undoubtedly, patients with muscle-invasive recurrence are best treated with radical cystectomy. However, the outcome in terms of presence of lymph node metastases and cancer-free survival may be inferior to patients with the same tumour stage, but who receive radical cystectomy at first presentation (15) (Level of evidence: 3). There is uncertainty about the treatment of patients who develop tumour recurrence in spite of BCG therapy because of different BCG therapy schedules and the absence of a uniform definition of BCG failure. It has been indicated that the recurrence (persistence) of tumour at 9 months in spite of BCG therapy is associated with a 30% chance of invasive tumours and death due to metastatic disease (16) (Level of evidence: 3). Solsona et al. demonstrated that 80% of patients who had persistent disease at 3 months progressed to muscle invasive disease (17) (Level of evidence: 3). In addition, adequate tissue sampling from the prostatic urethra is an essential factor in considering the outcome of conservative treatment, since urethral tumours are associated with a significant decrease in tumour-free survival (18) (Level of evidence: 3). However, with careful selection and surveillance a durable complete response can be achieved also in patients diagnosed with superficial bladder transitional cell carcinoma involving the prostatic urethra (19). Based on these findings, cystectomy should be performed in appropriate patients at least at 9 months, because additional BCG therapy yields a response rate of only 27% to 51% and of unknown duration (20, 21) (Grade of recommendation: C). Salvage chemotherapy is associated with minor responses and should not be offered (22, 23) (Level of evidence: 3). Patients with superficial disease recurring within 2 years of initial TUR plus BCG therapy have a better outcome than patients who already have muscle-invasive disease indicating that cystectomy should be performed at first recurrence, even in case of superficial disease (Level of evidence: 3; Grade of recommendation: C) (15).

5.2

Carcinoma in situ

Primary CIS confined to the bladder is treated with intravesical BCG, yielding a complete response rate of 83-93% (24, 25) (Level of evidence: 2). CIS associated with Ta/T1 is treated according to the overt tumour. Approximately 50% of patients develop recurrent disease with muscle invasion or extravesical tumour (24, 26) (Level of evidence: 2). Between 11% and 21% die of the disease within 5-7 years after an initial complete response (24, 27) (Level of evidence: 2). Non-responders or incomplete responders have a significant risk of tumour progression of 33% to 67% (17, 28) (Level of evidence: 2). Cystectomy should be performed in patients with an incomplete response at 9 months, tumour recurrence within the bladder, or extravesical recurrence (Grade of recommendation: B).

5.3

Recommendations

•

In all T1 tumours at high risk of progression (such as high grade, multifocality, CIS present, and tumour size, as outlined in the non-muscle-invasive bladder cancer EAU guideline), immediate radical cystectomy is an option (Grade of recommendation: B). In all T1 patients failing intravesical therapy, cystectomy is an option. A delay in cystectomy increases the risk of progression and cancer-specific death (Grade of recommendation: B).

•

5.4

References

1.

Hautmann RE, Gschwend JE, de Petriconi RC, Kron M, Volkmer BG. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. J Urol 2006;176(2):486-92. http://www.ncbi.nlm.nih.gov/pubmed/16813874 Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, Studer UE. Radical cystectomy for bladder cancer today–a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21(4):690-6. http://www.ncbi.nlm.nih.gov/pubmed/12586807 Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19(3):666-75. http://www.ncbi.nlm.nih.gov/pubmed/11157016

2.

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10.

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14.

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16.

17.

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19.

Brauers A, Buettner R, Jakse G. Second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? J Urol 2001;165(3):808-10. http://www.ncbi.nlm.nih.gov/pubmed/11176474 Herr WH. The value of second transurethral resection in evaluating patients with bladder tumors. J Urol 1999;162(1):74-6. http://www.ncbi.nlm.nih.gov/pubmed/10379743 Shelley MD, Court JB, Kynaston H, Wilt TJ, Coles B, Mason M. Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev. 2003;(3):CD003231. http://www.ncbi.nlm.nih.gov/pubmed/12917955 Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002;168(5):1964-70. http://www.ncbi.nlm.nih.gov/pubmed/12394686 Böhle A, Bock PR. Intravesical BCG versus mitomycin C in superficial bladder cancer: formal metaanalysis of comparative studies on tumour progression. Urology 2004;63(4):682-6. http://www.ncbi.nlm.nih.gov/pubmed/15072879 Serretta V, Pavone C, Ingargiola GB, Daricello G, Allegro R, Pavone-Macaluso M. TUR and adjuvant intravesical chemotherapy in T1G3 bladder tumors: recurrence, progression and survival in 137 selected patients followed up to 20 years. Eur Urol 2004;45(6):730-5. http://www.ncbi.nlm.nih.gov/pubmed/15149744 Oosterlinck W, Lobel B, Jakse G, Malmström PU, Stöckle M, Sternberg C; European Association of Urology (EAU) Working Group on Oncological Urology. Guidelines on bladder cancer. Eur Urol 2002;41(2):105-12. http://www.ncbi.nlm.nih.gov/pubmed/12074395 Pansadoro V, Emiliozzi P, de Paula F, Scarpone P, Pansadoro A, Sternberg CN. Long-term follow-up of G3T1 transitional cell carcinoma of the bladder treated with intravesical bacille Calmette-Guérin: 18-year experience. Urology 2002;59(2):227-31. http://www.ncbi.nlm.nih.gov/pubmed/11834391 Margel D, Tal R, Golan S, Kedar D, Engelstein D, Baniel J. Long-term follow-up of patients with Stage T1 high-grade transitional cell carcinoma managed by Bacille Calmette-Guérin immunotherapy. Urology 2007;69(1):78-82. http://www.ncbi.nlm.nih.gov/pubmed/17270621 Freeman JA, Esrig D, Stein JP, Simoneau AR, Skinner EC, Chen SC, Groshen S, Lieskovsky G, Boyd SD, Skinner DG. Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 1995;76(5):833-9. http://www.ncbi.nlm.nih.gov/pubmed/8625187 Stöckle M, Alken P, Engelmann U, Jacobi GH, Riedmiller H, Hohenfellner R. Radical cystectomy often too late?. Eur Urol 1987;13(6):361-7. http://www.ncbi.nlm.nih.gov/pubmed/3428318 Herr HW, Sogani PC. Does early cystectomy improve the survival of patients with high risk superficial bladder tumors?. J Urol 2001;166(4):1296-9. http://www.ncbi.nlm.nih.gov/pubmed/11547061 Merz VW, Marth D, Kraft R, Ackermann DK, Zingg EJ, Studer U.E. Analysis of early failures after intravesical instillation therapy with bacille Calmette-Guerin for carcinoma in situ of the bladder. Br J Urol 1995;75(2):180-4. http://www.ncbi.nlm.nih.gov/pubmed/7850322 Solsona E, Iborra I, Rubio J, Casanova J, Almenar S. The optimum timing of radical cystectomy for patients with recurrent high-risk superficial bladder tumour. BJU Int 2004;94(9):1258-62. http://www.ncbi.nlm.nih.gov/pubmed/15610101 Huguet J, Crego M, Sabaté S, Salvador J, Palou J, Villavicencio H. Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 2005;48(1):53-9. http://www.ncbi.nlm.nih.gov/pubmed/15967252 Taylor JH, Davis J, Schellhammer P. Long-term follow-up of intravesical bacillus Calmette-Guérin treatment for superficial transitional-cell carcinoma of the bladder involving the prostatic urethra. Clin Genitourin Cancer 2007;5(6):386-9. http://www.ncbi.nlm.nih.gov/pubmed/17956711

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20.

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27.

28.

Brake M, Loertzer H, Horsch R, Keller H. Recurrence and progression of stage T1, grade 3 transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus Calmette-Guerin. J Urol 2000;163(6):1697-701. http://www.ncbi.nlm.nih.gov/pubmed/10799163 Pansadoro V, Emiliozzi P, Defidio L, Donadio D, Florio A, Maurelli S, Lauretti S, Sternberg CN. Bacillus Calmette-Guerin in the treatment of stage T1 grade 3 transitional cell carcinoma of the bladder: longterm results. J Urol 1995;154(6):2054-8. http://www.ncbi.nlm.nih.gov/pubmed/7500457 Malmström PU, Wijkström H, Lundholm C, Wester K, Busch C, Norlén BJ. 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Swedish-Norwegian Bladder Cancer Study Group. J Urol 1999;161(4):1124-7. http://www.ncbi.nlm.nih.gov/pubmed/10081852 Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol 2000;163(3):761-7. http://www.ncbi.nlm.nih.gov/pubmed/10687972 Jakse G, Hall R, Bono A, Höltl W, Carpentier P, Spaander JP, van der Meijden AP, Sylvester R. Intravesical BCG in patients with carcinoma in situ of the urinary bladder: long-term results of EORTC GU Group phase II protocol 30861. Eur Urol 2001;40(2):144-50 http://www.ncbi.nlm.nih.gov/pubmed/11528191 Losa A, Hurle R, Lembo A. Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term results. J Urol 2000;163(1):68-71. http://www.ncbi.nlm.nih.gov/pubmed/10604316 Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000;163(4):1124-9. http://www.ncbi.nlm.nih.gov/pubmed/10737480 de Reijke TM, Kurth KH, Sylvester RJ, Hall RR, Brausi M, van de Beek K, Landsoght KE, Carpentier P; European Organization for the Research and Treatment of Cancer-Genito-Urinary Group. Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of Cancer--GenitoUrinary Group Phase III Trial (30906). J Urol 2005;173(2):405-9. http://www.ncbi.nlm.nih.gov/pubmed/15643181 Hudson MA, Herr WH. Carcinoma in situ of the bladder. J Urol 1995;53(3 Pt 1):564-72. http://www.ncbi.nlm.nih.gov/pubmed/7861485

6. NEOADJUVANT CHEMOTHERAPY The standard treatment for patients with muscle-invasive bladder cancer is radical cystectomy. However, this ‘gold standard’ only provides 5-year survival in about 50% of patients (1-5). In order to improve these unsatisfactory results, the use of peri-operative chemotherapy has been explored since the 1980s. There are many advantages of neoadjuvant chemotherapy, i.e. administering chemotherapy to patients with operable urothelial carcinoma of the urinary bladder before the planned definitive surgery (or radiation). These advantages include: • Chemotherapy is delivered at the earliest time point, when the burden of micrometastatic disease is expected to be low • In vivo chemosensitivity is tested • The tolerability of chemotherapy is expected to be better before than after cystectomy. The disadvantages of neoadjuvant chemotherapy include: • For clinical staging with CT or MRI, over- and under-staging is likely to happen with a staging accuracy of only 70% (6, 7). Overtreatment is the possible negative consequence • Delayed cystectomy might compromise the outcome in patients not sensitive to chemotherapy (8, 9) • Side effects of chemotherapy might affect outcome of surgery and type of urinary diversion.

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Several randomized phase III trials investigated the question of whether or not neoadjuvant chemotherapy improved survival, with conflicting results (10-27). Most patients were < 70 years old, had a performance status (PS) of 0-1 and a creatinine clearance of > 50-60 mL/minute, due to the kind of chemotherapy (single-agent cisplatin or cisplatin combination chemotherapy) scheduled. Differences in trial design were mainly the type of chemotherapy (i.e. single-agent cisplatin or combination chemotherapy) and the number of cycles planned. From the statistical point of view, the studies differed in size, patient characteristics (e.g. clinical T-stages included), and the kind of definitive treatment allowed (cystectomy or radiotherapy or both). Because of the lack of clarity, even though a considerable number of randomized trials had been performed, three meta-analyses were undertaken to answer the very important question of whether or not neoadjuvant chemotherapy prolongs survival (28-30). The first meta-analysis, published in 2003 (28), included 10 randomized trials (except for results of the INT 0080-study [20]) and showed a 13% reduction in the risk of death, equivalent to 5% absolute benefit at 5 years (increased overall survival from 45% to 50%). The second meta-analysis, published in 2004 (29), included 11 of 16 randomized trials with overall survival data of 2605 patients. A statistically significant decrease in the risk of death (10%) was seen, corresponding to an absolute improvement in overall survival of 5% (from 50% to 55%). In the most recent meta-analysis, published in 2005 (30), with updated independent patient data (IPD) of 11 randomized trials (3,005 patients), a statistically significant survival benefit in favour of neoadjuvant chemotherapy was also seen. The results of this analysis confirmed the previously published data and showed 5% absolute improvement in survival at 5 years. The Nordic combined trial showed an absolute benefit of 8% in survival at 5 years and in the subgroup clinical T3, 11%, translating into 9 patients needed to treat (26). Of note, only cisplatin combination chemotherapy with at least one additional chemotherapeutic agent resulted in a meaningful benefit (28, 30); the regimens tested were MVA(E)C, CMV, CM, cisplatin/adriamycin, cisplatin/5fluorouracil (5-FU), and CarboMV. To date, it is unknown if more modern chemotherapy regimen are as effective. The presence of micrometastases is postulated to be lower in smaller tumours (T2) compared to more extensive tumours (T3b-T4b). T4 stage tumours are prone to a higher degree of clinical understaging because macrometastic nodal deposits are detected more often in post-cystectomy specimens of these extensive tumours (31). Further data is in support of neoadjuvant chemotherapy in the subgroup of T2b-T3b tumours (former classification T3), which has been shown to provide a modest but substantial improvement in long-term survival and significant downstaging.

6.1

Conclusions

•

Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival by 5-7% at 5 years (Level of evidence: 1a), irrespective of the type of definitive treatment used. Neoadjuvant chemotherapy has its limitations regarding patient selection, current development of surgical technique, and current chemotherapy combinations.

•

6.2

Recommendations

•

Neoadjuvant cisplatin-containing combination chemotherapy should be considered in muscleinvasive bladder cancer, irrespective of definitive treatment (Grade of recommendation: A). Neoadjuvant chemotherapy is not recommended in patients with PS > 2 and impaired renal function (Grade of recommendation: B).

•

6.3

References

1.

Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006;24(3):296-304. http://www.ncbi.nlm.nih.gov/pubmed/16518661 Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19(3):666-75. http://www.ncbi.nlm.nih.gov/pubmed/11157016 Dalbagni G, Genega E, Hashibe M, Zhang ZF, Russo P, Herr H, Reuter V. Cystectomy for bladder cancer: a contemporary series. J Urol 2001;165(4):1111-6. http://www.ncbi.nlm.nih.gov/pubmed/11257649 Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, Pappagallo G, Pagano F. Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol 1999;161(5):1494-7. http://www.ncbi.nlm.nih.gov/pubmed/10210380

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Ghoneim MA, el-Mekresh MM, el-Baz MA, el-Attar IA, Ashamallah A. Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. J Urol 1997;158(2):393-9. http://www.ncbi.nlm.nih.gov/pubmed/9224310 Sternberg CN, Pansadoro V, Calabro F, Schnetzer S, Giannarelli D, Emiliozzi P, De Paula F, Scarpone P, De Carli P, Pizzo M, Platania A, Amini M. Can patient selection for bladder preservation be based on response to chemotherapy? Cancer 2003;97(7):1644-52. http://www.ncbi.nlm.nih.gov/pubmed/12655521 Herr HW, Scher HI. Surgery of invasive bladder cancer: is pathologic staging necessary? Semin Oncol 1990;17(5):590-7. http://www.ncbi.nlm.nih.gov/pubmed/2218571 Sanchez-Ortiz RF, Huang WC, Mick R, Van Arsdalen KN, Wein AJ, Malkowicz SB. An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol 2003;169(1):110-5; discussion 115. http://www.ncbi.nlm.nih.gov/pubmed/12478115 Stein JP. Contemporary concepts of radical cystectomy and the treatment of bladder cancer. J Urol 2003;169(1):116-7. http://www.ncbi.nlm.nih.gov/pubmed/12478116 Wallace DM, Raghavan D, Kelly KA, Sandeman TF, Conn IG, Teriana N, Dunn J, Boulas J, Latief T. Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol 1991;67(6):608-15. http://www.ncbi.nlm.nih.gov/pubmed/2070206 Font A, Saladie JM, Carles J, Pinsach L, Barnardas A, et al. Improved survival with induction chemotherapy in bladder cancer: preliminary results of a randomized trial. Ann Oncol 1994;5:71, abstr 355. Martinez-Pineiro JA, Gonzalez Martin M, Arocena F, Flores N, Roncero CR, Portillo JA, Escudero A, Jimenez Cruz F, Isorna S. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol 1995;153(3 Pt 2):964-73. http://www.ncbi.nlm.nih.gov/pubmed/7853584 Rintala E, Hannisdahl E, Fossa SD, Hellsten S, Sander S. Neoadjuvant chemotherapy in bladder cancer: a randomized study. Nordic Cystectomy Trial I. Scand J Urol Nephrol 1993;27(3):355-62. http://www.ncbi.nlm.nih.gov/pubmed/8290916 Malmstrom PU, Rintala E, Wahlqvist R, Hellstrom P, Hellsten S, Hannisdal E. Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 1996;155(6):1903-6. http://www.ncbi.nlm.nih.gov/pubmed/8618283 [No authors listed] Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscleinvasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet 1999;354(9178):533-40. http://www.ncbi.nlm.nih.gov/pubmed/10470696 Hall R. Updated results of a randomised controlled trial of neoadjuvant cisplatin (C), methotrexate (m) and vinblastin (V) chemotherapy for muscle-invasive bladder cancer. Proc Am Soc Clin Oncol 2002;21:178A, abstr 710. Bassi P PG, Cosciani S, Lembo A, Anselmo G, Sperandio P, et al . Neoadjuvant M-VAC chemotherapy of invasive bladder cancer: The G.U.O.N.E. multicenter phase III trial. Eur Urol 1998 (Suppl);33:142, abstr 567. Sherif A, Rintala E, Mestad O, Nilsson J, Holmberg L, Nilsson S, Malmström PU; Nordic Urothelial Cancer Group. Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer–Nordic cystectomy trial 2. Scand J Urol Nephrol 2002;36(6):419-25. http://www.ncbi.nlm.nih.gov/pubmed/12623505 Sengelov L, von der Maase H, Lundbeck F, Barlebo H, Colstrup H, Engelholm SA, Krarup T, Madsen EL, Meyhoff HH, Mommsen S, Nielsen OS, Pedersen D, Steven K, Sørensen B. Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncol 2002;41(5):447-56. http://www.ncbi.nlm.nih.gov/pubmed/12442921 Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9): 859-66. http://www.ncbi.nlm.nih.gov/pubmed/12944571

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30.

31.

Italian Bladder Cancer Study Group (GISTV). Neoadjuvant treatment for locally advanced bladder cancer: a randomized prospective clinical trial. J Chemother 1996;8(suppl 4):345-6. Orsatti M, Curotto A, Canobbio L, Guarneri D, Scarpati D, Venturini M, Franzone P, Giudici S, Martorana G, Boccardo F, et al. Alternating chemo-radiotherapy in bladder cancer: a conservative approach. Int J Radiat Oncol Biol Phys 1995;33(1):173-8. http://www.ncbi.nlm.nih.gov/pubmed/7642415 Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16(11):3576-83. http://www.ncbi.nlm.nih.gov/pubmed/9817278 Marcuello E TJ, Villavicencio H, Algaba F, Maroto P, Huidobro G, et al. A phase III trial of neoadjuvant chemotherapy (NCT) in patients (PTS) with invasive bladder cancer (IBC). Preliminary results: NCT improves pathological complete response rate. Eur J Cancer 1995;31A:S241, abstr 1155. Cannobio L CA, Boccardo F, Venturini M, Orsatti M, Vitale V, et al. A randomized study between neoadjuvant chemoradiotherapy (CT-RT) before radical cystectomy and cystectomy alone in bladder cancer. A 6 year follow-up. Proc Am Soc Clin Oncol 1995;14:245, abstr 654. Sherif A, Holmberg L, Rintala E, Mestad O, Nilsson J, Nilsson S, Malmström PU; Nordic Urothelial Cancer Group. Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies. Eur Urol 2004;45(3):297-303. http://www.ncbi.nlm.nih.gov/pubmed/15036674 Abol-Enein H E-MM, El Baz M, Ghoneim MA. Neo-adjuvant chemotherapy in the treatment of invasive transitional bladder cancer. A controlled prospective randomized study. Br J Urol 1997;79(Suppl 4):174. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003;361(9373):1927-34. http://www.ncbi.nlm.nih.gov/pubmed/12801735 Winquist E, Kirchner TS, Segal R, Chin J, Lukka H; Genitourinary Cancer Disease Site Group, Cancer Care Ontario Program in Evidence-based Care Practice Guidelines Initiative. Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. J Urol 2004;171(2 Pt 1):561-9. http://www.ncbi.nlm.nih.gov/pubmed/14713760 Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48(2):202-205; discussion 205-6. http://www.ncbi.nlm.nih.gov/pubmed/15939524 Sherif A HL, Rintala E, Mestad O, Nilsson J, Nilsson S, Malmstrom PU, Wijkström H; Nordic Urothelial Cancer Group. Downstaging and pathoanatomical outcome following neoadjuvant cisplatinum based combination chemotherapy for muscle invasive bladder carcinoma: An analysis of selected patients from two combined randomised prospective Nordic trials. Urology 2006;68(Suppl 1):137, MP-1307.

7. Radical surgery and urinary diversion 7.1

Removal of the tumour bearing bladder

7.1.1 Background Radical cystectomy is the standard treatment for localized muscle invasive bladder cancer in most countries of the Western Hemisphere (1, 2). New interest in quality-of-life issues has increased the trend toward bladder preservation treatment modalities, like radio- and/or chemotherapy (see Chapters 9 and 10). Performance status and age influence the choice of primary therapy, as well as type of urinary diversion with cystectomy being reserved for younger patients without concomitant disease and better performance status. The value of assessing overall health before recommending and proceeding with surgery was emphasized in a recent multivariate analysis, which demonstrated an association between co-morbid disease and adverse pathological and survival outcome following radical cystectomy (3). There is still controversy about age, radical cystectomy and the type of urinary diversion. Cystectomy is associated with the greatest risk reduction in disease-related and non-disease related death in patients older

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than 80 years (3). The largest retrospective single-institution study on cystectomy to date demonstrated that patients above 80 years did have an increased postoperative morbidity but not an increased mortality. Some patients even successfully underwent a neobladder procedure in this group, but the majority of patients were treated with an ileal conduit diversion (4). 7.1.2 Timing and delay of cystectomy In a retrospective series of 153 patients with a clear indication for radical surgery of locally advanced bladder cancer, a delay of treatment beyond 90 days of primary diagnosis caused a significant increase in extravesical disease (81 vs. 52%) (5). The delay of cystectomy not only affects the outcome but also the type of urinary diversion. In organconfined urothelial cancer of the bladder the average time from the primary diagnosis to cystectomy was 12.2 months in neobladder and 19.1 months in ileal conduit patients. It was even more striking for those patients who had an organ confined invasive cancer diagnosed; in neobladder patients the average time to surgery was 3.1 and in ileal conduit patients 15.1 months (6). Similar results have been observed in a series of 247 patients where superior recurrence-free survival and overall survival was significantly better in those treated within the 90 day period compared to others who were treated after a longer period (7). 7.1.3 Indications Traditionally radical cystectomy is recommended for patients with muscle-invasive bladder cancer T2-T4a, N0-Nx, M0 (1). Other indications include high-risk and recurrent superficial tumours, BCG-resistant Tis, T1G3 (see chapter 5), as well as extensive papillary disease that cannot be controlled with TUR and intravesical therapy alone. Salvage cystectomy is indicated for non-responders to conservative therapy, recurrences after bladder sparing treatments, non-urothelial carcinomas (these tumours respond poorly to chemo- and radiotherapy) and as a purely palliative intervention for e.g. fistula formation, pain or recurrent macrohematuria (see section 8.1: palliative cystectomy). 7.1.4 Technique and extent Radical cystectomy includes the removal of the bladder and adjacent organs, that is prostate and seminal vesicles in men, and uterus and adnexa in women (8). The inclusion of the entire prostate in male patients, and the extent of urethrectomy and vaginal resection in female patients, however, has recently been questioned (9, 10). Various techniques of partial prostate- sparing cystoprostatectomy in male patients with localized tumours have been proposed and results of series with a longer follow-up have been published (11, 12). A randomized study comparing patients with and without remnant portions of the prostate is lacking and will be difficult to perform. Autopsy studies as well as studies looking at the unsuspected incidence of prostate cancer in cystoprostatectomy specimens suggest that in approximately 23-54% of patients a prostate cancer is found in the cystoprostatectomy specimen. Up to twenty-nine percent of these cancers may be clinically significant, locally recurrent or even metastatic in patients with prostatic tissue preserving radical cystectomy (13-15). Furthermore urothelial cancer in the prostate was detected in 32 and 33% (69/240 cases and 77/235 cases, resp.) of patients undergoing radical cystoprostatectomy (14, 16). In another study 50/121 of the cystoprostatectomy specimens (41%) removed for urothelial cancer had unsuspected prostate cancer. Twenty-four of these 50 tumours (48%) were clinically significant. In the same study 58/121 patients (48%) had urothelial carcinoma in the prostate of which 19 (33%) had apical involvement (17). Overall in the above mentioned series only 26 to 33% of the patients undergoing cystoprostatectomy for bladder cancer had neither prostate cancer nor prostatic urothelial cancer in the specimen. Radical cystectomy also includes the dissection of regional lymph nodes. There is a substantial amount of literature about the extent of lymphadenectomy. Yet, data regarding its clinical significance are controversial. In retrospective studies extended lymphadenectomy (removal of the obturator, internal, external, common iliac and presacral nodes as well as nodes at the aortic bifurcation) has been reported to improve survival in patients with muscle invasive bladder cancer. The curative value of lymph node dissection, however, is still unknown and a standardized lymph node dissection has yet to be defined (18-20). There are several localization studies with regards to lymphadenectomy (21, 22) which demonstrated both retrospectively and prospectively that lymph nodes in bladder cancer patients are not found outside the pelvis if the pelvic lymph nodes are free of tumour. Furthermore progression free survival as well as overall survival might be correlated with the amount of lymph nodes removed during surgery. Removal of more than 15 lymph nodes has been postulated to be both sufficient for the evaluation of the lymph node status as well as beneficial for overall survival in retrospective studies (19, 22, 23). Interindividual differences in the number of pelvic and retroperitoneal lymph nodes and difficulties in processing of the removed tissue by pathologists

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were not taken into account in these studies (18). A distal ureteral segment (length not specified) should be resected and in case of CIS a frozen section for evaluation of the surgical margins should be performed (8, 24). Urethrectomy is recommended if there are positive margins at the level of urethral dissection, positive margins anywhere on the bladder specimen (in both sexes), if the primary tumour is located at the bladder neck or in the urethra (in women), or if tumour extensively infiltrates the prostate (1, 25, 26). 7.1.5 Laparoscopic cystectomy Laparoscopic cystectomy has been shown to be feasible both in male and female patients (27, 28). The cystectomy itself and the subsequent urinary diversion can be done hand-assisted, robot-assisted or unaided (29). With the currently available technology and when using intestinal segments for the urinary diversion, to date a majority of authors favour an extracorporeal approach (28). There are no data confirming or declining benefits of laparoscopic cystectomy for the patients’ quality of life, tumour specific and overall survival.

7.2

Urinary Diversion after radical cystectomy

From an anatomical standpoint three alternatives are presently used after cystectomy: • abdominal diversion such as ureterocutaneostomy, ileal or colonic conduit, and various forms of a cutaneous continent pouch • urethral diversion which includes various forms of gastrointestinal pouches attached to the urethra as a continent, orthotopic urinary diversion (neobladder, orthotopic bladder substitution • rectosigmoid diversions, such as uretero(ileo-)rectostomy. Different types of segments of the intestinal tract have been used for reconstruction of the urinary tract, including stomach, ileum, colon, and the appendix (30). Although several studies have compared certain aspects of health-related quality of life, like sexual function, urinary continence and body image in patient cohorts with different types of urinary diversion, more work is necessary in this field with regards to preoperative tumour stage and functional situation, socioeconomic status, time interval to primary surgery etc. Patients undergoing continent urinary diversion have to be both motivated to learn and manually skilful to deal with their diversion. Debilitating neurological and psychiatric illnesses, limited life expectancy, and impaired liver or renal function as well as TCC of the urethral margin or other surgical margins are contraindications to more complex forms of urinary diversion. Relative contraindications specific for an orthotopic neobladder are high-dose preoperative radiation therapy, complex urethral stricture disease and severe urethral sphincter related incontinence (31-33). 7.2.1 Ureterocutaneostomy Ureteral diversion to the abdominal wall is the simplest form of cutaneous diversion. It is considered as a safe procedure and therefore preferred in older or otherwise compromised patients in need of a supravesical diversion (34, 35). Others have demonstrated, however, that in carefully selected elderly patients all other forms of wet and dry urinary diversions including orthotopic bladder substitutions are possible (4). Technically either one ureter to which the other shorter one is attached end-to-side is connected to the skin (transuretero-ureterocutaneostomy) or both ureters are directly anastomosed to the skin. Due to the smaller diameter of the ureters stoma stenosis seems to be more frequent than with intestinal stomas (34). 7.2.2 Ileal conduit The ileal conduit is still an established option with well-known/predictable results. However, up to 48% of the patients develop early complications including urinary tract infections, pyelonephritis, uretero-ileal leakage and stenosis (36). Stomal complications in up to 24% and functional and/or morphological changes of the upper urinary tract in up to 30% are the main complications in long-term follow-up studies (37-39). An increase in complications was seen with increasing follow-up in the Berne series of 131 patients followed for a minimum of 5 years (median follow-up 98 months) (37): the rate of complications increased from 45% at 5 years to 94% in those surviving longer than 15 years. In the latter group 50% and 38% of the patients had upper urinary tract changes and urolithiasis, respectively. 7.2.3 Continent cutaneous urinary diversion A low-pressure detubularized ileal reservoir can be used as a continent cutaneous urinary diversion for selfcatheterization; gastric, ileocecal and sigma pouches have also been described (40-42). Different anti-reflux techniques can be used [8e]. Most patients have a well functioning reservoir with daytime and night time continence approaching 93% (43). A stomal stenosis in 23.5% of patients with appendix stoma and 15% with an efferent intussuscepted ileal nipple was observed in a study reviewing retrospectively the results of

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more than 800 patients. Stone formation in the pouch occurred in 10% of patients (43-45). In a small series of previously irradiated female patients incontinence and stomal stenosis was 18% (8/44 patients) (46). 7.2.4 Ureterocolonic diversion The oldest and most common form was primarily a refluxive and later an antirefluxive connection of ureters into the intact rectosigmoideum (uretero[recto]sigmoidostomy) (47, 48). Most of the indications for this procedure have become obsolete due to a high incidence of upper urinary tract infections and a long term risk of developing colon cancer (49, 50). Bowel frequency and urge incontinence were additional side effects of this type of urinary diversion. A possibility to circumvent the above mentioned problems is to interpose a segment of ileum between ureters and rectum or sigmoid in order to augment capacity and to avoid a direct interaction between urothelium, colonic mucosa, together with faeces and urine (51). 7.2.5 Orthotopic neobladder An orthotopic bladder substitution to the urethra is now commonly used both in men and women. Contemporary reports document the safety and long-term reliability of this procedure. In several large centres this has become the diversion of choice for a majority of patients undergoing cystectomy (33, 52). The gastrointestinal segment most frequently used for bladder substitution is the terminal ileum whereas there is less experience with ascending colon, including coecum, and the sigmoid (1). The emptying of the reservoir anastomosed to the urethra requires abdominal straining, intestinal peristalsis and sphincter relaxation. Early and late morbidity in up to 22 % of the patients is reported (53, 54). Long-term complications include diurnal and nocturnal incontinence (8-10 and 20 to 30%, resp.), ureterointestinal stenosis (3-18%), urinary retention (4-12%) both in males and female patients, metabolic disorders and vitamin B12 deficiency in series with 1,054 and more than 1,300 patients (33, 55). In a recent study, which compared cancer control and patterns of disease recurrence in neobladder and conduit patients, no cancer specific survival difference could be identified between the two groups when adjusting for pathological stage (56). Urethral recurrence in neobladder patients seems rare (1.5-7% both for male and female patients) (33, 57). These results indicate that the choice of a neobladder both in male and female patients does not compromise the oncological outcome of cystectomy. The advantage in the quality of life compared to a non-continent diversion remains a matter of debate (58-60. Various forms of upper tract reflux protection including a simple isoperistaltic tunnel, an ileal intussusception, a tapered ileal prolongation implanted subserosally, and a direct (sub)mucosal or subserosal ureteral implantation, have been described (45, 53, 54). According to the reported long term results the upper urinary tract is protected sufficiently by either method.

7.3

Morbidity and mortality

In a recent comprehensive study regarding long-term results in 1,054 patients, perioperative mortality was 3%, and early complications, defined as any complication within 3 months of surgery, were reported in 28% (52, 55). Late morbidity is usually due to the type of urinary diversion (see above). Early morbidity associated with radical cystectomy for non-muscle invasive disease (at high risk for disease progression) is similar and not less than that associated with muscle invasive tumours (61).

7.4

Survival

The outcome according to a multiinstitutional database of 888 consecutive patients undergoing cystectomy and lymphadenectomy for bladder cancer revealed a mean recurrence-free and bladder cancer specific survival of 58% and 66%, resp. at 5 years (62). The recurrence-free and overall survival in a large single centre study of 1,054 male and female patients was 68% and 66% at 5 years and 60% and 43%, at 10 years, respectively (2). In node positive patients, 10-year disease-specific and overall survival rates in another study have been reported to be 27.7% and 20.9% respectively (63). In this cohort, 10-year disease-specific and overall survival rates were 72.9% vs. 49.1% for organ confined (defined as < pT3a), and 33.3% vs. 22.8% for non-organ confined disease (63). In another study, 5-year recurrence-free survival was 76% in patients with pT1 tumours, 74% for pT2, 52% in pT3, and 36% in pT4 tumours (64). Tumour stage and nodal involvement are the only independent predictors of survival (65).

7.5

Conclusions

• •

Cystectomy is the preferred curative treatment for localised bladder neoplasm (Level of evidence: 3) Radical cystectomy includes removal of regional lymph nodes, the extent of which has not been sufficiently defined (Level of evidence: 3) Radical cystectomy in both sexes must not include the removal of the entire urethra in all cases, which may then serve as outlet for an orthotopic bladder substitution (Level of evidence: 3)

•

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• •

Terminal ileum and colon are the intestinal segments of choice for urinary diversion (Level of evidence: 3) The type of urinary diversion does not affect oncological outcome (Level of evidence: 3)

7.6

Recommendations

7.6.1 Recommendations for radical cystectomy • Radical cystectomy in T2-T4a, N0-NX, M0, and high risk non-muscle invasive BC as outlined above (Grade of recommendation: B) • No preoperative radiotherapy (Grade of recommendation: A) • Lymph node dissection should be an integral part of cystectomy, extent not established (Grade of recommendation: B) • Preservation of the urethra is reasonable if margins are negative. If no bladder substitution is attached the urethra must be checked regularly (Grade of recommendation: B) • Laparoscopic and robot assisted laparoscopic cystectomy may be an option. Current data, however, have not sufficiently proven its advantages or disadvantages (Grade of recommendation: C). 7.6.2 Recommendations for urinary diversion • Treatment is recommended at centers experienced in major types of diversion techniques and postoperative care (Grade of recommendation: B) • Before cystectomy, the patient should be counselled adequately regarding all possible alternatives, and the final decision should be based on a consensus between patient and surgeon (Grade of recommendation: B). • An orthotopic bladder substitute should be offered to male and female patients lacking any contraindications and who have no tumour in the urethra and at the level of urethral dissection (Grade of recommendation: B)

7.7

References

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Haber GP, Campbell SC, Colombo JR, Jr, Fergany AF, Aron M, Kaouk J, Gill IS. Perioperative outcomes with laparoscopic radical cystectomy: “pure laparoscopic” and “open-assisted laparoscopic” approaches. Urology 2007;70(5):910-5. http://www.ncbi.nlm.nih.gov/pubmed/18068447 Cathelineau X, Jaffe J. Laparoscopic radical cystectomy with urinary diversion: what is the optimal technique? Curr Opin Urol 2007;17(2):93-7. http://www.ncbi.nlm.nih.gov/pubmed/17285017 Stenzl A. Bladder substitution. Curr Opin Urol 1999;9(3):241-5. http://www.ncbi.nlm.nih.gov/pubmed/10726098 Tanrikut C, McDougal WS. Acid-base and electrolyte disorders after urinary diversion. World J Urol 2004;22(3):168-71. http://www.ncbi.nlm.nih.gov/pubmed/15290206 Farnham SB, Cookson MS. Surgical complications of urinary diversion. World J Urol 2004;22(3): 157-67. http://www.ncbi.nlm.nih.gov/pubmed/15316737 Hautmann RE, Volkmer BG, Schumacher MC, Gschwend JE, Studer UE. Long-term results of standard procedures in urology: the ileal neobladder. World J Urol 2006;24(3):305-14. http://www.ncbi.nlm.nih.gov/pubmed/16830152 Deliveliotis C, Papatsoris A, Chrisofos M, Dellis A, Liakouras C, Skolarikos A. Urinary diversion in highrisk elderly patients: modified cutaneous ureterostomy or ileal conduit?. Urology 2005;66(2): 299-304. http://www.ncbi.nlm.nih.gov/pubmed/16040096 Kilciler M, Bedir S, Erdemir F, Zeybek N, Erten K, Ozgok Y. Comparison of ileal conduit and transureteroureterostomy with ureterocutaneostomy urinary diversion. Urol Int 2006;77(3):245-50. http://www.ncbi.nlm.nih.gov/pubmed/17033213 Nieuwenhuijzen JA, de Vries RR, Bex A, van der Poel HG, Meinhardt W, Antonini N, Horenblas S. Urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions. Eur Urol, 2008;53(4):834-44. http://www.ncbi.nlm.nih.gov/pubmed/17904276 Madersbacher S, Schmidt J, Eberle JM, Thoeny HC, Burkhard F, Hochreiter W, Studer UE. Long-term outcome of ileal conduit diversion. J Urol 2003;169(3):985-90. http://www.ncbi.nlm.nih.gov/pubmed/12576827 Wood DN, Allen SE, Hussain M, Greenwell TJ, Shah P.J. Stomal complications of ileal conduits are significantly higher when formed in women with intractable urinary incontinence. J Urol 2004;172(6 Pt 1):2300-3. http://www.ncbi.nlm.nih.gov/pubmed/15538253 Neal DE. Complications of ileal conduit diversion in adults with cancer followed up for at least five years. Br Med J (Clin Res Ed) 1985;290(6483):1695-7. http://www.ncbi.nlm.nih.gov/pubmed/3924218 Benson MC, Olsson CA. Continent urinary diversion. Urol Clin North Am 1999;26(1):125-47, ix. http://www.ncbi.nlm.nih.gov/pubmed/10086055 Gerharz EW, Kohl UN, Melekos MD, Bonfig R, Weingartner K, Riedmiller H. Ten years’ experience with the submucosally embedded in situ appendix in continent cutaneous diversion. Eur Urol 2001;40(6):625-31. http://www.ncbi.nlm.nih.gov/pubmed/11805408 Jonsson O, Olofsson G, Lindholm E, Tornqvist H. Long-time experience with the Kock ileal reservoir for continent urinary diversion. Eur Urol 2001;40(6):632-40. http://www.ncbi.nlm.nih.gov/pubmed/11805409 Wiesner C, Bonfig R, Stein R, Gerharz EW, Pahernik S, Riedmiller H, Thuroff J.W. Continent cutaneous urinary diversion: long-term follow-up of more than 800 patients with ileocecal reservoirs. World J Urol 2006;24(3):315-8. http://www.ncbi.nlm.nih.gov/pubmed/16676186 Wiesner C, Stein R, Pahernik S, Hahn K, Melchior SW, Thuroff JW. Long-term followup of the intussuscepted ileal nipple and the in situ, submucosally embedded appendix as continence mechanisms of continent urinary diversion with the cutaneous ileocecal pouch (Mainz pouch I). J Urol 2006;176(1):155-9; discussion 159-60. http://www.ncbi.nlm.nih.gov/pubmed/16753391

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46.

47.

48. 49.

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Thoeny HC, Sonnenschein MJ, Madersbacher S, Vock P, Studer U.E. Is ileal orthotopic bladder substitution with an afferent tubular segment detrimental to the upper urinary tract in the long term? J Urol 2002;168(5):2030-4; discussion 2034. http://www.ncbi.nlm.nih.gov/pubmed/12394702 Leissner J, Black P, Fisch M, Hockel M, Hohenfellner R. Colon pouch (Mainz pouch III) for continent urinary diversion after pelvic irradiation. Urology 2000;56(5):798-802. http://www.ncbi.nlm.nih.gov/pubmed/11068305 Simon J. Ectopia Vesicae (Absence of the anterior walls of the Bladder and the pubic abdominal parietes) Operation for directing the orifices of the ureteres into the rectum, temporary success. JAMA 1911;56:398. Coffey R. Physiologic implantation of the severed ureter or common bile duct into the intestine. JAMA 1911;56:397. Azimuddin K, Khubchandani IT, Stasik JJ, Rosen L, Riether RD. Neoplasia after ureterosigmoidostomy. Dis Colon Rectum 1999;42(12):1632-8. http://www.ncbi.nlm.nih.gov/pubmed/10613486 Gerharz EW, Turner WH, Kalble T, Woodhouse CR. Metabolic and functional consequences of urinary reconstruction with bowel. BJU Int 2003;91(2):143-9. http://www.ncbi.nlm.nih.gov/pubmed/12519116 Kalble T, Busse K, Amelung F, Waldherr R, Berger MR, Edler L, Riedmiller H. Tumor induction and prophylaxis following different forms of intestinal urinary diversion in a rat model. Urol Res 1995;23(6):365-70. http://www.ncbi.nlm.nih.gov/pubmed/8788273 Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006;24(3):296-304. http://www.ncbi.nlm.nih.gov/pubmed/16518661 Stein J., Dunn MD, Quek ML, Miranda G, Skinner DG. The orthotopic T pouch ileal neobladder: experience with 209 patients. J Urol 2004;172(2):584-7. http://www.ncbi.nlm.nih.gov/pubmed/15247737 Abol-Enein H, Ghoneim M.A. Functional results of orthotopic ileal neobladder with serous-lined extramural ureteral reimplantation: experience with 450 patients. J Urol 2001;165(5):1427-32. http://www.ncbi.nlm.nih.gov/pubmed/11342891 Stein JP, Skinner DG. Results with radical cystectomy for treating bladder cancer: a ‘reference standard’ for high-grade, invasive bladder cancer. BJU Int 2003;92(1):12-7. http://www.ncbi.nlm.nih.gov/pubmed/12823375 Yossepowitch O, Dalbagni G, Golijanin D, Donat SM, Bochner BH, Herr HW, Fair WR, Russo P. Orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence. J Urol 2003;169(1):177-81. http://www.ncbi.nlm.nih.gov/pubmed/12478130 Stein JP, Clark P, Miranda G, Cai J, Groshen S, Skinner D.G. Urethral tumor recurrence following cystectomy and urinary diversion: clinical and pathological characteristics in 768 male patients. J Urol 2005;173(4):1163-8. http://www.ncbi.nlm.nih.gov/pubmed/15758728 Gerharz EW, Mansson A, Hunt S, Skinner EC, Mansson W. Quality of life after cystectomy and urinary diversion: an evidence based analysis. J Urol 2005;174(5):1729-36. http://www.ncbi.nlm.nih.gov/pubmed/16217273 Hobisch A, Tosun K, Kinzl J, Kemmler G, Bartsch G, Holtl L, Stenzl A. Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. Semin Urol Oncol 2001;19(1):18-23. http://www.ncbi.nlm.nih.gov/pubmed/11246729 Porter MP, Penson DF. Health related quality of life after radical cystectomy and urinary diversion for bladder cancer: a systematic review and critical analysis of the literature. J Urol 2005;173(4):1318-22. http://www.ncbi.nlm.nih.gov/pubmed/15758789 Cookson MS, Chang SS, Wells N, Parekh DJ, Smith JA Jr. Complications of radical cystectomy for nonmuscle invasive disease: comparison with muscle invasive disease. J Urol 2003;169(1):101-4. http://www.ncbi.nlm.nih.gov/pubmed/12478113 Shariat SF, Karakiewicz PI, Palapattu GS, Lotan Y, Rogers CG, Amiel GE, Vazina A, Gupta A, Bastian PJ, Sagalowsky AI, Schoenberg MP, Lerner S.P. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol 2006;176(6 Pt 1):2414-22; discussion 2422. http://www.ncbi.nlm.nih.gov/pubmed/17085118

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64.

65.

Gschwend JE, Dahm P, Fair W.R. Disease specific survival as endpoint of outcome for bladder cancer patients following radical cystectomy. Eur Urol 2002;41(4):440-8. http://www.ncbi.nlm.nih.gov/pubmed/12074817 Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, Studer UE. Radical cystectomy for bladder cancer today--a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21(4):690-6. http://www.ncbi.nlm.nih.gov/pubmed/12586807 Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, Pappagallo G, Pagano F. Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol 1999;161(5):1494-7. http://www.ncbi.nlm.nih.gov/pubmed/10210380

8. NON-RESECTABLE TUMOURS 8.1

Palliative cystectomy for muscle-invasive bladder carcinoma

For patients with inoperable locally advanced tumours (T4b, invading the pelvic or abdominal wall), radical cystectomy usually is not a therapeutic option (1). Treatment of these patients remains a clinical challenge. These patients are candidates for palliative treatments, such as palliative radiotherapy. Inoperable locally advanced tumours may be accompanied by several debilitating symptoms, including bleeding, pain, dysuria and urinary obstruction. There are several treatment options for patients with these symptoms. In advanced bladder cancer cases complicated by bleeding, cystectomy with urinary diversion is the most invasive treatment. It carries the greatest morbidity and should be considered only if there are no other options (1). In patients with locally advanced pelvic cancer and urinary bladder involvement, palliative radical cystectomy with urinary diversion using intestinal segments is usually performed for the relief of symptoms such as pain, recurrent bleeding, urgency and fistula formation (2). Zebic et al.(3) retrospectively analysed patients aged > 75 years, who had received radical cystectomies with either curative or palliative intent. The indications for palliative cystectomy were advanced pelvic malignancy with severe irritating voiding symptoms, severe pain and recurrent macrohaematuria requiring blood transfusions (3). Zebic et al. concluded that elderly people have a greater risk of perioperative morbidity and mortality, especially those with very advanced pelvic malignancies, who have undergone palliative cystectomy (3). Advanced muscle-invasive bladder cancer can be associated with ureteral obstruction. In invasive tumours, the mechanism of ureteral obstruction is probably caused by a combination of mechanical blockage by the tumour and invasion of ureteral orifices by tumour cells interfering with ureteral peristalsis. Bilateral ureteral obstruction, or unilateral obstruction to a solitary functioning kidney, can result in uraemia. Treatment of such patients is still a dilemma. El-Tabey et al.(4) retrospectively reviewed the records of patients who presented with bladder cancer and obstructive uraemia. Patients with inoperable locally advanced bladder tumours (23 patients, 37.7%) were treated with permanent nephrostomy tubes to relieve obstruction; radical cystectomy was not an option. In 10 patients (26.3%), who underwent surgery, palliative cystectomy without lymphadenectomy was carried out for advanced nodal involvement in four patients and locally advanced disease infiltrating the pelvic wall in six patients. In all patients, local pelvic recurrence was reported within the first year of follow-up (4). In one study post-operative outcome of primary radical cystectomy in 20 T4 bladder cancer patients (of which seven cases were T4b) was reported. The authors concluded that primary cystectomy for the treatment of T4 bladder cancer was technically feasible and had a very tolerable therapy-related morbidity and mortality (5).

8.2

Conclusions

• • •

Primary radical cystectomy in T4b bladder cancer is not a curative option. If there are symptoms, radical cystectomy may be a therapeutic/palliative option. Intestinal or non-intestinal forms of urinary diversion can be used with or without palliative cystectomy.

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8.3

Recommendations

•

For patients with inoperable locally advanced tumours (T4b), primary radical cystectomy is not a curative option (Grade of recommendation: B). The indication for performing a palliative cystectomy is symptom relief. Morbidity of surgery and quality of life should be weighed against other options (Level of evidence: 3; Grade of recommendation: B/C).

• •

8.4

References

1.

Ok JH, Meyers FJ, Evans CP. Medical and surgical palliative care of patients with urological malignancies. J Urol 2005;174(4 Pt 1):1177-82. http://www.ncbi.nlm.nih.gov/pubmed/16145365 Ubrig B, Lazica M, Waldner M, Roth S. Extraperitoneal bilateral cutaneous ureterostomy with midline stoma for palliation of pelvic cancer. Urology 2004;63(5):973-5. http://www.ncbi.nlm.nih.gov/pubmed/15134993 Zebic N, Weinknecht S, Kroepfl D. Radical cystectomy in patients aged > or = 75 years: an updated review of patients treated with curative and palliative intent. BJU Int 2005;95(9):1211-4. http://www.ncbi.nlm.nih.gov/pubmed/15892803 El-Tabey NA, Osman Y, Mosbah A, Mohsen T, Abol-Enein H. Bladder cancer with obstructive uremia: oncologic outcome after definitive surgical management. Urology 2005;66(3):531-5. http://www.ncbi.nlm.nih.gov/pubmed/16140072 Nagele U, Anastasiadis AG, Merseburger AS, Corvin S, Hennenlotter J, Adam M, Sievert KD, Stenzl A, Kuczyk MA. The rationale for radical cystectomy as primary therapy for T4 bladder cancer. World J Urol 2007;25(4):401-5. http://www.ncbi.nlm.nih.gov/pubmed/17525849

2.

3.

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5.

9. NEO-ADJUVANT RADIOTHERAPY IN MUSCLE-INVASIVE BLADDER CANCER 9.1

Pre-operative radiotherapy

9.1.1 Retrospective studies Several retrospective studies have looked at the effect of pre-operative radiotherapy in patients with bladder cancer. The largest retrospective series was from the MD Anderson Cancer Center in the USA (n = 526). It showed that 50 Gy pre-operative radiotherapy resulted in down-staging in 73% of cT3 patients versus 29% of patients who did not receive pre-operative radiotherapy (1, 2). Local control was also improved from 72% to 91% in pT3b patients (n = 91), but not in pT2 or pT3a patients. The improvement in survival in this retrospective series was from 40% to 52%. The results of a non-randomized study comparing 40 Gy, 5-20 Gy and no radiotherapy showed that only 40 Gy pre-operative radiotherapy improved the percentage of local recurrence from 27% to 11% and survival from 21% to 63% (3). Overall, nearly all the retrospective studies investigating the effect of pre-operative radiotherapy with doses of 40-50 Gy, followed after 4-6 weeks by cystectomy, showed (1-9): • down-staging of the tumour stage (40-65% of patients) • lower risk of local recurrence (10-42%) • improved survival (11-12%). Some studies found that the improvement in local control was highest for T3b tumours (2-4). Other studies found that achievement of a pathological complete remission (pCR) is a prognostic factor for survival (3-5). One retrospective study (5) found no significant increase in toxicity due to pre-operative radiotherapy (10% versus 3%). 9.1.2 Randomized studies There are five randomized studies investigating pre-operative radiotherapy. The largest randomized trial (234 evaluable patients), using pre-operative radiotherapy 45 Gy/1.8-2.2 Gy in muscle-invasive tumours, showed a significant increase in pCR (9% to 34%) in favour of pre-operative radiotherapy and no significant increase in 5-year survival of 33% to 45% (10). In patients who were not given adjuvant chemotherapy, survival was significantly better in those who received pre-operative radiotherapy (25–52%). pCR was a prognostic factor for better survival. A major drawback of this study is that almost 50% of patients did not receive the planned treatment and were excluded form the analysis. The Southwest Oncology Group (SWOG) trial (n = 124), which

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used a pre-operative dose of 5 x 4 Gy, did not show a survival advantage (11). A study from Egypt, dealing with patients with bladder cancer caused by bilharzia (predominantly squamous cell carcinoma, n = 92) also showed a significant survival advantage for > T3 tumours, but a marginal and non-significant difference for the whole group (12). A small, randomized study of 44 patients (13) also showed a significant increase in pCR (18–55%) and a small increase in 5-year survival (61–72%, not significant), but the disadvantages of this study were a small patient population and differing radiotherapy schedules (32-54 Gy). Finally, in another small, three-armed study (n = 72), patients were randomized between surgery, surgery with pre-operative radiotherapy (45 Gy in 4-5 weeks) and radiotherapy alone (50-60 Gy in 4-6 weeks) (14). Pre-operative radiotherapy resulted in 24% of patients achieving pCR. There were no significant differences in survival or toxicity between the three arms. There was no reported increase in toxicity due to pre-operative radiotherapy in any of the abovementioned studies. The effect on the local recurrence rate was not specifically documented in any of the studies. Three of the randomized studies looked at down-staging and found an increase in pCR following preoperative radiotherapy from 9% to 34% (10), 0% to 24% (14) and from 18% to 55% (13). Local recurrences were not reported (10, 14) nor were they similar (13). All six randomized studies looked at survival. The largest study found a significant survival advantage from 25% to 52% in those patients who did not receive adjuvant chemotherapy (10). The Egyptian study found a survival advantage only for T3 patients or higher (12). No study found a significant survival advantage for the whole group. A meta-analysis of the randomized trials on the value of pre-operative radiotherapy showed an odds ratio for the difference in 5-year survival of 0.71 (CI: 0.48-1.06). However, the meta-analysis was potentially biased by the many patients in the largest trial, who did not receive the planned treatment. When the results of the largest trial were excluded, the odds ratio became 0.95 (CI: 0.57-1.55), indicating that improved survival with pre-operative radiotherapy had not been proven (15, 16).

9.2

Conclusions

•

It is not proven that pre-operative radiotherapy for operable muscle-invasive bladder cancer increases survival (Level of evidence: 2). It is shown that pre-operative radiotherapy for operable muscle-invasive bladder cancer, using a dose of 45-50 Gy in fractions of 1.8-2 Gy results in down-staging after 4-6 weeks (Level of evidence: 2). Pre-operative radiotherapy with a dose of 45-50 Gy/1.8-2 Gy does not seem to significantly increase toxicity after surgery (Level of evidence: 3). There are suggestions in older literature that pre-operative radiotherapy will result in a decrease in local recurrence of muscle-invasive bladder cancer (Level of evidence: 3).

•

• •

9.3

Recommendations

• •

Pre-operative radiotherapy is not recommended to improve survival (Grade of recommendation: B). Pre-operative radiotherapy for operable muscle-invasive bladder cancer results in tumour downstaging after 4-6 weeks (Grade of recommendation: A-C).

9.4

References

1.

Pollack A, Zagars GK, Dinney CP, Swanson DA, von Eschenbach AC. Preoperative radiotherapy for muscle-invasive bladder carcinoma. Long term follow-up and prognostic factors for 338 patients. Cancer 1994;74(10):2819-27. http://www.ncbi.nlm.nih.gov/pubmed/7954243 Cole CJ, Pollack A, Zagars GK, Dinney CP, Swanson DA, von-Eschenbach AC. Local control of muscle-invasive bladder cancer: preoperative radiotherapy and cystectomy versus cystectomy alone. Int J Radiat Oncol Biol Phys 1995;32(2):331-40. http://www.ncbi.nlm.nih.gov/pubmed/7751174 Spera JA, Whittington R, Littman P, Solin LJ, Wein AJ. A comparison of preoperative radiotherapy regimens for bladder carcinoma. The University of Pennsylvania experience. Cancer 1988;61(2):25562. http://www.ncbi.nlm.nih.gov/pubmed/3334959 Pollack A, Zagars GK, Cole CJ, Dinney CP, Swanson DA, Grossman HB. Significance of downstaging in muscle-invasive bladder cancer treated with preoperative radiotherapy. Int J Radiat Oncol Biol Phys 1997;37(1):41-9. http://www.ncbi.nlm.nih.gov/pubmed/9054875

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16.

Chougule P, Aygun C, Salazar O, Young JJ Jr, Prempree T, Amin P. Radiation therapy for transitional cell bladder carcinoma. A ten-year experience. Urology 1988;32(2):91-5. http://www.ncbi.nlm.nih.gov/pubmed/3135646 Batata MA, Chu FC, Hilaris BS, Whitmore WF, Kim YS, Lee MZ. Bladder cancer in men and women treated by radiation therapy and/or radical cystectomy. Urology 1981;18(1);15-20. http://www.ncbi.nlm.nih.gov/pubmed/6789529 Fossa SD, Ous S, Berner A. Clinical significance of the “palpable mass” in patients with muscleinfiltrating bladder cancer undergoing cystectomy after pre-operative radiotherapy. Br J Urol 1991;67(1):54-60. http://www.ncbi.nlm.nih.gov/pubmed/1993277 Gilloz A, Heritier P. Comparative study of actuarial survival rates in P3 P4 (N+ Mo) transitional cell carcinoma of bladder managed by total cystectomy alone or associated with preoperative radiotherapy and pelvic lymphadenectomy. Prog Clin Biol Res 1984;162B:15-9. http://www.ncbi.nlm.nih.gov/pubmed/6504893 Smith JA, Batata M, Grabstald H, Sogani PC, Herr H, Whitmore WF Jr. Preoperative irradiation and cystectomy for bladder cancer. Cancer 1982;49:869-973. http://www.ncbi.nlm.nih.gov/pubmed/6800628 Slack NH, Bross ID, Prout GR. Five-year follow-up results of a collaborative study of therapies for carcinoma of the bladder. J Surg Oncol 1977;9:393-405. http://www.ncbi.nlm.nih.gov/pubmed/330958 Smith JA, Crawford ED Paradelo JC et al. Treatment of advanced bladder cancer with combined preoperative irradiation and radical cystectomy versus radical cystectomy alone: a phase III intergroup study. J Urol 1997;157:805-7; discussion 807-8. http://www.ncbi.nlm.nih.gov/pubmed/9072571 Ghoneim MA, Ashamallah AK, Awaad HK, Whitmore WF Jr. Randomized trial of cystectomy with or without preoperative radiotherapy for carcinoma of the bilharzial bladder. J Urol 1985;134(2):266-8. http://www.ncbi.nlm.nih.gov/pubmed/3894693 Anderstrom C, Johanson S, Nilsson S, Unsgaard B, Wahlqvist L. A prospective randomized study of preoperative irradiation with cystectomy or cystectomy alone for invasive bladder carcinoma. Eur Urol 1983;9(3):142-7. http://www.ncbi.nlm.nih.gov/pubmed/6861819 Blackard CE, Byar DP. Results of a clinical trial of surgery and radiation in stages II and III carcinoma of the bladder. J Urol 1972;108(6):875-8. http://www.ncbi.nlm.nih.gov/pubmed/5082739 Huncharek M, Muscat J, Geschwind JF. Planned preoperative radiation therapy in muscle invasive bladder cancer; results of a meta-analysis. Anticancer Res 1998;18(3b):1931-4. http://www.ncbi.nlm.nih.gov/pubmed/9677446 Widmark A, Flodgren P, Damber JE, Hellsten S, Cavallin-Stahl E. A systematic overview of radiation therapy effects in urinary bladder cancer. Acta Oncol 2003;42(5-6):567-81. http://www.ncbi.nlm.nih.gov/pubmed/14596515

10. BLADDER-SPARING TREATMENTS 10.1

Transurethral resection of bladder tumour

When patients, with an initially invasive bladder cancer, presenting with pT0 or pT1 status at second resection are selected for transurethral resection of bladder tumour (TURBT) alone, about half of them will have to undergo radical cystectomy for recurrent muscle-invasive cancer, with a disease-specific death rate ranging up to 47% within this group (1, 2). A disease-free status at restaging TUR appears to be crucial in making the decision not to perform radical cystectomy (3, 4). It is only possible to consider TUR alone as a therapeutic option if tumour growth is limited to the superficial muscle layer and if restaging biopsies are negative for residual tumour (5). TUR alone should only be considered as a therapeutic option, when the patient is unfit for cystectomy or a multimodality bladder-preserving approach or refuses open surgery (6).

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10.1.1 Conclusion and recommendation • TUR alone is not a curative treatment option in most patients (Level of evidence: 2a; Grade of recommendation: B). 10.1.2 References 1. Barnes RW, Dick AL, Hadley HL, Johnston OL. Survival following transurethral resection of bladder carcinoma. Cancer Res 1977;37(8 Pt 2):2895-7. http://www.ncbi.nlm.nih.gov/pubmed/872119 2. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19(1):89-93. http://www.ncbi.nlm.nih.gov/pubmed/11134199 3. Solsona E, Iborra I, Ricos JV, Monros JL, Casanova J, Calabuig C. Feasibility of transurethral resection for muscle infiltrating carcinoma of the bladder: long-term follow-up of a prospective study. J Urol 1998;159:95-98; discussion 98-99. http://www.ncbi.nlm.nih.gov/pubmed/9400445 4. Holmang S, Hedelin H, Anderstrom C, Johansson SL. Long-term follow-up of all patients with muscle invasive (stages T2, T3 and T4) bladder carcinoma in a geographical region. J Urol 1997;158(2):38992. http://www.ncbi.nlm.nih.gov/pubmed/9224309 5. Herr HW. Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol 1987;138(5):1162-3. http://www.ncbi.nlm.nih.gov/pubmed/3669160 6. Whitmore WF Jr, Batata MA, Ghoneim MA, Grabstald H, Unal A. Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J Urol 1977:118(1 Pt 2):184-7. http://www.ncbi.nlm.nih.gov/pubmed/875217

10.2

External beam radiotherapy

The target field usually comprises the bladder only, with a safety margin of 1.5-2 cm to allow for unavoidable organ movements (1-4). Any beneficial effect with larger pelvic fields has not been demonstrated. The target dose for curative radiotherapy for bladder cancer is 60-66 Gy, with a subsequent boost using external radiotherapy or interstitial brachytherapy. The daily dose is usually 1.8-2 Gy, and the course of radiotherapy should not extend beyond 6-7 weeks to minimize the repopulation of cancer cells. The use of modern standard radiotherapy techniques results in major, related, late morbidity of the urinary bladder or bowel in less than 5% of tumour free-patients (5-9). Besides the response to radiotherapy, important prognostic factors for outcome include tumour size, hydronephrosis and the completeness of the initial TURBT. Overall 5-year survival rates in patients with muscle-invasive bladder cancer range between 30% and 60%, with a cancer-specific survival rate of 20% and 50%, with or without a complete response following radiotherapy, respectively (10-14). Based on available trials, a Cochrane analysis has demonstrated that radical cystectomy has an overall survival benefit compared to radiotherapy (15). 10.2.1 Conclusions • External beam radiotherapy alone should only be considered as a therapeutic option when the patient is unfit for cystectomy or a multimodality bladder-preserving approach (Level of evidence: 3). • Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation because of extensive local tumour growth (Level of evidence: 3). 10.2.2 Recommendation • There is evidence that radiotherapy alone is less effective than curative therapy (surgery or trimodality treatment) (Grade or recommendation: B). 10.2.3 References 1. Gospodarowicz MK, Blandy JP. Radiation therapy for organ-conservation for invasive bladder carcinoma. In: Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS, eds. Comprehensive Textbook of Genitourinary Oncology. Lippincott: Williams and Wilkins, 2000; pp. 487-496. 2. Duncan W, Quilty PM. The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily treated by radical megavoltage X-ray therapy. Radiother Oncol 1986;7(4): 299-310. http://www.ncbi.nlm.nih.gov/pubmed/3101140

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3.

4.

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7.

8.

9.

10.

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12.

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14.

15.

10.3

Gospodarowicz MK, Hawkins NV, Rawlings GA, Connolly JG, Jewett MA, Thomas GM, Herman JG, Garrett PG, Chua T, Duncan W et al. Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. J Urol 1989;142(6):1448-53; discussion 1453-4. http://www.ncbi.nlm.nih.gov/pubmed/2585617 Gospodarowicz MK, Quilty PM, Scalliet P, Tsujii H, Fossa SD, Horenblas S, Isaka S, Prout R, Shipley WU, Wijnmaalen AJ et al. The place of radiation therapy as definitive treatment of bladder cancer. Int J Urol 1995;2(Suppl 2):41-8. http://www.ncbi.nlm.nih.gov/pubmed/7553304 Shipley WU, Zietman AL, Kaufman DS, Althausen AF, Heney NM. Invasive bladder cancer: treatment strategies using transurethral surgery, chemotherapy and radiation therapy with selection for bladder conservation. Int J Radiat Oncol Biol Phys 1997;39(4):937-43. http://www.ncbi.nlm.nih.gov/pubmed/9369144 Maciejewski B, Majewski S. Dose fractionation and tumor repopulation in radiotherapy for bladder cancer. Radiother Oncol 1991;21(3):163-70. http://www.ncbi.nlm.nih.gov/pubmed/1924851 De Neve W, Lybeert MLM, Goor C, Crommelin NA, Ribot JG. Radiotherapy for T2 and T3 carcinoma of the bladder: the influence of overall treatment time. Radiother Oncol 1995;36(3):183-8. http://www.ncbi.nlm.nih.gov/pubmed/8532904 Milosevic M, Gospodarowicz M, Zietman A, Abbas F, Haustermans K, Moonen L, Rodel C, Schoenberg M, Shipley W. Radiotherapy for bladder cancer. Urology 2007;69(1 Suppl):80-92. http://www.ncbi.nlm.nih.gov/pubmed/17280910 Whitmore WF Jr, Batata MA, Ghoneim MA, Grabstald H, Unal A. Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J Urol 1977;118(1 Pt 2):184-7. http://www.ncbi.nlm.nih.gov/pubmed/875217 Pollack A, Zagars GZ. Radiotherapy for stage T3b transitional cell carcinoma of the bladder. Semin Urol Oncol 1996;14(2):86-95. http://www.ncbi.nlm.nih.gov/pubmed/8734736 De Neve W, Lybeert ML, Goor C, Crommelin MA, Ribot JG. Radiotherapy for T2 and T3 carcinoma of the bladder: the influence of overall treatment time. Radiother Oncol 1995;36(3):183-8. http://www.ncbi.nlm.nih.gov/pubmed/8532904 Mameghan H, Fisher R, Mameghan J, Brook S. Analysis of failure following definitive radiotherapy for invasive transitional cell carcinoma of the bladder. Int J Radiat Oncol Biol Phys 1995;31(2):247-54. http://www.ncbi.nlm.nih.gov/pubmed/7836076 Herskovic A, Martz K, Al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326(24):1593-8. http://www.ncbi.nlm.nih.gov/pubmed/1584260 Naslund I, Nilsson B, Littbrand B. Hyperfractionated radiotherapy of bladder cancer. A ten-year followup of a randomized clinical trial. Acta Oncol 1994;33(4):397-402. http://www.ncbi.nlm.nih.gov/pubmed/8018372 Shelley MD, Barber J, Wilt T, Mason MD. Surgery versus radiotherapy for muscle invasive bladder cancer. Cochrane Database Syst Rev 2002;(1):CD002079. http://www.ncbi.nlm.nih.gov/pubmed/11869621

Chemotherapy

Chemotherapy alone rarely produces durable complete responses. A clinical complete response rate of up to 56% as reported in some series must be weighed against a staging error of > 60% (1-2). In the case of an initially incomplete TUR, a pathological complete response rate of 8-26% can be expected following an additional cisplatin-based systemic therapy (3-5). The use of cisplatin-based chemotherapy as the primary therapy for locally advanced (T3/T4) tumours has resulted in complete and partial local responses in 11% and 34% of cases, respectively (6-7). 10.3.1 Conclusion With cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected patients, complete and partial local responses have been reported (Level of evidence: 2b). 10.3.2 Recommendation Chemotherapy alone is not recommended as primary therapy for localized bladder cancer (Grade of recommendation: A).

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10.3.3 References 1. Scher HI, Yagoda A, Herr HW, Sternberg CN, Bosl G, Morse MJ, Sogani PC, Watson RC, Dershaw DD, Reuter V et al. Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) effect on the primary bladder lesion. J Urol 1988;139(3):470-4. http://www.ncbi.nlm.nih.gov/pubmed/3343728 2. Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol 1998;16(4):1298-301. http://www.ncbi.nlm.nih.gov/pubmed/9552029 3. Scattoni V, Da Pozzo L, Nava L, Broglia L, Galli L, Torelli T, Campo B, Maffezzini M, Rigatti P. Five-year results of neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy plus radical cystectomy in locally advanced bladder cancer. Eur Urol 1995;28(2):102-7. http://www.ncbi.nlm.nih.gov/pubmed/8529731 4. Igawa M, Ohkuchi T, Ueki T, Ueda M, Okada K, Usui T. Usefulness and limitations of methotrexate, vinblastine, doxorubicin and cisplatin for the treatment of advanced urothelial cancer. J Urol 1990;144(3):662-5. http://www.ncbi.nlm.nih.gov/pubmed/2388322 5. Angulo JC, Sanchez-Chapado M, Lopez JI, Flores N. Primary cisplatin, methotrexate and vinblastine aiming at bladder preservation in invasive bladder cancer: multivariate analysis on prognostic factors. J Urol 1996;155(6):1897-902. http://www.ncbi.nlm.nih.gov/pubmed/8618282 6. Roberts JT, Fossa SD, Richards B, Kaye SB, White EF, Robinson MC, Uscinska B, Parmar MK. Results of Medical Research Council phase II study of low dose cisplatin and methotrexate in the primary treatment of locally advanced (T3 and T4) transitional cell carcinoma of the bladder. Br J Urol 1991;68(2):162-8. http://www.ncbi.nlm.nih.gov/pubmed/1884143 7. Martinez-Piñeiro JA, Gonzalez Martin M, Arocena F, Flores N, Roncero CR, Portillo JA, Escudero A, Jimenez Cruz F, Isorna S. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol 1995;153(3 Pt 2):964-73. http://www.ncbi.nlm.nih.gov/pubmed/7853584

10.4

Multimodality treatment

Recent organ-preservation strategies combine TURBT, chemotherapy and radiation (1-5). The rationale for performing TURBT and radiation is to achieve local tumour control. Application of systemic chemotherapy, most commonly as methrotrexate, cisplatin and vinblastine (MCV), aims at the eradication of micrometastasis. Many protocols use cisplatin and/or 5-FU and, recently, gemcitabine with radiation because of their established role as radiosensitizers. Cisplatin-based chemotherapy in combination with radiotherapy, following TURBT, results in a complete response rate of 60-80%. It is recommended that early cystectomy is performed in individuals who do not achieve a complete response following combination therapy. This will allow about 40-45% of patients to survive with an intact bladder at 4-5 years (5). A comparable long-term survival rate of 50-60% at 5 years’ follow-up is reported by both multimodality bladder-preserving trials and cystectomy series. However, both therapeutic approaches have never been directly compared and patients in multimodality series are highly selected (5-7). A bladder-preserving multimodality strategy requires very close multidisciplinary co-operation and a high level of patient compliance. Even if a patient has shown a complete response to a multimodality bladder-preserving strategy, the bladder remains a potential source of recurrence. About half of patients can be expected to survive with their native bladder intact. A T0 status at repeat TUR after the initial transurethral resection of the primary tumor, followed by chemotherapy in combination with radiotherapy, was identified as a prognostically important variable. However, even the latter patients are at a life-long risk of developing intravesical tumor recurrences with the need for meticulous surveillance and multiple invasive procedures. It has been postulated that a delay in radical cystectomy due to an initial bladder-preserving approach increases the risk of lymph node metastases to a lymph-node positive rate of 26% when cystectomy becomes necessary due to treatment failure. 10.4.1 Conclusions • There are comparable long-term survival rates in cases of multimodality treatment success (Level of evidence: 3). • Delay in surgical therapy can compromise survival rates. (Level of evidence: 2b].

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10.4.2 Recommendations • TUR alone is not a curative treatment option in most patients (grade of recommendation: B). • Radiotherapy alone is less effective than surgery (grade of recommendation: B). • Chemotherapy alone is not recommended as primary therapy for localized bladder cancer (grade of recommendation: B). • Multimodality treatment is an alternative in selected, well-informed and compliant patients where cystectomy is not considered for clinical or personal reasons (Grade of recommendation: B). 10.4.3 References 1. Shipley WU, Kaufman DS, Zietman AL, Griffin PP, Heney NM, Althausen AF. Selective bladder preservation by combined modality therapy for invasive bladder cancer. Eur J Cancer 1995:31A(Suppl 5):S239. 2. Shipley WU, Kaufman DS, Heney NM, Althausen AF, Zietman AL. An update of selective bladder preservation by combined modality therapy for invasive bladder cancer. Eur Urol 1998;33 Suppl 4:324. http://www.ncbi.nlm.nih.gov/pubmed/9615208 3. Housset M, Dufour E, Maulard-Durtux C. Concomitant 5-fluouracil (5-FU)-cisplatin (CDDP) and bifractionated split course radiation therapy (BSCRT) for invasive bladder cancer. Proc Am Soc Clin Oncol 1997;16:1139A (abstr). http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_search_results_vi ew&selectedConfs=17,31,30,29,28&SearchFilter1=Title&SearchTerm1=cisplatin&SearchFilter2=Author &SearchTerm2=&SearchFilter3=Author&SearchTerm3=Housset 4. Weiss C, Wolze C, Engehausen DG, Ott OJ, Krause FS, Schrott KM, Dunst J, Sauer R, Rodel C. Radiochemotherapy after transurethral resection for high-risk T1 bladder cancer: an alternative to intravesical therapy or early cystectomy? J Clin Oncol 24(15):2318-24. http://www.ncbi.nlm.nih.gov/pubmed/16710030 5. Rodel C, Grabenbauer GG, Kuhn R, Papadopoulos T, Dunst J, Meyer M, Schrott KM, Sauer R. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002;20(14):3061-71. http://www.ncbi.nlm.nih.gov/pubmed/12118019 6. Zietman AL, Grocela J, Zehr E, Kaufman DS, Young RH, Althausen AF, Heney NM, Shipley WU. Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder. Urology 2001;58(3):380-5. http://www.ncbi.nlm.nih.gov/pubmed/11549485 7. Shipley WU, Kaufman DS, Zehr E, Heney NM, Lane SC, Thakral HK, Althausen AF, Zietman AL. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology 2002;60(1):62-7; discussion 67-8. http://www.ncbi.nlm.nih.gov/pubmed/12100923

11. ADJUVANT CHEMOTHERAPY Adjuvant chemotherapy for patients after radical cystectomy with pT3/4 and/or lymph node positive (N+) disease without clinically detectable metastases (M0) is under debate (1, 2). The benefits of chemotherapy in the adjuvant setting include: • Chemotherapy is administered after accurate pathological staging • Overtreatment in patients at low risk for micrometastases is avoided • No delay in definitive surgical treatment, especially in patients not sensitive to chemotherapy. The drawbacks of adjuvant chemotherapy are: • Assessment of in-vivo chemosensitivity of the tumour is not possible • Delay or intolerability of chemotherapy, due to post-operative morbidity. There is not enough evidence in favour of the routine use of adjuvant chemotherapy (2, 8). To date, there have been only five published randomized trials of adjuvant chemotherapy (3-7) and one meta-analysis (8), with updated individual patient data from six trials and a total of only 491 patients for survival analysis. Furthermore, all these trials are sub-optimal with serious deficiencies, such as low sample size (underpowered), use of substandard chemotherapy, early stopping of patient entry and flaws in design

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and statistical analysis, including irrelevant endpoints or a lack of recommendations concerning salvage chemotherapy for relapse or metastases (2). The data are not convincing enough to give an unequivocal recommendation for the use of adjuvant chemotherapy. From the evidence so far available, it is unclear whether immediate adjuvant chemotherapy or chemotherapy at the time of relapse is superior or if the two approaches are equivalent with respect to the end-point overall survival. In recent trial updates, cisplatin-based combination chemotherapy was able to produce long-term disease-free survival, even in metastatic disease, albeit mainly in patients with lymph node metastases only and in good PS (9-11). Patients with extravesical and/or node positive disease following cystectomy should be enrolled in clinical trials whenever possible. In non-protocol-eligible patients, adjuvant cisplatin-based chemotherapy is an option provided the patient is well informed about the scarce data available. Published trials of randomized adjuvant chemotherapy have used 3-4 cycles of CMV (cisplatin, methotrexate, vinblastine), CISCA (cisplatin, cyclophosphamide, and adriamycine), MVA(E)C (methotrexate, vinblastine, adriamycine or epirubicine, and cisplatin) and CM (cisplatin, methotrexate) (12). There is no evidence that more modern or carboplatin-containing chemotherapy combinations are as effective. Patients ineligible for cisplatin should not receive adjuvant chemotherapy.

11.1 Conclusion •

Adjuvant chemotherapy is under debate. Neither randomized trials nor a meta-analysis have provided sufficient data to support the routine use of adjuvant chemotherapy (Level of evidence: 1a).

11.2 Recommendation •

Adjuvant chemotherapy is advised within clinical trials, but not for routine use because it has not been studied sufficiently (Grade of recommendation: A).

11.3

References

1.

Cohen SM, Goel A, Phillips J, Ennis RD, Grossbard ML. The role of perioperative chemotherapy in the treatment of urothelial cancer. Oncologist 2006;11(6):630-40. http://www.ncbi.nlm.nih.gov/pubmed/16794242 Sylvester R, Sternberg C. The role of adjuvant combination chemotherapy after cystectomy in locally advanced bladder cancer: what we do not know and why. Ann Oncol 2000;11(7):851-6. http://www.ncbi.nlm.nih.gov/pubmed/10997813 Bono A, Benvenuti C, Gibba A, Guazzeri S, Cosciani-Cunico S, Anselmo G. Adjuvant chemotherapy in locally advanced bladder cancer. Final analysis of a controlled multicentre study. Acta Urol Ital 1997;11(1):5-8. Freiha F, Reese J, Torti FM. A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 1996;155(2):495-9; discussion 499-500. http://www.ncbi.nlm.nih.gov/pubmed/8558644 Stockle M, Meyenburg W, Wellek S, Voges GE, Rossmann M, Gertenbach U, Thuroff JW, Huber C, Hohenfellner R. Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience. J Urol 1995;153(1):47-52. http://www.ncbi.nlm.nih.gov/pubmed/7966789 Studer UE, Bacchi M, Biedermann C, Jaeger P, Kraft R, Mazzucchelli L, Markwalder R, Senn E, Sonntag RW. Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol 1994;152(1):81-4. http://www.ncbi.nlm.nih.gov/pubmed/8201695 Skinner DG, Daniels JR, Russell CA, Lieskovsky G, Boyd SD, Krailo M, Groshen S. Adjuvant chemotherapy following cystectomy benefits patients with deeply invasive bladder cancer. Semin Urol 1990;8(4):279-84. http://www.ncbi.nlm.nih.gov/pubmed/2284533 Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol 2005;48(2):189-199; discussion 99-201. http://www.ncbi.nlm.nih.gov/pubmed/15939530

2.

3.

4.

5.

6.

7.

8.

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9.

10.

11.

12.

von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23(21):4602-8. http://www.ncbi.nlm.nih.gov/pubmed/16034041 Sternberg CN. Perioperative chemotherapy in muscle-invasive bladder cancer to enhance survival and/or as a strategy for bladder preservation. Semin Oncol 2007;34(2):122-8. http://www.ncbi.nlm.nih.gov/pubmed/17382795 Stadler WM, Hayden A, von der Maase H, Roychowdhur D, Dogliotti L, Seymour L, Kaufmann D, Moore M. Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced transitional cell cancer. Urol Oncol 2002;7(4):153-7. http://www.ncbi.nlm.nih.gov/pubmed/12474531 Lehmann J, Retz M, Wiemers C, Beck J, Thuroff J, Weining C, Albers P, Frohneberg D, Becker T, Funke PJ, Walz P, Langbein S, Reiher F, Schiller M, Miller K, Roth S, Kalbe T, Sternberg D, Wellek S, Stockle M; AUO-AB 05/95. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). J Clin Oncol 2005;23(22):4963-74. http://www.ncbi.nlm.nih.gov/pubmed/15939920

12. METASTATIC DISEASE Approximately 30% of patients with urothelial cancer present with muscle-invasive disease; about half will relapse after radical cystectomy depending on the pathological stage of the primary tumour and the nodal status. Local recurrence accounts for about 30% of relapses, whereas distant metastases are more common. About 10-15% of patients are already metastatic at diagnosis (1). Before the development of effective chemotherapy, patients with metastatic urothelial cancer rarely exceeded the median survival of 3-6 months (2).

12.1

Prognostic factors and treatment decisions

Bladder cancer is a chemosensitive tumour. Response rates differ with respect to patient-related factors and pre-treatment disease. Prognostic factors for response and survival have been established. In a multivariate analysis, Karnofsky PS of 80% or less and the presence of visceral metastases were independently prognostic of poor survival after treatment with MVAC (methotrexate, vinblastine, adriamycine and cisplatin). These so-called ‘Bajorin’ prognostic factors (3) have also been validated for newer combination chemotherapies (4, 5) and are crucial for assessing phase II study results and stratifying phase III trials (6, 7). Additional data on the prognostic value of elevated alkaline phosphatase and the number of disease sites (> or < three) were generated prospectively (8). A retrospective analysis showed that, in elderly patients, an ECOG (Eastern Cooperative Oncology Group) PS 2-3 and a haemoglobin level of <10 mg/dl were independent predictors of poor survival (9). Age itself has no impact on response or toxic events (9). Besides these prognostic factors, treatment decisions should also be based on a patient’s renal function to decide whether a patient is ‘fit’ enough to receive a cisplatin-containing combination regimen (creatinine clearance > 60 mL/min, PS, co-morbidity) (10-14). So far, there is no generally accepted definition for ‘fit’ or ‘unfit’ patients (15).

12.2

Single-agent chemotherapy

Varying response rates of single-agent first-line chemotherapy have been reported with only 12% for cisplatin compared to MVAC (7), 12% for carboplatin (10), 42% for paclitaxel (16), 31% for docetaxel (17), 29% for methotrexate, 19% for adriamycin, 15% for epirubicin, 13% for mitomycin C, 35% for 5-FU, 14% for vinblastine, 29% for ifosfamide and 8% for cyclophosphamide (18, 19). The most robust single-agent data is a response rate of about 25% for gemcitabine for first- and second-line use in several, larger-sized, phase II trials (20-27). Responses with single agents are usually short-lived and complete responses are rare. Of note, no long-term disease-free survival has been reported with single-agent chemotherapy. The median survival in such patients is only about 6-9 months. Patients with PS WHO 3-4, with or without additional negative prognostic factors, are not expected to benefit from combination chemotherapy. The most appropriate approach for this patient group is best supportive care or, at most, single-agent chemotherapy.

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12.3

Standard first-line chemotherapy for ‘fit’ patients

Cisplatin-containing combination chemotherapy has been the standard of care since the late 1980s. MVAC has been superior to cisplatin monotherapy and CISCA (cisplatin, cyclophosphamide and adriamycine) (7, 28) and, more recently, to cisplatin/docetaxel (29). MVAC and gemcitabine/cisplatin (GC) have prolonged survival up to 14.8 and 13.8 months, respectively (30-32). Neither of the two combinations was proven to be superior over the other, but equivalence was not tested, with response rates of 46% and 49% for MVAC and GC, respectively. The long-term survival results confirmed the anticipated equivalence of the two regimens (8). The major difference between the above-mentioned combinations was toxicity, with GC being less toxic (32). MVAC is better tolerated with the use of GCSF (29, 33). High-dose intensity MVAC (HD-MVAC) with GCSF is less toxic and more efficacious than standard MVAC in terms of dose density, complete response and 2-year survival rate. However, there is no significant difference in median survival between the two regimens (34, 35). Further intensification of treatment using new triplets, dose-dense schedules or adding targeted therapies is still being investigated. These approaches should be reserved for clinical trials and are not considered suitable for routine use.

12.4

Carboplatin-containing chemotherapy in ‘fit’ patients

Carboplatin-containing chemotherapy is not proven to be equivalent to cisplatin combinations. However, it is probably inferior and therefore should not be considered interchangeable or standard. The only randomized phase III study of carboplatin-containing chemotherapy had a disappointing response rate of only 28.2% in the investigational arm (paclitaxel/carboplatin) compared to MVAC and had to be closed down early because of a low accrual rate. There is therefore no evidence that this doublet might have adequate efficacy for first-line use (36). Various carboplatin versus cisplatin combination chemotherapies in randomized phase II trials have produced lower complete response rates and a shorter overall survival for the carboplatin arms (37-39).

12.5

Non-platinum combination chemotherapy

Gemcitabine and paclitaxel combinations in different schedules have been studied as both first- and secondline treatments. Apart from severe pulmonary toxicity with a weekly schedule of both drugs, this combination has been well tolerated and produced response rates between 38% and 60% in both lines. Because there has not been a randomized comparison. Because there has not been a randomized comparison to standard cisplatin chemotherapy, non-platinum combination-chemotherapy is not recommended for first-line use in patients who are fit enough (27, 40-45).

12.6

Chemotherapy in patients ‘unfit’ for cisplatin

Up to 50% of patients are unfit for cisplatin-containing chemotherapy, either due to a poor PS and/or impaired renal function, or due to co-morbidity that forbids high-volume hydration (46, 47). In such cases, carboplatin combination or single-agent chemotherapy is reasonable (10, 11). Non-platinum combinations, as front-line chemotherapy in patients with two adverse prognostic factors (GFR < 50-60 mL/min and PS > 2) should be reserved for investigational use because they have not been tested in purely ‘unfit’ patients and might be too toxic. Trials with clearly defined ‘unfit’ patients or patients with multiple adverse prognostic factors are rare. However, the first randomized phase II/III trial in this setting is currently being conducted by the EORTC. It compares carboplatin/vinblastin/methotrexate and carboplatin/gemcitabine in patients unfit for cisplatin (www.eortc.be).

12.7

Second-line treatment

Second-line chemotherapy data are highly variable and prognostic factors are unclear in this setting. Suggested prognostic factors include the choice of front-line chemotherapy (adjuvant/neoadjuvant), prior chemosensitivity, PS and the ‘Bajorin’-prognostic factors. There is not yet enough data to define a chemotherapy standard in this setting. Re-exposition 12 months or more after response to a prior chemotherapeutic regimen is a reasonable strategy. Second-line response rates of paclitaxel (weekly), docetaxel, oxaliplatin, topotecan, lapatinib, gefitinib and bortezomib range between 0% and 13% in small phase II trials (48-55). Gemcitabine has been studied with excellent response rates also for second-line use (20, 24-27). However, most patients already receive this drug as part of their front-line treatment. Vinflunine, a new third-generation vinca-alcaloid, has shown objective response rates of 18% and disease control in 67% (56). Publication of a phase III trial of vinflunine randomized against best supportive care is awaited. In a phase II trial, pemetrexed 500 mg/m2, given every 3 weeks, showed a promising response rate of 28% and manageable toxicity with the addition of vitamin B12 and folinic acid supplementation and

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dexamethasone prophylaxis (57). The excellent response rate could not be confirmed by a second, smallersized trial; however, this may have been due to patient selection (58). Ifosfamide had a response rate of 20% but is prone to considerable toxicity (59). Paclitaxel/gemcitabine showed response rates of 38-60%, depending on pre-treatment response and indication of prior chemotherapy. Unfortunately, no randomized trial has been conducted to assess the true value of this second-line combination (2, 41, 45).

12.8

Low-volume disease and post-chemotherapy surgery

With cisplatin-containing combination chemotherapy, patients with lymph node metastases only, good PS and an adequate renal function may achieve excellent response rates, including a high degree of complete responses, with up to 20% of patients achieving long-term disease-free survival (8, 35, 60, 61). Stage migration may play a role in this positive prognostic development. A retrospective study of post-chemotherapy surgery after a partial or complete response indicated that post-chemotherapy surgery may contribute to long-term disease-free survival in selected patients (62-64).

12.9 Conclusions • •

•

• • •

• • •

Urothelial carcinoma is a chemosensitive tumour. Performance status and the presence or absence of visceral metastases are independent prognostic factors for survival. These factors are at least as important as the type of chemotherapy administered (Level of evidence: 3). Cisplatin-containing combination chemotherapy is able to achieve a median survival of up to 14 months, with long-term disease-free survival reported in about 15% of patients with nodal disease and good PS (Level of evidence: 1b). Single-agent chemotherapy provides low response rates of usually short duration (Level of evidence: 2a). Carboplatin-combination chemotherapy is less effective than cisplatin-based chemotherapy in terms of CR and survival (Level of evidence: 2a). Non-platinum combination chemotherapy has produced substantial responses in first- and secondline use, but has not been tested against standard chemotherapy in fit patients or in a purely unfit patient group (Level of evidence: 2a). To date, there is no defined standard chemotherapy for ‘unfit’ patients with advanced or metastatic urothelial cancer (Level of evidence: 2b). Small-sized phase II trials provide evidence of moderate response rates for single agents or nonplatinum combinations at second-line use (Level of evidence: 2a). Post-chemotherapy surgery after a partial or complete response may contribute to long-term disease-free survival (Level of evidence: 3).

12.10 Recommendations • • • • •

Prognostic factors guide treatment selection (Grade of recommendation: B). First-line treatment for fit patients: use cisplatin-containing combination chemotherapy with GC, MVAC, preferably with GCSF, or HD-MVAC with GCSF (Grade of recommendation: A). Carboplatin and non-platinum combination chemotherapy as first-line treatment in patients fit for cisplatin is not recommended (Grade of recommendation: B). First-line treatment in patients unfit for cisplatin: use carboplatin combination chemotherapy or single agents (Grade of recommendation: C). Second-line treatment: consider single agents or paclitaxel/gemcitabine if the patient has a good PS (Grade of recommendation: C).

12.11 References 1.

2.

3.

42

Rosenberg JE, Carroll PR, Small EJ. Update on chemotherapy for advanced bladder cancer. J Urol 2005;174(1):14-20. http://www.ncbi.nlm.nih.gov/pubmed/15947569 Sternberg CN, Vogelzang NJ. Gemcitabine, paclitaxel, pemetrexed and other newer agents in urothelial and kidney cancers. Crit Rev Oncol Hematol 2003;46(Suppl):S105-S115. http://www.ncbi.nlm.nih.gov/pubmed/12850531 Bajorin DF, Dodd PM, Mazumdar M, Fazzari M, McCaffrey JA, Scher HI, Herr H, Higgins G, Boyle MG. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999;17(10):3173-81. http://www.ncbi.nlm.nih.gov/pubmed/10506615

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4.

5.

6.

7.

8.

9.

10.

11.

12. 13.

14.

15.

16.

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Sternberg CN, de Mulder PH, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001;19(10):2638-46. http://www.ncbi.nlm.nih.gov/pubmed/11352955 Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC GenitoUrinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 2006;42(1):50-4. http://www.ncbi.nlm.nih.gov/pubmed/16330205 Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer 2004;100(8):1639-45. http://www.ncbi.nlm.nih.gov/pubmed/15073851 Petrioli R, Frediani B, Manganelli A, Barbanti G, De Capua B, De Lauretis A, Salvestrini F, Mondillo S, Francini G. Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer 1996;77(2):344-51. http://www.ncbi.nlm.nih.gov/pubmed/8625244 Carteni G, Dogliotti L, Crucitta E, Martoni A, Siena S, Onat H, Bertetto O, Bono A, Amadori D, Marini L. Phase II randomised trial of gemcitabine plus cisplatin (GP) and gemcitabine plus carboplatin (GC) in patients (pts) with advanced or metastatic transitional cell carcinoma of the urothelium (TCCU). Proc Am Soc Clin Oncol 2003;22: abstr 1543. http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid= 76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=23&abstractI D=102093 Bellmunt J, Ribas A, Eres N, Albanell J, Almanza C, Bermejo B, Sole LA, Baselga J. Carboplatinbased versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 1997;80(10):1966-72. http://www.ncbi.nlm.nih.gov/pubmed/9366300 Sternberg CN, Calabro F, Pizzocaro G, Marini L, Schnetzer S, Sella A. Chemotherapy with an every2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer 2001;92(12):2993-8. http://www.ncbi.nlm.nih.gov/pubmed/11753976 Meluch AA, Greco FA, Burris HA 3rd, O’Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol 2001;19(12):3018-24. http://www.ncbi.nlm.nih.gov/pubmed/11408496 Parameswaran R, Fisch MJ, Ansari RH, Fox EP, Sweeney CJ, Einhorn LH. A Hoosier Oncology Group phase II study of weekly paclitaxel and gemcitabine in advanced transitional cell (TCC) carcinoma of the bladder. Proc Am Soc Clin Oncol 2001;200:abstr 798. http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_ view&confID=10&abstractID=798 Guardino AE, Srinivas S. Gemcitabine and paclitaxel as second line chemotherapy for advanced urothelial malignancies. Proc Am Soc Clin Oncol 2002;21: abstr 2413. http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?abstractID= 2413&confID=16&index=y&vmview=abst_detail_view Fechner GH, Siener R, Reimann M et al. Randomized phase II trial of gemcitabine and paclitaxel with or without maintenance treatment in patients with cisplatin refractory transitional cell carcinoma. J Urol 2002;167(Suppl 4):abstr 284.

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Kaufman DS, Carducci MA, Kuzel T, Todd MB, Raghavan D, Oh WK, Smith MR, Nicol SJ, Stadler WW. Gemcitabine (G) and paclitaxel (P) every two weeks (GP2w): a completed multicenter phase II trial in locally advanced or metastatic urothelial cancer (UC). Proc Am Soc Clin Oncol 2002;21: abstr 767. http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_ view&confID=16&abstractID=767 Nogue-Aliguer M, Carles J, Arrivi A, Juan O, Alonso L, Font A, Mellado B, Garrido P, Saenz A; Spanish Cooperative Group. Gemcitabine and carboplatin in advanced transitional cell carcinoma of the urinary tract: an alternative therapy. Cancer 2003;97(9):2180-6. http://www.ncbi.nlm.nih.gov/pubmed/12712469 Balducci L. Evidence-based management of cancer in the elderly. Cancer Control 2000;7(4):368-76. http://www.ncbi.nlm.nih.gov/pubmed/10895132 Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol 2002;20(4):937-40. http://www.ncbi.nlm.nih.gov/pubmed/11844814 Papamichael D, Gallagher CJ, Oliver RT, Johnson PW, Waxman J. Phase II study of paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder and ureter. Br J Cancer 1997;75(4):606-7. http://www.ncbi.nlm.nih.gov/pubmed/9052419 McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol 1997;15(5):1853-7. http://www.ncbi.nlm.nih.gov/pubmed/9164195 Moore M, Winquist E, Vokes E, Hirte H, Hoving K, Stadler W. Phase II study of oxaliplatin in patients with inoperable, locally advanced or metastatic transitional cell carcinoma of the urothelial tract (TCC) who have received prior chemotherapy. Proc Am Soc Clin Oncol 2003;22: abstr 1638. http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&c onfID=23&abstractID=100319 Witte RS, Manola J, Burch PA, Kuzel T, Weinshel EL, Loehrer PJ Sr. Topotecan in previously treated advanced urothelial carcinoma: an ECOG phase II trial. Invest New Drugs 1998;16(2):191-5. http://www.ncbi.nlm.nih.gov/pubmed/9848585 Petrylak D, Faulkner J, Van Veldhuizen P, Mansukhani M, Crawford E. Evaluation of ZD1839 for advanced transitional cell carcinoma (TCC) of the urothelium: a Southwest Oncology Group Trial. Proc Am Soc Clin Oncol 2003;22: abstr 1619. http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&c onfID=23&abstractID=104215 Sridhar S, Stadler W, Le L, Hedley D, Pond G, Wright J, Vokes E, Thomas S, Moore M. Phase II study of bortezomib in advanced or metastatic urothelial cancer. A trial of the Princess Margaret Hospital [PMH] Phase II Consortium. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings, Vol 23, No 16S Part I of II (June 1 Suppl), 2005:4677. http://prostateca.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view &confID=34&abstractID=33648 Wulfing C, Machiels J, Richiels D, Grimm M, Treiber U, de Groot M, Beuzeboc P, Farrel J, Stone NL, Leopold L, El-Hariry I. A single arm, multicenter, open-label, ph II study of lapatinib as 2L treatment of pts with locally advanced/metastatic transitional cell carcinoma (TCC) of the urothelial tract. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings, Vol 23, No 16S, Part I of II (June 1 Suppl) 2005:4594. http://prostateca.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnex toid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abst ractID=31739 Culine S, Theodore C, De Santis M, Bui B, Demkow T, Lorenz J, Rolland F, Delgado FM, Longerey B, James N. A phase II study of vinflunine in bladder cancer patients progressing after first-line platinumcontaining regimen. Br J Cancer 2006;94(10):1395-401. http://www.ncbi.nlm.nih.gov/pubmed/16622447 Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, NicolSJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 2006;24(21):3451-7. http://www.ncbi.nlm.nih.gov/pubmed/16849761

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Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs 2007;25(3):265-70. http://www.ncbi.nlm.nih.gov/pubmed/17146733 Witte RS, Elson P, Bono B, Knop R, Richardson RR, Dreicer R, Loehrer PJ Sr. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol 1997;15(2):589-93. http://www.ncbi.nlm.nih.gov/pubmed/9053481 Stadler WM. Gemcitabine doublets in advanced urothelial cancer. Semin Oncol 2002;29(1 Suppl 3):15-9. http://www.ncbi.nlm.nih.gov/pubmed/11894003 Hussain M, Vaishampayan U, Du W, Redman B, Smith DC. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol 2001;19(9):2527-33. http://www.ncbi.nlm.nih.gov/pubmed/11331332 Herr HW, Donat SM, Bajorin DF. Post-chemotherapy surgery in patients with unresectable or regionally metastatic bladder cancer. J Urol 2001;165(3):811-4. http://www.ncbi.nlm.nih.gov/pubmed/1117647 Sweeney P, Millikan R, Donat M, Wood CG, Radtke AS, Pettaway CA, Grossman HB, Dinney CP, Swanson DA, Pisters LL. Is there a therapeutic role for post-chemotherapy retroperitoneal lymph node dissection in metastatic transitional cell carcinoma of the bladder? J Urol 2003;169(6):2113-7. http://www.ncbi.nlm.nih.gov/pubmed/12771730 Siefker-Radtke AO, Walsh GL, Pisters LL, Shen Y, Swanson DA, Logothetis CJ, Millikan RE. Is there a role for surgery in the management of metastatic urothelial cancer? The M. D. Anderson experience. J Urol 2004;171(1):145-8. http://www.ncbi.nlm.nih.gov/pubmed/14665863

13. QUALITY OF LIFE The evaluation of health-related quality of life (HRQL) considers physical, emotional and social functioning. Several questionnaires, e.g. FACT (Functional Assessment of Cancer Therapy)-G (1), EORTC QLQ-C30 (1) and SF (Short Form)-36 (3, 4), have been validated for assessing HRQL in patients with bladder cancer. A psychometrical test such as the FACT-BL should be used for recording bladder cancer morbidity. Recently, new intensive interviewing techniques add valuable information to our knowledge of HRQL, which greatly depends on patients’ individual preferences in life (5). Unfortunately, most retrospective studies do not evaluate the association between HRQL and bladder cancer-specific issues after cystectomy, such as incontinence or potency. Furthermore, important co-variables, such as a patient’s age, mental status, coping ability and gender, have only rarely been considered (6). It remains difficult to predict the impact of post-therapeutic symptoms because of individual differences in symptom tolerance. There is controversy about which type of urinary diversion is best for a patient’s quality of life (7). Some studies have not demonstrated any difference (8, 9). As a result of improvement in surgical techniques and orthotopic bladder substitution, some more recent studies are in favour of the continent bladder substitutes (10-17). In one study (17), a statistically significant difference in HRQL in favour of neobladders was observed. Notably, HRQL parameters have been shown to represent an independent prognostic parameter for overall survival (18). Patients with a continent bladder-substitute generally score more favourably than those with an incontinent diversion, as judged by body image, social activity and physical function (11, 16). In non-curative or metastatic bladder cancer, HRQL is reduced because of associated micturition problems, bleeding, pain and therefore disturbance of social and sexual life (19). Relief of bladder-related symptoms can be obtained by palliative surgery (20), radiotherapy (21) and/or chemotherapy (22), though there is limited literature describing HRQL in palliatively treated bladder cancer patients (23). Alternative definitive treatments of muscle-invasive bladder cancer, e.g. trimodality bladder-sparing procedures, have shown similar survival times compared to cystectomy. However, the impact on HRQL has been controversial (24-29).

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13.1 Conclusions • •

There is no randomized prospective HRQL study evaluating different forms of definitive treatment for invasive bladder cancer. The overall HRQL after cystectomy remains good in most patients, whichever type of urinary diversion is used. Some data suggests that continent diversions produce a better HRQL (Level of evidence: 2b).

13.2 Recommendations • •

HRQL in patients with muscle-invasive bladder cancer should be assessed using validated questionnaires (Grade of recommendation: A). Continent urinary diversions should be offered for reasons of HRQL, whenever a patient’s age, personality, coping ability and tumour variables are suitable (Grade of recommendation: C).

13.3

References

1.

Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993;11(3):570-9. http://www.ncbi.nlm.nih.gov/pubmed/8445433 Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76. http://www.ncbi.nlm.nih.gov/pubmed/8433390 Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30(6):473-83. http://www.ncbi.nlm.nih.gov/pubmed/1593914 Ware JE Jr, Keller SD, Gandek B, Brazier JE, Sullivan M. Evaluating translations of health status questionnaires. Methods from the IQOLA project. International Quality of Life Assessment. Int J Technol Assess Health Care 1995;11(3):525-51. http://www.ncbi.nlm.nih.gov/pubmed/7591553 Ramirez A, Perrotte P, Valiquette L, Benard F, McCormack M, Saad F, Fournier C, Shariat S, Karakiewicz PI. Exploration of health-related quality of life areas that may distinguish between continent diversion and ileal conduit patients. Can J Urol 2005;12(1):2537-42. http://www.ncbi.nlm.nih.gov/pubmed/15777491 Mansson A, Caruso A, Capovilla E, Colleen S, Bassi P, Pagano F, Mansson W. Quality of life after radical cystectomy and orthotopic bladder substitution: a comparison between Italian and Swedish men. BJU Int 2000;85(1):26-31. http://www.ncbi.nlm.nih.gov/pubmed/10619940 World Health Organization (WHO) Consensus Conference on Bladder Cancer, Hautmann RE, AbolEnein H, Hafez K, Haro I, Mansson W, Mills RD, Montie JD, Sagalowsky AI, Stein JP, Stenzl A, Studer UE, Volkmer BG. Urinary diversion. Urology 2007;69(1 Suppl):17-49. http://www.ncbi.nlm.nih.gov/pubmed/17280907 Mansson A, Davidsson T, Hunt S, Mansson W. The quality of life in men after radical cystectomy with a continent cutaneous diversion or orthotopic bladder substitution: is there a difference?. BJU Int 2002;90(4):386-90. http://www.ncbi.nlm.nih.gov/pubmed/12175394 Wright JL, Porter MP. Quality-of-life assessment in patients with bladder cancer. Nat Clin Pract Urol 2007;4(3):147-54. http://www.ncbi.nlm.nih.gov/pubmed/17347659 van der Veen JH, van Andel G, Kurth KH. Quality-of-life assessment in bladder cancer. World J Urol 1999;17(4):219-24. http://www.ncbi.nlm.nih.gov/pubmed/10460404 Dutta SC, Chang SC, Coffey CS, Smith JA Jr, Jack G, Cookson MS. Health related quality of life assessment after radical cystectomy: comparison of ileal conduit with continent orthotopic neobladder. J Urol 2002;168(1):164-7. http://www.ncbi.nlm.nih.gov/pubmed/12050514 Okada Y, Oishi K, Shichiri Y, Kakehi Y, Hamaguchi A, Tomoyoshi T, Yoshida O. Quality of life survey of urinary diversion patients: comparison of continent urinary diversion versus ileal conduit. Int J Urol 1997;4(1):26-31. http://www.ncbi.nlm.nih.gov/pubmed/9179663

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29.

Gerharz EW, Weingartner K, Dopatka T, Kohl UN, Basler HD, Riedmiller HN. Quality of life after cystectomy and urinary diversion: results of a retrospective interdisciplinary study. J Urol 1997;158(3 Pt 1):778-85. http://www.ncbi.nlm.nih.gov/pubmed/9258080 Hart S, Skinner EC, Meyerowitz BE, Boyd S, Lieskovsky G, Skinner DG. Quality of life after radical cystectomy for bladder cancer in patients with an ileal conduit, cutaneous or urethral kock pouch. J Urol 1999;162(1):77-81. http://www.ncbi.nlm.nih.gov/pubmed/10379744 Hara I, Miyake H, Hara S, Gotoh A, Nakamura I, Okada H, Arakawa S, Kamidono S. Health-related quality of life after radical cystectomy for bladder cancer: a comparison of ileal conduit and orthotopic bladder replacement. BJU Int 2002;89(1):10-13. http://www.ncbi.nlm.nih.gov/pubmed/11849152 Hardt J, Filipas D, Hohenfellner R, Egle UT. Quality of life in patients with bladder carcinoma after cystectomy: first results of a prospective study. Qual Life Res 2000;9(1):1-12. http://www.ncbi.nlm.nih.gov/pubmed/10981202 Hobisch A, Tosun K, Kinzl J, Kemmler G, Bartsch G, Holtl L, Stenzl A. Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. Semin Urol Oncol 2001;19(1):18-23. http://www.ncbi.nlm.nih.gov/pubmed/11246729 Roychowdhury DF, Hayden A, Liepa AM. Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer. J Clin Oncol 2003;21(4):673-8. http://www.ncbi.nlm.nih.gov/pubmed/12586805 Fossa SD, Aaronson N, Calais da Silva F, Denis L, Newling D, Hosbach G, Kaalhus O. Quality of life in patients with muscle-infiltrating bladder cancer and hormone-resistant prostatic cancer. Eur Urol 1989;16(5):335-9. http://www.ncbi.nlm.nih.gov/pubmed/2476317 Nagele U, Anastasiadis AG, Merseburger AS, Corvin S, Hennenlotter J, Adam M, Sievert KD, Stenzl A, Kuczyk MA. The rationale for radical cystectomy as primary therapy for T4 bladder cancer. World J Urol 2007;25(4):401-5. http://www.ncbi.nlm.nih.gov/pubmed/17525849 Fokdal L, Hoyer M, von der Maase H. Radical radiotherapy for urinary bladder cancer: treatment outcomes. Expert Rev Anticancer Ther 2006;6(2):269-79. http://www.ncbi.nlm.nih.gov/pubmed/17525849 Rodel C, Weiss C and Sauer R. Organ preservation by combined modality treatment in bladder cancer: the European perspective. Semin Radiat Oncol 2005;15(1):28-35. http://www.ncbi.nlm.nih.gov/pubmed/15662604 Mommsen S, Jakobsen A, Sell A. Quality of life in patients with advanced bladder cancer. A randomized study comparing cystectomy and irradiation–the Danish Bladder Cancer Study Group (DAVECA protocol 8201). Scand J Urol Nephrol Suppl 1989;125:115-20. http://www.ncbi.nlm.nih.gov/pubmed/2699072 Rodel C, Grabenbauer GG, Kuhn R, Papadopoulos T, Dunst J, Meyer M, Schrott KM, Sauer R. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002;20:3061-71. http://www.ncbi.nlm.nih.gov/pubmed/12118019 Merseburger AS, Kuczyk MA. The value of bladder-conserving strategies in muscle-invasive bladder carcinoma compared with radical surgery. Curr Opin Urol 2007;17(5):358-62. http://www.ncbi.nlm.nih.gov/pubmed/17762631 Milosevic M, Gospodarowicz M, Zietman A, Abbas F, Haustermans K, Moonen L, Rodel C, Schoenberg M, Shipley W. Radiotherapy for bladder cancer. Urology 2007;69(1 Suppl):80-92. http://www.ncbi.nlm.nih.gov/pubmed/17280910 Rodel C, Weiss C, Sauer R. Trimodality treatment and selective organ preservation for bladder cancer. J Clin Oncol 2006;24(35):5536-44. http://www.ncbi.nlm.nih.gov/pubmed/17158539 Zietman AL, Shipley WU, Kaufman DS. Organ-conserving approaches to muscle-invasive bladder cancer: future alternatives to radical cystectomy. Ann Med 2000;32(1):34-42. http://www.ncbi.nlm.nih.gov/pubmed/10711576 Lodde M, Palermo S, Comploj E, Signorello D, Mian C, Lusuardi L, Longhi E, Zanon P, Mian M, Pycha A. Four years experience in bladder preserving management for muscle invasive bladder cancer. Eur Urol 2005;47(6):773-8; discussion 778-9. http://www.ncbi.nlm.nih.gov/pubmed/15925072

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14. FOLLOW-UP An appropriate schedule for disease monitoring should be based on: • natural timing of recurrence • probability of disease recurrence • functional deterioration at particular sites • possibilities of treatment of a recurrence (1). Contemporary cystectomy series demonstrate a 5-15% chance of pelvic recurrence. Most recurrences manifest during the first 24 months, with many occurring within 6-18 months after surgery. However, there have been late recurrences up to 5 years after cystectomy. Variables associated with the development of a pelvic recurrence include the pathological stage (of the primary tumour) and lymph node status. Patients have a poor prognosis after pelvic recurrence; the median survival ranges from 4-8 months following diagnosis, despite treatment. Definitive therapy can sometimes provide a prolonged survival, but provides significant palliation of symptoms in most cases. Treatment is systemic chemotherapy, local surgery or radiotherapy. Distant recurrences are seen in up to 50% of patients treated with cystectomy. Most recurrences occur in the first 24 months, although progression has been observed after more than 10 years. Again, pathological stage of the primary tumour and nodal status are risk factors. The most likely sites for distant recurrences are the lungs, liver and bones (2). Upper urinary tract recurrence is rarely seen (2-7%), but when it develops, it usually does so within 22-40 months after cystectomy (1-4). Surveillance regimens often fail to detect tumours before symptoms develop. However, radical nephroureterectomy can provide prolonged survival (3). The incidence of secondary urethral tumour is 5-17% and is particularly likely to occur at 1-3 years after surgery. Prophylactic urethrectomy at the time of cystectomy is no longer justified in most patients. In men, the most important risk factor for the development of urethral recurrence is prostatic stromal invasion (21-64%) (5-7). In women, the risk factor is disease at the bladder neck (8). Multiple studies demonstrate that the risk of urethral recurrence after orthotopic diversion (0.9-4%) (5, 9-11) is significantly less than after nonorthotopic diversion (6.4-11.1%) (5,10). There is little data and agreement about the follow-up of the urethra. Some authors recommend routine surveillance urethral wash cytology and UCS (9), while others question the need for routine urethral surveillance (9, 12-14). Urethral washes and urine cytology do not appear to have any effect on survival (12, 15, 16). Treatment is influenced by the local stage and grade of a urethral occurrence: • In CIS in the urethra, BCG instillations have shown success rates of 83% (11). • In invasive disease, urethrectomy should be performed if the urethra is the only site of disease. • In distant disease, systemic chemotherapy is indicated (2).

14.1

Conclusions and recommendations according to condition

Condition Conclusion or recommendation Level of evidence or grade of recommendation Secondary Staging and treatment should be done as for primary 3 urethral tumour urethral tumour For non-invasive tumour, local organ conservative C treatment is advised In isolated invasive disease, a urethrectomy should B be performed Urethral washes and cytology are not recommended A for follow-up Pelvic recurrence The prognosis is poor 2b Treatment should be individualized depending on the local extent and symptoms Radiotherapy, chemotherapy and possibly surgery are C options for treatment, either alone or in combination Upper urinary tract Specific upper urinary tract imaging is only indicated in B recurrence case of clinical symptoms; radical nephroureterectomy can provide prolonged survival

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14.2

General recommendations for follow-up

This advice for follow-up is entirely based on expert opinion. General remarks are that follow up should be dependent on the stage of the initial tumour after cystectomy. This means that the higher the initial tumour stage, the larger the chance for subsequent tumour recurrence. A higher follow-up frequency will therefore result in identifying more recurrences. Non-oncological follow-up, for example monitoring of kidney function, seems indicated life long. After 5 years of follow-up, oncological surveillance may be stopped to be continued by functional surveillance. At every visit, the following should be performed: • History • Physical examination • Bone scan only when indicated.

14.3

References

1.

Malkowicz SB, van Poppel H, Mickisch G, Pansadoro V, Thuroff J, Soloway MS, Chang S, Benson M, Fukui I. Muscle-invasive urothelial carcinoma of the bladder. Urology 2007;69(1 Suppl):3-16. http://www.ncbi.nlm.nih.gov/pubmed/17280906 Bochner BH, Montie JE, Lee CT. Follow-up strategies and management of recurrence in urologic oncology bladder cancer: invasive bladder cancer. Urol Clin North Am 2003;30(4):777-89. http://www.ncbi.nlm.nih.gov/pubmed/14680314 Sanderson KM, Cai J, Miranda G, Skinner DG, Stein JP. Upper tract urothelial recurrence following radical cystectomy for transitional cell carcinoma of the bladder: an analysis of 1,069 patients with 10-year followup. J Urol 2007;177:2088-94. http://www.ncbi.nlm.nih.gov/pubmed/17509294 Stenzl A, Bartsch G, Rogatsch H. The remnant urothelium after reconstructive bladder surgery. Eur Urol 2002;41(2):124-31. http://www.ncbi.nlm.nih.gov/pubmed/12074398 Freeman JA, Tarter TA, Esrig D, Stein JP, Elmajian DA, Chen SC, Groshen S, Lieskovsky G, Skinner DG. Urethral recurrence in patients with orthotopic ileal neobladders. J Urol 1996;156(5):1615-9. http://www.ncbi.nlm.nih.gov/pubmed/8863551 Hardeman SW, Soloway MS. Urethral recurrence following radical cystectomy. J Urol 1990;144(3):666-9. http://www.ncbi.nlm.nih.gov/pubmed/2388323 Levinson AK, Johnson DE, Wishnow KI. Indications for urethrectomy in an era of continent urinary diversion. J Urol 1990;144(1):73-5. http://www.ncbi.nlm.nih.gov/pubmed/2359182 Stenzl A, Draxl H, Posch B, Colleselli K, Falk M, Bartsch G. The risk of urethral tumors in female bladder cancer: can the urethra be used for orthotopic reconstruction of the lower urinary tract? J Urol 1995;153(3 Pt 2):950-5. http://www.ncbi.nlm.nih.gov/pubmed/7853581 Huguet J, Palou J, Serrallach M, Sole Balcells FJ, Salvador J, Villavicencio H. Management of urethral recurrence in patients with Studer ileal neobladder. Eur Urol 2003;43(5):495-8. http://www.ncbi.nlm.nih.gov/pubmed/12705993 Nieder AM, Sved PD, Gomez P, Kim SS, Manoharan M, Soloway MS. Urethral recurrence after cystoprostatectomy: implications for urinary diversion and monitoring. Urology 2004;64(5):950-4. http://www.ncbi.nlm.nih.gov/pubmed/15533484 Varol C, Thalmann GN, Burkhard FC, Studer UE. Treatment of urethral recurrence following radical cystectomy and ileal bladder substitution. J Urol 2004;172(3):937-42. http://www.ncbi.nlm.nih.gov/pubmed/15311003 Lin DW, Herr HW, Dalbagni G. Value of urethral wash cytology in the retained male urethra after radical cystoprostatectomy. J Urol 2003;169(3):961-3. http://www.ncbi.nlm.nih.gov/pubmed/12576822 Sherwood JB, Sagalowsky AI. The diagnosis and treatment of urethral recurrence after radical cystectomy. Urol Oncol 2006;24(4):356-61. http://www.ncbi.nlm.nih.gov/pubmed/16818191 Slaton JW, Swanson DA, Grossman HB, Dinney CP. A stage specific approach to tumor surveillance after radical cystectomy for transitional cell carcinoma of the bladder. J Urol 1999;162(3 Pt 1):710-4. http://www.ncbi.nlm.nih.gov/pubmed/10458349

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

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15.

16.

52

Erckert M, Stenzl A, Falk M, Bartsch G. Incidence of urethral tumor involvement in 910 men with bladder cancer. World J Urol 1996;14(1):3-8. http://www.ncbi.nlm.nih.gov/pubmed/8646239 Clark PE, Stein JP, Groshen SG, Miranda G, Cai J, Lieskovsky G, Skinner DG. The management of urethral transitional cell carcinoma after radical cystectomy for invasive bladder cancer. J Urol 2004;172(4 Pt 1):1342-7. http://www.ncbi.nlm.nih.gov/pubmed/15371837

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15. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations

ARCO ARCON ASCO 5-ALA BC BCG CI CIS CISCA CM CMV CT EAU EBRT ECOG EORTC FACT 5-FU GC GFR GCSF HAL HD-MVAC HRQL IARC IPD ISUP IVU MCV MDCT MiM-BC MRC MR(I) MVAC MVA(E)C NAT OS PAHs PCR PET PS PUNLMP R-biopsies SF-36 SWOG TCC TNM TUR TURBT UICC UC US UUT WHO

accelerated radiotherapy with carbogen accelerated radiotherapy with carbogen nicotinamide American Society of Clinical Oncology 5-aminolaevulinic acid bladder cancer Bacille Calmette-Guérin confidence interval carcinoma in situ cisplatin, cyclophosphamide plus adriamycin cisplatin, methotrexate cisplatin, methotrexate plus vinblastine computed tomography European Association of Urology external beam radiation therapy Eastern Cooperative Oncology Group European Organization for Research and Treatment of Cancer Functional Assessment of Cancer Therapy 5-Fluorouracil gemcitabine plus cisplatin glomerular filtration rate granulocyte colony stimulating factor hexaminolaevulinate high-dose methotrexate, vinblastine, adriamycin plus cisplatin health-related quality of life International Agency for Research on Cancer independent patient data International Society of Urological Pathology Intravenous urography methrotrexate, cisplatin and vinblastine multidetector-row CT Muscle-invasive and metastatic bladder cancer Medical Research Council (UK) magnetic resonance (imaging) methotrexate, vinblastine, adriamycin plus cisplatin methotrexate, vinblastine, adriamycine or epirubicine, and cisplatin N-acetyltransferase overall survival polycyclic aromatic hydrocarbons pathological complete remission positron emission tomography performance status papillary urothelial neoplasms of low malignant potential random biopsies Short Form-36 Southwest Oncology Group transitional cell carcinoma Tumour, Node, Metastases transurethral resection transurethral resection of bladder tumour Union International Contre le Cancer urethrocystoscopy ultrasonography upper urinary tract World Health Organization

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Conflict of interest All members of the Muscle-Invasive and Metastatic Bladder Cancer guidelines writing panel have provided disclosure statements of all relationships which they have and which may be perceived as a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Prostate Cancer A. Heidenreich (chairman), M. Bolla, S. Joniau, T.H. van der Kwast, V. Matveev, M.D. Mason, N. Mottet, H-P. Schmid, T. Wiegel, F. Zattoni

© European Association of Urology 2009

TABLE OF CONTENTS

page

1

BACKGROUND 1.1 Reference

7 7

2.

BACKGROUND 2.1 References

8 8

3.

CLASSIFICATION 3.1 Gleason score 3.2 References

8 9 9

4.

RISK FACTORS 4.1 References

9 10

5.

SCREENING AND EARLY DETECTION 5.1 References

10 11

6. DIAGNOSIS 6.1 Digital rectal examination (DRE) 6.2 Prostate specific antigen (PSA) 6.2.1 Free/total PSA ratio (f/t PSA) 6.2.2 PSA velocity (PSAV), PSA doubling time (PSADT) 6.2.3 PCA3 marker 6.3 Transrectal ultrasonography (TRUS) 6.4 Prostate biopsy 6.4.1 Baseline biopsy 6.4.2 Repeat biopsy 6.4.3 Saturation biopsy 6.4.4 Sampling sites and number of cores 6.4.5 Diagnostic transurethral resection of the prostate (TURP) 6.4.6 Seminal vesicle biopsy 6.4.7 Transition zone biopsy 6.4.8 Antibiotics 6.4.9 Local anaesthesia 6.4.10 Fine-needle aspiration biopsy 6.4.11 Complications 6.5 Pathology of prostate needle biopsies 6.5.1 Grossing and processing 6.5.2 Microscopy and reporting 6.6 Pathohistology of radical prostatectomy (RP) specimens 6.6.1 Processing of the RP specimen 6.6.2 RP specimen report 6.6.2.1 Gleason score 6.6.2.2 Interpreting the Gleason score 6.6.2.3 Definition of extraprostatic extension 6.6.3 Prostate cancer volume 6.6.4 Surginal margin status 6.6.5 Other factors 6.7 References

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7.

24 24 26 27 28 28

2

STAGING 7.1 T-staging 7.2 N-staging 7.3 M-staging 7.4 Guidelines for the staging of prostate cancer (PCa) 7.5 References

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8. TREATMENT: DEFERRED TREATMENT (WATCHFUL WAITING [WW] / ACTIVE MONITORING 8.1 Introduction 8.1.1 Definition 8.2 Deferred treatment of localised PCa (stage T1-T2, Nx-N0, M0) 8.2.1 Watchful waiting (WW) 8.2.2 Active surveillance 8.3 Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0) 8.4 Deferred treatment for metastatic PCa (stage M1) 8.5 Summary of deferred treatment 8.5.1 Indications 8.5.2 Options 8.6 References

33 33 33 34 34 36 37 38 38 38 38 39

9. TREATMENT: RADICAL PROSTATECTOMY 9.1 Introduction 9.2 Low-risk localised PCa: cT1-T2a AND Gleason score 2-6 and PSA < 10 9.2.1 Stage T1a-T1b PCa 9.2.2 Stage T1c and T2a PCa 9.3 Intermediate-risk localised PCa: cT2b-T2c OR Gleason score = 7 or PSA 10-20 9.3.1 Oncological results of RP in low- and intermediate risk PCa 9.4 High-risk localised PCa: cT3a OR Gleason score 8-10 or PSA > 20 9.4.1 Locally-advanced PCa: cT3a 9.4.2 High-grade PCa: Gleason score 8-10 9.4.3 PCa with PSA > 20 9.5 Very high-risk localised PCa: cT3b-T4 N0 or any T, N1 9.5.1 cT3b-T4 N0 9.5.2 Any T, N1 9.5.2.1 Indication and extent of extended pelvic lymph node dissection (eLND) 9.5.2.2 Therapeutic role of eLND 9.5.2.3 Morbidity 9.5.2.4 Summary of eLND 9.6 Summary of RP in high-risk localised disease 9.7 Neoadjuvant hormonal therapy and RP 9.7.1 Summary of neoadjuvant and adjuvant hormonal treatment and RP 9.8 Complications and functional outcome 9.9 Summary of indications for nerve-sparing surgery 9.10 Guidelines and recommendations for RP 9.11 References

42 42 43 43 43 43 44 44 44 45 45 46 46 46 46 47 47 47 47 47 48 48 48 49 49

10. TREATMENT: DEFINITIVE RADIATION THERAPY 10.1 Introduction 10.2 Technical aspects: three dimensional conformal radiotherapy and intensity modulated external beam radiotherapy 10.3 Localised prostate cancer T1-2c N0, M0 10.3.1 T1a-T2a, N0, M0 and Gleason score ≤ 6 and PSA < 10 ng/mL (low-risk group) 10.3.2 T2b or PSA 10-20 ng/mL, or Gleason score 7 (intermediate-risk group) 10.3.3 T2c or Gleason score > 7 or PSA > 20 ng/mL (high-risk group) 10.3.4 Prophylactic irradiation of pelvic lymph nodes in high-risk localised prostate cancer 10.4 Innovative techniques 10.4.1 Intensity modulated radiotherapy 10.4.2 Proton beam and carbon ion beam therapy 10.5 Transperineal brachytherapy 10.6 Late toxicity 10.7 Immediate post-operative external irradiation for pathological tumour stage T3 N0 M0 10.8 Locally advanced prostate cancer: T3-4 N0, M0 10.8.1 Neoadjuvant and concomitant hormonal therapy 10.8.2 Concomitant and long-term adjuvant hormonal therapy 10.8.3 Long-term adjuvant hormonal therapy 10.8.4 Neoadjuvant, concomitant and long-term adjuvant hormonal therapy

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56 56 56 57 57 57 58 58 58 59 60 61 62 62 62 63 63

3

10.9 10.10 10.11

10.8.5 Short-term or long-term adjuvant hormonal treatment 10.8.6 Dose escalation with hormonal therapy Very high-risk prostate cancer: c or pN1 M0 Summary of definitive radiation therapy References

63 63 63 64 64

11. EXPERIMENTAL LOCAL TREATMENT OF PROSTATE CANCER 11.1 Background 11.2 Cryosurgery of the prostate (CSAP) 11.2.1 Indication for CSAP 11.2.2 Results of modern cryosurgery for PCa 11.2.3 Complications of CSAP for primary treatment of PCa 11.2.4 Summary of CSAP 11.3 High-intensity focused ultrasound (HIFU) of the prostate 11.3.1 Results of HIFU in PCa 11.3.2 Complications of HIFU 11.4 Radiofrequency interstitial tumour ablation (RITA) 11.5 Summary of experimental therapeutic options to treat clinically localized PCa 11.6 References

70 70 70 71 71 71 72 72 72 73 73 73 73

12. HORMONAL THERAPY 12.1 Introduction 12.2 Basics of hormonal control of the prostate 12.3 Different types of hormonal therapy 12.3.1 Testosterone-lowering therapy (castration) 12.3.1.1 Bilateral orchiectomy 12.3.1.2 Oestrogens 12.3.1.3 LHRH agonists 12.3.1.4 LHRH antagonists 12.3.2 Anti-androgens 12.3.2.1 Steroidal anti-androgens Cyproterone acetate (CPA) Megestrol acetate and medroxyprogesterone acetate 12.3.2.2 Non-steroidal anti-androgens Nilutamide Flutamide Bicalutamide 12.3.3 Combination therapies 12.3.3.1 Complete androgen blockade 12.3.3.2 Minimal androgen blockade (or peripheral androgen blockade) 12.3.3.3 Intermittent vs continuous androgen deprivation therapy 12.3.3.4 Immediate vs deferred ADT 12.4 Indications for hormonal therapy 12.5 Contraindications for various therapies 12.6 Outcome 12.7 Side-effects, QoL and cost of hormonal therapy 12.7.1 Side-effects 12.7.2 Quality of Life (QoL) 12.7.3 Cost-effectiveness of hormonal therapy options 12.8 Summary of hormonal therapy 12.9 References

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SUMMARY OF GUIDELINES ON PRIMARY TREATMENT OF PCa

14 FOLLOW-UP: AFTER PRIMARY TREATMENT WITH CURATIVE INTENT 14.1 Definition 14.2 Why follow-up? 14.3 How to follow-up? 14.3.1 PSA monitoring 14.3.2 Definition of PSA progression

4

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14.4 14.5 14.6

14.3.3 PSA monitoring after radical prostatectomy 14.3.4 PSA monitoring after radiation therapy 14.3.5 Digital rectal examination (DRE) 14.3.6 Transrectal ultrasonography (TRUS) and biopsy 14.3.7 Bone scintigraphy 14.3.8 Computed tomography (CT) and magnetic resonance imaging (MRI) When to follow-up? Guidelines for follow-up after treatment with curative intent References

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15. FOLLOW-UP AFTER HORMONAL TREATMENT 15.1 Introduction 15.2 Purpose of follow-up 15.3 Methods of follow-up 15.3.1 Prostate-specific antigen monitoring 15.3.2 Creatinine, haemoglobin and liver function monitoring 15.3.3 Bone scan, ultrasound and chest X-ray 15.4 When to follow-up 15.4.1 Stage M0 patients 15.4.2 Stage M1 patients 15.4.3 Hormone-refractory patients 15.5 Guidelines for follow-up after hormonal treatment 15.6 References

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16. TREATMENT OF BIOCHEMICAL FAILURE AFTER TRATMENT WITH CURATIVE INTENT 16.1 Background 16.2 Definitions 16.2.1 Definition of treatment failure 16.2.2 Definition of recurrence 16.3 Local or systemic relapse 16.3.1 Definition of local and systemic failure 16.4 Evaluation of PSA progression 16.5 Diagnostic procedures in patients with PSA relapse 16.6 Treatment of PSA-only recurrences 16.6.1 Radiation therapy for PSA-only recurrence after radical prostatectomy (RP) 16.6.2 Hormonal therapy 16.6.3 Observation 16.6.4 Management of PSA relapse after radical prostatectomy 16.7 Management of PSA failures after radiation therapy 16.7.1 Salvage cryosurgical ablation of the prostate (CSAP) for radiation failures 16.7.2 Salvage brachytherapy for radiation failures 16.7.3 Observation 16.7.4 Management of PSA-relapse after radiation therapy 16.8 Guidelines for second-line therapy after treatment with curative intent 16.9 References

106 106 106 106 106 106 107 108 109 109 109 110 111 111 111 112 112 112 113 113 113

17. HORMONE REFACTORY PROSTATE CANCER (HRPC) 17.1 Background 17.2 Definition of HRPC 17.3 Assessing treatment outcome in androgen-independent PCa 17.3.1 PSA level as marker of response 17.3.2 Other parameters 17.3.3 Trial end-points 17.4 Recommendations for assessing therapeutic response 17.5 Androgen deprivation in androgen-independent PCa 17.6 Secondary hormonal therapy 17.7 Anti-androgen withdrawal syndrome 17.8 Treatment alternatives after initial hormonal therapy 17.8.1 Bicalutamide 17.8.2 Switching to an alternative anti-androgen therapy

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17.8.3 Anti-androgen withdrawal accompanied by simultaneous ketoconazole 17.8.4 Oestogens 17.9 Non-hormonal therapy (cytotoxic agents) 17.9.1 Timing of chemotherapy in metastatic HRPC Taxanes in combination therapy Mitroxantrone combined with corticosteroids Alternative combination treatment approaches Estramustine in combination therapies Oral cyclophosphamide Suramin Salvage chemotherapy 17.10 Palliative therapeutic options 17.10.1 Painful bone metastases 17.10.2 Common complications due to bone mestatases 17.10.3 Bisphosphonates 17.11 Summary of treatment after hormonal therapy 17.12 Guidelines and recommendations for cytotoxic therapy in HRPC 17.13 Guidelines for palliative management of HRPC 17.14 Recommendations for palliative management of HRPC 17.15 References

122 122 123 123 123 124 124 124 124 124 124 125 125 125 125 126 126 126 126 126

18.

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ABBREVIATIONS USED IN THE TEXT

Update march 2009

1. BACKGROUND The European Association of Urology (EAU) Guidelines Group for Prostate Cancer have prepared this guidelines document to assist medical professionals assess the evidence-based management of prostate cancer. The multidisciplinary panel of experts include urologists, radiation oncologists, a medical oncologist and a pathologist.   The recommendations provided in the current guidelines are based on a systemic literature search using Medline, the Cochrane Central Register of Controlled Trials, and reference lists in publications and review articles. Where possible a level of evidence (LE) and/or grade of recommendation (GR) have been assigned (1). Recommendations are graded in order to provide transparency between the underlying evidence and the recommendation given (Tables 1 and 2). Prior to publication external review has taken place. It has to be emphasised that the current guidelines contain information for the treatment of an individual patient according to a standardised general approach. Publication history information: The Prostate Cancer Guidelines were first published in 2001, with partial updates in 2003 and 2007, followed by the current full text update. But for one section (Chapter 14), all topics have been revised. Additionally, a quick reference guide is available. All texts can be viewed and downloaded for personal use at the society website: http://www.uroweb.org/professional-resources/guidelines/. Table 1: Level of evidence Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Modified from Sackett et al. (1). Table 2: Grade of recommendation Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality Modified from Sackett et al. (1).

1.1

REFERENCE

1.

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998.  http://www.cebm.net/index.aspx?o=1025 [accessed February 2009].

   

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2. BACKGROUND Cancer of the prostate (PCa) is now recognized as one of the most important medical problems facing the male population. In Europe, PCa is the most common solid neoplasm, with an incidence rate of 214 cases per 1000 men, outnumbering lung and colorectal cancer (1). Furthermore, PCa is currently the second most common cause of cancer death in men (2). In addition, since 1985, there has been a slight increase in most countries in the number of deaths from PCa, even in countries or regions where PCa is not common (3). Prostate cancer affects elderly men more often than young men. It is therefore a bigger health concern in developed countries with their greater proportion of elderly men. Thus, about 15% of male cancers are PCa in developed countries compared to 4% of male cancers in undeveloped countries (4). It is worth mentioning that there are large regional differences in incidence rates of PCa. For example, in Sweden, where there is a long life expectancy and mortality from smoking-related diseases is relatively modest, PCa is the most common malignancy in males, accounting for 37% of all new cases of cancer in 2004 (5).

2.1

REFERENCES

1.

Boyle P, Ferlay J. Cancer incidence and mortality in Europe 2004. Ann Oncol 2005;16(3):481-8. http://www.ncbi.nlm.nih.gov/pubmed/15718248 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71-96. http://www.ncbi.nlm.nih.gov/pubmed/18287387 Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int 2002;90(2):162-73. http://www.ncbi.nlm.nih.gov/pubmed/12081758 Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000: the global picture. Eur J Cancer 2001;37(Suppl 8):S4-66. http://www.ncbi.nlm.nih.gov/pubmed/11602373 Cancer incidence in Sweden 2004. The National Board of Health and Welfare: Stockholm, 2005. http://www.socialstyrelsen.se/NR/rdonlyres/A23BCC9E-23B5-4747AAA923BB9CDF4B75/4753/20054291.pdf

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3. CLASSIFICATION The 2002 TNM (Tumour Node Metastasis) classification for PCa is shown in Table 3 (1). The new TNM system is due to be published early in 2009, but was not yet available for citation. Table 3: Tumour Node Metastasis (TNM) classification of PCa*. T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Clinically inapparent tumour not palpable or visible by imaging T1a Tumour incidental histological finding in 5% or less of tissue resected T1b Tumour incidental histological finding in more than 5% of tissue resected T1c Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA] level) T2 Tumour confined within the prostate1 T2a Tumour involves one half of one lobe or less T2b Tumour involves more than half of one lobe, but not both lobes T2c Tumour involves both lobes T3 Tumour extends through the prostatic capsule2 T3a Extracapsular extension (unilateral or bilateral) T3b Tumour invades seminal vesicle(s) T4 Tumour is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, or pelvic wall N - Regional lymph nodes3 NX Regional lymph nodes cannot be assessed

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N0 No regional lymph node metastasis N1 Regional lymph node metastasis M - Distant metastasis4 MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Non-regional lymph node(s) M1b Bone(s) M1c Other site(s) 1

 umour found in one or both lobes by needle biopsy, but not palpable or visible by imaging, is classified as T1c. T Invasion into the prostatic apex, or into (but not beyond) the prostate capsule, is not classified as T3, but as T2. 3 Metastasis no larger than 0.2 cm can be designated pN1mi. 4 When more than one site of metastasis is present, the most advanced category should be used. 2

*At the time of the publication of this document the updated TNM system was not yet available for citation.

3.1 Gleason score The Gleason score is the most commonly used system for grading adenocarcinoma of the prostate (2). The Gleason score can only be assessed using biopsy material (core biopsy or operative specimens). Cytological preparations cannot be used. The Gleason score is the sum of the two most common patterns (grades 1-5) of tumour growth found. The Gleason score ranges between 2 and 10, with 2 being the least aggressive and 10 the most aggressive. In needle biopsy, it is recommended that the worst grade always should be included, even if it is present in < 5% of biopsy material (3).

3.2

REFERENCES

1.

Sobin LH and Wittekind Ch (eds). TNM Classification of Malignant Tumours. 6th edn. Wiley-Liss: New York, 2002. http://www.wiley.com/WileyCDA/WileyTitle/productCd-0471222887.html Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 1974;111(1):58-64. http://www.ncbi.nlm.nih.gov/pubmed/4813554 Amin M, Boccon-Gibod L, Egevad L, Epstein JI, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R. Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. Scand J Urol Nephrol 2005 (Suppl);216:20-33. http://www.ncbi.nlm.nih.gov/pubmed/16019757

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4. RISK FACTORS The factors that determine the risk of developing clinical PCa are not well known, although a few have been identified. There are three well-established risk factors for PCa: increasing age, ethnical origin and heredity. If one first-line relative has PCa, the risk is at least doubled. If two or more first-line relatives are affected, the risk increases 5- to 11-fold (1, 2). A small subpopulation of individuals with PCa (about 9%) has true hereditary PCa. This is defined as three or more affected relatives or at least two relatives who have developed earlyonset disease, i.e. before age 55 (3). Patients with hereditary PCa usually have an onset 6-7 years prior to spontaneous cases, but do not differ in other ways (4). The frequency of autopsy-detected cancers is roughly the same in different parts of the world (5). This finding is in sharp contrast to the incidence of clinical PCa, which differs widely between different geographical areas, being high in the USA and Northern Europe and low in Southeast Asia (6). However, if Japanese men move from Japan to Hawaii, their risk of PCa increases; if they move to California their risk increases even more, approaching that of American men (7) (level of evidence: 2). These findings indicate that exogenous factors affect the risk of progression from so-called latent PCa to clinical PCa. Factors such as food consumption, pattern of sexual behaviour, alcohol consumption, exposure to ultraviolet radiation and occupational exposure have all been discussed as being of aetiological importance (8). Prostate cancer is an ideal candidate for exogenous preventive measures, such as dietary and pharmacological prevention, due to some specific features: high prevalence, long latency, endocrine dependency, availability of serum markers (PSA) and histological precursor lesions (PIN). Dietary/nutritional

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factors that may influence disease development include total energy intake (as reflected by body mass index), dietary fat, cooked meat, micronutrients and vitamins (carotenoids, retinoids, vitamins C, D, and E), fruit and vegetable intake, minerals (calcium, selenium), and phyto-oestrogens (isoflavonoids, flavonoids, lignans). Since most studies reported to date are case-control analyses, there remain more questions than evidence-based data available to answer them. Several ongoing large randomised trials are trying to clarify the role of such risk factors and the potential for successful prostate cancer prevention (9). In summary, hereditary factors are important in determining the risk of developing clinical PCa, while exogenous factors may have an important impact on this risk. The key question is whether there is enough evidence to recommend lifestyle changes (lowered intake of animal fat and increased intake of fruit, cereals and vegetables) in order to decrease the risk (10). There is some evidence to support such a recommendation and this information can be given to male relatives of PCa patients who ask about the impact of diet (level of evidence: 2-3).

4.1

REFERENCES

1.

Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of prostate cancer. Prostate 1990;17(4):337-47. http://www.ncbi.nlm.nih.gov/pubmed/2251225 Gronberg H, Damber L, Damber JE. Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 1996;77(1):138-43. http://www.ncbi.nlm.nih.gov/pubmed/8630920 Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992;89(8):3367-71. http://www.ncbi.nlm.nih.gov/pubmed/1565627 Bratt O. Hereditary prostate cancer: clinical aspects. J Urol 2002;168(3):906-13. http://www.ncbi.nlm.nih.gov/pubmed/12187189 Breslow N, Chan CW, Dhom G, Drury RAB, Franks LM, Gellei B, Lee YS, Lundberg S, Sparke B, Sternby NH, Tulinius H. Latent carcinoma of prostate at autopsy in seven areas. The International Agency for Research on Cancer, Lyons, France. Int J Cancer 1977;20(5):680-8. http://www.ncbi.nlm.nih.gov/pubmed/924691 Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int 2002;90(2):162-73. http://www.ncbi.nlm.nih.gov/pubmed/12081758 Zaridze DG, Boyle P, Smans M. International trends in prostatic cancer. Int J Cancer 1984;33(2): 223-30. http://www.ncbi.nlm.nih.gov/pubmed/6693200 Kolonel LN, Altshuler D, Henderson BE. The multiethnic cohort study: exploring genes, lifestyle and cancer risk. Nat Rev Cancer 2004;4(7):519-27. http://www.ncbi.nlm.nih.gov/pubmed/15229477 Schmid H-P, Engeler DS, Pummer K, Schmitz-Dräger B J. Prevention of prostate cancer: more questions than data. Cancer Prevention. Recent Results Cancer Res 2007;174:101-7. http://www.ncbi.nlm.nih.gov/pubmed/17302190 Schulman CC, Zlotta AR, Denis L, Schroder FH, Sakr WA. Prevention of prostate cancer. Scand J Urol Nephrol 2000;205(Suppl):50-61. http://www.ncbi.nlm.nih.gov/pubmed/11144904

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5. SCREENING AND EARLY DETECTION Population or mass screening is defined as the examination of asymptomatic men (at risk). It usually takes place as part of a trial or study and is initiated by the screener. In contrast, early detection or opportunistic screening comprises individual case findings, which are initiated by the person being screened (patient) and/or his physician. The primary endpoint of both types of screening has two aspects: 1. Reduction in mortality from PCa. The goal is not to detect more and more carcinomas, nor is survival the endpoint because survival is strongly influenced by lead-time from diagnosis. 2. The quality of life is important as expressed by quality-of-life adjusted gain in life years (QUALYs). Prostate cancer mortality trends range widely from country to country in the industrialised world (1). Decreased mortality rates due to PCa have occurred in the USA, Austria, UK and France, while in Sweden, 10

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the 5-year survival rate has increased from 1960 to 1988, probably due to increased diagnostic activity and greater detection of non-lethal tumours (2). However, this trend was not confirmed in a similar study from the Netherlands (3). The reduced mortality seen recently in the USA is often attributed to the widely adopted aggressive screening policy, but there is still no absolute proof prostate-specific antigen (PSA) screening reduces mortality due to PCa (4) (level of evidence: 2). A non-randomised screening project in Tyrol (Austria) may support the hypothesis that screening can be effective in reducing mortality from PCa. An early detection programme and free treatment have been used to explain the 33% decrease in the PCa mortality rate seen in Tyrol compared to the rest of Austria (5) (level of evidence: 2b). In addition, a Canadian study has claimed lower mortality rates in men randomised to active PCa screening (6), though these results have been challenged (7). Positive findings attributed to screening have also been contradicted by a comparative study between the US city of Seattle area (highly screened population) and the US state of Connecticut (seldom screened population) (8). The study found no difference in the reduction in the rate of PCa mortality (level of evidence: 2b), even allowing for the very great diversity in PSA testing and treatment. Prospective, preferably population-based, randomised trials are needed to properly evaluate the efficacy of PCa screening. Two large trials are underway, the PLCO (Prostate, Lung, Colorectal and Ovary) trial in the USA and the ERSPC (European Randomized Screening for Prostate Cancer) in Europe (9, 10). The main endpoint of these trials is difference in PCa mortality, with first results due in 2009 (level of evidence: 1b). Thus, there is currently no evidence for introducing widespread, population-based, screening programmes for early PCa detection in all men in a given population (4) (level of evidence: 2). A less controversial programme, which is also recommended by most guidelines, is using PSA with digital rectal examination (DRE) as an aid to early diagnosis (11) (see Section 6.1) (level of evidence: 3). Nevertheless, a few conclusions about screening intervals can be deduced from the ERSPC study (12): • A screening interval of 2 or 4 years had no impact on outcome in a cohort of 17,505 men aged 55-74 years • The rate of interval cancer, especially aggressive interval cancer, was low in this study (0.43% vs 0.74%) • Although the 2-year screening interval had a higher detection rate for PCa than the 4-year interval (13.14% vs 8.42%), it did not lead to lower incidences of interval PCa (0.11%) and aggressive interval PCa (0.12%) • A screening interval of 8 years might be enough in men with initial PSA levels ≤ 1 ng/ml (13) • A total of 1703 men had a PSA level ≤ 1 ng/ml when they first presented for screening. A total of 1327 men (79.3%) attended the second screening visit during which 13 men (0.98%) had PSA levels ≥ 3.0 ng/mL and three cancers were detected (0.23%) • A total of 1017 men (76.8%) attended the third screening visit during which 34 men (3.3%) had a PSA level ≥ 3.0 ng/mL and five cancers were detected (0.49%) • The 2344 subsequent PSA determinations during an 8-year period following the initial screening visit resulted in the detection of eight cancers (0.47%) • Thus, PSA screening every 8 years for men with PSA levels ≤ 1.0 ng/mL would mean fewer screening visits (with less cost and stress), with a minimal risk of missing aggressive cancer at a curable stage. The decision to undergo early PSA testing should be a shared decision between the patient and his physician (14, 15). PSA testing and digital rectal examination should be offered from the age of 45 years to men with a life expectancy of at least 10 years. The most recent research suggests further PSA testing is unnecessary in men ≥ 75 years and a PSA level ≤ 3 ng/mL at their first screening visit. This is because these men have a very low risk of dying from PCa (16).

5.1

REFERENCES

1.

Oliver SE, May MT, Gunnell D. International trends in prostate-cancer mortality in the ‘PSA-ERA’. Int J Cancer 2001;92(6):893-8. http://www.ncbi.nlm.nih.gov/pubmed/11351313 2. Helgesen F, Holmberg L, Johansson JE, Bergstrom R, Adami HO. Trends in prostate cancer survival in Sweden, 1960 through 1988, evidence of increasing diagnosis of non-lethal tumours. J Natl Cancer Inst 1996;88(17):1216-21. http://www.ncbi.nlm.nih.gov/pubmed/8780631

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Post PN, Kil PJ, Coebergh JW. Trends in survival of prostate cancer in southeastern Netherlands 1971-1989. Int J Cancer 1999;81(4):551-4. http://www.ncbi.nlm.nih.gov/pubmed/10225443 Ilic D, O’Connor D, Green S, Wilt T. Screening for prostate cancer: a Cochrane systematic review. Cancer Causes Control 2007;18(3):279-85. http://www.ncbi.nlm.nih.gov/pubmed/17206534 Bartsch G, Horninger W, Klocker H, Reissigl A, Oberaigner W, Schönitzer D, Severi G, Robertson C, Boyle P; Tyrol Prostate Cancer Screening Group. Prostate cancer mortality after introduction of prostate specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 2001;58(3):417-24. http://www.ncbi.nlm.nih.gov/pubmed/11549491 Labrie F, Candas B, Dupont A, Cusan L, Gomez JL, Suburu RE, Diamond P, Lévesque J, Belanger A. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999;38(2):83-91. http://www.ncbi.nlm.nih.gov/pubmed/9973093 Boer R, Schroeder FH. Quebec randomized controlled trial on prostate cancer screening shows no evidence of mortality reduction. Prostate 1999;40(2):130-4. http://www.ncbi.nlm.nih.gov/pubmed/10386474 Lu-Yao G, Albertsen PC, Stamford JL, Stukel TA, Walker-Corkery ES, Barry MJ. Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut. BMJ 2002;325(7367):740. http://www.ncbi.nlm.nih.gov/pubmed/12364300 De Koning HJ, Liem MK, Baan CA, Boer R, Schroder FH, Alexander FE. Prostate cancer mortality reduction by screening: power and time frame with complete enrolment in the European Randomized Screening for Prostate Cancer (ERSPC) trial. Int J Cancer 2002;98(2):268-73. http://www.ncbi.nlm.nih.gov/pubmed/11857418 Schröder FH, Bangma CH, Roobol MJ. Is it necessary to detect all prostate cancers in men with serum PSA levels < 3 ng/ml? A comparison of biopsy results of PCPT and outcome-related information from ERSPC. Eur Urol 2008;53(5):901-8. http://www.ncbi.nlm.nih.gov/pubmed/18262712 Schmid H-P, Riesen W, Prikler L. Update on screening for prostate cancer with prostate-specific antigen. Crit Rev Oncol Hematol 2004;50(1):71-8. http://www.ncbi.nlm.nih.gov/pubmed/15094160 Roobol MJ, Grenabo A, Schröder FH, Hugosson J. Interval cancers in prostate cancer screening: comparing 2- and 4-year screening intervals in the European Randomized Study of Screening for Prostate Cancer, Gothenburg and Rotterdam. J Natl Cancer Inst 2007;99(17):1296-303. http://www.ncbi.nlm.nih.gov/pubmed/17728218 Roobol MJ, Roobol DW, Schröder FH. Is additional testing necessary in men with prostate-specific antigen levels of 1.0 ng/mL or less in a population-based screening setting? (ERSPC, section Rotterdam). Urology 2005;65(2):343-6. http://www.ncbi.nlm.nih.gov/pubmed/15708050 Smith RA, Cokkinides V, von Eschenbach AC, Levin B, Cohen C, Runowicz CD, Sener S, Saslow D, Eyre HJ; American Cancer Society. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 2002;52(1):8-22. http://www.ncbi.nlm.nih.gov/pubmed/11814067 Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 2009;59:27-41. http://www.ncbi.nlm.nih.gov/pubmed/19147867 Carter HB, Kettermann AE, Ferrucci L, Landis P, Trock BJ, Metter EJ. Prostate specific antigen testing among the elderly: when to stop. J Urol 2008;179 (Suppl):600, abstract 1751.

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6. DIAGNOSIS* The main diagnostic tools used to look for evidence of PCa include DRE, serum concentration of PSA and transrectal ultrasonography (TRUS). Diagnosis depends on the presence of adenocarcinoma in operative specimens, prostate biopsy cores or aspiration needle cytology. Histopathological examination also allows grading of the tumour.

6.1

Digital rectal examination (DRE)

Most prostate cancers are located in the peripheral zone of the prostate and may be detected by DRE when the volume is about 0.2 mL or larger. A suspect DRE is an absolute indication for prostate biopsy. In about 18% of all patients, PCa is detected by a suspect DRE alone, irrespective of the PSA level (1) (level of evidence: 2a). A suspect DRE in patients with a PSA level of up to 2 ng/mL has a positive predictive value of 5-30% (2) (level of evidence: 2a).

6.2 Prostate-specific antigen (PSA) The measurement of PSA level has revolutionised the diagnosis of PCa (3). Prostate-specific antigen (PSA) is a kallikrein-like serine protease produced almost exclusively by the epithelial cells of the prostate. For practical purposes, it is organ-specific but not cancer-specific. Thus, serum levels may be elevated in the presence of benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. The level of PSA as an independent variable is a better predictor of cancer than suspicious findings on DRE or TRUS (4). There are many different commercial test kits for measuring PSA, but no commonly agreed international standard exists (5). The level of PSA is a continuous parameter: the higher the value, the more likely is the existence of PCa (Table 4). This means there is no universally accepted cut-off or upper limit. The finding that many men may harbour PCa, despite low levels of serum PSA, has been underscored by recent results from a US prevention study (6) (level of evidence: 2a). Table 4 gives the rate of PCa in relation to serum PSA for 2950 men in the placebo-arm and with normal PSA values. Table 4: Risk of PCa in relation to low PSA values PSA level (ng/mL) • 0-0.5 • 0.6-1 • 1.1-2 • 2.1-3 • 3.1-4

Risk of PCa 6.6% 10.1% 17.0% 23.9% 26.9%

PSA = prostate-specific antigen. These findings highlight an important issue about lowering the PSA-level threshold, which is how to avoid detecting insignificant cancers with a natural history unlikely to be life threatening (7). As yet, there is no long-term data to help determine the optimal PSA threshold value for detecting non-palpable, but clinically significant, PCa (level of evidence: 3). Several modifications of serum PSA value have been described, which may improve the specificity of PSA in the early detection of PCa. They include: PSA density, PSA density of the transition zone, age-specific reference ranges and PSA molecular forms. However, these derivatives and certain PSA isoforms (cPSA, proPSA, BPSA, iPSA) have limited usefulness in the routine clinical setting and have therefore not been considered for inclusion in these guidelines. 6.2.1 Free/total PSA ratio (f/t PSA) The free/total PSA ratio (f/t PSA) is the concept most extensively investigated and most widely used in clinical practice to discriminate BPH from PCa, and has been used to stratify the risk of PCa for men with total PSA levels between 4 and 10 ng/mL and with a negative DRE. In a prospective multicentre trial, PCa was found on biopsy in 56% of men with a f/t PSA < 0.10, but in only 8% of men with f/t PSA > 0.25 (8) (level of evidence: 2a). Nevertheless, the concept must be used with caution as several pre-analytical and clinical factors may influence the f/t PSA. For example, free PSA is unstable at both 4°C and at room temperature. In addition, * Acknowledgment: Section 6.4 is partly based on the Guidelines of the AUO Study Group Urologic Oncology of the Austrian Society of Urologists and Andrologists (W. Höltl, W. Loidl, M. Rauchenwald, M. Müller, M. Klimpfinger, A. Schratter-Sehn, C. Brössner). Update march 2009

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assay characteristics may vary and concomitant BPH in large prostates may result in a ‘dilution effect’ (9). Furthermore, f/t PSA is clinically useless in total serum PSA values > 10 ng/mL and in follow-up of patients with known PCa. 6.2.2 PSA velocity (PSAV), PSA doubling time (PSADT) There are two methods of measuring PSA over time. These are: • PSA velocity (PSAV), defined as an absolute annual increase in serum PSA (ng/mLyear) (10) (level of evidence: 1b). • PSA doubling time (PSADT), which measures the exponential increase of serum PSA over time reflecting a relative change (11). These two concepts may have a prognostic role in patients with treated PCa (12). However, they have limited use in the diagnosis of PCa because of several unresolved issues, including background noise (total volume of prostate, BPH), the interval between PSA determinations, and acceleration/deceleration of PSAV and PSADT over time. Prospective studies have not shown these measurements can provide additional information compared to PSA alone (13, 14). 6.2.3 PCA3 marker In contrast to the serum markers discussed above, PCA3 is measured in urine sediment obtained after prostatic massage (15). Determination of this PCa-specific gene is experimental. In the near future, several molecular diagnostic tests may move out of the laboratory into the clinical setting (16). So far, none of the above biomarkers can be used to counsel an individual patient on the need to perform a prostate biopsy to rule out PCa.

6.3

Transrectal ultrasonography (TRUS)

The classic picture of a hypoechoic area in the peripheral zone of the prostate will not always be seen (17). Gray-scale TRUS does not detect areas of PCa with adequate reliability. Replacing systematic biopsies by targeted biopsies of suspect areas is therefore unproductive. However, additional biopsies of suspect areas may be useful.

6.4 Prostate biopsy 6.4.1 Baseline biopsy The need for prostate biopsies should be determined on the basis of the PSA level and/or a suspicious DRE. The patient’s biological age, potential co-morbidities (ASA Index and Charlson Comorbidity Index) and the therapeutic consequences should also be considered. The first elevated PSA level should not prompt an immediate biopsy. The PSA level should be verified after a few weeks by the same assay under standardised conditions (i.e. no ejaculation and no manipulations, such as catheterisation, cystoscopy or TUR, and no urinary tract infections) in the same diagnostic laboratory, using the same methods (18, 19) (level of evidence: 2a). The ultrasound-guided perineal approach is a useful alternative in special situations, e.g. after rectal amputation. Its detection rates are comparable to those of the transrectal approach (20) (level of evidence: 1b). 6.4.2 Repeat biopsy Indications are rising and/or persistent PSA, suspicious DRE and atypical small acinar proliferation (ASAP). The optimal timing is uncertain and depends on the histological outcome of the baseline ASAP biopsy and the index of a persistent suspicion of PCa (high or dramatically rising PSA, suspect DRE, family history). The later the repeat biopsy is done, the higher the detection rate (21). High-grade prostatic intraepithelial neoplasia (PIN) is no longer considered an indication for re-biopsy (22) (level of evidence: 2a). A repeat biopsy should therefore be prompted by other clinical features, like DRE findings and PSA level. If PIN is extensive (i.e. in several biopsies) this could be a reason for early re-biopsy. 6.4.3 Saturation biopsy The incidence of PCa detected by saturation repeat biopsy is between 30% and 43% and depends on the number of cores sampled during earlier biopsies (23) (level of evidence: 2a). In special situations, saturation biopsy may be performed with the transperineal technique. This will detect an additional 38% of PCa. The high rate of urinary retention (10%) is a drawback (3D- stereotactic biopsy) (24) (level of evidence: 2b). 6.4.4 Sampling sites and number of cores On baseline biopsies, the sample sites should be as far posterior and lateral in the peripheral gland as possible. 14

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Additional cores should be obtained from suspect areas by DRE/TRUS. These should be chosen on an individual basis. Sextant biopsy is no longer considered adequate. At a glandular volume of 30-40 mL, at least eight cores should be sampled. More than 12 cores are not significantly more conclusive (25) (level of evidence: 1a). The British Prostate Testing for Cancer and Treatment Study has recommended 10-core biopsies (26) (level of evidence: 2a). 6.4.5 Diagnostic transurethral resection of the prostate (TURP) The use of diagnostic TURP instead of repeat biopsies is of minor importance. Its detection rate is no better than 8% and makes it a poor tool for cancer detection (27) (level of evidence: 2a). 6.4.6 Seminal vesicle biopsy Indications for seminal vesicle biopsies are not well defined. At PSA levels > 15-20 ng/mL, a biopsy is only useful if the outcome will have a decisive impact on treatment, i.e. if the biopsy result rules out radical removal for tumour involvement or radiotherapy with intent to cure. At PSA levels > 15-20 ng/L, the odds of tumour involvement are 20-25% (28) (level of evidence: 2a). 6.4.7 Transition zone biopsy Transition zone (TZ) sampling during baseline biopsies provides a very low detection rate and TZ sampling should therefore be confined to repeat biopsies (29) (level of evidence: 1b). 6.4.8 Antibiotics Oral or intravenous antibiotics are state-of-the-art treatment. Optimal dosing and treatment time vary. Quinolones are the drugs of choice, with ciprofloxacin superior to ofloxacin (30) (level of evidence: 1b). 6.4.9 Local anaesthesia Ultrasound-guided peri-prostatic block is state-of-the-art (31) (level of evidence: 1b). It does not make any difference whether the depot is apical or basal. Intrarectal instillation of a local anaesthetic is clearly inferior to peri-prostatic infiltration (32) (level of evidence: 1b). 6.4.10 Fine-needle aspiration biopsy Fine-needle aspiration biopsy is not as effective as TRUS-guided transrectal core biopsy because of the lack of uropathologists experienced in cytology. In addition, TRUS-guided transrectal core biopsies provide more information on the extent of the tumour. 6.4.11 Complications Complication rates are low (Table 5) (33). Minor complications include macrohaematuria and haematospermia. Severe post-procedural infections have been reported in < 1% of cases. The recent increase in the number of biopsy cores performed has not increased the rate of severe complications requiring treatment. Low-dose aspirin is no longer an absolute contraindication (34) (level of evidence: 1b). Table 5: Percentage given per biopsy session, irrespective of the number of cores* Complications • Haematospermia • Bleeding from urethra, urinary bladder (> 1 day) • Fever • Urosepsis • Rectal bleeding • Urine retention • Prostatitis • Epididymitis

% of biopsies 37.4 14.5 0.8 0.3 2.2 0.2 1.0 0.7

* Adapted from Consensus Guidelines NCCN, Version 1.2007 (33).

6.5 Pathology of prostate needle biopsies 6.5.1 Grossing and processing Prostate core biopsies taken from different sites are usually sent to the pathology laboratory in separate vials and should be processed in separate cassettes. Before processing, record the number of cores per vial and

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length of each core. There is a significant correlation between the length of prostate biopsy tissue on the histological slide and the detection rate of PCa (35). To achieve optimal flattening and alignment of individual cores, embed a maximum of three cores per cassette and use sponges or paper to keep the cores stretched and flat (36, 37). To optimise the detection of small lesions, blocks should be cut in three levels (38). It may be of help if intervening tissue sections are routinely mounted in case additional immunostaining is needed. 6.5.2 Microscopy and reporting Diagnosis of prostate cancer is based on histological examination. However, immunostaining may also be helpful (39, 40). Ancillary staining techniques (e.g. basal cell staining) and additional (deeper) sections should be considered if a suspect glandular lesion is identified (38, 40). For suspicious lesions in biopsies, diagnostic uncertainty may often be resolved by intradepartmental consultation and a second opinion from an external institution (39). Use concise clear terminology to report prostate biopsies (37) (Table 6) and avoid terms such as ’atypia‘, ’atypical glands‘ or ‘possibly malignant‘. Table 6: Diagnostic terms used to report prostate biopsy findings* • Benign/negative for malignancy. If appropriate, include a description (e.g. atrophy). Chronic inflammation may be added (optional) • Active inflammation, negative for malignancy • Atypical adenomatous hyperplasia/adenosis, no evidence of malignancy • Granulomatous inflammation, negative for malignancy • High-grade PIN, negative for adenocarcinoma • High-grade PIN with atypical glands suspicious for adenocarcinoma • Focus of atypical glands/lesion suspicious for adenocarcinoma • Adenocarcinoma *From Van der Kwast, 2003 (36). PIN = prostatic intra-epithelial neoplasia. For each biopsy site, report the proportion of biopsies positive for carcinoma and the Gleason score, using the system adopted in 2005 (41). According to current international convention, the (modified) Gleason score of cancers detected in a prostate biopsy consists of the Gleason grade of the dominant (most extensive) carcinoma component plus the highest grade, irrespective of its extent (no 5% rule). When the carcinoma largely consists of grade 4/5 carcinoma, identification of a small portion (< 5% of the carcinoma) of Gleason grade 2 or 3 glands should be ignored. A diagnosis of Gleason score 4 or lower should not be given on prostate biopsies (41). The presence of high-grade PIN and extraprostatic extension should be reported. In addition to a report of the carcinoma features for each biopsy site, provide an overall Gleason score based on findings in the individual biopsies. The presence of perineural invasion is usually reported, even though there is conflicting evidence about its usefulness as a prognosticator of unfavourable disease (42, 43). The proportion (%) or length (mm) of tumour involvement per biopsy site correlates with tumour volume, extraprostatic extension and prognosis after prostatectomy (43-45) and should therefore be recorded. The length of carcinoma (mm) and the percentage of carcinoma involvement of the biopsy have equal prognostic impact (46). The extent of a single, small focus of adenocarcinoma, which is located in only one of the biopsies, should be clearly stated (e.g. < 1 mm or < 1%), as this might be an indication for further diagnostic work-up before selecting therapy. In some studies, a finding of < 3 mm carcinoma in one biopsy with a Gleason score 5–6 has often been associated with insignificant cancer and with an increased risk of vanishing cancer (4749). A prostate biopsy that does not contain glandular prostate tissue could be reported as inadequate for diagnostics, except on staging biopsies. A recent study evaluated the concordance of pattern and change of prognostic groups for the conventional and the modified Gleason grading (50). The evaluation was based on 172 prostatic needle biopsies of patients who subsequently underwent RP. Four prognostic Gleason grading groups were considered, divided into scores of 2–4, 5–6, 7 and 8–10. To check the discriminative power of the modified Gleason grading, the time of biochemical progression-free outcome, according to prognostic groups, was compared between standard and revised grading. The greatest impact of the International Society of Urological Pathology consensus recommendations for Gleason grading was seen on the secondary pattern, which had the lowest percentage of concordance and was reflected in a change toward higher Gleason prognostic groups. Of 172 patients in whom the Gleason prognostic group was changed (to higher grades) based solely on the consensus criteria, 46 (26.7%) had a higher pre-operative PSA level, more extensive tumours and positive surgical

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margins, and a higher pathological stage. In this series, the revised Gleason grading identified more patients in the aggressive prognostic group Gleason score 8–10, who had a significantly shorter time to biochemical progression-free outcome after radical prostatectomy (log rank p = 0.011). These findings have shown that the recommendations of the International Society of Urological Pathology are a valuable refinement of the standard Gleason grading system.

6.6 Pathohistology of radical prostatectomy (RP) specimens 6.6.1 Processing of the RP specimen The histopathological examination of RP specimens aims to provide information about the actual pathological stage, grade and surgical margin status of the prostate cancer. The weight and dimensions of the specimen are recorded before embedding it for histological processing. It is generally recommended that RP specimens are totally embedded to enable the best assessment of location, multifocality and heterogeneity of the cancer. However, for cost-efficiency purposes, partial embedding using a standard method may also be considered, particularly for large-sized prostates (> 60 g). The most acceptable method includes the complete embedding of the posterior (dorsal) part of the prostate in addition to a single mid-anterior left and right section. Compared to total embedding, this method of partial embedding permitted detection of 98% of prostate cancers with a Gleason score ≥ 7 and accurate staging in 96% of cases (51). Upon receipt in the histopathology lab, the entire RP specimen is inked in order to appreciate the surgical margin status. The specimen is fixed in buffered formalin, preferably prior to incision of the sample, as incision causes distortion of the tissue. Generally, appropriate fixation is achieved by immersing the RP specimen in fixative for a few days. Fixation can be enhanced by injecting formalin using 21-gauge syringes, which provides a more homogeneous fixation and sectioning after 24 hours (52). After fixation, the apex is removed and cut with (para)sagittal or radial sections; the shave method is not recommended (53). Separate sagittal sectioning of the bladder neck is optional. The remainder of the RP specimen is generally cut in transverse sections at 3-4 mm steps, perpendicularly to the posterior surface. The resulting tissue slices can be embedded and processed either as whole-mounts or after quadrant sectioning. Whole-mount processing provides better topographic visualisation of the carcinoma and a faster histopathological examination. However, it is a more time-consuming and more expensive technique requiring specialised equipment and personnel. Although whole-mount sectioning may be necessary for research, its advantages do not outweigh its disadvantages for routine sectioning. Recommendations • Total embedding of a prostatectomy specimen is preferred, either by conventional (quadrant sectioning) or by whole-mount sectioning • The entire surface of RP specimens should be inked before cutting in order to evaluate the surgical margin status • The apex should be separately examined using the cone method with sagittal or radial sectioning.

6.6.2 RP specimen report The pathology report provides essential information on the prognostic characteristics relevant for making clinical decisions. The report includes: • typing (> 95% of PCa represent conventional (acinic) adenocarcinomas) • grading according to the Gleason score • (sub)staging and surgical margin status of the tumour • if appropriate, location and extent of extraprostatic extension, sidedness of extraprostatic extension or seminal vesicle invasion, location and extent of positive surgical margins • additional information may be provided on multifocality, diameter of the dominant tumour and the zonal location (transition zone, peripheral zone, anterior horn) of the dominant tumour. Given the complex information to be provided on each RP specimen, the use of synoptic-(like) or checklist reporting is recommended (see table 7). Synoptic reporting of surgical specimens results in more transparent and complete pathology reporting (54).

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Table 7: Example checklist - reporting of prostatectomy specimens Histologic type Type of carcinoma (e.g. conventional acinar, ductal, etc.) Histologic grade Primary (predominant) grade Secondary grade Tertiary grade (if applicable) Total / global Gleason score Approximate percentage of Gleason grade 4 or 5 (optional) Tumour quantitation (optional) Percentage of prostatic gland involved Tumour size of dominant nodule (if identified), greatest dimension in mm Pathologic staging (pTNM) Presence of extraprostatic extension (focal or extensive) If present: specify site(s) Presence of seminal vesicle invasion If applicable: Regional lymph nodes: - Location - Number of lymph nodes retrieved - Number of lymph nodes involved Surgical margins Presence of carcinoma at margin If present: specify site(s) and extra- or intraprostatic Other If identified: presence of angioinvasion Location (site, zone) of dominant tumour (optional) Perineural invasion (optional) If present: specify extra-or intra-prostatic 6.6.2.1. Gleason score Grading of conventional prostatic adenocarcinomas using the (modified) Gleason score system (41) is the single strongest prognostic factor for clinical behaviour and treatment response. The Gleason score is therefore one of the parameters incorporated in nomograms that predict the risk of recurrence after prostatectomy (55). 6.6.2.2. Interpreting the Gleason score The Gleason score is the sum of the most dominant and second most dominant (in terms of volume) Gleason grade. If only one grade is present, the primary grade is doubled. If a grade comprises ≤ 5% of the cancer volume, this grade is not incorporated in the Gleason score (5% rule). Both the primary and the secondary grade should be reported in addition to the Gleason score (e.g. Gleason score 7 [4 + 3]). A global Gleason score is given when there are multiple tumours, but a separate tumour focus with a higher Gleason score should also be mentioned. A tertiary Gleason grade 4 or 5, particularly if exceeding 5% of the prostate cancer volume, is an unfavourable prognosticator for biochemical recurrence. The presence of the tertiary grade and its approximate proportion of the cancer volume should also be reported (56), in addition to the Gleason score. 6.6.2.3 Definition of extraprostatic extension The TNM staging system of the International Union Against Cancer (UICC) is recommended for pathological staging of carcinomas of the prostate (53, 57). It measures the anatomical extension of the cancer, which may (e.g. pT3 substaging) or may not (e.g. pT2 substaging) be prognostic. Extraprostatic extension is the recommended term for the presence of tumour beyond the confines of the prostate. Extraprostatic extension is defined as carcinoma admixed with periprostatic adipose tissue, or bulging out beyond the contour of the prostate gland, e.g at the neurovascular bundle or the anterior prostate. It is useful to report not only the location, but also the extent of extraprostatic extension because the extension is related to the risk of recurrence (58, 59). There are no well-established and internationally accepted definitions of the terms ‘focal’ and ‘non-focal’ or ‘extensive extraprostatic extension’. Some authors describe focal as ‘a few glands‘ (60) or extension less than 1 high power field (59), while others measure the depth of extent in mm (61). Currently, it is considered clinically useful to measure the extent of extraprostatic extension (e.g. less or more than 1 high power field or 1 mm). At the site of the apex, there is no agreed definition on how to determine extraprostatic extension. Here,

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tumour admixed with skeletal muscle does not constitute extraprostatic extension, and it should be noted that at the apex, a diagnosis of stage pT4 is not rendered. In the bladder neck, microscopic invasion of small fibres of smooth muscle is not equated to bladder wall invasion (62). Some consider tumour invasion of large bundles of smooth muscle to be gross invasion (63), as determined by the urologist, or a positive bladder neck margin to be equivalent to pT4 (64). 6.6.3 Prostate cancer volume The prognostic value of determining the volume of PCa in RP specimens is controversial with several conflicting studies either demonstrating or refuting its independent prognostic impact (59, 65-68). Nevertheless, a prostate cancer volume cut-off of 0.5 mL continues to be an important parameter to distinguish insignificant from clinically relevant cancers (65). Furthermore, continued improvement in radio-imaging of the prostate glands has allowed more accurate measurements of cancer volume before surgery. For these reasons, it may be recommended that, if present, the greatest dimension of the dominant tumour nodule should be provided in millimeters. 6.6.4 Surgical margin status Surgical margin status is an independent risk factor for biochemical recurrence. It is usually possible to provide clear information about the surgical margin status: positive if tumour cells are in touch with the ink on the surface of the specimen, and negative if not. The margin is negative if tumour cells are very close to the inked surface of the margin (66) or when they are at the surface of the tissue lacking any ink. If the tissue has severe crush artifacts (usually at the apex), it may not be possible to assign a surgical margin status (69). Surgical margin status is independent of the pathological stage and a positive margin is not evidence of extraprostatic extension (70). There is insufficient evidence to prove a relationship between the extent of positive margin and the risk of recurrence (59). However, it is recommended that some indication is given of the (multi)-focality and extent of margin positivity (e.g. linear extent in millimeters, or number of blocks with positive margin involvement). 6.6.5 Other factors According to the College of American Pathologists consensus statement (71), additional potential biomarkers, such as perineural invasion, neuroendocrine differentiation, microvessel density, nuclear roundness, chromatin texture, other karyometric factors, proliferation markers, prostate-specific antigen derivatives, and other factors (oncogenes, tumor suppressor genes, apoptosis genes, etc) have not been sufficiently studied to demonstrate their additional prognostic value and clinical usefulness outside the standard patient care setting (category III).

6.7

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51.

Sehdev AE, Pan CC, Epstein JI. Comparative analysis of sampling methods for grossing radical prostatectomy specimens performed for nonpalpable (stage T1c) prostatic adenocarcinoma. Hum Pathol 2001;32(5):494-9. http://www.ncbi.nlm.nih.gov/pubmed/11381367 52. Ruijter ET, Miller GJ, Aalders TW, van de Kaa CA, Schalken JA, Debruyne FM, Boon ME. Rapid microwave-stimulated fixation of entire prostatectomy specimens. Biomed-II MPC Study Group. J Pathol 1997;183(3):369-75. http://www.ncbi.nlm.nih.gov/pubmed/9422995 53. Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL; ISUP grading committee. The 2005 International Society of Urologic Pathology (ISUP) Consensus Conference on Gleason grading of Prostatic Carcinoma. Am J Surg Pathol 2005;29(9):1228-42. http://www.ncbi.nlm.nih.gov/pubmed/16096414 54. Chan NG, Duggal A, Weir MM, Driman DK. Pathological reporting of colorectal cancer specimens: a retrospective survey in an academic Canadian pathology department. Can J Surg 2008;51(4):284-8. http://www.ncbi.nlm.nih.gov/pubmed/18815652 55. Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of the prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001;58(6):843-8. http://www.ncbi.nlm.nih.gov/pubmed/11744442 56. Harnden P, Shelley MD, Coles B, Staffurth J, Mason MD. Should the Gleason grading system for prostate cancer be modified to account for high-grade tertiary components? A systematic review and meta-analysis. Lancet Oncology 2007;8(5):411-9. http://www.ncbi.nlm.nih.gov/pubmed/17466898 57. Ohori M, Kattan M, Scardino PT, Wheeler TM. Radical prostatectomy for carcinoma of the prostate. Mod Pathol 2004;17(3):349-59. http://www.ncbi.nlm.nih.gov/pubmed/14765206 58. Wheeler TM, Dillioglugil O, Kattan MW, Arakawa A, Soh S, Suyama K, Ohori M, Scardino PT. Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-2 prostate cancer. Hum Pathol 1998;29(8):856-62. http://www.ncbi.nlm.nih.gov/pubmed/9712429 59. Marks M, Koch, Lopez-Beltran A, Montironi R, Juliar B, Cheng L. The relationship between the extent of surgical margin positivity and prostate specific antigen recurrence in radical prostatectomy specimens.  Human Pathology 2007;38(8):1207-11. http://www.ncbi.nlm.nih.gov/pubmed/17490720 60. Epstein JI, Carmichael MJ, Pizov G, Walsh PC. Influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term followup. J Urol 1993;150(1): 135-41. http://www.ncbi.nlm.nih.gov/pubmed/7685422 61. Sung MT, Lin H, Koch MO, Davidson DD, Cheng L. Radial distance of extraprostatic extension measured by ocular micrometer is an independent predictor of prostate-specific antigen recurrence: A new proposal for the substaging of pT3a prostate cancer. Am J Surg Pathol 2007;31(2):311-8. http://www.ncbi.nlm.nih.gov/pubmed/17255778 62. Aydin H, Tsuzuki T, Hernandez D, Walsh PC, Partin AW, Epstein JI. Positive proximal (bladder neck) margin at radical prostatectomy confers greater risk of biochemical progression. Urology 2004;64(3):551-5. http://www.ncbi.nlm.nih.gov/pubmed/15351591 63. Hoedemaeker RF, Vis AN, Van Der Kwast TH. Staging prostate cancer. Microsc Res Tech 2000;51(5):423-9. http://www.ncbi.nlm.nih.gov/pubmed/11074612 64. Srigley JR, Amin MB, Epstein JI, Grignon DJ, Humphrey PA, Renshaw AA, Wheeler TM; Members of the Cancer Committee, College of American Pathologists. Updated protocol for the examination of specimens from patients with carcinomas of the prostate gland. Arch Pathol Lab Med 2006;130(7):936-46. http://www.ncbi.nlm.nih.gov/pubmed/16831046 65. Stamey TA, Yemoto CM, McNeal JE, Sigal BM, Johnstone IM. Prostate cancer is highly predictable: a prognostic equation based on all morphological variables in radical prostatectomy specimens. J Urol 2000;163(4):1155-60. http://www.ncbi.nlm.nih.gov/pubmed/10737486

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66.

67.

68.

69.

70.

71.

Epstein JI, Amin M, Boccon-Gibod L, Egevad L, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic lymphadenectomy specimens. Scand J Urol Nephrol Suppl 2005;216:34-63. http://www.ncbi.nlm.nih.gov/pubmed/16019758 Kikuchi E, Scardino PT, Wheeler TM, Slawin KM, Ohori M. Is tumor volume an independent prognostic factor in clinically localized prostate cancer? J Urol 2004;172(2):508-11. http://www.ncbi.nlm.nih.gov/pubmed/15247716 Van Oort IM, Witjes JA, Kok DE, Kiemeney LA, Hulsbergen-vandeKaa CA. Maximum tumor diameter is not an independent prognostic factor in high-risk localized prostate cancer. World J Urol 2008;26(3):237-41. http://www.ncbi.nlm.nih.gov/pubmed/18265988 Evans AJ, Henry PC, Van der Kwast TH, Tkachuk DC, Watson K, Lockwood GA, Fleshner NE, Cheung C, Belanger EC, Amin MB, Boccon-Gibod L, Bostwick DG, Egevad L, Epstein JI, Grignon DJ, Jones EC, Montironi R, Moussa M, Sweet JM, Trpkov K, Wheeler TM, Srigley JR. Interobserver variability between expert urologic pathologists for extraprostatic extension and surgical margin status in radical prostatectomy specimens. Am J Surg Pathol 2008;32(10):1503-12. http://www.ncbi.nlm.nih.gov/pubmed/18708939 Chuang AY, Epstein JI. Positive surgical margins in areas of capsular incision in otherwise organconfined disease at radical prostatectomy: histologic features and pitfalls. Am J Surg Pathol 2008;32(8):1201-6. http://www.ncbi.nlm.nih.gov/pubmed/18580493 Bostwick DG, Grignon DJ, Hammond ME, Amin MB, Cohen M, Crawford D, Gospadarowicz M, Kaplan RS, Miller DS, Montironi R, Pajak TF, Pollack A, Srigley JR, Yarbro JW. Prognostic factors in prostate cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124(7):995-1000. http://www.ncbi.nlm.nih.gov/pubmed/10888774

7. STAGING The primary extension assessment of prostate cancer (PCa) is usually made by digital rectal examination (DRE), prostate-specific antigen (PSA) measurement and bone scan, supplemented with computed tomography (CT) or magnetic resonance imaging (MRI) and chest X-ray in specific situations.

7.1

T-staging

The first level is the assessment of local tumour stage, where the distinction between intracapsular (T1-T2) and extracapsular (T3-T4) disease has the most profound impact on treatment decisions. DRE often underestimates the tumour extension; a positive correlation between DRE and pathological tumour stage was found in fewer than 50% of cases (1). However, more extensive examinations for adequate T-staging are only recommended in selected cases when more precise staging directly affects the treatment decision, i.e. when curative treatment is an option. Serum PSA levels increase with advancing stage. Nevertheless, when PSA level is measured in an individual patient, it appears to have a limited ability to predict the final pathological stage accurately. Due to the production of PSA by benign and malignant prostatic tissue, there is no direct relationship between serum PSA concentration and the clinical and pathological tumour stage (2-4). A combination of serum PSA level, Gleason score on prostate biopsy and clinical T-stage, however, has been proven to be more useful in predicting the final pathological stage than the individual parameters per se (5). The ability of the molecular forms of PSA to predict T-stage is still controversial. Percentage-free serum PSA did not appear to be able to predict organ-confined disease in the overall population: it could significantly predict favourable pathology in a subset of patients where DRE is normal and total PSA ranges from 4.1-10.0 ng/mL (6). Total PSA and PSA complexed to antichymotrypsin (PSA-ACT) may be superior to their density derivatives in the prediction of post-surgical pathological stage, but it does not seem to justify the substitution of PSA-ACT data in the Partin’s nomogram (7). Large multicentre studies are needed before any form of PSA can be used as a single modality for staging.

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The most commonly used method for viewing the prostate is transrectal ultrasound (TRUS). However, only 60% of tumours are visible with TRUS, and the remainder are not recognised due to their echogenicity. A combination of DRE and TRUS can detect T3a PCa more accurately than either method alone (8). TRUS is not able to determine tumour extension with sufficient accuracy to be recommended for routine use in staging. About 60% of pT3 tumours will not be detected pre-operatively by TRUS (9) (level of evidence: 3). Three-dimensional ultrasound (3D-US) is a non-invasive method of reproducing whole volume images of solid structures with a suggested staging accuracy of 91% (10). Several adjuncts to 3D greyscale TRUS have been investigated. A greater sensitivity for cancer detection has been achieved with the addition of power colour Doppler and contrast agents: the presence or absence of vessels crossing the capsule to determine an extracapsular extension was considered a significant predictive sign (11, 12). Unfortunately, recognition of these findings is largely operator-dependent. Thus, differentiation between T2 and T3 tumours should not be based on TRUS alone (13, 14). Furthermore, in a large multi-institutional study, TRUS was no more accurate at predicting organ-confined disease than was DRE (15). These findings were supported by another large study, which showed that there was no meaningful superiority of TRUS over DRE (16). Seminal vesicle invasion is predictive of local relapse and distant failure. Seminal vesicle biopsies may be used to increase the accuracy of pre-operative staging (17). This is not recommended as a first-line examination, but should be reserved for patients with a substantial risk of seminal vesicle invasion in whom a positive seminal vesicle biopsy would modify treatment decisions. Patients with a clinical stage greater than T2a and a serum PSA level of more than 10 ng/mL could be candidates for seminal vesicle biopsies (18, 19). Patients with any of the basal biopsies positive for cancer are more likely to have positive seminal vesicle biopsies (20). The biopsy Gleason score, serum PSA level and clinical stage are known to be independent predictors of adverse pathological features after radical prostatectomy (RP). Of the prostate needle biopsy parameters examined, the percentage of tissue with cancer was the strongest predictor for positive surgical margins, seminal vesicle invasion and non-organ-confined disease (21). An increased number of biopsies involved with tumour independently predicts extracapsular extension, margin involvement and lymph node invasion (22). In a multivariate analysis, the best risk predictors of extracapsular extension on one side were the overall average of positive biopsy cores being 15% or greater, and the average from three ipsilateral biopsies being 15% or greater. When used in combination, these two factors yielded a model with a positive predictive value of 37%, and a negative predictive value of 95%. The high negative predictive value of the side-specific model identifies patients who are good candidates for nerve-sparing surgery (23). Furthermore, it may be useful to correlate the bioptic Gleason score with the final pathological stage: about 70% of patients have localised disease when the biopsy Gleason score is ≤ 6 (24). Both CT and MRI are now of a high technical standard, but neither modality is sufficiently reliable to make their use mandatory in the assessment of local tumour invasion (25-27). Endorectal MRI (e-MRI) may allow for more accurate local staging by complementing the existing clinical variables by improvements in spatial characterisation of the prostatic zonal anatomy and molecular changes (28). Image quality and localisation improves significantly with e-MRI compared with external coil MRI (29). When compared with DRE and TRUS prostate biopsy findings, e-MRI contributes significant incremental value for local PCa staging (30), particularly in the pre-operative identification of extracapsular extension (ECE) and seminal vesicle invasion (SVI) when interpreted by dedicated genitourinary radiologists (31, 32, 33). E-MRI could impact on the decision to preserve or resect the neurovascular bundle (NVB) at the time of radical surgery (34). Similarly, e-MRI could be accurate in evaluating the presence of SVI (35). Features associated with the identification of SVI include low signal intensity within the seminal vesicle, and lack of preservation of normal seminal vesicle architecture. Combining these features with the presence both of tumour at the base of the prostate and ECE is highly predictive for the presence of SVI (35, 36). When assessed for the ability to predict organ-confined PCa, the contribution of e-MRI to staging nomograms was significant in all risk categories, but the greatest benefit was seen in the intermediate and high risk groups (37). The combination of dynamic contrast-enhanced MR imaging and T2-weighted MR imaging yields improved assessment of ECE and better results for PCa staging compared with either technique independently (38) (level of evidence: 3). Update march 2009

25

MR spectroscopic imaging (MRSI) allows for the assessment of tumour metabolism by displaying the relative concentrations of citrate, choline, creatinine and polyamines. Differences in the concentrations of these chemical metabolites between normal and malignant prostate tissues allow for better tumour localisation within the peripheral zone, increasing the accuracy of ECE detection among less-experienced readers, and decreasing interobserver variability (39). Furthermore, correlations have been demonstrated between the metabolic signal pattern and a pathological Gleason score, suggesting the potential for a non-invasive assessment of PCa aggressiveness (40). Despite the proposed accuracy and benefit of e-MRI and MRSI in PCa characterisation and localisation, e-MRI has several limitations that hamper its widespread application in PCa staging, e.g. difficulties in interpreting signal changes related to post-biopsy haemorrhage and inflammatory changes of the prostate, and the unquantifiable but significant inter- and intra-observer variability seen between both non-dedicated and dedicated radiologists that may lead to under- or overestimation of tumour presence and the local extent of disease (level of evidence: 3). The overall accuracy of 11C-choline positron emission tomography (PET) in defining local tumour stage (pT2 and pT3a-4) has been reported to be around 70%. PET tends to understage PCa, and has a limited value for making treatment decisions in patients with clinically localised PCa, especially if a nerve-sparing procedure is being considered (41) (level of evidence: 2b).

7.2

N-staging

N-staging should be performed only when the findings will directly influence a treatment decision. This is usually the case in patients for whom potentially curative treatments are planned. High PSA values, stages T2b-T3 disease, poor tumour differentiation and peri-neural tumour invasion have been associated with a higher risk of the presence of nodal metastases (5, 42, 43). The measurement of PSA level alone is unhelpful in predicting the presence of lymph node metastases for an individual patient. The nomograms could be used to define a group of patients with a low risk of nodal metastasis (< 10%, see reference number 44). In such cases, patients with a serum PSA level of less than 20 ng/mL, stage T2a or less, and a Gleason score of 6 or less may be spared N-staging procedures before potentially curative treatment (5). The extent of the Gleason 4 pattern in sextant biopsies has also been used to define the risk of N1 disease. If any core had a predominant Gleason 4 pattern, or > three cores any Gleason 4 pattern, the risk of nodal metastases was found to be 20-45%. For the remaining patients, the risk was 2.5%, supporting the idea that nodal staging is unnecessary in selected patients (45). In the current published literature, the results indicate that CT and MRI perform similarly in the detection of pelvic lymph node metastases, although CT seems to be slightly superior (46) (level of evidence: 2a). In either case, the decision about whether nodal involvement is present rests solely on whether there is enlargement of the investigated lymph nodes. The centimetre threshold used to decide whether a lymph node is pathologically involved varies between 0.5 cm and 2 cm. A threshold of 1 cm in the short axis for the oval nodes, and 0.8 cm for the round nodes, has been recommended as the criteria for the diagnosis of lymph node metastases (47). A fine-needle aspiration biopsy (FNAB) might provide a decisive answer in cases of positive imaging results. However, the lymph node can be difficult to reach because of the anatomical position. In addition, FNAB is not a highly sensitive staging procedure, and a false-negative rate of 40% has been reported (47). High-resolution MRI with lymphotrophic ultra-small super-paramagnetic iron oxide particles (USPIO) was more recently suggested in the detection of small and otherwise occult lymph node metastases in patients with PCa (48, 49). These iron nanoparticles are taken up by circulating macrophages, which travel to normal nodal tissue. The presence of the nanoparticles causes normal nodal tissue to turn black, and because malignant nodal tissue is unable to take up the agent, metastases will have a signal intensity higher than normal nodes, even in those that do not meet the standard size criteria for metastasis (50). In asymptomatic patients with newly diagnosed PCa and a serum PSA level of less than 20 ng/mL, the likelihood of positive findings on CT or MRI is approximately 1% (37). CT scanning may therefore be warranted in patients with a very high risk of harbouring lymph node metastases, as the specificity of a positive scan is high (93-96%). Patients with nodal metastases on CT can thus be spared operative lymphadenectomy (51). Radio-immunoscintigraphy and PET have been investigated in order to improve the diagnosis of metastatic disease to the lymph nodes. Both methods are still under investigation, and further evaluation is needed before they can be recommended for routine use in clinical practice, especially as negative results should

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be interpreted with caution (52). The results obtained using 18F-choline PET/CT scans for initial N-staging were discouraging, especially in terms of inability to detect small metastases/micrometastases (< 5 mm) (53). Furthermore, 11C-choline PET/CT has quite a low sensitivity for the detection of lymph node metastases, but performed better than clinical nomograms, with equal sensitivity and better specificity (54). The gold standard for N-staging is operative lymphadenectomy, either by open or laparoscopic techniques. It is worth pointing out that recent studies with more extensive lymphadenectomy have shown that the obturator fossa is not always the primary site for metastatic deposits in the lymph nodes, and pelvic lymph node dissection that is limited to the obturator fossa will therefore miss about 50% of lymph node metastases (55, 56). When deciding on pelvic lymph node dissection, extended lymphadenectomy should be considered, despite its disadvantages: it requires surgical experience; it is time-consuming; and it often leads to more complications than the limited procedures. Furthermore, it may fail to identify lymph node metastases, however present, even outside the region of extended dissection (57). The primary removal of the so-called sentinel lymph node (SLN), defined as the first lymph node that receives lymphatic drainage from PCa, has the main aim of reducing the eventual morbidity associated with an extended pelvic node dissection, while preserving maximal sensitivity for diagnosis of metastatic disease (58) (level of evidence: 3) (see section 9.5.2.1 ‘Treatment: radical prostatectomy, indication and extent of LND’).

7.3

M-staging

The axial skeleton is involved in 85% of patients who die from PCa (59). The presence and extent of bone metastases accurately reflect the prognosis for an individual patient. Elevated skeletal alkaline phosphatase levels may indicate the presence of bony metastasis in 70% of affected patients (60). Furthermore, the measurement of skeletal alkaline phosphatase and PSA at the same time increases clinical effectiveness to approximately 98% (61). In a prospective study, multiple regression analysis showed the extent of bone disease to be the only variable influencing the serum levels of skeletal alkaline phosphatase and PSA. However, in contrast to serum PSA, skeletal alkaline phosphatase demonstrated a statistical correlation with the extent of bone disease (62). Early detection of bone metastases will alert the clinician to the possible complications inherent in skeletal destruction. Bone scintigraphy remains the most sensitive method of assessing bone metastases, being superior to clinical evaluation, bone radiographs, serum alkaline phosphatase measurement and prostatic acid phosphatase (PAP) determination (63, 64). Technetium diphosphonates are the optimum radiopharmaceuticals currently available because of their extremely high bone-to-soft tissue ratio (65). A semi-quantitative grading system based on the extent of disease observed on the bone scan was found to correlate with survival (66). Increased 18F-fluoride uptake in malignant bone lesions reflects the increase in regional blood flow and bone turnover that characterise these lesions. Studies have shown that 18F-fluoride PET/CT is a highly sensitive and specific imaging modality for detection of bone metastases (67, 68). However, no definitive results have been obtained and therefore no final recommendations can be made (69). Besides bone, PCa may metastasise to any organ, but most commonly it affects distant lymph nodes, lung, liver, brain and skin. Clinical examination, chest X-ray, ultrasound, CT and MRI scans are appropriate methods of investigation, but only if symptoms suggest the possibility of soft-tissue metastasis. The need for reliable serum markers to improve the pre-treatment staging of patients with PCa has long been recognised. At present, PSA is the marker of choice. A pre-treatment serum PSA level greater than 100 ng/ mL has been found to be the single most important indicator of metastatic disease, with a positive predictive value of 100% (70). Furthermore, it has helped to reduce the number of patients with newly diagnosed PCa who require a bone scan. Patients with a low serum PSA concentration have only rarely been found to harbour detectable skeletal metastases. The correlation between serum PSA and bone scintigraphy in patients with newly diagnosed untreated PCa has been further investigated (71-75). Results suggest that a staging bone scan may be superfluous if the serum PSA concentration is less than 20 ng/mL in asymptomatic patients with well or moderately differentiated tumours. In contrast, in patients with poorly differentiated tumours and locally advanced disease, a staging bone scan should be obtained irrespective of the serum PSA value (76, 77).

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7.4 Guidelines for the staging of PCa

1.

An abnormal DRE result or elevated serum PSA measurement could indicate PCa. The exact cut-off level of what is considered to be a normal PSA value has not been determined, but values of approximately < 2-3 ng/mL are often used for younger men. 2. The diagnosis of PCa depends on histopathological (or cytological) confirmation. • Biopsy and further staging investigations are only indicated if they affect the management of the patient. 3. TRUS-guided systemic biopsy is the recommended method in most cases of suspected PCa. A minimum of 10 systemic, laterally directed, cores are recommended, with perhaps more cores in larger: • transition zone biopsies are not recommended in the first set of biopsies due to low detection rates • one set of repeat biopsies is warranted in cases with persistent indication (abnormal DRE, elevated PSA or histopathological findings suggestive of malignancy at the initial biopsy) for prostate biopsy • overall recommendations for further (three or more) sets of biopsies cannot be made; the decision must be made based on an individual patient. 4. Transrectal peri-prostatic injection with a local anaesthetic can be offered to patients as effective analgesia when undergoing prostate biopsies. 5. Local staging (T-staging) of PCa is based on findings from DRE and possibly MRI. Further information is provided by the number and sites of positive prostate biopsies, the tumour grade and the level of serum PSA. Despite its high specificity in the evaluation of ECE and SVI, TRUS is limited by poor contrast resolution, resulting in low sensitivity and tendency to understage PCa. Even with the advent of colour and power Doppler to assist in identifying tumour vascularity, the accuracy of TRUS in local staging remains inadequate. In comparison with DRE, TRUS, and CT, MRI demonstrates higher accuracy for the assessment of uni- or bilobar disease (T2), ECE and SVI (T3), as well as the invasion of adjacent structures (T4). However, the literature shows a wide range in the accuracy of T-staging by MRI, from 50-92%. The addition of dynamic contrast-enhanced MRI (DCE-MRI) can be helpful in equivocal cases. The addition of MRSI to MRI also increases accuracy and decreases interobserver variability in the evaluation of ECE. 6. Lymph node status (N-staging) is only important when potentially curative treatment is planned. Patients with stage T2 or less, PSA < 20 ng/mL and a Gleason score ≤ 6 have a lower than 10% likelihood of having node metastases and can be spared nodal evaluation. Given the significant limitations of pre-operative imaging in the detection of small metastases (< 5 mm), pelvic lymph node dissection remains the only reliable staging method in clinically localised. Currently, it seems that only methods of histological detection of lymph node metastases with high sensitivity, such as sentinel lymph node dissection or extended pelvic lymph node dissection, are suitable for lymph node staging in PCa. 7. Skeletal metastasis (M-staging) is best assessed by bone scan. This may not be indicated in asymptomatic patients if the serum PSA level is less than 20 ng/mL in the presence of well or moderately differentiated tumours. In equivocal cases, 18F-fluorodeoxyglucose-PET or PET/CT could be of value, especially to differentiate active metastases and healing bones. GR = grade of recommendation

7.5

GR C

B C B

C B

C A C

C

B

C

B

C

REFERENCES

1.

Spigelman SS, McNeal JE, Freiha FS, Stamey TA. Rectal examination in volume determination of carcinoma of the prostate: clinical and anatomical correlations. J Urol 1986;136(6):1228-30. http://www.ncbi.nlm.nih.gov/pubmed/3773095 2. Hudson MA, Bahnson RR, Catalona WJ. Clinical use of prostate-specific antigen in patients with prostate cancer. J Urol 1989;142(4):1011-7. http://www.ncbi.nlm.nih.gov/pubmed/2477559

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Lange PH, Ercole CJ, Lightner DJ, Fraley EE, Vessella R. The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol 1989;141(4):873-9. http://www.ncbi.nlm.nih.gov/pubmed/2467013 4. Partin AW, Carter HB, Chan DW, Epstein JI, Oesterling JE, Rock RC, Weber JP, Walsh PC. Prostate specific antigen in the staging of localized prostate cancer: influence of tumour differentiation, tumour volume and benign hyperplasia. J Urol 1990;143(4):747-52. http://www.ncbi.nlm.nih.gov/pubmed/1690309 5. Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of the prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001;58(6):843-8. http://www.ncbi.nlm.nih.gov/pubmed/11744442 6. Morote J, Encabo G, de Torres IM. Use of percent free prostate-specific antigen as a predictor of the pathological features of clinically localized prostate cancer. Eur Urol 2000 Aug;38(2):225-9. http://www.ncbi.nlm.nih.gov/pubmed/10895016 7. Custovic Z, Kraus O, Tomaskovic I, Tarle M. Serum tPSA, cPSA, related density parameters and chromogranin A as predictors of positive margins after radical prostatectomy. Anticancer Res 2007;27(4C):2817-21. http://www.ncbi.nlm.nih.gov/pubmed/17695453 8. Hsu CY, Joniau S, Oyen R, Roskams T, Van Poppel H. Detection of clinical unilateral T3a prostate cancer – by digital rectal examination or transrectal ultrasonography? BJU Int 2006;98(5):982-5. http://www.ncbi.nlm.nih.gov/pubmed/16945120 9. Enlund A, Pedersen K, Boeryd B, Varenhorst E. Transrectal ultrasonography compared to histopathological assessment for local staging of prostatic carcinoma. Acta Radiol 1990;31(6):597600. http://www.ncbi.nlm.nih.gov/pubmed/2278785 10. Mitterberger M, Pinggera GM, Pallwein L, Gradl J, Frauscher F, Bartsch G, Strasser H, Akkad T, Horninger W The value of three-dimensional transrectal ultrasonography in staging prostate cancer. BJU Int 2007;100(1):47-50. http://www.ncbi.nlm.nih.gov/pubmed/17433033 11. Sauvain JL, Palascak P, Bourscheid D, Chabi C, Atassi A, Bremon JM, Palascak R. Value of power Doppler and 3D vascular sonography as a method for diagnosis and staging of prostate cancer. Eur Urol 2003;44(1):21-30; discussion 30-1. http://www.ncbi.nlm.nih.gov/pubmed/12814671 12. Zalesky M, Urban M, Smerhovský Z, Zachoval R, Lukes M, Heracek J. Value of power Doppler sonography with 3D reconstruction in preoperative diagnostics of extraprostatic tumor extension in clinically localized prostate cancer. Int J Urol 2008;15(1):68-75; discussion 75. http://www3.interscience.wiley.com/journal/119407751 13. Oyen RH. Imaging modalities in diagnosis and staging of carcinoma of the prostate. In: Brady LW, Heilmann HP, Petrovich Z, Baert L, Brady LW, Skinner DG (eds). Carcinoma of the Prostate. Innovations & Management, 1996, Springer Verlag, Berlin, pp. 65-96. 14. Rorvik J, Halvorsen OJ, Servoll E, Haukaas S. Transrectal ultrasonography to assess local extent of prostatic cancer before radical prostatectomy. Br J Urol 1994;73(1):65-9. http://www.ncbi.nlm.nih.gov/pubmed/8298901 15. Smith JA Jr, Scardino PT, Resnick MI, Hernandez AD, Rose SC, Egger MJ. Transrectal ultrasound versus digital rectal examination for the staging of carcinoma of the prostate: results of a prospective multi-institutional trial. J Urol 1997;157(3):902-6. http://www.ncbi.nlm.nih.gov/pubmed/9072596 16. Liebross RH, Pollack A, Lankford SP, Zagars GK, von Eshenbach AC, Geara FB. Transrectal ultrasound for staging prostate carcinoma prior to radiation therapy: an evaluation based on disease outcome. Cancer 1999;85(7):1577-85. http://www.ncbi.nlm.nih.gov/pubmed/10193949 17. Saliken JC, Gray RR, Donnelly BJ, Owen R, White LJ, Ali-Ridha N, So B, Ting PT. Extraprostatic biopsy improves the staging of localized prostate cancer. Can Assoc Radiol J 2000;51(2):114-20. http://www.ncbi.nlm.nih.gov/pubmed/10786920 18. Stone NN, Stock RG, Unger P. Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node dissection in men with localized carcinoma of the prostate. J Urol 1995;154(4):1392-6. http://www.ncbi.nlm.nih.gov/pubmed/7658545 19. Allepuz Losa CA, Sans Velez JI, Gil Sanz MJ, Mas LP, Rioja Sanz LA. Seminal vesicle biopsy in prostate cancer staging. J Urol 1995;154(4):1407-11. http://www.ncbi.nlm.nih.gov/pubmed/7544842

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Guillonneau B, Debras B, Veillon B, Bougaran J, Chambon E, Vallancien G. Indications for preoperative seminal vesicle biopsies in staging of clinically localized prostatic cancer. Eur Urol 1997;32(2):160-5. http://www.ncbi.nlm.nih.gov/pubmed/9286646 21. Freedland SJ, Csathy GS, Dorey F, Aronson WJ. Percent prostate needle biopsy tissue with cancer is more predictive of biochemical failure or adverse pathology after radical prostatectomy than prostate specific antigen or Gleason score. J Urol 2002;167(2 PT 1):516-20. http://www.ncbi.nlm.nih.gov/pubmed/11792909 22. Quinn DI, Henshall SM, Brenner PC, Kooner R, Golovsky D, O’Neill GF, Turner JJ, Delprado W, Grygiel JJ, Sutherland RL, Stricker PD. Prognostic significance of preoperative factors in localized prostate carcinoma treated with radical prostatectomy: importance of percentage of biopsies that contain tumor and the presence of biopsy perineural invasion. Cancer 2003;97(8):1884-93. http://www.ncbi.nlm.nih.gov/pubmed/12673714 23. Elliott SP, Shinohara K, Logan SL, Carroll PR. Sextant prostate biopsies predict side and sextant site of extracapsular extension of prostate cancer. J Urol 2002;168(1):105-9. http://www.ncbi.nlm.nih.gov/pubmed/12050501 24. Narayan P, Gajendran V, Taylor SP, Tewari A, Presti JC Jr, Leidich R, Lo R, Palmer K, Shinohara K, Spaulding JT. The role of transrectal ultrasound-guided biopsy-based staging, preoperative serum prostate-specific antigen, and biopsy Gleason score in prediction of final pathological diagnosis in prostate cancer. Urology 1995;46(2):205-12. http://www.ncbi.nlm.nih.gov/pubmed/7542823 25. Lee N, Newhouse JH, Olsson CA, Benson MC, Petrylak DP, Schiff P, Bagiella E, Malyszko B, Ennis RD. Which patients with newly diagnosed prostate cancer need a computed tomography scan of the abdomen and pelvis? An analysis based on 588 patients. Urology 1999;54(3):490-4. http://www.ncbi.nlm.nih.gov/pubmed/10475360 26. May F, Treumann T, Dettmar P, Hartnung R, Breul J. Limited value of endorectal magnetic resonance imaging and transrectal ultrasonography in the staging of clinically localized prostate cancer. BJU Int 2001;87(1):66-9. http://www.ncbi.nlm.nih.gov/pubmed/11121995 27. Jager GJ, Severens JL, Thornbury JR, de la Rosette JJ, Ruijs SH, Barentsz JO. Prostate cancer staging: should MR imaging be used? A decision analytic approach. Radiology 2000;215(2):445-51. http://www.ncbi.nlm.nih.gov/pubmed/10796923 28. Masterson TA, Touijer K. The role of endorectal coil MRI in preoperative staging and decision-making for the treatment of clinically localized prostate cancer. MAGMA 2008;21(6):371-7. http://www.springerlink.com/content/x762r7un2ml1117k/ 29. Heijmink SW, Fütterer JJ, Hambrock T, Takahashi S, Scheenen TW, Huisman HJ, Hulsbergen-Van de Kaa CA, Knipscheer BC, Kiemeney LA, Witjes JA, Barentsz JO. Prostate cancer: body-array versus endorectal coil MR imaging at 3 T – comparison of image quality, localization, and staging performance. Radiology 2007;244(1):184-95. http://radiology.rsnajnls.org/cgi/content/full/244/1/184 30. Mullerad M, Hricak H, Kuroiwa K, Pucar D, Chen HN, Kattan MW. Comparison of endorectal magnetic resonance imaging, guided prostate biopsy and digital rectal examination in the preoperative anatomical localization of prostate cancer. J Urol 2005;174(6): 2158-63. http://www.ncbi.nlm.nih.gov/pubmed/16280755 31. Sala E, Akin O, Moskowitz CS, Eisenberg HF, Kuroiwa K, Ishill NM, Rajashanker B, Scardino PT, Hricak H. Endorectal MR imaging in the evaluation of seminal vesicle invasion: diagnostic accuracy and multivariate feature analysis. Radiology 2006;238(3):929-37. http://radiology.rsnajnls.org/cgi/content/full/238/3/929 32. Mullerad M, Hricak H, Wang L, Chen HN, Kattan MW, Scardino PT. Prostate cancer: detection of extracapsular extension by genitourinary and general body radiologists at MRI imaging. Radiology 2004;232(1):140-6. http://radiology.rsnajnls.org/cgi/content/full/232/1/140 33. Wang L, Mullerad M, Chen HN, Eberhardt Sc, Kattan MW, Scardino PT. Prostate cancer: incremental value of endorectal MRI findings for prediction of extracapsular extension. Radiology 2004;232(1): 133-9. http://radiology.rsnajnls.org/cgi/content/full/232/1/133 34. Hricak H, Wang L, Wei DC, Coakley FV, Akin O, Reuter VE. The role of preoperative endorectal MRI in the decision regarding whether to preserve or resect neurovascular bundles during radical retropubic prostatectomy. Cancer 2004;100(12):2655-63. http://www.ncbi.nlm.nih.gov/pubmed/15197809

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Sala E, Akin O, Moskowitz CS, Eisemberg HF, Kuroiwa K, Ishill NM. Endorectal MRI in the evaluation of seminal vesicle invasion: diagnostic accuracy and multivariate feature analysis. Radiology 2006;238(3):929-37. http://radiology.rsnajnls.org/cgi/content/full/238/3/929 36. Wang L, Hricak H, Kattan MW, Chen HN, Kuroiwa K, Eisemberg HF. Prediction of seminal vesicle invasion in prostate cancer: incremental value of adding endorectal MRI to the Kattan Nomogram. Radiology 2007;242(1):182-8. http://radiology.rsnajnls.org/cgi/content/full/242/1/182 37. Wang L, Hricak H, Kattan MW, Chen HN, Scardino PT, Kuroiwa K. Prediction of organ confined prostate cancer: incremental value of MRI and MRI sprectroscopic imaging to staging nomograms. Radiology 2006;238(2):597-603. http://radiology.rsnajnls.org/cgi/content/full/238/2/597 38. Fuchsjager M, Shukla-Dave A, Akin O, Barentsz, Hricak H. Prostate cancer imaging. Acta Radiol 2008;49:107-20. http://www.informaworld.com/smpp/1906288645-11741620/content~db=all?content=10.1080/02841 850701545821 39. Scheidler J, Hricak H, Vigneron DB, Yu KK, Sokolov DL, Huang LR, Zaloudek CJ, Nelson SJ, Carroll PR, Kurhanewicz J. Prostate cancer: localization with three-dimensional proton MR spectroscopic imaging – clinicopathologic study. Radiology 1999;213(2):473-80. http://radiology.rsnajnls.org/cgi/content/full/213/2/473 40. Zakian KL, Sircar K, Hricak H, Chen HN, Shukla-Dave A, Eberhardt S. Correlation of proton MR spectroscopic imaging with Gleason score based on step section pathologic analysis after radical prostatectomy. Radiology 2005;234(3):804-14. http://radiology.rsnajnls.org/cgi/content/full/234/3/804 41. Rinnab L, Blumstein NM, Mottaghy FM, Hautmann RE, Küfer R, Hohl K, Reske SN. 11C-choline positron-emission tomography/computed tomography and transrectal ultrasonography for staging localized prostate cancer. BJU Int 2007;99(6):1421-6. http://www.ncbi.nlm.nih.gov/pubmed/17355373 42. Stone NN, Stock RG, Parikh D, Yeghiayan P, Unger P. Perineural invasion and seminal vesicle involvement predict pelvic lymph node metastasis in men with localized carcinoma of the prostate. J Urol 1998;160(5):1722-6. http://www.ncbi.nlm.nih.gov/pubmed/9783940 43. Pisansky TM, Zincke H, Suman VJ, Bostwick DG, Earle JD, Oesterling JE. Correlation of pretherapy prostate cancer characteristics with histologic findings from pelvic lymphadenectomy specimens. Int J Radiat Oncol Biol Phys 1996;34(1):33-9. http://www.ncbi.nlm.nih.gov/pubmed/12118563 44. Cagiannos I, Karakiewicz P, Eastham JA, Ohori M, Rabbani F, Gerigk C, Reuter V, Graefen M, Hammerer PG, Erbersdobler A, Huland H, Kupelian P, Klein E, Quinn DI, Henshall SM, Grygiel JJ, Sutherland RL, Stricker PD, Morash CG, Scardino PT, Kattan MW. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol 2003;170(5):1798-803. 45. Haese A, Epstein JI, Huland H, Partin AW. Validation of a biopsy-based pathologic algorithm for predicting lymph node metastases in patients with clinically localized prostate carcinoma. Cancer 2002;95(5):1016-21. http://www.ncbi.nlm.nih.gov/pubmed/12209685 46. Hoivels AM, Heesakkers RAM, Adang EM., Jager GJ, Strum S, Hoogeveen YL, Severens JL, Barentsz JO. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. Clinical Radiology 2008;63:387-95. http://linkinghub.elsevier.com/retrieve/pii/S0009-9260(07)00334-0 47. GJ Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Ruijs SJH. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR-imaging with a three-dimensional T1-weighted magnetizationprepared-rapid gradient-echo sequence. Am J Roentgenol 1996;167(6):1503-7. http://www.ncbi.nlm.nih.gov/pubmed/8956585 48. Harisinghani MG, Barentsz J, Hahn PF, Deserno WM, Tabatabaei S, van de Kaa CH, de la Rosette J, Weissleder R. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003;348(25):2491-9. http://www.ncbi.nlm.nih.gov/pubmed/12815134

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49. Heesakkers RA, Fütterer JJ, Hövels AM, van den Bosch HC, Scheenen TW, Hoogeveen YL, Barentsz JO. Prostate cancer evaluated with ferumoxtran-10-enhanced T2*-weighted MR imaging at 1.5 and 3.0 T: early experience. Radiology 2006;239(2):481-7. http://www.ncbi.nlm.nih.gov/pubmed/16641354 50. Bellin MF, Roy C, Kinkel K, Thoumas D, Zaim S, Vanel D, Tuchmann C, Richard F, Jacqmin D, Delcourt A, Challier E, Lebret T, Cluzel P. Lymph node metastases: safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles – initial clinical experience. Radiology 1998;207(3):799-808. http://www.ncbi.nlm.nih.gov/pubmed/9609907 51. Wolf JS Jr, Cher M, Dall’era M, Presti JC Jr, Hricak H, Carroll PR. The use and accuracy of crosssectional imaging and fine needle aspiration cytology for detection of pelvic lymph node metastases before radical prostatectomy. J Urol 1995;153(3Pt2):993-9. http://www.ncbi.nlm.nih.gov/pubmed/7853590 52. Salminen E, Hogg A, Binns D, Frydenberg M, Hicks R. Investigations with FDG-PET scanning in prostate cancer show limited value for clinical practice. Acta Oncol 2002;41(5):425-9. http://www.ncbi.nlm.nih.gov/pubmed/12442917 53. Husarik DB, Miralbell R, Dubs M, John H, Giger OT, Gelet A, Cservenyàk T, Hany TF. Evaluation of [(18)F]-choline PET/CT for staging and restaging of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35(2):253-63. http://www.ncbi.nlm.nih.gov/pubmed/17926036 54. Schiavina R, Scattoni V, Castellucci P, Picchio M, Corti B, Briganti A, Franceschelli A, Sanguedolce F, Bertaccini A, Farsad M, Giovacchini G, Fanti S, Grigioni WF, Fazio F, Montorsi F, Rigatti P, Martorana G. (11)C-choline positron emission tomography/computerized tomography for preoperative lymphnode staging in intermediate-risk and high-risk prostate cancer: comparison with clinical staging nomograms. Eur Urol 2008;54(2):392-401. http://www.ncbi.nlm.nih.gov/pubmed/18456393 55. Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002;167(4):1681-6. http://www.ncbi.nlm.nih.gov/pubmed/11912387 56. Bader P, Burkhard FC, Markwalder R, Studer UE. Is a limited lymph node dissection an adequate staging procedure for prostate cancer? J Urol 2002;168(2):514-18, discussion 518. http://www.ncbi.nlm.nih.gov/pubmed/12131300 57. Weckermann D, Dorn R, Holl G, Wagner T, Harzmann R. Limitations of radioguided surgery in highrisk prostate cancer. Eur Urol 2007;51(6):1549-56. http://www.ncbi.nlm.nih.gov/pubmed/16996201 58. Weckermann D, Dorn R, Trefz M, Wagner T, Wawroschek F, Harzmann R. Sentinel lymph node dissection for prostate cancer: experience with more than 1,000 patients. J Urol 2007;177(3): 916-20. http://www.ncbi.nlm.nih.gov/pubmed/17296375 59. Whitmore WF Jr. Natural history and staging of prostate cancer. Urol Clin North Am 1984;11(2): 205-20. http://www.ncbi.nlm.nih.gov/pubmed/6375067 60. Wolff JM, Ittel TH, Borchers H, Boekels O, Jakse G. Metastatic workup of patients with prostate cancer employing alkaline phosphatase and skeletal alkaline phosphatase. Anticancer Res 1999;19(4A):2653-5. http://www.ncbi.nlm.nih.gov/pubmed/10470213 61. Lorente JA, Morote J, Raventos C, Encabo G, Valenzuela H. Clinical efficacy of bone alkaline phosphatase and prostate specific antigen in the diagnosis of bone metastasis in prostate cancer. J Urol 1996;155(4):1348-51. http://www.ncbi.nlm.nih.gov/pubmed/8632571 62. Lorente JA, Valenzuela H, Morote J, Gelabert A. Serum bone alkaline phosphatase levels enhance the clinical utility of prostate specific antigen in the staging of newly diagnosed prostate cancer patients. Eur J Nucl Med 1999;26(6):625-32. http://www.ncbi.nlm.nih.gov/pubmed/10369948 63. McGregor B, Tulloch AG, Quinlan MF, Lovegrove F. The role of bone scanning in the assessment of prostatic carcinoma. Br J Urol 1978;50(3):178-81. http://www.ncbi.nlm.nih.gov/pubmed/753456 64. O’Donoghue EP, Constable AR, Sherwood T, Stevenson JJ, Chisholm GD. Bone scanning and plasma phosphatases in carcinoma of the prostate. Br J Urol 1978;50(3):172-7. http://www.ncbi.nlm.nih.gov/pubmed/753455

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Buell U, Kleinhans E, Zorn-Bopp E, Reuschel W, Muenzing W, Moser EA, Seiderer M. A comparison of bone imaging with Tc-99m DPD and Tc-99m MDP: concise communication. J Nucl Med 1982;23(3):214-17. http://www.ncbi.nlm.nih.gov/pubmed/6460854 Soloway MS, Hardemann SW, Hickey D, Raymond J, Todd B, Soloway S, Moinuddin M. Stratification of patients with metastatic prostate cancer based on the extent of disease on initial bone scan. Cancer 1988;61(1):195-202. http://www.ncbi.nlm.nih.gov/pubmed/3334948 Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, singleand multifield-of-view SPECT, 18F-fluoride PET/CT. J Nucl Med 2006;47(2):287-97. http://www.ncbi.nlm.nih.gov/pubmed/16455635 Beheshti M, Vali R, Langsteger W. [18F]Fluorocholine PET/CT in the assessment of bone metastases in prostate cancer. Eur J Nucl Med Mol Imaging 2007;34(8):1316-7. http://www.ncbi.nlm.nih.gov/pubmed/17476505 Bouchelouche K, Oehr P. Recent developments in urologic oncology: positron emission tomography molecular imaging. Curr Opin Oncol 2008;20(3):321-6. http://www.ncbi.nlm.nih.gov/pubmed/18391633 Rana A, Karamanis K, Lucas MG, Chisholm GD. Identification of metastatic disease by T category, Gleason score and serum PSA level in patients with carcinoma of the prostate. Br J Urol 1992;69(3):277-81. http://www.ncbi.nlm.nih.gov/pubmed/1373666 Chybowski FM, Keller JJ, Bergstrahl EJ, Oesterling JE. Predicting radionuclide bone scan findings in patients with newly diagnosed, untreated prostate cancer: prostate specific antigen is superior to all other parameters. J Urol 1991;145(2):313-8. http://www.ncbi.nlm.nih.gov/pubmed/1703240 Kemp PM, Maguire GA, Bird NJ. Which patients with prostatic carcinoma require a staging bone scan? Br J Urol 1997;79(4):611-4. http://www.ncbi.nlm.nih.gov/pubmed/9126094 Lee N, Fawaaz R, Olsson CA, Benson MC, Petrylak DP, Schiff PB, Bagiella E, Singh A, Ennis RD. Which patients with newly diagnosed prostate cancer need a radionuclide bone scan? An analysis based on 631 patients. Int J Radiat Oncol Biol Phys 2000;48(5):1443-6. http://www.ncbi.nlm.nih.gov/pubmed/11121646 O’Donoghue JM, Rogers E, Grimes H, McCarthy P, Corcoran M, Bredin H, Given HF. A reappraisal of serial isotope bone scans in prostate cancer. Br J Radiol 1993;66(788):672-6. http://www.ncbi.nlm.nih.gov/pubmed/7536607 Wolff JM, Bares R, Jung PK, Buell U, Jakse G. Prostate-specific antigen as a marker of bone metastasis in patients with prostate cancer. Urol Int 1996;56(3):169-73. http://www.ncbi.nlm.nih.gov/pubmed/8860738 Wolff JM, Zimny M, Borchers H, Wildberger J, Buell U, Jakse G. Is prostate-specific antigen a reliable marker of bone metastasis in patients with newly diagnosed cancer of the prostate? Eur Urol 1998;33(4):376-81. http://www.ncbi.nlm.nih.gov/pubmed/9612680 Bruwer G, Heyns CF, Allen FJ. Influence of local tumour stage and grade on reliability of serum prostate-specific antigen in predicting skeletal metastases in patients with adenocarcinoma of the prostate. Eur Urol 1999;35(3):223-7. http://www.ncbi.nlm.nih.gov/pubmed/10072624

8. TREATMENT: DEFERRED TREATMENT (WATCHFUL WAITING/ACTIVE MONITORING) 8.1

Introduction

8.1.1 Definition There is a great difference between the incidence of and mortality from prostate cancer (PCa): in the USA in 2007, there were 218,900 new cases with only 27,050 deaths (1).

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Several autoptic studies of people dying from different causes have shown that while 60-70% of older men have histological PCa (2, 3), a large proportion of these tumours will not progress. PCa is diagnosed in only 15-20% of men during their lifetime, with a 3% lifetime risk of death (4). The incidence of small, localised, well-differentiated PCa is increasing, mainly as a result of prostate-specific antigen (PSA) screening and ‘multi-core’ schemes of prostate biopsy. These data suggest that a lot of the men with localised PCa would not, in fact, benefit from a definitive treatment. With the aim of reducing the risk of overtreatment in this subgroup of patients, two conservative management strategies have been proposed: • Watchful waiting (WW)  Also known as ‘deferred treatment’ or ‘symptom-guided treatment’, this term was coined in the pre-PSA screening era (before 1990) and referred to the conservative management of PCa until the development of local or systemic progression, at which point the patient would be treated palliatively (transurethral resection of the prostate [TURP] or other procedures for urinary tract obstruction, and hormonal therapy or radiotherapy for the palliation of metastatic lesions). • Active surveillance (AS)  Also known as ‘active monitoring’, this is the new term for the conservative management of PCa. Introduced in the past decade, it includes an active decision not to treat the patient immediately; to follow him with close surveillance and treat at pre-defined thresholds that classify progression (short PSA doubling time and deteriorating histopathological factors on repeat biopsy). In these cases, the treatment options are intended to be curative.

8.2

Deferred treatment of localised PCa (stage T1-T2, Nx-N0, M0)

8.2.1 Watchful waiting (WW) The rationale behind WW is the observation that PCa often progresses slowly, and is diagnosed in older men in whom there is a high incidence of co-morbidity and related high competitive mortality (5). WW can be considered as an option for treating patients with localised PCa in whom life expectancy is limited, or older patients with less aggressive cancers. There have been several attempts to summarise the key papers dealing with deferred treatment in patients with presumed localised PCa (6-10). Most of them present the same results as they analyse roughly the same series, but with a somewhat different methodology. The outcome studies on WW usually include patients whose PSA readings are not always available, and in whom the lesions are predominantly palpable, which would currently be defined as intermediate-risk tumours as described by D’Amico et al. (11). These studies include patients with a follow-up of up to 25 years, having as endpoints overall survival (OS) and disease-specific survival (DSS). Several WW series show a very consistent DSS ratio at 10 years, ranging from 82-87% (6, 12-17). In three studies with data beyond 15 years, the DSS was 80%, 79% and 58%, respectively (14, 16, 17). Two of them reported a 20-year DSS of 57% and 32%, respectively (14, 16). Chodak and co-workers reported a pooled analysis of the original data from 828 patients treated by WW (6). The paper is based on patients from six non-randomised studies (10, 18-23). The results describe cancerspecific survival (CSS) and metastasis-free survival after five and 10 years of follow-up (6) (level of evidence: 2b). Tumour grade is clearly significant, with very low survival rates for grade 3 tumours. Although the 10-year CSS rate is equally good (87%) for grade 1 and 2 tumours, the latter have a significantly higher progression rate, with 42% of these patients developing metastases (Table 8). Table 8: O  utcome of deferred treatment in localised PCa in relation to tumour grade (6): percentage of patients (95% confidence interval) surviving at five and 10 years. Grade Disease-specific survival Grade 1 Grade 2 Grade 3 Metastasis-free survival Grade 1 Grade 2 Grade 3

34

5 years (%)

10 years (%)

98 (96-99) 97 (93-98) 67 (51-79)

87 (81-91) 87 (80-92) 34 (19-50)

93 (90-95) 84 (79-89) 51 (36-64)

81 (75-86) 58 (49-66) 26 (13-41)

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The importance of tumour grade on survival after conservative management of PCa was also underlined in a large register study utilising the Surveillance, Epidemiology and End Results (SEER) database of the National Cancer Institute in the USA (12) (level of evidence: 3). Patients with grade 1, 2 and 3 tumours had 10-year CSS rates of 92%, 76% and 43%, respectively, correlating with the data from the pooled analysis. The paper by Chodak and co-workers also specifically described the outcome for stage T1a patients (6), with cancer-specific 10-year survival rates of 96% and 94%, respectively, for grade 1 and 2 tumours. The metastasis-free survival rate was 92% for patients with grade 1 tumours, but 78% for those with grade 2 tumours, indicating a higher risk of progression in individuals with moderately differentiated tumours. This difference in progression rate correlates with other studies on stage T1a disease (24, 25). In order to stage patients accurately and not overlook the presence of more extensive and/or more poorly differentiated tumours, repeat examinations with PSA measurement, transrectal ultrasound (TRUS) and needle biopsy of the prostate remnant have been advocated, especially in younger males with a long life expectancy (26). The impact of grade on the risk of tumour progression and ultimately death from PCa is also described in a paper by Albertsen and co-workers (27). They re-evaluated all biopsy specimens using the more widely accepted Gleason score, and showed that the risk of PCa death was very high in Gleason 7-10 tumours, intermediate in Gleason 6 tumours, but low in Gleason 2-5 cancers (Table 9) (28, 29) (level of evidence: 3). This paper also showed that Gleason 6-10 tumours carry a continuously increasing risk of ending the patient’s life for up to 15 years of follow-up after conservative management. The CSS curves for this group of patients have been published in a recent discussion article on different methods of assessing outcome in treatment for localised PCa (28). Table 9: The 15-year risk of dying from PCa in relation to Gleason score at diagnosis in patients with localised disease aged 55-74 years (27, 28). Gleason score Risk of cancer death* (%) Cancer-specific mortality† (%) 2-4 4-7 8 5 6-11 14 6 18-30 44 7 42-70 76 8-10 60-87 93 * The figures on the risk of cancer death differ for different age groups and represent the true risk in the studied population (taking actual competing mortality from other causes into consideration). † The cancer-specific mortality compensates for differences in competing mortality and indicates the outcome if the patient actually lived for 15 years. Three randomised clinical trials have reported long-term follow-up of patients randomised to WW or radical prostatectomy (RP): the first was in the pre-PSA screening era (29); the second was at the beginning of PSA screening (30); and the third was a recent study, the results from which are not yet mature (1). The Veterans Administration Cooperative Urological Research Group between 1967 and 1975, randomised 142 patients affected by clinical localised PCa. The study was underpowered to detected treatment differences (31). Between 1989 and 1999, the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) randomised 695 patients with clinical stage T1-T2 to WW (348) or RP (347) (Table 10) (30). This study began after PSA screening was introduced into clinical practice, but only 5% of men were diagnosed by screening. After a median followup of 10.8 years, this study showed a significant decrease in cancer-specific mortality, overall mortality, metastatic risk progression and local progression in patients treated with RP vs WW (level of evidence: 1b).

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Table 10: O  utcome of Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) at 10 years of follow-up (median of 8.2 years) (30). Disease-specific mortality Overall mortality Metastatic progression Local progression

RP (n 347) % (n) 9.6 (30) 27 (83) 15.2 (50) 19.2 (64)

WW (n 348) % (n) 14.9 (50) 32 (106) 35.4 (79) 44.3 (149)

Relative risk (95% CI) 0.56 (0.36-0.88) 0.74 (0.56-0.86) 0.60 (0.42-0.44) 0.33 (0.25-0.44)

p value 0.01 0.04 0.004 < 0.001

The results of three more years of follow-up were published recently. At 12 years’ follow-up, the group of patients treated with RP presented a favourably significant difference of 5.4% in PCa-specific mortality and 6.7% in non-metastatic progression (Table 11) (32) (level of evidence: 1b). Table 11: Outcome of Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) at 12 years of follow-up (median of 10.8 years) (32). Disease-specific mortality Metastatic progression

RP (n 347) % (n) 12.5 (43) 19.3

WW (n 348) % (n) 17.9 (68) 26

Relative risk (95% CI) 0.65 (0.2-11.1) 0.65 (0.47-0.88)

p value 0.03 0.006

The Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT) (1) is an ongoing controlled multicentre randomised clinical trial comparing RP with WW in patients with clinical stage T1-T2 disease. Between 1994 and 2002, 731 patients with a median age of 67 years were enrolled. The median PSA was 7.8 ng/mL (mean 10.2 ng/mL). Three-quarters of the men had clinical stage T1c disease. Using previously developed tumour risk categorisations incorporating PSA levels, Gleason histological grade and tumour stage, approximately 43% had low-risk, 36% had medium-risk and 20% had high-risk PCa. Follow-up is planned for 15 years, and the primary endpoint is the overall mortality. PIVOT enrolees are more representative of men being diagnosed and treated in contemporary clinical practice than were those enrolled in SPCG-4. In summary: • Clinical stage T1c currently represents 40-50% of new cases of PCa (33). The incidence of small, localised, well-differentiated PCa is increasing, mainly as a result of PSA screening and ‘multi-core’ schemes of prostate biopsy. • The SPCG-4 study demonstrated significant advantages for RP over WW, but only 5% of those studied were PSA-screened patients. • During the past 20 years, there has apparently been a shift towards higher Gleason scoring levels (34), even in cases evaluating microscopic foci of PCa. Some tumours previously given a Gleason score of 6 (3 + 3), might be scored as 7 (3 + 4) or more today. • The lead time in PSA screening is about 10 years (35, 36). It is therefore possible that the cancer mortality from untreated, non-screen-detected PCa in patients with contemporary Gleason scores of 6 might be as low as 10% at 20-year follow-up (37). It would seem that many small, localised, well-differentiated PCas will not progress, and radical therapy may lead to substantial overtreatment with consequent problems in terms of quality of life and socio-economic costs. 8.2.2 Active surveillance AS was conceived with the aim of reducing the ratio of overtreatment in patients with clinically confined lowrisk PCa, without giving up radical treatment, as happened with the WW strategy. Only data from non-mature randomised clinical trials of AS with follow-up < 10 years are currently available. A multicentre clinical trial of AS versus immediate treatment was opened in the USA in 2006. Its results are expected in 2025. Choo, Klotz and co-workers were the first to report on a prospective AS protocol (38, 39). They enrolled 331 patients with clinical stage T1c or T2a, PSA ≤ 10 ng/mL and a Gleason score ≤ 6 (PSA ≤ 15 and Gleason score ≤ 7 [3 + 4] in patients above the age of 70 years). At a median follow-up of eight years, the overall survival was

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85%, DSS and metastasis-free survival were 99%. The median value of the PSA doubling time was 7 years; in 42% of patients it was > 10 years, and in 22% < 3 years. Thirty-three per cent of the patients subsequently underwent a radical treatment: 20% for a PSA doubling time < 3 years; 5% for Gleason score progression on repeat biopsies; and 10% because of patient preference. Soloway et al., evaluating 175 patients with a median follow-up of four years, reported no PCa deaths or metastatic disease and a ratio of only 8% having delayed treatment (40). Carter et al., looking at 407 patients with a median follow-up of 3.4 years, reported no PCa deaths (41). All these studies confirm that, in well selected patients with low-risk disease, there is a very low rate of progression and cancer-specific death, and only a few patients require delayed radical intervention. However, another five to seven more years of follow-up will be necessary in order to obtain definitive results. Different series have identified several eligibility criteria for enrollers: • clinically confined PCa (T1-T2) • Gleason score ≤ 7 • PSA < 15-20 ng/mL (5). Moreover, different criteria were applied to define cancer progression (5), although all groups used: • a PSA doubling time with a cut off ranging between ≤ 2 and ≤ 4years • Gleason score progression to ≥ 7 at re-biopsy, at intervals ranging from one to four years. These indicators are poorly validated and, currently, it is impossible to make evidence-based recommendations on when to intervene in patients with a long life expectancy. Data that include PSA and PSA changes over time are relatively sparse in the literature. In a recent review article, it was pointed out that patients with a PSA of < 3 ng/mL had no mortality from PCa within the first 10 years, and that PSA changes over time were relatively unreliable in determining the risk for tumour progression (42). The data above indicate a high risk of tumour progression after conservative treatment for some patients with apparently localised PCa. This has been supported by the results of other studies in which patients with a life expectancy exceeding 10 years have been shown to have a higher mortality rate from PCa when left without curative treatment (43-45). Long-term follow-up of the Johansson series shows the same outcome: there is a higher risk of dying from PCa in patients surviving more than 15 years with well and moderately differentiated tumours at diagnosis (46) (level of evidence: 3). For patients who choose deferred treatment, the risk of delaying hormone therapy until disease progression has occurred appears to be modest, although shorter CSS times have been reported after deferred therapy compared with immediate hormone therapy in presumed localised PCa (not utilising PSA for staging) after 15 years of follow-up (47). In contradiction of Lundgren et al. (47), the report of the Casodex Early Prostate Cancer Trialists’ Group programme showed higher mortality in a group of men with localised PCa treated with bicalutamide 150 mg than in those who received placebo (48). In summary, it seems that hormonal therapy should be withheld until there is definitive proof of disease activity (progression), but it is open to speculation whether there might be some benefit in delivering it before the patient develops metastatic disease (see below).

8.3

Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0)

The literature reporting on deferred treatment for locally advanced PCa is sparse. There are no randomised studies that compare more aggressive treatments, such as radiotherapy or surgery, with or without hormones. Most patients whose disease progresses after deferred treatment of locally advanced PCa will be candidates for hormone therapy. There are reports from non-randomised studies showing that hormone treatment may safely be delayed until metastatic progression occurs, as no survival advantage was noted between patients treated with immediate orchiectomy compared with delayed treatment (49, 50). In a recent prospective randomised clinical phase III trial (EORTC 30981), 985 patients with T0-4 N0-2 M0 prostate cancer were randomly assigned to immediate androgen-deprivation therapy (ADT) or received ADT

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37

only on symptomatic disease progression or occurrence of serious complications (51, 52). After a median follow-up of 7.8 years, the overall survival hazard ratio was 1.25 (95% CI, 1.05-1.48; non-inferiority p > 0.1) favouring immediate treatment, seemingly due to fewer deaths of non-prostatic cancer causes (p = 0.06). The time from randomisation to progression of hormone refractory disease did not differ significantly, nor did prostate cancer-specific survival. The median time to the start of deferred treatment after study entry was seven years. In this group, 126 patients (25.6%) died without ever needing treatment (44% of the deaths in this arm). The conclusion drawn from this study is that immediate ADT resulted in a modest but statistically significant increase in overall survival but no significant difference in prostate cancer mortality or symptomfree survival. Furthermore, the authors identified significant risk factors associated with a significantly worse outcome: in both arms, patients with a baseline PSA > 50 ng/mL were at a > 3.5-fold higher risk of dying of PCa than patients with a baseline PSA ≤ to 8 ng/mL. If the baseline PSA was between 8 ng/mL and 50 ng/ mL, the risk of PCa death was approximately 7.5-fold higher in patients with a PSA doubling time < 12 months than in patients with a PSA doubling time > 12 months. The time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness. However, when early and delayed treatments were compared in a large randomised trial carried out by the Medical Research Council (MRC), a survival benefit for immediate hormone therapy was demonstrated (53), comparable with the results of the Lundgren et al. study mentioned above (47) (level of evidence: 1b). Also, a comparison of bicalutamide, 150 mg/day, with placebo showed that progression-free survival was better with early treatment in patients with locally advanced PCa (48) (level of evidence: 1b). Fifty selected asymptomatic patients (mean age 71 years) with highly or moderately differentiated stage T3 M0 PCa were followed up for 169 months (54). The five- and 10-year CSS rates were 90% and 74%, respectively, and the likelihood of being without treatment at five and 10 years was 40% and 30%, respectively. The authors concluded that WW might be a treatment option for selected patients with non-poorly differentiated T3 tumours and a life expectancy of less than 10 years (level of evidence: 3).

8.4

Deferred treatment for metastatic PCa (stage M1)

There are only very sparse data on this subject. The only candidates for such treatment should be asymptomatic patients with a strong wish to avoid treatment-related side-effects (level of evidence: 4). As the median survival time is about two years, the time without any treatment (before symptoms occur) is very short in most cases. The MRC trial highlighted the risk of developing symptoms (pathological fractures, spinal cord compression), and even death from PCa, without receiving the possible benefit from hormone treatment (53, 55) (level of evidence:1b). If a deferred treatment policy is chosen for a patient with advanced PCa, close follow-up must be possible.

8.5 Summary of deferred treatment 8.5.1 Indications In presumed localised PCa (Nx-N0, M0): • Stage T1a: well and moderately differentiated tumours. In younger patients with a life expectancy of > 10 years, re-evaluation with PSA, TRUS and biopsies of the prostatic remnant is recommended (level of evidence: 2a). • Stage T1b-T2b: well and moderately differentiated tumours. In asymptomatic patients with a life expectancy of < 10 years (level of evidence: 2a). 8.5.2 Options In presumed localised PCa (Nx-N0, M0): • stage T1b-T2b patients who are well informed and have well differentiated (or Gleason 2-4) PCa and a life expectancy of 10-15 years • all patients not willing to accept side-effects of active treatment • well informed, asymptomatic patients with high PSA levels for whom cure is unlikely (level of evidence: 3). In locally advanced disease (stage T3-T4): • asymptomatic patients with well or moderately differentiated cancer, PCa and a short life expectancy (level of evidence: 3) • PSA < 50 ng/mL and PSA doubling time > 12 months (level of evidence: 1).

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In metastatic disease (M1): • a very rare patient without any symptoms and the possibility of close follow-up (level of evidence: 4).

8.6

REFERENCES

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Wilt TJ, Brawer MK, Barry MJ, Jones KM, Kwon Y, Gingrich JR, Aronson WJ, Nsouli I, Iyer P, Cartagena R, Snider G, Roehrborn C, Fox S. The Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer. Contemp Clin Trials 2009;30(1):81-7. http://www.ncbi.nlm.nih.gov/pubmed/18783735 Rullis I, Schaeffer JA, Lilien OM. Incidence of prostatic carcinoma in the elderly. Urology 1975;6(3):295-7. http://www.ncbi.nlm.nih.gov/pubmed/1172317 Sakr, WA, Grignon, DJ, Crissman JD, Heilbrun LK, Cassin BJ, Pontes JJ, Haas GP. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases. In Vivo 1994;8(3):439-43. http://www.ncbi.nlm.nih.gov/pubmed/7803731 Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer statistics, 2006. CA Cancer J Clin 2006;56(2):106-30. http://caonline.amcancersoc.org/cgi/content/full/56/2/106 Adolfsson J .Watchful waiting and active surveillance: the current position. BJU Int 2008;102(1):10-4. http://www.ncbi.nlm.nih.gov/pubmed/18422774 Chodak GW, Thisted RA, Gerber GS, Johansson JE, Adolfsson J, Jones GW, Chisholm GD, Moskovitz B, Livne PM, Warner J. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330(4):242-8. http://www.ncbi.nlm.nih.gov/pubmed/8272085 Middleton RG, Thompson IM, Austenfeld MS, Cooner WH, Correa RJ, Gibbons RP, Miller HC, Oesterling JE, Resnick MI, Smalley SR, Wasson JH. Prostate Cancer Clinical Guidelines Panel Summary report on the management of clinically localized prostate cancer. The American Urological Association. J Urol 1995;154(6):2144-8. http://www.ncbi.nlm.nih.gov/pubmed/7500479 Thompson IM. Observation alone in the management of localized prostate cancer: the natural history of untreated disease. Urology 1994;43(2Suppl.):41-6. http://www.ncbi.nlm.nih.gov/pubmed/8272085 Schellhammer PF. Contemporary expectant therapy series: a viewpoint. Urology Symposium 1994;44(6A):47-52. Adolfsson J, Steineck G, Whitmore WF Jr. Recent results of management of palpable clinically localized prostate cancer. Cancer 1993;72(2):310-22. http://4www.ncbi.nlm.nih.gov/pubmed/8319164 D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280(11):969-74. http://jama.ama-assn.org/cgi/content/full/280/11/969 Lu-Yao GL, Yao SL. Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 1997;349(9056):906-10. http://www.ncbi.nlm.nih.gov/pubmed/9093251 Sandblom G, Dufmats M, Varenhorst E. Long-term survival in a Swedish population-based cohort of men with prostate cancer. Urology 2000;56(3):442-7. http://www.ncbi.nlm.nih.gov/pubmed/10962312 Johansson JE, Adami HO, Andersson SO, Bergström R, Krusemo UB, Kraaz W. Natural history of localized prostatic cancer. A population-based study in 223 untreated patients. Lancet 1989;1(8642):799-803. http://www.ncbi.nlm.nih.gov/pubmed/2564901 Bill-Axelson A, Holmberg L, Ruutu M, Häggman M, Andersson SO, Bratell S, Spångberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlén BJ, Johansson JE; for the Scandinavian Prostate Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352(19):1977-84. http://content.nejm.org/cgi/content/full/352/19/1977

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Adolfsson J, Tribukait B, Levitt S. The 20-yr outcome in patients with well- or moderately differentiated clinically localized prostate cancer diagnosed in the pre-PSA era: the prognostic value of tumour ploidy and comorbidity. Eur Urol 2007 Oct;52(4):1028-35. http://www.ncbi.nlm.nih.gov/pubmed/17467883 17. Jonsson E, Sigbjarnarson HP, Tomasson J, Benediktsdottir KR, Tryggvadottir L, Hrafnkelsson J, Olafsdottir EJ, Tulinius H, Jonasson JG. Adenocarcinoma of the prostate in Iceland: a populationbased study of stage, Gleason grade, treatment and long-term survival in males diagnosed between 1983 and 1987. Scand J Urol Nephrol 2006;40(4):265-71. http://www.ncbi.nlm.nih.gov/pubmed/16916765 18. Moskovitz B, Nitecki A, Richter Levin D. Cancer of the prostate: is there a need for aggressive treatment? Urol Int 1987;42(1):49-52. http://www.ncbi.nlm.nih.gov/pubmed/3590404 19. Goodman CM, Busuttil A, Chisholm GD. Age, and size and grade of tumour predict prognosis in incidentally diagnosed carcinoma of the prostate. Br J Urol 1988;62(6):576-80. http://www.ncbi.nlm.nih.gov/pubmed/3219513 20. Jones GW. Prospective, conservative management of localized prostate cancer. Cancer 1992;70(1Suppl.):307-10. http://www.ncbi.nlm.nih.gov/pubmed/1600492 21. Whitmore WF Jr, Warner JA, Thompson IM Jr. Expectant management of localized prostatic cancer. Cancer 1991;67(4):1091-6. http://www.ncbi.nlm.nih.gov/pubmed/1991257 22. Adolfsson J, Carstensen J, Löwhagen T. Deferred treatment in clinically localised prostatic carcinoma. Br J Urol 1992;69(2):183-7. http://www.ncbi.nlm.nih.gov/pubmed/1537031 23. Johansson JE, Adami HO, Andersson SO, Bergström R, Holmberg L, Krusemo UB. High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 1992;267(16):2191-6. http://www.ncbi.nlm.nih.gov/pubmed/1556796 24. Lowe BA. Management of stage T1a Prostate cancer. Semin Urol Oncol 1996;14(3):178-82. http://www.ncbi.nlm.nih.gov/pubmed/8865481 25. Loughlin KR, Renshaw AA, Kumar S. Expectant management of stage A-1 (T1a) prostate cancer utilizing serum PSA levels: a preliminary report. J Surg Oncol 1999;70(1):49-53. http://www.ncbi.nlm.nih.gov/pubmed/9989421 26. Griebling TL, Williams RD. Staging of incidentally detected prostate cancer: role of repeat resection, prostate-specific antigen, needle biopsy, and imaging. Semin Urol Oncol 1996;14(3):156-64. http://www.ncbi.nlm.nih.gov/pubmed/8865478 27. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280(11): 975-80. http://www.ncbi.nlm.nih.gov/pubmed/9749479 28. Albertsen P, Hanley JA, Murphy-Setzko M. Statistical considerations when assessing outcomes following treatment for prostate cancer. J Urol 1999;162(2):439-44. http://www.ncbi.nlm.nih.gov/pubmed/10411053 29. Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K; Scandinavian Prostatic Cancer Group. Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J Urol 2004 Nov;172(5Pt1):1871-6. http://www.ncbi.nlm.nih.gov/pubmed/15540741 30. Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Haggman M, Andersson SO, Spangberg A, Busch C, Nordling S, Palmgren J, Adami HO, Johansson JE, Norlen BJ; Scandinavian Prostatic Cancer Group Study Number 4. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med. 2002;347(11):781-9. http://www.ncbi.nlm.nih.gov/pubmed/12226148 31. Iversen P, Madsen PO, Corle DK. Radical prostatectomy versus expectant treatment for early carcinoma of the prostate. Twenty-three year follow-up of a prospective randomized study. Scand J Urol Nephrol Suppl 1995;172:65-72. http://www.ncbi.nlm.nih.gov/pubmed/8578259

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32.

Bill-Axelson A, Holmberg L, Filén F, Ruutu M, Garmo H, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Adami HO, Johansson JE; Scandinavian prostate cancer Group Study Number 4. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst 2008;100(16):1144-54. http://jnci.oxfordjournals.org/cgi/content/full/100/16/1144 33. Klotz L. Active surveillance for prostate cancer: trials and tribulations. World J Urol 2008;26(5):437-42. http://www.ncbi.nlm.nih.gov/pubmed/18813934 34. Albertsen PC, Hanley JA, Barrows GH, Penson DF, Kowalczyk PD, Sanders MM, Fine J. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005;97(17):1248-53. http://www.ncbi.nlm.nih.gov/pubmed/16145045 35. Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis RA, Schröder FH, de Koning HJ. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for prostate cancer. J Natl Cancer Inst 2003;95(12):868-78. http://www.ncbi.nlm.nih.gov/pubmed/12813170 36. Törnblom M, Eriksson H, Franzén S, Gustafsson O, Lilja H, Norming U, Hugosson J. Lead time associated with screening for prostate cancer. Int J Cancer 2004;108(1):122-9. http://www.ncbi.nlm.nih.gov/pubmed/14618626 37. Klotz L. Active surveillance for favorable-risk prostate cancer: who, how and why? Nat Clin Pract Oncol 2007;4(12):692-8. http://www.nature.com/ncponc/journal/v4/n12/full/ncponc0966.html 38. Choo R, Klotz L, Danjoux C, Morton GC, DeBoer G, Szumacher E, Fleshner N, Bunting P, Hruby G. Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. J Urol 2002;167(4):1664-9. http://www.ncbi.nlm.nih.gov/pubmed/11912384 39. Choo R, DeBoer G, Klotz L, Danjoux C, Morton GC, Rakovitch E, Fleshner N, Bunting P, Kapusta L, Hruby G. PSA doubling time of prostate carcinoma managed with watchful observation alone. Int J Radiat Oncol Biol Phys 2001;50(3):615-20. http://www.ncbi.nlm.nih.gov/pubmed/11395227 40. Soloway MS, Soloway CT, Williams S, Ayyathurai R, Kava B, Manoharan M. Active surveillance; a reasonable management alternative for patients with prostate cancer: the Miami experience. BJU Int 2008;101(2):165-9. http://www.ncbi.nlm.nih.gov/pubmed/17850361 41. Carter HB, Kettermann A, Warlick C, Metter EJ, Landis P, Walsh PC, Epstein JI. Expectant management of prostate cancer with curative intent: an update of the Johns Hopkins experience. J Urol 2007;178(6):2359-64. http://www.ncbi.nlm.nih.gov/pubmed/17936806 42. Schmid HP, Adolfsson J, Aus G. Active monitoring (deferred treatment or watchful waiting) in the treatment of prostate cancer. A review. Eur Urol 2001;40(5):488-94. http://www.ncbi.nlm.nih.gov/pubmed/11752854 43. Aus G, Hugosson J, Norlén L. Long-term survival and mortality in prostate cancer treated with noncurative intent. J Urol 1995;154(2 PT 1):460-5. http://www.ncbi.nlm.nih.gov/pubmed/7541864 44. Hugosson J, Aus G, Bergdahl C, Bergdahl S. Prostate cancer mortality in patients surviving more than 10 years after diagnosis. J Urol 1995;154(6):2115-17. http://www.ncbi.nlm.nih.gov/pubmed/7500471 45. Brasso K, Friis S, Juel K, Jorgensen T, Iversen P. Mortality of patients with clinically localized prostate cancer treated with observation for 10 years or longer: a population based study. J Urol 1999;161(2):524-8. http://www.ncbi.nlm.nih.gov/pubmed/9915440 46. Johansson JE, Andrén O, Andersson SO, Dickman PW, Holmberg L, Magnuson A, Adami HO. Natural history of early, localized prostate cancer. JAMA 2004;291(22):2713-19. http://www.ncbi.nlm.nih.gov/pubmed/15187052 47. Lundgren R, Nordle O, Josefsson K. Immediate estrogen or estramustine phosphate therapy versus deferred endocrine treatment in nonmetastatic prostate cancer: a randomized multicentre study with 15 years of followup. The South Sweden Prostate Cancer Study Group. J Urol 1995;153(5):1580-6. http://www.ncbi.nlm.nih.gov/pubmed/7714978 48. Wirth MP, See WA, McLeod DG, Iversen P, Morris T, Carroll K; Casodex Early Prostate Cancer Trialists’ Group. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at

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49.

50.

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53.

54.

55.

median followup of 5.4 years. J Urol 2004;172(5Pt1):1865-70. http://www.ncbi.nlm.nih.gov/pubmed/15540740 Rana A, Chisholm GD, Khan M, Rashwan HM, Elton RA. Conservative management with symptomatic treatment and delayed hormonal manipulation is justified in men with locally advanced carcinoma of the prostate. Br J Urol 1994;74(5):637-41. http://www.ncbi.nlm.nih.gov/pubmed/7827816 Parker MC, Cook A, Riddle PR, Fryatt I, O’Sullivan J, Shearer RJ. Is delayed treatment justified in carcinoma of the prostate? Br J Urol 1985;57(6):724-8. http://www.ncbi.nlm.nih.gov/pubmed/4084734 Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, Loidl W, Isorna S, Sundaram SK, Debois M, Collette L. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 2006;24(12):1868-76. http://www.ncbi.nlm.nih.gov/pubmed/16622261 Studer UE, Collette L, Whelan P, Albrecht W, Casselman J, de Reijke T, Knönagel H, Loidl W, Isorna S, Sundaram SK, Debois M; EORTC Genitourinary Group. Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891). Eur Urol 2008;53(5):941-9. http://www.ncbi.nlm.nih.gov/pubmed/18191322 The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997;79(2):235-46. [No authors listed.] http://www.ncbi.nlm.nih.gov/pubmed/9052476 Adolfsson J, Steineck G, Hedlund PO. Deferred treatment of locally advanced non-metastatic prostate cancer: a long-term followup. J Urol 1999;161(2):505-8. http://www.ncbi.nlm.nih.gov/pubmed/9915436 Walsh PC. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. J Urol 1997;158(4):1623-4. http://www.ncbi.nlm.nih.gov/pubmed/9302187

9. TREATMENT: RADICAL PROSTATECTOMY 9.1

Introduction

The surgical treatment of prostate cancer (PCa) consists of radical prostatectomy (RP), which is the removal of the entire prostate gland between the urethra and the bladder, with resection of both seminal vesicles. In men with localised PCa and a life expectancy of 10 years or more, the goal of an RP by any approach must be eradication of the disease (1). There is no age threshold for RP. A patient should not be denied this procedure on the grounds of age alone (2). In fact, increasing co-morbidity with age greatly increases the risk of dying from non-PCa related causes (3, 4). Life expectancy estimation is paramount in the counselling of a patient for surgery. Radical prostatectomy was first applied at the beginning of the 20th century by Young (5) using a perineal approach, while Memmelaar and Millin were the first to perform retropubic RP (6). In 1982, Walsh and Donker described the anatomy of the dorsal venous complex and the neurovascular bundles. This resulted in a significant reduction of blood loss and improved continence and potency rates (7). Currently, radical prostatectomy is the only treatment for localised PCa that has shown a cancer-specific survival benefit when compared with conservative management in a prospective, randomised trial (8). Surgical expertise has decreased the complication rates and improved cancer cure (9-12). The retropubic approach is more commonly performed, as it enables simultaneous pelvic lymph node assessment to be carried out, which is an advantage over the perineal approach. It has been suggested that perineal radical prostatectomy might result in positive surgical margins more often than the retropubic approach (13), but this has not been confirmed (14). In the past 5-10 years, several European centres have acquired considerable experience with laparoscopic radical prostatectomy (15-18). More recently, the robotic-assisted laparoscopic RP has been developed. It is

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likely that laparoscopic, robot-assisted and perineal prostatectomies have lower morbidity than the retropubic operation, but randomised studies are as yet unavailable. Functional and short-term oncological outcomes of laparoscopic and robot-assisted RP seem comparable with the open technique in high-volume centres. However, long-term oncological outcomes are still unavailable (19).

9.2

Low-risk, localised PCa: cT1-T2a and Gleason score 2-6 and PSA < 10

9.2.1 Stage T1a-T1b PCa Stage T1a PCa is defined as an incidental histological finding of cancer in 5% or less of resected prostatic tissue (transurethral resection of the prostate [TURP] or open adenomectomy). Stage T1b PCa is defined as > 5% cancer. A recent Swedish register-based study in 23,288 men with incidental PCa detected at TURP or open adenoma enucleation showed a 10-year PCa mortality of 26.6%. No details on prostate-specific antigen (PSA) or Gleason score were provided. Neither were details available on the numbers of cases with cT1a or cT1b PCa (20). Although the risk of disease progression of untreated T1a PCa after five years is only 5%, these cancers can progress in about 50% of cases after 10-13 years (21). Thus, in younger patients with a life-expectancy of 15 years or more, the chance of disease progression is real. An RP may also be offered when the Gleason score is > 6. In contrast, most patients with T1b tumours are expected to show disease progression after five years, and aggressive treatment is often warranted (21). Patients with T1b lesions are offered RP when they have a life expectancy of 10 years or more. It is consequently very important to distinguish between T1a and T1b tumours. Systematic prostate biopsies of the remnant prostate may be useful to detect concomitant peripheral zone cancer, or to ascertain a more correct tumour grade. RP may be very difficult after a thorough TURP, when almost no residual prostate is left behind (22). 9.2.2 Stage T1c and T2a PCa Clinically unapparent tumour identified by needle biopsy because of an elevated PSA (cT1c) has become the most prevalent PCa. In an individual patient, it is difficult to differentiate between clinically insignificant and life-threatening PCa. Most reports, however, stress that cT1c tumours are mostly significant and should not be left untreated since up to 30% of cT1c tumours are locally advanced disease at final histopathology (23). The proportion of insignificant tumours varies between 11% and 16% (24, 25). Increasing the number of biopsies might carry the risk of detecting a higher number of insignificant cancers. However, a recent study has shown that increasing the number of biopsies to 12 did not increase the number of insignificant tumours (26). The major problem is how to recognise those tumours that do not need RP. The biopsy findings and the free PSA ratio are helpful in predicting insignificant disease (27). Partin tables may be very helpful in better selecting patients requiring surgical treatment because of their ability to provide an estimation of the final pathological stage (28). Other authors have suggested the incorporation of biopsy information, such as the number of cores or the percentage of cores invaded (29). When only one or a few cores are invaded and the percentage of invasion in one core is limited, the chance of finding an insignificant PCa is more likely, certainly when the lesion is of low Gleason grade (30). It might be reasonable to follow up some patients whose tumours are most likely to be insignificant. In general, however, RP should be advocated for patients with T1c tumours, bearing in mind that significant tumours will be found in most of these individuals. T2a patients with a 10-year life expectancy should be offered RP since 35-55% of them will have disease progression after five years if not treated. If watchful waiting (WW) is proposed for low-grade T2 cancer, it should be remembered that pre-operative assessment of tumour grade by needle biopsy is often unreliable (31). As a rule of thumb, an extended pelvic lymph node dissection (eLND) is not necessary in low-risk, localised PCa, as the risk for positive lymph nodes does not exceed 7% (32). A limited lymph node dissection should no longer be performed, as this will miss at least half of the nodes involved.

9.3

Intermediate-risk, localised PCa: cT2b-T2c or Gleason score = 7 or PSA 10-20

RP is one of the recommended standard treatments for patients with intermediate-risk PCa and a life

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expectancy of more than 10 years (33). The prognosis is excellent when the tumour is confined to the prostate based on pathological examination (34, 35). A policy of WW has been proposed for some patients with intermediate-risk localised tumours (36). However, when the tumour is palpable or visible on imaging and clinically still confined to the prostate, disease progression can be expected in most long-term survivors. The median time to progression of untreated T2 disease is reported to be 6-10 years. T2b cancer still confined to the prostate but involving more than half of a lobe or both lobes will progress in more than 70% of patients within five years (37). These data have been confirmed by a large randomised trial comparing RP and WW that included mostly T2 PCa patients showing a significant reduction in disease-specific mortality in favour of RP (8). Total surgical removal is an excellent option, and, if performed by an experienced surgeon, the patient’s subsequent quality of life should be satisfactory. Lower rates of positive surgical margins for high-volume surgeons suggest that experience and careful attention to surgical details, adjusted for the characteristics of the cancer being treated, can decrease positive surgical margin rates and improve cancer control with RP (38). As a rule of thumb, an eLND should be performed if the estimated risk for positive lymph nodes exceeds 7% (32). In all other cases, an eLND can be omitted, accepting a low risk of missing positive nodes. A limited lymph node dissection should no longer be performed, as this will miss at least half of the nodes involved. 9.3.1 Oncological results of RP in low-and intermediate risk PCa The results achieved in a number of studies involving RP are shown in Table 12. Table 12: Oncological results of RP in organ-confined disease Reference (no.) Han et al. (2001) (39) Catalona and Smith (1994) (40)

2404 925

Mean follow-up (months) 75* 28

Hull et al. (2002) (41)

1000

53

–

75

601

34

69

47

3170

60

70

52

Trapasso et al. (1994) (42) Zincke et al. (1994) (43) * = 15-year, 66%.

9.4

No. of patients

5-year PSA-free survival (%) 84 78

10-year PSA-free survival (%) 74 65

High-risk localised PCa: cT3a or Gleason score 8-10 or PSA > 20

The widespread use of PSA testing has led to a significant migration of stage and grade of PCa, with > 90% of men in the current era diagnosed with clinically localised disease (44). Despite the trends towards lower risk PCa, 20-35% of patients with newly diagnosed PCa are still classified as high risk, based on either PSA > 20 ng/mL, Gleason score > 8, or an advanced clinical stage (45). There is no consensus regarding the optimal treatment of men with high-risk PCa. 9.4.1 Locally advanced PCa: cT3a T3a cancer is defined as cancer that has perforated the prostate capsule. In the past, locally advanced PCa was seen in about 40% of all clinically diagnosed tumours. This figure is lower today, although its management remains controversial. Surgical treatment of clinical stage T3 PCa has traditionally been discouraged (46), mainly because patients have an increased risk of positive surgical margins and lymph node metastases and/or distant relapse (47, 48). Several randomised studies on radiotherapy with androgen-deprivation therapy (ADT) vs radiotherapy alone showed a clear advantage for the combination treatment. However, no trial has ever shown this approach to be superior to RP (49). Another problem is ‘contamination’ by the additional use of either adjuvant radiotherapy or immediate or delayed hormonal treatment in most of the series reporting the treatment of clinical T3 PCa. In recent years, there has been renewed interest in surgery for locally advanced PCa, and several retrospective case-series have been published. Although still controversial, it is increasingly evident that surgery has a place in treating locally advanced disease (50-55). Overstaging of cT3 PCa is relatively frequent and occurs in 13-27% of cases. These pT2 patients and patients with specimen-confined pT3 disease have similarly good biochemical and clinical PFS (54, 55). In about 33.5-

44

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66% of patients, positive section margins will be present, and 7.9-49% will have positive lymph nodes (56). Thus, 56-78% of patients primarily treated by surgery eventually require adjuvant or salvage radiotherapy or hormonal therapy (54, 55). Nevertheless, excellent 5-, 10- and 15-year overall survival (OS) and cancer-specific survival (CSS) rates have been published (Table 2). These rates surpass radiotherapy-alone series and are no different from radiotherapy combined with adjuvant hormonal therapy series (49). The problem remains the selection of patients before surgery that have neither lymph node involvement nor seminal vesicle invasion. Nomograms, including PSA level, stage and Gleason score, can be useful in predicting the pathological stage of disease (28, 56). In addition, nodal imaging with computed tomography (CT), and seminal vesicle imaging with magnetic resonance imaging (MRI), or directed specific puncture biopsies of the nodes or seminal vesicles can be helpful in recognising those patients unlikely to benefit from a surgical approach (57). RP for clinical T3 cancer requires sufficient surgical expertise to keep the level of morbidity acceptable. Increased overall surgical experience must contribute to a decreased operative morbidity and to better functional results after RP for clinical T3 cancer (54, 58). Table 13: Overall and cancer-specific survival rates for prostate cancer Survival no. of Median and/ OS (%) CSS (%) BPFS (%) CPFS (%) rate patients or mean 5 y 10 y 15 y 5 y 10 y 15 y 5 y 10 y 15 y 5 y 10 y 15 y survival rate Yamada 57 Median, 5.4 y 91.2 - - 45.5 - 81.4 et al. (77.6 at 7.5 y) (PSA > 0.4) (1994) (50) Gerber 242 Mean, 39 m - 85 57 - - 72 32 et al. Median, 26 m (meta free) (1997) (51) Van den 83 Median, 52 m 75 60 - 85 72 - 29 59 31 Ouden (PSA > 0.1) et al. (1998) (52) Isorna 83 Mean, 68.7 m 97.6 94.8 - 100 - 59.8 - Martinez (cT3a only) (PSA > 0.3) de la Riva et al. (2004) (53) Ward 841 Median, 10.3 y 90 76 53 95 90 79 58 43 38 85 73 67 et al. (PSA > 0.4) (2005) (54) Hsu et al. 200 Mean, 70.6 m 95.9 77 - 98.7 91.6 - 59.5 51.1 - 95.9 85.4 (2007) (55) (cT3a only) (PSA > 0.2) BPFS = biochemical progression-free survival; CSS = cancer-specific survival; CPFS = clinical progression-free survival; OS = overall survival; PSA = prostate-specific antigen. 9.4.2 High-grade PCa: Gleason score 8-10 Although most poorly differentiated tumours extend outside the prostate, the incidence of organconfined disease is between 26% and 31%. Patients with high-grade tumours confined to the prostate at histopathological examination still have a good prognosis after RP. Furthermore, one third of patients with a biopsy Gleason score ≥ 8 may in fact have a specimen Gleason score ≤ 7 with better prognostic characteristics. PSA value and the % of positive prostate biopsies may be helpful in selecting men with highgrade prostate cancer most likely to benefit from RP (59). 9.4.3 PCa with PSA > 20 Yossepowitch et al. reported the results of RP as a monotherapy in men with PSA > 20 ng/mL in a cohort with mostly clinically organ-confined tumours, and found a PSA failure rate of 44% and 53% at five and 10 years, respectively (60). D’Amico et al. found that men with PSA levels > 20 ng/mL had a 50% risk of PSA failure at five years after RP (61). Tiguert and co-workers presented the outcome for an identical cohort of patients who had a disease-free survival of 65% at five years after RP (62). More recently, Inman and co-workers described

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the long-term outcomes of RP with multimodal adjuvant therapy in men with PSA ≥ 50. Systemic progressionfree survival rates at 10 years were 83% and 74% for PSA 50-99 and ≥ 100, respectively, while overall CSS was 87%. These results argue for aggressive management with RP as initial step (63). As a rule of thumb, an eLND should be performed in all high-risk cases, as the estimated risk for positive lymph nodes will be in the range 15-40% (32). A limited lymph node dissection should no longer be performed, as this will miss at least half of the nodes involved.

9.5

Very high-risk localised prostate cancer: cT3b-T4 N0 or any T, N1

9.5.1 cT3b-T4 N0 Men with very high-risk PCa generally have a significant risk of disease progression and cancer-related death if left untreated. Very high-risk patients present two specific challenges. There is a need for local control as well as a need to treat any microscopic metastases likely to be present but undetectable until disease progression. The optimal treatment approach will therefore often necessitate multiple modalities. The exact combinations, timing and intensity of treatment continue to be strongly debated. Management decisions should be made after all treatments have been discussed by a multidisciplinary team (including urologists, oncologists, radiologists and pathologists), and after the balance of benefits and side-effects of each therapy modality has been considered by the patient with regard to his own individual circumstances. Provided that the tumour is not fixed to the pelvic wall, or that there is no invasion of the urethral sphincter, RP may be considered a reasonable first step in a selection of patients with low tumour volume. 9.5.2 Any T, N1 The indication for RP in all previously described stages assumes the absence of nodal involvement. Lymph node-positive (N+) disease will mostly be followed by systemic disease progression, and all patients with significant N+ disease will ultimately fail treatment. Nevertheless, the combination of RP and simultaneous hormonal treatment has been shown to achieve a 10-year CSS rate of 80% (64). However, it is questionable whether or not these results could also have been obtained with hormonal treatment alone. Most urologists are reluctant to perform RP for clinical N+ disease, or will cancel surgery if a frozen section shows lymph node invasion. It should also be noted that the definitive pathological examination after RP can show microscopic lymph node invasion. The incidence of tumour progression is lower in patients with fewer positive lymph nodes and in those with microscopic invasion only (65, 66). Clinical N+ patients usually have significant nodal involvement and will be treated with hormonal manipulation only. In patients who prove to be pN+ after RP, adjuvant hormonal treatment can be advocated, but the benefits should be judged against the side-effects of long-term hormonal therapy. PSA follow-up and hormonal treatment in the case of an increase in PSA level is therefore an acceptable option in selected cases. The most accurate staging method for the assessment of lymph node involvement is eLND. This includes removal of al node-bearing tissue from the area bounded by the external iliac vein anteriorly, the lateral pelvic side wall, the bladder wall medially, the floor of the pelvis posteriorly, Cooper’s ligament distally, and the internal iliac artery proximally. During recent years, there has been increasing interest in eLND, but controversy regarding indication and extent of ELND, its therapeutic role and morbidity remain. 9.5.2.1 Indication and extent of extrended pelvic lymph node dissectiori (eLND) Although it is generally accepted that eLND provides important information for prognosis (number of nodes involved, tumour volume, capsular perforation) that cannot be matched by any other current procedures, consensus has not been reached as to when eLND is indicated and to what extent it should be performed. When making such decisions, many physicians rely on nomograms based on pre-operative biochemical markers and biopsies (28). According to these nomograms, patients with a PSA value < 10 ng/mL and a biopsy Gleason score < 7 have a low risk of lymph node metastasis and, therefore, eLND might not be beneficial. However, the fact that most of these nomograms are based on a limited eLND (obturator fossa and external iliac vein) probably results in underestimation of the incidence of patients with positive nodes (32). Lymphography studies have shown that the prostate drains not only to the obturator and external iliac but also to the internal iliac and pre-sacral lymph nodes. Performing an eLND results in removal of all lymph nodes in these particular anatomical regions, producing a higher yield of removed lymph nodes (mean of 20 nodes) compared with limited LND (mean of 8-10 nodes). In patients with a PSA value < 10 and a Gleason score ≥ 7, an incidence of 25% nodal involvement was reported (67). Different reports mention that 19-35% of positive lymph nodes are found exclusively outside the area of the traditionally limited LND (68, 69).

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Update march 2009

9.5.2.2 Therapeutic role of eLND Besides being a staging procedure, (extended) pelvic lymph node dissection might be curative, or at least beneficial, in a subset of patients with limited lymph node metastases (70-72). For an eLND to be representative, a mean of 20 lymph nodes should be removed (73). In some series, the number of nodes removed during lymphadenectomy correlated significantly with time to progression (74). At present, however, lymph node metastases are considered to be a sign of systemic disease. Whenever lymph node metastases are found, prognosis worsens and systemic therapy is advised. 9.5.2.3 Morbidity An eLND remains a surgical procedure, which adds morbidity to the treatment of PCa. When comparing limited vs extended LND, threefold higher complication rates were reported by some authors (75). Complications consist of lymphocoeles, lymphoedema, deep venous thrombosis and pulmonary embolism. Other authors, however, reported more acceptable complication rates (76, 77). 9.5.2.4 • • •

Summary of eLND eLND can play a role in the treatment of PCa for a subset of patients. The number of lymph nodes removed correlates with the time to progression. Concomitant morbidity has to be balanced against the therapeutic effects, and a decision will have to be made based on individual cases.

9.6

Summary of RP in high-risk localised disease

•

 P is a reasonable treatment option in selected patients with cT3a PCa, Gleason score 8-10 or PSA > R 20. If RP is performed, an extended pelvic lymphadenectomy must be performed, as lymph node involvement is frequent. The patient must be informed about the likelihood of a multimodal approach. In case of adverse tumour characteristics (positive section margin, extracapsular extension, seminal vesicle invasion), adjuvant RT may be reasonably used after recuperation from surgery.

• •

Recently, Thompson and colleagues reported the results of a trial enrolling 431 men with pT3N0M0 PCa treated with RP. Patients were randomised to receive 60-64 Gy adjuvant RT or observation. Metastasis-free survival and OS were significantly better with radiotherapy (78). In cases of positive lymph nodes at final histopathology, adjuvant ADT may be considered. Messing et al. examined the role of immediate ADT vs observation in patients with positive lymph nodes found at initial surgery. At a median follow-up of 11.9 years, those receiving immediate ADT had a significant improvement in OS over those managed with observation (79).

9.7

Neoadjuvant hormonal therapy and RP

Generally, neoadjuvant or up-front therapy is defined as therapy given prior to definitive local curative treatment (e.g. surgery or radiation therapy). As PCa is an androgen-dependent tumour, neoadjuvant hormonal therapy (NHT) is an appealing concept. Attempts to decrease the size of the prostate before RP were first reported by Vallett as early as 1944 (80). In a recent Cochrane review and meta-analysis, the role of neoadjuvant and adjuvant hormonal therapy and prostatectomy were studied (81). Patients had predominantly localised T1 and T2 disease, low- and intermediate-grade, with Gleason scores < 7, and PSA < 20 ng/mL in most patients. The Cochrane review made the following observations: • Neoadjuvant hormonal therapy before RP does not provide a significant OS advantage over prostatectomy alone (pooled odds ratio [OR] 1.11; 95% confidence interval [CI] 0.67-1.85). • Neoadjuvant hormonal therapy before RP does not provide a significant advantage in disease-free survival over prostatectomy alone (pooled OR 1.24; 95% CI 0.97-1.57). • Neoadjuvant hormonal therapy before RP does substantially improve local pathological variables such as organ-confined rates, pathological down-staging, positive surgical margins and rate of lymph node involvement. • Adjuvant hormonal therapy following RP: the pooled data for five-year OS showed an OR of 1.50 and 95% CI 0.79-2.84. This was not statistically significant, although there was a trend favouring adjuvant hormonal therapy. Similarly, there was no survival advantage at 10 years. • Adjuvant hormonal therapy following RP: the pooled data for disease-free survival gave an overall OR of 3.73 and 95% CI 2.3-6.03. The overall effect estimate was highly statistically significant (p < 0.00001) in favour of the hormonal arm. • It is noteworthy that the Early Prostate Cancer Trialists’ Group (EPC) trial was not included in the

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47

•

9.7.1 • • •

• •

9.8

Cochrane review. The third update from this large randomised trial of bicalutamide, 150 mg once daily, in addition to standard care in localised and locally advanced, non-metastatic PCa was published in November 2005 (82). Median follow-up was 7.2 years. There was a significant improvement in objective progression-free survival (PFS) in the RP group. This improvement was only statistically significant in the locally advanced disease group (HR 0.75; 95% CI 0.61-0.91). There was no significant improvement in OS in the RP group, both the localised and locally advanced disease groups. In the WW group, there was an OS trend in favour of WW alone in the localised disease group (HR 1.16; 95% CI 0.99-1.37). Summary of neoadjuvant and adjuvant hormonal treatment and RP Neoadjuvant hormonal therapy before RP does not provide a significant OS advantage over prostatectomy alone. Neoadjuvant hormonal therapy before RP does not provide a significant advantage in disease-free survival over prostatectomy alone. Neoadjuvant hormonal therapy before RP does substantially improve local pathological variables such as organ-confined rates, pathological down-staging, positive surgical margins and rate of lymph node involvement. Adjuvant hormonal therapy following RP shows no survival advantage at 10 years. Adjuvant hormonal therapy following RP: the overall effect estimate was highly statistically significant (p < 0.00001) in favour of the hormonal arm.

Complications and functional outcome

The post-operative complications of RP are listed in Table 14. The mortality rate is 0-1.5% (75); urinary fistulas are seen in 1.2-4% of patients (83); and urinary incontinence persists after one year in 7.7% (84). In men undergoing prostatectomy, the rates of post-operative and late urinary complications are significantly reduced if the procedure is performed in a high-volume hospital and by a surgeon who performs a large number of such procedures (85-87). Erectile dysfunction used to occur in nearly all patients, but nerve-sparing techniques can be applied in early-stage disease (88). Patients who benefit from nerve-sparing RP may have a higher chance of local disease recurrence and should therefore be selected carefully. Table 14: Complications of RP Complication • Peri-operative death • Major bleeding • Rectal injury • Deep venous thrombosis • Pulmonary embolism • Lymphocoele • Urine leak, fistula • Slight stress incontinence • Severe stress incontinence • Impotence • Bladder neck obstruction • Ureteral obstruction • Urethral stricture

Incidence (%) 0.0-2.1 1.0-11.5 0.0-5.4 0.0-8.3 0.8-7.7 1.0-3.0 0.3-15.4 4.0-50.0 0.0-15.4 29.0-100.0 0.5-14.6 0.0-0.7 2.0-9.0

9.9 Summary of indications for nerve-sparing surgery* Reference name Pre-operative selection criteria Stage > T2 PSA > 10 Biopsy Gleason score 7 Biopsy Gleason score 8-10 Partin tables Side with > 50% tumour in biopsy Side with peri-neural invasion

48

Sofer (89) Walsh (90) + +

+

Alsikafi (91) Graefen (92) +

+

Bianco (93) +

+ +

+ + +/-

+ + +

Update march 2009

Intra-operative selection criteria Side of palpable tumour + Side of positive biopsy Induration of lateral pelvic fascia + Adherent to neurovascular bundles + Positive section margins 24% 5% 11% *Clinical criteria used by different authors when NOT to perform a nerve-sparing RP.

+ + + 5%

15.9%

 erve-sparing RP can be performed safely in most men undergoing RP (94, 95). In the past decade, a dramatic N shift towards lower-stage tumours has become evident. More importantly, men are younger at the time of diagnosis and more interested in preserving sexual function. Nevertheless, clear contraindications are those patients in whom there is a high risk of extracapsular disease, such as any cT3 PCa, cT2c, any Gleason score > 7 on biopsy, or more than one biopsy > 6 at the ipsilateral side. Partin tables will help guide decision-making (28). If any doubt remains regarding residual tumour, the surgeon should remove the neurovascular bundle. Alternatively, the use of intra-operative frozen-section analysis can help guide these decisions. The patient must be informed before surgery about the risks of nerve-sparing surgery, the potency rates of the surgeon, and the possibility that, to ensure adequate cancer control, the nerves may be sacrificed despite any pre-operative optimism favouring the potential for their salvage. The early administration of intracavernous injection therapy could improve the definitive potency rates (96, 97) and the significance of sural nerve transplant needs further multicentre study (98). Finally, the early use of PDE-5 inhibitors in penile rehabilitation remains controversial. A recent study showed no benefit of daily early administration of vardenafil versus on-demand vardenafil in the postoperative period (99).

9.10 Guidelines and recommendations for RP LE Indications • In patients with low and intermediate risk localised PCa (cT1b-T2 and Gleason score 2-7 and PSA < 20) and a life expectancy > 10 years. Optional • Patients with stage T1a disease and a life expectancy > 15 years or Gleason score 7. • Selected patients with low-volume high-risk localised PCa (cT3a or Gleason score 8-10 or PSA > 20). • Highly selected patients with very high-risk localised PCa (cT3b-T4 N0 or any T N1) in the context of multimodality treatment. Recommendations • Short-term (three months) neoadjuvant therapy with gonadotrophin releasing-hormone analogues is not recommended in the treatment of stage T1-T2 disease. • Nerve-sparing surgery may be attempted in pre-operatively potent patients with low risk for extracapsular disease (T1c, Gleason score < 7 and PSA < 10 ng/mL or see Partin tables/ nomograms). • Unilateral nerve-sparing procedures are an option in stage T2a disease

1b

3 3 3

1a 3

4

LE = level of evidence

9.11

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Andrèn O, Garmo H, Mucci L, Andersson SO, Johansson JE, Fall K. Incidence and mortality of incidental prostate cancer: a Swedish register-based study. Br J Cancer 2009;100(1):170-3. http://www.ncbi.nlm.nih.gov/pubmed/19088721 Lowe BA, Listrom MB. Incidental carcinoma of the prostate: an analysis of the predictors of progression. J Urol 1988;140(6):1340-4. http://www.ncbi.nlm.nih.gov/pubmed/3193495 Van Poppel H, Ameye F, Oyen R, Van de Voorde W, Baert L. Radical prostatectomy for localized prostate cancer. Eur J Surg Oncol 1992;18(5):456-62. http://www.ncbi.nlm.nih.gov/pubmed/1426296 Elgamal AA, Van Poppel HP, Van de Voorde WM, Van Dorpe JA, Oyen RH, Baert LV. Impalpable invisible stage T1c prostate cancer: characteristics and clinical relevance in 100 radical prostatectomy specimens – a different view. J Urol 1997;157(1):244-50. http://www.ncbi.nlm.nih.gov/pubmed/8976263 Oesterling JE, Suman VJ, Zincke H, Bostwick DG. PSA-detected (clinical stage T1c or B0) prostate cancer. Pathologically significant tumours. Urol Clin North Am 1993;20(4):687-93. http://www.ncbi.nlm.nih.gov/pubmed/7505977 Epstein JI, Walsh PC, Brendler CB. Radical prostatectomy for impalpable prostate cancer: the Johns Hopkins experience with tumours found on transurethral resection (stages T1A and T1B) and on needle biopsy (stage T1C). J Urol 1994;152(5 Pt 2):1721-9. http://www.ncbi.nlm.nih.gov/pubmed/7523719 Singh H, Canto EI, Shariat SF, Kadmon D, Miles BJ, Wheeler TM, Slawin KM. Improved detection of clinically significant, curable prostate cancer with systematic 12-core biopsy. J Urol 2004;171(3): 1089-92. http://www.ncbi.nlm.nih.gov/pubmed/14767277 Epstein JI, Chan DW, Sokoll LJ, Walsh PC, Cox JL, Rittenhouse H, Wolfert R, Carter HB. Nonpalpable stage T1c prostate cancer: prediction of insignificant disease using free/total prostate specific antigen levels and needle biopsy findings. J Urol 1998;160(6 Pt 2): 2407-11. http://www.ncbi.nlm.nih.gov/pubmed/9817393 Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001;58(6):843-8. http://www.ncbi.nlm.nih.gov/pubmed/11744442 D’Amico AV, Whittington R, Malkowicz SB, Wu YH, Chen M, Art M, Tomaszewski JE, Wein A. Combination of preoperative PSA level, biopsy Gleason score, percentage of positive biopsies and MRI T-stage to predict early failure in men with clinically localized prostate cancer. Urology 2000;55(4):572-7. http://www.ncbi.nlm.nih.gov/pubmed/10736506 Epstein JI. Gleason score 2-4 adenocarcinoma of the prostate on needle biopsy: a diagnosis that should not be made. Am J Surg Pathol 2000;24(4):477-8. http://www.ncbi.nlm.nih.gov/pubmed/10757394 Epstein JI, Steinberg GD. The significance of low grade prostate cancer on needle biopsy. A radical prostatectomy study of tumour grade, volume, and stage of the biopsied and multifocal tumour. Cancer 1990;66(9):1927-32. http://www.ncbi.nlm.nih.gov:/pubmed/1699655 Briganti A, Chun FK, Salonia A, Gallina A, Farina E, Da Pozzo LF, Rigatti P, Montorsi F, Karakiewicz PI. Validation of a nomogram predicting the probability of lymph node invasion based on the extent of pelvic lymphadenectomy in patients with clinically localized prostate cancer. BJU Int 2006;98(4): 788-93. http://www.ncbi.nlm.nih.gov/pubmed/16796698 Schroder FH, Van den Ouden D, Davidson P. The role of surgery in the cure of prostatic carcinoma. Eur Urol Update Series 1992;1:18-23. Gibbons RP. Total prostatectomy for clinically localized prostatic cancer: long-term surgical results and current morbidity. NCI Monogr 1988;(7):123-6. http://www.ncbi.nlm.nih.gov/pubmed/3173498 Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997;24(2):395-406. http://www.ncbi.nlm.nih.gov/pubmed/9126237 Johansson JE, Andersson SO. Deferred treatment in localized prostatic cancer. Acta Oncol 1991;30(2):221-3. http://www.ncbi.nlm.nih.gov/pubmed/2029410

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Graversen PH, Nielsen KT, Gasser TC, Corle DK, Madsen PO. Radical prostatectomy versus expectant primary treatment in stages I and II prostatic cancer. A fifteen-year follow-up. Urology 1990;36(6):493-8. http://www.ncbi.nlm.nih.gov/pubmed/2247914 38. Eastham JA, Kattan MW, Riedel E, Begg CB, Wheeler TM, Gerigk C, Gonen M, Reuter V, Scardino PT. Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J Urol 2003;170(6 Pt 1):2292-5. http://www.ncbi.nlm.nih.gov/pubmed/14634399 39. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-free and cancerspecific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001;28(3):555-65. http://www.ncbi.nlm.nih.gov/pubmed/11590814 40. Catalona WJ, Smith DJ. 5-year tumour recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152 (5 Pt 2):1837-42. http://www.ncbi.nlm.nih.gov/pubmed/7523731 41. Hull GW, Rabbani F, Abbas F, Wheeler TM, Kattan MW, Scardino PT. Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol 2002;167(2 Pt 1):528-34. http://www.ncbi.nlm.nih.gov/pubmed/11792912 42. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 1994;152(5 Pt 2):1821-5. http://www.ncbi.nlm.nih.gov/pubmed/7523728 43. Zincke H, Oesterling JE, Blute ML, Bergstralh EJ, Myers RP, Barrett DM. Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J Urol 1994;152(5Pt2):1850-7. http://www.ncbi.nlm.nih.gov/pubmed/7523733 44. Makarov DV, Trock BJ, Humphreys EB, Mangold LA, Walsh PC, Epstein JI, Partin AW. Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005. Urology 2007 Jun;69(6):1095-101. http://www.ncbi.nlm.nih.gov/pubmed/17572194 45. Cooperberg MR, Lubeck DP, Mehta SS, Carroll PR; CaPSURE. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE). J Urol 2003;170(6 Pt 2): S21-S25; discussion S26-27. http://www.ncbi.nlm.nih.gov/pubmed/14610406 46. Hodgson D, Warde P, Gospodarowicz M. The management of locally advanced prostate cancer. Urol Oncol 1998;4:3-12. 47. Fallon B, Williams RD. Current options in the management of clinical stage C prostatic carcinoma. Urol Clin North Am 1990;17(4):853-66. http://www.ncbi.nlm.nih.gov/pubmed/2219582 48. Boccon-Gibod L, Bertaccini A, Bono AV, Dev Sarmah B, Höltl W, Mottet N, Tunn U, Zamboglou N. Management of locally advanced prostate cancer: a European Consensus. Int J Clin Pract 2003;57(3):187-94. http://www.ncbi.nlm.nih.gov/pubmed/12723722 49. Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A, Pierart M. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002:360(9327):103-6. http://www.ncbi.nlm.nih.gov/pubmed/12126818 50. Yamada AH, Lieskovsky G, Petrovich Z, Chen SC, Groshen S, Skinner DG. Results of radical prostatectomy and adjuvant therapy in the management of locally advanced, clinical stage TC, prostate cancer. Am J Clin Oncol 1994;17(4):277-85. http://www.ncbi.nlm.nih.gov/pubmed/8048388 51. Gerber GS, Thisted RA, Chodak GW, Schroder FH, Frohmuller HG, Scardino PT, Paulson DF, Middleton AW Jr, Rukstalis DB, Smith JA Jr, Ohori M, Theiss M, Schellhammer PF. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. Eur Urol 1997;32(4):385-90. http://www.ncbi.nlm.nih.gov/pubmed/9412793

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van den Ouden D, Hop WC, Schroder FH. Progression in and survival of patients with locally advanced prostate cancer (T3) treated with radical prostatectomy as monotherapy. J Urol 1998;160(4):1392-7. http://www.ncbi.nlm.nih.gov/pubmed/9751362 53. Isorna Martinez de la Riva S, Belón López-Tomasety J, Marrero Dominguez R, Alvarez Cruz E, Santamaria Blanco P. [Radical prostatectomy as monotherapy for locally advanced prostate cancer (T3a): 12 years follow-up]. Arch Esp Urol 2004;57(7):679-92. [article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/15536949 54. Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int 2005;95(6):751-6. http://www.ncbi.nlm.nih.gov/pubmed/15794776 55. Hsu CY, Joniau S, Oyen R, Roskams T, Van Poppel H. Outcome of surgery for clinical unilateral T3a prostate cancer: a single-institution experience. Eur Urol 2007;51(1):121-8; discussion 128-9. http://www.ncbi.nlm.nih.gov/pubmed/16797831 56. Joniau S, Hsu CY, Lerut E, Van Baelen A, Haustermans K, Roskams T, Oyen R, Van Poppel H. A pretreatment table for the prediction of final histopathology after radical prostatectomy in clinical unilateral T3a prostate cancer. Eur Urol 2007;51(2):388-96. http://www.ncbi.nlm.nih.gov/pubmed/16901622 57. Van Poppel H, Ameye F, Oyen R, Van de Voorde W, Baert L. Accuracy of combined computerized tomography and fine needle aspiration cytology in lymph node staging of localized prostatic carcinoma. J Urol 1994;151(5):1310-14. http://www.ncbi.nlm.nih.gov/pubmed/8158777 58. Van Poppel H, Vekemans K, Da Pozzo L, Bono A, Kliment J, Montironi R, Debois M, Collette L. Radical prostatectomy for locally advanced prostate cancer: results of a feasibility study (EORTC 30001). Eur J Cancer 2006;42(8):1062-7. http://www.ncbi.nlm.nih.gov/pubmed/16624554 59. Van Poppel H, Joniau S. An analysis of radical prostatectomy in advanced stage and high-grade prostate cancer. Eur Urol 2008;53(2):253-9. http://www.ncbi.nlm.nih.gov/pubmed/17949893 60. Yossepowitch O, Eggener SE, Bianco FJ Jr, Carver BS, Serio A, Scardino PT, Eastham JA. Radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. J Urol 2007;178(2):493-9;discussion 499. http://www.ncbi.nlm.nih.gov/pubmed/17561152 61. D’Amico AV, Whittington R, Malkowicz SB, Fondurulia J, Chen MH, Kaplan I, Beard CJ, Tomaszewski JE, Renshaw AA, Wein A, Coleman CN. Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol 1999;17(1):168-72. http://www.ncbi.nlm.nih.gov/pubmed/10458230 62. Tiguert LL, Harrel F, Fradet Y. Disease outcome of patients with a PSA > 20 treated by radical prostatectomy: analysis of 177 patients. J Urol 2006;175:311A. 63. Inman BA, Davies JD, Rangel LJ, Bergstralh EJ, Kwon ED, Blute ML, Karnes RJ, Leibovich BC. Longterm outcomes of radical prostatectomy with multimodal adjuvant therapy in men with a preoperative serum prostate-specific antigen level > or = 50 ng/mL. Cancer 2008;113(7):1544-51. http://www.ncbi.nlm.nih.gov/pubmed/18680171 64. Ghavamian R, Bergstralh EJ, Blute ML, Slezak J, Zincke H. Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. J Urol 1999;161(4):1223-7; discussion 1277-8. http://www.ncbi.nlm.nih.gov/pubmed/10081874 65. Briganti A, Karnes JR, Da Pozzo LF, Cozzarini C, Gallina A, Suardi N, Bianchi M, Freschi M, Doglioni C, Fazio F, Rigatti P, Montorsi F, Blute ML. Specific survival in patients with node positive prostate cancer. a new proposal based on a two-institution experience on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node dissection and adjuvant therapy. Eur Urol 2008. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18838212 66. Schumacher MC, Burkhard FC, Thalmann GN, Fleischmann A, Studer UE. Good outcome for patients with few lymph node metastases after radical retropubic prostatectomy. Eur Urol 2008;54(2):344-52. http://www.ncbi.nlm.nih.gov/pubmed/18511183

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Schumacher MC, Burkhard FC, Thalmann GN, Fleischmann A, Studer UE. Is pelvic lymph node dissection necessary in patients with a serum PSA<10ng/mL undergoing radical prostatectomy for prostate cancer? Eur Urol 2006;50(2):272-9. http://www.ncbi.nlm.nih.gov/pubmed/16632187 68. Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002;167(4):1681-6. http://www.ncbi.nlm.nih.gov/pubmed/11912387 69. Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure? J Urol 2003;169(3): 849-54. http://www.ncbi.nlm.nih.gov/pubmed/12576797 70. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281(17):1591-7. http://www.ncbi.nlm.nih.gov/pubmed/10235151 71. Aus G, Nordenskjöld K, Robinson D, Rosell J, Varenhorst E. Prognostic factors and survival in nodepositive (N1) prostate cancer – a prospective study based on data from a Swedish population-based cohort. Eur Urol 2003;43(6):627-31. http://www.ncbi.nlm.nih.gov/pubmed/12767363 72. Cheng L, Zincke H, Blute ML, Bergstrahl EJ, Scherer B, Bostwick DG. Risk of prostate carcinoma death in patients with lymph node metastasis. Cancer 2001;91(1):66-73. http://www.ncbi.nlm.nih.gov/pubmed/11148561 73. Weingärtner K, Ramaswamy A, Bittinger A, Gerharz EW, Vöge D, Riedmiller H. Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J Urol 1996;156(6):1969-71. http://www.ncbi.nlm.nih.gov/pubmed/8911367 74. Bader P, Burkhard FC, Markwalder R, Studer UE. Is a limited lymph node dissection an adequate staging procedure for prostate cancer? J Urol 2002;168(2):514-8;discussion 518. http://www.ncbi.nlm.nih.gov/pubmed/12131300 75. Briganti A, Chun FK, Salonia A, Suardi N, Gallina A, Da Pozzo LF, Roscigno M, Zanni G, Valiquette L, Rigatti P, Montorsi F, Karakiewicz PI. Complications and other surgical outcomes associated with extended pelvic lymphadenectomy in men with localized prostate cancer. Eur Urol 2006;50(5): 1006-13. http://www.ncbi.nlm.nih.gov/pubmed/16959399 76. Heidenreich A et al. Extended pelvic lymphadenectomy in men undergoing radical retropubic prostatectomy (RRP) – an update on > 300 cases. J Urol 2004;171:a312. 77. Burkhard FC, Schumacher M, Studer UE. The role of lymphadenectomy in prostate cancer. Nat Clin Pract Urol 2005;2(7):336-42. http://www.ncbi.nlm.nih.gov/pubmed/16474786 78. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, Messing E, Forman J, Chin J, Swanson G, Canby-Hagino E, Crawford ED. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/19167731 79. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di’SantAgnese PA, Trump D; Eastern Cooperative Oncology Group study EST 3886. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006;7(6):472-9. http://www.ncbi.nlm.nih.gov/pubmed/16750497 80. Vallett BS. Radical perineal prostatectomy subsequent to bilateral orchiectomy. Delaware Med J 1944;16:19-20. 81. Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neoadjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. Cochrane Database Syst Rev 2006;(4):CD006019. http://www.ncbi.nlm.nih.gov/pubmed/17054269 82. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP; Casodex Early Prostate Cancer Trialists’ Group. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006;97(2):247-54. http://www.ncbi.nlm.nih.gov/pubmed/16430622

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83. Hautmann RE, Sauter TW, Wenderoth UK. Radical retropubic prostatectomy: morbidity and urinary continence in 418 consecutive cases. Urology 1994;43(2 Suppl.):47-51. http://www.ncbi.nlm.nih.gov/pubmed/8116133 84. Murphy GP, Mettlin C, Menck H, Winchester DP, Davidson AM. National patterns of prostate cancer treatment by radical prostatectomy: results of a survey by the American College of Surgeons Commission on Cancer. J Urol 1994;152(5 Pt 2):1817-9. http://www.ncbi.nlm.nih.gov/pubmed/7523727 85. Begg CB, Riedel ER, Bach PB, Kattan MW, Schrag D, Warren JL, Scardino PT. Variations in morbidity after radical prostatectomy. N Engl J Med 2002;346(15):1138-44. http://www.ncbi.nlm.nih.gov/pubmed/11948274 86. Potosky AL, Legler J, Albertsen PC, Stanford JL, Gilliland FD, Hamilton AS, Eley JW, Stephenson RA, Harlan LC. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcome Study. J Natl Cancer Inst 2000;92(19):1582-92. http://www.ncbi.nlm.nih.gov/pubmed/11018094 87. Van Poppel H, Collette L, Kirkali Z, Brausi M, Hoekstra W, Newling DW, Decoster M, EORTC GU Group. Quality control of radical prostatectomy: a feasibility study. Eur J Cancer 2001;37(7):884-91. http://www.ncbi.nlm.nih.gov/pubmed/11313177 88. Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 1994;152(5Pt2):1831-6. http://www.ncbi.nlm.nih.gov/pubmed/7523730 89. Sofer M, Savoie M, Kim SS, Civantos F, Soloway MS. Biochemical and pathological predictors of the recurrence of prostatic adenocarcinoma with seminal vesicle invasion. J Urol 2003;169(1):153-6. http://www.ncbi.nlm.nih.gov/pubmed/12478125 90. Walsh RM, Thompson IM. Prostate cancer screening and disease management: how screening may have an unintended effect on survival and mortality-the camel’s nose effect. J Urol 2007;177(4): 1303-6. http://www.ncbi.nlm.nih.gov/pubmed/17382719 91. Alsikafi NF, Brendler CB. Surgical modifications of radical retropubic prostatectomy to decrease incidence of positive surgical margins. J Urol 1998;159(4):1281-5. http://www.ncbi.nlm.nih.gov/pubmed/9507853 92. Graefen M. Is the open retropubic radical prostatectomy dead? Eur Urol 2007 Nov;52(5):1281-3. http://www.ncbi.nlm.nih.gov/pubmed/17764828 93. Bianco FJ Jr, Scardino PT, Eastham JA. Radical prostatectomy: long-term cancer control and recovery of sexual and urinary function (‘trifecta’). Urology 2005; 66(5 Suppl.):83-94. http://www.ncbi.nlm.nih.gov/pubmed/16194712 94. Gontero P, Kirby RS. Nerve-sparing radical retropubic prostatectomy: techniques and clinical considerations. Prostate Cancer Prostatic Dis 2005;8(2):133-9. http://www.ncbi.nlm.nih.gov/pubmed/15711608 95. Sokoloff MH, Brendler CB. Indications and contraindications for nerve-sparing radical prostatectomy. Urol Clin North Am 2001;28(3):535-43. http://www.ncbi.nlm.nih.gov/pubmed/11590812 96. Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, Nava L, Barbieri L, Rigatti P, Pizzini G, Miani A. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 1997;158(4):1408-10. http://www.ncbi.nlm.nih.gov/pubmed/9302132 97. Nandipati K, Raina R, Agarwal A, Zippe CD. Early combination therapy: intracavernosal injections and sildenafil following radical prostatectomy increases sexual activity and the return of natural erections. Int J Impot Res 2006;18(5):446-51. http://www.ncbi.nlm.nih.gov/pubmed/16482200 98. Secin FP, Koppie TM, Scardino PT, Eastham JA, Patel M, Bianco FJ, Tal R, Mulhall J, Disa JJ, Cordeiro PG, Rabbani F. Bilateral cavernous nerve interposition grafting during radical retropubic prostatectomy: Memorial Sloan-Kettering Cancer Center experience. J Urol 2007;177(2):664-8. http://www.ncbi.nlm.nih.gov/pubmed/17222654 99. Montorsi F, Brock G, Lee J, Shapiro J, Van Poppel H, Graefen M, Stief C. Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 2008 Oct;54(4):924-31. http://www.ncbi.nlm.nih.gov/pubmed/18640769

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10. TREATMENT: DEFINITIVE RADIATION THERAPY 10.1

Introduction

There are no randomised studies comparing radical prostatectomy with either external beam therapy or brachytherapy for localised prostate cancer, but the National Institutes of Health (NIH) consensus set up in 1988 (1) remains available: external irradiation offers the same long-term survival results as surgery; moreover, external irradiation provides a quality of life at least as good as that provided by surgery (2). Three-dimensional conformal radiotherapy (3D-CRT) is the gold standard and, at the beginning of the third millennium, intensity modulated radiotherapy (IMRT), an optimised form of 3D-CRT, is gradually gaining ground in centres of excellence. In addition to external irradiation, there has been continued and growing interest in transperineal low dose or high dose brachytherapy. In localised and locally advanced prostate cancer, several randomised phase III trials conducted by radiation therapy scientific societies, such as the Radiation Therapy Oncology Group (RTOG) and European Organisation for Research and Treatment of Cancer (EORTC), have established the indications for the combination of external irradiation and androgen deprivation treatment (ADT). Whatever the technique, the choice of treatment after the appropriate assessment of tumour extension must be based on a multidisciplinary approach taking account of: • the 2002 tumour node metastasis (TNM) classification • the Gleason score defined on a sufficient number of core biopsies (at least 12) • the baseline prostate-specific antigen (PSA) • the age of the patient • his co-morbidity, life expectancy and quality of life • d’Amico’s prognostic factor classification. Obtaining a patient’s consent is essential after giving full information regarding diagnosis, the therapeutic modalities and morbidity. Additional information on the various aspects of radiotherapy in the treatment of prostate cancer is available in a newly published extensive overview (3).

10.2

Technical aspects: three dimensional conformal radiotherapy and intensity modulated external beam radiotherapy

Anatomical data acquired by scanning the patient in a treatment position, are transferred to the 3D treatment planning system where the clinical target volume is visualised, following which a (surrounding) safety margin is added. At the time of irradiation, a multileaf collimator automatically and, in the case of IMRT, continuously, adapts to the contours of the target volume seen by each beam. Real-time verification of the irradiation field by means of portal imaging allows for comparison of the treated and simulated fields, and correction of deviations where displacement is more than 5 mm. Three-dimensional CRT improves local control through dose escalation without increasing the risk of morbidity. The use of IMRT is possible with linear accelerators equipped with the latest multileaf collimators and specific software. Movement of the leaves during the course of the irradiation allows for a more complex distribution of the dose to be delivered within the treatment field, and provides concave isodose curves, which are particularly useful as a means to spare the rectum. Whatever the techniques and their sophistication, quality assurance plays a major role in the management of radiotherapy, mandating the involvement of physicians, physicists, dosimetrists, radiographers, radiologists and computer scientists.

10.3

Localised prostate cancer T1-2c N0, M0

10.3.1 T1a-T2a, N0, M0 and Gleason score ≤ 6 and PSA < 10 ng/mL (low-risk group) Retrospective, non-randomised studies have shown that biochemical disease-free survival is significantly higher with a radiation dose ≥ 72 Gy compared with < 72 Gy (p = 0.04) (4). Two randomised trials focusing on clinical stages T1-3 N0 M0 paved the way for dose escalation: • The MD Anderson study compared 78 Gy with 70 Gy conventional radiotherapy: it included 305 stage T1-3 patients with a pre-treatment PSA level of more than 10 ng/mL and, with a median follow-up of

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•

8.7 years, showed a significant increase in freedom from biochemical and/or clinical failure for low-risk patients (p = 0.04) (5). The PROG 95-09 evaluated 393 T1b-T2b patients, of whom 75% had a Gleason score ≤ 6 and a PSA < 15 ng/mL. Patients were randomised to receive an initial boost to the prostate alone, using conformal protons of either 19.8 Gy or 28.8 Gy, and then 50.4 Gy to a larger volume. With a median follow-up of 5.5 years, there was a significant increase in five-year freedom from biochemical failure (p < 0.001) in favour of low-risk patients, who were given a higher dose (79.2 Gy), compared with those receiving a conventional dose (70.2 Gy) (6).

In daily practice, a minimum dose of 74 Gy is recommended. 10.3.2 T2b or PSA 10-20 ng/mL, or Gleason score 7 (intermediate-risk group) Many non-randomised studies have shown dose escalation to have a significant impact on five-year survival without biochemical relapse for patients classified as cT1c-T3, with a dose ranging from 76-81 Gy (4, 7, 8). A Dutch randomised phase III trial comparing 68 Gy with 78 Gy showed a significant increase in five-year freedom from clinical or biochemical failure for patients in an intermediate-risk group (9). The phase III trial of the French Federation of Cancer Centres compared 70 Gy with 80 Gy in 306 patients with a pelvic lymph node involvement risk of < 10% (Partin) or pN0, with no hormonal therapy allowed before, during or after radiotherapy. With a median follow-up of 59 months, high dose should provide a better five-year biological outcome in intermediate-risk patients, especially if the initial PSA > 15ng/mL (10). Patients who are reluctant to accept short-term hormonal treatment (11) can receive definitive radiotherapy alone provided that a dose escalation up to 78-80 Gy is proposed. 10.3.3 T2c or Gleason score > 7 or PSA > 20 ng/mL (high-risk group) External irradiation with dose escalation is mandatory since it improves the five-year biochemical disease-free survival, as shown in several phase III randomised trials. • The Dutch study comparing 68 Gy with 78 Gy showed a 10% increase in the five-year freedom from clinical or biochemical failure (p = 0.02) (9). • The MRC study comparing 64 Gy with 74 Gy, with neoadjuvant hormonal therapy, has shown an 11% difference in five-year biochemical disease-free survival (12). • The PROG 95-09 study, with a significant increase in five-year freedom from biochemical failure (p < 0.02) in favour of high-risk patients given a higher dose (79.2 Gy) vs those receiving a conventional dose (70.2 Gy) (9). • The MD Anderson study showed a significant increase in freedom from biochemical and/or clinical failure for high-risk patients (p = 0.004) (5). • The EORTC trial 22991, comparing 3D-CRT +/- IMRT with a choice of three levels of dose (70 Gy, 74 Gy and 78 Gy), with or without six months of neoadjuvant and concomitant hormonal therapy, was closed in April 2008 after recruiting 800 patients, and its results are awaited (13). In daily practice, a combination of external irradiation with short-term androgen deprivation is recommended, based on the results of a phase III randomised trial. This trial, which included 206 patients with a PSA of at least 10 ng/mL (maximum 40 ng/mL), a Gleason score of at least 7 (range 5-10), or radiographic evidence of extra-prostatic disease, compared 3D-CRT alone or in combination with six months of ADT. After a median follow-up of 7.6 years, intermediate- or high-risk patients without moderate or severe co-morbidity randomised to receive 3D-CRT plus ADT had a 13% improvement in overall survival rate (p < 0.001) (11). 10.3.4 Prophylactic irradiation of pelvic lymph nodes in high-risk localised prostate cancer Invasion of the pelvic lymph nodes is a poor prognostic factor and mandates systemic medical treatment because radiotherapy alone is insufficient (14). Prophylactic whole pelvis irradiation has been abandoned since randomised trials failed to show that patients benefited from prophylactic irradiation of the pelvic lymph nodes in high-risk cases (46-50 Gy). Such studies include the RTOG study with 484 T1b-T2 patients (15), the Standford study with only 91 patients (16), and the GETUG-01 trial, which included 444 T1b-T3 N0 pNx M0 patients (17). In order better to select patients who might benefit from pelvic lymph node irradiation, and to supplement the use of Partin’s tables (18) and/or the Roach formula (19), pelvic lymphadenectomy might be required, particularly for young patients, because its results will enable radiation oncologists to tailor both the planning target volume and the duration of ADT: specifically, no pelvic irradiation for pN0 patients, but pelvic irradiation for pN1 patients with long term ADT.

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10.4

Innovative techniques

10.4.1 Intensity modulated radiotherapy IMRT enables radiation oncologists to increase radiation doses homogeneously up to as much as 86 Gy within the target volume, while respecting the tolerance doses in organs at risk. Certainly, for dose escalation beyond 80 Gy, using conventional 2 Gy fraction sizes, or for dose escalation using hypofractionated radiotherapy, in which there has been renewed interest, IMRT is the only safe means of treatment delivery, although both treatment scenarios should be performed only within the confines of a properly designed clinical trial. The Memorial Sloan-Kettering Cancer Center has the largest experience with this technique, and its results have now been updated, reporting on disease control and toxicity in two cohorts of patients. In the first, 561 patients with organ-confined disease were treated with a dose of 81 Gy. The eight-year actuarial PSA relapse-free survival rates for patients in favourable, intermediate and unfavourable risk groups were 85%, 76% and 72%, respectively, according to the then-current American Society for Radiation Oncology (ASTRO) definition (20). In the second cohort, 478 patients with organ-confined disease were treated with a dose of 86.4 Gy. The fiveyear actuarial PSA relapse-free survival according to the nadir plus 2 ng/mL definition was 98%, 85% and 70% for the low-, intermediate-, and high-risk groups, respectively (21). To date, no randomised trials have been published comparing dose escalation using IMRT and 3D-CRT. However, several such trials are ongoing (UK NCRI, MD Anderson, Fox Chase, and Ottawa Health Research Institute), although one (Ottawa) is studying helical tomotherapy (see below), and two (NCRI and MD Anderson) are studying hypofractionated, doseescalated radiotherapy. With dose escalation using IMRT, organ movement becomes a critical issue, in terms of both tumour control and treatment toxicity, and evolving techniques will combine IMRT with some form of image-guided radiotherapy (IGRT), in which organ movement can be visualised and corrected for in real time, although the optimum means of achieving this is still unclear (22). Another evolving technique for the delivery of IMRT is tomotherapy, which uses a linear accelerator mounted on a ring gantry that rotates as the patient is delivered through the centre of the ring, analogous to spiral computed tomography (CT) scanning. Preliminary data suggest that this technique is feasible in prostate cancer treatment (23). 10.4.2 Proton beam and carbon ion beam therapy In theory, proton beams are an attractive alternative to photon beam radiotherapy for prostate cancer because they deposit almost all their radiation dose at the end of the particle’s path in tissue (the Bragg peak), in contrast to photons, which deposit radiation along their path. Additionally, there is a very sharp fall-off for proton beams beyond their deposition depth, meaning that critical normal tissues beyond this depth could be effectively spared, in contrast to photon beams, which will continue to deposit energy up to and including an exit dose as they leave the body. In practice, however, this has the disadvantage that dose distributions from protons are highly sensitive to changes in internal anatomy, such as might occur with bladder or rectal filling, and prostate proton therapy is usually delivered with lateral beams. It is also possible that high linear energy transfer (LET) radiation therapy using protons or carbon ions offers inherent biological advantages over photons, having more capacity for DNA damage dose-for-dose. Only one randomised trial has incorporated proton therapy in one arm: the Loma Linda/Massachusetts General Hospital trial discussed above compared standard-dose conformal radiotherapy with dose-escalated radiotherapy using protons for the boost dose (6). This trial cannot, however, be used as evidence for the superiority of proton therapy per se, as its use here could be viewed merely as a sophisticated method for dose escalation. In order to compare the efficacy of protons versus photons, a randomised trial using equivalent doses, comparing proton beam therapy with IMRT, would be needed, and such a study is under consideration by the RTOG. Two recent planning studies comparing conformal proton therapy with IMRT have yielded conflicting results, one suggesting that the two are equivalent in terms of rectal dose sparing, but IMRT is actually superior in terms of bladder sparing (24), and the other suggesting a clearer advantage to protons (25). Further studies are clearly needed, and in the interim, proton therapy must be regarded as a promising but experimental alternative to photon beam therapy. Theoretically, proton therapy might be associated with a lower risk of secondary

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cancers compared with IMRT, because of the lower integral dose of radiation, but there are no data in patients treated for prostate cancer to support this. Carbon ions offer similar theoretical advantages as protons as an alternative to photon beam therapy. In a phase II study, 175 patients with T1-3, N0-1, M0 prostate cancer were treated with carbon ions in a dose equivalent to 66 Gy in 20 fractions over five weeks (26). Treatment appeared to be well tolerated, with no RTOG grade 3 or 4 bowel or genitourinary toxicity, and an overall four-year biochemical disease-free rate of 88% (25). As with protons, a randomised trial comparing carbon ions with IMRT and using equivalent doses is required.

10.5

Transperineal brachytherapy

Transperineal brachytherapy is a safe and effective technique that generally requires fewer than two days of hospitalisation. There is consensus on the following eligibility criteria: • stage cT1b- T2a N0, M0, • a Gleason score ≤ 6 assessed on a sufficient number of random biopsies • an initial PSA level of≤ 10 ng/mL • ≤ 50% of biopsy cores involved with cancer • a prostate volume of < 50 cm3 • a good International Prostatic Symptom Score (IPSS) (27). Patients with low-risk prostate cancer are the most suitable candidates for low-dose rate (LDR) brachytherapy. Further guidelines on technical aspects of brachytherapy have been published recently, and are strongly recommended (28). In 1983, Holm et al. described the transperineal method with endorectal sonography in which the patient is positioned in a dorsal decubitus gynaecological position (29). Implantation is undertaken under general anaesthesia or spinal block, and involves a learning curve for the whole team: the surgeon for the delineation of the prostate and the placement of the needles, the physicist for real-time dosimetry, and the radiation oncologist for source loading. The sonography probe introduced into the rectum is fixed in a stable position. No randomised trials have been performed comparing brachytherapy with other curative treatment modalities, and outcomes are based on unrandomised case series. Results of permanent implants have been reported from different institutions, with a median follow-up ranging between 36 and 120 months (30). Recurrence-free survival after five and 10 years was reported to range from 71-93% and from 65-85%, respectively (31-38). A significant correlation has been shown between the implanted dose and recurrence rates (39). Patients receiving a D90 of > 140 Gy demonstrated a significantly higher biochemical control rate (PSA < 1.0 ng/mL) at four years than patients receiving less than 140 Gy (92% vs 68%). There is no benefit from adding neoadjuvant or adjuvant androgen deprivation to LDR brachytherapy (30). Some patients experience significant urinary complications following implantation, such as urinary retention (1.5-22%), post-implant transurethral resection of the prostate (TURP) (up to 8.7%), and incontinence (0-19%). A small randomised trial has suggested that prophylactic tamsulosin does not reduce the rates of acute urinary retention, but may improve urinary morbidity (40). This observation could usefully be further studied in a larger number of patients. Chronic urinary morbidity can occur in up to 20% of patients, depending on the severity of symptoms prior to brachytherapy. Previous TURP for benign prostatic hyperplasia increases the risk of postimplant incontinence and urinary morbidity. Brachytherapy-induced rectal morbidity with grade II/III proctitis occurs in 5-21% of patients. Erectile dysfunction develops in about 40% of patients after three to five years. In a recent retrospective analysis of 5621 men who had undergone LDR brachytherapy (41), urinary, bowel and erectile morbidity rates were 33.8%, 21% and 16.7%, respectively, with invasive procedure rates of 10.3%, 0.8% and 4%, respectively. In cases of permanent implants, iodine-125 in granular form is the radio-element of reference, while palladium-103 may be used for less differentiated tumours with a high doubling time. The dose delivered to the planning target volume is 160 Gy for iodine-125, and 120 Gy for palladium-103. A Gleason score of 7 remains a ‘grey area’, but patients with a Gleason score of 4 + 3 show no difference in outcome (42). A small randomised trial has suggested that, as one might expect, the use of stranded rather than loose seeds is associated with better seed retention and less seed migration, and this should be the standard choice (43).

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In cases of intermediate or high-risk localised prostate cancer, its combination with supplemental external irradiation (44) or neoadjuvant hormonal treatment (45) may be considered. The optimum dose of supplemental external beam radiation therapy (EBRT) is unclear. A randomised trial comparing 44 Gy with 20 Gy of EBRT plus palladium-103 brachytherapy closed early, showing no difference in biochemical outcomes (46). Non-permanent transperineal interstitial prostate brachytherapy using a high-dose rate iridium-192 stepping source and a remote afterloading technique can be applied with a total dose of 12-20 Gy in two to four fractions combined with fractionated external radiotherapy of 45 Gy (47). Higher doses of supplemental EBRT than this may best be delivered with IMRT, and a report from Memorial Sloan-Kettering indicates that such an approach is safe and feasible (48). Recent data suggest an equivalent outcome in terms of biochemical disease-free survival compared with high-dose EBRT (HD EBRT) (49). In a retrospective analysis of modern series (50, 51), biochemical diseasefree survival rates of 85.8%, 80.3% and 67.8% in men with low-, intermediate- and high-risk prostate cancer, respectively, are reported after a mean follow-up of 9.43 years. Quality-of-life changes are similar between HD EBRT and high-dose rate (HDR) brachytherapy in terms of diarrhoea and insomnia (52). However, the frequency of erectile dysfunction is significantly increased with HDR brachytherapy (86% vs 34%). A single randomised trial of EBRT versus EBRT plus HDR brachytherapy has been reported (53). A total of 220 patients with organ-confined prostate cancer were randomised to EBRT alone with a dose of 55 Gy in 20 fractions, or EBRT with a dose of 35.75 Gy in 13 fractions, followed by HDR brachytherapy with a dose of 17 Gy in two fractions over 24 hours. A significant improvement in biochemical relapse-free survival was seen in favour of the combined brachytherapy schedule (p = 0.03). There were no differences in the rates of late toxicity. Patients randomised to brachytherapy had significantly better quality of life as measured by their Functional Assessment of Cancer Therapy-prostate (FACT-P) score at 12 weeks (53). There is still a need to compare dose escalated EBRT plus hormone therapy, with the same plus a brachytherapy boost, in intermediate- and high-risk patients. For T1-2 N0 M0 disease, the five-year biochemical failure rates are similar for permanent seed implantation, high-dose (> 72 Gy) external radiation, combination seed/external irradiation, and radical prostatectomy. These were the results from a study that included 2991 patients diagnosed with T1-2 consecutive localised prostate cancer treated between 1990 and 1998 at the Cleveland Clinic Foundation and Memorial Sloan-Kettering Cancer Center with a minimum of one-year follow-up (49).

10.6

Late toxicity

Patients must be informed about the potential late genitourinary or gastrointestinal toxicity that may occur, as well as the impact of irradiation on erectile function. Late toxicity was analysed using a dose of 70 Gy in the prospective EORTC randomised trial 22863 (1987-1995) (54), in which 90% of patients were diagnosed as stage T3-4. A total of 377 patients (91%) out of 415 enrolled were evaluable for long-term toxicity, graded according to a modified RTOG scale. Eighty-six (22.8%) patients had grade ≥ 2 urinary or intestinal complications or leg oedema, of which 72 had grade 2 (moderate) toxicity, 10 had grade 3 (severe) toxicity, and four died due to grade 4 (fatal) toxicity. Although four (1%) late treatment-related deaths occurred, longterm toxicity was limited, with fewer than 5% grade 3 or 4 late complications being reported (Table 15). These data can be used as a baseline for comparison with irradiation techniques currently in use, such as 3D-CRT or IMRT. Table 15: Incidence of late toxicity by RTOG grade (from EORTC trial 22863) Toxicity

Grade 2

Grade 3

Grade 4

Cystitis Haematuria Urinary stricture Urinary incontinence Overall GU toxicity Proctitis

No. 18 18 18 18 47 31

No. 2 0 5 2 9 0

No. 0 0 4 0 4† 0

60

% 4.7 4.7 4.7 4.7 12.4 8.2

% 0.5 0 1.3 0.5 2.3

% 0 0 1 0 1† 0

Any significant toxicity (> grade 2) No. % 20 5.3 18 4.7 27 7.1 20 5.3 60 15.9 31 8.2

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Chronic diarrhoea Small bowel obstruction Overall GI toxicity Leg oedema Overall toxicity*

14 1 36 6 72

3.7 0.2 9.5 1.5 19.0

0 1 1 0 10

0.2 0.2 0 2.7

0 0 0 0 4

0 0 0 0 1

14 2 37 6 86

3.7 0.5 9.8 1.5 22.8

GU = genitourinary; GI = gastrointestinal. * Overall toxicity included genitourinary and gastrointestinal toxicity and leg oedema. As most patients had more than one type of toxicity, the overall toxicity does not result from simple addition. † Two of the grade 4 patients were irradiated with cobalt-60. Note: there was no other significant (≥ grade 2) toxicity among patients irradiated with cobalt-60 (n = 15) except for two patients with grade 4 genitourinary toxicity (stated above) and only one patient with grade 2 gastrointestinal toxicity. Radiotherapy affects erectile function to a lesser degree than surgery according to retrospective surveys of patients (2). A recent meta-analysis has shown that the one-year rate of probability for maintaining erectile function was 0.76 after brachytherapy, 0.60 after brachytherapy plus external irradiation, 0.55 after external irradiation, 0.34 after nerve-sparing radical prostatectomy, and 0.25 after standard radical prostatectomy. When studies with more than two years of follow-up were selected (i.e. excluding brachytherapy), the rates became 0.60, 0.52, 0.25, and 0.25, respectively, with a greater spread between the radiation techniques and surgical approaches (55). Recent studies have demonstrated a significantly increased risk of developing secondary malignancies of the rectum and bladder following EBRT (56, 57). In a retrospective evaluation of 30,552 and 55,263 men who had undergone either EBRT or radical prostatectomy, the risk of being diagnosed with rectal cancer increased 1.7fold in comparison with the surgery group (56). Another analysis (57) showed that the relative risk of developing bladder cancer increased by 2.34-fold compared with a healthy control population. Corresponding data on late toxicity has also been reported by the Memorial Sloan-Kettering Cancer Center group, from its experience in 1571 patients with T1-T3 disease treated with either 3D-CRT or IMRT in doses of between 66 Gy and 81 Gy, with a median follow-up of 10 years (58). Both acute GI and GU toxicity appeared to predict for corresponding late toxicity. The overall rates of NCIC-CTC grade 2 or more GI toxicity was 5% with IMRT, compared with 13% with 3D-CRT. The incidence of grade 2 or more late GU toxicity was 20% in patients treated with 81 Gy, compared with 12% in patients treated with lower doses. The overall incidence of grade 3 GI toxicity was 1%, and grade 3 GU toxicity was 3%. These data suggest that IMRT can successfully protect against late GI toxicity, but, interestingly, with dose escalation, GU toxicity may take over as the dominant morbidity (58).

10.7

Immediate post-operative external irradiation for pathological tumour stage T3 N0, M0

Extracapsular invasion (pT3) is associated with a risk of local recurrence, which can be as high as 30% (59). In a multifactorial analysis, the predictors of biochemical relapse are: • PSA level (p = 0.005) • Gleason score of the surgical specimen (p = 0.002) • positive surgical margins (p < 0.001) (60). Three prospective randomised trials have assessed the role of immediate post-operative radiotherapy. The EORTC study 22911, with a target sample size of 1005 patients, compared immediate post-operative radiotherapy (60 Gy) with radiotherapy delayed until local recurrence (70 Gy) in patients classified as pT3 pN0 after retropubic radical prostatectomy. Immediate post-operative radiotherapy proved to be well tolerated, with a risk of grade 3-4 urinary toxicity of less than 3.5% (61), without significant differences regarding the rate of incontinence and/or stricture of anastomosis (62). The study concludes that immediate post-operative radiotherapy after surgery significantly improves five-year clinical or biological survival: 72.2% vs 51.8% (p < 0.0001) (63). However, the EORTC study has not yet demonstrated improved metastasis-free and cancer-specific survival in this cohort of patients. The most suitable candidates for immediate radiation therapy might be those with multifocal positive surgical margins and a Gleason score > 7. The conclusions of the ARO trial 96-02 – based on a cohort of 385 patients – echoed those of EORTC since after a median follow-up of 54 months, biochemical progression-free survival was significantly improved in the radiotherapy group: 72% vs 54% (p = 0.0015) (64).

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In the same way, the SWOG 8794 trial randomised 425 pT3 patients, and the updated results (65), with a median follow-up of 11.5 years, show that adjuvant radiation significantly improved metastasis-free survival, with a 15-year metastasis-free survival of 46% vs 38% (p = 0.036) and a 15-year overall survival of 47% vs 37% (p = 0.053). Thus, for patients classified as T1-2 N0 (or T3 N0 with selected prognostic factors), pT3 pN0 with a high risk of local failure after radical prostatectomy due to capsular rupture, positive margins and/or invasion of the seminal vesicles, who present with a PSA level of < 0.1 ng/mL one month after surgery, two options can be offered within the frame of an informed consent: • either an immediate radiotherapy to the surgical bed (66) upon recovery of urinary function • or clinical and biological monitoring followed by salvage radiotherapy when the PSA exceeds 0.5 ng/ mL (67); 1.0 ng/mL seems to be a breakpoint above which the likelihood of local control is significantly reduced (68). A retrospective analysis based on 635 patients undergoing prostatectomy from 1982-2004, followed up through to December 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (397) or salvage radiotherapy alone (160) within two years of biochemical recurrence has shown that salvage radiotherapy was associated with a threefold increase in prostate cancer-specific survival relative to those who received no salvage treatment (p < 0.001) (69). These two approaches, together with the efficacy of neo-adjuvant hormone therapy, are currently being compared in the UK MRC RADICALS randomised trial, and the role of short-term hormone therapy in combination with radiotherapy in the EORTC 22043 randomised trial.

10.8

Locally advanced prostate cancer: T3-4 N0, M0

The incidence of locally advanced prostate cancer has declined as a result of individual or mass screening. Pelvic lymph node irradiation is optional for N0 patients, but the results of radiotherapy alone are very poor (70). Because of the hormonal dependence of prostate cancer (71), ADT has been combined with external irradiation with the aim of: • reducing the risk of distant metastases by potentially sterilising micrometastases already present at the moment of diagnosis • decreasing the risk of non-sterilisation and/or local recurrence as a source of secondary metastases (72) through the effect of radiation-induced apoptosis (73, 74). Numerous randomised trials have confirmed the value of long-term administration. 10.8.1 Neoadjuvant and concomitant hormonal therapy The RTOG study 86-10 included 471 patients with bulky (5 x 5 cm) tumours T2-4N0-X M0. ADT was administered two months before irradiation and during irradiation, or in the case of relapse in the control arm. Thirty-two per cent of patients were diagnosed as T2, 70% as T3-4, and 91% as N0. The hormone treatment consisted of oral eulexine, 250 mg three times daily, and goserelin acetate (Zoladex), 3.6 mg every four weeks by subcutaneous injection. The pelvic target volume received 45 Gy, and the prostatic target volume received 20-25 Gy. The 10-year overall survival estimates – 43% vs 34% – favoured ADT and irradiation, but the difference was not significant (p = 0.12). There was a significant improvement in the 10-year disease-specific mortality (23% vs 36%; p = 0.01), disease-free survival (11% vs 3%; p < 0.0001), and biochemical failure (65% vs 80%; p < 0.0001), with the addition of ADT having no statistical impact on the risk of fatal cardiac events (75). 10.8.2 Concomitant and long-term adjuvant hormonal therapy The EORTC study 22863 recruited 415 patients diagnosed with T1-2 grade 3 WHO (World Health Organization), T3-4, N0 M0 and any histological grade, and compared radiotherapy plus adjuvant ADT, with radiotherapy alone. ADT was allowed in cases of relapse. A total of 82% of patients was diagnosed as T3, 10% as T4, and 89% as N0. The hormone treatment consisted of oral cyproterone acetate (CPA), 50 mg three times daily for one month, beginning one week before the start of radiotherapy, and goserelin acetate (Zoladex), 3.6 mg subcutaneously every four weeks for three years, starting on the first day of radiotherapy. The pelvic target volume received was 50 Gy, and the prostatic target volume was 20 Gy. With a median follow-up of 66 months, combination therapy compared with radiotherapy alone yielded significantly better survival (78% vs 62%, p = 0.001) (76). At a median follow-up of 9.1 years, the 10-year overall survival remained significantly higher – 58.1% vs 39.8%

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(p < 0.0001) – as did clinical progression-free survival – 47.7% vs 22.7% (p < 0.0001). The 10-year cumulative incidence of prostate cancer mortality was 11. 1% vs 31% (p < 0.0001), and the 10-year cumulative incidence of cardiovascular mortality was 11.1% vs 8.2% (p = 0.75) (77). 10.8.3 Long-term adjuvant hormonal therapy The RTOG study 85-31 recruited 977 patients diagnosed with T3-4 N0-1 M0, or pT3 after radical prostatectomy. ADT was begun in the last week of irradiation and continued up to relapse (group I) or was started at recurrence (group II). A total of 15% of patients in group I and 29% in group II had undergone radical prostatectomy, while 14% of patients in group I and 26% in group II were pN1. Goserelin acetate, 3.6 mg subcutaneously, was administered every four weeks. The pelvis received 45 Gy and the prostatic bed received 20-25 Gy. Patients diagnosed with stage pT3 received 60-65 Gy. With a median follow-up time of 7.6 years for all patients, the 10-year overall survival was significantly greater for the adjuvant arm, at 49% vs 39% (p = 0.002) (78). National Cancer Institute (NCI) of Canada /Medical Research Council intergroup PR3/PR07 study, including patients diagnosed with stage cT3-4 N0 M0, compared complete androgen blockade (CAB) (goserelin acetate 3.6 mg subcutaneously every four weeks and flutamide 750 mg/ day) alone and in combination with radiation 65-69 Gy (79, 80). The results are awaited. The SPCG-7/SFUO-3 randomised study (81) compared endocrine treatment alone, three months of CAB followed by continuous endocrine treatment using flutamide (439 patients) with the same treatment combined with radiotherapy (436 patients). After a median follow-up of 7.6 years, the 10-year cumulative incidence for prostate cancer-specific mortality was respectively 23.9% and 11.9% (difference 12%; 95% CI; 4.9-19.1%), and the 10-year cumulative incidence for overall mortality was 39.4% in the endocrine treatment alone group, and 29.6% in the endocrine plus radiotherapy group (difference 9.8%; 0.8-18%). 10.8.4 Neoadjuvant, concomitant and long-term adjuvant hormonal therapy The RTOG 92-02 trial closed in 1995 after accruing 1554 patients. Statistically significant improvements were observed in actuarial biochemical freedom from disease (bNED) control, distant metastatic failure, local control, and disease-free survival in patients receiving long-term ADT (LDAT) (before, during, and two years after radiotherapy), compared with short-term androgen deprivation (STAD) (two months before and during radiotherapy). With a median follow-up of 5.8 years, the LTAD treatment arm showed significant improvement over the STAD arm in all efficacy end-points except five-year overall survival, which was 80% vs 78.5% (p = 0.73), respectively. In a subset of patients that was not part of the original study design, with Gleason score 8-10 tumours, the LTAD arm showed significantly better overall survival after five years than the STAD arm, with 81% vs 70.7% (p = 0.04) (82). 10.8.5 Short-term or long-term adjuvant hormonal treatment Further to EORTC trial 22863, EORTC equivalence trial 22961 was set up to test whether similar survival could be achieved in patients who underwent irradiation (to 70 Gy) and six months of combined ADT without further ADT, i.e. STADT arm, compared with patients with 2.5 years of further treatment with luteinising hormonereleasing hormone analogue (LHRHa), i.e. LTADT arm. Eligible patients had T1c-2b N1-2 or pN1-2, or T2c-4 N0-2 (UICC 1992) M0 prostate cancer with PSA < 150 ng/mL. Non-inferior survival was defined as a mortality hazard ratio (HR) = 1.35 for SADT vs LADT. A total of 970 patients were randomised. With a 5.2-year median follow-up, the five-year overall survival rate was 85.3% on LADT, and 80.6% on SADT (HR = 1.43; 96.4% CI; 1.04-1.98), and failed to prove non-inferiority (83). 10.8.6 Dose escalation with hormonal therapy For bulky locally advanced prostate cancer, there might be a role for dose escalation as suggested by the excellent results of a retrospective series by the Memorial Sloan-Kettering Cancer Center devoted to 296 patients: 130 cT3a N0-X M0 and 166 cT3bN0-X M0. The prescribed doses to the prostate gland ranged from 66 Gy to 86.4 Gy; 95 patients received IMRT with dose escalation beyond 81 Gy. ADT was given for three months prior to radiotherapy to 189 patients (64%), and was continued during the course of radiotherapy for patients with high-grade disease. With a median follow-up of eight years, the five- and 10-year overall survival and cause-specific survival were respectively 91% and 65%, 95% and 83% (84).

10.9

Very high-risk prostate cancer: c or pN1, M0

Patients with a pelvic lymph node involvement lower than the iliac regional nodes, younger than 80 years old with WHO performance status 0-1 and no severe co-morbidity may be candidates for external beam irradiation plus immediate long-term hormonal manipulation. The RTOG 85-31 randomised phase III trial has shown, with

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a median follow-up of 6.5 years, that 95 patients out of the 173 pN1 patients who received pelvic radiotherapy with immediate hormonal therapy had better five and nine-year progression-free survival (PSA < 1.5 ng/mL), with 54% and 10% respectively versus 33% and 4% with radiation alone and hormonal manipulation instituted at the time of relapse (p < 0.0001). Multivariate analysis revealed this combination as having a statistically significant impact on overall survival, disease-specific failure, metastatic failure and biochemical control (85).

10.10 Summary of definitive radiation therapy

•

•

•

•

•

In localised prostate cancer T1c-T2c N0 M0, 3D-CRT with or without IMRT is recommended even for young patients who refuse surgical intervention. There is fairly strong evidence that low-, intermediate- and high-risk patients benefit from dose escalation For patients in the high-risk group, short-term ADT prior to and during radiotherapy results in increased overall survival. Transperineal interstitial brachytherapy with permanent implants is an option for patients with cT1T2a, Gleason score < 7 (or 3 + 4), PSA ≤ 10 ng/mL, prostate volume ≤ 50 mL, without a previous TURP and with a good IPSS. Immediate post-operative external irradiation after radical prostatectomy for patients with pathological tumour stage T3 N0 M0 improves biochemical and clinical disease-free survival. An alternative option is to give radiation at the time of biochemical failure, but before PSA rises above 1ng/mL. In locally advanced prostate cancer T3-4 N0 M0, overall survival is improved by concomitant and adjuvant hormonal therapy for a total duration of three years, with external irradiation for patients with a WHO 0-1 performance status. For a subset of patients with T2c-T3 N0-x and a Gleason score of 2- 6, short-term ADT before and during radiotherapy may favourably influence overall survival. In very high-risk prostate cancer, c-pN1 M0 with no severe co-morbidity, pelvic external irradiation and immediate long-term adjuvant hormonal treatment improve overall survival, disease-specific failure, metastatic failure and biochemical control.

LE 2

2a 2b

1 3 1

1b 2b

LE = level of evidence

10.11 REFERENCES 1.

2.

3.

4.

5.

6.

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Pilepich MV, Winter K, Lawton C, Krisch RE, Wolkov H, Movsas B, Hug E, Asbell S, Grignon D. Phase III trial of androgen suppression adjuvant to definitive radiotherapy. Long term results of RTOG study 85-31. Proc Am Society Clin Oncol 2003;22:(abstr.1530). http://pediatricca.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnex toid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=23&abst ractID=101094 79. Warde P, Intergroup (NCIC CTG, CUOG, ECOG, CALGB, SWOG). Phase III randomized trial comparing total androgen blockade versus total androgen blockade plus pelvic irradiation in clinical stage T3-4, N0, M0 adenocarcinoma of the prostate. National Cancer Institute of Canada, Clinical Trials Group, 1995. https://www.swogstat.org/ROS/ROSBooks/Spring%202002/Intergroup/NCIC/PR3-2001.pdf 80. Mason M, Warde P, Sydes M, Cowan R, James N, Kirkbride P, Langley R, Latham J, Moynihan C, Anderson J, Millet J, Nutall J, Moffat L, Parulekar W, Parmar M; The National Cancer Institute of Canada Clinical Trials Group PR3/; Medical Research Council PR07 Trial Management Group. Defining the need for local therapy in locally advanced prostate cancer: an appraisal of the MRC PR07 study. Clin Oncol (R Coll Radiol) 2005;17(4):217-8. http://www.ncbi.nlm.nih.gov/pubmed/15997913 81. Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JÅ, Tasdemir I, Hoyer M, Wiklund F, Fosså SD for the Scandinavian Prostate Cancer Group Study, the Swedish Association for Urological Oncology. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomized phase III trial. Lancet 2008;373(9660):301-8. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61815-2/abstract 82. Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. RTOG 92-02: Phase III trial of long term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate. J Clin Oncol 2003;21(21):3972-8. http://www.ncbi.nlm.nih.gov/pubmed/14581419 83. Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh AC, Van der Meijden AP, Poortmans PM, Gez E, Kil P, Piérart M, Collette L. Concomitant and adjuvant androgen deprivation (ADT) with external beam irradiation (RT) for locally advanced prostate cancer: 6 months versus 3 years ADT: Results of the randomized EORTC Phase III trial 22961. J Clin Oncol 2007;25:238s(abstr.5014). 84. Zelefsky MJ, Yamada Y, Kollmeier MA, Shippy AM, Nedelka MA. Long term outcome following threedimensional conformal/intensity modulated external-beam radiotherapy for clinical stage T3 prostate cancer. Eur Urol 2008;53(6):1172-9. http://www.ncbi.nlm.nih.gov/pubmed/18222596 85. Lawton CA, Winter K, Grignon D, Pilepich MV. Androgen suppression plus radiation versus radiation alone for patients with D1/pathologic node-positive adenocarcinoma of the prostate: updated results based on a national prospective randomized trial, RTOG 85-31. J Clin Oncol 2005;23(4):800-7. http://www.ncbi.nlm.nih.gov/pubmed/15681524

11. EXPERIMENTAL LOCAL TREATMENT OF PROSTATE CANCER 11.1

Background

Besides radical prostatectomy, external beam radiation and/or brachytherapy, cryosurgical ablation of the prostate (CSAP) and high-intensity focused ultrasound (HIFU) have emerged as alternative therapeutic options in patients with clinically localised prostate cancer (PCa) (1-4). Whereas HIFU is still considered to be an experimental treatment, CSAP has been recognised as a true therapeutic alternative as recommended by the guidelines of the American Urological Association. Both techniques have been developed as minimally invasive procedures that potentially have the same therapeutic efficacy as the established surgical and non-surgical options associated with reduced therapy-associated morbidity.

11.2

Cryosurgery of the prostate (CSAP)

Cryosurgery uses freezing techniques to induce cell death by:

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• • • •

dehydration resulting in protein denaturation direct rupture of cellular membranes by ice crystals vascular stasis and microthrombi, resulting in stagnation of the microcirculation with consecutive ischaemia apoptosis (1-4).

Freezing of the prostate is ensured by the placement of 12-15 17 G cryoneedles under transrectal ultrasound (TRUS) guidance, placement of thermosensors at the level of the external sphincter and the bladder neck, and insertion of a urethral warmer. Two freeze-thaw cycles are used under TRUS guidance, resulting in a temperature of -40 °C in the mid-gland and at the neurovascular bundle. 11.2.1 Indication for CSAP Patients who are ideal candidates for CSAP are those who have organ-confined PCa and those identified to have minimal extension beyond the prostate (1-3). The prostate should be ≤ 40 mL in size. Prostate glands that are > 40mL should be hormonally downsized in order to prevent technical difficulties in placing cryoprobes under the pubic arch. Prostate-specific antigen (PSA) serum levels should be < 20 ng/mL, and the biopsy Gleason score should be < 7. Since there are no, or only very few, data on the long-term outcome in terms of cancer control at 10 and 15 years, patients with a life expectancy > 10 years must be informed accordingly. 11.2.2 Results of modern cryosurgery for PCa When comparing treatment modalities, it is important to bear in mind that in modern radical prostatectomy series of patients with clinically organ-confined PCa, the risk of dying from PCa 10 years after surgery is as low as 2.4% (5). Therapeutic results have improved over time with enhanced techniques in terms of gas-driven probes and transperineal probe placement as used in third-generation cryosurgery (6-11). Objective assessment of PSA outcome is not easily performed because some institutions use PSA values < 0.1 ng/mL as an indicator of therapeutic success, whereas others use the American Society of Therapeutic Radiology and Oncology (ASTRO) criteria with three consecutive PSA increases. With regard to second-generation CSAP, if a PSA nadir < 0.5 ng/mL is used, biochemical-free survival at five years is 60% and 36% for low-risk and high-risk patients, respectively (6, 7). The seven-year biochemical-free survival, however, is 92% if ASTRO criteria are used. Long et al. (6) retrospectively analysed the multicentre pooled CSAP results of 975 patients who were stratified into three risk groups. Using PSA thresholds of 1.0 ng/mL and < 0.5 ng/mL at a mean follow-up of 24 months, the five-year actuarial biochemical progression-free rate was 76% and 60%, respectively, for the low-risk group, 71% and 45%, respectively, for the intermediate-risk group, and 61% and 36%, respectively, for the high-risk group. However, in a recent meta-analysis of 566 publications related to cryosurgery, it was demonstrated that no controlled trial was available for analysis, no survival data were presented, and no validated biochemical surrogate end-points were available (12). Cryosurgery showed a progression-free survival of 36-92% (projected one- to seven-year data), depending on risk groups and the definition of failure. Negative biopsies were seen in 72-87%, but no biopsy data were available for the currently used thirdgeneration cryotherapy machines. With regard to third-generation cryosurgery, clinical follow-up is short, with only 110/175 (63%) patients having a PSA follow-up at 12 months (6-11). Of these, 80 (73%) patients remain with a PSA nadir < 0.4 ng/mL, and 42/65 (76%) low-risk patients remain free from biochemical progression using the 0.4 ng/mL cut-off. A longer follow-up was reported by Bahn et al. (9) analysing the therapeutic results of 590 patients undergoing CSAP for clinically localised and locally advanced PCa. Using a PSA cut-off level of < 0.5 ng/mL, the sevenyear biochemical-free survival for low-, medium- and high-risk groups was 61%, 68% and 61%, respectively. Nerve-sparing cryosurgery, as reported recently (13), must still be considered to be an experimental therapeutic option. Nerve-sparing surgery was performed in nine patients with unilateral PCa confirmed on repeated biopsies, with CSAP being carried out on the side of the positive biopsy, whereas the negative biopsy side was spared from freezing. 11.2.3 Complications of CSAP for primary treatment of PCa Erectile dysfunction occurs in about 80% of patients and remains a consistent complication of the CSAP procedure, independent of the generation of the system used. The complication rates described with the third

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generation of cryosurgery include tissue sloughing in about 3%, incontinence in 4.4%, pelvic pain in 1.4% and urinary retention in about 2% (6-11). The development of fistula is usually rare, with < 0.2% in modern series. About 5% of all patients require transurethral resection of the prostate (TURP) for subvesical obstruction. Quality of life and sexuality following CSAP have been investigated in a clinical phase II trial recruiting 75 men (14). Quality-of-life analysis by the prostate-specific FACT-P questionnaire revealed that most subscales had returned to pre-treatment levels by 12 months after CSAP. Furthermore, no significant changes could be determined when comparing the 36-month with the 12-month data. With regard to sexuality, 37% of the men were able to have intercourse at three years after CSAP. 11.2.4 Summary of CSAP • Patients with low-risk PCa (PSA < 10 ng/mL, ≤ T2a, Gleason score ≤ 6) or intermediate-risk PCa (PSA > 10 ng/mL, or Gleason score ≥ 7, or stage ≥ 2b) represent potential candidates for CSAP. • Prostate size should be < 40 mL at the time of therapy. • Long-term results are lacking, and five-year biochemical progression-free rates are inferior to those achieved by radical prostatectomy in low-risk patients. Patients must be informed accordingly.

11.3

High-intensity focused ultrasound (HIFU)

HIFU consists of focused ultrasound waves emitted from a transducer to cause tissue damage by mechanical and thermal effects as well as by cavitation (15). The goal of HIFU is to heat malignant tissues above 65 °C in order to destroy them by coagulative necrosis. HIFU is performed under general or spinal anesthesia, with the patient in the lateral (Ablatherm®) or supine (Sonablate® 500) position; the procedure is time-consuming, with about 10 g prostate tissue being treated in one hour. In a recent review, 150 papers related to HIFU were identified and evaluated with regard to various oncological and functional outcome parameters (12). No controlled trial was available for analysis, and no survival data were presented. No validated biochemical, surrogate end-point was available for HIFU therapy. 11.3.1 Results of HIFU in PCa As with CSAP, it appears to be difficult to interpret oncological outcome in patients undergoing HIFU since various PSA thresholds are defined and no international consensus exists on objective response criteria. The results of HIFU are limited, with outcome data from fewer than 1000 PCa cases having been published in the literature. According to the recent review paper mentioned above (12), HIFU showed progression-free survival (based on PSA +/- biopsy data) of 63-87% (projected three- to five-year data), but median follow-up in the studies ranged from 12-24 months only. In one of the largest single-centre studies, 227 patients with clinically organ confined PCa were treated with HIFU and their outcome data were analysed after a mean follow-up of 27 months (range = 12-121 months) (16). The projected five-year biochemical disease-free survival was 66%, and or only 57% if patients had exhibited a pre-therapeutic PSA value of 4-10 ng/mL. Incontinence and bladder neck stricture decreased over time from 28% and 31% to 9% and 6%, respectively. In one of the studies (17), a significant decrease in pre-treatment PSA serum levels from 12 ng/mL to 2.4 ng/mL was observed. However, 50% of the 14 patients demonstrated positive prostate biopsies during follow-up. In another study (18), a complete response rate defined by PSA < 4 ng/mL and six negative biopsies was achieved in 56% of the patients. Summarising the efficacy results of a European multicentre study comprising the data of 559 patients with mainly low- and intermediate-risk PCa, Thüroff et al. (18) reported on a negative biopsy rate of 87.2% in 288 men with a follow-up of at least six months. A PSA nadir after six months follow-up could be determined in 212 patients, and it was as high as 1.8 ng/mL. However, it could be demonstrated that the PSA nadir might be reached at 12-18 months following the initial procedure. Blana et al. reported on 146 patients undergoing HIFU with a mean follow-up of 22.5 months (19). The mean PSA level at initiation of therapy was 7.6 ng/mL; the PSA nadir achieved after three months was 0.07 ng/mL. However, after 22 months the median PSA level was 0.15 ng/mL. Of the 137 men available for analysis, 93.4% demonstrated a negative control biopsy. The PSA nadir appears to be strongly associated with treatment failure (20) (p < 0.001). Patients with a PSA nadir of 0.0-0.2 ng/mL have a treatment failure rate of only 11%, compared with 46% in patients with a PSA nadir of 0.21-1.00 ng/mL, and 48% with a PSA nadir of >1.0 ng/mL. Recently, the group updated its results, with a total of 163 men treated for clinically organ-confined PCa. Within

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the 4.8 +/- 1.2 years of follow-up, the actuarial disease-free survival rate at five years was 66%, with salvage treatment initiated for 12% of the patients (21). 11.3.2 Complications of HIFU Urinary retention appears to be one of the most common side-effects of HIFU, developing in almost all patients, with the mean interval of catheterisation via a suprapubic tube varying between 12 and 35 days (1517). Grade I and II urinary stress incontinence occurs in about 12% of patients. Subsequent TURP or bladder neck incision to treat subvesical obstruction is common, and is sometimes even performed at the time of HIFU. Post-operative impotence will occur in approximately 55-70% of patients.

11.4

Radio-frequency interstitial tumour ablation (RITA)

Radio-frequency interstitial tumour ablation (RITA) is a recently developed minimally invasive therapeutic option delivering radio-frequency energy via a needle electrode placed inside the prostate and resulting in coagulative necrosis by heating the tissue up to 100 °C. Clinical application so far has been limited to two small studies demonstrating the feasibility and safety of the procedure (22, 23). However, there are reliable data with regard to oncological control of PCa.

11.5

Summary of experimental therapeutic options to treat clinically localised PCa

Recommendation GR • CSAP has evolved from an investigational therapy to a possible alternative treatment for PCa in C patients who are unfit for surgery or with a life expectancy < 10 years • All other minimally invasive treatment options – such as HIFU, RITA, microwave and electro- C surgery – are still experimental or investigational. For all of these procedures, a longer follow-up is mandatory to assess their true role in the management of PCa GR = grade of recommendation

11.6

REFERENCES

1.

Fahmy WE, Bissada NK. Cyrosurgery for prostate cancer. Arch Androl 2003;49(5):397-407. http://www.ncbi.nlm.nih.gov/pubmed/12893518 2. Rees J, Patel B, Macdonagh R, Persad R. Cryosurgery for prostate cancer. BJU Int 2004;93(6):710-4. http://www.ncbi.nlm.nih.gov/pubmed/15049977 3. Han KR, Belldegrun AS. Third–generation cryosurgery for primary and recurrent prostate cancer. BJU Int 2004;93(1):14-8. http://www.ncbi.nlm.nih.gov/pubmed/14678360 4. Beerlage HP, Thüroff S, Madersbacher S, Zlotta AR, Aus G, de Reijke TM, de la Rosette JJMCH. Current status of minimally invasive treatment options for localized prostate carcinoma. Eur Urol 2000;37(1):2-13. http://www.ncbi.nlm.nih.gov/pubmed/10671777 5. Hull GW, Rabbani F, Abbas F, Wheeler TM, Kattan MW, Scardino PT. Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol 2002;167(2 Pt 1):528-34. http://www.ncbi.nlm.nih.gov/pubmed/11792912 6. Long JP, Bahn D, Lee F, Shinohara K, Chinn DO, Macaluso JN Jr. Five-year retrospective, multiinstitutional pooled analysis of cancer-related outcomes after cryosurgical ablation of the prostate. Urology 2001;57(3):518-23. http://www.ncbi.nlm.nih.gov/pubmed/11248631 7. Donelly BJ, Saliken JC, Ernst DS, Ali-Ridha N, Brasher PMA, Robinson JW, Rewcastle JC. Prospective trial of cryosurgical ablation of the prostate: five year results. Urology 2002;60(4):645-9. http://www.ncbi.nlm.nih.gov/pubmed/12385926 8. Han K, Cohen J, Miller R, Pantuck AJ, Freitas DG, Cuevas CA, Kim HL, Lugg J, Childs SJ, Shuman B, Jayson MA, Shore ND, Moore Y, Zisman A, Lee JY, Ugarte R, Mynderse LA, Wilson TM, Sweat SD, Zincke H, Belldegrun AS. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicentre experience. J Urol 2003;170(4 Pt 1):1126-30. http://www.ncbi.nlm.nih.gov/pubmed/14501706 9. Bahn DK, Lee F, Baldalament R, Kumar A, Greski J, Chernick M. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology 2002;60(2 Suppl 1): 3-11. http://www.ncbi.nlm.nih.gov/pubmed/12206842

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10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

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Koppie TM, Shinohara K, Grossfeld GD, Presti JC Jr, Carroll PR. The efficacy of cryosurgical ablation of prostate cancer: the University of California, San Francisco experience. J Urol 1999;162(2):427-32. http://www.ncbi.nlm.nih.gov/pubmed/10411051 De La Taille A, Benson MC, Bagiella E, Burchardt M, Shabsigh A, Olsson CA, Katz AE. Cryoablation for clinically localized prostate cancer using an argon-based system: complication rates and biochemical recurrence. BJU Int 2000;85(3):281-6. http://www.ncbi.nlm.nih.gov/pubmed/10671882 Aus G. Current status of HIFU and cryotherapy in prostate cancer – a review. Eur Urol 2006;50(5): 927-34. http://www.ncbi.nlm.nih.gov/pubmed/16971038 Onik G, Narayan P, Vaughan D, Dineen M, Brunelle R. Focal ‘nerve-sparing’ cryosurgery for treatment of primary prostate cancer: a new approach to preserving potency. Urology 2002;60(1):109-14. http://www.ncbi.nlm.nih.gov/pubmed/12100934 Robinson JW, Donnelly BJ, Saliken JC, Weber BA, Ernst S, Rewcastle JC. Quality of life and sexuality of men with prostate cancer 3 years after cryosurgery. Urology 2002;60(2 Suppl 1):12-8. http://www.ncbi.nlm.nih.gov/pubmed/12206843 Madersbacher S, Marberger M. High-energy shockwaves and extracorporeal high-intensity focused ultrasound. J Endourol 2003;17(8):667-72. http://www.ncbi.nlm.nih.gov/pubmed/14622487 Poissonnier L, Chapelon JY, Rouviere O, Curiel L, Bouvier R, Martin X, Dubernard JM, Gelet A. Control of prostate cancer by transrectal HIFU in 227 patients. Eur Urol 2007;51(2):381-7. http://www.ncbi.nlm.nih.gov/pubmed/16857310 Gelet A, Chapelon JY, Bouvier R, Pangaud C, Lasne Y. Local control of prostate cancer by transrectal high intensity focused ultrasound therapy: preliminary results. J Urol 1999;161(1):156-62. http://www.ncbi.nlm.nih.gov/pubmed/10037389 Thüroff S, Chaussy C, Vallancien G, Wieland W, Kiel HJ, Le Duc A, Desgrandschamps F, de la Rosette JJMCH, Gelet A. High-intensity focused ultrasound and localized prostate cancer: efficacy from the European multicentric study. J Endourol 2003;17(8):673-7. http://www.ncbi.nlm.nih.gov/pubmed/14622488 Blana A, Walter B, Rogenhofer S, Wieland W. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology 2004;63(2)297-300. http://www.ncbi.nlm.nih.gov/pubmed/14972475 Uchida T, Illing RO, Cathcart PJ, Emberton M. To what extent does the prostate-specific antigen nadir predict subsequent treatment failure after transrectal high-intensity focused ultrasound therapy for presumed localized adenocarcinoma of the prostate? BJU Int 2006;98(3):537-9. http://www.ncbi.nlm.nih.gov/pubmed/16925749 Blana A, Rogenhofer S, Ganzer R, Lunz JC, Schostak M, Wieland WF, Walter B. Eight years’ experience with high-intensity focused ultrasonography for treatment of localized prostate cancer. Urology 2008;72(6):1329-33. http://www.ncbi.nlm.nih.gov/pubmed/18829078 Zlotta AR, Djavan B, Matis C, Noel JC, Peny MO, Silverman DE, Marberger M, Schulman CC. Percutaneous transperineal radiofrequency ablation of prostate tumour: safety, feasibility and pathological effects on human prostate cancer. Br J Urol 1998;81(2):265-75. http://www.ncbi.nlm.nih.gov/pubmed/9488071 Djavan B, Zlotta AR, Susani M, Heinz G, Shariat S, Silverman DE, Schulman CC, Marberger M. Transperineal radiofrequency interstitial tumour ablation of the prostate: correlation of magnetic resonance imaging with histopathologic examination. Urology 1997;50(6):986-92. http://www.ncbi.nlm.nih.gov/pubmed/9426739

12. HORMONAL THERAPY 12.1

Introduction

In 1941, Huggins and Hodges assessed the favourable effect of surgical castration and oestrogen administration on the progression of metastatic prostate cancer (PCa), demonstrating for the first time the responsiveness of PCa to androgen deprivation (1, 2). Since their pivotal studies, androgen-suppressing strategies have become the mainstay of the management of

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advanced PCa. Recently, however, there has been an evolution towards the use increasing use of hormonal treatment in younger men with earlier (i.e. non-metastatic) stages of disease or recurrent disease after definitive treatment, either as the primary single-agent therapy or as a part of a multimodality approach (3). Even if hormonal treatment effectively palliates the symptoms of advanced disease, there is no conclusive evidence at present that it can extend life.

12.2

Basics of hormonal control of the prostate

Prostate cells are physiologically dependent on androgens to stimulate growth, function and proliferation. Testosterone, although not tumorigenic, is essential for the growth and perpetuation of tumour cells (4). The testes are the source of most of the androgens, with only 5-10% (androstenedione, dihydroepiandrosterone and dihydroepiandrosterone sulphate) being derived from adrenal biosynthesis. Testosterone secretion is regulated by the hypothalamic-pituitary-gonadal axis. The hypothalamic luteinising hormone-releasing hormone (LHRH) stimulates the anterior pituitary gland to release luteinising hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the Leydig cells of the testes to secrete testosterone. Within the prostate cells, testosterone is converted by the enzyme 5-∝-reductase into 5-∝-dihydrotestosterone (DHT), which is an androgenic stimulant approximately 10 times more powerful than the parent molecule (5). Circulating testosterone is peripherally aromatised and converted into oestrogens, which, together with circulating androgens, exert a negative feedback control on hypothalamic LH secretion. If prostate cells are deprived of androgenic stimulation, they undergo apoptosis (programmed cell death). Any treatment ultimately resulting in the suppression of androgen activity is referred to as androgen deprivation therapy (ADT).

12.3

Different types of hormonal therapy

Androgen deprivation can be achieved either by suppressing the secretion of testicular androgens by means of surgical or medical castration, or by inhibiting the action of the circulating androgens at the level of their receptor in prostate cells using competing compounds known as anti-androgens. Alternatively, these two modalities can be combined to achieve what is commonly known as complete (or maximal or total) androgen blockade (CAB). 12.3.1 Testosterone-lowering therapy (castration) 12.3.1.1 Bilateral orchiectomy Surgical castration is still considered the ‘gold standard’ for ADT against which all other treatments are rated. By removing the testicular source of androgens, a hypogonadal status with a considerable decline of testosterone concentrations is induced, although a very low level of testosterone (known as the ‘castration level’) persists. The standard castrate level is below 50 ng/dL. It was defined more than 40 years ago, when testosterone level testing was limited. Current methods, using chemiluminescence technology, have shown a mean value after surgical castration of 15 ng/dL (6). This observation has led to a revisiting of the current definition of castration, with some authors suggesting the use of a level below 20 ng/dL. Bilateral orchiectomy, either total or by means of a subcapsular technique (i.e. with preservation of tunica albuginea and epididymis), is a simple and virtually complication-free surgical procedure that can easily be performed under local anaesthesia (7). It is the quickest way to achieve a castration level, which is usually obtained in less than 12 hours. The main drawback of orchiectomy is that it may have a negative psychological effect: some men consider it to be an unacceptable assault on their manhood. In addition, it is irreversible and does not allow for intermittent treatment. The use of bilateral orchiectomy has declined recently, which can be attributed to the effects of stage migration towards earlier disease, and the introduction of equally effective pharmacological modalities of castration (8). 12.3.1.2 Oestrogens There are several mechanisms of action: • down-regulation of LHRH secretion • androgen inactivation

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• •

direct suppression of Leydig cell function direct cytotoxicity to the prostate epithelium (in vitro evidence only) (9).

The most commonly used oestrogen is diethylstilboestrol (DES). Early studies by the Veterans Administration Co-operative Urological Research Group (VACURG) (10) tested oral DES at a dosage of 5 mg/day. However, the treatment was associated with high cardiovascular morbidity and mortality due to first-pass hepatic metabolism and the formation of thrombogenic metabolites. Accordingly, subsequent studies (11) tested lower oral dosages, namely 3 mg and 1 mg. Both regimens provided a therapeutic efficacy comparable to that of bilateral orchiectomy, but the former was still associated with high cardiotoxicity. Although a 1 mg dose was associated with substantially fewer adverse cardiovascular events than the 5 mg dosage, the side-effects were still significantly greater than with castration. Because of these concerns, and the advent of LHRH agonists and anti-androgens, the use of DES had fallen out of favour until recently. There are three main reasons for the renewed interest in oestrogens. • First, as a response to the number of deleterious side-effects and high cost of long-term ADT with the widespread use of LHRH agonists: oestrogens suppress testosterone levels and do not seem to lead to bone loss and cognitive decline (12) (level of evidence: 3). • Second, in phase II trials with patients diagnosed with hormone-refractory prostate cancer (HRPC), oestrogenic compounds (DES, DES-diphosphate) have been shown to induce prostate-specific antigen (PSA) response rates as high as 86%. • Third, a new oestrogen receptor-β (ER-β), possibly involved in prostate tumorigenesis, has been discovered (9). Two different strategies have been used to try to neutralise the cardiotoxicity that is the main drawback of oestrogen therapy. These strategies use the parenteral route of administration, which avoids first-pass hepatic metabolism, plus the addition of cardiovascular protecting agents. The final analysis of the Scandinavian Prostatic Cancer Group Study 5, a prospective randomised trial of more than 900 men with metastatic PCa that compared a parenteral oestrogen (polyoestradiol phosphate) with CAB (orchiectomy or LHRH agonist plus flutamide), showed neither a significant difference in disease-specific and overall survival between the treatment arms, nor a significant increase in cardiovascular mortality in the oestrogen arm, although the occurrence of non-fatal adverse cardiovascular events was significantly higher in this group (increase in ischaemic heart and heart decompensation events) (13, for update see 14). On the other hand, three recent, though small, phase II trials of patients with advanced PCa or HRPC evaluated the combination of DES (1 mg/day or 3 mg/day), with either low dose (1 mg/day) warfarin sodium or low dose (75-100 mg/day) aspirin for the prevention of cardiovascular toxicity, and found a persistent rate of thromboembolic complications (15-17). In conclusion, DES is one of the classic forms of hormonal therapy. Although its efficacy was demonstrated many years ago and recently reconfirmed in a meta-analysis as comparable to that of bilateral orchiectomy (18) (level of evidence: 1a), the significant cardiovascular side-effects, even at lower dosages, remain a concern. Further data are needed before oestrogens will be readmitted into clinical practice as a standard first-line treatment option. 12.3.1.3 LHRH agonists Long-acting LHRH agonists (buserelin, goserelin, leuprorelin and triptorelin) have been used in advanced PCa for more than 15 years and are currently the predominant forms of ADT (3, 19). They are synthetic analogues of LHRH, generally delivered as depot injections on a one-, two-, three-, or six-monthly basis, that interfere with the hypothalamic-pituitary-gonadal axis. They initially stimulate pituitary LHRH receptors, inducing a transient rise in LH and FSH release, and consequently elevate testosterone production (known as ‘testosterone surge’ or ‘flare up’ phenomenon), which begins within approximately two or three days of the first injection and lasts through approximately the first week of therapy (20). Chronic exposure to LHRH agonists eventually results in down-regulation of LHRH-receptors, with subsequent suppression of pituitary LH and FSH secretion and testosterone production. The level of testosterone decreases to castration levels usually within two to four weeks (21, 22). However, approximately 10% of patients treated with LHRH agonists fail to achieve castration levels (23), or up to 15% if the threshold is defined as 20 ng/dL.

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In a recent meta-analysis evaluating single-therapy ADT for advanced PCa, LHRH agonists were shown to have comparable efficacy to orchiectomy and DES (18) (level of evidence: 1a). This observation questions the clinical impact of changing the castrate testosterone level definition from 50 ng/dL to 20 ng/dL. In addition, although only based on an indirect comparison, all seemed equally effective whatever their formulation (18) (level of evidence: 3). Today, LHRH agonists have become the ‘standard of care’ in hormonal therapy because they avoid the physical and psychological discomfort associated with orchiectomy, and lack the potential cardiotoxicity associated with DES. However, the main concerns associated with the administration of LHRH agonists are the potentially detrimental effects associated with the ‘flare phenomenon’ in advanced disease, namely increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and fatal cardiovascular events due to hypercoagulation status. A recent review (24) addressing these issues concluded that clinical flare needs to be distinguished from the more common biochemical flare (i.e. increasing levels of PSA), and even from asymptomatic radiographic evidence of progression, and that patients at risk for clinical flare are overwhelmingly those with high volume, symptomatic, bony disease, accounting for only 4-10% of M1 patients. Concomitant therapy with an anti-androgens definitely decreases the incidence of clinical relapse, but it does not completely remove the possibility of its occurrence. Based on pharmacokinetic considerations, it is recommended that administration of anti-androgens should be started on the same day as the depot injection, and treatment should be continued for a two-week period. However, for patients with impending spinal cord compression, alternative strategies for immediately ablating testosterone levels must be considered, such as bilateral orchiectomy or LHRH-antagonists. Apart from those patients, the clinical impact of the flare up observation is unknown. Finally, some mini-flares have also been observed with the long-term use of analogues, with an unknown clinical impact. 12.3.1.4 LHRH antagonists In contrast to the agonists, LHRH antagonists bind immediately and competitively to LHRH receptors in the pituitary gland. The effect is a rapid decrease in LH, FSH and testosterone levels without any flare. This seemingly more desirable mechanism of action has made LHRH antagonists very attractive since their introduction, but practical shortcomings have limited clinical studies. Indeed, many of these compounds have been associated with serious and life-threatening histamine-mediated side-effects and, until recently, no depot formulation was available. Two recently published phase III randomised multicentre trials comparing the LHRH antagonist abarelix with the LHRH agonist leuprorelin acetate (25) and with CAB (26) in patients with metastatic or recurrent PCa showed no difference in achieving and maintaining castration levels of testosterone and in reducing serum PSA. The biochemical ‘flare up’ phenomenon was not reported in the abarelix arms, and the overall incidence of severe adverse events (including allergic reactions) was similar across all treatment groups. Data on survival end-points and long-term safety are not yet available. Abarelix has recently been licensed for clinical use by the US Food and Drug Administration, but its use is restricted to those patients with metastatic and symptomatic PCa for whom no other treatment option is available (27). Recently, another antagonist, called degarelix, has been presented with preliminary promising results. In a phase II dose-finding study of 187 men, most patients had a testosterone level below 0.5 ng/mL at day 3, with a sustained effect at one year and no testosterone surge. The median testosterone value at one year for the 78.6% of patients with a level below 0.5 ng/mL was 0.12 ng/mL. No patient reported any systemic allergic reaction (28). Overall, even if this new family appears appealing, its real advantages over LHRH agonists are far from being proven. So far its use is limited by a monthly formulation, compared with three-month and six-month depot formulations. The clinical advantage of the suppression of the initial flare up is only clinically relevant in a minority of metastatic patients, and finally antagonists must confirm their efficacy in the long-term, most available trials being limited to a one-year follow-up period.

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12.3.2 Anti-androgens Anti-androgens compete with testosterone and DHT for binding sites on their receptors in the prostate cell nucleus, thus promoting apoptosis and inhibiting PCa growth (29). These orally administered compounds are classified according to their chemical structure as steroidal (e.g. cyproterone acetate [CPA], megestrol acetate and medroxyprogesterone acetate) and non-steroidal or pure (e.g. nilutamide, flutamide and bicalutamide). Both classes compete with androgens at the receptor level, but while this is the sole action of non-steroidal anti-androgens, steroidal anti-androgens additionally have progestational properties with central inhibition of the pituitary gland. As a consequence, non-steroidal anti-androgens do not lower testosterone levels, which remain normal or, conversely, slightly elevated. 12.3.2.1 Steroidal anti-androgens These compounds are synthetic derivatives of hydroxyprogesterone. In addition to peripherally blocking androgen receptors, they have progestational properties and inhibit gonadotrophin (LH and FSH) release and suppress adrenal activity. At high doses, megestrol acetate is cytotoxic. Since steroidal anti-androgens lower testosterone levels, the main pharmacological side-effects are loss of libido and erectile dysfunction; gynaecomastia is quite rare. The non-pharmacological side-effects are cardiovascular toxicity (4-40% for CPA) and hepatotoxicity. Cyproterone acetate (CPA) CPA was the first anti-androgen to be licensed. It is the most widely used drug, but the less studied one, leaving most questions unanswered (such as the optimal dose), or unclear (e.g. comparison with standard forms of castration – surgical or with an agonist). There is only one randomised trial (30) comparing CPA with standard hormonal therapy (i.e. medical castration). Patients in arm A (no contraindications to DES) were randomly assigned to CPA, goserelin or DES, while patients in arm B (contraindications to DES) were assigned to CPA or goserelin. In arm A, treatment with CPA was associated with significantly poorer median overall survival (OS) than goserelin only; adjusting for baseline characteristics did not account for this difference. Two other studies on CPA monotherapy have been performed, but one did not report survival data (31), and the other used a non-standard treatment combination (DES and medroxyprogesterone acetate [32]). It is therefore difficult to draw any definite conclusions from these data about the relative efficacy of CPA and castration. As no dose-finding studies of CPA monotherapy have been conducted, the most effective dose is still unknown. Although CPA has a relatively long half-life (30-40 hours), it is usually administered in two or three fractionated doses of 100 mg each (33). The only comparative study on anti-androgens as monotherapy was recently published by the European Organisation for Research and Treatment of Cancer (EORTC). The final analysis of Protocol 30892 (a randomised trial of 310 patients comparing CPA with flutamide in metastatic PCa), showed no difference in cancer-specific survival (CSS) and OS at a median follow-up of 8.6 years, although the study was underpowered (34) (level of evidence: 1b). Megestrol acetate and medroxyprogesterone acetate Very limited information is available on these two compounds. Early studies with megestrol acetate demonstrated a symptomatic and partially beneficial clinical response, both in previously untreated metastatic PCa (35-37) and, to a lesser extent, in HRPC (38). No apparent dose response correlation was shown to exist in a recent trial (39). The overall poor efficacy precluded megestrol acetate and medroxyprogesterone acetate from being recommended as a primary or second-line hormonal therapy option. The only prospective randomised trial evaluating medroxyprogesterone acetate as primary therapy in advanced (M0-1) PCa is the EORTC 30761 study mentioned above (31), in which 236 patients were assigned to receive CPA, DES or medroxyprogesterone acetate. While no difference in CSS and OS was evident between CPA and DES, treatment with medroxyprogesterone acetate had a less favourable course with a shorter survival time and time to progression than either of the other two drugs tested. 12.3.2.2 Non-steroidal anti-androgens Non-steroidal anti-androgens have been promoted in monotherapy for quality of life (QoL) and compliance benefits over castration: since they do not suppress testosterone secretion, it is claimed that libido, overall physical performance and bone mineral density are preserved (40).

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Although no direct comparisons have been undertaken in a monotherapy setting, the three available drugs do not appear to differ in the severity of pharmacological side-effects, namely gynaecomastia, breast pain and hot flashes. However, there are differences in the non-pharmacological side-effects, with bicalutamide showing a more favourable safety and tolerability profile than nilutamide and flutamide (41). They all share a common liver toxicity, and liver enzymes must be checked on a regular basis when they are used. Nilutamide There are no comparative trials on nilutamide monotherapy with castration or with other anti-androgens (42). Only one non-comparative study has been carried out, including 26 patients with M1 PCa who received nilutamide 100 mg three times daily. The results showed that as few as 38.5% of patients experienced an objective response; the median progression-free survival (PFS) time was nine months and the median OS was 23 months (43). One large randomised controlled trial of 457 patients with M1, which compared orchiectomy plus nilutamide, 300 mg/day, with orchiectomy plus placebo, showed a significant benefit in CSS and OS for the combined therapy (44). Recently, nilutamide has been tested as a second-line hormonal therapy in HRPC with encouraging results (45, 46). Non-pharmacological side-effects are visual disturbances (i.e. delayed adaptation to darkness), alcohol intolerance, nausea, hepatotoxicity, and interstitial pneumonitis. The latter, even if exceptional, is potentially life-threatening and is specific to this drug. Nilutamide is not licensed for monotherapy. Flutamide Flutamide was the first non-steroidal anti-androgen available for clinical use, and has been studied as monotherapy for more than 20 years, but no dose-finding studies against a currently accepted end-point (e.g. PSA response) have been published. Flutamide is a pro-drug, and the half-life of the active metabolite is five to six hours, so it must be administered three times per day in order to maintain therapeutic serum levels. The recommended daily dosage is 750 mg (33). Early phase II trials demonstrated flutamide to be effective in the treatment of advanced PCa, albeit that the reported response rates cannot be correlated with currently recommended end-points. The main advantage shown in these studies was the preservation of sexual function, which was maintained in up to 80% of patients with no pre-treatment erectile dysfunction (47-50). This rate has not been confirmed in the above mentioned EORTC trial 30892 (34), in which as few as 20% of men treated with flutamide maintained sexual activity for up to seven years. Although several phase III studies have been conducted, the results are often difficult to evaluate because of several drawbacks, such as the use of non-standard combinations, short-term follow-up and underpowering. Of these studies, only two phase III randomised trials comparing flutamide monotherapy with standard therapy (orchiectomy [51] and CAB [52]) for advanced PCa have reported survival data; both showed no significant difference in OS for flutamide or castration for patients with a PSA < 100 ng/mL (52). At higher PSA, flutamide was inferior. Both trials were underpowered, however. Results are eagerly awaited from an ongoing Swedish study in which 700 patients with M1 PCa have been randomised to flutamide 250 mg three times daily or CAB (40). The non-pharmacological side-effects are diarrhoea and hepatotoxicity (occasionally fatal). Bicalutamide Early reports with bicalutamide monotherapy related only to the 50 mg dosage, which was that licensed for use in CAB. An overall analysis of these studies showed that, although bicalutamide 50 mg/day had clinical benefits, it was inferior to castration in terms of OS (median difference 97 days) (53). Subsequent dose-ranging studies established that bicalutamide 150 mg once daily achieved a PSA response similar to that seen with castration while maintaining a good tolerability profile (54). Accordingly, the 150 mg dosage was chosen for further evaluation as both primary and adjuvant monotherapy. As primary monotherapy, bicalutamide 150 mg/day has been compared with medical or surgical castration in two large prospective randomised trials with identical study designs, including a total of 1435 patients with locally advanced M0 or M1 PCa (55). A pooled analysis showed: • In M1 patients, an improvement in OS with castration, although the difference in median survival between the groups was only six weeks (55); a further post hoc analysis showed a survival benefit only for patients with higher PSA levels (> 400 ng/mL) at study entry (56).

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•

In M0 patients (N = 480), no significant difference was noted in OS (57) based on the Kaplan Meier test, with median survival being 63.5 months in the bicalutamide arm compared with 69.9 months in the castration one.

In two smaller randomised trials, high-dose bicalutamide was compared with CAB. In the first trial (251 patients with predominantly M1 stage), no difference in OS was apparent (58). In the second trial (220 patients with M0 and M1 stage), there was no difference in OS for well or moderately well differentiated tumours (59) (level of evidence: 1b), but both studies were underpowered, and the first one has not yet been fully published. As for the adjuvant setting, the ongoing Early Prostate Cancer Programme (EPCP), a study comprising three different clinical trials of similar design and including 8113 patients worldwide, was designated to evaluate the efficacy and tolerability of high-dose (150 mg/day) bicalutamide vs placebo given in addition to standard primary care (i.e. radical prostatectomy, radiotherapy and watchful waiting) in localised (T1-2, N0-X) or locally advanced (T3-4, any N, or any T N+) PCa. The first combined analysis of the programme showed that, after a median follow-up of three years, adjuvant bicalutamide provided a reduction of 42% in the risk of objective disease progression compared with standard care alone (60). After a median follow-up of 5.4 years, the positive effects of bicalutamide were obvious in patients with locally advanced disease (stage M0), but patients with localised disease given bicalutamide appeared to have a reduced survival compared with those given placebo (61). However, results obtained after a median follow-up of 7.4 years showed there was no benefit to PFS from the addition of bicalutamide to standard care in localised PCa, and identified a trend (hazard ratio [HR] 1.16, 95% CI 0.99-1.37, p = 0.07) towards decreased survival in patients otherwise undergoing watchful waiting (WW). However, in locally advanced disease, bicalutamide significantly improved PFS, irrespective of standard care. The same overall results were observed in the most recent arm 24 analysis (62). Bicalutamide significantly improved OS in patients receiving radiotherapy (HR 0.65, 95% CI 0.44-0.95, p = 0.03), which was driven by a lower risk of PCa-related deaths. Bicalutamide produced a trend towards improved OS in patients with locally advanced disease otherwise undergoing WW (HR 0.81, 95% CI 0.66-1.01, p = 0.06). No survival difference was evident in the prostatectomy subgroup (61). Even though the EPCP is a combination of three trials and among the largest ever conducted in prostate cancer patients, clear conclusions are difficult to present as many problems are apparent with these protocols (63). For example, three trials were grouped for analysis, but they are different in terms of patients (80% prostatectomy in trial 23 compared with 13% in trial 25). The treatment duration was two years in trial 23, but prolonged until progression in trials 24 and 25. The OS benefit claimed with radiotherapy is mainly driven by a respiratory or cardiovascular improvement, and not by a CSS benefit, which is different from other trials with LHRH agonists (64). Furthermore, the trials are underpowered for locally advanced patients, compared with oriented trials such as the Bolla (65) or Pilepich (66) trials. Finally, direct protocol analysis reveals quite different results, such as those from the EPCP 23 (80% prostatectomy, 19% radiotherapy) (67). At a median 7.7 years of follow-up, no PFS benefit was observed (HR 1.00; CI 0.84, 1.19, p = 0.991). Likewise, OS did not differ. Even after stratifying for disease stage, no PFS benefit was apparent. No QoL benefit has been demonstrated, as is claimed, as the EPCP trial did not use a QoL questionnaire. The only QoL data come from a specific questionnaire and a limited population. The observed benefit was only significant for physical capacity and sexual interest (not function!). For all other items considered (emotional well-being, vitality, social function, pain, activity limitation and bed disability), there was no difference compared with castration (68). The breast problems related to bicalutamide must also be discussed, as they might lead to a 16.4% treatment cessation (69). The clear trend (even if not statistically significant) suggesting a decreased OS in localised disease treated with WW is a clear argument against its use in such situations (61). The mechanisms remain unclear. Many questions are still debatable with this drug, such as the practical management after progression under bicalutamide, as no data are available. In conclusion, high-dose bicalutamide has emerged as an alternative to castration for patients with locally advanced (M0) if PFS is the target, and in highly selected, well-informed cases of M1 PCa with a low PSA, but should be avoided in patients with localised PCa. The QoL benefit over castration that was expected is, however, far from being proven. The survival benefit observed with an adjuvant use after radiotherapy in locally

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advanced situations must be considered with caution, as these three trials are far from having the power of any trial conducted with LHRH agonists. Non-pharmacological side-effects are mainly gynaecomastia (70%) and breast pain (68%). These might be prevented by anti-oestrogens (70, 71), prophylactic radiotherapy (72), or treatment with surgical mastectomy or radiotherapy (73). 12.3.3 Combination therapies 12.3.3.1 Complete androgen blockade Although serum testosterone levels are reduced by up to 95% by castration, the intraprostatic androgen stimulus is sustained by the conversion of circulating androgens of adrenal origin into DHT within the prostate cells. The action of these adrenal androgens is blocked by the addition of an anti-androgen to either surgical or pharmacological castration, a concept known as complete (or maximal or total) androgen blockade (CAB). A plethora of studies evaluating CAB over monotherapy have been carried out with contrasting results. From the most recent systematic reviews and meta-analyses it appears that at a follow-up of five years, CAB provides a small survival advantage (less than 5%) when compared with monotherapy (74-78, level of evidence: 1a), although some of the largest trials included are methodologically flawed (79). It remains debatable whether this small advantage, if any, can be meaningful when applied to everyday clinical practice. The benefit seems to be limited to patients taking non-steroidal anti-androgens and to appear only after five years of follow-up. Gastrointestinal, ophthalmological, and haematological side-effects are worse with combined androgen blockade. LHRH analogues and non-steroidal anti-androgens have the highest estimated quality-adjusted survival, but have an incremental cost of more than US$1 million per quality-adjusted live-year over orchiectomy alone. 12.3.3.2 Minimal androgen blockade (or peripheral androgen blockade) This derives from the combination of finasteride and a non-steroidal anti-androgen. The rationale behind the combination is that finasteride reduces intraprostatic levels of DHT by inhibiting 5-∝-reductase, while antiandrogen competes with the binding of the residual DHT to its receptor. The result is that testosterone levels are maintained within normal ranges to ensure acceptable sexual function and a reasonable QoL. In several phase II trials (80-84), the association of finasteride and flutamide, either in a concomitant or sequential regimen, has been evaluated in terms of PSA response rate in patients with advanced or biochemically recurrent PCa. Notwithstanding the small sample and short follow-up, nearly all patients experienced a substantial decline in PSA (by up to 96% compared with the level at entry). An update of one of these studies, at a long-term follow-up, reported on stronger end-points, such as castration-free survival (median: 37 months), androgen-independent PCa-free survival (median: 48.6 months) and OS rate (65% at five years). It was concluded that combination therapy can induce an overall period of hormone responsive disease exceeding four years (85). In all these trials, sexual function was reported to be preserved in between 55% and 86% of the men studied. The preliminary data make this treatment option most attractive in the management of patients for whom QoL is the primary issue. However, while awaiting the results of follow-up and larger controlled trials, this treatment is still regarded as investigational. 12.3.3.3 Intermittent vs continuous androgen deprivation therapy For reasons that as yet remain unclear, long-term CAB, which stimulates prostate cell apoptosis, fails to eliminate the entire malignant cell population, so that after a variable period (averaging 24 months) the tumour inevitably relapses, being characterised by an androgen-independent state of growth. Experimental data indicate that androgen-independent progression may begin early after the administration of hormonal therapy, coinciding with the cessation of androgen-induced differentiation of stem cells (86). It is therefore theoretically possible that if androgen deprivation is stopped prior to the progression of androgen-independent cells, any subsequent tumour growth would then be solely sustained by the proliferation of androgen-dependent stem cells, which should be susceptible once again to androgen withdrawal. In this way, cyclical ADT would delay the emergence of the androgen-independent clone. Thus, intermittent ADT may result in two other benefits: namely the preservation of QoL in the off-therapy periods and the reduction of cost. Several phase II trials have demonstrated the feasibility of intermittent androgen blockade (IAB) in metastatic

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or biochemically recurrent disease, with PSA response rates and symptom improvement similar to that of CAB, but phase III prospective, randomised controlled trials are still underway, and data on survival endpoints and QoL are not mature (87). Preliminary results of clinical phase III trials have demonstrated not significantly different efficacy for intermittent vs continuous ADT in men with PSA progression following radical prostatectomy and in advanced metastatic PCa (88-90). The South West Oncology Group (SWOG) trial 9346 randomised 1134 men with stage D2 PCa to intermittent and continuous ADT after seven months’ induction ADT with PSA reduction < 4 ng/mL. No significant differences with regard to survival in a very preliminary analysis were identified between treatment groups (88). A PSA reduction to < 0.2 ng/mL, < 4 ng/mL and > 4 ng/mL was identified as a significant prognostic factor with regard to survival, achieving 13 months, 44 months and 75 months, respectively. In some other trials, 75 patients were considered for IAD if they had achieved PSA serum levels < 4 ng/mL or at least 90% reduction of pre-treatment levels after 9 months of ADT (89). Patients went on when PSA values rose > 20 ng/mL at which the 9-month cycle of ADT was repeated. 86% of the men are alive at a median of 134 months, with a median survival of 95 months from the initial ADT cycle. A 100% and 70% survival at 5 years was calculated for those presenting with locally advanced disease and metastases at initial presentation, respectively. A prospective randomised multicentre trial including 68 patients with a mean follow-up of 31 months have been reported (90). In the intermittent androgen deprivation (IAD) group, the median cycle length was 9.5 months and the median percentage of time off therapy was 59.5%. The median three-year progression rate was significantly lower in the IAD group (7%) than in the CAD group (38.9%), suggesting that IAD maintains the androgen-dependent state of advanced PCa at least as long as does CAD. Another trial came to the same conclusions, but, once again this presented-only German study was underpowered and had too short a followup (91). The most recent and convincing data were presented during the 2007 American Society of Clinical Oncology (ASCO) meeting (92). In a prospective trial including 478 patients with M1 (40%) or N+ (N1 to 3) disease, 335 were randomised after six months of maximal androgen blockade if the PSA was below 4 ng/mL or if a decrease of more than 90% was observed. The mean initial PSA was 158 ng/mL in the intermittent arm, and 139 ng/mL in the continuous arm, respectively. In the intermittent arm, the treatment was resumed if the PSA was above 10 ng/mL and stopped when it went below 4 ng/mL. The main question was PFS. After a median follow up of 50.5 months, no significant difference was observed in the median PFS (16.6 months in the intermittent arm compared with 11.5 months in the continuous arm [p = 0.17], neither in the entire population nor in the N+ or M1 populations. In the IAD arm, 88% of patients were off treatment for more than 50% of the time, and normalised their testosterone in a mean of 70 days after stopping treatment. Recently a published randomised trial suggested a different IAD regimen, with fixed six-month periods of treatment (CAB) and surveillance (93). The PSA was not used to direct the treatment in this heterogeneous population (N = 129). After a mean of 44.8 months of follow up, no difference was observed in either OS, CSS or PFS. The QoL was also no different between the two groups, except that painkillers were required more often in the IAD arm, and the ability to get and maintain an erection was better in the IAD arm. IAD has not been shown to be associated with prolonged hormone-sensitive status. This treatment modality is well accepted by patients and increases their QoL during the periods without treatment, although still to a questionable level (94-96), and testosterone levels recover in most studies (97, 98), leading to an intermittent castration (not just an intermittent treatment delivery). Other benefits, such as a reduction in impact on the bones (99) or sexual activity (96), are also suspected. It must be acknowledged that, so far, IAD raises more questions than it has precise answers for, especially with regard to defining the best candidates, (100, 101). In addition, the threshold at which the ADT must be stopped or resumed are empirical (100). Nevertheless, several points are clear (102): • IAD is based on intermittent castration, and therefore only drugs leading to castration should be considered. • It is unclear if an LHRH agonist may be used alone, as the published experiences are based on CAB. • The initial (induction) cycle must last between six and nine months, otherwise testosterone recovery is unlikely. • The treatment is stopped only if patients have fulfilled all the following criteria: - well informed and compliant patient - no clinical progression

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•

•

• •

- a clear PSA response, empirically defined as a PSA below 4 ng/mL in metastatic patients, or 0.5 ng/mL in relapsing patients. A strict follow-up must then be applied, with clinical examination every three to six months (the more advanced the disease, the closer the follow-up), with PSA measurements at the same time and always performed in the same laboratory. The treatment is resumed when the patient reaches either a clinical progression, or a PSA value above a predetermined empirically fixed threshold (usually 4 ng/mL in non-metastatic situations, or 10-15 ng/mL in metastatic patients). The same treatment is used for at least three to six months. The next cycles are based on the same rules until the first sign of hormone refractory status.

In conclusion, IAD is currently widely offered to patients with PCa in various clinical settings, and its status should no longer be regarded as investigational (level of evidence: 2). 12.3.3.4 Immediate vs deferred ADT The most appropriate time to introduce hormonal therapy in patients with advanced PCa is still controversial, particularly whether ADT for locally advanced and asymptomatic metastatic disease delivered immediately at diagnosis favourably influences survival and QoL compared with ADT deferred while signs and symptoms of clinical progression remain a matter of debate. This point was partially discussed in section 8.3. The dispute derives from the lack of properly conducted, randomised, controlled trials, with many being methodologically flawed because of small size and underpowering, and the heterogeneity of patient enrolment with advanced PCa (i.e. locally advanced, nodal and metastatic stages of disease), as well as variability in the hormone treatments administered and of follow-up schedules and modalities used. Bearing these limitations in mind, evidence on immediate vs deferred ADT is provided by three systematic reviews of the literature (one of which is a meta-analysis). A report by the Agency for Health Care Policy and Research indicated that a possible survival advantage for early ADT existed in single studies where hormone treatment was the primary therapy, while the combined analysis showed no significant benefit. Furthermore, androgen suppression was shown to be the most cost-effective if initiated after patients had experienced symptoms from metastatic disease (74, 103). The Cochrane Library review extracted four good quality randomised controlled trials (namely VACURG I and II studies [10, 11], the MRC trial (104) and the Eastern Cooperative Oncology Group [ECOG] 7887 study [105]), which were all conducted in the pre-PSA era and included patients with advanced PCa who received early vs deferred ADT as primary therapy or adjuvant to radical prostatectomy, but not to radiotherapy. According to the analysis, early androgen suppression significantly reduces disease progression and complication rates due to the progression itself, but does not improve CSS, and provides a relatively small benefit in OS, with an absolute risk reduction of 5.5%, which does not become evident until after 10 years (106). Since 2002, the level 1 evidence suggesting immediate ADT in every pN+ patient after a prostatectomy has been questioned for several reasons. Some were discussed earlier (see section 9.7) such as the impact of a micronodal metastasis in a single node (107), which is far from being equivalent to a massive nodal involvement, as present in the Messing trial. Recently, the analysis of 719 patients from the SEER (Surveillance, Epidemiology and End Results, part of the US National Cancer Institute) database questioned the real impact of immediate ADT in pN+ patients after a radical prostatectomy (108). In the PSA era, the EORTC 30891 (109) gave the same results, namely a small benefit in OS, but no CSS benefit. Furthermore, only young patients with a high PSA might clearly benefit. Based on a systematic review of the literature, the recently published ASCO guidelines on initial hormonal treatment for androgen-sensitive metastatic, recurrent or progressive PCa concluded that no recommendation on when to start hormonal therapy in advanced asymptomatic PCa can be made until data from studies using modern diagnostic and biochemical tests and standardised follow-up schedules become available (110). Based on the meta-analysis, published treatment was most cost-effective when started after the onset of symptoms. Based on exploratory analysis, treatment with anti-androgen monotherapy does not lead to a survival benefit in men with localised PCa managed with non-definitive therapy, and the impact is still questionable after external beam therapy. This was explored in detail in section 12.3.2.2 with regard to the EPCP trials.

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For asymptomatic patients with locally or regionally advanced PCa who undergo radiotherapy, there is good evidence from several randomised controlled trials that concomitant and/or adjuvant hormonal therapy provides longer time-to-disease progression and/or longer OS than radiotherapy alone followed by androgen suppression at progression (111-114) (level of evidence: 1b).

12.4

Indications for hormonal therapy

Table 16 lists the indications for hormonal therapy. Table 16: Indications for hormonal therapy Hormonal therapy Indications for castration M1 symptomatic

M1 asymptomatic

N+

Locally advanced M0 Locally advanced symptomatic Locally advanced treated with radiotherapy

Locally advanced asymptomatic unfit for local definitive treatment Anti-androgens Short-term administration

Non-steroidal anti-androgen monotherapy

Benefits

LE

• To palliate symptoms and to reduce the risk for potentially catastrophic sequelae of advanced disease (spinal cord compression, pathological fractures, ureteral obstruction, extraskeletal metastasis) • Even without controlled randomised trail, this is the standard of care and must be applied and considered as level 1 evidence • Immediate castration to defer progression to a symptomatic stage and prevent serious disease progression-related complications (104) • An active clinical surveillance protocol might be an acceptable option in clearly informed patients if survival is the main objective • Immediate castration to prolong PFS and even OS (105) • Might be questioned in single micrometastasis after extended lymph node dissection and radical prostatectomy (115) • Immediate castration to improve cancer-free survival • (116) • High risk d’Amico: combined and prolonged ADT • Intermediate risk d’Amico: • if low dose (< 75 Gy) radiotherapy: six months of ADT • if high dose (> 75 Gy) radiotherapy: ADT questionable • Limited OS improvement not related to a CSS benefit (109)

1

1

1b

3

1b 3

1b 4 1 1b 2 1

• To reduce the risk of the ‘flare up’ phenomenon in patients 1b with advanced metastatic disease who are to receive an LHRH agonist (117, 118) 2 • Primary monotherapy as an alternative to castration in patients with locally advanced PCa (T3-4, any N, or any T N+) (57) (level of evidence: 2) • No place in localised disease as single treatment modality • Combined with radiotherapy: no clear recommendation is possible at the present time • Combined with radical prostatectomy: no place so far in an adjuvant setting

LE = level of evidence

12.5

Contraindications for various therapies (Table 17)

Table 17 lists the contraindications for various therapies. Table 17: Contraindications for various therapies Therapy Bilateral orchiectomy

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Contraindications • Psychological reluctance to undergo surgical castration

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Oestrogens LHRH agonists alone Anti-androgens

12.6

• Known cardiovascular disease • Patients with metastatic disease at high risk for clinical ‘flare up’ phenomenon • Localised PCa as primary therapy • Known hepatic dysfunction

Outcome

Outcome depends on the stage and grade of disease at diagnosis. In M1 cases, the median OS ranges between 28 and 53 months (74); only 7% of patients with metastatic cancer treated with hormonal therapy are reported to live 10 years or more (119). Survival is likely to depend on the PSA level at diagnosis, the Gleason score, the volume of metastatic disease, and the presence of bony symptoms. In locally advanced M0 patients, the median OS is frequently reported to exceed 10 years (75).

12.7

Side-effects, QoL and cost of hormonal therapy

Many patients with PCa for whom long-term ADT is indicated are still young and physically and sexually active, so QoL is an issue of paramount importance when considering the various hormonal treatment options. In view of this, in selected patients, monotherapy with a non-steroidal anti-androgen (e.g. bicalutamide) is gaining increasing popularity because of its ability to maintain normal (or even higher) serum testosterone levels and its good tolerability profile. 12.7.1 Side-effects The many deleterious side-effects of long-term ADT have been well known for years. Some of these can have a detrimental effect on QoL, especially in young men, while others may contribute to an increased risk of serious health concerns associated with age. Loss of libido and erectile dysfunction are well known side-effects. The management of erectile dysfunction is not specific. Hot flashes are probably the most common side-effect of ADT. They appear three months after starting the treatment, persist in the long term in most patients, and have a significant impact on the QoL (120). Treatment modalities include hormonal therapy and antidepressants. Oestrogen receptor modulators or lowdose oestrogen therapies (0.5-1 mg/day), such as diethylstilboestrol, reduce their frequency and severity, but both are associated with a risk of cardiovascular complications (121). Soya phytoestrogens have shown efficacy for hot flushes in breast cancer patients (122), but have not yet been evaluated in men. Progesterone-based treatments, such as megestrol acetate, medroxyprogesterone acetate and CPA, have also demonstrated efficacy, with 80% of patients having shown improvement with CPA (123) or chlormadinone (124). Antidepressants may also have some efficacy. For example, venlafaxine (a non-specific selective noradrenaline and serotonin reuptake inhibitor) has shown efficacy in breast cancer patients, while the selective serotonin reuptake inhibitor sertraline appears to be effective in men with PCa (125). Other products have also been tested, including clonidine and veralipride, and even acupuncture (126). With a placebo effect influencing up to 30% of patients (127), few treatments are approved for the control of hot flashes in men with PCa. There is a lack of large, prospective randomised controlled trials in this area. More recently, other systemic side-effects have been described and must be paid increased attention. These include: bone problems, obesity and sarcopenia, lipid alterations and insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease (128). ADT increases the non-metastatic fracture risk as a result of increased bone turn-over and decreased bone mineral density (BMD) in a time-dependent manner. This leads to an increased risk of fracture of up to 45% relative risk in the long term (129). This is a significant side-effect, as hip fractures in men are associated with a significant risk of death (130). Increased exercise and calcium supplementation are protective. Recently, bisphosphonates such as pamidronate, alendronate or zoledronic acid have been shown to increase the BMD in hip and spine by up to 7% in one year. The optimal regimen for zoledronic acid is still unclear. It is recommended once every four weeks in one study (131), while a yearly injection gave similar results in another (132). The optimal regimen is a very important question because of the risk of jaw necrosis, which might be dose and time-related (133).

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Before starting long term ADT, patients should be encouraged to adopt lifestyle changes (e.g. increase physical activity, stop smoking, decrease alcohol consumption and normalise their body mass index). A precise evaluation of the BMD should be performed by dual X-ray absorptiometry before starting long term ADT. An initial low BMD (T-score above 2.5 or above 1 in conjunction with other risk factors) indicates a high risk of subsequent non-metastatic fracture, suggesting the early use of preventive bisphosphonate therapy. Obesity and sarcopenia are common and often occur early on during the first year of ADT. An increase in body fat mass by up to 10%, and a decrease in lean tissue mass by up to 3% are expected (134). Both are linked to an increased risk of fracture. Lipid alterations are also frequent, and occur as early as the first three months of treatment (135). ADT also decreases insulin sensitivity and increases fasting plasma insulin levels (135), a marker of insulin resistance. Once again, exercise must be recommended as a protective tool. Metabolic syndrome is an association of independent cardiovascular disease risk factors often associated with insulin resistance. These include: • waist circumference > 102 cm • serum triglyceride > 1.7 mmol/L • blood pressure > 130/80 mmHg • HDL cholesterol < 1 mmol/L • glycaemia > 6.1 mmol/L. Its prevalence is higher during ADT compared with untreated men (136). ADT has been associated with an increased risk of diabetes mellitus, cardiovascular disease, and myocardial infarction in one study (137), and with a 20% increased risk of new cardiovascular disease after one year of treatment in another (138). Recently the analysis of the RTOG 92-02 data confirmed this increased cardiovascular risk (139) with no relationship with the duration of the ADT. These observations have, however, been up for discussion recently, as no increased cardiovascular mortality was demonstrated in RTOG 8610 (140), EORTC 30891 (109) or EORTC 22863 (64). In summary, if even six or fewer months of ADT might be associated with increased cardiovascular morbidity, the data on cardiovascular mortality are so far inconsistent. Again, prevention is associated with non-specific measures such as loss of weight, increased exercise, better nutrition and the cessation of smoking. 12.7.2 Quality of Life (QoL) Data on QoL during hormone treatment are scant because of a lack of solid evidence. The only large, prospective, randomised study is a double-blind placebo-controlled trial including 739 patients with M1 PCa, which compared orchiectomy plus flutamide vs orchiectomy plus placebo. The QoL was assessed in the first six months of treatment. Combined therapy resulted in lower QoL, with statistically significant differences in two QoL parameters, namely more frequent diarrhoea and worse emotional functioning, than castration alone (141). A prospective, non-randomised, observational study including 144 patients with locally advanced PCa or PSA failure after definitive local treatment showed that patients who received immediate ADT (by means of bilateral orchiectomy, LHRH agonist or CAB) reported a lower overall QoL (increased fatigue, emotional distress, and decreased physical functioning) than patients in the deferred hormone treatment arm (142) (level of evidence: 2a). A retrospective, non-randomised study including 431 patients with stage PCa who received orchiectomy or LHRH agonists as their primary therapy within 12 months of initial diagnosis, assessed healthrelated quality of life (HRQoL) outcomes at 12-months follow-up. Men receiving LHRH agonists reported more worry and physical discomfort and poorer overall health, and were less likely to believe themselves free of cancer than were orchiectomised patients. The stage at diagnosis had no significant independent effect on health outcome. However, the study was insufficiently powered (143) (level of evidence: 2b). A recent, small, randomised, controlled trial evaluated the HRQoL of patients with non-localised PCa allocated to leuprorelin, goserelin, CPA or no treatment at one-year follow-up. Both sexual and cognitive function significantly declined in men on all forms of androgen suppression, while emotional distress significantly increased in those assigned to CPA and no treatment (144) (level of evidence: 1b).

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IAD might be associated with an improved overall QoL based on the normal testosterone levels during the off treatment periods. So far the results are inconclusive, showing either no or a marginal QoL benefit. As for LHRH agonists, QoL was evaluated in the previously mentioned studies of bicalutamide monotherapy by means of a specific questionnaire covering 10 domains (sexual interest, sexual function, physical capacity, emotional well-being, vitality, social function, activity limitation, pain, bed disability and overall health). Separate analyses of data for M0 and M1 patients were performed at 12-month follow-up, and in both patient categories bicalutamide showed a significant advantage over castration in the domains of physical capacity and sexual interest (not sexual function) (57) (level of evidence: 1b). A further post hoc analysis, including only patients with sexual interest at study entry, found that significantly more patients receiving bicalutamide 150 mg/day maintained their interest in sex and felt that they were still sexually attractive than did those randomised to castration (145, 146). Data on QoL are also available from the early report of the study of Boccardo et al. (147), and support the findings of the two larger combined trials in that more men in the bicalutamide group than in the castration group reported a preserved libido and erectile function. Furthermore, a recent, small, prospective, randomised trial, including 103 patients with localised or locally advanced PCa who received bicalutamide 150 mg/day or medical castration, evaluated the changes in BMD after 96 weeks of treatment and showed it to be maintained with bicalutamide therapy (148) (level of evidence: 1b). The most common side-effects during non-steroidal anti-androgen monotherapy are gynaecomastia and breast pain, which are caused by an imbalance in the androgen:oestrogen ratio within the breast tissue. In the bicalutamide studies, these events were reported by up to 66% and 73% of patients, respectively, and might lead to a 16.4% treatment cessation. 12.7.3 Cost-effectiveness of hormonal therapy options A recent formal meta-analysis and literature review evaluated the cost-effectiveness of various long-term androgen suppression options in advanced PCa (e.g. bilateral orchiectomy, DES, LHRH-agonist, non-steroidal anti-androgen monotherapy, CAB with non-steroidal anti-androgens). For the analysis, a sophisticated statistical model was generated, assuming the base case at entry to be a 65-year-old man with a clinically evident, local recurrence of PCa and no distant metastases, followed for a 20-year time horizon. The study concluded that, for men who can accept it, bilateral orchiectomy is the most cost-effective form of ADT providing a higher quality-adjusted survival, while CAB is the least economically attractive option, yielding small health benefits for a high relative cost. Furthermore, the greatest QoL gains and least costs may be obtained by starting ADT when symptoms from distant metastases have occurred (103) (level of evidence: 1a). Finally, once ADT is started, if a clear response is obtained (see section 11.3.3. above), then IAD might be a useful way to lower treatment costs.

12.8

• • • •

•

•

Summary of hormonal therapy

In advanced PCa, ADT delays progression, prevents potentially catastrophic complications, and palliates symptoms effectively, but it does not prolong survival. In advanced PCa, all forms of castration as monotherapy (e.g. orchiectomy, LHRH and DES) have equivalent therapeutic efficacy. Non-steroidal anti-androgen monotherapy (e.g. bicalutamide) is an alternative to castration in patients with locally advanced disease. In metastatic PCa, the addition of a non-steroidal anti-androgen to castration (CAB) results in a small advantage in OS over castration alone, but is associated with increased adverse events, reduced QoL, and high costs. Intermittent ADT should no longer be regarded as experimental, even though long-term data from prospective randomised clinical trials are still awaited. ‘Minimal’ ADT should, however, continue to be seen as experimental In advanced PCa, immediate ADT (given at diagnosis) significantly reduces disease progression as well as the complication rate due to progression itself compared with deferred ADT (delivered at symptomatic progression).

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LE 1b 1b 2 1a

2

1b

87

•

However, the survival benefit is at best marginal and not related to an increased CSS. Bilateral orchiectomy might be the most cost-effective form of ADT, especially if initiated after the occurrence of symptoms from metastatic disease.

1b 3

LE = level of evidence

12.9

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13. SUMMARY OF GUIDELINES ON PRIMARY TREATMENT OF PCa Stage T1a

Treatment Watchful waiting

Radical prostatectomy Radiotherapy

T1b-T2b

Hormonal Combination Watchful waiting

Radical prostatectomy Radiotherapy

Hormonal

Combination

T3-T4

Watchful waiting

Radical prostatectomy Radiotherapy

Hormonal Combination

N+, M0

Watchful waiting

M+

Radical prostatectomy Radiotherapy Hormonal Combination Watchful waiting

Radical prostatectomy Radiotherapy Hormonal

98

Comment Standard treatment for well-, and moderately, differentiated tumours and < 10-year life expectancy. In patients with > 10-year life expectancy, re-staging with TURP and biopsy is advised Optional in young patients with a long life expectancy, especially for poorly differentiated tumours Optional in younger patients with a long life expectancy, especially for poorly differentiated tumours. Higher complication risks after TURP, especially with interstitial radiation Not an option Not an option Asymptomatic patients with well-, and moderately, differentiated tumours and a life expectancy < 10 years. Patients who do not accept treatment-related complications Standard treatment for patients with life expectancy > 10 years who accept treatment-related complications Patients with a life expectancy > 10 years who accept treatment-related complications. Patients with contraindications for surgery. Unfit patients with 5-10 years of life expectancy and poorly differentiated tumours (combination therapy is recommended; see below) Symptomatic patients, who need palliation of symptoms, unfit for curative treatment Anti-androgens are associated with a poorer outcome compared to ‘watchful waiting’ and are not recommended For high-risk patients, neoadjuvant hormonal treatment (NHT) and concomitant hormonal therapy + radiotherapy results in increased overall survival. Option in asymptomatic patients with T3, well-differentiated and moderately differentiated tumours, and a life expectancy < 10 years Optional for selected patients with T3a and a life expectancy > 10 years T3 with > 5-10 years of life expectancy. Dose escalation > 70 Gy seems to be of benefit. A combination with hormonal therapy should be recommended (see below) Symptomatic patients, extensive T3-T4, high PSA level (> 25-50 ng/mL), PSA-DT < 1 year. Patient-driven, unfit patients Overall survival is improved by concomitant and adjuvant hormonal therapy (3 years) combined with external irradiation NHT + radical prostatectomy: no indication Asymptomatic patients. Patient driven (PSA < 20-50 ng/mL), PSA DT > 12 months. Requires very close follow-up No standard option No standard option Standard therapy in N > N1 No standard option. Patient-driven No standard option. May have worse survival/more complications than with immediate hormonal therapy. Requires very close follow-up Not an option Not an option (given for cure) Standard therapy. Mandatory in symptomatic patients

GR B

B B

A C B

A B

C A A

C

C A

A A B B C C A B B

C C A

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Combination

Must be otherwise systematically discussed Not an option

C

GR = grade of recommendation; TURP = transrectal urethral resection of prostate; NHT = neoadjuvant hormonal therapy; PSA = prostate-specific antigen; PSA-DT = prostate-specific doubling time.

14. FOLLOW-UP: AFTER TREATMENT WITH CURATIVE INTENT 14.1

Definition

Curative treatment is defined as radical prostatectomy or radiotherapy, either by external beam radiation or an interstitial technique, or any combination of these. Alternative treatment options that are not fully established, such f.i. HIFU, do not have a well-defined, validated PSA-cut-point to define biochemical failure but do generally follow the outlines given below.

14.2

Why follow-up?

The first question to be answered is: ‘If failure after curative treatment is so common, are follow-up efforts worthwhile?’ The answer to this question is definitely ‘Yes’. Recurrences will occur in a substantial number of patients who received treatment with intent to cure at various time points after the primary therapy. The second question to be answered is: ‘What is the reason for follow-up?’ Reasons may vary depending on the treatment given, patient age, comorbidity and the patient’s own wishes. In general, patients who receive curative therapy may be followed-up for any of the following reasons: • good responsible patient care • possibility of second-line treatment with curative intent • possibility of early hormonal therapy after failure • as part of a study protocol. Section 16 discusses treatment options after failure of primary therapy.

14.3

How to follow-up?

The procedures indicated at follow-up visits vary depending on the clinical situation. The examinations discussed below are routinely used for the detection of PCa progression or residual disease. The PSA level, and eventually DRE, are the only tests that need to be carried out routinely. A disease-specific history should be mandatory at every follow-up visit and should include psychological aspects, signs of disease progression and treatment-related complications. The examinations used for the evaluation of treatment-related complications must be individualized and are beyond the scope of these guidelines. The examinations used most often for cancer-related follow-up after curative surgery or radiation treatment are discussed below. 14.3.1 PSA monitoring The measurement of PSA level is a cornerstone in the follow-up after curative treatment. There is a difference in what can be expected after radical prostatectomy and radiotherapy, but PSA recurrence nearly always precedes clinical recurrence after either treatment, in some cases by many years (1-5). It is recommended that the finding of a single, elevated, serum PSA level should be re-confirmed before second-line therapy is started solely based on the PSA elevation. 14.3.2 Definition of PSA progression The level of PSA at which to define treatment failure differs between radical prostatectomy cases and radiation treated cases. Following radical retropubic prostatectomy, two consecutive values of 0.2 ng/mL or greater appear to represent an international consensus defining recurrent cancer (6, 7). Other authors have argued for an even higher cut-off of 0.4 ng/mL to better define patients with a high risk for clinical progression (5). It has been shown that patients with a PSA level between 0.1 ng/mL and 0.2 ng/mL after radical prostatectomy had neither clinical nor biochemical disease progression (8). Therefore, the use of an ultra-sensitive PSA assay is not justified for routine follow-up after radical prostatectomy (4). If ongoing randomized trials show that early adjuvant treatment after radical prostatectomy (given before PSA reaches > 0.2 ng/mL) improves survival, this issue should be reconsidered. Following radiation therapy, until recently, the definition of biochemical relapse was three consecutive increases according to the recommendation of ASTRO from 1996 (9). At the 2006 RTOG-ASTRO Consensus

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conference a new definition of radiation failure was established with as the main aim to establish a better correlation between the definition and clinical outcome. The new definition of radiation failure is a rise of 2 ng/mL above the post-treatment PSA-nadir (lowest value) (10). This definition is applicable for patients treated with or without hormonal therapy. After HIFU or cryotherapy, a variety of definitions for PSA-relapse have been used (11). Most of these are based on a cut-off of around 1 ng/mL, eventually combined with a negative post-treatment biopsy. As yet, none of these end-points have been validated against clinical progression or survival and therefore it is not possible to give firm recommendations on the definition of biochemical failure. 14.3.3 PSA monitoring after radical prostatectomy PSA is expected to be undetectable within 3 weeks after a successful radical prostatectomy (12). A persistently elevated PSA level means that PSA-producing tissue remains in the body. In patients treated with radical prostatectomy, this is generally thought to be residual cancer due to either micrometastases that were not detected or undetectable beforehand, or residual disease in the pelvis possibly due to positive surgical margins. A rapidly increasing PSA level (high PSA velocity, short PSA doubling time) indicates distant metastases, while a later and slowly increasing concentration of PSA is most likely to indicate local disease recurrence. The time to PSA recurrence and tumour differentiation are also important predictive factors distinguishing between local and systemic recurrence (13, 14). Both local treatment failure and distant metastases have been shown to occur with undetectable PSA levels. This is very rare and occurs almost only in patients with unfavourable pathology (undifferentiated tumours) (15, 16). This means that, in patients with a relatively favourable pathology (< pT3, pN0, Gleason score < 8), PSA measurement, together with the disease-specific history, could stand as the single test in follow-up after radical prostatectomy. 14.3.4 PSA monitoring after radiation therapy The PSA level falls slowly after radiotherapy compared with radical prostatectomy. The optimal cut-off value for a favourable PSA nadir after radiotherapy is somewhat controversial. Achieving a PSA nadir of less than 0.5 ng/mL seems to be associated with a favourable outcome (17). The interval before reaching the nadir PSA may be very long and can sometimes take up to 3 years or more. A PSA rising more than 2 ng/mL above the nadir PSA is the current definition of biochemical failure after radiotherapy (10). Also, after radiotherapy, the PSA doubling time has been shown to correlate to the site of recurrence; patients with local recurrence had a doubling time of 13 months compared to 3 months for those with distant failure (18). 14.3.5 Digital rectal examination (DRE) DRE is performed to assess whether or not there is any sign of local disease recurrence. It is very difficult to interpret the findings of DRE after curative therapy, especially after radiotherapy. A newly detected nodule should raise the suspicion of local disease recurrence. As mentioned previously, a local disease recurrence after curative treatment is possible without a concomitant rise in PSA level (15, 16). However, this has only been proven in patients with unfavourable pathology, i.e. those with undifferentiated tumours. Thus, PSA measurement and DRE comprise the most useful combination of tests as first-line examination in follow-up after radiotherapy or radical prostatectomy, but PSA measurement may well be the only test in cases with favourable pathology (19). 14.3.6 Transrectal ultrasonography (TRUS) and biopsy TRUS and biopsy have no place in the routine follow-up of asymptomatic patients and nowadays only rarely after biochemical failure. TRUS cannot stand alone as a diagnostic tool, but must usually be combined with biopsy to establish the presence of local disease recurrence. The purpose of the investigation is to confirm a histological diagnosis of local disease recurrence. It is only warranted if the finding of a local recurrence affects the treatment decision (see Section 16 for a more detailed discussion). 14.3.7 Bone scintigraphy The purpose of bone scintigraphy is to detect skeletal metastases. It is not recommended for the routine follow-up of asymptomatic patients, but may be indicated in individuals with elevated PSA levels for whom the findings will affect the treatment decision. It is also indicated in patients with symptoms arising from the skeleton, since metastatic disease may occur even if PSA is undetectable (15, 16). 14.3.8 Computed tomography (CT) or magnetic resonance imaging (MRI) CT or MRI have no place in the routine follow-up of asymptomatic patients. They may be used selectively in the evaluation after biochemical failure before treatment decisions are made (see Section 16).

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14.4

When to follow-up?

Most patients who fail treatment for PCa do so early, even if failure only becomes clinically obvious after years. The patient should therefore be followed-up more closely during the first years after treatment when the risk of failure is highest. PSA measurement, disease-specific history and DRE are recommended at the following intervals: 3, 6 and 12 months postoperatively, every 6 months thereafter until 3 years, and then annually. The purpose of the first clinic visit is mainly to detect treatment-related complications and to assist patients in coping with the new situation. Tumour or patient characteristics may allow alterations to this schedule. For example, patients with poorly differentiated and locally advanced tumours or with positive margins may be followed-up more closely than those with a well-differentiated, intracapsular or specimenconfined tumour. Obviously, advanced age or associated comorbidity may make further follow-up in asymptomatic patients superfluous.

14.5 Guidlines for follow-up after treatment with curative intent

• In asymptomatic patients, a disease-specific history and a serum PSA measurement supplemented by DRE are the recommended tests for routine follow-up. These should be performed at 3, 6 and 12 months after treatment, then every 6 months until 3 years, and then annually. • After radical prostatectomy, a serum PSA level of more than 0.2 ng/mL can be associated with residual or recurrent disease. • After radiation therapy, a rising PSA level over 2 ng/mL above the nadir PSA, rather than a specific threshold value, is the most reliable sign of persistent or recurrent disease. • Both a palpable nodule and a rising serum PSA level can be signs of local disease recurrence. • Detection of local recurrence by TRUS and biopsy is only recommended if it will affect the treatment plan. In most cases TRUS and biopsy are not necessary before second-line therapy. • Metastasis may be detected by pelvic CT/MRI or bone scan. In asymptomatic patients, these examinations may be omitted if the serum PSA level is less than 30 ng/mL but data on this topic are sparse. • Routine bone scans and other imaging studies are not recommended in asymptomatic patients. If a patient has bone pain, a bone scan should be considered irrespective of the serum PSA level.

GR B

B B B B C

B

GR = grade of recommendation

14.6

REFERENCES

1. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-free and cancerspecific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001;28(3)555-65. http://www.ncbi.nlm.nih.gov/pubmed/11590814 2. Rosser CJ, Chichakli R, Levy LB, Kuban DA, Smith LG, Pisters LL. Biochemical disease-free survival in men younger than 60 years with prostate cancer treated with external beam radiation. J Urol 2002;168(2):536-41. http://www.ncbi.nlm.nih.gov/pubmed/12131304. 3. Horwitz EM, Thames HD, Kuban DA, Levy LB, Kupelian PA, Martinez AA, Michalski JM, Pisansky TM, Sandler HM, Shipley WU, Zelefsky MJ, Hanks GE, Zietman AL. Definitions of biochemical failure that best predict clinical failure in patients with prostate cancer treated with external beam radiation alone: a multi-institutional pooled analysis. J Urol 2005;173(3):797-802. http://www.ncbi.nlm.nih.gov/pubmed/15711272. 4. Taylor JA III, Koff SG, Dauser DA, McLeod DG. The relationship of ultrasensitive measurements of prostate-specific antigen levels to prostate cancer recurrence after radical prostatectomy. BJU Int 2006;98(3):540-3. http://www.ncbi.nlm.nih.gov/pubmed/16925750.

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5.

Stephenson AJ, Kattan MW, Eastham JA, Dotan ZA, Bianco Jr FJ, Lilja H, Scardino PT. Defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol 2006;24(24):3973-8. http://www.ncbi.nlm.nih.gov/pubmed/16921049 6. Boccon-Gibod L, Djavan WB, Hammerer P, Hoeltl W, Kattan MW, Prayer-Galetti T, Teillac P, Tunn UW. Management of prostate-specific antigen relapse in prostate cancer: a European Consensus. Int J Clin Pract 2004;58(4):382-90. http://www.ncbi.nlm.nih.gov/pubmed/15161124 7. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol 2000;163(6):1632-42. http://www.ncbi.nlm.nih.gov/pubmed/10799151 8. Schild SE, Wong WW, Novicki DE, Ferrigni RG, Swanson SK. Detection of residual prostate cancer after radical prostatectomy with the Abbott Imx PSA assay. Urology 1996;47(6):878-81. http://www.ncbi.nlm.nih.gov/pubmed/8677580 9. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37(5):1035-41. http://www.ncbi.nlm.nih.gov/pubmed/9169810 10. Roach III M, Hanks G, Thames jr H, Schelhammer P, Shipley WU, Sokol GE, Sandler H. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix consensus conference. Int J Radiat Oncol Biol Phys 2006;65(4):965-74. http://www.ncbi.nlm.nih.gov/pubmed/16798415 11. Aus G. Current status of HIFU and cryotherapy in prostate cancer – a review. Eur Urol 2006;50(5): 927-34. http://www.ncbi.nlm.nih.gov/pubmed/16971038 12. Stamey TA, Kabalin JN, McNeal JE, Johnstone IM, Freiha F, Redwine EA, Yang N. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 1989;141(5):1076-83. http://www.ncbi.nlm.nih.gov/pubmed/2468795 13. Partin AW, Pearson JD, Landis PK, Carter HB, Pound CR, Clemens JQ, Epstein JI, Walsh PC. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994;43(5):649-59. http://www.ncbi.nlm.nih.gov/pubmed/7513108 14. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 1994;152(5 Pt 2):1821-5. http://www.ncbi.nlm.nih.gov/pubmed/7523728 15. Oefelein MG, Smith N, Carter M, Dalton D, Schaeffer A. The incidence of prostate cancer progression with undetectable serum prostate specific antigen in a series of 394 radical prostatectomies. J Urol 1995;154(6):2128-31. http://www.ncbi.nlm.nih.gov/pubmed/7500474 16. Leibman BD, Dilliouglugil O, Wheeler TM, Scardino PT. Distant metastasis after radical prostatectomy in patients without an elevated serum prostate specific antigen level. Cancer 1995;76(12):2530-4. http://www.ncbi.nlm.nih.gov/pubmed/8625081 17. Ray ME, Thames HD, Levy LB, Horwitz EM, Kupelian PA, Martinez AA, Michalski JM, Pisansky TM, Shipley WU, Zelefsky MJ, Zietman AL, Kuban DA. PSA nadir predicts biochemical and distant failure after external beam radiotherapy for prostate cancer: a multi-institutional analysis. Int J Radiat Oncol Biol Phys 2006;64(4):1140-50. http://www.ncbi.nlm.nih.gov/pubmed/16198506 18. Hancock SL, Cox RS, Bagshaw MA. Prostate specific antigen after radiotherapy for prostate cancer: a reevaluation of long-term biochemical control and the kinetics of recurrence in patients treated at Stanford University. J Urol 1995;154(4):1412-17. http://www.ncbi.nlm.nih.gov/pubmed/7544843 19. Chaplin BM, Wildhagen MF, Schroder FH, Kirkels WJ, Bangma CH. Digital rectal examination is no longer necessary in the routine follow-up of men with undetectable prostate specific antigen after radical prostatectomy: the implications for follow-up. Eur Urol 2005;48(6):906-10. http://www.ncbi.nlm.nih.gov/pubmed/16126322

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15. Follow-up after hormonal treatment 15.1

Introduction

A large proportion of patients treated with hormonal therapy have either metastatic or locally advanced tumours at diagnosis. This will affect the scheme of follow-up because biochemical failure is often associated with rapid symptomatic progression.

15.2 Purpose of follow-up The main objectives of following-up these patients are: • to monitor the response to treatment • to ensure compliance with treatment • to detect potential complications of endocrine therapy • to guide the modalities of palliative symptomatic treatment at the time of hormonal escape. However, the usefulness of complementary investigations at various stages of the disease must be clarified in order to avoid unnecessary examinations and excessive economic cost to the community. On the other hand, strict recommendations for follow-up procedures are only useful if effective therapeutic strategies can be offered to patients in cases of disease progression. To date, the issue of early vs late initiation of non-hormonal treatment in hormone-refractory prostate cancer (HRPC) has still not been resolved, so follow-up should be performed on an individual basis. Based on current knowledge, it is not possible to formulate strict guidelines for follow-up procedures following hormonal therapy.

15.3

Methods of follow-up

15.3.1 Prostate-specific antigen monitoring Prostate-specific antigen (PSA) is a good marker for following the course of metastatic prostate cancer (PCa). The prognostic value of PSA (the prediction of the duration of response to endocrine treatment), based on either the initial pre-treatment value or the PSA decrease during the first three to six months, has been used to monitor prostate cancer over the past few decades (1, 2). The initial PSA level can reflect the extent of metastatic disease, although some poorly differentiated tumours do not secrete PSA. The prognostic value of the pre-treatment PSA value is variably assessed in the literature and should not be used solely to predict the duration of response to treatment (3). Treatment response may be assessed utilising the change in serum PSA level as a surrogate end-point for survival in patients with newly diagnosed metastatic PCa after hormonal treatment has been initiated. Patients with the lowest absolute value of serum PSA (< 0.2 ng/mL) also had the best survival compared with those obtaining a value of 0.2-4.0 ng/mL or > 4.0 ng/mL (4). Similar results have been seen in other studies of locally advanced and metastatic PCa (5, 6). The PSA response has been shown to be equally important for patients treated with hormonal therapy because of a rising PSA after treatments with curative intent (radical prostatectomy, radiation therapy). Patients with the best response also had the best survival (7, 8). Despite its usefulness in determining treatment response in individual patients, the role of PSA as a surrogate end-point in clinical trials is more controversial (9). After the initial phase of response to endocrine treatment, patients should be regularly monitored in order to detect and treat any complications of endocrine escape, as clinical disease progression occurs after a median interval of about 12-18 months of treatment in patients with stage M1 disease. It is well established that regular PSA control in asymptomatic patients allows the earlier detection of biochemical escape, as the rise in PSA level usually precedes the onset of clinical symptoms by several months. However, it must be stressed that the PSA level is not a reliable marker of escape and cannot stand alone as a follow-up test. Clinical disease progression (usually bone pain) with normal PSA levels has been reported to occur. 15.3.2 Creatinine, haemoglobin and liver function monitoring Creatinine monitoring has some value because it can detect upper urinary tract obstruction in cases of advanced cancer that might need to be relieved by, for example, percutaneous nephrostomy or double J-stent. Haemoglobin and liver function tests could suggest disease progression and/or toxicity of hormonal treatment, which can lead to interruption of hormonal treatment (i.e. liver toxicity from non-steroidal anti-androgens). The fact that haemoglobin levels will decrease by about 20% with androgen deprivation must be taken into consideration (10).

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Alkaline phosphatase and its bone-specific isoenzymes may be used to monitor patients with stage M1b disease. These markers have the advantage of not being directly influenced by hormonal therapy compared with PSA. It should be remembered that increases in serum concentrations of alkaline phosphatase might also be due to osteoporosis induced by androgen deprivation (11). In this scenario, the determination of bonespecific alkaline phosphatase might be helpful. 15.3.3 Bone scan, ultrasound and chest X-ray In routine practice, asymptomatic patients with a normal PSA level should not have a bone scan at regular intervals as disease progression is more reliably detected by PSA monitoring, which also has a lower cost (1214). Moreover, the interpretation of bone scans is sometimes difficult, and the appearance of a new site of uptake or deterioration of pre-existing lesions in an asymptomatic patient does not modify the therapeutic approach. In cases where there is a clinical or laboratory suspicion of disease progression, a chest X-ray or renal and hepatic ultrasound may be indicated. Imaging modalities must also be guided by symptoms. However, these examinations are not recommended for routine use in asymptomatic patients. In hormone-refractory disease, follow-up examinations should be individualised with the aim of maintaining the patient’s quality of life. During long term androgen deprivation therapy (ADT), regular measurement of bone mineral density (BMD) might be recommended (level of evidence: 3) based on the initial T-score (15): every two years if the initial T-score < 1.0, or yearly if the T-score is between 1.0 and 2.5 in the absence of associated risk factors. Otherwise an active treatment should have started at the initiation of ADT.

15.4

When to follow-up

After initiation of hormonal treatment, it is recommended that patients be followed-up at three and six months. These guidelines must be individualised, and each patient should be told to contact his physician in the event of troublesome symptoms. 15.4.1 Stage M0 patients If there is a good treatment response, i.e. symptomatic improvement, good psychological coping, good treatment compliance and a serum PSA level of less than 4 ng/mL, follow-up visits are scheduled every six months. 15.4.2 Stage M1 patients If there is a good treatment response, i.e. good symptomatic improvement, good psychological coping, good treatment compliance and a serum PSA level of less than 4 ng/mL, follow-up is scheduled every three to six months. Patients should be advised of clinical symptoms that could suggest spinal cord compression and told to consult a physician immediately should they occur. 15.4.3 Hormone-refractory patients Patients whose disease progresses, or who do not respond according to the criteria mentioned above, warrant an individualised follow-up scheme.

15.5 Guidelines for follow-up after hormonal treatment Recommendation • Patients should be evaluated at three and six months after the initiation of treatment. As a minimum, tests should include serum PSA measurement, digital rectal examination (DRE), and careful evaluation of symptoms in order to assess the treatment response and the side-effects of the treatments given • Follow-up should be tailored for the individual patient, according to symptoms, prognostic factors and the treatment given • In patients with stage M0 disease with a good treatment response, follow-up is scheduled every six months, and should include as a minimum a disease-specific history, DRE and serum PSA determination

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C • In patients with stage M1 disease with a good treatment response, follow-up is scheduled for every three to six months. • As a minimum, this should include a disease-specific history, DRE and serum PSA determination, and is frequently supplemented with haemoglobin, serum creatinine and alkaline phosphatase measurements • Patients (especially if M1b status) should be advised on the clinical signs that could suggest spinal cord compression • When disease progression occurs, or if the patient does not respond to the treatment given, the C follow-up needs to be individualised • Routine imaging of stable patients is not recommended B GR = grade of recommendation

15.6

REFERENCES

1.

Ercole CJ, Lange PH, Mathisen M, Chiou RK, Reddy PK, Vessella RL. Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer. J Urol 1987;138(5):1181-4. http://www.ncbi.nlm.nih.gov/pubmed/2444720 2. Mecz Y, Barak M, Lurie A. Prognostic importance of the rate of decrease in prostatic specific antigen (PSA) levels after treatment of patients with carcinoma of prostate. J Tumour Marker Oncol 1989;4:323-8. 3. Petros JA, Andriole GL. Serum PSA after antiandrogen therapy. Urol Clin North Am 1993;20(4):749-56. http://www.ncbi.nlm.nih.gov/pubmed/7505983 4. Hussain M, Tangen CM, Higano C, Schelhammer PF, Faulkner J, Crawford DE, Wilding G, Akdas A, Small EJ, Donnelly B, MacVicar G, Raghavan D. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006;24(24):3984-90. http://www.ncbi.nlm.nih.gov/pubmed/16921051 5. Kwak C, Jeong SJ, Park MS, Lee E, Lee SE. Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol 2002;168(3):995-1000. http://www.ncbi.nlm.nih.gov/pubmed/12187207 6. Collette L, de Reijke TM, Schröder FH; EORTC Genito-Urinary Group. Prostate specific antigen: a prognostic marker of survival in good prognosis metastatic prostate cancer? (EORTC 30892). Eur Urol 2003;44(2):182-9. http://www.ncbi.nlm.nih.gov/pubmed/12875936 7. D’Amico AV, Moul JW, Carroll PR, Cote K, Sun L, Lubeck D, Renshaw AA, Loffredo M, Chen M. Intermediate end point for prostate cancer-specific mortality following salvage hormonal therapy for prostate-specific antigen failure. J Natl Cancer Inst 2004;96(7):509-15. http://www.ncbi.nlm.nih.gov/pubmed/15069112 8. Stewart AJ, Scher HI, Chen MH, McLeod DG, Carroll PR, Moul JW, D’Amico AV. Prostate-specific antigen nadir and cancer-specific mortality following hormonal therapy for prostate-specific antigen failure. J Clin Oncol 2005;23(27):6556-60. http://www.ncbi.nlm.nih.gov/pubmed/16170163 9. Collette L, BurzyKowski T, Carroll KJ, Newling D, Morris T and Schroder FH. Is prostate antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals. J Clin Oncol 2005;23(25):6139-48. http://www.ncbi.nlm.nih.gov/pubmed/16135480 10. Strum SB, McDermed JE, Scholz MC, Johnson H, Tisman G. Anaemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade. Br J Urol 1997;79(6):933-41. http://www.ncbi.nlm.nih.gov/pubmed/9202563 11. Daniell HW. Osteoporosis due to androgen deprivation therapy in men with prostate cancer. Urology 2001;58(2 Suppl 1):101-7. http://www.ncbi.nlm.nih.gov/pubmed/11502461 12. Miller PD, Eardley I, Kirby RS. Prostate specific antigen and bone scan correlation in the staging and monitoring of patients with prostatic cancer. Br J Urol 1992;70(3):295-8. http://www.ncbi.nlm.nih.gov/pubmed/1384920 13. Oesterling JE. Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol 1991;145(5):907-23. http://www.ncbi.nlm.nih.gov/pubmed/1707989

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14.

Sissons GR, Clements MA, Peeling WB, Penney MD. Can serum prostate-specific antigen replace bone scintigraphy in the follow-up of metastatic prostatic cancer? Br J Radiol 1992;65(778):861-4. http://www.ncbi.nlm.nih.gov/pubmed/1384917 15. Higano CS. Bone loss and the evolving role of bisphosphonate therapy in prostate cancer. Urol Oncol 2003;21(5):392-8. http://www.ncbi.nlm.nih.gov/pubmed/14670551

16. TREATMENT OF BIOCHEMICAL FAILURE AFTER TREATMENT WITH CURATIVE INTENT 16.1

Background

Primary curative procedures such as radical prostatectomy and radiotherapy are well established therapeutic options in the management of localised prostate cancer (PCa). Technical advances in surgery and radiation therapy have improved therapeutic efficacy and decreased treatment-associated morbidity and toxicity, respectively. However, despite these improvements, there is still a significant risk of cancer recurrence after therapy, with between 27% and 53% of all patients undergoing radiation therapy or radical prostatectomy developing local or distant recurrences within 10 years of initial therapy, and 16-35% of patients receiving second-line treatment within five years of initial therapy (1-5, 6).

16.2

Definitions

16.2.1 Definition of treatment failure In previous years, treatment failure was defined as recurrence on digital rectal examination (DRE) or the development of metastatic disease. Currently, treatment failure is defined as a rising prostate-specific antigen (PSA) level based on a study of Pound et al. (7), which demonstrated that no patient followed for more than five years developed any recurrence without a concomitant rise in PSA. The level of PSA that defines treatment failure differs between radical prostatectomy cases and those treated with radiotherapy. Following radical retropubic prostatectomy, two consecutive values of PSA > 0.2 ng/mL appear to represent an international consensus defining recurrent cancer (6, 8). However, the most appropriate definition of biochemical progression after radical prostatectomy is still uncertain. In a retrospective analysis of 2782 men who had undergone radical prostatectomy for clinically localised PCa, Amling et al. (9) determined the best PSA cut-off point to be used to define biochemical recurrence. The authors demonstrated that once PSA recurrence was detected, a subsequent increase in PSA was noted in 49%, 62% and 72% of patients who had PSA levels of 0.2 ng/mL, 0.3 ng/mL and 0.4 ng/mL, respectively. These data indicate that only half the patients with a PSA of 0.2 ng/mL will progress further, and that they can therefore initially be managed by surveillance. Similar data have been presented by Stephenson et al. (10), who identified a PSA value ≥ 0.4 ng/mL as the best cut-off to explain the development of distant metastasis among 10 candidate definitions based on retrospective review of 75 patients who developed distant metastases after radical prostatectomy. Therefore, a cut-off of 0.4 ng/mL is appropriate for the definition of progression with clinical relevance necessitating salvage treatment. Following radiotherapy, a reasonable definition of biochemical relapse is three consecutive increases, according to the recommendation of the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel (11). The new definition indicates a relapse if the PSA increase is ≥ 2 ng/mL higher than the PSA nadir value, independent of the serum concentration of the nadir (12). 16.2.2 Definition of recurrence Following radical prostatectomy, PSA values > 0.4 ng/mL represent recurrent cancer. Following radiotherapy, a PSA value of 2 ng/mL above the nadir after radiotherapy represents recurrent cancer.

16.3

Local or systemic relapse

With regard to further management once PSA relapse has been diagnosed, it is of major importance to determine whether the recurrence has developed at local or distant sites. About 50% of patients who underwent radical retropubic prostatectomy will have local disease, and the remainder will have either distant

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disease alone, or distant and local disease (11). Important parameters to help differentiate between local or distant relapse (Table 18) include: • the timing of the PSA increase after surgery • PSA velocity • PSA doubling time (PSADT) • the pathohistological stage • the Gleason score of the prostatectomy specimen. PSA elevations developing within the first two years following surgery are associated with distant recurrences (12). It has been shown that a median PSADT of 4.3 months is associated with distant relapse, whereas a median PSADT of 11.7 months predicts local failure (13). According to a recent study (14), PSA velocity of < 0.75 ng/mL/y was observed in 94% of patients with local recurrence, whereas 56% of patients with distant metastases demonstrated a PSA velocity of > 0.75 ng/mL/y. Table 18: Important clinical and pathohistological parameters predicting local and systemic relapse following radical prostatectomy Parameter • Interval to PSA relapse ≤ 1 year 1-2 years > 2 years > 3 years • PSA doubling time • Gleason score 2-4 5-6 7 8-10 • Pathological stage Organ confined (≤ pT2b) pT3a, R0 pT3a, R1 pT3b pTxpN1

Local recurrence

Systemic recurrence

7% 10% 61% 74% 11.7 months

93% 90% 39% 26% 4.3 months

0% 55% 39% 11%

0% 45% 61% 89%

40% 54% 48% 16% 7%

60% 46% 52% 84% 93%

With radiotherapy, any continuously rising PSA following a nadir after radiation is an indicator for local recurrence, systemic metastatic spread or a combination of both (11, 14-16). However, due to the well known PSA bounce phenomenon, biochemical recurrence is defined by three consecutive PSA rises above the nadir level according to ASTRO guidelines. After radiotherapy, a late and slowly rising PSA is a sign of local failure only. Local recurrence is defined by: • a prostatic biopsy demonstrating malignant cells 18 months or longer after initial radiotherapy • plus an associated rise in PSA • plus no evidence of metastatic spread documented by computed tomography (CT) or magnetic resonance imaging (MRI) and bone scintigraphy. 16.3.1 Definition of local and systemic failure • Local failure following radical prostatectomy is predicted with an 80% probability by PSA increase > three years after radical prostatectomy, a PSADT ≥ 11 months, a Gleason score ≤ 6, and stage ≤ pT3a pN0, pTx R1. • Systemic failure following radical prostatectomy is predicted with > 80% accuracy by a PSA increase < one year after radical prostatectomy, a PSADT of four to six months, a Gleason score of 8-10, and stage pT3b, pTxpN1. • Local failure after radiotherapy is documented by a positive prostatic biopsy and negative imaging studies.

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•

 rostatic biopsy after radiotherapy is necessary only if local procedures such as salvage P prostatectomy are indicated in an individual patient.

16.4

Evaluation of PSA progression

In recent years, most patients with PSA progression following initial therapy with curative intent underwent physical and sonographic examinations, radiographic studies or biopsies of the prostatic fossa and the vesicourethral anastomosis to confirm the recurrence identified by serological studies. For patients with asymptomatic PSA-only progression, the yield is very low, and Lange et al. (14) have shown that biochemical failure precedes clinical disease by 6-48 months. In general, DRE is not useful in men with undetectable or very low PSA levels. In a recent study by Öbek et al. (17), it was shown that only 4/72 patients (5.5%) with a PSA recurrence following radical prostatectomy had an abnormal DRE. Traditionally, bone scans and abdominal CT scans have been used to evaluate PSA elevations following primary treatment. Both imaging studies, however, are characterised by a low sensitivity and specificity and might be safely omitted in the routine work-up of relapsing patients. Recently, Cher et al. (18) studied 144 bone scans in 93 patients with PSA recurrence after radical retropubic prostatectomy, of which 122 patients had undergone radical prostatectomy without any hormone treatment, whereas 22 patients had received either neoadjuvant or adjuvant androgen-deprivation therapy (ADT). Only 4.1% and 27% of the bone scintigrams were positive for metastatic disease; the lowest PSA associated with positive findings was 46 ng/mL in the absence of adjuvant ADT, whereas the lowest PSA value was 15.47 ng/mL in patients who had received hormonal therapy. The probability of a positive bone scan remains ≤ 5% until serum PSA reaches at least 40 ng/mL. Similar data have been achieved by other groups that have demonstrated that patients with a true positive bone scan had an average PSA level of > 60 ng/mL and a PSA velocity of 22 ng/mL/y (19, 20). On logistic regression analysis, PSA and PSA velocity predicted the findings on bone scan, and PSA velocity predicted the CT scan result. The probability of a positive bone scan and a positive CT scan was 9.4% and 14%, respectively, among the 132 patients with biochemical recurrence. However, there might be a slight difference between patients after radical retropubic prostatectomy compared with patients after radiation therapy, as demonstrated by Johnstone et al. (21) in whose study 5% and 30%, respectively, of the bone scans, were positive. In summary, bone scintigraphy and CT scans are of no additional diagnostic value unless the PSA serum levels are higher than 20 ng/mL or the PSA velocity is more than 20 ng/mL/y. Endorectal coil imaging has been described as a useful technique to detect local recurrences after radical prostatectomy (22). In a series of 48 patients, local recurrence was correctly identified in 81%, with the mean PSA at time of diagnosis being 2 ng/mL. Positron emission tomography (PET) has been successfully applied in many human cancers for early identification of local or systemic recurrences. In PCa, there are few, but promising, published data on the clinical efficacy of PET in detecting local recurrences after radical prostatectomy (23, 24). However, it must be borne in mind that the uptake of 11C-choline is not specific for PCa and might also be due to inflammatory intraprostatic lesions. In a series of 31 patients with biochemical progression after radical prostatectomy, (11C)acetate-PET demonstrated a high sensitivity and specificity for the detection of local recurrences if the PSA serum level was > 1 ng/mL (23). In another recent series of 43 patients with newly diagnosed prostate cancer, there was a significant correlation between the 11C-choline uptake and the intraprostatic location of PCa as analysed in radical prostatectomy specimens (25). Similar results have been reported for the detection of locally recurrent PCa after radiation therapy (26). However, sensitivity with regard to extraprostatic extension was significantly lower for 11C-PET when compared with MRI. The most recent series to evaluate the role of 11C-choline PET/CT in patients with biochemical recurrence after radical prostatectomy identified a significant PSA relationship: the sensitivity to identify the localisation of metastases was 20-36% at PSA levels ≤ 1 ng/mL, and increased to 63-83% in men with PSA levels ≥ 3 ng/mL (27-30). The role of choline PET/CT to detect local or systemic recurrences in men with PSA relapse following radiotherapy is unclear and based on very few studies (31). Thus no final recommendations can be made. Its sensitivity and specificity with regard to the detection of lymph node metastases is less reliable, and the routine use of 11C-PET cannot therefore be recommended, especially not for PSA values < 1 ng/mL. 108

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Immunoscintigraphy using a radiolabelled monoclonal antibody based on prostate-specific membrane antigen for messenger RNA (PSMA), called 111-indium capromab pendetide, might represent an innovative diagnostic approach, with an overall accuracy of up to 81% to detect the site of relapse in PSA-only recurrences following radical retropubic prostatectomy (23, 24, 32, 33). Independent of the PSA serum concentration, a capromab pendetide scan shows a diagnostic yield of 60-80%, and may help to stratify therapy according to the location of positive sites. A recent study (33) investigating 255 patients with PSA-only recurrence < 4.0 ng/mL after radical prostatectomy, showed capromab pendetide uptake in 72% throughout the range of post-operative PSA serum levels (0.1-4.0 ng/mL). Approximately 31%, 42% and 25% of patients exhibited local uptake, locoregional uptake and distant uptake, respectively, enabling therapy to be targeted according to the differentiation of local versus systemic relapse. It has been common practice to perform transrectal ultrasound- (TRUS) guided biopsies of the prostatic fossa, the anastomosis or the prostate gland to exclude local recurrence after radical retropubic prostatectomy or radiotherapy. However, according to available studies, routine biopsy of the vesicourethral anastomosis appears not to be justified based on a verification rate of only 54% (34-38). Only in the presence of a palpable lesion or a hypoechoic lesion on TRUS can the diagnostic yield of the biopsy be improved to approximately 80%. Furthermore, there is a strong correlation between the positive biopsy rate and PSA serum concentrations (34-38); 28% and 70% of the biopsies were positive if the PSA level was, respectively, below 0.5 ng/mL or greater than 2.0 ng/mL. It is common sense, nowadays, that routine anastomotic biopsy is not indicated, and the use of PSA and PSADT is sufficient for clinical practice. In addition, PSA-free survival in biopsy-proven recurrences does not differ significantly compared with PSA-only recurrences. With regard to PSA relapses following radiation therapy, routine prostate biopsy should no longer be performed for the evaluation of PSA-only recurrences, according to an ASTRO consensus recommendation (15). However, prostate biopsy documenting local recurrence represents the main cornerstone in the decision-making process for salvage radical prostatectomy in patients with rising PSA levels following a nadir after radiation therapy (3941). It is a general recommendation to wait about 18 months and three months following radiation therapy or seeds, and cryotherapy or high-intensity focused ultrasound (HIFU), respectively.

16.5

Diagnostic procedures in patients with PSA relapse

•

 ollowing radical prostatectomy, CT scans of the pelvis and abdomen are of low sensitivity and F specificity in patients with PSA levels < 20 ng/mL or a PSA velocity of < 20 ng/mL/y Endorectal MRI or PET scans may help to detect local recurrences if PSA is > 1-2.0 ng/mL, but is not yet routine clinical practice If available, a capromab pendetide scan shows a diagnostic yield of 60-80% independent of the PSA serum level Following radiation therapy, local recurrence is documented by a positive biopsy > 18 months after the procedure.

• • •

16.6

Treatment of PSA-only recurrences

The timing and mode of treatment of PSA-only recurrence after radical prostatectomy or radiation therapy remains controversial. After radical retropubic prostatectomy observation, radiation therapy to the prostatic bed, (complete) androgen blockade, intermittent androgen deprivation (IAD), a combination of anti-androgens with 5-α-reductase inhibitors, and even early chemohormonal approaches are therapeutic options. The same therapeutic options may be applied for PSA recurrences following radiation therapy. In addition, salvage prostatectomy, cryotherapy and brachytherapy might be indicated in carefully selected patients. 16.6.1 Radiation therapy for PSA-only recurrence after radical prostatectomy Considering the numerous studies on the use of radiation therapy for PSA-only recurrence following radical retropubic prostatectomy, there is a growing body of parameters predicting outcome that might be helpful to differentiate between observation, radiation and hormonal therapy. As confirmed by various studies, the pre-radiation PSA level appears to be of critical importance for obtaining optimal treatment results (42-50). Applying a pre-radiation cut-off of < 2.5 ng/mL, Wu et al. (42) and Schild et al. (43) reported disease-free survival rates of 53% and 76%, compared with 8% and 26%, respectively, for patients with PSA serum levels > 2.5 ng/mL. Forman et al. (44) demonstrated a disease-free survival rate of 83% compared with 33% in patients with a PSA-only recurrence of less than 2.0 ng/mL and greater than 2.0 ng/mL, respectively. Nudell et al. (45) even reported progression-free survival rates of 58% and 21% in patients having undergone radiation of the prostate bed if PSA serum levels were below 1.0 ng/mL or greater than 1.0 ng/mL, respectively. Based on

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these data, ASTRO has published a consensus paper recommending a dose of at least 64 Gy when the PSA level is < 1.5 ng/mL after radical retropubic prostatectomy (15). These data of early salvage radiation therapy are corroborated by recent papers (51-53) demonstrating a significant difference with regard to the five-year biochemical-free and overall survival rates in patients being treated for PSA recurrence only or for palpable locally recurrent cancer. The analysis of patterns of treatment failure in SWOG 8974, a prospective randomised clinical trial to address whether high-risk post-prostatectomy patients benefited from immediate radiation therapy to the prostate fossa, identified a 77% freedom from PSA failure in a subgroup of patients with post-operative PSA levels ≤ 0.2 ng/mL (52). In men with PSA levels of > 0.2 ng/mL and ≤ 1.0 ng/mL, the five-year PSA recurrence-free survival was 34%, and 0% in patients post-operative PSA serum levels > 1.0 ng/mL. These data indicated that adjuvant radiation therapy is effective even in high-risk patients, and that the therapeutic benefit is most evident in the presence of minimal PSA serum levels. In another study, Stephenson et al. (53) evaluated prognostic models to predict the outcome of salvage radiation therapy on a cohort of 1603 men with PSA progression after radical prostatectomy who were operated on in 17 North American tertiary referral centres. The authors identified a significant relationship between PSA serum concentration at the time of radiation therapy and therapeutic outcome: the six-year biochemical-free survival was 48% in men with PSA < 0.5 ng/mL, whereas it was only 40%, 28% and 18% in men with PSA levels of 0.51-1 ng/mL, 1.01-1.5 ng/mL and > 1.5 ng/mL, respectively. Egewa et al. (49) reported five-year biochemical-free and overall survival rates of 69% and 96%, compared with 45% and 78%, respectively, in the group with palpable disease. However, there is still a lack of data from prospective randomised trials, and all of the studies being performed lack long-term follow-up, so the impact on survival is unknown. 16.6.2 Hormonal therapy In patients with a high pre-radical prostatectomy PSA > 20 ng/mL, a Gleason grade > 7, an extensive positive surgical margin and extensive extraprostatic tumour growth (pT3b, pTxpN1), immediate hormonal therapy might be indicated (46-50). The impact of early ADT on long-term survival is still unknown, however. In a retrospective observational multicentre study including 1352 patients with PSA recurrence following radical prostatectomy (51), early ADT resulted in a significant reduction of the development of clinical metastases compared with delayed ADT. There was, however, no significant effect on long-term survival. These recommendations are corroborated by a study (54) demonstrating that none of the patients with a Gleason score of 8, pT3b or pTxpN1 PCa remained disease-free following radiation therapy for PSA-only recurrence after radical prostatectomy. It is difficult to make recommendations for the optimal therapeutic management for PSA-only recurrences following radical prostatectomy or radiation therapy because of the lack of prospective randomised trials. There are only very few studies analysing the clinical utility of early androgen deprivation in locally advanced (M0) and metastatic PCA (54, 55). It is believed that for the M0 category of patients with pTxN1 disease who have undergone radical prostatectomy reflecting PSA-only recurrences, hormonal therapy would appear to be beneficial for some with a high probability of occult systemic metastases. There is some evidence that combined androgen blockade (CAB) has a pronounced survival benefit in patients with minimal metastatic disease, so patients with PSA-only recurrences might have a similarly improved survival with combined androgen deprivation (56, 57). Considering the speculative benefits, the sideeffects of traditional hormonal therapy – such as hot flushes, loss of libido, impotence, decreased muscle mass and osteoporosis – must not be underestimated. The use of anti-androgens alone might overcome these side-effects as demonstrated in recent studies. Although gynaecomastia and breast tenderness were the most predominant side-effects for the treatment of organ-confined and locally advanced PCa, the incidence of hot flushes, loss of libido and impotence was significantly lower than expected for luteinising hormone-releasing hormone (LHRH) agonists and CAB (58). Furthermore, the risk of objective progression of the disease was significantly reduced in patients receiving bicalutamide 150mg (59). Anti-androgens may represent a viable alternative to other modes of androgen deprivation for the management of PSA-only recurrences, especially in young and otherwise healthy men. Non-traditional ways of using hormonal therapy for PSA-only recurrence include IAD and oral therapies combining anti-androgens with 5-α-reductase inhibitors (60-67). In the setting of PSA-only recurrences, however, no prospective randomised trials and no clinical studies with sufficient data on long-term efficacy

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are available to justify a routine clinical application of IAD, despite its potential benefits. Summarising the series in which PSA-only recurrences were treated by IAD (60-64), PSA threshold levels at study-entry varied significantly, as did the PSA level at discontinuation of hormonal therapy. Only the study of 150 patients by Tunn (64) had a sufficiently appropriate study design to allow the drawing of important clinical conclusions. Patients were started on IAD for nine months when the postprostatectomy PSA serum level was greater than 3.0 ng/mL, and all patients reached a nadir of less than 0.5 ng/mL. IAD was restarted when PSA increased to more than 3.0 ng/mL. After a mean follow-up of 48 months, and a mean duration of hormonal therapy of 26.6 months, none of the patients had progressed to hormonerefractory disease. In some studies, finasteride and flutamide have been combined to manage PSA-only recurrences since both agents work additively by blocking the intraprostatic conversion of testosterone to dihydrotestosterone (DHT), and blocking the intracytoplasmic DHT receptor (65-67). In the latest report (66), including 73 patients, the application of finasteride (10 mg/day) and low-dose flutamide (250 mg/day) resulted in a mean PSA nadir of 1.35 ng/mL within six months. However, only 62% of the patients studied reached a PSA nadir of < 0.2 ng/mL. After a mean follow-up of 15 months, none of the patients had progressed to traditional hormonal therapy. However, longer follow-up of a larger patient cohort is needed, and randomised phase III trials using modern anti-androgens with fewer gastrointestinal and hepatic side-effects are mandatory. 16.6.3 Observation Observation until the development of clinically evident metastatic disease might represent a viable option for patients with a Gleason score ≤ 7, PSA recurrence longer than two years after surgery, and a PSADT longer than 10 months. In these patients, the median actuarial time for the development of metastasis will be eight years, and the median time from metastasis to death will be another five years. 16.6.4 Management of PSA relapse after radical prostatectomy Recommendations GR • Local recurrences are best treated by salvage radiation therapy with 64-66 Gy at a PSA serum B level ≤ 1.5 ng/mL • Expectant management is an option for patients with presumed local recurrence who are too B unfit or unwilling to undergo radiation therapy • PSA recurrence indicative of systemic relapse is best treated by early ADT resulting in decreased B frequency of clinical metastases • LHRH analogues/orchiectomy or bicalutamide 150 mg/day can both be used when there is A indication for hormonal therapy GR = grade of recommendation

16.7

Management of PSA failures after radiation therapy

In a recent review of the data of the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) comprising 2336 patients with PCa, Grossfeld et al. (68) demonstrated that 92% of patients initially irradiated received ADT for secondary treatment of PSA progression. In the absence of salvage procedures, the mean time interval from biochemical to clinical progression is approximately three years. Therapeutic options in these patients are ADT or local procedures, such as salvage radical prostatectomy, cryotherapy and interstitial radiation therapy (69-74). Salvage radical retropubic prostatectomy has not, however, gained widespread acceptance because of its associated morbidity, namely incontinence, local recurrences and rectal injuries. However, in well selected patients, the procedure might result in long-term disease-free survival. One has to consider that most series reporting on salvage radical prostatectomy include patients who were treated in the pre-PSA era without modern radiotherapeutic techniques, and local recurrences were usually detected at a late stage. Complications associated with the procedure were therefore quite high, with up to 65% of patients suffering from treatment-related morbidities. Up to 60% of patients in whom salvage radical prostatectomy was planned, had to undergo anterior or total exenteration for locally extensive disease associated with a high rate of local recurrences and a mean time to progression of only 1.3 years (46, 49, 52, 53). Recent reports analysing patients who were operated on during the past decade, have described far more optimistic outcomes after salvage radical prostatectomy. In the series examined by Gheiler et al. (73), 40 patients with a mean PSA of 14 ng/mL underwent salvage radical prostatectomy. When stratified by PSA less than or greater than 10 ng/mL, the three-year disease-specific survival was 68% and 26%, respectively.

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In the series reported by Garzotto and Wajsman (74), 24 patients underwent radical cystoprostatectomy or radical prostatectomy with neoadjuvant ADT. Neoadjuvant ADT was associated with a lower rate of positive surgical margins (21%) compared with patients in whom androgen deprivation failed and who exhibited a positive surgical margin rate of 80%. The authors demonstrated that disease-specific survival correlated strongly with the surgical margin status. At a mean follow-up of five years, the disease-specific survival rate was 95% and 44% for those with negative and positive surgical margins, respectively. Vaidya and Soloway (75) demonstrated a low complications rate, good post-operative continence and only one biochemical recurrence 36 months after salvage radical prostatectomy. Similar data have been achieved by Stephenson et al. (76), who reported on 100 consecutive patients undergoing radical salvage prostatectomy associated with a very low rate of peri-operative complications. The five-year progression-free rates have improved, and the results are similar to those of standard radical prostatectomy in cases of similar pathological stages. The 10-year cancer-specific and overall survival rates are in the ranges 70-75% and 60-66%, respectively, in contemporary series. In most contemporary series, organ-confined disease, negative surgical margins and the absence of seminal vesicle and/or lymph node metastases are favourable prognosticators associated with a better disease-free survival of approximately 70-80%, compared with 40-60% in patients with locally advanced PCa (77). In general, salvage radical retropubic prostatectomy should be considered only in patients with a low co-morbidity, a life expectancy of at least 10 years, an organ-confined PCa < T2, Gleason grade < 7, and presurgical PSA < 10 ng/mL. In all other patients, accurate pre-surgical staging is not easily defined after radiation therapy, increasing the risk not only for the necessity of anterior and total extirpation procedures, but also for associated complications and decreased long-term disease-specific survival. 16.7.1 Salvage cryosurgical ablation of the prostate (CSAP) for radiation failures Salvage cryosurgery has been proposed as an alternative to salvage prostatectomy as it has the potential advantage of less morbidity but equal efficacy. Only very few studies are available, and the results are not very promising. Pisters et al. (78) reported on 150 patients who had undergone CSAP for PSA recurrences following radiotherapy (n = 110) or other extensive pre-treatment (n = 40). After a mean follow-up of 13.5 months, 58% of patients exhibited biochemical failure, and only 31% demonstrated undetectable PSA serum levels. The complications associated with salvage CSAP were significant, and occurred in virtually all patients, with the main complications being urinary incontinence (73%), obstructive symptoms (67%), impotence (72%) and severe perineal pain (8%). After a one-year follow-up, incontinence resolved in the majority of patients, with persistent significant incontinence in 22% of patients (53%). According to a recent study by Cespedes et al. (79), the risk for urinary incontinence and impotence at least 12 months after CSAP are as high as 28% and 90%, respectively. In addition, 8-40% of patients complained about persistent rectal pain, and an additional 4% of men had undergone surgical procedures for the management of treatment-associated complications. With regard to oncological outcome, recent studies demonstrated that a durable PSA-response can be achieved in about 50% of patients with a pre-cryosurgery PSA of < 10 ng/mL (80). 16.7.2 Salvage brachytherapy for radiation failures The experience with salvage brachytherapy for radiation failures is very limited and there is only one study that includes a representative number of patients and a mean follow-up of 64 months (81-84). Grado et al. (83) treated 49 patients with transperineal TRUS-guided brachytherapy and reported three- and five-year disease-free survival rates of 48% and 43%, respectively. Beyer (84) reported a five-year biochemical freedom from relapse in 34-53% of patients, with local cancer control achieved in 98% of patients. However, the complication rate was quite severe, with 27% of the patients becoming incontinent, 14% needing palliative transurethral resection of the prostate (TURP) due to acute urinary retention, another 4% suffering from rectal ulcers, and 2% requiring permanent colostomy. 16.7.3 Observation Patients with signs of local recurrence only (low-risk patients with late recurrence and a slow PSA rise) who are not opting for second-line curative options are best managed by observation alone. A retrospective cohort analysis of hormonal therapy versus watchful waiting in 248 men with PSA failure after radiotherapy showed no advantage for hormonal therapy in the subgroup of men with a PSADT of > 12 months after radiotherapy. The five-year metastasis-free survival rate was 88% with hormonal therapy vs 92% with watchful waiting (p = 0.74) (85).

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16.7.4 Management of PSA relapse after radiation therapy Recommendation GR • Local recurrences may be treated by salvage radical prostatectomy in carefully selected patients C • CSAP and interstitial brachytherapy are alternative procedures in patients not suitable for surgery C • ADT is an option in patients with presumed systemic relapse B GR = grade of recommendation

16.8 Guidelines for second-line therapy after treatment with curative intent Recommendation GR • Presumed local failure Patients with presumed local failure only may be candidates for salvage B after radical radiotherapy radiotherapy. This should be given with at least 66 Gy and preferably prostatectomy before PSA has risen above 1.0 ng/mL. Other patients are best offered a period of watchful waiting (active monitoring), with possible hormonal therapy later on • Presumed local failure  Selected patients may be candidates for salvage radical prostatectomy C after radiotherapy although patients should be informed about the comparatively high risk of complications. Other patients are best offered a period of watchful waiting (active monitoring), with possible hormonal therapy later on • Presumed distant failure  There is some evidence that early hormonal therapy may be of benefit B in +/– local failure, delaying progression, and possibly achieving a survival benefit in comparison with delayed therapy. The results are not without controversy. Local therapy is not recommended except for palliative reasons GR = grade of recommendation

16.9

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Vees H, Buchegger F, Albrecht S, Khan H, Husarik D, Zaidi H, Soloviev D, Hany TF, Miralbell R. 18F-choline and/or 11C-acetate positron emission tomography: detection of residual or progressive subclinical disease at very low prostate-specific antigen values (<1 ng/mL) after radical prostatectomy. BJU Int 2007;99(6):1415-20. http://www.ncbi.nlm.nih.gov/pubmed/17428249 27. Rinnab L, Mottaghy FM, Simon J, Volkmer BG, de Petriconi R, Hautmann RE, Wittbrodt M, Egghart G, Moeller P, Blumstein N, Reske S, Kuefer R. [11C]Choline PET/CT for targeted salvage lymph node dissection in patients with biochemical recurrence after primary curative therapy for prostate cancer. Preliminary results of a prospective study. Urol Int 2008;81(2):191-7 http://www.ncbi.nlm.nih.gov/pubmed/18758218 28. Krause BJ, Souvatzoglou M, Tuncel M, Herrmann K, Buck AK, Praus C, Schuster T, Geinitz H, Treiber U, Schwaiger M. The detection rate of [11C]Choline-PET/CT depends on the serum PSAvalue in patients with biochemical recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2008 Jan;35(1):18-23 http://www.ncbi.nlm.nih.gov/pubmed/17891394 29. Husarik DB, Miralbell R, Dubs M, John H, Giger OT, Gelet A, Cservenyàk T, Hany TF. Evaluation of [(18)F]-choline PET/CT for staging and restaging of prostate cancer. Eur J Nucl Med Mol Imaging 2008 Feb;35(2):253-63. http://www.ncbi.nlm.nih.gov/pubmed/17926036 30. Pelosi E, Arena V, Skanjeti A, Pirro V, Douroukas A, Pupi A, Mancini M. Role of whole-body 18F-choline PET/CT in disease detection in patients with biochemical relapse after radical treatment for prostate cancer. Radiol Med 2008 Sep;113(6):895-904. http://www.ncbi.nlm.nih.gov/pubmed/18414809 31. Heidenreich A, Semrau R, Thüer D, Pfister D. Radical salvage prostatectomy: Treatment of local recurrence of prostate cancer after radiotherapy. Urologe A 2008 Nov;47(11):1441-6. http://www.ncbi.nlm.nih.gov/pubmed/18806991 32. Hinkle GH, Burgers JK, Neal CE, Texter JH, Kahn D, Williams RD, Maguire R, Rogers B, Olsen JO, Badalament RA. Multicentre radioimmunoscintigraphic evaluation of patients with prostate carcinoma using indium-111 capromab pendetide. Cancer 1998;83(4):739–47. http://www.ncbi.nlm.nih.gov/pubmed/9708939 33. Levesque PE, Nieh PT, Zinman LN, Seldin DW, Libertino JA. Radiolabelled monoclonal antibody indium 111-labeled CYT-356 localizes extraprostatic recurrent carcinoma after prostatectomy. Urology 1998;51(6):978-84. http://www.ncbi.nlm.nih.gov/pubmed/9609636 34. Kahn D, Williams RD, Manyak MJ, Haseman MK, Seldin DW, Libertino JA, Maguire RT. 111Indium capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy. The ProstScint Study Group. J Urol 1998;159(6):2041-6;discussion 2046-7. http://www.ncbi.nlm.nih.gov/pubmed/9598514 35. Raj GV, Partin AW, Polascik TJ. Clinical utility of Indium 111-capromab pendetide immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical prostatectomy. Cancer 2002;94(4):987-96. http://www.ncbi.nlm.nih.gov/pubmed/11920467 36. Foster LS, Jajodia P, Fournier G Jr, Shinohara K, Carroll P, Narayan P. The value of prostate specific antigen and transrectal ultrasound guided biopsy in detecting prostatic fossa recurrences following radical prostatectomy. J Urol 1995;149(5):1024-8. http://www.ncbi.nlm.nih.gov/pubmed/7683341 37. Fowler JE Jr, Brooks J, Pandey P, Seaver LE. Variable histology of anastomotic biopsies with detectable prostate specific antigen after radical prostatectomy. J Urol 1995;153(3 Pt 2):1011-4. http://www.ncbi.nlm.nih.gov/pubmed/7531783 38. Connolly JA, Shinohara K, Presti JC Jr, Carroll PR. Local recurrence after radical prostatectomy: characteristics in size, location, and relationship to prostate-specific antigen and surgical margins. Urology 1996;47(2):225-31. http://www.ncbi.nlm.nih.gov/pubmed/8607239 39. Vaidya A, Soloway MS. Salvage radical prostatectomy for radiorecurrent prostate cancer: morbidity revisited. J Urol 2000;164(6):1998-2001. http://www.ncbi.nlm.nih.gov/pubmed/11061900 40. Shekarriz B, Upadhyay J, Pontes JE. Salvage radical prostatectomy. Urol Clin North Am 2001;28(3):545-53. http://www.ncbi.nlm.nih.gov/pubmed/11590813

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Eastham JA, DiBlasio CJ, Scardino PT. Salvage radical prostatectomy for recurrence of prostate cancer radiation therapy. Curr Urol Rep 2003;4(3):211-5. http://www.ncbi.nlm.nih.gov/pubmed/12756084 42. Wu JJ, King SC, Montana GS, McKinstry CA, Anscher MS. The efficacy of postprostatectomy radiotherapy in patients with an isolated elevation of serum prostate-specific antigen. Int J Radiat Oncol Biol Phys 1995;32(2):317-23. http://www.ncbi.nlm.nih.gov/pubmed/7538500 43. Schild SE, Buskirk SJ, Wong WW, Halyard MY, Swanson SK, Novicki DE, Ferrigni RG. The use of radiotherapy or patients with isolated elevation of prostate specific antigen following radical prostatectomy. J Urol 1996;156(5):1725-9. http://www.ncbi.nlm.nih.gov/pubmed/8863580 44. Forman JD, Meetze K, Pontes E, Wood DP Jr, Shamsa F, Rana T, Porter AT. Therapeutic irradiation for patients with an elevated postprostatectomy prostate specific antigen level. J Urol 1997;158(4):1436-9; discussion 1439-40. http://www.ncbi.nlm.nih.gov/pubmed/9302138 45. Nudell DM, Grossfeld GD, Weinberg VK, Roach M 3rd, Carroll PR. Radiotherapy after radical prostatectomy: treatment outcomes and failure patterns. Urology 1999;54(6):1049-57. http://www.ncbi.nlm.nih.gov/pubmed/10604707 46. Carroll P. Rising PSA after a radical treatment. Eur Urol 2001;40(Suppl 2):9-16. http://www.ncbi.nlm.nih.gov/pubmed/11684859  47. Cadeddu JA, Partin AW, DeWeese TL, Walsh PC. Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol 1998;159(1):173-7;discussion 177-8. http://www.ncbi.nlm.nih.gov/pubmed/9400465 48. Haab F, Meulemans A, Boccon-Gibbod L, Dauge MC, Delmas V, Hennequin C, Benbunan D, BocconGibbod L. Effect of radiation therapy after radical prostatectomy on serum prostate-specific antigen measured by an ultrasensitive assay. Urology 1995;45(6):1022-7. http://www.ncbi.nlm.nih.gov/pubmed/7539559 49. Egewa S, Matsumoto K, Suyama K, Soh S, Kuwao S, Iwamura M. Limited suppression of prostate specific antigen after salvage radiotherapy for its isolated elevation after radical prostatectomy. Urology 1999;53(1):148-55. http://www.ncbi.nlm.nih.gov/pubmed/9886604 50. Vicini FA, Ziaja EL, Kestin LL, Brabbins DS, Stromberg JS, Gonzalez JA, Martinez AA. Treatment outcome with adjuvant and salvage irradiation after radical prostatectomy for prostate cancer. Urology 1999;54(1):111-17. http://www.ncbi.nlm.nih.gov/pubmed/10414736 51. MacDonald OK, Schild SE, Vora S, Andrews PE, Ferrigni RG, Novicki V, Swanson SK, Wong WW. Salvage radiotherapy for men with isolated rising PSA or local palpable recurrence after radical prostatectomy: do outcomes differ? Urology 2004;64(4):760-4. http://www.ncbi.nlm.nih.gov/pubmed/15491716 52. Swanson GP, Hussey MA, Tangen CM, Chin J, Messing E, Canby-Hagino E, Forman JD, Thompson IM, Crawford ED. Predominant treatrment failure in postprostatectomy patients is local: analysis of patterns of treatment failure in SWOG 8794. J Clin Oncol 2007;25(16):222– 9. http://www.ncbi.nlm.nih.gov/pubmed/17538167 53. Stephenson AJ, Scardino PT, Kattan MW, Pisansky TM, Slawin KM, Klein EA, Anscher MS, Michalski JM, Sandler HM, Lin DW, Forman JD, Zelefsky MJ, Kestin LL, Roehrborn CG, Catton CN, DeWeese TL, Liauw SL, Valicenti RK, Kuban DA, Pollack A. Predicting outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25(15):2035–41 http://www.ncbi.nlm.nih.gov/pubmed/17513807 54. The MRC Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the MRC trial. Br J Urol 1997;79(2):235-46. http://www.ncbi.nlm.nih.gov/pubmed/9052476 55. Messing E, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. New Engl J Med 1999;341(24):1781-8. http://www.ncbi.nlm.nih.gov/pubmed/10588962 56. Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. New Engl J Med 1989;321(7):419-24. http://www.ncbi.nlm.nih.gov/pubmed/2503724

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Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, Bono A, Sylvester R. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. EORTC Genito-Urinary Tract Cancer Cooperative Group and EORTC Data Cancer. Eur Urol 1998;33(2):144-51. http://www.ncbi.nlm.nih.gov/pubmed/9519355 58. Wirth M, Tyrrell C, Wallace M, Delaere KP, Sanchez-Chapado M, Ramon J, Hetherington J, Pina F, Heynes CF, Borchers TM, Morris T, Stone A. Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression. Urology 2001;58(2):146-51. http://www.ncbi.nlm.nih.gov/pubmed/11489683 59. Wirth M. Delaying/reducing the risk of clinical tumour progression after primary curative procedures. Eur Urol 2001;40(Suppl 2):17-23. http://www.ncbi.nlm.nih.gov/pubmed/11684860 60. Goldenberg SL, Gleave ME, Taylor D, Bruchovsky N. Clinical experience with intermittent androgen suppression in prostate cancer: minimum of 3 years’ follow-up. Mol Urol 1999;3(3):287-92. http://www.ncbi.nlm.nih.gov/pubmed/10851335 61. Higano CS, Ellis W, Russell K, Lange PH. Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. Urology 1996;48(5):800-4. http://www.ncbi.nlm.nih.gov/pubmed/8911533 62. Tunn UW. Intermittent endocrine therapy of prostate cancer. Eur Urol 1996;30(Suppl 1):22-5, discussion 38-9. http://www.ncbi.nlm.nih.gov/pubmed/8977986 63. Grossfeld GD, Small EJ, Carroll PR. Intermittent androgen deprivation for clinically localized prostate cancer: initial experience. Urology 1998;51(1):137-44. http://www.ncbi.nlm.nih.gov/pubmed/9457309 64. Tunn U, Eckhart O, Kienle E, Hillger H. Intermittent androgen deprivation in patients with PSA-relapse after radical prostatectomy - first results of a randomized prospective phase III clinical trial (AUO study AP06/95). Eur Urol (Suppl) 2003;1:24, no.86. 65. Ziada AM, Crawford ED. Advanced prostate cancer. Prostate Cancer Prostatic Dis 1999;2(S1):21-6. http://www.ncbi.nlm.nih.gov/pubmed/12496853 66 Harding P, Moul JW, McLeod DG. Combination flutamide and finasteride in PSA-only recurrence after prior local prostate cancer therapy. J Urol 1998;159(Suppl):130 (abstr). 67. Lisle T, Makenzie S, Ziada AM, Harding P, Rosenblum M, Stenner J, Moul JW, Crawford ED. Androgen deprivation therapy using finasteride and low-dose flutamide to treat PSA failure following therapy for clinically localized adenocarcinoma of the prostate. J Urol 1999;161(Suppl):299 (abstr). 68. Grossfeld GD, Li YP, Lubeck DP, Broering JM, Mehta SS, Carroll PR. Predictors of secondary cancer treatment in patients receiving local therapy for prostate cancer: data from cancer of the prostate strategic urologic research endeavor. J Urol 2002;168(2):530-5. http://www.ncbi.nlm.nih.gov/pubmed/12131303 69. Ahlering TE, Lieskovsky G, Skinner DG. Salvage surgery plus androgen deprivation for radioresistant prostatic carcinoma. J Urol 1992;147(3 Pt 2):900-2. http://www.ncbi.nlm.nih.gov/pubmed/1538492 70. Zincke H. Radical prostatectomy and exenterative procedures for local failure after radiotherapy with curative intent: comparison of outcomes. J Urol 1992;147(3 Pt 2):894-9. http://www.ncbi.nlm.nih.gov/pubmed/1538491 71. Lerner SE, Blute ML, Zincke H. Critical evaluation of salvage surgery for radio-recurrent/resistant prostate cancer. J Urol 1995;154(3):1103-9. http://www.ncbi.nlm.nih.gov/pubmed/7543608 72. Rogers E, Ohori M, Kassabian S, Wheeler TM, Scardino PT. Salvage radical prostatectomy: outcome measured by serum prostate specific antigen levels. J Urol 1995;153(1):104-10. http://www.ncbi.nlm.nih.gov/pubmed/7526002 73. Gheiler EL, Tefilli MV, Tiguert R, Grignon D, Cher ML, Sakr W, Pontes JE, Wood DP Jr. Predictors for maximal outcome in patients undergoing salvage surgery for radio-recurrent prostate cancer. Urology 1998;51(5):789-95. http://www.ncbi.nlm.nih.gov/pubmed/9610593 74. Garzotto M, Wajsman Z. Androgen deprivation with salvage surgery for radiorecurrent prostate cancer: result of a 5-year follow-up. J Urol 1998;159(3):950-4;discussion 954-5. http://www.ncbi.nlm.nih.gov/pubmed/9474190 75.  Vaidya A, Soloway MS. Salvage radical prostatectomy for radiorecurrent prostate cancer: morbidity revisited. J Urol 2000;164(6):1998-2001. http://www.ncbi.nlm.nih.gov/pubmed/11061900

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Stephenson AJ, Scardino PT, Bianco FJ, DiBlasio CJ, Fearn PA, Eastham JA. Morbidity and functional outcomes of salvage radical prostatectomy for locally recurrent prostate cancer after radiation therapy. J Urol 2004;172(6 Pt 1):2239–43. http://www.ncbi.nlm.nih.gov/pubmed/15538239 77. Heidenreich A, Ohlmann C, Ozgür E, Engelmann U. [Functional and oncological outcome of salvage prostatectomy of locally recurrent prostate cancer following radiation therapy] Urologe A 2006;45(4):474-81. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/16465521 78.  Pisters LL, von Eschenbach AC, Scott SM, Swanson DA, Dinney CPM, Pettaway CA, Babaian RJ. The efficacy and complications of salvage cryotherapy of the prostate. J Urol 1997;157(3):921-5. http://www.ncbi.nlm.nih.gov/pubmed/9072600 79. Cespedes RD, Pisters LL, von Eschenbach AC, McGuire EJ. Long-term follow-up of incontinence and obstruction after salvage cryosurgical ablation of the prostate: results in 143 patients. J Urol 1997;157(1):237-40. http://www.ncbi.nlm.nih.gov/pubmed/8976261 80. Clarke HS Jr, Eskridge MR, El-Zawahry AM, Keane TE. Salvage cryosurgical ablation of the prostate for local recurrence after radiation therapy: improved outcomes utilizing a capromab pendetide scan and biopsy algorithm. Can J Urol 2007 Dec;14 Suppl 1:24-7 http://www.ncbi.nlm.nih.gov/pubmed/18163941 81.       Wallner KE, Nori D, Morse MJ, Sogani PC, Whitmore WF, Fuks Z. 125iodine reimplantation for locally progressive prostatic carcinoma. J Urol 1990;144(3):704-6. http://www.ncbi.nlm.nih.gov/pubmed/2388332 82.       Parker CC, Dearnaley DP. The management of PSA failure after radical radiotherapy for localized prostate cancer. Radiother Oncol 1998;49(2):103-10. http://www.ncbi.nlm.nih.gov/pubmed/10052875 83.        Grado GL, Collins JM, Kriegshauser JS, Balch CS, Grado MM, Swandon GP, Larson TR, Wilkes MM, Navickis RJ. Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology 1999;53(1):2-10. http://www.ncbi.nlm.nih.gov/pubmed/9886580 84.        Beyer DC. Permanent brachytherapy as salvage treatment for recurrent prostate cancer. Urology 1999;54(5):880-3. http://www.ncbi.nlm.nih.gov/pubmed/10565751 85.        Pinover WH, Horwitz EM, Hanlon AL, Uzzo RG, Hanks GE. Validation of a treatment policy for patients with prostate specific antigen failure after three-dimensional conformal prostate radiation therapy. Cancer 2003;97(4):1127-33. http://www.ncbi.nlm.nih.gov/pubmed/12569615

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17. Hormone refractory prostate cancer (HRPC) 17.1

Background

Cancer of the prostate is a heterogeneous disease and our knowledge of the mechanisms involved in androgen independence remains incomplete (1-5). It is known that androgen ablation provides a selective advantage to androgen-independent cells that grow and eventually comprise most of the tumour. An alteration in normal androgen signalling is thought to be central in the pathogenesis of androgen-independent PCa (6). Androgen independence is thought to be mediated through two main, overlapping, mechanisms, which are androgen-receptor (AR)-independent and AR-dependent. Androgen-receptor-independent mechanisms may be associated with the deregulation of apoptosis through the deregulation of oncogenes. High levels of bcl-2 expression are seen with greater frequency as PCa progress and the regulation of microtubule integrity may be a mechanism through which bcl-2 induces its anti-apoptotic effect (7-9). Indeed, most active chemotherapeutics in hormone-resistant prostate cancer (HRPC) work by inhibiting microtubule formation. The tumour suppressor gene p53 is more frequently mutated in androgen-independent PCa. Over-expression of bcl-2 and p53 in prostatectomy specimens has been shown to predict an aggressive clinical course (10-12). Clinical trials are underway to target the bcl-2 pathway (13) as the MDM2 oncogene (14). The PTEN (phosphatase and tensin homolog) suppressor gene may also be involved (15). However, direct AR-dependent mechanisms comprise the main pathway. Ligand-independent AR activation has been suspected, such as tyrosine kinase activated pathway (IGF-1, KGF, EGF). Epidermal growth factor (EGF) is a potent mitogen of prostate stromal and epithelial cells. It is produced in high levels locally and acts as a paracrine stimulator. In AR-independent tumours, autocrine stimulation may become more important, which could allow unregulated growth (16). Androgen receptor amplification is observed in one-third of HRPC tissues (17) and may lead to AR hypersensitivity. Androgen receptor mutations may lead to a functional change in AR function (3-5) (18). Because AR mutations are found in only a subpopulation of tumour cells, they are unlikely to be responsible for the entire spectrum of the AR-independent state (19). The AR mutations might be related to the selective pressure of anti-androgens (20). The recent discovery of gene fusion between the androgen-driven TMPRSS2 and the EGR-ETS oncogene family (21) raises the question of oncogene regulation through androgen regulation pathways. The mechanism of gene fusion is based on the association of an androgen-responsive element from an androgene-regulated gene with genes that are usually not androgen-regulated leading to their androgen regulation. Their implication in HRPC is currently only theoretical. Even in castrated patients, metastatic tissues have repeatedly shown high levels of androgens, suggesting a high level of intracrine synthesis (22, 23). It is possible that a high intraprostatic cholesterol level can activate specific androgen pathways (1).

17.2

Definition of HRPC

Hormone-refractory prostate cancer is a very heterogeneous disease. It includes different patient cohorts with significantly different median survival times (Table 19). Table 19: Estimated natural mean survival of patients with HRPC presenting with different clinical scenarios Patient characteristics Asymptomatic PSA ↑ • No metastases • Minimal metastases • Extensive metastases Symptomatic PSA ↑ • Minimal metastases • Extensive metastases

Estimated mean survival 24-27 months 16-18 months 9-12 months 14-16 months 9-12 months

The precise definition of recurrent or relapsed CaP remains controversial and several groups have recently published practical recommendations for defining HRPC (23, 24, 25, 26). Various different terms have been used to describe prostate cancers that relapse after initial hormonal ablation therapy, including HRPC, androgen-independent cancers and hormone-independent cancers (1). Androgen-independent, but hormone-sensitive PCa, must be differentiated from true HRPC. Although the former responds to secondary hormonal manipulations, such as anti-androgen withdrawal, oestrogens and

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corticosteroids, true HRPC is resistant to all hormonal measures, including ketoconazole and, in the future, abiraterone (see below) (27, 28). Table 20 lists the key defining factors of HRPC. Table 20: Definition of HRPC • Serum castration levels of testosterone (testosterone < 50 ng/dL, or < 1.7 nmol/L) • Three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL • Anti-androgen withdrawal for at least 4 weeks* • PSA progression, despite secondary hormonal manipulations* • Progression of osseous lesions: progression or appearance of two or more lesions on bone scan or soft tissue lesions using the RECIST criteria** and with nodes ≥ 2 cm in diameter * Either anti-androgen withdrawal or one secondary hormonal manipulation should have been done in order to fulfil the criteria for HRPC. ** From Therasse et al., 2000 (29).

17.3

Assessing treatment outcome in androgen-independent PCa

In general, the therapeutic outcome should be assessed using the guidelines for the evaluation of treatment response in solid tumours, recently published by the RECIST group (Response Evaluation Criteria In Solid Tumours) (29). However, 80-90% of patients do not have bi-dimensionally measurable disease. Patients with primarily soft tissue cancers often have a different prognosis to those with only osseous metastases. Osteoblastic bone metastases remain difficult to quantify accurately. Magnetic resonance imaging (MRI) might be an interesting tool for axial metastases (30). Because the cause of death in PCa patients is often unreliable, a more valid end-point may be an overall survival rate rather than a disease-specific one (31). 17.3.1 PSA level as marker of response Many contemporary studies use PSA as a marker of response, even though there is no consensus about the magnitude and duration of decline in PSA level. Prostate-specific antigen is being used as a rapid screening tool to test new agents for activity. However, conflicting evidence is emerging regarding the role of PSA as a marker for response. In addition, wide fluctuations have been seen in PSA values due to a transient effect of drugs on PSA production. The effects of drugs on PSA expression need to be considered when interpreting PSA response data, which must be viewed together with other clinical data (32-39). Nevertheless, it has been reproducibly shown that ≥ 50% PSA decline in pre-treatment PSA following therapy is associated with a significant survival advantage (40, 41). Kelly et al. (40) reported a statistically significant survival advantage in 110 patients with ≥ 50% PSA decline (> 25 months) compared to those who did not (8.6 months), while Smith et al. (41) showed that a PSA decline ≥ 50% for at least 8 weeks resulted in a longer mean survival time of 91 weeks versus only 38 weeks in patients with a smaller PSA reduction. An improved PSA response was also associated with prolonged survival in the TAX 327 study with a median survival of 33 months when the PSA was normalised (< 4 ng/mL) versus 15.8 months for abnormal PSA levels. However, it was clear in this trial that a PSA response was not a surrogate marker because the same PSA response rate was found in both docetaxel arms (45%), while improved survival was only apparent with the 3 weeks’ docetaxel regimen. 17.3.2 Other parameters The evaluation of molecular markers is just beginning. It includes a possible correlation between the positive findings of reverse transcriptase-polymerase chain reaction (RT-PCR) and poor survival (42); however, these data have to be corroborated in other trials before clinical recommendations can be made. In patients with symptomatic osseous lesions, pain reduction or complete pain relief may be used as parameters to assess palliative therapeutic response (43). 17.3.3 Trial end-points An increasing number of investigators advocate subjective end-points. However, investigators should currently apply the following: • use clearly defined end-points in trials, sufficiently powered to answer the hypothesis • report each response parameter individually, rather than as a complete or partial response • use PSA response, only with other clinical parameters of response • consider QoL end-points independently in symptomatic patients. However, in everyday practice, the evaluation of treatment response must be based on symptom improvement, prolonged survival, or other pre-defined targets.

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17.4

Recommendations for assessing therapeutic response

Recommendations • PSA decline ≥ 50% maintained for 8 weeks is associated with a significantly better outcome compared to a PSA decline < 50% • In non-osseous metastases from HRPC, assessment should adhere to the RECIST criteria • In patients with advanced symptomatic metastatic HRPC, therapeutic response can be assessed best by improvement of symptoms LE = level of evidence

17.5

LE 1a 1b 1b

Androgen deprivation in androgen-independent PCa

The existence of androgen-independent PCa demonstrates that disease progression occurs despite castration. The castration levels of testosterone must therefore be documented and a serum testosterone level < 50 ng/mL (1.7 nmol/L) should be documented at initial relapse on hormonal therapy (24, 44). The overall effect of continued testicular androgen suppression in HRPC is minimal. The recommendation to continue androgen deprivation with LHRH analogues, despite PSA progression, is based on the data of Manni et al. (45), which demonstrated significantly lower survival rates in patients without continuous androgen blockade. Two recent trials have challenged these data by showing only a marginal survival benefit for patients remaining on LHRH analogues during second- and third-line therapies (46, 47). However, in the absence of prospective data, the modest potential benefits outweigh the minimal risk of treatment and androgen suppression should be continued indefinitely in these patients. 17.6 Secondary hormonal therapy For the patient with progressive disease after androgen deprivation, there are many therapeutic options. They include anti-androgen withdrawal, addition of anti-androgens, anti-androgen replacement, oestrogenic compounds, adrenolytic agents and novel approaches (48). Figure 1 summarises the treatment modalities and expected responses. Figure 1: Flowsheet of the potential therapeutic options after PSA progression following initial hormonal therapy Mean Duration Metastic prostate cancer PSA ⇓ > 50% of Response LHRH-analogues

100%

Addition of antiandrogens

60-80%

Subcapsular orchiectomy

Addition of antiandrogens

CAB

36 months

Anti-androgen withdrawn

4-6 months

25-40%

Substitution of anti-androgen

4-6 months

30-40%

Anti-androgen withdrawal

5-6 months

40-60%

Secondary hormonal manipulation such as adrenal testosterone inhibitors, low-dose DES, steroids

4-8 months

50-70%

Non-hormonal therapy such as chemotherapy

10-12 months

LHRH = luteinising hormone releasing hormone; CAB = complete androgen blockade; DES = diethylstilboesterol.

17.7

Anti-androgen withdrawal syndrome

In 1993, Kelly and Scher (49) reported clinical and PSA responses in men who discontinued flutamide therapy upon development of progressive disease. The anti-androgen withdrawal syndrome was a critical discovery in Update march 2009

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terms of understanding the biology of androgen independence, interpreting clinical trials, and treating patients (50-53). Approximately one-third of patients respond to anti-androgen withdrawal, as indicated by a ≥ 50% PSA decrease, for a median duration of approximately 4 months (Table 21). Anti-androgen withdrawal responses have also been reported with bicalutamide and megestrol acetate (54-60). Recently, in the SWOG 9426 trial, the results were reported of a subgroup of 210 patients, with a tumour stage of M0 or M1, who showed PSA progression despite CAB. A PSA response was observed in 21%, even though there was no radiographic response. Median progression-free survival was 3 months, with 19% (all MO) having 12 months’ or greater progression-free survival. Factors associated with increased progression-free and overall survival were a longer period of non-steroidal use, lower PSA at baseline and M0-stage. These results were obtained with patients on CAB following androgen withdrawal treatment. No data were available on the withdrawal effect following second-line anti-androgen treatment. In conclusion, androgen withdrawal should be systematically considered as a first-line modality in relapsing patients, even if its efficacy is limited (level of evidence: 2). Table 21: Frequency and duration of PSA response following anti-androgen withdrawal Anti-androgen Flutamide Flutamide Flutamide Flutamide Bicalutamide Combined results

17.8

No. of patients 57 82 39 21 17 210

> 50% decrease in PSA No. of patients (%) 16 (28%) 12 (15%) 11 (28%) 7 (33%) 5 (29%) 44 (21%)

Duration (months) 4.0 3.5 3.7 3.7 5.0 3 (median)

Treatment alternatives after initial hormonal therapy

Except in patients with non-castration testosterone levels, it is difficult to predict which subset of patients is most likely to respond to secondary hormonal strategies (61). 17.8.1 Bicalutamide Bicalutamide is a non-steroidal anti-androgen with a dose response, with higher doses producing a greater reduction in PSA level (62). Addition of an anti-androgen, such as bicalutamide or flutamide, to gonadal suppression at the time of PSA failure appears to result in declining PSA in only a few patients (63-65). 17.8.2 Switching to an alternative anti-androgen therapy There has been recent interest in another simple modality: the alternative anti-androgen therapy (66). After CAB in 232 progressing patients (76% being M1b), a withdrawal effect was observed in 31 men (15.1%). A secondline hormonal treatment was performed by giving an alternative non-steroidal drug (i.e. initial flutamide was replaced by bicalutamide and vice versa). An overall > 50% decline in PSA was observed in 83 men (35.8%), irrespective of any previous withdrawal effect, and lasting more than 6 months. The higher the PSA at the start of second-line therapy, the shorter the efficacy. 17.8.3 Anti-androgen withdrawal accompanied by simultaneous ketoconazole The adrenal glands secrete approximately 10% of circulating androgen in humans. Some tumour cells in androgen-independent states must retain androgen sensitivity, as a clinical response is induced by a further decrease in circulating androgen levels following bilateral adrenalectomy or administration of drugs inhibiting adrenal steroidogenesis. Aminoglutethimide, ketoconazole and corticosteroids act mainly via this mechanism (67-71) to produce a PSA response in about 25% of patients for about 4 months. However, the simultaneous addition of ketoconazole to anti-androgen withdrawal, produced a significantly increased PSA response (32% vs 11%) and a longer time to PSA progression (8.6 vs 5.9 months) compared to anti-androgen withdrawal alone (71). 17.8.4 Oestrogens Prostate cancer usually expresses oestrogen receptors, which are upregulated after androgen ablation in animal models. In-vitro oestrogens can activate mutant androgen receptors isolated from androgenindependent PCa, while high-dose oestrogens have achieved objective salvage responses. This may be due to the mitotic arrest of direct cytotoxic effects on the cells, perhaps through an apoptotic mechanism (72, 73). Recently, DES (74-76) achieved a positive PSA response between 24% and 80%, with an overall estimated survival of 63% at 2 years. However, even at low doses of DES, about one-third (31%) of patients developed

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deep venous thrombosis and 7% experienced myocardial infarction. A very promising drug, the CYP17 inhibitor abiraterone acetate, has achieved more 50% PSA decrease in clinical trials in patients with HRPC (77), including patients previously treated with ketokonazole (78) or even by docetaxel (79). A large phase III trial is underway, enrolling 1158 men, with overall survival as the primary objective. This new compound raises questions about HRPC definition status, as a clear response is apparent even in highly pretreated patients initially considered to be hormone-refractory.

17.9

Non-hormonal therapy (cytotoxic agents)

Several proven chemotherapeutic options are available for metastatic disease in HRPC (Table 22). A significant improvement in median survival of about 2 months occurred with docetaxel-based chemotherapy compared to mitoxantrone + prednisone therapy (80, 81). In the SWOG 99-16 trial, pain relief was similar in both groups, though side-effects occurred significantly more often with docetaxel than with mitoxantrone. Table 22: PSA response rates, mean survival, time to progression, and pain reduction in the large prospective randomised phase III trials of chemotherapy in patients with HRPC Study n PSA decrease Decrease in Survival TTP > 50% pain Tax 327 Mitoxantrone 32% 22% 16.5 months __ Docetaxel, 75 mg/m2 45%1 35%3 18.9 months1 __ Docetaxel, 30 mg/m2 48%1 31% 17.4 months __ SWOG 99-16 Mitoxantrone 336 50%1 __ 17.5 months2 6.3 months1 Docetaxel/EMP 338 27% __ 15.6 months 3.2 months CALGB 9182 Hydrocortisone 123 38%4 __ 12.3 months 2.3 months Mitoxantrone/HC 119 22% __ 12.6 months 3.7 months4 Tannock et al. Prednisone 81 22% 12% __ 43 weeks1 2 Mitoxantrone/Pred 80 33% 29% __ 18 weeks TTP = median time to progression; EMP = estramustine; HC = hydrocortisone; Pred = prednisone. 1p < 0.000; 2p = 0.001; 3p = 0.01; 4p < 0.03. 17.9.1 Timing of chemotherapy in metastatic HRPC The timing of chemotherapy varies in metastatic HRPC. In symptomatic patients, immediate use is advisable, every 3 weeks if possible as this schedule is associated with a survival improvement. However, a weekly regimen will result in the same symptom improvement. It must be considered in patients unable to receive the optimal regimen (level of evidence: 1b), as it is more effective than the best supportive care (82). In asymptomatic patients, timing is not so clear and must be discussed individually. Several poor prognostic factors have been described, such as PSA level > 114 ng/mL, a PSA doubling time (PSA–DT) < 55 days, or the presence of visceral metastases (83). A C-reactive protein (CRP) level below 8 mg/L (HR, 2.96) has also been suggested as predicting better survival (84). if (84).Age Ageby byitself itselfisisnot not aa contraindication to docetaxel (85). Currently, the only indication for chemotherapy in HRPC non-metastatic patients is inside clinical trials and patients should be advised to participate. Taxanes in combination therapy In an effort to improve treatment results further, several phase I and phase II trials are underway combining taxanes with anti-bcl-2, calcitriol (trial stopped due to unexpected toxicity), exisulid, and thalidomide, resulting in PSA responses of about 60% (86-89). In a randomised phase II trial of docetaxel + thalidomide (86), 75 men with chemotherapy-naïve HRPC were randomised to receive either docetaxel at 30 mg/m2 for 5 of every 6 weeks or docetaxel at the same dose and schedule plus thalidomide at 200 mg orally each day. A PSA decline of ≥ 50% was higher in the combination-treated group (53%) compared to the docetaxel-alone treated group (37%) (not statistically significant). Median progression-free survival and overall survival with combination treatment were 5.9 months and 68%, respectively, at 18 months versus 3.7 months and 43% in the docetaxelalone group (not statistically significant). However, there were considerable side-effects, with thromboembolic events occurring in 28% of the combination arm compared to no such events in the docetaxel arm. A recent phase III trial in HRPC patients confirmed the potential interest of thalidomide compared to placebo in nonmetastatic patients with a progression-free survival of 15 months versus 9.6 months (p = 0.0002) (90).

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Mitoxantrone combined with corticosteroids Mitoxantrone combined with corticosteroids (37, 91) has been extensively studied primarily in patients with symptomatic osseous lesions due to HRPC. In the CALGB 9182 study (91), 244 patients with symptomatic metastatic HRPC were randomised to receive either mitoxantrone + hydrocortisone, 12 mg/m2 every 3 weeks, or hydrocortisone alone. No differences were observed with regard to survival, PSA response, and median time to progression. However, the QoL was significantly improved in the combination arm. In another trial (37), 161 men with painful osseous metastases due to HRPC were randomised to receive mitoxantrone + prednisone versus prednisone alone. There was a significant benefit in pain reduction in the combination group (29%) versus prednisone alone (12%, p = 0.01). Furthermore, the duration of palliation was longer in patients who received mitoxantrone (43 vs 18 weeks, p < 0.0001). There were no significant differences with regard to PSA response and median survival time. However, again, QoL was improved significantly due to pain reduction. Alternative combination treatment approaches Encouraging results have been seen with alternative treatments evaluated in prospective clinical phase II trials, including pegylated doxorubicin, vinorelbine, a combination of paclitaxel, carboplatin and estramustine, a combination of vinblastine, doxorubicin and radionuclides, and a combination of docetaxel and mitoxantrone (92-98). The lack of representative randomised phase III trials and unknown long-term efficacy are major problems associated with all these studies. Estramustine in combination therapies The synergy observed for estramustine combined with other drugs that target microtubule action has generated promising results in prospective clinical trials (99). Estramustine + vinblastine has been the most studied estramustine combination. Although different doses of estramustine and vinblastine have been used in prospective randomised trials, significant PSA and measurable responses have been reported in three separate studies. Although time to progression and frequency of ≥ 50% PSA decrease was significantly higher in the combination arm, median survival did not differ significantly between the estramustine and the estramustine + vinblastine arms (100). A recent meta-analysis on estramustine (101) concluded that the addition of estramustine to chemotherapy increased the time to PSA progression and overall survival. However, there was a significant increased risk of thromboembolic events, up to 7% (102), requiring systematic prevention with coumadin. Oral cyclophosphamide Intravenous cyclophosphamide has been tested in many trials. However, there is currently interest in on oral cyclophosphamide, which seems to be less toxic than intravenous cyclophosphamide and may have greater activity (103, 104). A study of the oral cyclophosphamide + oral etoposide in 20 patients was similarly encouraging (105, 106). Cisplatin and carboplatin have activity against PCa as single agents and a welldocumented synergy with etoposide or paclitaxel in vitro in the treatment of other malignancies, such as lung and ovarian cancer. As estramustine is also synergistic with these drugs, combinations of three agents are now being tested. A combination of estramustine, etoposide and cisplatin (or carboplatin) has significant activity against poorly differentiated HRPC. A combination of estramustine, etoposide and paclitaxel has produced high response rates (107). Suramin Suramin activity against HRPC is likely to be mediated through the inhibition of binding of growth factors (e.g. transforming growth factor beta) to their receptors. Recent results have renewed interest in suramin’s initial promise in the treatment of HRPC (108-110). Salvage chemotherapy Since all patients who receive docetaxel-based chemotherapy for HRPC will progress within 6 to 8 months, there have been many clinical trials investigating the role of salvage chemotherapy. The results suggest the most appropriate approaches are intermittent docetaxel chemotherapy (111, 112), molecular-targeted therapy 113, 114) and second-line satraplatin (115). Second-line intermittent docetaxel has been used by several groups in clearly responding patients to first-line docetaxel (111, 112, 116 ). In general, a PSA response can be achieved in about 60% of patients with a median time to progression of about 6 months, while treatment-associated toxicity is minimal and similar to that of first-line docetaxel. Another, recently identified approach is molecular-targeted therapy (111-117, 118), though more research is needed in larger groups of patients. Platinum-based chemotherapeutic regimes have been investigated in patients with HRPC. Although

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the platinum complex, satraplatin, has shown activity against HRPC and some promise in clinical trials (39, 41), it was rejected for HRPC by the FDA in 2008. Many new drugs, such as gefitinib, bevasusimab (phase III trial CALB 90401), oblimersen (phase III trial EORTC 30021), and also a vaccine, G-Vax (119), are being tested in phase III trials. Patients should be advised to participate.

17.10 Palliative therapeutic options 17.10.1 Painful bone metastases Most patients with HRPC have painful bone metastases. External beam radiotherapy is highly effective (120), even as single fraction (121). The two radioisotopes, strontium-89 and samarium-153, can partially or completely decrease bone pain in up to 70% of patients, but should not be given too late when the pain is intractable. Early use can give rise to myelosuppression making subsequent chemotherapy more difficult (106, 122), even though a recent phase I trial has demonstrated manageable haematological toxicity with repeated administration of docetaxel and samarium-153 (123). The use of samarium-153 as consolidation therapy, following a clear docetaxel response, may also help with initially painful bone metastases (124). Palliative treatment with another radioisotope emitter, radium-233 has shown very promising phase II results in patients with painful bone metastases in terms of palliation and overall survival, and only a mild haematological toxicity (125). 17.10.2 Common complications due to bone metastases Common complications due to skeletal metastases include bone pain, vertebral collapse or deformity pathological fractures and spinal cord compression. Osteoporosis may also cause fractures and should be prevented (see above). Cementation is an effective treatment of painful fracture, clearly improving both pain and QoL (126). However, it is still important to offer standard palliative surgery, which can be very effective at managing osteoblastic metastases (127, 128). Impending spinal cord compression is an emergency. It must be recognised early and patients educated to recognise the warning signs. Once suspected, high-dose corticosteroids must be given and an MRI performed as soon as possible. A systematic neurosurgery consultation should be planned to discuss a possible decompression (129). Otherwise, external beam radiotherapy is the treatment of choice. 17.10.3 Bisphosphonates Recently, bisphosphonates have been used to inhibit osteoclast-mediated bone resorption and osteoclast precursors in HRPC to provide effective treatment of skeletal complications and to reduce pain or provide total pain relief. In the largest single phase III trial (130), 643 patients who had HRPC with bone metastases were randomised to receive zoledronic acid, 8 mg or 4 mg every 3 weeks for 15 consecutive months, or placebo. At 15 and 24 months of follow-up, patients treated with only 4 mg of zoledronic acid had fewer skeletalrelated events compared to the placebo group (44% vs 33%, p = 0.021) and fewer pathological fractures (13.1% vs 22.1%, p = 0.015). Furthermore, the time to first skeletal-related event was longer in the zoledronate group, so improving QoL. Patients were initially randomised to 4 or 8 mg of zoledronic acid, but the 8 mg dosage was later modified to 4 mg because of toxicity. Currently, bisphosphonates could be proposed to patients with HRPC bone metastases to prevent skeletal complications, even if the best dosing interval is unclear, but at present is every 3 weeks or less. The toxicity, e.g. jaw necrosis, of these drugs, especially aminobisphosphonate, must always be kept in mind (131). Patients should have a dental examination before starting a bisphosphonate. The risk of jaw necrosis is increased by a history of trauma, dental surgery or dental infection, as well as intravenous long-term bisphosphonate administration (132). Pain due to osseous metastases is one of the most debilitating complications of HRPC. Bisphosphonates have been highly effective with a response rate of 70-80% in small, open trials, which, associated with a low frequency of side-effects, makes bisphosphonates an ideal medication for palliative therapy of advanced HRPC (43, 133). Bisphosphonates should be considered early in the management of symptomatic HRPC. Critical issues of palliation must be addressed when considering additional systemic treatment, including management of pain, constipation, anorexia, nausea, fatigue and depression, which often occur (i.e. palliative external beam radiation, cortisone, analgesics and antiemetics). Hormone-refractory PCa is usually a debilitating disease, often affecting the elderly male. A multidisciplinary approach is required with input from medical oncologists, radiation oncologists, urologists, nurses, psychologists and social workers (134).

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17.11 Summary of treatment after hormonal therapy Recommendations GR • It is recommended to stop anti-androgen therapy once PSA progression is documented B • Four to six weeks after discontinuation of flutamide or bicalutamide, an eventual anti-androgen B withdrawal effect is apparent • No clear-cut recommendation can be made for the most effective drug for secondary hormonal C manipulations because data from randomised trials are scarce GR = grade of recommendation

17.12 Guidelines and recommendations for cytotoxic therapy in HRPC Guidelines and recommendations GR • Cytotoxic therapy should only be used to treat non-metastatic HRPC in clinical trials • In patients with a PSA rise only, two consecutive increases of PSA serum levels above a previous B reference level should be documented • Prior to treatment, PSA serum levels should be > 5 2 ng/mL to assure correct interpretation of B therapeutic efficacy • Potential benefits of cytotoxic therapy and expected side-effects should be discussed with each C individual patient • In patients with metastatic HRPCA, and who are candidates for cytotoxic therapy, docetaxel at A 75 mg/m2 every 3 weeks has shown a significant survival benefit • In patients with symptomatic osseous metastases due to HRPCA, either docetaxel or A mitoxantrone with prednisone or hydrocortisone are viable therapeutic options • Second-line docetaxel should be considered in previously responding patients to docetaxel B Otherwise, treatment is tailored to the individual patient GR = grade of recommendation

17.13 Guidelines for palliative management of HRPC Recommendations • Patients with symptomatic and extensive osseous metastases cannot benefit from medical treatment with regard to prolongation of life • Management of these patients has to be directed at improvement of QoL and mainly pain reduction • Effective medical management with the highest efficacy and a low frequency of side-effects is the major goal of therapy

17.14 Recommendations for palliative management of HRPC Recommendations GR • Bisphosphonates may be offered to patients with skeletal masses (mainly zoledronic acid has A been studied) to prevent osseous complications. However, the benefits must be balanced against the toxicity of these agents, in particular jaw necrosis must be avoided • Palliative treatments such as radionuclides, external beam radiotherapy, adequate use of B analgesics should be considered early in the management of painful osseous metastases • Spine surgery or decompressive radiotherapy might be an emergency A GR = grade of recommendation

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Sternberg CN, Hetherington J, Paluchowska B, Slee PHTJ., Collette L, Debois M, Zurlo A. Randomized phase III trial of a new oral platinum, satraplatin (JM-216) plus prednisone or prednisone alone in patients with hormone refractory prostate cancer. Proc Am Soc Clin Oncol 2003;22, abstract 1586. http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=7 6f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=23&index=y&a bstractID=100833 Porter AT, McEwan AJ, Powe JE, Reid R, McGowan DG, Lukka H, Sathyanarayana JR, Yakemchuk VN, Thomas GM, Erlich LE, Crook J, Gulenchyn KY, Hong KE, Wesolowski C, Yardlye J. Results of a randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 1993;25(5):805-13. http://www.ncbi.nlm.nih.gov/pubmed/8478230 Smith DC, Chay CH, Dunn RL, Fardig J, Esper P, Olson K, Pienta KJ. Phase II trial of paclitaxel, estramustine, etoposide and carboplatin in the treatment of patients with hormone-refractory prostate cancer. Cancer 2003;98(2):269-76. http://www.ncbi.nlm.nih.gov/pubmed/12872344 Dawson NA, Cooper MR, Figg WD, Headlee DJ, Thibault A, Bergan RC, Steinberg SM, Sausville EA, Myers CE, Sartor O. Antitumour activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables. Cancer 1995;76(3):453-62. http://www.ncbi.nlm.nih.gov/pubmed/8625127 Kelly WK, Curley T, Liebretz C, Dnistrian A, Schwartz M, Scher Hl. Prospective evaluation of hydrocortisone and suramin in patients with androgen-independent prostate cancer. J Clin Oncol 1995;13(9):2208-13. http://www.ncbi.nlm.nih.gov/pubmed/7545218 Small EJ, Halabi S, Ratain MJ, Rosner G, Stadler W, Palchak D, Marshall E, Rago R, Hars V, Wilding G, Petrylak D, Vogelzang NJ. Randomized study of three different doses of suramin administered with a fixed dosing shedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukaemia group B 9480. J Clin Oncol 2002;20(16):3369-75. http://www.ncbi.nlm.nih.gov/pubmed/12177096 Ohlmann C, Ozgur E, Engelmann U, Heidenreich A. Molecular triggered therapy in hormone refractory prostate cancer. Eur Urol Suppl 2006;5(2):93, abstr 281. Beer TM, Garzotto M, Henner WD, Eilers KM, Wersinger EM. Multiple cycles of intermittent chemotherapy in metastatic androgen-independent prostate cancer. Br J Cancer 2004;91(8):1425-7. http://www.ncbi.nlm.nih.gov/pubmed/15467765 Ohlmann C, Ozgur E, Wille S, Engelmann U, Heidenreich A. Second-line chemotherapy with docetaxel for prostate-specific antigen relapse in men with hormone refractory prostate cancer previously treated with docetaxel based chemotherapy. Eur Urol Suppl 2006;5(2):93, abstract 289. Lara PN Jr, Twardowski P, Quinn DI. Angiogenesis-targeted therapies in prostate cancer. Clin Prostate Cancer 2004;3(3):165-73. http://www.ncbi.nlm.nih.gov/pubmed/15636683 Sternberg CN, Hetherington J, Paluchowska B, Slee PHTJ, Collette L, Debois M, Zurlo A. Randomized phase III trial of a new oral platinum, satraplatin (JM-216) plus prednisone or prednisone alone in patients with hormone refractory prostate cancer. Proc Am Soc Clin Oncol: 2003;22, abstract 1586. http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=7 6f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=23&index=y&a bstractID=100833 Ansari J, Hussain SA, Zarkar A, Bliss J, Tanguay JD, Glaholm J. Docetaxel re-treatment for metastatic hormone refractory prostate cancer. Abstract. J Clin Oncol 2008;26(15S): #16016. http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/16066 Lara PN Jr, Twardowski P, Quinn DI. Angiogenesis-targeted therapies in prostate cancer. Clin Prostate Cancer 2004;3(3):165-73. http://www.ncbi.nlm.nih.gov/pubmed/15636683 Periman PO, Sonpavde G, Bernold DM, Weckstein DJ, Williams AW, Zhan F, Boehm KA, Asma L, Hutson TE. Sunitinib malate for metastatic castration resistant prostate cancer following docetaxelbased chemotherapy. Abstract. J Clin Oncol 2008;26(15S): #5157. http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/5157

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Small EJ, Schellhamme PF, Higano CS, Neumanaitis J, Valone F, Hershberg R. Results of a placebocontrolled phase III trial of immunotherapy with APC8015for patients with hormone refractory prostate Cancer (HRPC). Abstract. J Clin Oncol 2005;23(16S): #4500. http://meeting.ascopubs.org/cgi/content/abstract/23/16_suppl/4500 120. Dy SM, Asch SM, Naeim A, Sanati H, Walling A, Lorenz KA. Evidence-based standards for cancer pain management. J Clin Oncol 2008;26(23):3879-85. http://www.ncbi.nlm.nih.gov/pubmed/18688056 121. Hartsell WF, Scott CB, Bruner DW, Scarantino CW, Ivker RA, Roach M 3rd, Suh JH, Demas WF, Movsas B, Petersen IA, Konski AA, Cleeland CS, Janjan NA, DeSilvio M. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. Natl Cancer Inst 2005;97(11):798-804. http://www.ncbi.nlm.nih.gov/pubmed/15928300 122. Heidenreich A, Sommer F, Ohlmann CH, Schrader AJ, Olbert P, Goecke J, Engelmann UH. Prospective randomized phase II trial of pegylated doxorubicin in the management of symptomatic hormone refractory prostate carcinoma. Cancer 2004;101(5):948-56. http://www.ncbi.nlm.nih.gov/pubmed/15329902 123. Morris MJ, Pandit-Taskar N, Stephenson RD, Hong C, Slovin SF, Solit D, Rathkopf DE, Carrasquillo JA, Larson SM, Scher HI. Phase I study of docetaxel (Tax) and 153Sm repetitively administered for castrate metastatic prostate cancer (CMPC). ). Abstract. J Clin Oncol 2008;26(15S): #5001. http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/5001 124. Laplanche A, Beuzeboc P, Lumbroso J, Massard C, Plantade A, Escudier B, Di Palma M, Bouzy J, Haddad V, Fizazi K. A phase II trial of docetaxel and samarium in patients with bone metastases from castration-refractory prostate cancer (CRPC). Abstract. J Clin Oncol 2007;25(18S): #5122. http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/5122 125. Nilsson S, Franzén L, Tyrrell C, Blom R , Tennvall JT, Lennernäs B, Johannessen DC, Sokal M, Parker C, Bruland ØS. Radium-223 in the treatment of metastatic hormone refractory prostate cancer (HRPC): Results from a randomized, placebo-controlled, phase II study. Abstract. J Clin Oncol 2007;25(18S): #5071. http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/5071 126. Dutka J, Sosin P. Time of survival and quality of life of the patients operatively treated due to pathological fractures due to bone metastases. Ortop Traumatol Rehabil 2003;5(3):276-83. http://www.ncbi.nlm.nih.gov/pubmed/18034018 127. Frankel BM, Jones T, Wang C. Segmental polymethylmethacrylate-augmented pedicle screw fixation in patients with bone softening caused by osteoporosis and metastatic tumor involvement: a clinical evaluation. Neurosurgery 2007;61(3):531-7; discussion 537-8. http://www.ncbi.nlm.nih.gov/pubmed/17881965 128. Marco RA, Sheth DS, Boland PJ, Wunder JS, Siegel JA, Healey JH. Functional and oncological outcome of acetabular reconstruction for the treatment of metastatic disease. J Bone Joint Surg Am 2000;82(5):642-51. http://www.ncbi.nlm.nih.gov/pubmed/10819275 129. George R, Jeba J, Ramkumar G, Chacko AG, Leng M, Tharyan P. Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database Syst Rev 2008:8;(4):CD006716. http://www.ncbi.nlm.nih.gov/pubmed/18843728 130. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goad JA, Chen B. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94(19):1458-68. http://www.ncbi.nlm.nih.gov/pubmed/12359855 131. Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, Crinò L, Dirix L, Gnant M, Gralow J, Hadji P, Hortobagyi GN, Jonat W, Lipton A, Monnier A, Paterson AH, Rizzoli R, Saad F, Thürlimann B. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008;19(3):420-32. http://www.ncbi.nlm.nih.gov/pubmed/17906299 132. Diel IJ, Fogelman I, Al-Nawas B, Hoffmeister B, Migliorati C, Gligorov J, Väänänen K, Pylkkänen L, Pecherstorfer M, Aapro MS. Pathophysiology, risk factors and management of bisphosphonateassociated osteonecrosis of the jaw: Is there a diverse relationship of amino- and nonaminobisphosphonates? Crit Rev Oncol Hematol 2007;64(3):198-207. http://www.ncbi.nlm.nih.gov/pubmed/17855108

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133. Heidenreich A, Elert A, Hofmann R. Ibandronate in the treatment of prostate cancer associated painful osseous metastases. Prostate Cancer Prostatic Dis 2002;5(3):231-5. http://www.ncbi.nlm.nih.gov/pubmed/12496987 134. Esper PS, Pienta KJ. Supportive care in the patient with hormone refractory prostate cancer. Semin Urol Oncol 1997;15(1):56-64. http://www.ncbi.nlm.nih.gov/pubmed/9050140

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18. ABBREVIATIONS USED IN THE TEXT This list is not comprehensive for the most common abbreviations 3D-US ADT AS ASCO ASTRO AUA BMD bNED CAB CaP CPA CRT CSAP CSS CT DES DRE DHT DSS EBRT ECE ECOG eLND ELND e-MRI EORTC EPC EPCP ER-β ESRPC FACT-P FNAB FSH GI GR GU HD EBRT HDR HIFU HR HRPC HRQoL IAD IGRT IMRT IPSS LDAT LDR LE LET LH LHRH LHRHa LND MRC MRI MRSI

three-dimensional ultrasound androgen-deprivation therapy active surveillance American Society of Clinical Oncology American Society for Therapeutic Radiology and Oncology American Urological Association bone mineral density actuarial biochemical freedom from disease complete (or maximal or total) androgen blockade cancer of the prostate cyproterone acetate conformal radiotherapy cryosurgical ablation of the prostate cancer-specific survival computed tomography diethylstilboestrol digital rectal anticipation dihydrostestosterone disease-specific survival electron beam radiation therapy extracapsular extension Eastern Cooperative Oncology Group extended lymph node dissection elective lymph node dissection endorectal MRI European Organisation for Research and Treatment of Cancer Early Prostate Cancer Trialists’ Group Early Prostate Cancer Programme oestrogen receptor-β European Randomized Screening for Prostate Cancer Functional Assessment of Cancer Therapy-prostate fine-needle aspiration biopsy follicle-stimulating hormone gastrointestinal grade of recommendation genitourinary high-dose EBRT high-dose rate high-intensity focused ultrasound hazard ratio hormone-refractory prostate cancer health-related quality of life intermittent androgen deprivation image-guided radiotherapy intensity modulated radiotherapy International Prostatic Symptom Score long-term ADT low-dose rate (LDR) level of evidence linear energy transfer luteinising hormone luteinising hormone-releasing hormone luteinising hormone-releasing hormone analogue lymph node dissection Medical Research Council magnetic resonance imaging magnetic resonance spectroscopy imaging

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NHT neoadjvant hormonal therapy NIH National Institutes of Health NVB neurovascular bundle OR odds ratio OS  overall survival PAP prostate acid phosphatase PCa prostate cancer PET positron emission tomography PFS progression-free survival PIN prostatic intraepithelial neoplasia PIVOT Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 PLCO Prostate, Lung, Colorectal and Ovary PSA prostate-specific antigen PSA-ACT PSA complexed to antichymotrypsin PSADT PSA doubling time PSAV PSA velocity PSMA prostate-specific membrane antigen for messenger RNA QoL quality of life QUALYs quality of life adjusted gain in life RITA radio-frequency interstitial tumour ablation RP     radical prostatectomy RTOG Radiation Therapy Oncology Group SEER Surveillance, Epidemiology, and End Results SLN sentinel lymph node SPCG-4 Scandinavian Prostate Cancer Group Study Number 4 STAD short-term androgen deprivation SVI seminal vesicle invasion SWOG South West Oncology Group TNM Tumour Node Metastasis TZ transition zone TRUS transrectal ultrasound TURP transurethral resection of the prostate UICC Union Against Cancer USPIO ultra-small super-paramagnetic iron oxide particles VACURG Veterans Administration Co-operative Urological Research Group WHO World Health Organization WW watchful waiting

Aknowledgement The Prostate Cancer guidelines panel gratefully acknowledge the assistance of the following experts in the review process: Prof.Dr. L. Egevad, Prof.Dr. R. Montironi and Prof.Dr. H. Van Poppel. Conflict of interest All members of the Prostate Cancer Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Renal Cell Carcinoma B. Ljungberg, D.C. Hanbury, M.A. Kuczyk, A.S. Merseburger, P.F.A. Mulders, J-J. Patard, I.C. Sinescu

© European Association of Urology 2009

TABLE OF CONTENTS

page

1

INTRODUCTION 1.1 Reference

4 4

2.

EPIDEMIOLOGY AND AETIOLOGY 2.1 Conclusion 2.2 References

4 5 5

3. DIAGNOSIS AND STAGING 3.1 Symptoms 3.1.1 Physical examination 3.1.2 Laboratory findings 3.2 Radiological investigations 3.3 Conclusion 3.4 References

6 6 6 6 6 6 7

4. CLASSIFICATION AND PROGNOSTIC FACTORS 4.1 Classification 4.2 Prognostic factors 4.2.1 Anatomical factors 4.2.2 Histological factors 4.2.3 Clinical factors 4.2.4 Molecular factors 4.2.5 Prognostic systems and nomograms 4.3 Conclusion 4.4 References

8 8 9 9 9 10 10 10 10 10

5. TREATMENT OF LOCALISED DISEASE 5.1 Surgery 5.1.1 Embolisation 5.1.1.1 Conclusion 5.1.2 Nephron-sparing surgery 5.1.2.1 Conclusion 5.1.3 Laparoscopic nephrectomy 5.1.3.1 Conclusion 5.1.4 Partial laparoscopic nephrectomy 5.1.4.1 Conclusion 5.2 Alternative treatments to surgery 5.2.1 Conclusion 5.3 Adjuvant therapy 5.3.1 Conclusion 5.4 Surgical treatment of metastatic RCC (tumour nephrectomy) 5.4.1 Conclusion 5.5 Resection of metastases 5.5.1 Conclusion 5.6 Radiotherapy for metastases in RCC 5.6.1 Conclusion 5.7 References

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6. SYSTEMIC THERAPY FOR METASTATIC RCC 6.1 Chemotherapy 6.1.1 Conclusion 6.2 Immunotherapy 6.2.1 Interferon-alpha monotherapy and combined with bevacizumab 6.2.1.1 Conclusion 6.2.2 Interleukin-2 6.2.2.1 Conclusion 6.3 Angiogenesis inhibitor drugs 6.3.1 Sorafenib 6.3.2 Sunitinib

20 20 20 21 21 21 21 21 21 21 21

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6.3.3 Bevacizumab monotherapy and combined with interferon-alpha 6.3.4 Mammalian target of rapamycin (mTOR) inhibitors 6.3.4.1 Temsirolimus 6.3.4.2 Everolimus 6.3.5 Conclusion 6.4 References

22 22 22 22 22 23

7.

SURVEILLANCE FOLLOWING RADICAL SURGERY FOR RCC 7.1 Introduction 7.2 Which investigations for which patient, and when? 7.3 Imaging modalities 7.4 Conclusion 7.5 References

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8.

Summary of major amendments of the 2009 RCC guidelines update

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9. ABBREVIATIONS USED IN THE TEXT

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3

1. INTRODUCTION The EAU Guideline Group for renal cell carcinoma (RCC) have prepared these guidelines to help urologists assess the evidence-based management of RCC and to help them incorporate the guidelines recommendations into their clinical practice. Publications concerning RCC are mostly retrospective analyses, which include some larger multicentre studies and well-designed controlled studies. As only a few randomised controlled trials are available, there is a lack of data with a strong evidence base. The recommendations provided in the current guideline are based on a systemic literature search using Medline, the Cochrane Central Register of Controlled Trials, and reference lists in publications and review articles. Where possible a level of evidence (LE) and/or grade of recommendation (GR) have been assigned (1). Recommendations are graded in order to provide transparency between the underlying evidence and the recommendation given (Tables 1 and 2). There is clearly a need for continuous re-evaluation at regular intervals by the RCC Guideline Group of the information provided in these guidelines. It has to be emphasised that the current guidelines contain information for the treatment of an individual patient according to a standardised general approach. The information should be considered as providing recommendations without legal implications. A summary of major amendments of the 2009 RCC guidelines update can be found on page 27 of this document. Publication history information: The Renal Cell Cancer Guidelines were first published in 2000. A partial update was achieved in 2001, followed by a full text update in 2007. The current 2009 version presents a partial update. Additionally, a quick reference guide is available. All texts can be viewed and downloaded for personal use at the society website: http://www.uroweb.org/professional-resources/guidelines/.

Table 1: Level of evidence Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Modified from Sackett et al. (1). Table 2: Grade of recommendation Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality Modified from Sackett et al. (1).

1.2

REFERENCE

1.

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998.  http://www.cebm.net/index.aspx?o=1025 [accessed February 2009].

2. EPIDEMIOLOGY AND AETIOLOGY Renal cell carcinoma represents 2-3% of all cancers (1), with the highest incidence occurring in Western countries. There is a worldwide and European annual increase in incidence of approximately 2%, though in Denmark and Sweden a continuing decrease has been observed during the last 20 years (2). In 1998, about

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30,000 patients were diagnosed with kidney cancer within the EU and approximately 15,000 died of the disease (3). Renal cell carcinoma is the most common solid lesion within the kidney. It comprises different RCC types with specific histopathological and genetic characteristics (4). There is a 1.5:1 predominance of men over women, with peak incidence occurring between 60 and 70 years of age. Aetiological factors include lifestyle factors, such as smoking, obesity and antihypertensive therapy (2, 5, 6). The most effective prophylaxis is to avoid cigarette smoking. Due to the increased detection of tumours by imaging techniques, such as ultrasound (US) and computerised tomography (CT), the number of incidentally diagnosed RCCs has increased. These tumours are more often smaller and of lower stage (7-9). However, despite the increased incidental detection rate, after the early 1990s mortality from RCC has stabilized showing a tendency towards decline (10).

2.1

Conclusion

A number of aetiological factors have been identified including smoking, obesity and antihypertensive drugs. Cigarette smoking is a definite risk factor for RCC (level of evidence: 2a). The roles of obesity and prolonged intake of antihypertensive medication as risk factors for RCC remain to be definitively clarified (level of evidence: 2a). Recommendation GR •T  he most important primary prevention for RCC is to eliminate cigarette smoking and to avoid B obesity GR = grade of recommendation

2.2

REFERENCES

1.

European Network of Cancer Registries. Eurocim version 4.0. European incidence database V2.3, 730 entity dictionary (2001), Lyon, 2001. Lindblad P. Epidemiology of renal cell carcinoma. Scand J Surg 2004;93(2):88-96. http://www.ncbi.nlm.nih.gov/pubmed/15285559 EUCAN. http://www-dep.iarc.fr/eucan/eucan.htm Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, Eble JN, Fleming S, Ljungberg B, Medeiros LJ, Moch H, Reuter VE, Ritz E, Roos G, Schmidt D, Srigley JR, Storkel S, van den Berg E, Zbar B. The Heidelberg classification of renal cell tumours. J Pathol 1997;183(2):131-3. http://www.ncbi.nlm.nih.gov/pubmed/9390023 Bergstrom A, Hsieh CC, Lindblad P, Lu CM, Cook NR, Wolk A. Obesity and renal cell cancer - a quantitative review. Br J Cancer 2001;85(7):984-90. http://www.ncbi.nlm.nih.gov/pubmed/11592770 Pischon T, Lahmann PH, Boeing H, Tjonneland A, Halkjaer J, Overvad K, Klipstein-Grobusch K, Linseisen J, Becker N, Trichopoulou A, Benetou V, Trichopoulos D, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Monninkhof E, Peeters PH, Bueno-de-Mesquita HB, Buchner FL, Ljungberg B, Hallmans G, Berglund G, Gonzalez CA, Dorronsoro M, Gurrea AB, Navarro C, Martinez C, Quiros JR, Roddam A, Allen N, Bingham S, Khaw KT, Kaaks R, Norat T, Slimani N, Riboli E. Body size and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 2006;118(3):728-38. http://www.ncbi.nlm.nih.gov/pubmed/16094628 Patard JJ, Rodriguez A, Rioux-Leclercq N, Guille F, Lobel B. Prognostic significance of the mode of detection in renal tumours. BJU Int. 2002;90(4):358-63. http://www.ncbi.nlm.nih.gov/pubmed/12175389 Kato M, Suzuki T, Suzuki Y, Terasawa Y, Sasano H, Arai Y. Natural history of small renal cell carcinoma: evaluation of growth rate, histological grade, cell proliferation and apoptosis. J Urol 2004;172(3):863-6. http://www.ncbi.nlm.nih.gov/pubmed/15310984 Tsui KH, Shvarts O, Smith RB, Figlin R, de Kernion JB, Belldegrun A. Renal cell carcinoma: prognostic significance of incidentally detected tumors. J Urol 2001;163(2):426-30. http://www.ncbi.nlm.nih.gov/pubmed/10647646 Levi F, Ferlay J, Galeone C, Lucchini F, Negri E, Boyle P, La Vecchia C. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int 2008;101(8):949-58 http://www.ncbi.nlm.nih.gov/pubmed/18241251

2. 3. 4.

5.

6.

7.

8.

9.

10.

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3. DIAGNOSIS AND STAGING 3.1

Symptoms

Many renal masses remain asymptomatic and non-palpable until late in the natural course of the disease (1) (level of evidence: 4). Today, more than 50% of RCCs are detected incidentally using non-invasive imaging to evaluate a variety of non-specific symptom complexes (1) (level of evidence: 4). The classic triad of flank pain, gross haematuria and palpable abdominal mass is now rare (6-10%) (2, 3) (level of evidence: 3). Paraneoplastic syndromes are found in around 30% of patients with symptomatic RCC, the most common of these being: hypertension, cachexia, weight loss, pyrexia, neuromyopathy, amyloidosis, elevated erythrocyte sedimentation rate, anaemia, abnormal liver function, hypercalcaemia, polycythaemia, etc. (1) (level of evidence: 4). A minority (25-30%) of patients are diagnosed as a result of symptoms due to metastatic disease, such as bone pain or persistent cough (1) (level of evidence: 4). 3.1.1 Physical examination Physical examination has a limited role in diagnosing RCC. However, it is valuable in some cases such as: • palpable abdominal mass • palpable cervical lymphadenopathy • non-reducing varicocele • bilateral lower extremity oedema, which suggests venous involvement. These findings should initiate radiological examinations. 3.1.2 Laboratory findings The most commonly assessed laboratory parameters are serum creatinine, haemoglobin, erythrocyte sedimentation rate, alkaline phosphatase and serum calcium (1, 4) (level of evidence: 4). The glomerular filtration rate (GFR) and separate bilateral renal function should be estimated when (5, 6) (level of evidence: 4): • renal function is of relevant clinical concern, as in patients with a solitary kidney tumour or bilateral tumours • renal function is compromised, as indicated by an increased concentration of serum creatinine, and in patients at risk for future renal impairment from intercurrent disorders such as diabetes, chronic pyelonephritis, renovascular, stone or renal polycystic disease.

3.2

Radiological investigations

Most renal tumours are diagnosed by abdominal ultrasound (US) and CT performed for various reasons (level of evidence: 4). Detection of a solid renal mass with US should be further investigated with a high-quality CT scan using contrast medium. This will confirm a diagnosis of RCC and provides information on the function and morphology of the contralateral kidney (5) (level of evidence: 3). • Abdominal CT assesses primary tumour extension with extrarenal spread and provides information on venous involvement, enlargement of locoregional lymph nodes, and condition of adrenal glands and the liver (level of evidence: 3). • Chest CT is the most accurate investigation for chest staging (6-13) (level of evidence: 3). However, at the very least, routine chest radiography, as a less accurate alternative to chest CT imaging, must be done for metastatic evaluation (level of evidence: 3). Magnetic resonance imaging (MRI) can be reserved primarily for patients with locally advanced malignancy, possible venous involvement, renal insufficiency or allergy to intravenous contrast (14-18) (level of evidence: 3). It is also an option for the evaluation of inferior vena cava tumour thrombus extension and unclassified renal masses (level of evidence: 3). Evaluation of the tumour thrombus can also be performed with Doppler US (19) (level of evidence: 3). In patients with any sign of impaired renal function, a renal scan and total renal function evaluation should be considered in order to optimise the treatment decision, e.g. the need to preserve renal function (6) (level of evidence: 2a). There is consensus that most bone and brain metastases are symptomatic at the time of diagnosis so that a routine bone scan or brain CT are not generally indicated (20, 21). However, if indicated by clinical or laboratory signs and symptoms, other diagnostic procedures may be applied, such as a bone scan, brain CT or MRI (level of evidence: 3). Renal arteriography, inferior venacavography or fine-needle biopsy (22-24) have only a limited role in the work-up of selected patients with RCC (level of evidence: 3).

3.3

Conclusion

In Europe, a large number of patients with RCC are still diagnosed due to clinical symptoms, such as palpable

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mass and haematuria, paraneoplastic and metastatic symptoms (level of evidence: 3). However, the number of incidentally detected RCCs is significantly increasing. Accurate staging of RCC with abdominal and chest CT or MRI is obligatory (level of evidence: 3). Chest CT is the most sensitive approach for chest staging. There is no role for routine bone scan or CT of the brain in the standard clinical work-up of asymptomatic patients. There is only a limited indication for fine-needle biopsy (level of evidence: 3). Recommendations GR • In a patient with one or more laboratory or physical findings, the possible presence of RCC A should be suspected • A plain chest X-ray can be sufficient for assessment of the lung in low-risk patients, but chest CT A is most sensitive • Abdominal CT and MRI are recommended for the work-up of patients with RCC and are the most A appropriate imaging modalities for TNM classification prior to surgery • In high-risk patients for bone metastases (raised alkaline phosphatase or bone pain), further A evaluation using an imaging approach should be done • Evaluation of renal function is recommended A GR = grade of recommendation

3.4

REFERENCES

1.

Novick AC, Campbell SC. Renal tumours. In: Walsh PC, Retik, AB, Vaughan ED, Wein AJ, eds. Campbell’s Urology. Philadelphia: WB Saunders, 2002, pp. 2672-2731. Lee CT, Katz J, Fearn PA, Russo P. Mode of presentation of renal cell carcinoma provides prognostic information. Urol Oncol 2002;7(4):135-40. http://www.ncbi.nlm.nih.gov/pubmed/12474528 Patard JJ, Leray E, Rodriguez A, Rioux-Leclercq N, Guille F, Lobel B. Correlation between symptom graduation, tumor characteristics and survival in renal cell carcinoma. Eur Urol 2003;44(2):226-32. http://www.ncbi.nlm.nih.gov/pubmed/12875943 Sufrin G, Chasan S, Golio A, Murphy GP. Paraneoplastic and serologic syndromes of renal adenocarcinoma. Semin Urol 1989;7(3):158-71. http://www.ncbi.nlm.nih.gov/pubmed/2690260 Song C, Bang JK, Park HK, Ahn H. Factors influencing renal function reduction after partial nephrectomy. J Urol 2009;181(1):48-53; discussion 53-4. http://www.ncbi.nlm.nih.gov/pubmed/19012914 Uzzo RG, Novick AC. Nephron sparing surgery for renal tumors: indications, techniques and outcomes. J Urol 2001;66(1):6-18. http://www.ncbi.nlm.nih.gov/pubmed/11435813 Bechtold RE, Zagoria RJ. Imaging approach to staging of renal cell carcinoma. Urol Clin North Am 1997;24(3):507-22. http://www.ncbi.nlm.nih.gov/pubmed/9275976 Heidenreich A, Ravery V; European Society of Oncological Urology. Preoperative imaging in renal cell cancer. World J Urol 2004;22(5):307-15. http://www.ncbi.nlm.nih.gov/pubmed/15290202 Sheth S, Scatarige JC, Horton KM, Corl FM, Fishman EK. Current concepts in the diagnosis and management of renal cell carcinoma: role of multidetector CT and three-dimensional CT. Radiographics 2001;21 Spec No:S237-54. http://www.ncbi.nlm.nih.gov/pubmed/11598260 Miles KA, London NJ, Lavelle JM, Messios N, Smart JG. CT staging of renal carcinoma: a prospective comparison of three dynamic computed tomography techniques. Eur J Radiol 1991;13(1):37-42. http://www.ncbi.nlm.nih.gov/pubmed/1889427 Lim DJ, Carter MF. Computerized tomography in the preoperative staging for pulmonary metastases in patients with renal cell carcinoma. J Urol 1993;150(4):1112-4. http://www.ncbi.nlm.nih.gov/pubmed/8371366 Doda SS, Mathur RK, Buxi TS. Role of computed tomography in staging of renal cell carcinoma. Comput Radiol 1986;10(4):183-8. http://www.ncbi.nlm.nih.gov/pubmed/3791984 Fritzsche PJ, Millar C. Multimodality approach to staging renal cell carcinoma. Urol Radiol 1992;14(1):3-7. http://www.ncbi.nlm.nih.gov/pubmed/1615571

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McClennan BL, Deyoe LA. The imaging evaluation of renal cell carcinoma: diagnosis and staging. Radiol Clin North Am 1994;32(1):55-69. http://www.ncbi.nlm.nih.gov/pubmed/8284361 15. Tammela TL, Leinonen AS, Kontturi MJ. Comparison of excretory urography, angiography, ultrasound and computed tomography for T category staging of renal cell carcinoma. Scand J Urol Nephrol 1991;25(4):283-6. http://www.ncbi.nlm.nih.gov/pubmed/1780704 16. Hricak H, Demas BE, Williams RD, McNamara MT, Hedgcock MW, Amparo EG, Tanagho EA. Magnetic resonance imaging in the diagnosis and staging of renal and perirenal neoplasms. Radiology 1985;154(3):709-15. http://www.ncbi.nlm.nih.gov/pubmed/3969475 17. Janus CL, Mendelson DS. Comparison of MRI and CT for study of renal and perirenal masses. Crit Rev Diagn Imaging 1991;32(2):69-118. http://www.ncbi.nlm.nih.gov/pubmed/1863349 18. Krestin GP, Gross-Fengels W, Marincek B. [The importance of magnetic resonance tomography in the diagnosis and staging of renal cell carcinoma.] Radiologe 1992;32(3):121-6. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/1565792 19. Nishimura K, Hida S, Okada K, Yoshida O, Nishimuara K. Staging and differential diagnosis of renal cell carcinoma: a comparison of magnetic resonance imaging (MRI) and computed tomography (CT). Hinyokika Kiyo 1988;34(8):1323-31. http://www.ncbi.nlm.nih.gov/pubmed/3195400 20. Kabala JE, Gillatt DA, Persad RA, Penry JB, Gingell JC, Chadwick D. Magnetic resonance imaging in the staging of renal cell carcinoma. Br J Radiol 1991;64(764):683-9. http://www.ncbi.nlm.nih.gov/pubmed/1884119 21. Gupta NP, Ansari MS, Khaitan A, Sivaramakrishna MS, Hemal AK, Dogra PN, Seth A. Impact of imaging and thrombus level in management of renal cell carcinoma extending to veins. Urol Int 2004;72(2):129-34. http://www.ncbi.nlm.nih.gov/pubmed/14963353 22. Hendriksson C, Haraldsson G, Aldenborg F, Lindberg S, Pettersson S. Skeletal metastases in 102 patients evaluated before surgery for renal cell carcinoma. Scand J Urol Nephrol 1992;26(4):363-6. http://www.ncbi.nlm.nih.gov/pubmed/1292074 23. Marshall ME, Pearson T, Simpson W, Butler K, McRoberts W. Low incidence of asymptomatic brain metastases in patients with renal cell carcinoma. Urology 1990;36(4):300-2. http://www.ncbi.nlm.nih.gov/pubmed/2219605 24. Seaman E, Goluboff ET, Ross S, Sawczuk IS. Association of radionuclide bone scan and serum alkaline phosphatase in patients with metastatic renal cell carcinoma. Urol 1996;48(5):692-5. http://www.ncbi.nlm.nih.gov/pubmed/8911510 25. Brierly RD, Thomas PJ, Harrison NW, Fletcher MS, Nawrocki JD, Ashton-Key M. Evaluation of fine needle aspiration cytology for renal masses. BJU Int 2000;85(1):14-8. http://www.ncbi.nlm.nih.gov/pubmed/10619937 26. Dechet CB, Zincke H, Sebo TJ, King BF, LeRoy AJ, Farrow GM, Blute ML. Prospective analysis of computerized tomography and needle biopsy with permanent sectioning to determine the nature of solid renal masses in adults. J Urol 2003;169(1):71-4. http://www.ncbi.nlm.nih.gov/pubmed/12478106

4. CLASSIFICATION AND PROGNOSTIC FACTORS 4.1

Classification

The 2002 TNM stage classification system is generally recommended for clinical and scientific use (1). It is unclear whether the current TNM classification is optimal for the prediction of survival in patients with RCC and it may require re-classification. The pT1 substratification, introduced in 2002 (1), has been validated by several studies (2-4) (level of evidence: 3). However, refinements are needed for pT3 tumours. Firstly, it has not been established whether renal sinus fat invasion only carries the same prognosis as does perinephric fat invasion (5, 6). Secondly, many studies have suggested that adrenal invasion is a very poor prognostic factor and that RCCs with this feature should be classified as T4 tumours (7, 8). Furthermore, it is still not clear whether the stratification of RCCs with venous invasion in T3b and T3c

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is accurate. More research is needed to investigate the independent prognostic value of vena caval invasion compared to renal vein invasion (9). More recently, the accuracy of the N1-N2 subclassification has been questioned (10). For adequate M-staging of patients with RCC, accurate pre-operative imaging (currently, chest and abdominal CT) should be performed (11, 12).

4.2 Prognostic factors Factors influencing prognosis can be classified into: anatomical, histological, clinical and molecular (13). 4.2.1 Anatomical factors Anatomical factors include tumour size, venous invasion, renal capsule invasion, adrenal involvement, and lymph node and distant metastasis. These factors are commonly gathered together in the universally used 2002 TNM staging classification system (Table 3). Table 3: The 2002 TNM staging classification system T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Tumour < 7 cm in greatest dimension, limited to the kidney T1a Tumour < 4 cm in greatest dimension, limited to the kidney T1b Tumour > 4 cm but < 7 cm in greatest dimension T2 Tumour > 7 cm in greatest dimension, limited to the kidney T3 Tumour extends into major veins or directly invades adrenal gland or perinephric tissues but not beyond Gerota’s fascia T3a Tumour directly invades adrenal gland or perinephric tissues1 but not beyond Gerota’s fascia T3b Tumour grossly extends into renal vein(s)2 or its segmental branches, or the vena cava below the diaphragm T3c Tumour grossly extends into vena cava or its wall above diaphragm T4 Tumour directly invades beyond Gerota’s fascia N- Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single regional lymph node N2 Metastasis in more than 1 regional lymph node pN0 lymphadenectomy specimen ordinarily includes 8 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pN0. M-

Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

TNM stage grouping Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1, T2, T3 N1 M0 Stage IV T4 N0, N1 M0 Any T N2 M0 Any T Any N M1 1 Includes renal sinus (prepelvic fat). 2 Includes segmental (muscle-containing branches). A help desk for specific questions about TNM classification is available at http://www.uicc.org/tnm. 4.2.2 Histological factors Histological factors include Fuhrman grade, histological subtype, sarcomatoid features, microvascular invasion, tumour necrosis and collecting system invasion. Fuhrman nuclear grade is the most widely accepted histological grading system in RCC (14). Although affected by intra- and inter-observer discrepancies, it is an

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independent prognostic factor (15) (level of evidence: 3). According to the World Health Organization (WHO) classification (16), three major histological subtypes of RCC exist (level of evidence: 4): • conventional (clear cell) (80-90%) • papillary (10-15%) • chromophobe (4-5%). Many studies have shown a trend towards a better prognosis for patients with chromophobe, papillary and conventional (clear cell) RCCs, respectively (17, 18). However, the prognostic information provided by the RCC subtype is lost when stratified to tumour stage (18). Among papillary RCCs, two subgroups with different outcomes have been identified (19): • Type I are low-grade tumours with a chromophilic cytoplasm and a favourable prognosis. • Type II are mostly high-grade tumours with an eosinophilic cytoplasm and a great propensity for developing metastases (level of evidence: 3). The RCC type subclassification has been confirmed at the molecular level by cytogenetic and genetic analyses (20-22). 4.2.3 Clinical factors Clinical factors include patient performance status, localised symptoms, cachexia, anaemia and platelet count (23-27) (level of evidence: 3). 4.2.4 Molecular factors Numerous molecular markers being investigated include: carbonic anhydrase IX (CaIX), vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF), Ki67 (proliferation), p53, PTEN (phosphatase and tensin homolog) (cell cycle), E-cadherin, and CD44 (cell adhesion) (21, 22) (level of evidence: 3). As yet, these markers are not in widespread use. Recently, gene expression profiling has identified 259 genes, which predict survival independent of clinical prognostic factors in conventional RCCs, indicating that genetic information will improve prognostication (28). 4.2.5 Prognostic systems and nomograms Post-operative prognostic systems and nomograms that combine independent prognostic factors have been developed and externally validated (29-35). These systems may be more accurate than TNM stage or Fuhrman grade alone for predicting survival (level of evidence: 3). A substantial advantage of nomograms is their ability to measure predictive accuracy (PA), which enables objective evaluation of all new predictive parameters. Recently, new pre-operative nomograms with excellent PA have been designed (36, 37).

4.3

Conclusion

In patients with RCC, TNM stage, nuclear grade according to Fuhrman and RCC subtype (WHO, 2004; 16), should be performed because they contribute important prognostic information (level of evidence: 2). There are currently no prognostic integrated systems or molecular markers recommended for routine clinical use. Prognostic systems or nomograms can be useful for the stratified inclusion of patients into clinical trials (level of evidence: 2). Recommendations GR •T  he current TNM classification system is recommended since it has consequences for prognosis B and therapy •T  he Fuhrman grading system and classification of RCC subtype should be used B •T  he use of integrated prognostic systems or nomograms is not routinely recommended, although B these systems can provide a rationale for enrolling patients into clinical trials •N  o molecular prognostic marker is currently recommended for routine clinical use B GR = grade of recommendation

4.4

REFERENCES

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Sobin LH, Wittekind CH, eds. International Union Against Cancer (UICC). TNM classification of malignant tumours. 6th edn. New York: Wiley-Liss, 2002, pp. 193-195. Frank I, Blute ML, Leibovich BC, Cheville JC, Lohse CM, Zincke H. Independent validation of the 2002 American Joint Committee on cancer primary tumor classification for renal cell carcinoma using a large, single institution cohort. J Urol 2005;173(6):1889-92. http://www.ncbi.nlm.nih.gov/pubmed/15879769

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Salama ME, Guru K, Stricker H, Peterson E, Peabody J, Menon M, Amin MB, De Peralta-Venturina M. pT1 substaging in renal cell carcinoma: validation of the 2002 TNM staging modification of malignant renal epithelial tumors. J Urol 2005;173(5):1492-5. http://www.ncbi.nlm.nih.gov/pubmed/15821466 Ficarra V, Schips L, Guille F, Li G, De La Taille A, Prayer Galetti T, Cindolo N, Novara G, Zigeuner RE, Bratti E, Tostain J, Altieri V, Abbou CC, Artibani W, Patard JJ. Multiinstitutional European validation of the 2002 TNM staging system in conventional and papillary localized renal cell carcinoma. Cancer 2005;104(5):968-74. http://www.ncbi.nlm.nih.gov/pubmed/16007683 Bonsib SM. The renal sinus is the principal invasive pathway: a prospective study of 100 renal cell carcinomas. Am J Surg Pathol 2004;28(12):1594-600. http://www.ncbi.nlm.nih.gov/pubmed/15577678 Thompson RH, Leibovich BC, Cheville JC, Webster WS, Lohse CM, Kwon ED, Frank I, Zincke H, Blute ML. Is renal sinus fat invasion the same as perinephric fat invasion for pT3a renal cell carcinoma? J Urol 2005;174(4 Pt 1):1218-21. http://www.ncbi.nlm.nih.gov/pubmed/16145373 Han KR, Bui MH, Pantuck AJ, Freitas DG, Leibovich BC, Dorey FJ, Zisman A, Janzen NK, Mukouyama H, Figlin RA, Belldegrun AS. TNM T3a renal cell carcinoma: adrenal gland involvement is not the same as renal fat invasion. J Urol 2003;169(3):899-903; discussion 903-4. http://www.ncbi.nlm.nih.gov/pubmed/12576809 Thompson RH, Leibovich BC, Cheville JC, Lohse CM, Frank I, Kwon ED, Zincke H, Blute ML. Should direct ipsilateral adrenal invasion from renal cell carcinoma be classified as pT3a? J Urol 2005;173(3):918-21. http://www.ncbi.nlm.nih.gov/pubmed/15711327 Thompson RH, Cheville JC, Lohse CM, Webster WS, Zincke H, Kwon ED, Frank I, Blute ML, Leibovich BC. Reclassification of patients with pT3 and pT4 renal cell carcinoma improves prognostic accuracy. Cancer 2005;104(1):53-60. http://www.ncbi.nlm.nih.gov/pubmed/15895375 Terrone C, Cracco F, Porpiglia F, Bollito E, Scoffone C, Poggio M, Berutti A, Ragni F, Cossu M, Scarpa RM, Rosetti SR. Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 2006;49(2):324-31. http://www.ncbi.nlm.nih.gov/pubmed/16386352 Heidenreich A, Ravery V; European Society of Oncological Urology. Preoperative imaging in renal cell cancer. World J Urol 2004;22(5):307-15. http://www.ncbi.nlm.nih.gov/pubmed/15290202 Sheth S, Scatarige JC, Horton KM, Corl FM, Fishman EK. Current concepts in the diagnosis and management of renal cell carcinoma: role of multidetector CT and three-dimensional CT. Radiographics 2001;21 Spec No:S237-S254. http://www.ncbi.nlm.nih.gov/pubmed/11598260 Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005;173(6):1853-62. http://www.ncbi.nlm.nih.gov/pubmed/15879764 Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6(7):655-63. http://www.ncbi.nlm.nih.gov/pubmed/7180965 Lang H, Lindner V, de Fromont M, Molinie V, Letourneux H, Meyer N, Martin M, Jacqmin D. Multicenter determination of optimal interobserver agreement using the Fuhrman grading system for renal cell carcinoma: assessment of 241 patients with > 15-year follow-up. Cancer 2005;103(3):625-9. http://www.ncbi.nlm.nih.gov/pubmed/15611969 Eble JN, Sauter G, Epstein JI, Sesterhenn IA (eds). In: Pathology and genetics of tumours of the urinary system and male genital organs. World Health Organization Classification of Tumours. Lyons: IARC Press, 2004, p. 7. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histological subtypes of renal cell carcinoma. Am J Surg Pathol 2003;27(5):612-24. http://www.ncbi.nlm.nih.gov/pubmed/12717246 Patard JJ, Leray E, Rioux-Leclercq N, Cindolo L, Ficarra V, Zisman A, De LaTaille A, Tostain J, Artibani W, Abbou CC, Lobel B, Guille F, Chopin DK, Mulders PF, Wood CG, Swanson DA, Figlin RA, Belldegrun AS, Pantuck AJ. Prognostic value of histological subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol 2005;23(12):2763-71. http://www.ncbi.nlm.nih.gov/pubmed/15837991

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Delahunt B, Eble JN, McCredie MR, Bethwaite PB, Stewart JH, Bilous AM. Morphologic typing of papillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases. Hum Pathol 2001;32(6):590-5. http://www.ncbi.nlm.nih.gov/pubmed/11431713 Linehan WM, Vasselli J, Srinivasan R, Walther MM, Merino M, Choyke P, Vocke C, Schmidt L, Isaacs JS, Glenn G, Toro J, Zbar B, Bottaro D, Neckers L. Genetic basis of cancer of the kidney: diseasespecific approaches to therapy. Clin Cancer Res 2004;10(18 Pt 2):6282S-9S. http://www.ncbi.nlm.nih.gov/pubmed/15448018 Furge KA, Lucas KA, Takahashi M, Sugimura J, Kort EJ, Kanayama HO, Kagawa S, Hoekstra P, Curry J, Yang XJ, Teh BT. Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles. Cancer Res 2004;64(12):4117-21. http://www.ncbi.nlm.nih.gov/pubmed/15205321 Yang XJ, Tan MH, Kim HL, Ditlev JA, Betten MW, Png CE, Kort EJ, Futami K, Furge KA, Takahashi M, Kanayama HO, Tan PH, Teh BS, Luan C, Wang K, Pins M, Tretiakova M, Anema J, Kahnoski R, Nicol T, Stadler W, Vogelzang NG, Amato R, Seligson D, Figlin R, Belldegrun A, Rogers CG, Teh BT. A molecular classification of papillary renal cell carcinoma. Cancer Res 2005;65(13):5628-37. http://www.ncbi.nlm.nih.gov/pubmed/15994935 Kim HL, Belldegrun AS, Freitas DG, Bui MH, Han KR, Dorey FJ, Figlin RA. Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J Urol 2003;170(5):1742-6. http://www.ncbi.nlm.nih.gov/pubmed/14532767 Kim HL, Han KR, Zisman A, Figlin RA, Belldegrun AS. Cachexia-like symptoms predict a worse prognosis in localized T1 renal cell carcinoma. J Urol 2004;171(5):1810-3. http://www.ncbi.nlm.nih.gov/pubmed/15076282 Patard JJ, Leray E, Cindolo L, Ficarra V, Rodriguez A, De La Taille A, Tostain J, Artibani W, Abbou CC, Guille F, Chopin DK, Lobel B. Multi-institutional validation of a symptom based classification for renal cell carcinoma. J Urol 2004;172(3):858-62. http://www.ncbi.nlm.nih.gov/pubmed/15310983 Bensalah K, Leray E, Fergelot P, Rioux-Leclercq N, Tostain J, Guille F, Patard JJ. Prognostic value of thrombocytosis in renal cell carcinoma. J Urol 2006;175(3 Pt 1):859-63. http://www.ncbi.nlm.nih.gov/pubmed/16469566 Patard JJ, Leray E, Rodriguez A, Rioux-Leclercq N, Guille F, Lobel B. Correlation between symptom graduation, tumor characteristics and survival in renal cell carcinoma. Eur Urol 2003;44(2):226-32. http://www.ncbi.nlm.nih.gov/pubmed/12875943 Zhao H, Ljungberg B, Grankvist K, Rasmuson T, Tibshirani R, Brooks JD. Gene expression profiling predicts survival in conventional renal cell carcinoma. PLoS Med 2006;3(1):e13. http://www.ncbi.nlm.nih.gov/pubmed/16318415 Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. J Urol 2001;166(1):63-7. http://www.ncbi.nlm.nih.gov/pubmed/11435824 Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001;19(6):1649-57. http://www.ncbi.nlm.nih.gov/pubmed/11250993 Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 2002;168(6):2395-400. http://www.ncbi.nlm.nih.gov/pubmed/12441925 Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, Weaver AL, Parker AS, Zincke H. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 2003;97(7):1663-71. http://www.ncbi.nlm.nih.gov/pubmed/12655523 Patard JJ, Kim HL, Lam JS, Dorey FJ, Pantuck AJ, Zisman A, Ficarra V, Han KR, Cindolo L, De La Taille A, Tostain J, Artibani W, Dinney CP, Wood CG, Swanson DA, Abbou CC, Lobel B, Mulders PF, Chopin DK, Figlin RA, Belldegrun AS. Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study. J Clin Oncol 2004;22(16):3316-22. http://www.ncbi.nlm.nih.gov/pubmed/15310775

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Karakiewicz PI, Briganti A, Chun FK, Trinh QD, Perrotte P, Ficarra V, Cindolo L, De la Taille A, Tostain J, Mulders PF, Salomon L, Zigeuner R, Prayer-Galetti T, Chautard D, Valeri A, Lechevallier E, Descotes JL, Lang H, Mejean A, Patard JJ. Multi-institutional validation of a new renal cancer-specific survival nomogram. J Clin Oncol 2007;25(11):1316-22. http://www.ncbi.nlm.nih.gov/pubmed/17416852 Zigeuner R, Hutterer G, Chromecki T, Imamovic A, Kampel-Kettner K, Rehak P, Langner C, Pummer K. External validation of the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for clear-cell renal cell carcinoma in a single European centre applying routine pathology. Eur Urol 2008; Nov 28. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/19062157 Karakiewicz PI, Suardi N, Capitanio U, Jeldres C, Ficarra V, Cindolo L, de La Taille A, Tostain J, Mulders PF, Bensalah K, Artibani W, Salomon L, Zigeuner R, Valeri A, Descotes JL, Rambeaud JJ, Mejean A, Montorsi F, Bertini R, Patard JJ. A preoperative prognostic model for patients treated with nephrectomy for renal cell carcinoma. Eur Urol 2008; Jul 25. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18715700 Raj GV, Thompson RH, Leibovich BC, Blute ML, Russo P and Kattan MW. Preoperative nomogram predicting 12-year probability of metastatic renal cancer. J Urol 2008;179(6):2146-51; discussion 2151. http://www.ncbi.nlm.nih.gov/pubmed/18423735

5. TREATMENT OF LOCALIsED DISEASE 5.1

Surgery

Until recently, radical nephrectomy that included the removal of the tumour-bearing kidney was the gold standard for curative therapy for localised RCC and it still offers a reasonable chance of curing the disease (1). There is no evidence to favour a specific surgical approach. The evidence also indicates that a routine adrenalectomy is not necessary during the surgical treatment of RCC, provided tumour staging is negative according to pre-operative imaging (CT, MRI). There are two exceptions to this general rule, which are: • a large upper pole tumour, which is associated with a risk of direct invasion of the adrenal gland • a tumour of > 7 cm maximum diameter, which is associated with a higher risk of intra-adrenal metastatic spread. Radical lymph node dissection does not improve survival in patients without clinically detectable lymph nodes and distant metastases (2) (level of evidence: 1a). In patients with palpable or CT-detected enlarged lymph nodes, lymph node dissection should still be performed to obtain adequate stage information. 5.1.1 Embolisation Indications for tumour embolisation include: • patients with gross haematuria who are not fit for surgical intervention • prior to surgical resection of large paravertebral metastases. There is no benefit in performing tumour embolisation before routine radical nephrectomy (level of evidence: 3) (3-9). 5.1.1.1 Conclusion Radical nephrectomy according to Robson is no longer the gold standard treatment for smaller renal tumours (level of evidence: 2b). Adrenalectomy is not recommended provided the adrenal is normal on pre-operative CT scan (level of evidence: 3). About half of adrenal metastases develop from larger upper pole tumours (level of evidence: 3). Extended lymphadenectomy does not improve survival in patients without clinically detectable lymph nodes and distant metastases and should be restricted to staging purposes in palpable and CT-detected enlarged lymph nodes (2) (level of evidence: 1b). Renal cell carcinomas with tumour thrombi have a higher stage and grade (level of evidence: 2b). Distant or lymph node metastases are twice as common (level of evidence: 3). This increased biological aggressiveness determines the clinical prognosis more than the presence or the cranial extension of intracaval thrombosis (level of evidence: 3) (10-23). Recommendations GR •S  urgical therapy is the only curative therapeutic approach for the treatment of RCC. Routine A extended lymph node dissection in patients without detectable lymph nodes does not improve survival and can be restricted to staging purposes Update march 2009

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•A  drenalectomy, together with nephrectomy, except in the case of large upper pole tumours where direct invasion of the adrenal gland is likely, can be spared in most patients . •E  mbolisation as a palliative approach can be beneficial in patients unfit for surgery with massive haematuria or profound local pain GR = grade of recommendation

B C

5.1.2 Nephron-sparing surgery Standard indications for nephron-sparing surgery are divided into the following categories: • absolute (anatomical or functional solitary kidney) • relative (functioning opposite kidney that is affected by a condition that might impair renal function in future) • elective (localised unilateral RCC with a healthy contralateral kidney). Relative indications also include patients with hereditary forms of RCC, who are at high risk of developing a tumour in the contralateral kidney in the future. 5.1.2.1 Conclusion Nephron-sparing surgery for RCC, when performed in patients with a solitary tumour < 4 cm maximum diameter, provides recurrence-free and long-term survival rates similar to those observed after a radical surgical procedure (level of evidence: 2b) (24-26). Nephron-sparing surgery carried out for absolute rather than elective indications has an increased complication rate and higher risk of developing locally recurrent disease, probably due to the larger tumour size (level of evidence: 3) (27, 28). There is some evidence that radical nephrectomy compared to nephron-sparing surgery carries an increased risk of impaired renal function, resulting in chronic renal insufficiency and proteinuria (level of evidence: 3) (29-31). In a few series, even patients with larger tumours (up to 7 cm), who have undergone nephron-sparing surgery, have shown oncological outcomes equivalent to those of radical surgery. If the tumour is completely resected, the thickness of the surgical margin does not impact on the likelihood of local recurrence (level of evidence: 3). Recommendations GR •N  ephron-sparing surgery is an established curative approach for the treatment of RCC B •N  ephron-sparing surgery for tumours > 4-7 cm maximum diameter can be performed in centres B with expertise in selected patients •A  minimal tumour-free surgical margin following partial resection of RCC appears appropriate to B avoid the increased risk of local recurrence • If tumours of larger size are treated with nephron-sparing surgery, follow-up should be intensified B due to an increased risk of intrarenal recurrence GR = grade of recommendation 5.1.3 Laparoscopic nephrectomy Since its introduction, laparoscopic nephrectomy for RCC has become an established surgical procedure worldwide. Whether done retro- or trans-peritoneally, the laparoscopic approach must duplicate established open surgical oncological principles, which are: • early control of the renal vessels before tumour manipulation • wide specimen mobilisation external to Gerota’s fascia • avoidance of specimen traumatisation or rupture • intact specimen extraction. In the hands of experienced laparoscopic urological surgeons, and adhering to these principles of open radical nephrectomy, laparoscopic radical nephrectomy may now be considered a standard of care for patients with T1-2 RCCs. Intermediate outcome data indicate equivalent cancer-free survival rates when compared with open radical nephrectomy. 5.1.3.1 Conclusion Laparoscopy for radical nephrectomy has a lower morbidity when compared with open surgery (level of evidence: 3). Tumour control rates appear equivalent for T1-2 and possible T3a tumours in experienced hands (level of evidence: 3).

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Recommendation GR • Laparoscopic tumour nephrectomy should be performed in centres with laparoscopic expertise B • Laparoscopic tumour nephrectomy is likely to become a widely distributed treatment option. B It can be promoted in specialised centres treating kidney tumours GR = grade of recommendation 5.1.4 Partial laparoscopic nephrectomy In experienced hands, laparoscopic partial nephrectomy is an alternative to open nephron-sparing surgery for selected patients (32-35). The optimal indication for laparoscopic nephron-sparing surgery is a relatively small and peripheral renal tumour. It has been suggested that the oncological outcome following laparoscopic partial nephrectomy duplicates that of open nephron-sparing surgery (36, 37). However, currently, there are no larger studies able to reveal reliable long-term equivalence. Suggested disadvantages of the laparoscopic approach are the longer warm ischaemia time and increased intra-operative and post-operative complications compared with open surgery (38-40). 5.1.4.1 Conclusion Partial nephrectomy by laparoscopic surgery is technically feasible (level of evidence: 2b). Recommendations GR • Open partial nephrectomy currently remains the standard of care C • Laparoscopic partial nephrectomy should be limited to experienced centres C GR = grade of recommendation

5.2

Alternative treatments to surgery

Suggested alternatives to the surgical treatment of RCC have included image-guided percutaneous and minimally invasive techniques, e.g. percutaneous radiofrequency (RF) ablation (41, 42), cryoablation (43), microwave ablation, laser ablation and high-intensity focused ultrasound ablation (HIFU) (level of evidence: 2b) (44). Possible advantages of these and other techniques include reduced morbidity, outpatient therapy, and the ability to treat high-risk surgical candidates (level of evidence: 2b). Indications for minimally invasive techniques, including RF ablation, are small, incidentally found, renal cortical lesions in elderly patients, patients with genetic predisposition to multiple tumours, or patients with a solitary kidney, or bilateral tumours (level of evidence: 2b). Contraindications to the above-mentioned procedures include a poor life expectancy of < 1 year, multiple metastases, or difficulty for successful treatment due to size or location of tumour. In general, tumours > 5 cm or tumours in the hilum, the proximal ureter or central collecting system are not typically recommended for RF ablation (45). Absolute contraindications include irreversible coagulopathies or severe medical instability, such as sepsis. Although, even in high-risk patients, the reported complication rates are low, greater multicentre experience is needed to define the oncological success and complications of these procedures as an alternative to open or laparoscopic surgery. 5.2.1 Conclusion The formerly mentioned, minimally invasive approaches currently have the status of experimental treatment options for kidney cancer. Their efficacy should be further evaluated within clinical trials. Their disadvantage is a lack of adequate histopathological evaluation. However, their advantage is decreased invasiveness, enabling treatment of less well patients with a poor performance status and unfit for conventional surgery (level of evidence: 3). Recommendation GR •C  urrently, patients not suitable for open or laparoscopic surgery due to a poor performance status B with smaller peripheral tumours should be considered for non-surgical alternative techniques • These techniques include image-guided percutaneous and minimally invasive techniques, e.g. B percutaneous radiofrequency ablation, cryoablation, microwave ablation, laser ablation and high-intensity focused ultrasound ablation GR = grade of recommendation

5.3

Adjuvant therapy

There is evidence that adjuvant tumour vaccination might improve the duration of the progression-free survival of selected subgroups of patients undergoing nephrectomy for T3 renal carcinomas. However, further confirmation is needed regarding the impact on overall survival (level of evidence: 1b) (46-50). Prognostic

Update march 2009

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algorithms might identify patients likely to benefit most from adjuvant vaccination therapy. 5.3.1 Conclusion Adjuvant therapy with cytokines does not improve survival after nephrectomy (level of evidence: 1b). Recommendation GR • Outside controlled clinical trials, there is no indication for adjuvant therapy following surgery A GR = grade of recommendation

5.4

Surgical treatment of metastatic RCC (tumour nephrectomy)

Tumour nephrectomy is curative only if surgery can excise all tumour deposits. For most patients with metastatic disease, tumour nephrectomy is palliative and other systemic treatments are necessary. A meta-analysis of two randomised studies comparing nephrectomy + immunotherapy versus immunotherapy only showed that long-term survival increased in patients subjected to tumour nephrectomy (51). Nephrectomy in patients with metastatic disease is indicated for patients who are both suitable for surgery and have a good performance status (52). 5.4.1 Conclusion Tumour nephrectomy in combination with interferon-alpha (IFN-alpha) improves the survival of patients with metastatic RCC (mRCC) and a good performance status (level of evidence: 1b). Recommendation GR •T  umour nephrectomy is recommended for metastatic RCC patients with a good performance status A when combined with IFN-alpha GR = grade of recommendation

5.5

Resection of metastases

Complete removal of metastatic lesions contributes to an improvement of clinical prognosis. Immunotherapy, where there has been complete resection of metastatic lesions or isolated local recurrences, does not contribute to an improvement in clinical prognosis (level of evidence: 2b) (52-56). 5.5.1 Conclusion Metastasectomy in patients with RCC has a definite role in improving the clinical prognosis (level of evidence: 3). Recommendations GR • In patients with synchronous metastatic spread, metastasectomy should be performed when B disease is resectable and the patient has a good performance status •T  he clinical prognosis is worse in patients who have surgery for metachranous metastases B •M  etastasectomy should be performed in patients with residual and resectable metastatic lesions B previously responding to immunotherapy and/or a limited (solitary lesion) number of metachranous metastases in order to improve the patient’s prognosis GR = grade of recommendation

5.6

Radiotherapy for metastases in RCC

Radiotherapy can be used for selected symptomatic patients with non-resectable brain or osseous lesions who do not respond to other conservative treatment approaches (57, 58). 5.6.1 Conclusion Radiotherapy of metastases from RCC can induce significant relief from symptoms, e.g. reduction of pain from a single bony deposit (level of evidence: 2b). Recommendation GR • In individual cases, radiotherapy for brain metastases (whole brain irradiation or stereotactic B approach) and osseous lesions can induce relief from symptoms due to mRCC (59, 60) GR = grade of recommendation

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5.7

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50. Jocham D, Richter A, Hoffmann L, Iwig K, Fahlenkamp D, Zakrzewski G, Schmitt E, Dannenberg T, Lehmacher W, von Wietersheim J, Doehn C. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 2004;363(9409):594-9. http://www.ncbi.nlm.nih.gov/pubmed/14987883 51. Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004;171(3): 1071-6. http://www.ncbi.nlm.nih.gov/pubmed/14767273 52. Ljungberg B, Landberg G, Alamdari FI. Factors of importance for prediction of survival in patients with metastatic renal cell carcinoma, treated with or without nephrectomy. Scand J Urol Nephrol 2000;34(4):246-51. http://www.ncbi.nlm.nih.gov/pubmed/11095082 53. Pongracz N, Zimmerman R, Kotz R. Orthopaedic management of bony metastases of renal cancer. Semin Surg Oncol 1988;4(2):139-42. http://www.ncbi.nlm.nih.gov/pubmed/3393777 54. Tongaonkar HB, Kulkarni JN, Kamat MR. Solitary metastases from renal cell carcinoma: a review. J Surg Oncol 1992;49(1):45-8. http://www.ncbi.nlm.nih.gov/pubmed/1548881 55. van der Poel HG, Roukema JA, Horenblas S, van Geel AN, Debruyne FM. Metastasectomy in renal cell carcinoma: A multicenter retrospective analysis. Eur Urol 1999;35(3):197-203. http://www.ncbi.nlm.nih.gov/pubmed/10072620 56. Jackson RJ, Loh SC, Gokaslan ZL. Metastatic renal cell carcinoma of the spine: surgical treatment and results. J Neurosurg 2001;94(1 Suppl):18-24. http://www.ncbi.nlm.nih.gov/pubmed/11147860 57. Fossa SD, Kjolseth I, Lund G. Radiotherapy of metastases from renal cancer. Eur Urol 1982;8(6): 340-2. http://www.ncbi.nlm.nih.gov/pubmed/6183119 58. Gez E, Libes M, Bar-Deroma R, Rubinov R, Stein M, Kuten A. Postoperative irradiation in localized renal cell carcinoma: the Rambam Medical Center experience. Tumori 2002;88(6):500-2. http://www.ncbi.nlm.nih.gov/pubmed/12597146 59. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik M, Demas W, Ryj J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran WJ Jr. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004;363(9422):1665-72. http://www.ncbi.nlm.nih.gov/pubmed/15158627 60. Kavolius JP, Mastorakos DP, Pavlovich C, Russo P, Burt ME, Brady MS. Resection of metastatic renal cell carcinoma. J Clin Oncol 1998;16(6):2261-6. http://www.ncbi.nlm.nih.gov/pubmed/9626229

6. SYSTEMIC THERAPY FOR METASTATIC RCC 6.1

Chemotherapy

Since RCCs develop from the proximal tubules, they have high levels of expression of the multiple-drug resistance protein P-glycoprotein and are therefore resistant to most chemotherapies. Chemotherapy seems to be effective only if 5-fluorouracil (5FU) is combined with immunotherapeutic agents (1). 6.1.1 Conclusion Only 5FU in combination with immunotherapy seems to be effective in patients with mRCC (level of evidence: 3). Recommendation GR • Chemotherapy as monotherapy should not be considered effective in patients with mRCC B GR = grade of recommendation

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6.2

Immunotherapy

6.2.1 Interferon-alpha monotherapy and combined with bevacizumab In randomised studies, IFN-alpha has proven superiority for survival over hormonal therapy in patients with mRCC (2). Interferon-alpha provided a response rate of 6-15%, together with a 25% decrease in the risk for tumour progression, and a modest survival benefit of 3-5 months when compared with placebo-equivalent (3, 4). Recently, bevacizumab + IFN-alpha demonstrated increased response rates and progression-free survival in first-line therapy compared to IFN-alpha monotherapy (5, 6). All recent randomised studies comparing antiangiogenic drugs in a first-line setting to IFN-alpha monotherapy have demonstrated a superiority for either sunitinib, bevacizumab + IFN-alpha or temsirolumus (5-8). 6.2.1.1 Conclusion Interferon-alpha monotherapy is no longer recommended as first-line therapy for mRCC (level of evidence: 1b). 6.2.2 Interleukin-2 Interleukin-2 (IL-2) has been used to treat mRCC since 1985 with response rates ranging from 7-27% (8-10). The optimal IL-2 regimen is not clear, but long-term (> 10 years) complete responders have been achieved with high-dose bolus IL-2 (11). The toxicity of IL-2 is substantially higher than that of IFN-alpha. It seems that only clear cell type RCC responds to immunotherapy. Interleukin-2 has not been validated in controlled randomised studies compared with best supportive care (4). 6.2.2.1 Conclusion Interleukin-2 has more side-effects than INF-alpha. High-dose IL-2 gives durable complete responders in a limited number of patients. Interleukin-2 remains the only cytokine suitable for monotherapy in selected patients with a good prognosis profile. Recommendations GR •M  onotherapy with IFN-alpha can no longer be recommended as a first-line treatment for mRCC. A •B  evacizumab + IFN-alpha is recommended as first-line therapy in low- and intermediate-risk B patients. Only selected patients with mRCC, revealing a good risk profile, and clear cell subtype histology, show clinical benefit from immunotherapy with IL-2. • Cytokine combinations, with or without additional chemotherapy, do not improve overall survival A compared with monotherapy GR = grade of recommendation

6.3

Angiogenesis inhibitor drugs

Recent advances in molecular biology have led to the development of several novel agents for the treatment of mRCC (Table 4). In sporadic clear cell RCC, HIF accumulation due to von Hippel Landau (VHL) inactivation, results in overexpression of VEGF and PDGF (platelet-derived growth factor), both of which promote neo-angiogenesis (12-14). This process substantially contributes to the development and progression of RCC. At present, four targeting drugs have been approved both in the USA and in Europe for the treatment of mRCC: • sorafenib (Nexavar®) • sunitinib (Sutent®) • bevacizumab (Avastin®) combined with IFN-alpha • temsirolimus (Torisel®). Several other new agents targeting angiogenesis are under investigation, as well as combinations of these new agents with each other or with cytokines. 6.3.1 Sorafenib Sorafenib is an oral multikinase inhibitor with activity against Raf-1 serine/threonine kinase, B-Raf, vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT-3) and c-KIT. A phase III trial comparing sorafenib and placebo after failure of a prior systemic immunotherapy reported a 3-month improvement in progression-free survival in favour of sorafenib (15). Survival seems to improve in patients crossed over from placebo to sorafenib treatment (16). 6.3.2 Sunitinib Sunitinib is an oxindol tyrosine kinase (TK) inhibitor. It selectively inhibits PDGFR, VEGFR, KIT and FLT-3 and has anti-tumour and anti-angiogenic activity. Phase II trials with sunitinib as second-line monotherapy in patients with mRCC demonstrated a partial response rate in 34-40% of patients and stable disease > 3 months in 27-29% of patients (17).

Update march 2009

21

In a recent phase III trial of first-line monotherapy that compared treatment with sunitinib to IFN-alpha, sunitinib achieved a longer progression-free survival than with IFN-alpha (11 vs 5 months, p < 0.000001). Results suggested monotherapy with IFN-alpha was inferior compared to sunitinib in low- and intermediaterisk patients with mRCC (18). Overall survival was 26.4 and 21.8 months in the sunitinib and IFN-alpha arms, respectively (p = 0.05) (18). In patients crossed over from IFN-alpha to sunitinib (n = 25), median survival times were 26.4 versus 20.0 months for sunitinib and IFN-alpha, respectively (p = 0.03). In patients who did not receive any post-study treatment, the median overall survival reached 28.1 months in the sunitinib group versus 14.1 months in the IFN-alpha group (p = 0.003). 6.3.3 Bevacizumab monotherapy and combined with interferon-alpha Bevacizumab is a humanised monoclonal antibody that binds isoforms of VEGF-A. Bevacizumab, 10 mg/kg every 2 weeks, in patients refractory to immunotherapy showed an increase in overall response (10%) and in progression-free survival versus placebo (19). A recent double-blind phase III trial (n = 649) in mRCC compared bevacizumab + IFN-alpha to IFN-alpha monotherapy (5).The median overall response was 31% in the bevacizumab + IFN-alpha group versus 13% in the IFN-alpha only group (p < 0.0001). Median progression-free survival increased significantly from 5.4 months with IFN-alpha to 10.2 months for bevacizumab + IFN-alpha (p < 0.0001), but only in low-risk and intermediate-risk patients. No benefit was seen in high-risk patients. No mature data are yet available on overall survival. 6.3.4 Mammalian target of rapamycin (mTOR) inhibitors 6.3.4.1 Temsirolimus Temsirolimus is a specific inhibitor of mammalian target of rapamycin (mTOR) (20). Patients with high-risk mRCC were randomised to receive first-line treatment with temsirolimus or IFN-alpha monotherapy or in combination. In the temsirolimus group, overall survival was 10.9 months versus 7.3 months in the IFN- group (p < 0.0069). However, overall survival in the temsirolimus + IFN-alpha group was not significantly improved (7). 6.3.4.2 Everolimus Everolimus is an oral mTOR inhibitor. A recent phase III study compared everolimus plus best supportive care (BSC) versus placebo plus BSC in patients who had failed previous anti-VEGF-R treatment. Median progression-free survival was 4 months with everolimus versus 1.9 months with placebo (p < 0.001) (12, 21). Table 4: Updated recommendations for first- and second-line systemic therapy in mRCC Treatment • 1st-line therapy

• 2nd-line therapy

Risk or prior treatment Low- or intermediate-risk High risk Prior cytokine Prior VEGFR Prior mTOR(-)

Recommended agent Sunitinib Bevacizumab + IFN-alpha Temsirolimus Sorafenib Everolimus Clinical trials

6.3.5 Conclusion Tyrosine kinase inhibitors (TKIs) increase progression-free survival and or overall survival as both first- and second-line treatment of mRCC (level of evidence: 1b). Sorafenib has proven efficacy as second-line treatment after failure of cytokine therapy (level of evidence: 1b). Sunitinib is more effective than IFN-alpha in treatmentnaïve, low- and intermediate-risk tumours (level of evidence: 1b). The association between bevacizumab and IFN-alpha is more effective than IFN-alpha in treatment-naïve, low- and intermediate-risk tumours (level of evidence: 1b). Temsirolimus monotherapy in high-risk mRCC patients is more effective than IFN-alpha or temsirolimus + IFN-alpha (level of evidence: 1b). Everolimus prolongs progression-free survival in patients who have failed treatment with TKIs. The role of the new drugs is still under development and combination studies are ongoing. To date, no data are available indicating the new agents have a curative effect. These agents appear to promise to stabilise mRCC for a prolonged period of time. However, their promise has to be balanced against their toxicity profile and the patient’s quality of life (level of evidence: 4).

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Update march 2009

Recommendations GR • Sunitinib is recommended as first-line therapy in low- and intermediate-risk patients A • Bevacizumab + IFN-alpha is recommended as first-line therapy in low- and intermediate-risk patients A • Sorafenib is recommended as a second-line treatment for mRCC after cytokine failure A • Temsirolimus is recommended as first-line treatment in high-risk patients A • Everolimus can be recommended as second-line treatment after failure of tyrosine kinase inhibitors A GR = grade of recommendation

6.4

REFERENCES

1.

Stadler WM, Huo D, George C, Yang X, Ryan CW, Karrison T, Zimmerman TM, Vogelzang NJ. Prognostic factors for survival with gemcitabine plus 5-fluorouracil based regimens for metastatic renal cancer. J Urol 2003;170(4 Pt 1):1141-5. http://www.ncbi.nlm.nih.gov/pubmed/14501711 Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 1999;353(9146):14-7. http://www.ncbi.nlm.nih.gov/pubmed/10023944 Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20(1):289-96. http://www.ncbi.nlm.nih.gov/pubmed/11773181 Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev 2005;(1):CD001425. http://www.ncbi.nlm.nih.gov/pubmed/15674877 Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103-11. http://www.ncbi.nlm.nih.gov/pubmed/18156031 Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356(2):115-24. http://www.ncbi.nlm.nih.gov/pubmed/17215529 Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356(22:2271-81. http://www.ncbi.nlm.nih.gov/pubmed/17538086 Rosenberg SA, Lotze MT, Yang JC, Topalian SL, Chang A E, Schwartzentruber DJ, Aebersold P, Leitman S, Linehan WM, Seipp CA et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 1993;21(85):622-32. http://www.ncbi.nlm.nih.gov/pubmed/8468720 Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13(3):688-96. http://www.ncbi.nlm.nih.gov/pubmed/7884429 McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith, JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005;23(1):133-41. http://www.ncbi.nlm.nih.gov/pubmed/15625368 Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21(16):3127-32. http://www.ncbi.nlm.nih.gov/pubmed/12915604 Patel PH, Chadalavada RS, Chaganti RS, Motzer RJ. Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res 2006;12(24):7215-20. http://www.ncbi.nlm.nih.gov/pubmed/17189392

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

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13.

14.

15.

16.

17.

18.

19.

20.

21.

Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349(5):427-34. http://www.ncbi.nlm.nih.gov/pubmed/12890841 Patard JJ, Rioux-Leclercq N, Fergelot P. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006;49(4):633-43. http://www.ncbi.nlm.nih.gov/pubmed/16481093 Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356(2):125-34. http://www.ncbi.nlm.nih.gov/pubmed/17215530 Bellmunt J, Négrier S, Escudier B, Awada A, Aapro M; SIOG Taskforce. The medical treatment of metastatic renal cell cancer in the elderly: position paper of a SIOG Taskforce. Crit Rev Oncol Hematol 2009;69(1):64-72. http://www.ncbi.nlm.nih.gov/pubmed/18774306 Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24(1):16-24. http://www.ncbi.nlm.nih.gov/pubmed/16330672 Figlin RA, Hutson TE, Tomczac P, Michaelson MD, Bukowski RM, Négrier S, Huang X, Kim ST, Chen I, Motzer RJ, et al. Overall survival with sunitinib versus interferon alfa as first-line treatment in metastatic renal-cell carcinoma. ASCO Annual Meeting Proceedings 2008. J Clin Oncol 2008;26(Suppl.):Abstr 5024. http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_ view&confID=55&abstractID=32895 Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349(5):427-34. http://www.ncbi.nlm.nih.gov/pubmed/12890841 Larkin JM, Eisen T. Kinase inhibitors in the treatment of renal cell carcinoma. Crit Rev Oncol Hematol 2006; 60(3):216-26. http://www.ncbi.nlm.nih.gov/pubmed/16860997 Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebocontrolled phase III trial. Lancet 2008;372(9637):449-56. http://www.ncbi.nlm.nih.gov/pubmed/18653228

7. SURVEILLANCE FOLLOWING RADICAL SURGERY FOR RCC 7.1

Introduction

Surveillance after radical surgery allows the urologist to monitor or identify: • post-operative complications • renal function • local recurrence • recurrence in the contralateral kidney • development of metastases. The method and timing of investigation has been the subject of many publications. There is no consensus on surveillance after radical surgery of the kidney. Post-operative complications and renal function are readily assessed by history, physical examination and measurement of serum creatinine. Repeated long-term monitoring of creatinine levels is indicated if there is impaired renal function before surgery or a post-operative significant increase in the serum creatinine level (1). Local recurrence is rare (1.8%), but early diagnosis is useful since the most effective treatment is

24

Update march 2009

cytoreductive surgery (2, 3). Recurrence in the contralateral kidney is also rare (1.2%) and is related to positive margins, multifocality and grade (4). The reason for surveillance is to identify metastases early. This is because a greater extension of tumour growth can reduce the possibility of surgical resection, which is considered the standard therapy in cases of resectable and, preferably solitary, metastatic lesions. In addition, within clinical trials, an early diagnosis of tumour recurrence might enhance the efficacy of a systemic treatment if the tumour burden is low.

7.2

Which investigations for which patients, and when?

Repeated intensive radiological surveillance for all patients is unnecessary because, for example, the outcome after surgery for small, well-differentiated tumours is almost always excellent. It is therefore reasonable to modify follow-up, taking into account the risk of developing recurrence or metastases. No randomised evidence exists, but there are large studies with long follow-up from which some conclusions can be drawn (level of evidence: 4). Prognostic factors can be classified into: anatomical (tumour size and stage, venous invasion, adrenal involvement, lymph node status), histological (grade, sarcoma, necrosis and collecting system invasion), clinical (performance status, anaemia, platelet count, cachexia) and molecular (5, 6). Although many molecular markers, using immunotherapy, vaccine, gene and angiogenesis techniques, are being investigated, none are yet in widespread use. Detailed information on molecular markers can be found in Section 4.2 Prognostic factors.

7.3

Imaging modalities

Where there is a low likelihood of relapse, chest X-ray and US are appropriate. Where the risk is intermediate or high, the investigation of choice is CT of chest and abdomen, though the significant morbidity of radiation dose with repeated CT scans should be taken into account (7). Dependent on the availability of new effective treatments, more strict follow-up schedules may be required. A problematic issue is the optimal duration of follow-up. It can be argued that follow-up by imaging is not cost effective after 5 years (8). Late metastases are more frequently solitary and justify more aggressive therapy with curative intent. Also, patients with small tumours in the contralateral kidney (2-3%) can be treated with nephron-sparing surgery. Furthermore, for tumours < 4 cm, there seems to be no difference in recurrence between partial and radical nephrectomy (9). Using many of these variables, several groups have designed scoring systems and algorithms to stratify patients into low-, intermediate- and high-risk groups for developing tumour recurrence or metastases. The frequency and type of investigation are different for each group (10-13). Examples of these scoring systems are shown in Tables 5 and 6. Table 5: S  coring algorithm to predict metastases after nephrectomy in patients with clear cell RCC according to the Mayo Scoring System (13). Feature Primary tumour/T-stage T1a pT1b pT2 pT3-pT4 Tumour size < 10cm > 10cm Regional lymph node status pNx/pN0 pN1-pN2 Nuclear grade Grade 1-2 Grade 3 Grade 4 Tumour necrosis No necrosis Necrosis

Score 0 2 3 4 0 1 0 2 0 1 3 0 1

Risk groups can be stratified according to the Mayo Scoring System (13) into low-risk, 0-2, intermediate-risk,

Update march 2009

25

3-5, and high-risk, > 6. The use of scoring systems, such as the Mayo System, helps the urologist to select the use of imaging and to appropriately target those patients most in need of intensive surveillance. Table 6: A  ccumulated risk of metastases (%) after nephrectomy in patients with clear cell RCC as defined in risk groups according to the Mayo Scoring System (13). Risk group • Low • Intermediate • High

7.4

Year 1 0.5 9.6 42.3

Year 3 2.1 20.2 62.9

Year 5 2.9 26.2 68.8

Year 10 7.5 35.7 76.4

Conclusion

In cases with a very low risk for tumour recurrence or systemic tumour progression, CT scans can be omitted as routine follow-up examinations. In these patients, a CT scan is only justified in cases of possible tumourassociated symptoms. In the intermediate-risk group, an intensified follow-up that includes CT scans at regular time intervals should be performed according to a risk-stratified nomogram. In high-risk patients, the follow-up examinations should include routine CT scans (level of evidence: 4). Recommendation GR •T  he intensity of the follow-up programme for an individual patient should be adapted according to C the risk of tumour recurrence or systemic tumour progression, as determined by a risk nomogram developed for risk stratification GR = grade of recommendation

7.5

REFERENCES

1.

Lau WK, Blute ML, Weaver AL, Torres VE, Zincke H. Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc 2000;75(12):1236-42. http://www.ncbi.nlm.nih.gov/pubmed/11126830 Itano NB, Blute ML, Spotts B, Zincke H. Outcome of isolated renal fossa recurrence after nephrectomy. J Urol 2000;164(2):322-5. http://www.ncbi.nlm.nih.gov/pubmed/10893575 Sandhu SS, Symes A, A’Hern R, Sohaib SA, Eisen T, Gore M, Christmas TJ. Surgical excision of isolated renal-bed recurrence after radical nephrectomy for renal cell carcinoma. BJU Int 2005;95(4):522-5. http://www.ncbi.nlm.nih.gov/pubmed/15705072 Bani-Hani AH, Leibovich BC, Lohse CM, Cheville JC, Zincke H, Blute ML. Associations with contralateral recurrence following nephrectomy for renal cell carcinoma using a cohort of 2,352 patients. J Urol 2005;173(2):391-4. http://www.ncbi.nlm.nih.gov/pubmed/15643178 Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005;173(6):1853-62. http://www.ncbi.nlm.nih.gov/pubmed/15879764 Patard JJ, Leray E, Rioux-Leclercq N, Cindolo L, Ficarra V, Zisman A, De La Taille A, Tostain J, Artibani W, Abbou CC, Lobel B, Guille F, Chopin DK, Mulders PF, Wood CG, Swanson DA, Figlin RA, Belldegrun AS, Pantuck AJ. Prognostic value of histological subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol 2005;23(12):2763-71. http://www.ncbi.nlm.nih.gov/pubmed/15837991 Ionising Radiation (Medical Exposures) Regulations 2000. National Radiation Protection Board 2000 www.hpa.org.uk http://www.hpa.org.uk/radiation/understand/radiation_topics/medical/diagnostic_radiology/national_ reference_doses.html http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1195733806727?p=11589346 078298 Montie J. Follow-up after partial or total nephrectomy for renal cell carcinoma. Urol Clin North Am 1994;21(4):725-7. http://www.ncbi.nlm.nih.gov/pubmed/7974900

2.

3.

4.

5.

6.

7.

8.

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9.

10.

11.

12.

13.

Patard JJ , Shvarts O, Lam JS, Pantuck AJ, Kim HL, Ficarra V, Cindolo L, Han KR, De La Taille A, Tostain J, Artibani W, Abbou CC, Lobel B, Chopin DK, Figlin RA, Mulders PF, Belldegrun AS. Safety and efficacy of partial nephrectomy for all T1 tumors based on an international multicenter experience. J Urol 2004;171(6 Pt 1):2181-5; quiz 2435. http://www.ncbi.nlm.nih.gov/pubmed/15126781 Ljungberg B, Alamdari FI, Rasmuson T, Roos G. Follow-up guidelines for nonmetastatic renal cell carcinoma based on the occurrence of metastases after radical nephrectomy. BJU Int 1999;84(4):40511. http://www.ncbi.nlm.nih.gov/pubmed/10468753 Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. J Urol 2001;166(1):63-7. http://www.ncbi.nlm.nih.gov/pubmed/11435824 Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognosticated nomogram and risk group stratification system. J Urol 2005;174(2):466-72; discussion 472; quiz 801. http://www.ncbi.nlm.nih.gov/pubmed/16006866 Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, Weaver AL, Parker AS, Zincke H. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 2003;97(7):1663-71. http://www.ncbi.nlm.nih.gov/pubmed/126555238.

The current document provides a limited update, with a summary of the amendments provided below.  

8.

Summary of major amendments of the 2009 RCC guidelines update

Prognosis • Prognostic nomograms have been validated and one advantage of nomograms is their ability to measure predictive accuracy. Treatment • Interferon-alpha (IFN-alpha) is not recommended in a first-line setting as monotherapy in the treatment of metastatic RCC (mRCC) • Bevacizumab + IFN-alpha is recommended as first-line therapy in low- and intermediate-risk patients • Everolimus can be recommended as second-line therapy after tyrosine kinase inhibitor (TKI) failure

UPDATE MARCH 2009

27

9. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations

5FU BSC CT FLT-3 HIF HIFU IFN-alpha IL-2 mRCC MRI mTOR PA PDGF PDGFR RCC RF TNM US VEGF VEGFR VHL WHO

5-fluorouracil best supportive care computerised tomography FMS-like tyrosine kinase 3 hypoxia inducible factor high-intensity focused ultrasound interferon-alpha interleukin-2 metastatic renal cell carcinoma magnetic resonance imaging mammalian target of rapamycin predictive accuracy platelet-derived growth factor platelet-derived growth factor receptor renal cell carcinoma radiofrequency Tumour Node Metastasis abdominal ultrasound vascular endothelial growth factor vascular endothelial growth factor receptor von Hippel-Lindau World Health Organization

Conflict of interest All members of the Renal Cell Cancer Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Update march 2009

Guidelines on

Penile Cancer G. Pizzocaro (Chairman), F. Algaba, S. Horenblas, E. Solsona, S. Tana, H. Van Der Poel, N. Watkin

© European Association of Urology 2009

TABLE OF CONTENTS

PAGE

1.

Introduction

4

2.

METHODOLOGY 2.1 References

4 4

3. DEFINITION OF PENILE CANCER

5

4.

EPIDEMIOLOGY 4.1 References

5 6

5. RISK FACTORS AND PREVENTION 5.1 References

6 7

6. TNM CLASSIFICATION AND PATHOLOGY 6.1 TNM classification 6.1.1 References 6.2 Pathology 6.2.1 Penile biopsy 6.2.2.1 Pathological categories 6.2.2.2 Histology and metastatic risk 6.2.3 References

8 8 9 9 10 10 10 10

7. DIAGNOSIS AND STAGING 7.1 Primary lesion 7.2 Regional lymph nodes 7.2.1 Lymphatic drainage of the penis 7.2.2 Non-palpable nodes 7.2.3 Risk factors 7.2.4 Palpable nodes 7.3 Distant metastases 7.4 Guidelines for the diagnosis of penile cancer 7.5 References

11 11 11 11 12 12 12 12 13 13

8. TREATMENT 8.1 Primary tumour 8.1.1 Category Tis and Ta 8.1.2 Category T1G1 8.1.3 Category T1G2-3 8.1.4 Category T2 (of the glans) 8.1.5 Category T2 (of the corpora) and T3 8.1.6 Category T4 8.1.7 Local disease recurrence 8.1.8 Technical aspects 8.1.8.1 Conservative surgery 8.1.8.2 Radical amputation 8.1.9 Radiotherapy 8.1.9.1 Recommendations for radiotherapy 8.1.10 Guidelines for treatment strategies for primary tumour 8.2 Treatment of regional lymph nodes 8.2.1 Management of patients with non-palpable inguinal nodes 8.2.1.1 Surveillance 8.2.1.2 Prognostic factors 8.2.1.3 Sentinel node biopsy (SNB) 8.2.2 Management of patients with palpable inguinal nodes 8.2.2.1 Inguinal LAD 8.2.2.2 Modified inguinal LAD 8.2.2.3 The role of pelvic LAD 8.2.2.4 Video-endoscopic inguinal and pelvic LAD

16 16 16 16 16 17 17 17 17 17 17 17 17 18 18 19 19 19 19 19 19 20 20 20 20

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Update march 2009

8.2.3 Adjuvant chemotherapy 8.2.4 Management of patients with fixed or relapsed inguinal nodes 8.2.5 The role of radiotherapy 8.2.6 Guidelines for treatment strategies for nodal metastases 8.3 References

20 21 21 22 22

9.

27 27 27 27 27 28 28

FOLLOW-UP 9.1 How to follow-up 9.2 When to follow-up 9.3 Primary tumour 9.4 Regional recurrences 9.5 Guidelines for follow-up in penile cancer 9.6 References

10. QUALITY OF LIFE 10.1 Sexuality and fertility after penile cancer 10.1.1 Sexual activity and quality of life after penile cancer laser treatment 10.1.2 Sexual function after partial penectomy for penile cancer 10.2 Sexual mutilation, relapse and death 10.3 References

29 29 29 29 29 30

11.

31

ABBREVIATIONS USED IN THE TEXT

Update march 2009

3

1. INTRODUCTION The European Association of Urology (EAU) Guidelines Group on Penile Cancer has prepared this guidelines document to assist medical professionals in the management of penile cancer. The guidelines aim to provide detailed, up-to-date information, based on recent developments in our understanding and management of penile squamous cell carcinoma (SCC). However, it must be emphasised that these guidelines provide a standardised general approach to treating a patient and that the Guidelines provide guidance and recommendations without legal authority or implications. Publication history information: The Penile Cancer Guidelines were first published in 2001 and updated in 2004, followed by this full text update in 2009.

2. METHODOLOGY To update the last published guidelines in 2004, a meticulous PubMed literature search between October 2003 and October 2008 was carried out by all members of the Penile Cancer Consensus Group according to their field of interest (1). A total of 980 abstracts published on SCC of the penis were identified. Only one evidence-based peer-reviewed document was published during the period 2004 to 2008. This was the physician data query (PDQ) on ‘Penile Cancer Treatment’ (Health Professional Version) published by the National Cancer Institute , National Institutes of Health (Bethseda, USA) (2). No randomised controlled trials or Cochrane reviews were published. References used in the text have been assessed according to their level of scientific evidence (Table 1) and guideline recommendations have been graded (Table 2) according to the Oxford Centre for Evidence-based Medicine Levels of Evidence (3). The aim of grading recommendations is to provide transparency between the underlying evidence and the recommendation given. Publication history: The EAU Penile Cancer Guidelines were first published in 2000. Partial updates were achieved in 2001 and 2004, followed by the current version which presents a full text update. Additionally, a quick reference guide is available. All texts can be viewed and downloaded for personal use at the society website: http://www.uroweb.org/professional-resources/guidelines/. Table 1: Level of evidence Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Table 2: Grade of recommendation Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality *modified from Sackett et al. (3)

2.1

REFERENCES

1.

Solsona E, Algaba F, Horenblas S, Pizzocaro G, Windahl T. EAU guidelines on penile cancer. Eur Urol 2004;46(1):1-8. http://www.ncbi.nlm.nih.gov/pubmed/15183542

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2. National Cancer Institute. Penile Cancer Treatment (PDQ). Health Professional Version. US National Institutes of Health, 2008, pp. 1-13. http://www.cancer.gov/cancertopics/pdq/treatment/penile/healthprofessional/allpages 3. Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [Access date February 2009]

3. DEFINITION OF PENILE CANCER Penile cancer is a relatively rare SCC. It usually originates in the epithelium of the inner prepuce and glans. It shares a similar pathology and natural history with SCC of the oropharynx, female genitalia (cervix, vagina and vulva) and anus. Phimosis, poor hygiene and smoking are the major risk factors for penile cancer. Typing has been done of the human papillomaviruses (HPV) responsible for the sexual transmission of genital warts, condyloma acuminata SCC of the penis. An improved understanding of the natural history of the disease, earlier diagnosis, better technology, research group collaboration and centralisation of patients in centres of excellence has improved the cure rate for penile cancer from 50% in the 1990s to 80% in 2008.

4. EPIDEMIOLOGY In Western countries, primary malignant penile cancer is uncommon, with an incidence of less than 1.00 per 100,000 males in Europe and the United States of America (USA) (1, 2). There are, however, important geographical variations, with several European regions (Figure 1) reporting an incidence greater than 1.00 per 100,000 males (3). Incidence is also affected by race and ethnicity in North America (1), with the highest incidence of penile cancer found in white Hispanics (1.01 per 100,000), followed by Alaskan, Native/American Indians (0.77 per 100,000), Blacks (0.62 per 100,000) and White non-Hispanics (0.51 per 100,000). In contrast, in the non-Western world, the incidence rate of penile cancer is much higher and can represent 10-20% of malignant disease in men ranging from an age-adjusted incidence of 0.7 to 3 per 100,000 people in India to 8.3 per 1000,000 men in Brazil and even higher in Uganda, where it is the most commonly diagnosed cancer. Important risk factors include social and cultural habits, hygienic and religious practices (4). Penile carcinoma is rare in communities that practise circumcision in newborns or before puberty (Jews, Muslims and the Ibos of Nigeria). Early circumcision reduces the risk of penile cancer by 3 to 5 times. Adult circumcision does not protect against penile cancer. In the USA, the overall age-adjusted incidence rate decreased considerably between 1973 and 2002 from 0.84 per 100,000 in 1973-1982 to 0.69 per 100,000 in 1983-1992 and further to 0.58 per 100,000 in 19932002 (1). In European countries, the incidence during the 1980s and 1990s was stable or increased slightly (2). The incidence rate continuously increases with age (2); however, the disease has been reported in younger men and in children.

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Figure 1: Annual incidence rate (world standardised) by European region/country* Penis: ASR (World) (per 100,000) (All ages) Spain, Albacete Malta Switzerland, Neuchatel France, Haut-Rhin Italy, Ragusa Province UK, Scotland Denmark Austria, Tyrol Norway Spain, Asturias France, Bas-Rhin *UK, England Estonia Slovakia *Switzerland, Ticino The Netherlands *Belgium Flanders (excl. Limburg) Italy, Torino Poland, Warsaw city Germany, Saarland *Portugal, Vila Nova de Gaia Slovenia Italy, Sassari 0

0.5

1.0

1.5

2.0

*From Parkin et al. (2003) (3).

4.1

REFERENCES

1.

Barnholtz-Sloan JS, Maldonado JL, Pow-sang J, Giuliano AR. Incidence trends in primary penile cancer. Urol Oncol 2007;25(5):361-7. http://www.ncbi.nlm.nih.gov/pubmed/17826651 ENCR (European Network of Cancer Registries). Eurocim version 4.0. European incidence database V2.2 (1999). Lyon, France: IARC, 2001. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB (eds). Cancer Incidence in Five Continents. Vol. VIII. IARC Scientific Publications. No. 155. Lyon, France: IARC, 2002. http://www.iarc.fr/en/Publications/PDFs-online/Cancer-Epidemiology/IARC-Scientific-PublicationNo.-155 Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol 2004;5(4):240-7. http://www.ncbi.nlm.nih.gov/pubmed/15050955

2. 3.

4.

5. RISK FACTORS AND PREVENTION Risk factors for penile cancer were identified by the Karolinska Institute from a Medline search of published literature from 1966-2000 (1). Strong risk factors (OR > 10) identified by case-control studies included (level of evidence: 2a): • phimosis • chronic inflammatory conditions, e.g. balanoposthitis, lichen sclerosus and atrophicus (balanitis xerotica obliterans) • treatment with sporalene and ultraviolet A photochemotherapy. Sexual history (multiple partners, early age of first intercourse) and a self-reported history of condylomata were associated with a 3- to 5-fold increased risk of penile cancer. Smoking is also a risk factor. Cervical cancer in the wife was not consistently associated with penile cancer in the husband.

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In many case series, HPV DNA was identified in 70-100% intraepithelial neoplasia and in 40-50% of cases with invasive penile cancer. These results were confirmed by a population-based case control study (2). Among men not circumcised in childhood, phimosis was strongly associated with the development of invasive penile cancer (OR = 11.4; 95% CI 5.0-25.9), while cigarette smoking was associated with a 4.5-fold increased risk (95% CI 2.0-10.1). Human papillomavirus DNA was detected in 80% of tumour specimens; 69% were positive for HPV-16 (level of evidence: 2a). Smegma as a carcinogen has been clearly excluded (3). The risk of cancer among patients with condyloma acuminata increased for vulva, vagina, penis and anus (4) (level of evidence: 2b). Human papillomavirus-16 and -18 have a causal role in 70% of cancers of the cervix, vagina and anus and about 30-40% of cancers of the vulva, penis and oropharynx. Other cofactors are very likely to be necessary for progression from HPV infection to cancer (5). In June 2006, the US Food and Drug Administration (FDA) licensed the first vaccine to prevent cervical cancer and other HPV-associated diseases in women (6). The vaccine protects against infection with HPV-6, HPV-11, HPV-16 and HPV-18, which together are responsible for 70% of cervical cancers and 90% of genital warts. Human papillomavirus is highly transmissible, with a peak incidence soon after the onset of sexual activity. The recommended age for vaccination in females is 11-12 years (7), with catch-up vaccination recommended in females aged 13-26 years. However, vaccination is not a substitute for routine cervical cancer screening and vaccinated females should continue to have cervical cancer screening. Vaccination against HPV has also been recommended in males (8). Although a study found that mid-adult (25 years or older) women have a high level of acceptance for HPV vaccination (9), only 33% of males wanted the HPV vaccine, 27% did not and 40% were undecided (10). Interestingly, the presence of high-risk HPV DNA in penile cancer does not compromise prognosis. An early study (11) found no difference between HPV DNA-negative and HPV DNA-positive patients in lymph node metastases and 10-year survival rate. In a more recent study (12), disease-specific 5-year survival in the high-risk HPV-negative group was 78% versus 93% in the high-risk HPV-positive group (log rank test p = 0.03). This suggests the presence of high-risk HPV confers a survival advantage in patients with penile cancer. The virus plays an important role in oncogenesis through interaction with oncogenes and tumour suppressor genes (P53 and Rb-gene) (13).

5.1

REFERENCES

1. Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl 2000;(205):189-93. http://www.ncbi.nlm.nih.gov/pubmed/11144896 2. Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA, Carter JJ, Porter PL, Galloway DA, McDougall JK, Krieger JN. Penile cancer: importance of circumcision, human papillomavirus and smoking in situ and invasive disease. Int J Cancer 2005;116(4):606-16. http://www.ncbi.nlm.nih.gov/pubmed/15825185 3. Van Howe RS, Hodges FM. The carcinogenicity of smegma: debunking a myth. Eur Acad Dermatol Venereol 2006;20(9):1046-54. http://www.ncbi.nlm.nih.gov/pubmed/16987256 4. Nordenvall C, Chang ET, Adami HO, Ye W. Cancer risk among patients with condylomata acuminata. Int J Cancer 2006;119(4):888-93. http://www.ncbi.nlm.nih.gov/pubmed/16557590 5. Munoz N, Castelisague X, de Gonzalez AB, Gissmann L. HPV in the etiology of human cancer. Vaccine 2006;24(Suppl 3):S3/1-10. http://www.ncbi.nlm.nih.gov/pubmed/16949995 6. Huang CM. Human papillomavirus and vaccination. Mayo Clin Proc 2008;83(6):701-6. http://www.ncbi.nlm.nih.gov/pubmed/18533087 7. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Quadrivalent Human Papillomavirus Vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-2):1-24. http://www.ncbi.nlm.nih.gov/pubmed/17380109 8. Giuliano AR. Human papillomavirus vaccination in males. Gynecol Oncol 2007;107(2 Suppl 1):S24S26. http://www.ncbi.nlm.nih.gov/pubmed/17938015

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9.

10.

11.

12.

13.

Ferris DG, Waller JL, Owen A and Smith J. Midadult women’s attitudes about receiving the prophylactic human papillomavirus vaccine. J Low Genit Tract Dis 2007;11(3):166-72. http://www.ncbi.nlm.nih.gov/pubmed/17596762 Ferris DG, Waller JL, Miller J, Patel P, Jackson L, Price GA, Wilson C. Men’s attitudes toward receiving the human papillomavirus vaccine. J Low Genit Tract Dis 2008;12(4):276-81. http://www.ncbi.nlm.nih.gov/pubmed/18820541 Bezerra AL, Lopes A, Santiago GH, Ribeiro KC, Latorre MR, Villa LL. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer 2001;15;91(12):5-21. http://www.ncbi.nlm.nih.gov/pubmed/11413520 Lont AP, Kroon BK, Horenblas S, Gallee MP, Berkhof J, Meijer CJ, Snijders PJ. Presence of high risk human papilllomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer 2006;119(5):1078-81. http://www.ncbi.nlm.nih.gov/pubmed/16570278 Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and genetic pathways in penile cancer. Lancet Oncol 2007;8(5):420-9. http://www.ncbi.nlm.nih.gov/pubmed/17466899

6. TNM CLASSIFICATION AND PATHOLOGY 6.1

TNM classification

The 2002 UICC Tumour Node Metastasis (TNM) classification (1) for penile cancer is shown in Table 3. Table 3: 2002 TNM (Tumour, Node, Metastasis) classification of penile cancer T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ Ta Non-invasive verrucous carcinoma T1 Tumour invades subepithelial connective tissue T2 Tumour invades corpus spongiosum or cavernosum T3 Tumour invades urethra or prostate T4 Tumour invades other adjacent structures N - Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No evidence of lymph node metastasis N1 Metastasis in a single inguinal lymph node N2 Metastasis in multiple or bilateral superficial lymph nodes N3 Metastasis in deep inguinal or pelvic lymph nodes, unilateral or bilateral M - Distant metastases MX Distant metastases cannot be assessed M0 No evidence of distant metastases M1 Distant metastases This classification is in need of an update, particularly the definition of T2 category, as the prognosis of patients with tumour invasion of the corpus spongiosum is much better than invasion of the corpus cavernosum (2, 3). Rees et al. (2) reported on 72 patients with T2 tumours. Both local recurrence (35% vs 17%) and mortality (30% vs 21%) rates were higher in patients with tunical or cavernosal involvement after a mean follow-up of 3 years (level of evidence: 2b). The authors proposed defining T2a patients by spongiosum-only invasion and T2b patients by involvement of tunica or corpus cavernosum. However, a deeper analysis resulted in severe criticism and a new proposal for classification (3). A retrospective analysis of the records of 513 patients treated between 1956 and 2006 confirmed the above-mentioned difference between tumour invasion of corpus spongiosum and cavernosum. It also confirmed that there were no differences in long-term survival between T2 and T3, and no

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significant differences between N1 and N2 in the 1987-2002 TNM classification (level of evidence: 2a). A new TNM classification was therefore proposed for T2, T3, T4 and N1, N2, N3 (Table 4) (3). In the new proposed classification, retroperitoneal node metastases are considered to be distant metastases as for the neck, lung and other visceral organs. The new classification is much more appropriate than the present TNM categories, but it needs to be confirmed by UICC. Table 4: Proposed modification to 1987-2002 TNM classification* T - Primary tumour TX, T0, Tis, Ta and T1 Unchanged T2 Tumour invades corpus spongiosum T3 Tumour invades corpus cavernosum T4 Tumour invades adjacent structures (e.g. urethra, prostate) N - Regional lymph nodes Nx and N0 Unchanged N1 Unilateral inguinal metastases, mobile N2 Bilateral inguinal metastases N3 Fixed inguinal metastases or metastases in pelvic lymph nodes *From Leiitje et al. (2008) (3). 6.1.1 References 1. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours. Philadelphia, PA: Wiley-Liss, 2002. 2. Rees RW, Freeman A, Borley N, Ralf DJ, Minhas S. PT2 penile squamous cell carcinomas: cavernosus vs. spongiosus invasion. Eur Urol Suppl 2008;7(3):111 (abstr 163). 3. Leijte JA, Gallee M, Antonini N, Horenblas S. Evaluation of current TNM classification of penile carcinoma. J Urol 2008;180(3):933-8; discussion 938. http://www.ncbi.nlm.nih.gov/pubmed/18635216

6.2

Pathology

Squamous cell carcinoma accounts for more than 95% of cases of malignant disease of the penis. Malignant melanomas and basal cell carcinoma are much less common. It is not known how often SCC is preceded by premalignant lesions (1). Although SCC is the most common penile neoplasia, different types and varying growth patterns have been identified (2-4) (Tables 5 and 6). Table 5: Premalignant lesions Lesions sporadically associated with SCC of the penis • Cutaneous horn of the penis • Bowenoid papulosis of the penis • Balanitis xerotica obliterans (lichen sclerosus et atrophicus) Lesions at high risk of developing SCC of the penis (up to one-third transform to invasive SCC) • Penile intraepithelial neoplasia (carcinoma in situ): erythroplasia of Queyrat and Bowen’s disease LE = level of evidence; SCC = squamous cell carcinoma. Table 6: Penile SCC Types of SCC • Classic • Basaloid • Verrucous and its varieties (2): - Warty (condylomatous) carcinoma - Verrucous carcinoma - Papillary carcinoma - Hybrid verrucous carcinoma - Mixed carcinomas (warty basaloid, adenobasaloid carcinoma) • Sarcomatoid • Adenosquamous

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Growth patterns of SCC • Superficial spread • Nodular or vertical-phase growth • Verrucous Differentiation grading systems for SCC • Broders’ system (5) • Maiche’s system score (6) SCC = squamous cell carcinoma. 6.2.1 Penile biopsy There is no need for biopsy if: • There is no doubt about the diagnosis and/or • Treatment of the lymph nodes is postponed after treatment of the primary tumour and/ or after histological examinations of the sentinel node(s). There is a need for histological confirmation if: • There is doubt about the exact nature of the lesion (metastasis, melanoma, etc) • Treatment of the lymph nodes is based on pre-operative histological information (risk-adapted strategy). In these cases an adequate biopsy is advised. When performing a biopsy, it is important to consider the findings from a study of biopsy size. The study of biopsies with an average size of 1.1 cm found there was: • difficulty in evaluating the extent of depth in 91% of biopsies • discordance between the grade at biopsy and the final specimen in 30% of cases • failure to detect cancer in 3.5% (1) • Thus, although a punch biopsy may be sufficient for superficial lesions, an excisional biopsy is preferred. 6.2.2.1 Pathological categories Traditionally, squamous cell carcinomas were considered as superficial or invasive. However, Cubilla et al. (2) has divided penile carcinoma into four categories: • superficial spreading • vertical growth • verrucous • multicentric. Different types of growth have different prognoses (3) and different ways of dissemination. The limits of surgical partial resections must therefore be set according to the growth pattern at the time of evaluation of the frozen sections (4). If the margins are studied following these criteria (including urethral and periurethral tissue), only 3-4 mm of tumourfree tissue is sufficient to consider the surgical margins to be negative (7). Basaloid SSC is a cellular subtype that is better recognised than before. It is highly aggressive. (8) 6.2.2.2 Histology and metastatic risk Histological subtypes carry different risks of developing metastatic lymph nodes: • condylomatous: 18.2% • SCC: 56.7% • sarcomatoid carcinoma: 89% (9). Similarly, invasion pattern (10) and vascular invasion (10, 11) are correlated with lymph node metastases, with 23.1% of positive lymph nodes associated with a nodular pattern and 64.6% with an infiltrative pattern. 6.2.3 1.

References Velazquez EF, Barreto JE, Rodriguez I, Piris A, Cubilla AL. Limitations in the interpretation of biopsies in patients with penile squamous cell carcinoma. Int J Surg Pathol 2004;12(2):139-46. http://www.ncbi.nlm.nih.gov/pubmed/15173919 2. Cubilla AL, Barreto J, Caballero C, Ayala G, Riveros M. Pathologic features of epidermoid carcinoma of the penis. A prospective study of 66 cases. Am J Surg Pathol 1993;17(8):753-63. http://www.ncbi.nlm.nih.gov/pubmed/8338190

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3.

Villavicencio H, Rubio-Briones J, Regalado R, Chéchile G, Algaba F, Palou J. Grade, local stage and growth pattern as prognostic factors in carcinoma of the penis. Eur Urol 1997;32(4):442-7. http://www.ncbi.nlm.nih.gov/pubmed/9412803 4. Velazquez EF, Soskin A, Bock A, Codas R, Barreto JE, Cubilla AL. Positive resection margins in partial penectomies: sites of involvement and proposal of local routes of spread of penile squamous cell carcinoma. Am J Surg Pathol 2004;28(3):384-9. http://www.ncbi.nlm.nih.gov/pubmed/15104302 5. Broders AC. Squamous cell epithelioma of the skin: A study of 256 cases. Ann Surg 1921;73(2):141160. http://www.ncbi.nlm.nih.gov/pubmed/17864409 6. Maiche AG, Pyrhönen S, Karkinen M. Histological grading of squamous cell carcinoma of the penis: a new score system. Br J Urol 1991;67(5):522-526. http://www.ncbi.nlm.nih.gov/pubmed/1710163 7. Minhas S, Kayes O, Hegarty P, Kumar P, Freeman A, Ralph D. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int 2005;96(7):1040-3. http://www.ncbi.nlm.nih.gov/pubmed/16225525 8. Cubilla AL, Reuter V, Velazquez E, Piris A, Saito S, Young RH. Histologic classification of penile carcinoma and its relation to outcome in 61 patients with primary resection. Int J Surg Pathol 2001;9(2):111-20. http://www.ncbi.nlm.nih.gov/pubmed/11484498 9. Bezerra AL, Lopes A, Landman G, Alencar GN, Torloni H, Villa LL. Clinicopathologic features and human papillomavirus DNA prevalence of warty and squamous cell carcinoma of the penis. Am J Surg Pathol 2001;25(5):673-8. http://www.ncbi.nlm.nih.gov/pubmed/11342782 10. Guimarães GC, Lopes A, Campos RS, Zequi Sde C, Leal ML, Carvalho AL, da Cunha IW, Soares FA. Front pattern of invasion in squamous cell carcinoma of the penis: new prognostic factor for predicting risk of lymph node metastases. Urology 2006;68(1):148-53. http://www.ncbi.nlm.nih.gov/pubmed/16844455 11. Busby JE, Pettaway CA. What’s new in the management of penile cancer? Curr Opin Urol 2005;15(5):350-7. http://www.ncbi.nlm.nih.gov/pubmed/16093861

7. DIAGNOSIS AND STAGING The primary tumour and regional lymph nodes must be staged correctly to enable the most appropriate treatment.

7.1

Primary lesion

Physical examination of a patient with penile cancer includes: • diameter of the penile lesion(s) or suspicious areas • location of lesion(s) on the penis • number of lesions • morphology of lesion(s): papillary, nodular, ulcerous or flat • relationship of lesion(s) to other structures, e.g. submucosa, tunica albuginea, urethra, • corpus spongiosum and corpus cavernosum • colour and boundaries of lesion(s) • penis length. Accurate histological diagnosis and staging of both the primary tumour and regional nodes are necessary in making treatment decisions (1). In a small series, physical examination alone was more reliable than imaging with ultrasound and/or MRI to judge infiltration into the corpora (2). Artificial erection with prostaglandin E1 (alprostadil) in combination with magnetic resonance imaging (MRI) was helpful in identifying the depth of tumour invasion of the corpora cavernosa and whether or not conservative surgery should be used (3, 4).

7.2

Regional lymph nodes

7.2.1 Lymphatic drainage of the penis Primary lymphatic drainage of penile cancer occurs to the inguinal nodes. A recent imaging study (5) has

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shown that all sentinel nodes are located in the superior and central inguinal zones with most found in the medial superior zone. No lymphatic drainage was observed from the penis to the inferior two regions of the groin and no direct drainage to the pelvic nodes was visualised. These findings confirm earlier studies (6-8). 7.2.2 Non-palpable nodes A careful inguinal physical examination is necessary. In the absence of palpable abnormalities, an inguinal ultrasound (7.5 mHz) may reveal abnormal nodes and can be used as a guide for fine-needle aspiration biopsy (9, 10). A sentinel node biopsy (SNB) (8) is not recommended because of a high rate of false-negative results (25%, range 9-50%) (11). However, recent reports suggest that dynamic SNB (using isosulphan blue and/ or technetium-99m (99mTc)-colloid sulphur) improved survival compared to a ‘wait-and-see’ policy (level of evidence: 3) and reduced toxicity compared to inguinal lymphadenectomy (LAD) (12, 13). A prospective study found dynamic SNB had 100% specificity and 78-80% sensitivity (14-18) (level of evidence: 2a). As analysis of dynamic SNB is operator-dependent (19) and relies on experience, the procedure is only available in a few centres. Because iliac lymph node metastases do not occur in the absence of inguinal metastases (19), an abdominal computed tomography (CT) scan is not necessary in patients with no inguinal node metastases. A conventional CT or MRI scan cannot detect micrometatases (20). Large studies are required to confirm promising results reported with nanoparticle-enhanced MRI and positron emission tomography (PET) or CT imaging (21, 22). 7.2.3 Risk factors The presence of lymph node metastases may be predicted from tumour characteristics other than T and G categories. Risk factors identified from retrospective studies include pathological subtype, perineural invasion, lymphovascular invasion, tumour depth or thickness, anatomical site, size and growth pattern, front of invasion, positive margins and urethral invasion (23). Several large series have identified lymphovascular invasion alone (24), lymphovascular invasion plus absent koilocytosis (25), lymphovascular invasion plus palpable inguinal nodes (26), high histological grade plus perineural invasion (27). The most important adverse pathological prognostic factors appear to be perineural invasion, vascular invasion and high histological grade (23). Nomograms can be used to evaluate the predictive power of clinical and pathological indicators (23, 26). 7.2.4 Palpable nodes Palpable nodes should be described as follows: • node consistency • node location(s) • diameter of node(s) or mass(es) • unilateral or bilateral localisation • number of nodes identified in each inguinal area • mobile or fixed nodes or masses • relationship (e.g. infiltration, perforation, etc) to other structures, such as the skin or Cooper ligament • oedema on leg and/or scrotum. Lymph node metastases in palpable nodes can be diagnosed using a percutaneous needle aspiration biopsy (cytology and/or histology punction). At the time of diagnosis of penile cancer, as many as 50% of palpable inguinal nodes will be reactive rather than due to lymph node metastasis. In contrast, during follow-up, nearly 100% of enlarged nodes are metastatic (28-30) (level of evidence: 2a). Thus, after allowing time for inflammatory reactions to subside, regional nodes should be evaluated within a few weeks after treatment of the primary tumour. Histological diagnosis can be done using fine-needle aspiration biopsy, tissue core biopsy or open biopsy, according to the preference of the pathologist (31, 32) (level of evidence: 2b). In the case of a negative biopsy and clinically suspicious nodes, a repeat biopsy or excisional biopsy should be performed. Imaging techniques (CT, MRI) are widely used, but are only useful for staging in patients with proven lymph node metastases. So far no imaging modality can identify microspcopic invasion. Imaging using PET (33) and the use of molecular biology are under investigation (34, 35).

7.3

Distant metastases

An assessment of distant metastases should be performed in patients with proven positive inguinal nodes (36) (level of evidence: 2b). Pelvic or abdominal CT scan should be used to identify pelvic (and retroperitoneal) adenopathies in patients with inguinal metastases. While this is not a very reliable diagnostic method, the detection of pelvic masses has a considerable impact on therapy and prognosis (39). Routine blood determination and chest X-rays are usually performed, despite the fact that lung metastasis

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is exceptionally rare. The value of SCC antigen determination as a staging tool is unclear and therefore not recommended for routine use (34). Biological studies are investigational (37). A diagnostic schedule is summarised in Table 7. Table 7: Diagnostic schedule for penile cancer Lesion level Primary tumour

Regional disease

• Non-palpable nodes • Palpable node

Distant metastases

Procedures Mandatory Advisable Physical examination Cytology or histology Physical examination Dynamic sentinel Ultrasound node biopsy* Ultra-sound (FNAC)* Cytology or histology Pelvic CT, if positive Abdominal CT inguinal nodes (chest X-rays)

Optional MRI Ultrasound

Bone scan in symptomatic patients

FNAC=fine needle aspiration biopsy;MRI = magnetic resonance imaging; PGE1 = prostaglandin E1; CT = computed tomography. *Dual techmique: isosulphan blue with technetium-99m (99mTc) colloid sulphur (8, 19). Regional lymph nodes are the regional disease.

7.4

Guidelines for the diagnosis of penile cancer

Primary tumour • Physical examination is mandatory, recording morphological and physical characteristics of the lesion • Cytological or histological diagnosis is mandatory Regional lymph node disease • Physical examination is mandatory • If nodes are non-palpable, ultrasound-guided FNAB • If FNAB is tumour-negative, dynamic SNB is indicated • If nodes are palpable, it is mandatory to record nodal morphological and physical and physical characteristics and to perform FNAB for histological diagnosis

GR B B

B B B B

Distant metastasis (beside inguinal nodes) • A pelvic CT scan is indicated if metastatic inguinal nodes are present B • An abdominal CT scan and chest X-ray are advisable if pelvic CT scan is positive B • A bone scan is advisable in M1 symptomatic patients C • Biological laboratory determinations for penile cancer are investigational None GR = grade of recommendation, MRI = magnetic resonance imaging; PGE1 = prostaglandin E1; FNAB = fine-needle aspiration biopsy; DSNB = sentinel node biopsy; CT = computed tomography.

7.5

REFERENCES

1.

Solsona E, Iborra I, Rubio J, Casanova JL, Ricós JV, Calabuig C. Prospective validation of the association of local tumor stage grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol 2001;165(5): 1506-9. http://www.ncbi.nlm.nih.gov/pubmed/11342906 Horenblas S. The accuracy of ultrasound in squamous cell carcinoma. In: The Management of Penile Squamous Cell Carcinoma. A Retrospective and Prospective Study. Thesis. Amsterdam Zoetermeer: BV Export drukkerij, 1993, pp. 71-83. Kayes O, Minhas S, Allen C, Harc C, Freeman A, Ralph D. The role of magnetic resonance imaging in the local staging of penile cancer. Eur Urol 2007;51(5):1313-8. http://www.ncbi.nlm.nih.gov/pubmed/17113213

2.

3.

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4.

Lont AP, Besnard AP, Gallee MP, van Tinteren H, Horenblas S. A comparison of physical examination and imaging in determining the extent of primary penile carcinoma. BJU Int 2003;91(6):493-5. http://www.ncbi.nlm.nih.gov/pubmed/12656901 5. Leijte JA, Valdés Olmos RA, Nieweg OE, Horenblas S. Anatomical mapping of lymphatic drainage in penile carcinoma with SPECT-CT: implications for the extent of inguinal lymph node dissection. Eur Urol 2008;54(4):885-90. http://www.ncbi.nlm.nih.gov/pubmed/18502024 6. Daseler EH, Anson BJ, Reimann AF. Radical excision of the inguinal and iliac lymph glands: a study based upon 450 anatomical dissections and upon supportive clinical observations. Surg Gynecol Obstet 1948;87(6):679-94. http://www.ncbi.nlm.nih.gov/pubmed/18120502 7. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977;39(2):456-66. http://www.ncbi.nlm.nih.gov/pubmed/837331 8. Catalona WJ. Modified inguinal lymphadenectomy for carcinoma of the penis with preservation of saphenous veins: technique and preliminary results. J Urol 1988;140(4):306-10. http://www.ncbi.nlm.nih.gov/pubmed/3418818 9. Saisorn I, Lawrentschut N, Leewansangtong S, Bolton DM. Fine-needle aspiration cytology predicts inguinal lymph node metastases without antibiotic pretreatment in penile carcinoma. BJU Int 2006;97(6):1125-8. http://www.ncbi.nlm.nih.gov/pubmed/16686716 10. Kroon BK, Horenblas S, Deurloo EE, Nieweg OE, Teertstra HJ. Ultrasonography-guided fineneedle aspiration cytology before sentinel node biopsy in patients with penile carcinoma. BJU Int 2005;95(4):517-21. http://www.ncbi.nlm.nih.gov/pubmed/15705071 11. Pettaway CA, Pisters LL, Dinney CPN, Jularbal F, Swanson DA, von Eschenbach AC, Ayala A. Sentinel lymph node dissection for penile carcinoma: the MD Anderson Cancer Center Experience. J Urol 1995;154(6):1999-2003. http://www.ncbi.nlm.nih.gov/pubmed/7500444 12. Horenblas S. Surgical management of carcinoma of the penis and scrotum. In: Petrovich Z, Baert L, Brady LW (eds). Medical Radiology. Diagnostic Imaging and Radiation Oncology. Carcinoma of the Kidney and Testis, and Rare Urologic Malignancies. Berlin: Springer-Verlag, 1999, pp. 341-54. 13. Pettaway CA, Jularbal FA, Babaian RJ, Dinney CPN, Pisters LL. Intraoperative lymphatic mapping to detect inguinal metastases in penile carcinoma: results of a pilot study. J Urol 1999;161:159 (abstr 612). 14. Akduman B, Fleshner NE, Ehrlich L, Klotz L. Early experience in intermediate-risk penile cancer with sentinel node identification using the gamma probe. Urology 2001;58(1):65-8. http://www.ncbi.nlm.nih.gov/pubmed/11445481 15. Perdonà S, Gallo L, Claudio L, Marra L, Gentile M, Gallo A. [Role of crural inguinal lymphadenectomy and dynamic sentinel lymph node biopsy in lymph node staging in squamous-cell carcinoma of the penis. Our experience.] Tumori 2003;89(4 Suppl):276-9. [article in Italian] http://www.ncbi.nlm.nih.gov/pubmed/12903620 16. Tanis PJ, Lont AP, Meinhardt W, Olmos RA, Nieweg OE, Horenblas S. Dynamic sentinel node biopsy for penile cancer: reliability of a staging technique. J Urol 2002;168(1):76-80. http://www.ncbi.nlm.nih.gov/pubmed/12050496 17. Wawroschek F, Vogt H, Bachter D, Weckermann D, Hamm M, Harzmann R. First experience with gamma probe guided sentinel lymph node surgery in penile cancer. Urol Res 2000;28(4):246-9. http://www.ncbi.nlm.nih.gov/pubmed/11011963 18. Lont AP, Horenblas S, Tanis PJ, Gallee MP, Van Tinteren H, Nieweg OE. Management of clinically node negative penile carcinoma: improved survival after the introduction of dynamic sentinel node biopsy. J Urol 2003;170(3):783-6. http://www.ncbi.nlm.nih.gov/pubmed/12913697 19. Leijte JA, Kroon BK, Valdés Olmos RA, Nieweg OE, Horenblas S. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol 2007;52(1):170-7. 20. Mueller-Lisse UG, Scher B, Scherr MK, Seitz M. Functional imaging in penile cancer: PET/computed tomography, MRI, and sentinel lymph node biopsy. Curr Opin Urol 2008;18(1):105-10. http://www.ncbi.nlm.nih.gov/pubmed/18090498 21. Tabatabaei S, Harisinghani M, McDougal WS. Regional lymph node staging using lymphotropic nanoparticle enhanced magnetic resonance imaging with ferumoxtran-10 in patients with penile cancer. J Urol 2005;174:923-7; discussion 927. http://www.ncbi.nlm.nih.gov/pubmed/16093989

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Scher B, Seitz M, Albinger W, Reiser M, Schlenker B, Stief C, Mueller-Lisse U, Dresel S. Value of PET and PET/CT in the diagnostics of prostate and penile cancer. Recent Results Cancer Res 2008;170:159-79. http://www.ncbi.nlm.nih.gov/pubmed/18019625 23. Cubilla AL. The role of pathologic prognostic factors in squamous cell carcinoma of the penis. World J Urol 2008 Sep 3. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18766352 24. Lopes A, Hidalgo GS, Kowalski LP, Torloni H, Rossi BM, Fonseca FP. Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy J Urol 1996;156(5):1637-42. http://www.ncbi.nlm.nih.gov/pubmed/8863559 25. Ornellas AA, Nóbrega BL, Wei Kin Chin E, Wisnescky A, da Silva PC, de Santos Schwindt AB. Prognostic factors in invasive squamous cell carcinoma of the penis: analysis of 196 patients treated at the Brazilian National Cancer Institute. J Urol 2008;180(4):1354-9. http://www.ncbi.nlm.nih.gov/pubmed/18707720 26. Ficarra V, Zattoni F, Artibani W, Cunico SC, Fandella A, Martignoni G, Novara G, Galetti TP, Zattoni F; GUONE Penile Cancer Project Members. Nomogram predictive of pathological inguinal lymph nodes involvement in patients with squamous cell carcinoma of the penis. J Urol 2006;175(6):1700-5. http://www.ncbi.nlm.nih.gov/pubmed/16697813 27. Velazquez EF, Ayala G, Liu H, Chaux A, Zanotti M, Torres J, Cho SI, Barreto JE, Soares F, Cubilla AL. Histologic grade and perineural invasion are more important than tumor thickness as predictor of nodal metastasis in penile squamous cell carcinoma invading 5 to 10 mm. Am J Surg Pathol 2008;32(7):974-9. http://www.ncbi.nlm.nih.gov/pubmed/18460979 28. Horenblas S, Van Tinteren H, Delamarre JFM, Moonen LM, Lustig V, van Waardenburg EW. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol 1993;149(3): 492-7. http://www.ncbi.nlm.nih.gov/pubmed/8437253 29. Ornellas AA, Seixas AL, Marota A, Wisnescky A, Campos F, de Moraes JR. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994;151(5):1244-9. http://www.ncbi.nlm.nih.gov/pubmed/7512656 30. Pizzocaro G, Piva L, Nicolai N. Treatment of lymphatic metastasis of squamous cell carcinoma of the penis: experience at the National Tumor Institute of Milan. Arch Ital Urol Androl 1996;68(3):169-72. http://www.ncbi.nlm.nih.gov/pubmed/8767505 31. Senthil Kumar MP, Ananthakrishnan N, Prema V. Predicting regional node metastasis in carcinoma of the penis: a comparison between fine-needle aspiration cytology, sentinel lymph node biopsy and medial inguinal lymph node biopsy. Br J Urol 1998;81(3):453-7. http://www.ncbi.nlm.nih.gov/pubmed/9523669 32. Skoog L, Collins BT, Tani E, Ramos RR. Fine-needle aspiration cytology of penile tumors. Acta Cytol 1998;42(2):1336-40. http://www.ncbi.nlm.nih.gov/pubmed/9568135 33. Ravizzini GC, Wagner M, Borges-Neto S. Positron emission tomography detection of metastatic penile squamous cell carcinoma. J Urol 2001;165(5):1633-4. http://www.ncbi.nlm.nih.gov/pubmed/11342941 34. Laniado ME, Lowdell C, Mitchell H, Christsmas TJ. Squamous cell carcinoma antigen: a role in the early identification of nodal metastases in men with squamous cell carcinoma of the penis. BJU Int 2003;92(3):248-5. http://www.ncbi.nlm.nih.gov/pubmed/12887477 35. Lopez A, Bezena AL, Pinto CA, Serrano SV, de Mello CA, Villa LL. p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol 2002;168:81-6. http://www.ncbi.nlm.nih.gov/pubmed/12050497 36. Zhu Y, Zhang SL, Ye DW, Yao XD, Jiang ZX, Zhou XY Predicting pelvic lymph node metastases in penile cancer patients: a comparison of computed tomography, Cloquet’s node, and disease burden of inguinal lymph nodes. Onkologie. 2008;31:37-41. 37. Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and genetic pathways in penile cancer. Lancet Oncol 2007;8(5):420-9. http://www.ncbi.nlm.nih.gov/pubmed/17466899

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Lont AP, Kroon BK, Gallee MP, van Tinteren H, Moonen LM, Horenblas S. Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival. J Urol 2007;177(3):947-52; discussion 952. http://www.ncbi.nlm.nih.gov/pubmed/17296384

8. TREATMENT The primary tumour and regional lymph nodes are usually treated separately. It is important to avoid both overtreatment, which may lead to side-effects, and undertreatment, which may impair survival.

8.1

Primary tumour

8.1.1 Category Tis and Ta Tis and Ta are superficial lesions that can be treated with several conservative techniques: • topical 5-fluorouracil for Tis (1) • imiquimod 5% cream, an immune response modifier with good cosmetic and functional results on flat lesions (2) • laser therapy with carbon dioxide (CO2) or neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers (3, 4) • photodynamic therapy (5) • Mohs’ micrographic surgery for Ta lesions (6, 7). However, conservative treatment may not be suitable in cases of multifocal lesions, which are responsible for 15% of recurrences. Total treatment of the glans surface combined with concomitant circumcision is strongly recommended (4) to avoid multiple recurrences (grade of recommendation: A). Cure with secondary healing was obtained in 94% of 106 Tis patients treated with peniscopically controlled CO2 laser excision. However, five patients had multiple recurrences and two required penile amputation (7). A recent paper on photodynamic therapy reported seven responses in 10 treated patients, but only four patients were recurrence-free after a mean follow-up of 35 months (5). Non-invasive verrucous carcinoma (Ta) needs a correct pre-operative diagnosis to avoid unnecessary extensive surgery (6). Furthermore, a recent report on Mohs’ micrographic surgery demonstrated a significant local recurrence rate for Tis and verrucous carcinoma as well as invasive SCC (7). In conclusion, the best results are achieved with laser surgery (level of evidence: 2b; grade of recommendation: B). 8.1.2 Category T1G1 For lesions limited (level of evidence: 2a) to the foreskin and sulcus, wide local excision with circumcision may provide adequate treatment. Pathological assessment of the surgical margin is mandatory; a margin of 3-4 mm is sufficient (8). For T1 tumours of the glans, peniscopically controlled CO2 laser excision alone cured 86% of 78 patients with histologically superficial infiltration (≤ 1 mm) of lamina propria (4). Another 40 patients had deeper infiltration (> 1 mm) with exophytic warty-like or plaque tumours. These patients received neo-adjuvant vinblastine, bleomycin and methotrexate (VBM) chemotherapy, with cure achieved in 33 (82%) patients. Of 18 (15%) relapsed patients, only eight (7%) needed penile amputation or radiotherapy (level of evidence: 2b). An alternative treatment of glans resurfacing (9) has shown promising results for preinvasive lesions (level of evidence: 2a). 8.1.3 Category T1G2-3 For patients who can guarantee they will attend for regular follow-up, a penis-preserving strategy is strongly recommended using wide local laser excision plus reconstructive surgery (10, 11) or glansectomy (12-14) (level of evidence: 2a). Treatment choice is influenced by tumour size and position on the glans and the side-effects of treatment. Meticulous follow-up is essential to enable immediate treatment of any local disease recurrence. There is no difference in the local recurrence rate (15% or more) between external radiation therapy, interstitial brachytherapy (BRT) laser therapy and wide local excision. Glansectomy has the lowest recurrence rate of 2% (13). Pathological assessment of surgical margins is essential when using these procedures to reduce the rate of local recurrence (12, 13, 15) (level of evidence: 2b). Generally, early diagnosis of local recurrence does not have a negative impact on survival (16) (level of evidence: 3).

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8.1.4 Category T2 (of the glans) A conservative strategy of total glansectomy, with or without resurfacing of the corporeal heads, is recommended (5, 14) (level of evidence: 2a). Partial glansectomy is an alternative in very carefully selected patients with tumours that include less than half of the glans and in whom close follow-up is possible (17) (level of evidence: 2b). Consider partial amputation in patients unfit for more conservative reconstructive surgery (13). 8.1.5 Category T2 (of the corpora) and T3 For tumours involving the tips of the corpora, partial amputation is standard treatment (18, 19) (level of evidence : 2a) . Reconstructive surgery with negative margins at frozen section analysis is an alternative in carefully selected patients (level of evidence: 2b). For large tumours involving more than the distal corpora, partial or radical amputation is standard (level of evidence: 2a). Traditionally, partial amputation has required removal of 2-cm tumour-free margins. This is almost certainly more than is necessary. However, it is essential to achieve tumour-free margins with pathological confirmation. A surgical margin of 5-10 mm is safe (15, 20, 21) (level of evidence: 2b). 8.1.6 Category T4 Deeply infiltrating tumours involving adjacent structures are often associated with disseminated disease at presentation and a short life expectancy. Palliative care may be most appropriate. In selected cases, downstaging with chemotherapy may be considered prior to total penectomy. Alternatives include surgery with adjuvant external beam irradiation (level of evidence: 3). 8.1.7 Local disease recurrence For local recurrence after conservative therapy, a second conservative procedure is strongly advised if there is no corpora cavernosa invasion (22) (level of evidence: 2b). However, if there is a large or deep infiltrating recurrence, partial or total amputation is strongly recommended. The incidence of local recurrence increases with penis preservation, but can be treated in most cases. Local recurrence after penile amputation has a poor prognosis (23). Combined chemotherapy and radiotherapy as for advanced head and neck cancer has not yet been tried. 8.1.8 Technical aspects of surgery 8.1.8.1 Conservative surgery The most important factors in the choice of conservative management are simplicity, morbidity of the procedure and the surgeon’s experience. Small areas of ablated/excised epithelium can heal without grafting. For a larger area, a skin graft provides a better cosmetic result in a shorter time (level of evidence: 3). 8.1.8.2 Partial/total amputation Stenosis of the neo-meatus or perineal urethrostomy is seen in approximately 7-10% and can be prevented by a spatulated repair. Orchidectomy should not be performed routinely (level of evidence: 3). 8.1.9 Radiotherapy External beam irradiation (ERT), brachytherapy (BRT) or both techniques together can be used. The ERT treatment is delivered with high-energy photons (4-6 MV) and uses CT scanning to define the target volume and to optimise dosage distribution. Different types of BRT can be used including external isotope mould, lowdose rate BRT, pulse-dose rate BRT or high-dose rate BRT. Primary tumour radiotherapy is an alternative organ-preserving approach with excellent results in selected patients with T1-2 lesions less than 4 cm in diameter (level of evidence: 2a). There have been no prospective studies or randomised trials to evaluate the different modalities of radiation treatment. A local control rate of about 60% has been reported using ERT, while BRT has achieved better control rates ranging from 70% to 90% (24-28). However, it is difficult to compare results using ERT and BRT because patients with large volume lesions (> 4 cm) are excluded from BRT. In addition, the different dosages used in different retrospective studies, even within the same institution, make it very difficult to compare results and side-effects. Local failure rates after radiotherapy were higher than after adequate partial penectomy, but salvage surgery can restore local control (28, 29). The high doses of radiation needed to achieve local control can cause iatrogenic complications. Urethral stenosis (20-35%), glans necrosis (10-20%) and late fibrosis are the most serious types of tissue damage and can result in a non-functioning penis.

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The penile preservation rate after radiotherapy is approximately 80%. The local control rate after BRT was recently reported as 90%, with an actuarial penile preservation rate of 87% at 5 years (29). Because of postradiation changes (necrosis, scars, ulcers), it may be difficult to differentiate radiation sequelae from persistent or recurrent tumour and very close follow-up is recommended. 8.1.9.1 Recommendations for radiation therapy Radiotherapy should be considered in two groups of patients with two different aims: • Organ-preserving treatment: in men with T1-2 glans or coronal sulcus lesions (< 4 cm), who are compliant for close follow-up. Both ERT combined with a BRT boost, or BRT alone, may be used to deliver the prescribed dose (> 60 Gy). • Palliative radiotherapy: in men with advanced or metastatic disease requiring palliative local treatment, the treatment of choice is ERT (40-50 Gy). 8.1.10 Guidelines for treatment strategies in primary tumour Primary tumour Category: Tis and Ta

LE 2a

GR B

2a

B

• Multifocal lesions and HPV-16 infection

Conservative therapy: CO2 or Nd:YAG lasers surgery are recommended Total glans resurfacing and circumcision are strongly recommended to prevent multiple recurrences

Category T1G1

T1G1 tumours are suitable for conservative surgery

2a

B

For glans lesions, CO2 laser surgery or resurfacing are appropriate For lesions of foreskin and sulcus, wide local excision with circumcision are appropriate with assessment of surgical margins Deeper infiltration may need adjuvant chemotherapy Penile-preserving treatment with wide local laser excision for complying patients with follow-up, or glansectomy are indicated Assessment of surgical margins reduces rate of local recurrence In these cases early diagnosis of local recurrence does not have an adverse impact on survival Total glansectomy, with or without resurfacing of corporeal heads Partial glansectomy is an alternative in very carefully selected patients with tumours less than half the glans and suitable for follow-up Consider partial amputation in patients unfit for follow-up Moderate partial amputation for tumours involving only tips of the corpora Partial or total amputation for larger tumours involving more than the distal corpora Traditionally, partial amputation has required removal of 2-cm tumour-free margins. A surgical margin of 5-10 mm is safe with pathological confirmation Deeply infiltrating tumours involving adjacent structures are often associated with disseminated disease at presentation . For patients in poor conditions with short life expectancy, palliative radiotherapy may be most appropriate Some patients may be suitable for down-staging with chemotherapy prior to surgery. Alternatives include adjuvant external beam irradiation if surgery is not possible. Local recurrence is more likely with penis preservation but it is usually treatable

2a

B

2a

B

2a 2a

B B

2b 2b

B C

2a

B

2b

B

2b 2a

B B

2a

B

2b

B

2a

C

2a

B

2a

B

2a

B

2a

B

Category T1G2-3

Category T2 (of glans)

Category T2 (of the corpora) and T3

Category T4

Local disease recurrence after conservative therapy

Second conservative procedure is strongly advised in absence of corpora cavernosa invasion Partial or total amputation is strongly recommended for large or deep infiltrating recurrence

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Main uses of radiotherapy

8.2

Local recurrence after penile amputation has a poor prognosis Organ-preserving treatment in selected patients with T1-2 glans or coronal sulcus lesions < 4 cm Palliative in advanced or metastatic disease not responsive to chemotherapy

2a 2b

B B

2b

B

Treatment of regional lymph nodes

Lymphadenectomy is the necessary surgical procedure for patients with inguinal lymph node metastases. Bilateral LAD is often followed by prolonged lymph leakage, which can result in leg and scrotal lymphoedema. Other surgical complications include skin flap necrosis, wound infection and haemorrhage from exposed femoral vessels. The procedure requires careful skin flap management, meticulous lymph node dissection, prophylactic antibiotics, compressive stoking and early ambulation. These complications occur in 30-70% of patients. Lymphadenectomy should therefore preferably only be performed in a therapeutic setting, where removal of lymph node metastases is indisputable. 8.2.1 Management of patients with non-palpable inguinal nodes 8.2.1.1 Surveillance In the past, patients with low-stage tumours and clinically unaffected inguinal nodes have often undergone surveillance strategies. The 2004 EAU guidelines ‘strongly’ recommended surveillance only in patients with superficial and well-differentiated tumours: Tis, TaG1-2, T1G1 and T1G2 with superficial growth and no vascular invasion (30). This approach was criticised following a study that found 82% of 100 consecutive patients had undergone unnecessary prophylactic LAD (31). 8.2.1.2 Prognostic factors For a long time, urologists have been oriented to look at pathological risk factors for metastases and pT3-T4 and all G3 patients were unequivocal candidates for bilateral LAD. In an old series (32), nodal metastases were found in 100% of pT3-T4, in 82% of pT2 and 23% of pT1. In particular, 16.5% of metastases were found in pT1G1 and 60% in pT1G2-3. No metastases were found in Ta or Tis. In a very recent series (33), lymph node metastases were found in 12% of pT1G2, a category that has therefore been defined as ‘intermediate risk’. A high histological grade and perineural invasion (21) or depth of invasion (34) are significant predictors of lymph node metastases. A nomogram (34) has identified palpable groin lymph nodes and vascular and/or lymphatic invasion as the most important predictors of lymph node metastases. A new nomogram with a larger international series of patients is ongoing (level of evidence: 2b). 8.2.1.3 Sentinel node biopsy (SNB) Catalona’s SNB (35) was a failure, but dynamic SNB appears very promising (36-39). The concept behind dynamic SNB assumes there is a stepwise and orderly progression of the primary node (the so-called sentinel node) to secondary lymph nodes. There may be more than one sentinel node. To identify the sentinel node(s), 99mTc-nanocolloid is injected around the penile tumour intradermally the day before surgery. The sentinel lymph node(s) are detected intra-operatively with a gamma X-ray detection probe and patent blue dye staining before being dissected and removed. If there is a positive histology, either on frozen section or definitive histology, a formal complete inguinal LAD is performed. The technique has been extensively studied in a few specialised centres. The Netherlands Cancer Institute group initially reported a high rate of false-negative cases (36). However, following modification of the technique, they reported a markedly reduced false-negative rate of 4.8% (39). However, the technique has been criticised for its steep learning curve and the need for the surgeon to perform a minimal number of 20 procedures per year (40) (level of evidence: 2a). 8.2.2 Management of patients with palpable inguinal nodes In patients with penile cancer, moderately enlarged palpable inguinal nodes, which are not fixed, may or may not signify metastatic disease. The rate of false-positive nodes has been reported as high as 50% (41), but recently much lower figures of 30% have been reported (42). Ultrasound with fine-needle aspiration biopsy provides an excellent, rapid and easy way to detect metastatic involvement. Of course this is only reliable in tumour-positive patients. In suspected cases with tumour-negative findings, fine-needle aspiration biopsy should be repeated. Dynamic SNB is not reliable in this group of patients and should not be used (43, 44). Thus, in all tumour-positive patients, early LAD should be performed (45, 46); bilateral LAD is the standard

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procedure. In contralateral non-palpable lymph nodes, surgical staging is recommended either by dynamic SNB or lymph node dissection (level of evidence: 2a). 8.2.2.1 Inguinal LAD Significant morbidity has been described including wound infection, skin necrosis, wound dehiscence, lymphoedema and lymphocele (47, 48). Optimal skin handling and careful dissection of skin flaps are two of the most important factors in preventing complications. Skin rotation flaps and myocutaneous flaps should be used for primary wound closure in advanced cases (49) (level of evidence: 2b). 8.2.2.2 Modified inguinal LAD This procedure is associated with less morbidity than standard LAD (50, 51). The rate of early complications was 6.8% (vs 41.4%) and the rate of late complications was 3.4% (vs 43.1%) for patients with modified LAD (51). However, reducing the field of dissection increased the possibility of falsenegative cases (level of evidence: 2b). The high false-negative rate described by Lopes et al. (52) should be considered in the light of recent findings concerning lymphatic drainage to the lateral superior Daseler’s zone, which was not dissected in this approach (53, 54). Current knowledge of lymphatic drainage at the penis suggests that a contemporary modified LAD should dissect the central and both superior Daseler’s zones of the inguinal region (grade of recommendation: B). 8.2.2.3 The role of pelvic LAD There is no direct lymphatic drainage from penile cancer to the pelvic lymph nodes (54, 55). Thus, if there is no involvement of inguinal nodes, pelvic LAD is not warranted. In contrast, if the Cloquet node or other two inguinal nodes are involved on one side, a contemporary pelvic lymph node dissection must be performed through an upward muscle-splitting incision. Pathological predictors for the potential involvement of pelvic nodes in patients with involved inguinal nodes are the number of positive inguinal lymph nodes and extracapsular extent of metastatic disease (56) (level of evidence: 2a). Pelvic LAD may be necessary as a secondary procedure. If bilateral dissection is indicated, it can be performed though a midline suprapubic extraperitoneal incision. The rate of positive pelvic nodes was 23% in cases with no more than two positive inguinal nodes and 56% for more than two positive inguinal nodes or if there is extracapsular extent in at least one inguinal node (57-59). If very aggressive histological subtypes of penile cancer (i.e. basaloid) are present, or there is strong expression of p53, pelvic lymph node dissection should be considered if any inguinal node is involved (60) (grade of recommendation: B). 8.2.2.4 Video-endoscopic inguinal and pelvic LAD This recently described technique is derived from laparoscopic surgery and has been evaluated only in small pilot studies (61, 62). It seems to carry a lower risk of skin complications, but a higher risk of lymphocele formation compared to an open approach; the reported overall complication rate was 23% (63). The reliability of this technique has not yet been assessed (level of evidence: 4). Laparoscopic pelvic node dissection for bilateral pelvic lymph node removal, following positive bilateral inguinal LAD, is a rational approach, but only if the dissection can be performed with similar accuracy as open surgery. 8.2.3 Adjuvant chemotherapy Adjuvant chemotherapy after resection of nodal metastases has been reported in a few series. There has been only one study group who reported consistent results with adjuvant post-operative chemotherapy in N+ patients (64, 65). Twenty-five consecutive patients with resected lymph node metastases from SCC of the penis received 12 weekly courses of adjuvant VBM (vincristine, bleomycin, methotrexate) chemotherapy between 1979 and 1990. All patients underwent ilioinguinal lymph node dissection and received adjuvant chemotherapy. Only four (16%) patients relapsed, and the other 21 had a long-term disease-free survival of 84%. These results compared favourably with a previous series of 31 patients, who underwent ilioinguinal lymph node dissection, alone or with adjuvant radiotherapy, between 1960 and 1978. The 5-year disease-free survival was only 37%. Among these 31 patients, only the involvement of a single, intranodal inguinal node metastasis was associated with good prognosis. In contrast, in the series of 25 patients treated with adjuvant chemotherapy (VBM), only bilateral and/or pelvic node involvement were significantly associated with poor prognosis, with 4 of 8 patients dying of penile cancer (level of evidence: 2a).

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Since 1991, pN2-N3 patients have been treated with three courses of adjuvant cisplatin and 5-fluorouracil (PF) with only two relapses (6.7%) in the first 30 treated patients (65) (level of evidence: 2a). 8.2.4 Management of patients with fixed or relapsed inguinal nodes Fourteen patients were treated with locally advanced or metastatic penile cancer with cisplatin, methotrexate and bleomycin (BMP) chemotherapy on days 2 to 5 (66). Toxicity was severe. Only three of the eight partial responders underwent surgery, while another two entered complete remission. In a confirmatory study by the Southwest Oncology Group (SWOG) (67), only six of 40 evaluable patients completed chemotherapy. Five complete and eight partial remissions were achieved, but at the cost of 11% treatment-related mortality and 17% life-threatening toxicity. Another study (68) of BMP chemotherapy in 13 patients reported one death from treatment-related toxicity and no complete remissions (level of evidence: 2a). A review was performed of 20 patients who had received neo-adjuvant chemotherapy, including BMP, for unresectable lymph node metastases during the period 1972 to 2005 (69). Twelve of 19 evaluable patients showed an objective tumour response. Five different chemotherapeutic regimens were used. Nine responders underwent subsequent surgery, of whom eight became long-term survivors without evidence of recurrent disease. Chemotherapy-related toxicity was fatal in three out of 10 patients treated with BMP (level of evidence: 2b). At the MD Anderson Cancer Center (Houston, TX, USA) (70), 10 patients were treated with surgical consolidation following a stable, partial, or complete response to four to five courses of the following chemotherapeutic regimens: paclitaxel, ifosfamide and cisplatin (ITP) in five patients, paclitaxel and carboplatin (PC) in two patients, and BMP in three patients. Three of the five patients treated with ITP had a pathologically documented complete remission and two of them are long-term survivors. The two patients treated with PC became disease-free with post-chemotherapy surgery. All three patients treated with BMP suffered severe toxicity and died of the disease. Systematic use of post-chemotherapy surgery in responsive patients was of main importance in the latter two studies (69, 70) (level of evidence: 2a). In addition, a preliminary report (71) on taxol combined with PF (TPF) chemotherapy in six consecutive patients with unresectable or relapsed inguinopelvic lymph node metastases from SCC of the penis suggests that TPF could have improved activity compared to PF alone in this clinical situation (65), as has been demonstrated in SCC of the head and neck in three randomised trials (72-74). In conclusion, adjuvant chemotherapy is strongly recommended in pN2-3 patients, and neo-adjuvant chemotherapy with taxanes seems to be active in unresectable or recurrent lymph node metastases (level of evidence: 2a, grade of recommendation: B). 8.2.5 The role of radiotherapy Prophylactic radiotherapy in clinical N0 patients is not recommended for the following reasons: • radiotherapy fails to prevent the development of metastatic lymph nodes (75) • complications of radiotherapy (76) • follow-up is more difficult due to fibrotic changes. Pre-operative radiotherapy in patients with fixed nodes can make the nodes operable, but it is not known whether node fixation is an inflammatory reaction or malignant growth (75, 76). Adjuvant radiotherapy may improve loco-regional control in patients with extensive metastases and/or extranodal spread. However, severe side-effects include oedema and pain (75).

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8.2.6 Guidelines for treatment strategies for nodal metastases Regional lymph nodes No palpable inguinal nodes

Palpable inguinal nodes

Pelvic nodes

Adjuvant chemotherapy

Patients with fixed or relapsed inguinal nodes

Radiotherapy

Management of regional lymph nodes is fundamental in the treatment of penile cancer Tis, Ta G1, T1G1: surveillance > T1G2: DSNB (NB: Inguinal LAD if histology is positive.) If DSNB not available: risk factors / nomogram decision-making Ultrasound-guided FNAB (NB: DSNB is unsuitable for palpable nodes) Negative biopsy: surveillance (repeat biopsy) Positive biopsy: inguinal LAD on positive side (NB: Modified LAD must include the central zone and both superior Daseler’s zones.) Pelvic LAD if there are: extranodal metastases; Cloquet node involved; > 2 inguinal node metastases Unilateral pelvic LAD if unilateral lymph node metastases with prolonged inguinal incision Bilateral pelvic LAD if bilateral inguinal metastases In patients with > 1 intranodal metastasis (pN2 pN3) after radical LAD, survival is improved by adjuvant chemotherapy (2 or 3 courses of cisplatin, fluorouracil (PF) chemotherapy) Neo-adjuvant chemotherapy is strongly recommended in patients with unresectable or recurrent lymph node metastases. Taxanes seems to improve the efficacy of standard PF chemotherapy Curative radiotherapy may be used for primary tumours of the glans penis and sulcus < 4 cm or for palliation Prophylactic radiotherapy in clinical N0 patients is not indicated

LE

GR

2a

B

2a

B

3 2a

C B

2a

B

2b

B

2a 2b

B B

2a

B

2a

B

2a

B

LE = level of evidence; GR = grade of recommendation; LAD = lymphadenectomy; FNAB = fine-needle aspiration biopsy; DSNB = sentinel node biopsy.

8.3

REFERENCES

1.

Goette DK, Carson TE. Erythroplasia of Queyrat: treatment with topical 5-fluorouracil. Cancer 1976;38(4):1498-502. http://www.ncbi.nlm.nih.gov/pubmed/991073 2. Taliaferro SJ, Cohen GF. Bowen’s disease of the penis treated with topical imiquimod 5% cream. J Drugs Dermatol 2008;7(5):483-5. http://www.ncbi.nlm.nih.gov/pubmed/18505144 3. van Bezooijen BP, Horenblas S, Meinhardt W, Newling DW. Laser therapy for carcinoma in situ of the penis. J Urol 2001;166(5):1670-1. http://www.ncbi.nlm.nih.gov/pubmed/11586199 4. Bandieramonte G, Colecchia M, Mariani L, Lo Vullo S, Pizzocaro G, Piva L, Nicolai N, Salvioni R, Lezzi V, Stefanon B, De Palo G. Peniscopically controlled CO2 laser excision for conservative treatment of in situ and T1 penile carcinoma: report on 224 patients. Eur Urol 2008;54(4):875-84. http://www.ncbi.nlm.nih.gov/pubmed/18243513 5. Paoli J, Ternesten Bratel A, Löwhagen GB, Stenquist B, Forslund O, Wennberg AM. Penile intraepithelial neoplasia: results of photodynamic therapy. Acta Derm Venereol 2006;86(5):418-21. http://www.ncbi.nlm.nih.gov/pubmed/16955186 6. Hatzichristou DG, Apostolidis A, Tzortzis V, Hatzimouratidis K, Ioannides E, Yannakoyorgos K. Glansectomy: an alternative surgical treatment for Buschke-Löwenstein tumors of the penis. Urology 2001;57(5):966-9. http://www.ncbi.nlm.nih.gov/pubmed/11337304 7. Shindel AW, Mann MW, Lev RY, Sengelmann R, Petersen J, Hruza GJ, Brandes SB. Mohs micrographic surgery for penile cancer: management and long-term followup. J Urol 2007;178(5):1980-5. http://www.ncbi.nlm.nih.gov/pubmed/17869306

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8.

Penile Cancer Treatment (PDQ®) Health Professional Version. National Cancer Institute, US National Institutes of Health, 2008, pp. 6-7. http://www.cancer.gov/cancertopics/pdq/treatment/penile/healthprofessional/allpages/print 9. Hadway P, Corbishley CM, Watkin NA. Total glans resurfacing for premalignant lesions of the penis: initial outcome data. BJU Int 2006;98(3):532-6. http://www.ncbi.nlm.nih.gov/pubmed/16925748 10. Frimberger D, Hungerhuber E, Zaak D, Waidelich R, Hofstetter A, Schneede P. Penile carcinoma. Is Nd:YAG laser therapy radical enough?. J Urol 2002;168(6):2418-21. http://www.ncbi.nlm.nih.gov/pubmed/12441930 11. Windalh T, Andersson SO. Combined laser treatment for penile carcinoma: results after long-term follow up. J Urol 2003;169(6):2118-21. http://www.ncbi.nlm.nih.gov/pubmed/12771731 12. Bissada NK, Yakout HH, Fahmy WE, Gayed MS, Touijer AK, Greene GF, Hanash KA. Multiinstitutional long-term experience with conservative surgery for invasive penile carcinoma. J Urol 2003;169(2): 500-2. http://www.ncbi.nlm.nih.gov/pubmed/12544296 13. Smith Y, Hadway P, Biedrzycki, Perry MJA, Corbishley C, Watkin NA. Reconstructive surgery forinvasive squamous cell carcinoma of the glans penis. Eur Urol 2007;52(4):1179-85. http://www.ncbi.nlm.nih.gov/pubmed/17349734 14. Davis JW, Schellhammer PF, Schlossberg SM. Conservative surgical therapy for penile and urethralcarcinoma. Urology 1999;53(2):386-92. http://www.ncbi.nlm.nih.gov/pubmed/9933060 15. Algaba F, Arce Y, López-Beltán A, Montironi R, Mikuz G, Bono AV. Intraoperative frozen section diagnosis in Urological Oncology. Eur Urol 2005;47(2):129-36. http://www.ncbi.nlm.nih.gov/pubmed/15661406 16. Gotsadze D, Matveev, B, Zak, B, Mamaladze V. Is conservative organ-sparing treatment of penile carcinoma justified? Eur Urol 2000;38(3):306-12. http://www.ncbi.nlm.nih.gov/pubmed/10940705 17. Minhas S, Kayes O, Hegarty P, Kumar P, Freeman A, Ralph D. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int 2005;96(7):1040-3. http://www.ncbi.nlm.nih.gov/pubmed/16225525 18. Ornellas AA, Seixas ALC, Marota A, Wisnescky A, Campos F, de Moraes JR. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994;151(5):1244-9. http://www.ncbi.nlm.nih.gov/pubmed/7512656 19. Lont AP, Gallee MP, Meinhardt W, van Tinteren H, Horenblas S. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol 2006;176(2):575-80;discussion 580. http://www.ncbi.nlm.nih.gov/pubmed/16813892 20. Velázquez EF, Soskin A, Bock A, Codas R, Barreto JE, Cubilla AL. Positive resection margins in partial penectomies. Sites of involvement and proposal of local routes of spread of penile squamous cell carcinoma. Am J Surg Pathol 2004;28(3):384-9. http://www.ncbi.nlm.nih.gov/pubmed/15104302 21. Horenblas S, Van Tinteren H, Delemarre JFM, Boon TA, Moonen LMF, Lustig V. Squamous cell carcinoma of the penis. II. Treatment of the primary tumor. J Urol 1992;147(6):1533-8. http://www.ncbi.nlm.nih.gov/pubmed/1593683 22. Koch MO, Smith JA Jr. Local recurrence of squamous cell carcinoma of the penis. Urol Clin North Am 1994;21(4):739-43. http://www.ncbi.nlm.nih.gov/pubmed/7974902 23. Gotsadze D, Matveev B, Zak B, Mamaladze V. Is conservative organ-sparing treatment of penile carcinoma justified? Eur Urol 2000;38(3):306-12. http://www.ncbi.nlm.nih.gov/pubmed/10940705 24. Sarin R, Norman AR, Steel GG. Treatment results and prognostic factors in 101 men treated for squamous carcinoma of the penis. Int J Radiat Oncol Biol Phys 1997;38(4):713-22. http://www.ncbi.nlm.nih.gov/pubmed/9240637 25. Kiltie AE, Elwell C, Close A, Ash DV. Iridium-192 implantation for node-negative carcinoma of the penis: The Cookridge Hospital Experience. Clin Oncol (R Coll Radiol) 2000;12(1):25-31. http://www.ncbi.nlm.nih.gov/pubmed/10749016

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26.

Azrif M, Logue GP, Swindell R, Cowan RA, Wylie JP, Livsey JE. External-beam radiotherapy in T1-2 N0 penile carcinoma. Clin Oncol (R Coll Radiol) 2006;18(4):320-5. http://www.ncbi.nlm.nih.gov/pubmed/16703750 27. Rozan R, Albuisson E, Giraud B, Donnarieix D, Delannes M, Pigneux J, Hoffstetter S, Gerbaulet A, Chinet-Charrot P, Goupil A, et al. Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients). Radiother Oncol 1995;36(2):83-93. http://www.ncbi.nlm.nih.gov/pubmed/7501816 28. Zouhair A, Coucke PA, Jeanneret W, Douglas P, Do HP, Jichilinski P, Mirimanoff RO, Ozsahin M. Radiation therapy alone or combined surgery and radiation therapy in squamous-cell carcinoma of the penis? Eur J Cancer 2001;37(2):198-203. http://www.ncbi.nlm.nih.gov/pubmed/11166146 29. Crook JM, Grimard L, Esche B, Pond G. Penile brachytherapy: results for 60 patients. Brachytherapy 2007;6:82. 30. Solsona E, Algaba F, Horenblas S, Pizzocaro G, Windahl T. EAU Guidelines on Penile Cancer. Eur Urol 2004;46(1):1-8. http://www.ncbi.nlm.nih.gov/pubmed/15183542 31. Hegarty PK, Kayes O, Freeman A, Christopher N, Ralph DJ, Minhas S. A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines. BJU Int 2006;98(3):526-31. http://www.ncbi.nlm.nih.gov/pubmed/16925747 32. Pizzocaro G, Piva L, Nicolai N. [Treatment of lymphatic metastases for squamous cell carcinoma of the penis: experience at the National Tumor Institute of Milan.] Arch Ital Urol Androl 1996:68(3):169-72. [article in Italian] http://www.ncbi.nlm.nih.gov/pubmed/8767505 33. Hughes B, Leijte J, Shabbir M, et al. Lymphnode metastassis in intermediate risk penile squamous cell cancer. A multicentre experience. Eur Urol Suppl 2008;7(3):110 (abstract 160). 34. Ficarra V, Zattoni F, Artibani W. Cunico SC, Fandella A, Martignoni G, Novara G, Galetti TP, Zattoni F; GUONE Penile Cancer Project Members. Nomogram predictive of pathological inguinal lymph nodes involvement in patients with squamous cell carcinoma of the penis. J Urol 2006;175(6):1700-5. http://www.ncbi.nlm.nih.gov/pubmed/16697813 35. Catalona WJ. Modified inguinal lymphadenectomy for carcinoma of the penis with preservation of saphenous vein: technique and preliminary results. J Urol 1988;140(2):306-10. http://www.ncbi.nlm.nih.gov/pubmed/3398125 36. Horenblas S, Jansen L, Meinhardt W, Hoefnagel CA, de Jong D, Nieweg OE. Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 2000;163(1):100-4. http://www.ncbi.nlm.nih.gov/pubmed/10604324 37. Perdonà S, Autorino R, Gallo L, Di Lorenzo G, Cascini GL, Lastoria F, Marra L, De Sio M, Damiano R, Gallo A. Role of dynamic sentinel node biopsy in penile cancer: our experience. J Surg Oncol 2006;93(3):181-5. http://www.ncbi.nlm.nih.gov/pubmed/16482606 38. Kroon BK, Horenblas S, Estourgie SH, Lont AP, Valdes Olmos RA, Nieweg OE. How to avoid falsenegative dynamic sentinel node procedures in penile carcinoma. J Urol 2004;171(6 Pt 1):2191-4. http://www.ncbi.nlm.nih.gov/pubmed/15126783 39. Leijte JAP, Kroon BK, Valdes Olmos RD, Nieweg OE, Horenblas S. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol 2007;52(1):170-7. http://www.ncbi.nlm.nih.gov/pubmed/17316967 40. Ficarra V, Galfano A. Should the dynamic sentinel node biopsy (DSNB) be considered the gold standard in the evaluation of lymph node status in patients with penile carcinoma?. Eur Urol 2007;52(1):17-19; discussion 20-1. Epub 2007. http://www.ncbi.nlm.nih.gov/pubmed/17376585 41. Persky L, deKernion J. Carcinoma of the penis. CA Cancer J Clin 1986;36(5):258-73. http://www.ncbi.nlm.nih.gov/pubmed/3093013 42. Velasquez EF, Ayala C, Liu H, Chaux A, Zanotti M, Torres J, Cho SI, Barreto JE, Soares F, Cubilla AL. Histologic grade and perineal invasion are more important than tumor thickness as predictor of nodal metastases in penile squamous cell carcinoma invading 5 to 10 mm. Am J Surg Pathol 2008;32(7):974-9. http://www.ncbi.nlm.nih.gov/pubmed/18460979

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43.

Horenblas S. Lymphadenectomy for squamous cell carcinoma of the penis. Part 1: diagnosis of lymph node metastasis. BJU Int 2001;88:467-72. http://www.ncbi.nlm.nih.gov/pubmed/11589659 44. Preis E, Jakse G. [The significance of inguinal lymphadenectomy in carcinoma of the penis.] Urologe A 2006;45(Suppl 04):176-80. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/16933120 45. Kroon BK, Horenblas S, Estourgie SH, Lont AP, Valdes Olmos RA, Nieweg OE. How to avoid falsenegative dynamic sentinel node procedures in penile carcinoma. J Urol 2004;171(6 Pt 1):2191-4. http://www.ncbi.nlm.nih.gov/pubmed/15126783 46. Hungerhuber E, Schlenker B, Frimberger D, Linke R, Karl A, Stief CG, Schneede P. Lymphoscintigraphy in penile cancer: limited value of sentinel node biopsy in patients with clinically suspicious lymph nodes. World J Urol 2006;24(3):319-24. http://www.ncbi.nlm.nih.gov/pubmed/16688459 47. Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol 2005;173(3):816-9 http://www.ncbi.nlm.nih.gov/pubmed/15711276 48. Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (eds). Campbell-Walsh Urology. 9th edn. Philadelphia, PA: Saunders Elsevier, 2007. 49. Horenblas S. Lymphadenectomy for squamous cell carcinoma of the penis. Part 2: the role and technique of lymph node dissection. BJU Int 2001;88(5):473-83. http://www.ncbi.nlm.nih.gov/pubmed/11589660 50. Bevan-Thomas R, Slaton JW, Pettaway CA. Contemporary morbidity from lymphadenectomy for penile squamous cell carcinoma: the MD Anderson Cancer Center Experience. J Urol 2002;167(4):1638-42. http://www.ncbi.nlm.nih.gov/pubmed/11912379 51. Bouchot O, Rigaud J, Maillet F, Hetet JF, Karam G. Morbidity of inguinal lymphadenectomy for invasive penile carcinoma. Eur Urol 2004;45(6):761-5; discussion 765-6. http://www.ncbi.nlm.nih.gov/pubmed/15149749 52. Lopes A, Rossi BM, Fonseca FP, Morini S. Unreliability of modified inguinal lymphadenectomy for clinical staging of penile carcinoma. Cancer 1996;77(10):2099-102. http://www.ncbi.nlm.nih.gov/pubmed/8640676 53. Daseler EH, Anson BJ, Reimann AF. Radical excision of inguinal and iliac lymph glands: a study based upon 450 anatomical dissections and upon supportive clinical observations. Surg Gynecol Obstet 1948;87(6):679-94. http://www.ncbi.nlm.nih.gov/pubmed/18120502 54. Leijte JAP, Valdés Olmos RA, Nieweg OE, Horenblas S. Anatomical mapping of lymphatic drainage in penile cancer with SPECT-TC: implications for the extent of inguinal lymph node dissection. Eur Urol 2008;54(4):885-90. http://www.ncbi.nlm.nih.gov/pubmed/18502024 55. Cabanas RM. An approach for treatment of penile carcinoma. Cancer 1977;39(2):456-66. http://www.ncbi.nlm.nih.gov/pubmed/837331 56. Lont AP, Kroon BK, Gallee MP, van Tinteren H, Moonen LM, Horenblas S. Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival. J Urol 2007;177(3):947-52; discussion 952. http://www.ncbi.nlm.nih.gov/pubmed/17296384 57. Ornellas AA, Seixas AL, Marota A, Wisnescky A, Campos F, de Moraes JR. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994;151(5):1244-9. http://www.ncbi.nlm.nih.gov/pubmed/7512656 58. Culkin DJ, Beer TM. Advanced penile carcinoma. J Urol 2003;170(2 Pt 1):359-65. http://www.ncbi.nlm.nih.gov/pubmed/12853775 59. Lopes A, Bezerra AL, Serrano SV, Hidalgo GS. Iliac nodal metastases from carcinoma of the penis treated surgically. BJU Int 2000;86(6):690-3. http://www.ncbi.nlm.nih.gov/pubmed/11069378 60. Zhu Y, Zhang SL, Ye DW, Yao XD, Jiang ZX, Zhou XY. Predicting pelvic lymph node metastases in penile cancer patients: a comparison of computed tomography, Cloquet’s node, and disease burden of inguinal lymph nodes. Onkologie 2008;31(1-2):37-41. http://www.ncbi.nlm.nih.gov/pubmed/18268397

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61. Tobias-Machado M, Tavares A, Ornellas AA, Molina WR Jr, Juliano RV, Wroclawski ER. Video endoscopic inguinal lymphadenectomy: a new minimally invasive procedure for radical management of inguinal nodes in patients with penile squamous cell carcinoma. J Urol 2007;177(3):953-7;discussion 958. http://www.ncbi.nlm.nih.gov/pubmed/17296386 62. Tobias-Machado M, Tavares A, Silva MN, Molina Jr WR, Forseto PH, Juliano RV, Wroclawski ER. Can video endoscopic inguinal lymphadenectomy achieve a lower morbidity than open lymph node dissection in penile cancer patients?. J Endourol 2008;22(8):1687-91. http://www.ncbi.nlm.nih.gov/pubmed/18657031 63. Sotelo R, Sanchez-Salas R, Carmona O, Garcia A, Mariano M, Neiva G, Trujillo G, Novoa J, Cornejo F, Finelli A. Endoscopic lymphadenectomy for penile carcinoma. J Endourol 2007;21(4):364-7;discussion 367. http://www.ncbi.nlm.nih.gov/pubmed/17451323 64. Pizzocaro G, Piva L. Adjuvant and neoadjuvant vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis. Acta Oncol 1988;27(6b):823-4. http://www.ncbi.nlm.nih.gov/pubmed/2466471 65. Pizzocaro G, Piva L, Bandieramonte G, Tana S. Up-to-date management of carcinoma of the penis. Eur Urol 1997;32(1):5-15. http://www.ncbi.nlm.nih.gov/pubmed/9266225 66. Dexeus F, Logothetis C, Sella A, Amato R, Kilbourn R, Fitz K, Striegel A. Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract. J Urol 1991;146(5):1284-7. http://www.ncbi.nlm.nih.gov/pubmed/1719241 67. Haas G, Blumenstein B, Gagliano R, Russell CA, Rivkin SE, Culkin DJ, Wolf M, Crawford ED. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol 1999;161(6):1823-5. http://www.ncbi.nlm.nih.gov/pubmed/10332445 68. Hakenberg OW, Nippgen JB, Froehner M, Zastrow S, Wirth MP. Cisplatin, methotrexate and bleomycin for treating advanced penile carcinoma. BJU Int 2006;98(6):1225-7. http://www.ncbi.nlm.nih.gov/pubmed/17125480 69. Lijte JA, Kerst JM, Bais E, Antonini N, Horenblas S. Neoadjuvant chemotherapy in advanced penile carcinoma. Eur Urol 2007;52(2):488-94. http://www.ncbi.nlm.nih.gov/pubmed/17316964 70. Barmejo C, Busby JK, Spiess PE, Heller L, Pagliaro LC, Pettaway CA. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol 2007;177(4):1335-8. http://www.ncbi.nlm.nih.gov/pubmed/17382727 71. Pizzocaro G, Nicolai N, Milani A. Taxanes in combination with cisplatin and fluorouracil for advanced penile cancer: preliminary results. Eur Urol 2008 Jul 14. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18649992 72. Hitt R, López-Pousa A, Martínez-Trufero J et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005;23(34):8636-45. http://jco.ascopubs.org/cgi/content/full/23/34/8636 73. Posner MR, Hershock DM, Blajman CR et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357(17):1705-15. http://content.nejm.org/cgi/content/abstract/357/17/1705 74. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357(17):1695-704. http://content.nejm.org/cgi/content/abstract/357/17/1695 75. Kulkarni JN, Kamat MR. Prophylactic bilateral groin node dissection versus prophylactic radiotherapy and surveillance in patients with N0 and N1-2A carcinoma of the penis. Eur Urol 1994;26(2):123-8. http://www.ncbi.nlm.nih.gov/pubmed/7957466 76. Ravi R, Chaturvedi HK, Sastry DV. Role of radiation therapy in the treatment of carcinoma of the penis. Br J Urol 1994;74(5):646-51. http://www.ncbi.nlm.nih.gov/pubmed/7530129

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9. FOLLOW-UP Follow-up in penile carcinoma is important for several reasons: • It enables early detection of recurrence, which is important because most local and/or loco-regional recurrences are potentially curable • It is the only way to assess treatment and anticipate early and late complications • It is also important for patient (and physician) education. A rational follow-up scheme requires an understanding of the patterns of recurrence. Preferably, follow-up should be introduced within the framework of a randomised study. Based on a retrospective study, a follow-up schedule for penis cancer has been published (1).

9.1

How to follow-up

The aim of follow-up is to detect local and/or regional recurrences because they may be cured. In contrast, metastases at distant sites are always fatal (2). Risk stratification for recurrence is also helpful. Traditional follow-up methods have been inspection and physical evaluation. Modern ultrasound imaging is a useful adjunct, with promising results from new imaging modalities, such as PET scan and laser-directed MRI (3).

9.2

When to follow-up

The follow-up interval and strategies for patients with penile cancer are directed by the initial treatment of the primary lesion and regional lymph nodes. In the above-mentioned multicentre study (1), during the first 2 years of follow-up, the following occurred: • 74.3% of all recurrences • 66.4% of local recurrences • 86.1% of regional recurrences • 100% of distant recurrences. Of all recurrences, 92.2% occurred within the first 5 years (1). All recurrences after 5 years were local recurrences or new primaries. Thus, an intensive programme of follow-up during the first 2 years is rational with less intensive follow-up needed thereafter. In well-educated and motivated patients, follow-up can stop after 5 years, although they must continue to carry out regular self-examination.

9.3

Primary tumour

Local recurrence has been reported in up to 30% of patients treated with penile-preserving surgery, during the first 2 years following treatment. Local recurrence is more likely with all types of local therapy, i.e. local resection, laser therapy, BRT, Mohs’ procedure, and associated therapies (1, 4). However, in contrast to regional recurrences, local recurrences do not impact on survival (1, 4). Local recurrences are easily detected by the patient, his partner or doctor. Patient education is an important part of follow-up and the patient should be urged to visit a specialist if any changes are seen. Despite the fact that late local recurrences are well documented, it is reasonable to stop follow-up after 5 years, provided the patient will report local changes immediately (5). This is possible because life-threatening regional and distant metastases no longer occur, while recurrences that are local only are not life-threatening. The emphasis should be placed on patient self-examination. In patients who are unlikely to self-examine, long-term follow-up may be necessary. Following penile-preserving treatment, a follow-up visit every 3 months is advised in the first 2 years. We then advise a follow-up visit every half year, provided that the patient and partner have been well instructed to examine the penis regularly and to return if any abnormality is observed. It is important to stress that the patient must continue to carry out regular self-examination even after 5 years’ follow-up. After amputation, a less frequent time interval of every 6 months is advised. The risk of local recurrence is not more than 5% (1, 4).

9.4

Regional recurrences

Stringent follow-up is advised for the 2 years following surgery. This is because most regional recurrences occur within 2 years, whether a ‘wait-and-see’ policy has been followed or the patient has undergone SNB or inguinal LAD. Previous follow-up recommendations have relied heavily on physical examination of the inguinal regions. However, experience with ‘wait and see’ and dynamic SNB have shown that, despite intensive followup, regional recurrences have shown up unexpectedly (6). Ultrasound and immediate fine-needle aspiration

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have been encouraging in finding occult metastases (6, 7) and it seems reasonable to add ultrasound to a physical examination. Patients managed with a ‘wait-and-see’ policy have a higher risk of recurrence (9%) than patients staged surgically (2.3%), whether staging has been performed by LAD or dynamic SNB. This finding only applies to patients without histopathological evidence of lymph node metastases. Patients treated surgically because of lymph node metastases have an increased risk of recurrence (19%) (1). Based on these findings, a change in the follow-up scheme is proposed. For patients in a ‘wait-and-see’ programme and patients given LAD for proven lymph node metastases, follow-up should be every 3 months and should include ultrasound investigation of the groin. This intensive follow-up programme should be for 2 years, which is the period when recurrence is most likely. Imaging using CT has been replaced by ultrasound scanning with immediate fine-needle aspiration biopsy, although CT scans are still used in patients with a regional recurrence. So far, other imaging modalities have not proven reliable at detecting pelvic and retroperitoneal recurrences. Bone scan and other tests are only recommended in symptomatic patients. The role of PET scan is unclear and therefore not advised as a routine procedure.

9.5

Guidelines for follow-up in penile cancer

Table 8 provides a follow-up schedule for penile cancer with grades of recommendation. Table 8: Follow-up schedule for penile cancer Interval of follow-up

Examinations and Investigations

Years 1 and 2 Years 3, 4 and 5 Recommendations for follow-up of primary tumour Penile-preserving 3 months 6 months treatment Amputation

6 months

1 year

Maximum length of follow-up

Regular physician or 5 years self-examination Regular physician or 5 years self-examination

GR

C C

Recommendations for follow-up of the inguinal lymph nodes ‘Wait-and-see’

3 months

6 months

pN0

6 months

1 year

pN+

3 months

6 months

Regular physician or self-examination Ultrasound with FNAB Regular physician or self-examination Ultrasound with FNAB Regular physician or self-examination Ultrasound with FNAB

5 years

C

5 years

C

5 years

C

GR = grade of recommendation; FNAB = fine-needle aspiration biopsy.

9.6

REFERENCES

1.

Leijte JAP, Kirrander P, Antonini N, Windahl T, Horenblas S. Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol 2008;54(1):161-8. http://www.ncbi.nlm.nih.gov/pubmed/18440124 Horenblas S, van Tinteren H, Delamarre JFM, Moonen LM, Lustig V, van Waardenburg EW. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol 1993;149(3):492-7. http://www.ncbi.nlm.nih.gov/pubmed/8437253. Lont AP, Gallee MP, Meinhardt W, van Tinteren H, Horenblas S. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol 2006;176(2):575-80;discussion 580. http://www.ncbi.nlm.nih.gov/pubmed/16813892

2.

3.

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4.

5.

6.

7.

Horenblas S, Newling DW. Local recurrence tumour after penis-conserving therapy. A plea for longterm follow-up. Br J Urol 1993;72(6):976-9. http://www.ncbi.nlm.nih.gov/pubmed/8306171 Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol 2005;173(3): 816-9. http://www.ncbi.nlm.nih.gov/pubmed/15711276 Kroon BK, Horenblas S, Deurloo EE, Nieweg OE, Teertstra HJ. Ultrasonography-guided fineneedle aspiration cytology before sentinel node biopsy in patients with penile carcinoma. BJU Int 2005;95(4):517-21. http://www.ncbi.nlm.nih.gov/pubmed/15705071 Krishna RP, Sistla SC, Smile R, Krishnan R. Sonography: An underutilized diagnostic tool in the assessment of metastatic groin nodes. Clin Ultrasound 2008;36(4):212-7. http://www.ncbi.nlm.nih.gov/pubmed/17960822

10. QUALITY OF LIFE .

10.1

Sexuality and fertility after cancer

As more people achieve long-term survival after cancer, sexual dysfunction and infertility are increasingly recognised as negative consequences affecting quality of life (1). 10.1.1 Sexual activity and quality of life after penile cancer laser treatment A retrospective, face-to-face, structured interview study was carried out on Swedish patients treated with laser for localised penile carcinoma during 1986 to 2000 (2). Sixty-seven patients were treated, with 58 of them (mean age 63 years) still alive in 2006. Forty-six (79%) agreed to participate in the interview. Nearly all patients could recall their first symptom, with 37% reporting that they delayed seeking treatment for more than 6 months. Patients had a greater lifetime number of sexual partners and a greater lifetime prevalence of sexually transmitted infections than the comparable general Swedish population. Following laser treatment, there was a marked decrease in some sexual practices, such as manual stimulation or caressing and fellatio. Patient satisfaction with life overall was similar to that of the general population. In conclusion, some patients delayed seeking treatment for a considerable period despite awareness of the first local symptoms. Men with laser-treated localised penile carcinoma resumed their sexual activities to a large extent. Except for satisfaction with somatic health, a similar (or higher) proportion of patients were satisfied with life overall and with other domains of life including sexual life. 10.1.2 Sexual function after partial penectomy for penile cancer To compare sexual function and satisfaction before and after partial penectomy, 18 Brazilian patients were given a personal interview and answered the International Index of Erectile Function (IIEF) questionnaire to determine erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction with sexual life (3). The median patient age was 52 years. The medium penile length after partial penectomy was 4 cm in the flaccid state, with 55.6% of patients reporting erectile function that allowed sexual intercourse. The main reason given for not resuming sexual intercourse in 50% of sexually abstinent patients was feeling shame because of a small penis and the absence of the glans penis. Surgical complications also compromised resumption of sexual activity after amputation in 33.3% of these patients. However, 66.7% sustained the same frequency and level of sexual desire prior to surgery and 72.2% continued to have ejaculation and orgasm every time they had sexual stimulation or intercourse. Nevertheless, only 33.3% maintained their pre-operative sexual intercourse frequency and were satisfied with their sexual relationships with their partners and their overall sex life. In conclusion, the pre-operative and post-operative scores were statistically worse for all domains of sexual function after partial penectomy.

10.2

Sexual mutilation, relapse and death

Today, nearly 80% of penile cancer patients can be cured. Experience in management of this rare tumour is helpful (4). Referral to centers with experience is recommended. Psychological support is very important for these patients. Penile-sparing surgery obviously allows a better quality of life than penile amputation and must be considered whenever feasible

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10.3

REFERENCES

1.

Schover LR. Sexuality and fertility after cancer. Hematology Am Soc Hematol Educ Program 2005;523-7. http://www.ncbi.nlm.nih.gov/pubmed/16304430 2. Skeppner E, Windahl T, Andersson S, Fugl-Meyers KS. Treatment-seeking, aspects of sexual activity and life satisfaction in men with laser-treated penile carcinoma. Eur Urol 2008;54(3):631-9. http://www.ncbi.nlm.nih.gov/pubmed/18788122 3. Romero FR, Romero KR, Mattos MA, Garcia CR, Fernandes Rde C, Perez MD. Sexual function after partial penectomy for penile cancer. Urology 2005;66(6):1292-5. http://www.ncbi.nlm.nih.gov/pubmed/16360459 4. Leijte JA, Gallee M, Antonini N, Horenblas S. Evaluation of current TNM classification of penile carcinoma. J Urol 2008;180(3):933-8. http://www.ncbi.nlm.nih.gov/pubmed/18635216

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11. ABBREVIATIONS USED IN THE TEXT This list is not comprehensive for the most common abbreviations.

BMP cisplatin, methotrexate and bleomycin BRT brachytherapy CT computed tomography DSNB dynamic sentinel node biopsy EAU European Association of Urology ERT external beam irradiation FDA [US] Food and Drug Administration FNAB fine-needle aspiration biopsy HDR high-dose rate (brachytherapy) HPV human papillomavirus IIEF International Index of Erectile Function questionnaire ITP paclitaxel, ifosfamide and cisplatin LAD lymphadenectomy LDR low-dose rate (brachytherapy) MRI magnetic resonance imaging NCI National Cancer Institute Nd-YAG neodynium:yttrium-aluminum-garnet PC paclitaxel and carboplatin PDQ physician data query PDR pulse-dose rate (brachytherapy) PET positron emission tomography PF cisplatin and fluorouracil PGE1 prostaglandin E1 (alprostadil) SCC squamous cell carcinoma SNB sentinel node biopsy SWOG Southwest Oncology Group 99mTC technetium 99m TNM tumour, node, metastasis TPF taxanes combined with PF (cisplatin and fluorouracil) VBM vinblastine, bleomycin, methotrexate

Conflict of interest All members of the Penile Cancer Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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32

Update march 2009

Guidelines on

Testicular Cancer P. Albers (chairman), W. Albrecht, F. Algaba, C. Bokemeyer, G. Cohn-Cedermark, K. Fizazi, A. Horwich, M.P. Laguna

© European Association of Urology 2009

TABLE OF CONTENTS

page

1

BACKGROUND 1.1 Methods

4 4

2

PATHOLOGICAL CLASSIFICATION

5

3

DIAGNOSIS 3.1 Clinical examination 3.2 Imaging of the testis 3.3 Serum tumour markers at diagnosis 3.4 Inguinal exploration and orchidectomy 3.5 Organ-sparing surgery 3.6 Pathological examination of the testis 3.7 Diagnosis and treatment of carcinoma in situ (Tin) 3.8 Screening

5 5 5 6 6 6 6 7 7

4

STAGING 4.1 Diagnostic tools 4.2 Serum tumour markers: post-orchidectomy half-life kinetics 4.3 Retroperitoneal, mediastinal and supraclavicular lymph nodes and viscera 4.4 Staging and prognostic classifications 4.5 Prognostic risk factors

7 7 8 8 9 11

5

IMPACT ON FERTILITY AND FERTILITY-ASSOCIATED ISSUES

11

6

GUIDELINES ON DIAGNOSIS AND STAGING OF TESTICULAR CANCER

12

7 TREATMENT: STAGE I GERM CELL TUMOURS 7.1 Stage I seminoma 7.1.1 Surveillance 7.1.2 Adjuvant chemotherapy 7.1.3 Adjuvant radiotherapy 7.1.4 Retroperitoneal lymph node dissection (RPLND) 7.1.5 Risk-adapted treatment 7.2 Guidelines for the treatment of seminoma stage I 7.3 NSGCT stage I 7.3.1 Surveillance 7.3.2 Primary chemotherapy 7.3.3 Risk-adapted treatment 7.3.4 Retroperitoneal lymph node dissection 7.4 CS1S with (persistently) elevated serum tumour markers 7.5 Guidelines for the treatment of NSGCT stage I

12 12 12 12 12 13 13 13 13 13 14 14 14 15 15

8 TREATMENT: METASTATIC GERM CELL TUMOURS 8.1 Low-volume metastatic disease (stage IIA/B) 8.1.1 Stage IIA/B seminoma 8.1.2 Stage IIA/B non-seminoma 8.2 Advanced metastatic disease 8.2.1 Primary chemotherapy 8.3 Restaging and further treatment 8.3.1 Restaging 8.3.2 Residual tumour resection 8.3.3 Consolidation chemotherapy after secondary surgery 8.4 Systemic salvage treatment for relapse or refractory disease 8.4.1 Seminoma 8.4.2 Non-seminoma 8.4.3 Late relapse (≥ 2 years after end of first-line treatment) 8.5 Salvage surgery 8.6 Treatment of brain metastases

17 17 17 17 18 18 19 19 19 19 20 20 20 21 21 21

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8.7

Guidelines for the treatment of metastatic germ cell tumours

21

9 FOLLOW-UP AFTER CURATIVE THERAPY 9.1 General considerations 9.2 Follow-up: stage I non-seminoma 9.2.1 Follow-up investigations during surveillance 9.2.2 Follow-up after nerve-sparing RPLND 9.2.3 Follow-up after adjuvant chemotherapy 9.3 Follow-up: stage I seminoma 9.3.1 Follow-up after radiotherapy 9.3.2 Follow-up during surveillance 9.3.3 Follow-up after adjuvant chemotherapy 9.4 Follow-up: stage II and advanced (metastatic) disease

22 22 22 22 23 23 23 24 24 24 24

10 TESTICULAR STROMAL TUMOURS 10.1 Background 10.2 Methods 10.3 Classification 10.4 Leydig cell tumours 10.4.1 Epidemiology 10.4.2 Pathology of Leydig cell tumours 10.4.3 Diagnosis 10.4.4 Treatment 10.4.5 Follow-up 10.5 Sertoli cell tumour 10.5.1 Epidemiology 10.5.2 Pathology of Sertoli cell tumours 10.5.2.1 Classification 10.5.3 Diagnosis 10.5.4 Treatment 10.5.5 Follow-up 10.6 Granulosa cell tumour 10.7 Thecoma/fibroma group of tumours 10.8 Other sex cord/gonadal stromal tumours 10.9 Tumours containing germ cell and sex cord/gonadal stromal (gonadoblastoma) 10.10 Miscellaneous tumours of the testis 10.10.1 Tumours of ovarian epithelial types 10.10.2 Tumours of the collecting ducts and rete testis 10.10.3 Tumours (benign and malignant) of non-specific stroma

25 25 25 25 26 26 26 26 26 27 27 27 27 27 27 28 28 28 28 28 28 28 28 28 29

11.

REFERENCES 11.1 Germ cell tumours 11.2 Non-germ cell tumours

29 29 48

12.

ABBREVIATIONS USED IN THE TEXT

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3

1. Background Testicular cancer represents between 1% and 1.5% of male neoplasms and 5% of urological tumours in general, with 3-6 new cases occurring per 100,000 males/per year in Western society (1, 2). An increase in the incidence of testicular cancer was detected during the 1970s and 1980s, particularly in Northern European countries, and there is a clear trend towards an increased testicular cancer incidence in the last 30 years in the majority of the industrialised countries in North America, Europe and Oceania, although surprising differences in incidence rates are seen between neighbouring countries (3). Data from the Surveillance Epidemiology and End Results Program during the years 1973 to 1998 show a continuing increased risk among Caucasian men in the USA only for seminoma (4). Only 1-2% of cases are bilateral at diagnosis. The histological type varies, although there is a clear predominance (90-95%) of germ cell tumours (1). Peak incidence is in the third decade of life for nonseminoma, and in the fourth decade for pure seminoma. Familial clustering has been observed, particularly among siblings (5). Genetic changes have been described in patients with testicular cancer. A specific genetic marker (an isochromosome of the short arm of chromosome 12 – i(12p) – has been described in all histological types of germ cell tumours (5). Intratubular germ cell neoplasia (testicular intraepithelial neoplasia, Tin) shows the same chromosomal changes, and alterations in the p53 locus have been found in 66% of cases of testicular Tin (6). A deregulation in the pluripotent programme of fetal germ cells (identified by specific markers such as M2A, C-KIT and OCT4/NANOG) is probably responsible for the development of Tin and germ cell neoplasia. There is overlap in the development to seminoma and embryonal carcinoma as shown by genome-wide expression analysis and detection of alpha-fetoprotein (AFP) mRNA in some atypical seminoma (7, 8). Epidemiological risk factors for the development of testicular tumours are: a history of cryptorchidism or undescended testis, Klinefelter’s syndrome, familial history of testicular tumours among first-grade relatives (father/brothers), the presence of a contralateral tumour or Tin, and infertility (9-14). Tallness was associated with a risk of germ cell cancer, although further confirmation is needed (15). Testicular tumours show excellent cure rates. The main factors contributing to this are: careful staging at the time of diagnosis; adequate early treatment based on chemotherapeutic combinations, with or without radiotherapy and surgery; and very strict follow-up and salvage therapies. In the past decade, a decrease in the mean time delay to diagnosis and treatment has been observed (16). In the treatment of testicular cancer, the choice of centre where this treatment is going to be administered is of utmost importance. Although early stages can be successfully treated in a non-reference centre, the relapse rate is higher (17). In poor prognosis non-seminomatous germ cell tumours, it has been shown that overall survival within a clinical trial depended on the number of patients treated at the participating centre (worse < 5 patients enrolled) (18).

1.1

Methods

These guidelines represent implementation of previously published texts: the latest EAU guidelines were formally published as a review paper in 2005 (19) and as an EAU guideline, which was distributed among EAU members, in March 2006. As in 2006, this edition contains a separate chapter on testicular stromal tumours. A multidisciplinary team of urologists, medical oncologists, radiotherapists and a pathologist were involved in producing this text, which is based on a non-structured review of the literature through to October 2007 in the case of both the germ cell tumour and non-germ cell parts. Also, data from meta-analysis studies, Cochrane evidence, and the recommendations of the European Germ Cell Cancer Collaborative Group Meeting in Amsterdam in November 2006, as well as other available guidelines, have been included (20-27). Whenever possible, references have been labelled according to the principles of evidence-based medicine (EBM) (28). The nature of the recommendations in these guidelines is labelled according to the level of evidence (28).

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2. PATHOLOGICAL CLASSIFICATION The recommended pathological classification (modified from the 2004 version of the World Health Organization [WHO] guidance) is shown below (29). 1. Germ cell tumours • Intratubular germ cell neoplasia • Seminoma (including cases with syncytiotrophoblastic cells) • Spermatocytic seminoma (mention if there is sarcomatous component) • Embryonal carcinoma • Yolk sac tumour • Choriocarcinoma • Teratoma (mature, immature, with malignant component) • Tumours with more than one histological type (specify percentage of individual components). 2. Sex cord/gonadal stromal tumours • Leydig cell tumour • Malignant Leydig cell tumour • Sertoli cell tumour - lipid-rich variant - sclerosing - large cell calcifying • Malignant Sertoli cell tumour • Granulosa cell tumour - adult type - juvenile type • Thecoma/fibroma group of tumours • Other sex cord/gonadal stromal tumours - incompletely differentiated - mixed • Tumours containing germ cell and sex cord/gonadal stromal (gonadoblastoma). 3. Miscellaneous non-specific stromal tumours • Ovarian epithelial tumours • Tumours of the collecting ducts and rete testis • Tumours (benign and malignant) of non-specific stroma

3. DIAGNOSIS 3.1

Clinical examination

Testicular cancer generally affects young men in the third or fourth decade of life. It normally appears as a painless, unilateral mass in the scrotum or the casual finding of an intrascrotal mass (30). In approximately 20% of cases, the first symptom is scrotal pain, and up to 27% of patients with testicular cancer may have local pain (1). Occasionally, trauma to the scrotum may reveal the presence of a testicular mass. Gynaecomastia appears in 7% of cases and is more common in non-seminomatous tumours. Back and flank pain are present in about 11% of cases (16). Reduction in testis size can precede a testicular tumour (31). In about 10% of cases, a testicular tumour can mimic an orchioepididymitis, with consequent delay of the correct diagnosis (1, 2). Ultrasound must be performed in any doubtful case. Physical examination reveals the features of the mass and must always be carried out in conjunction with a general examination in order to find possible (supraclavicular) distant metastases, a palpable abdominal mass or gynaecomastia. A correct diagnosis must be established in all patients with an intrascrotal mass (32).

3.2

Imaging of the testis

Currently, diagnostic ultrasound serves to confirm the presence of a testicular mass and to explore the

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5

contralateral testis. Its sensitivity in detecting a testicular tumour is almost 100%, and it has an important role in determining whether a mass is intra- or extratesticular (33). Ultrasound is an inexpensive test, but it is unnecessary when the presence of a testicular tumour is clinically evident (34). Ultrasound of the testis has to be performed in young men without a palpable testicular mass who have retroperitoneal or visceral masses or elevated serum human chorionic gonadotrophin (hCG) or AFP (35-38). Ultrasound is recommended in the follow-up of the contralateral testis in the follow-up of patients at risk (39). Magnetic resonance imaging (MRI) offers higher sensitivity and specificity than ultrasound for diagnosing tumours (40-42) and may be able to differentiate seminomatous from non-seminomatous tumours. MRI of the scrotum offers a sensitivity of 100% and a specificity of 95-100% (43), but its high cost does not justify its use for diagnosis.

3.3

Serum tumour markers at diagnosis

Serum tumour markers are prognostic factors and contribute to diagnosis and staging (44). The following markers should be determined: • AFP (produced by yolk sac cells) • hCG (expression of trophoblasts). Lactate dehydrogenase (LDH) (marker of tissue destruction) is recommended for patients with metastatic disease. Globally, there is an increase in these markers in 51% of cases of testicular cancer (16, 30). Alphafetoprotein increases in 50-70% of patients with non-seminomatous germ cell tumour (NSGCT), and a rise in hCG is seen in 40-60% of patients with NSGCT. About 90% of non-seminomatous tumours present with a rise in one or two of the markers. Up to 30% of seminomas can present or develop an elevated hCG level during the course of the disease (45, 46). LDH is a less specific marker, and its concentration is proportional to tumour volume. Its level may be elevated in 80% of patients with advanced testicular cancer (45). It should be noted that negative marker levels do not exclude the diagnosis of a germ cell tumour. Other markers studied include placental alkaline phosphatase (PLAP), which may be of value in monitoring patients with pure seminoma. Cytogenetic and molecular markers are available in specific centres, but at present only contribute to research studies. Measurement of serum AFP, hCG and LDH (in advanced tumours) is mandatory, while that of PLAP is optional.

3.4

Inguinal exploration and orchidectomy

Every patient with a suspected testicular mass must undergo inguinal exploration with exteriorisation of the testis within its tunics. Immediate orchidectomy with division of the spermatic cord at the internal inguinal ring must be performed if a tumour is found. If the diagnosis is not clear, a testicular biopsy is taken for frozen section histological examination. In cases of disseminated disease and life-threatening metastases, it is current practice to start with up-front chemotherapy, and orchidectomy may be delayed until clinical stabilisation has occurred.

3.5

Organ-sparing surgery

Although organ-sparing surgery is not indicated in the presence of non-tumoural contralateral testis, it can be attempted in special cases with all the necessary precautions. In synchronous bilateral testicular tumours, metachronous contralateral tumours, or in a tumour in a solitary testis with normal pre-operative testosterone levels, organ preserving surgery can be performed when the tumour volume is less than 30% of the testicular volume and surgical rules are respected. In those cases, the rate of associated Tin is high (at least up to 82%), and all patients must be treated with adjuvant radiotherapy (20 Gy) at some point (47). Infertility will result after radiotherapy and the risk of long-term Leydig cell insufficiency after radiotherapy of a solitary testis is increased (48). Radiation treatment may be delayed in fertile patients who wish to father children. The option must be carefully discussed with the patient and surgery performed in a centre with experience (49, 50).

3.6 Pathological examination of the testis Mandatory pathological requirements: • Macroscopic features: side, testis size, maximum tumour size and macroscopic features of epididymis, spermatic cord and tunica vaginalis.

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•

• • •

 ampling: a 1 cm2 section for every centimetre of maximum tumour diameter, including normal S macroscopic parenchyma (if present), albuginea and epididymis, with selection of suspected areas. At least one proximal and one distal section of spermatic cord plus any suspected area. Microscopic features and diagnosis: histological type (specify individual components and estimate amount as percentage) according to WHO 2004 (29): - presence or absence of peri-tumoural venous and/or lymphatic invasion - presence or absence of albuginea, tunica vaginalis, rete testis, epididymis or spermatic cord invasion - presence or absence of intratubular germ cell neoplasia (Tin) in non-tumour parenchyma intratubular germ cell neoplasia pT category according to Tumour Node Metastasis (TNM) 2002 Immunohistochemical studies: in seminoma and mixed germ cell tumour, AFP and hCG.

Advisable immunohistochemical markers, in cases of doubt, are: • in seminoma: cytokeratins (CAM 5.2), PLAP, c-kit • in intratubular germ cell neoplasia: PLAP, c-kit • other advisable markers: chromogranine A (Cg A), Ki-1 (MIB-1).

3.7 Diagnosis and treatment of carcinoma in situ (Tin) Contralateral biopsy has been advocated to rule out the presence of Tin (51). Although this is routine policy in some countries, the low incidence of Tin and contralateral metachronous testicular tumours (up to 9% and approximately 2.5%, respectively) (52, 53), the morbidity of Tin treatment, and the fact that most of these metachronous tumours are at a low stage at presentation make it controversial to recommend a systematic contralateral biopsy in all patients (54-56). It is still difficult to reach a consensus on whether the existence of contralateral Tin must be identified in all cases. However, biopsy of the contralateral testis should be offered to high-risk patients for contralateral Tin with a testicular volume of less than 12 mL, a history of cryptorchidism, or poor spermatogenesis (Johnson Score 1-3). A contralateral biopsy is not necessary for patients older than 40 years (57-62). A double biopsy is preferred to increase sensitivity. Once Tin is diagnosed, local radiotherapy (20 Gy in single fractions of 2 Gy) is the treatment of choice. Because this may produce infertility, the patient must be carefully counselled before treatment commences (54, 63). In addition to infertility, Leydig cell function and testosterone production may be impaired long-term following radiotherapy for Tin (49). Radiation treatment may be delayed in fertile patients who wish to father children (59).

3.8

Screening

Although there are no surveys proving the advantages of screening programmes, it has been demonstrated that stage and prognosis are directly related to early diagnosis. In the presence of clinical risk factors, selfphysical examination by the affected individual is advisable.

4. STAGING To determine the presence of metastatic or occult disease, the half-life kinetics of serum tumour markers must be assessed, the nodal pathway must be screened, and the presence of visceral metastases ruled out. Consequently, it is mandatory to assess: • the post-orchidectomy half-life kinetics of serum tumour markers • the status of retroperitoneal and supraclavicular lymph nodes, and the liver • the presence or absence of mediastinal nodal involvement and lung metastases • the status of brain and bone, if any suspicious symptoms are present.

4.1 Diagnostic tools The currently available tests include: • serial blood sampling • chest X-ray • abdominopelvic and thoracic computed tomography (CT) scan • abdominal and retroperitoneal ultrasound • MRI

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• •

positron emission tomography (PET) scan other specific examinations, depending on clinical suspicion.

4.2

Serum tumour markers: post-orchidectomy half-life kinetics

The mean serum half-life of AFP and hCG is 5-7 days and 2-3 days, respectively (45). Tumour markers have to be re-evaluated after orchidectomy to determine half-life kinetics. Marker decline in patients with clinical stage I disease should be assessed until normalisation has occurred. Post-orchidectomy markers are important to classify the patient according to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification. The persistence of elevated serum tumour markers after orchidectomy might indicate the presence of metastatic disease (macro- or microscopically), while the normalisation of marker levels after orchidectomy does not rule out the presence of tumour metastases. During chemotherapy, the markers should decline; persistence has an adverse prognostic value.

4.3 Retroperitoneal, mediastinal and supraclavicular lymph nodes and viscera Retroperitoneal and mediastinal lymph nodes are best assessed by means of a CT scan. The supraclavicular nodes are best assessed by physical examination. Abdominopelvic CT scanning offers a sensitivity of 70-80% in determining the state of the retroperitoneal nodes. Its accuracy depends on the size of the nodes; sensitivity and the negative predictive value increase using a 3 mm threshold to define metastatic nodes in the landing zones (62). Those figures decrease slightly in stages I and II (63, 64), with a rate of understaging of 25-30% (65). New generations of CT scans do not seem to improve the sensitivity. Magnetic resonance imaging produces similar results to CT scanning in the detection of retroperitoneal nodal enlargement (66). Again, the main objections to its routine use are its high cost and limited access to it. Nevertheless, MRI can be helpful when abdominopelvic CT or ultrasound are inconclusive (66), when CT scan is contraindicated because of allergy to contrast media, or when the physician or the patient are concerned about radiation dose. MRI is an optional test, and there are currently no indications for its systematic use in the staging of testicular cancer. Chest X-ray is the routine thorax examination. An anteroposterior and lateral chest X-ray could be considered as the only thoracic examination in seminoma when retroperitoneal and pelvic CT scans are negative (67). A chest CT scan is the most sensitive way to evaluate the thorax and mediastinal nodes. This exploration has to be recommended in patients with NSGCT because up to 10% of cases can present with small subpleural nodes that are not visible radiologically (1). The CT scan has high sensitivity but low specificity (66). A chest CT is mandatory in all patients with NSGCT, and in those patients with seminoma and a positive abdominopelvic CT scan (67). There is not enough evidence to support the use of the fluorodeoxyglucose-PET (FDG-PET) scan in the staging of testis cancer. It is recommended in the follow-up of patients with seminoma with any residual mass at least 4 weeks after chemotherapy in order to decide on watchful waiting or active treatment (68-71). Other examinations, such as brain or spinal CT, bone scan or liver ultrasound, should be performed if there is suspicion of metastases to these organs. A CT or MRI scan of the skull is advisable in patients with NSGCT and widespread lung metastases. Table I shows the recommended test at staging. Table 1: Recommended tests for staging at diagnosis Test Recommendation grade B Recommendation grade C Serum tumour markers Alpha-fetoprotein hCG LDH (for advanced tumours) Abdominopelvic CT scan All patients Slim adolescent Chest X-ray Seminoma* Chest CT scan NSGCT Testis ultrasound Clinical suspicion and normal scrotum at palpation MRI When abdominal CT is inconclusive All cases PET scan† Follow-up residual masses in seminoma Other If clinical suspicion

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Recommended further investigations Fertility investigations Total testosterone, LH, FSH, semen analysis, (should be offered) sperm banking hCG = human chorionic gonadotrophin; LDH = lactate dehydrogenase; CT = computed tomography; NSGCT = non-seminomatous germ cell tumour; MRI = magnetic resonance imaging; PET = positron emission tomography; LH = luteinising hormone; FSH = follicle-stimulating hormone. *If negative, abdominopelvic CT scan. †There is currently no indication for PET scan at diagnosis.

4.4

Staging and prognostic classifications

The staging system recommended in these guidelines is the 2002 TNM of the International Union Against Cancer (UICC) (Table 2) (72). This includes: • determination of the anatomical extent of disease • assessment of serum tumour markers, including nadir values of hCG, AFP and LDH after orchidectomy (S category) • clear definition of regional nodes • some N-category modifications related to node size. Table 2: TNM classification for testicular cancer (UICC, 2002, 6th edn [72]) pT Primary tumour1 pTX Primary tumour cannot be assessed (see note 1) pT0 No evidence of primary tumour (e.g. histological scar in testis) pTis Intratubular germ cell neoplasia (carcinoma in situ) pT1 Tumour limited to testis and epididymis without vascular/lymphatic invasion: tumour may invade tunica albuginea but not tunica vaginalis pT2 Tumour limited to testis and epididymis with vascular/lymphatic invasion, or tumour extending through tunica albuginea with involvement of tunica vaginalis pT3 Tumour invades spermatic cord with or without vascular/lymphatic invasion pT4 Tumour invades scrotum with or without vascular/lymphatic invasion N Regional lymph nodes clinical NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis with a lymph node mass 2 cm or less in greatest dimension or multiple lymph nodes, none more than 2 cm in greatest dimension N2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, any one mass more than 2 cm but not more than 5 cm in greatest dimension N3 Metastasis with a lymph node mass more than 5 cm in greatest dimension pN Pathological pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Metastasis with a lymph node mass 2 cm or less in greatest dimension and 5 or fewer positive nodes, none more than 2 cm in greatest dimension pN2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence or extranodal extension of tumour pN3 Metastasis with a lymph node mass more than 5 cm in greatest dimension M Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Non-regional lymph node(s) or lung M1b Other sites S Serum tumour markers Sx Serum marker studies not available or not performed S0 Serum marker study levels within normal limits

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S1 S2 S3

LDH (U/l) < 1.5 x N and 1.5-10 x N or > 10 x N or

hCG (mIU/ml) < 5,000 and 5,000-50,000 or > 50,000 or

AFP (ng/ml) < 1,000 1,000-10,000 > 10,000

N indicates the upper limit of normal for the LDH assay. LDH, lactate dehydrogenase; hCG = human chorionic gonadotrophin; AFP = alpha-fetoprotein. 1Except for pTis and pT4, where radical orchidectomy is not always necessary for classification purposes, the extent of the primary tumour is classified after radical orchidectomy; see pT. In other circumstances, TX is used if no radical orchidectomy has been performed. According to the 2002 TNM classification, stage I testicular cancer includes the following substages: Stage IA Stage IB Stage IS

pT1 pT2, pT3 or pT4 Any patient/TX

N0 N0 N0

M0 M0 M0

S0 S0 S1-3

Stage IA patients have primary tumours limited to the testis and epididymis, with no evidence of microscopic vascular or lymphatic invasion by tumour cells on microscopy, no sign of metastases on clinical examination or imaging, and post-orchidectomy serum tumour marker levels within normal limits. Marker decline in patients with clinical stage I disease should be assessed until normalisation. Stage IB patients have a more locally invasive primary tumour, but no sign of metastatic disease. Stage IS patients have persistently elevated (and usually increasing) serum tumour marker levels after orchidectomy, which is evidence of subclinical metastatic disease (or possibly a second germ cell tumour in the remaining testis). If serum tumour marker levels are declining according to the expected half-life decay after orchidectomy, the patient is usually followed up until normalisation. In large population-based patient series, 75-80% of seminoma patients, and about 55% of patients with NSGCT cancer have stage I disease at diagnosis (73, 74). True stage IS (persistently elevated or increasing serum marker levels after orchidectomy) is found in about 5% of non-seminoma patients. If a staging retroperitoneal lymph node dissection (RPLND) was to be performed in stage IS patients, nearly all patients would be found to have pathological stage II disease (pN+) (1, 2, 5, 73). In 1997, the IGCCCG defined a prognostic factor-based staging system for metastatic testis tumour based on identification of some clinical independent adverse factors. This staging system has been incorporated into the TNM Classification and uses histology, location of the primary tumour, location of metastases and prechemotherapy marker levels in serum as prognostic factors to categorise patients into ‘good’, ‘intermediate’ or ‘poor’ prognosis (Table 3) (75). Table 3: Prognostic-based staging system for metastatic germ cell cancer (International Germ Cell Cancer Collaborative Group). Good-prognosis group Non-seminoma (56% of cases) 5-year PFS 89% 5-year survival 92% Seminoma (90% of cases) 5-year PFS 82% 5-year survival 86% Intermediate prognosis group Non-seminoma (28% of cases) 5 years PFS 75% 5-year survival 80%

10

All of the following criteria: • Testis/retroperitoneal primary • No non-pulmonary visceral metastases • AFP < 1,000 ng/mL • hCG < 5,000 IU/L (1,000 ng/mL) • LDH < 1.5 x ULN All of the following criteria: • Any primary site • No non-pulmonary visceral metastases • Normal AFP • Any hCG • Any LDH All of the following criteria: • Testis/retroperitoneal primary • No non-pulmonary visceral metastases • AFP > 1,000 and < 10,000 ng/mL or

Limited update march 2009

• hCG > 5,000 and < 50,000 IU/L or • LDH > 1.5 and < 10 x ULN Seminoma (10% of cases) Any of the following criteria: 5-year PFS 67% • Any primary site 5-year survival 72% • Non-pulmonary visceral metastases • Normal AFP • Any hCG • Any LDH Poor prognosis group Non-seminoma (16% of cases) Any of the following criteria: 5-year PFS 41% • Mediastinal primary 5-year survival 48% • Non-pulmonary visceral metastases • AFP > 10,000 ng/mL or • hCG > 50,000 IU/L (10,000 ng/mL) or • LDH > 10 x ULN Seminoma No patients classified as poor prognosis PFS = progression-free survival; AFP = alpha-fetoprotein; hCG = human chorionic gonadotrophin; LDH = lactate dehydrogenase.

4.5 Prognostic risk factors For seminoma stage I, tumour size (> 4 cm) and invasion of the rete testis have been identified as the most important predictors for relapse in multivariate analysis (20). For non-seminoma stage I, vascular invasion of the primary tumour in blood or lymphatic vessels is the most important predictor of occult metastatic disease. The proliferation rate, as well as the percentage of embryonal carcinoma, are additional predictors that improve upon the positive and negative predictive value of vascular invasion (76, 77). The significant prognostic pathological risk factors for stage I and clinical risk factors for metastatic disease are listed in Table 4. Table 4: Prognostic factors for occult metastatic disease in testicular cancer For seminoma Pathological (for stage I) Histopathological type • Tumour size (> 4 cm) • Invasion of the rete testis Clinical (for metastatic disease) • Primary location • Elevation of tumour marker levels • Presence of non-pulmonary visceral metastasis

For non-seminoma • Vascular/lymphatic in or peri-tumoural invasion • Proliferation rate > 70% • Percentage of embryonal carcinoma > 50%

5. IMPACT ON FERTILITY AND FERTILITY- ASSOCIATED ISSUES Sperm abnormalities are frequently found in patients with testis tumours. Furthermore, chemotherapy and radiation treatment can also impair fertility. In patients in the reproductive age group, pre-treatment fertility assessment (testosterone, luteinising hormone [LH] and FSH levels) should be performed, and semen analysis and cryopreservation should be offered. If cryopreservation is desired, it should be performed before or after orchidectomy, but in any case prior to chemotherapy treatment (48, 78-84). In cases of bilateral orchidectomy or low testosterone levels after treatment of Tin, life-long testosterone supplementation is necessary (85). For more detailed information, the reader is referred to the EAU Male Infertility Guidelines.

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6. GUIDELINES ON DIAGNOSIS AND STAGING OF TESTICULAR CANCER 1. 2.

3.

4.

Testicular ultrasound is mandatory (grade of recommendation: B). Orchidectomy and pathological examination of the testis are necessary to confirm the diagnosis and to define the local extension (pT category) (grade of recommendation: B). In a life-threatening situation due to extensive metastasis, chemotherapy must be started before orchidectomy. Serum determination of tumour markers (AFP, hCG, and LDH in metastatic disease) must be performed before and after orchidectomy for staging and prognostic reasons (grade of recommendation: B). The state of the retroperitoneal, mediastinal and supraclavicular nodes and viscera must be assessed in testicular cancer. In seminoma, a chest CT scan is not necessary if the abdominal nodes are negative (grade of recommendation: B).

7. TREATMENT: STAGE I GERM CELL TUMOURS 7.1

Stage I seminoma

After modern staging procedures, about 15-20% of stage I seminoma patients have subclinical metastatic disease, usually in the retroperitoneum, and will relapse after orchidectomy alone (86). 7.1.1 Surveillance Several prospective non-randomised studies of surveillance have been conducted during the past decade, the largest study coming from Canada with > 1500 patients (87). Previous meta-analysis from four studies showed an actuarial 5 years’ relapse-free rate of 82.3%. The Princess Margaret Hospital series (n = 1559) showed an overall relapse rate in unselected patients of 16.8%. The actuarial relapse rate is in the order of 15-20% at 5 years, and most of the relapses are first detected in infra-diaphragmatic lymph nodes (86, 88-90). Chemotherapy with dosing according to IGCCCG classification is a possible treatment for seminoma relapse under surveillance. However, 70% of patients with relapse are suitable for treatment with radiotherapy alone because of small volume disease at the time of recurrence. Only about 20% of these patients relapse again after salvage radiotherapy and then need salvage chemotherapy. The overall cancer-specific survival rate reported with surveillance performed by experienced centres is 97-100% for seminoma stage I (89, 90). The main drawback of surveillance is the need for more intensive follow-up, especially with repeated imaging examinations of the retroperitoneal lymph nodes, for at least 5 years after orchidectomy. This compares with the very low risk of subdiaphragmatic relapse after adjuvant radiotherapy. There is a small but clinically significant risk of relapse more than 5 years after orchidectomy for stage I seminoma which supports the need for long term surveillance (88). Cost analyses of surveillance compared with radiotherapy indicate that it is more expensive (91), but estimates vary, mainly depending on the follow-up schedules (92, 93). 7.1.2 Adjuvant chemotherapy A joint trial by the Medical Research Council (MRC) and the European Organisation for Research and Treatment of Cancer (EORTC) (MRC TE 19 trial), which compared one cycle of carboplatin (area under curve [AUC] 7) with adjuvant radiotherapy, did not show a significant difference with regard to recurrence rate, time to recurrence and survival after a median follow-up of 4 years (94). Therefore, adjuvant carboplatin therapy is an alternative to radiotherapy or surveillance in stage I seminoma (89, 90, 94). Two courses of adjuvant carboplatin seem to further reduce the relapse rate to the order of 1-3% (95, 96), but further experience and long-term observations are needed. 7.1.3 Adjuvant radiotherapy Seminoma cells are extremely radiosensitive. Adjuvant radiotherapy to a para-aortic (PA) field or to a hockeystick field (para-aortic and ipsilateral iliac nodes), with moderate doses (total 20-24 Gy), will reduce the relapse rate to only 1-3% (97-100). After modern radiotherapy, nearly all relapses will first occur outside the irradiated

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field (supradiaphragmatic lymph nodes or in the lungs) (97, 100). Based on the results of a large randomised MRC trial, Fossa et al. (97, 98) recommended radiotherapy to a PA field as standard treatment for patients with testicular seminoma stage I, T1-T3 and with undisturbed lymphatic drainage. Acute toxicity was reduced and the sperm count within the first 18 months was significantly higher after PA irradiation than after irradiation of the traditional dog-leg field. On the other hand, the relapse rate in the iliac lymph nodes was about 2% (all of them on the right side) after PA and 0% after dog-leg irradiation. Another possible site of failure is in the left renal hilum. PA irradiation should be tailored according to the site of the primary tumour. Adjuvant irradiation of supradiaphragmatic lymph nodes is not indicated in seminoma stage I. With regard to the irradiation dose, the MRC recently finished a large randomised trial of 20 Gy versus 30 Gy PA radiation in stage I seminoma that showed equivalence for both doses in terms of recurrence rates (98). The rate of severe radiation-induced long-term toxicity is less than 2%. Moderate chronic gastrointestinal (GI) sideeffects are seen in about 5% of patients, and moderate acute GI toxicity in about 60% (97). The main concern surrounding adjuvant radiotherapy is the potentially increased risk of radiation-induced secondary non-germcell malignancies (101-104). A scrotal shield can be of benefit during adjuvant radiotherapy in order to prevent scattered radiation toxicity in the contralateral testis (104). It is currently difficult to evaluate the long-term risks after adjuvant radiotherapy for stage I seminoma because former treatment procedures included larger fields, higher doses of radiotherapy and/or the use of alkylating chemotherapy. 7.1.4 Retroperitoneal lymph node dissection (RPLND) In a prospective, non-randomised study comparing radiotherapy and RPLND in stage I seminoma, there was a trend towards a higher incidence of retroperitoneal relapses (9.5%) after RPLND as primary treatment. Therefore this policy should not be recommended in stage I seminoma (105). 7.1.5 Risk-adapted treatment Using tumour size > 4 cm and rete testis invasion, patients with seminoma stage I may be subdivided into a low-and high-risk group of occult metastatic disease. Patients with and without both risk factors have a risk of occult disease of 32% and 12%, respectively. These risk factors were introduced by a meta-analysis of retrospective trials (20). A prospective trial based on these risk factors (no risk factors: surveillance; both risk factors: two courses of carboplatin AUC 7) showed the feasibility of a risk-adapted approach. Early data with limited follow-up indicate that patients without either risk factor have a 6.0% risk of relapse at 5 years. Patients at high risk treated with carboplatin experienced a 3.3% relapse rate (106).

7.2 Guidelines for the treatment of seminoma stage I 1. Surveillance (if facilities available and patient compliant) (grade of recommendation: B). 2. Carboplatin-based chemotherapy (one course at AUC 7) can be recommended as an alternative to radiotherapy and surveillance (grade of recommendation: A). 3. Adjuvant radiotherapy to a PA or hockey-stick field, to a total dose of 20 Gy (grade of recommendation: A).

7.3

NSGCT stage I

Up to 30% of NSGCT patients with clinical stage I (CS1) disease have subclinical metastases and will relapse if surveillance alone is applied after orchidectomy. 7.3.1 Surveillance Improvements in clinical staging and follow-up methods, and the availability of effective salvage treatment with cisplatin-based chemotherapy and post-chemotherapy surgery, have led to studies of only close surveillance after orchidectomy in CS1 NSGCT patients. The largest reports of the surveillance strategy indicate a cumulative relapse rate of about 30%, with 80% of relapses occurring during the first 12 months of follow-up, 12% during the second year and 6% during the third year, decreasing to 1% during the fourth and fifth years, and occasionally even later (107-110). About 35% of relapsing patients have normal levels of serum tumour markers at relapse. About 60% of relapses are in the retroperitoneum. Despite very close follow-up, 11% of relapsing patients presented with large-volume recurrent disease. The somewhat lower relapse rates reported from surveillance studies compared with some series of patients staged by RPLND (111) can be explained by the fact that some patients (presumably at risk) are excluded once surveillance is advised. Based on the overall cancer-specific survival data, surveillance within an experienced surveillance programme may be offered to patients with non-risk stratified clinical stage I non-seminoma as long as they are compliant and informed about the expected recurrence rate as well as the salvage treatment (112).

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7.3.2 Primary chemotherapy Several studies involving two courses of chemotherapy with cisplatin, etoposide and bleomycin (PEB) as primary treatment for high-risk patients (having about 50% risk of relapse) have been reported (113-118). In these series, involving more than 200 patients, some with a median follow-up of nearly 8 years (113), a relapse rate of only 2.7% was reported, with very little long-term toxicity. Two cycles of cisplatin-based adjuvant chemotherapy do not seem to adversely affect fertility or sexual activity (119). It is important to be aware of the slow-growing retroperitoneal teratomas after primary chemotherapy and of the risk of late chemoresistant cancer relapse (120). The need for repeated and long-term follow-up with imaging of the retroperitoneum after primary chemotherapy is not yet clear. The results of cost analyses comparing surveillance, RPLND and primary chemotherapy show different results among the reported studies, possibly because of differences in intensity and costs related to follow-up procedures (121). With a low frequency of follow-up CTs (such as has been proven effective for the surveillance strategy in non-seminoma CS1), the costs of follow-up can be considerably reduced (122). 7.3.3 Risk-adapted treatment Risk-adapted treatment is currently based on the risk factor vascular invasion. Stratifying patients with CS1 NSGCT according to their presumed risk of relapse is a rational option, as several studies have reported similar survival rates and a final cure rate close to 100% with all available treatment options using the risk-stratifying approach (113-118, 123-125). Risk-adapted treatment is therefore an equally effective alternative treatment of choice in CS1 NSGCT. Patients with vascular invasion are recommended to undergo adjuvant chemotherapy with two cycles of PEB, and patients without vascular invasion are recommended to undergo surveillance. Only if patients or doctors are not willing to accept the consequent risk-adapted treatment, or if there are circumstances that militate against the risk-adapted treatment option, should the remaining treatments be considered. Thus, the decision about treatment should be based on a thorough discussion with the patients, taking into account the described advantages and disadvantages, as well as the individual situation of the patient and/or the treatment centre. The Swedish-Norwegian Testicular Cancer Project (SWENOTECA) recently showed that in a large population-based study with a risk-adapted approach within a management programme and a median follow-up of 4.7 years, the relapse rate was 3.2% for patients with vascular invasion treated with only one adjuvant PEB (126). 7.3.4 Retroperitoneal lymph node dissection If RPLND is performed, about 30% of patients are found to have retroperitoneal lymph node metastases, which corresponds to pathological stage II (PS2) disease (105, 127, 128). If no retroperitoneal metastases are found at RPLND (PS1), approximately 10% of the PS1 patients relapse at distant sites (77, 111, 129-131). The main predictor of relapse in CS1 NSGCT managed by surveillance, for having PS2 disease and for relapse in PS1 after RPLND, is histopathological evidence of vascular invasion by tumour cells in, or near, the primary tumour in the testis (77, 107, 111, 131, 132). The presence of vascular invasion seems to be a very robust parameter, and is clinically usable even without centralised review by an expert panel (123, 131). Vascular invasion was the most predictive of stage in a multifactorial analysis. The absence of vascular invasion has a negative predictive value of 77%, thus allowing for surveillance in low-risk compliant patients (77). Patients without vascular invasion constitute about 50-70% of the CS1 population, and these patients have only a 15-20% risk of relapse on surveillance, compared with a 50% relapse rate in patients with vascular invasion. The risk of relapse for PS1 patients is less than 10% for those without vascular invasion and about 30% for those with vascular invasion (123, 131, 133, 134). If CS1 patients with PS2 are followed up only after RPLND, about 30% relapse, mainly at sites outside the abdomen and pelvis. The risk of relapse depends upon the amount of retroperitoneal disease resected (135137). If two (or more) courses of cisplatin-based chemotherapy are given adjuvant to RPLND in PS2 cases, the relapse rate is reduced to less than 2%, including teratoma relapse (111, 132, 138). The risk of retroperitoneal relapse after a properly performed nerve-sparing RPLND is very low (less than 2%), as is the risk of ejaculatory disturbance or other significant side-effects (132, 135, 136). The follow-up after RPLND is much simpler and less costly than that carried out during post-orchidectomy surveillance because of the reduced need for abdominal CT scans (132). A laparoscopic RPLND may become

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a good alternative to an open staging RPLND, but cannot currently be recommended as a standard diagnostic tool (139-142). In a randomised comparison of RPLND with one course of PEB chemotherapy, adjuvant chemotherapy significantly increased the 2-year recurrence-free survival to 99.41% (confidence interval [CI] 95.87%, 99.92%) as opposed to surgery, which had a 2-year recurrence-free survival of 92.37% (CI 87.21%, 95.50%). The difference was 7.04%, CI 2.52%, 11.56%. The hazard ratio to experience a tumour recurrence with surgery as opposed to chemotherapy was 7.937, CI 1.808, 34.48. Therefore, one course of adjuvant PEB is superior to RPLND with regard to recurrence rates in patients unstratified for risk factors (143). In the SWENOTECA data mentioned in section 7.3.3 it was also found that one adjuvant PEB reduced the number of recurrences for 90% for patients, whether vascular invasion was present or not (126).

7.4

CS1S with (persistently) elevated serum tumour markers

Serum tumour markers should be followed closely until levels fall into the reference values according to the expected half-life values for AFP and hCG. If the marker level increases after orchidectomy, the patient has residual disease. If RPLND is performed, up to 87% of these patients have pathologically documented nodes in the retroperitoneum (144). An ultrasound examination of the contralateral testicle must be performed, if this was not done initially. The treatment of true CS1S patients is still controversial. They may be treated with three courses of primary PEB chemotherapy and with follow-up as for CS1B patients (high risk, see below) after primary chemotherapy (145), or by RPLND (121). The presence of vascular invasion may strengthen the indication for primary chemotherapy as most CS1S with vascular invasion will need chemotherapy sooner or later anyway.

7.5 Guidelines for the treatment of NSGCT stage I CS1 risk-adapted treatments based on vascular invasion or surveillance are recommended treatment options (grade of recommendation: B) (Table 5). Table 5: Risk-adapted treatments for CS1 based on vascular invasion or surveillance GR CS1A (pT1, no vascular invasion): low risk 1. If the patient is willing and able to comply with a surveillance policy, long-term (at least B 5 years) close follow-up should be recommended. 2. Adjuvant chemotherapy or nerve-sparing RPLND in low-risk patients remain options for A those not willing to undergo surveillance. If RPLND reveals PN+ (nodal involvement) disease, chemotherapy with two courses of PEB should be considered. CS1B (pT2-pT4): high risk 1. Primary chemotherapy with two courses of PEB should be recommended. B 2. Surveillance or nerve-sparing RPLND in high-risk patients remain options for those not A willing to undergo adjuvant chemotherapy. If pathological stage II is revealed at RPLND, further chemotherapy should be considered. GR = grade of recommendation.

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Figure 1 provides a treatment algorithm for patients with NSGCT stage I. Figure 1: T  reatment algorithm after orchidectomy according to individual risk factors in patients with non-seminoma NSGCT CS1 (22) Non-seminoma CS I

Low risk no vascular invasion

Standard option

Option if conditions against surveillance

High risk Vascular invasion present

Option if conditions against surveillance and chemotherapy

Option if conditions against chemotherapy

Standard option

OR

Surveillance

Adjuvant chemotherapy 2 cycles PEB

Nerve-sparing (NS) RPLND

Adjuvant chemotherapy 2 cycles PEB

NS RPLND

Surveillance

Relapse

Treatment according to the IGCCCCG classification (3-4 cycles PEB [or VIP] followed by resection in case of residual tumour) PEB = cisplatin, etoposide, bleomycin; CS = clinical stage; IGCCCG = International Germ Cell Cancer Collaborative Group; RLNPD = retroperitoneal lymph node dissection; VIP = etoposide, cisplatin, ifosfamide

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8. TREATMENT: METASTATIC GERM CELL TUMOURS The treatment of metastatic germ cell tumours depends on: • the histology of the primary tumour • prognostic groups as defined by the IGCCCG based on 5202 non-seminoma and 660 seminoma cases (Table 3) (146).

8.1

Low-volume metastatic disease (stage IIA/B)

8.1.1 Stage IIA/B seminoma So far, the standard treatment for stage IIA/B seminoma has been radiotherapy. The radiation dose delivered in stage IIA and IIB is approximately 30 Gy and 36 Gy, respectively. The standard radiation field compared with stage I will be extended from the PA region to the ipsilateral iliac field (the hockey-stick field). In stage IIB, the lateral borders should include the metastatic lymph nodes with a safety margin of 1.0-1.5 cm. This technique yields a relapse-free survival after 6 years for stage IIA and IIB of 95% and 89%, respectively. Overall survival is almost 100% (61, 89). In stage IIB chemotherapy (4 x etoposide and cisplatin [EP] or 3 x PEB in good prognosis) is an alternative to radiotherapy. Although more toxic in the short term, it appears that 4 x EP or 3 x PEB achieve a similar level of disease control (147). Single-agent carboplatin is not an alternative to standard PEB chemotherapy (148). 8.1.2 Stage IIA/B non-seminoma There is a general consensus that treatment should start with initial chemotherapy in all advanced cases of NSGCT except for stage II NSGCT disease without elevated tumour markers, which alternatively can be treated with primary RPLND or surveillance (149, 150). If surveillance is chosen, one follow-up after 6 weeks is indicated to document whether the lesion is growing, remaining stable or shrinking. A shrinking lesion is likely to be of non-malignant origin and should be observed further. A stable or growing lesion indicates either teratoma or an undifferentiated malignant tumour. If the lesion is growing without a corresponding increase in the tumour markers AFP or beta-hCG, RPLND should be performed by an experienced surgeon because of suspected teratoma. Patients with a growing lesion and a concomitant increase in the tumour markers AFP or beta-hCG should not undergo surgery; they require chemotherapy with PEB according to the treatment algorithm for patients with metastatic disease and IGCCCG recommendations (151-153) (Figure 2). There is no proven role for PET scans in this situation. Patients not willing to undergo primary chemotherapy have the option of primary nerve-sparing RPLND with adjuvant chemotherapy (two cycles of PEB) in case of metastatic disease (pII A/B). Primary chemotherapy and primary RPLND are comparable options in terms of outcome but side-effects and toxicity are different, allowing for involvement of the patient in selecting the treatment of choice (154). The cure rate with either approach will be close to 98% (138, 155-160).

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Figure 2: Treatment options in patients with non-seminoma clinical stage IIA (23) IIA Marker +

CS IIA, marker – either

Chemotherapy PEB X 3

Residual tumour

Follow-up after 6 weeks

NS-RPLND

PS I

PS IIA/B

either

Resection

or

Follow-up Independent of vascular invasion

Follow-up

PD

or

2 cycles PEB

+

marker

3 cycles PEB +/resection of residual tumour

NC

Regression

-

NS-RPLND or chemotherapy

NS-RPLND

Further follow-up

PEB = cisplatin, etoposide, bleomycin; NS = nerve-sparing; RPLND = retroperitoneal lymph node dissection; PS = pathological stage; PD = progressive disease; NC = no change.

8.2

Advanced metastatic disease

8.2.1 Primary chemotherapy The primary treatment of choice for advanced disease is three or four cycles of PEB combination chemotherapy (Table 6), depending on the IGCCCG risk classification (see Table 3). This regimen has proven superiority to cisplatin, vinblastine and bleomycin (PVB) in patients with advanced disease (161-163). Data support a 3-day regimen of administering combination chemotherapy to be equally effective as a 5-day regimen, but associated with increased toxicity (164). Table 6: PEB regimen (interval 21 days). Drug Dosage Duration of cycles Cisplatin 20 mg/m2 Days 1-5* Etoposide 100 mg/m2 Days 1-5 Bleomycin 30 mg (bolus) Days 1, 8, 15 *Plus hydration. PEB = cisplatin, etoposide, bleomycin For patients with a ‘good prognosis’, according to the IGCCCG Classification (146), standard treatment consists of three cycles of PEB or, in cases where bleomycin is contraindicated, four cycles of EP (146,163167). Therapy should be given without reduction of the doses at 21-day intervals; delaying the following chemotherapy cycle is justified only in cases of fever with granulocytopenia < 1000/mm3 or thrombocytopenia < 100,000/IU. There is no indication for prophylactic application of haematopoietic growth factors such as, for example, granulocyte colony-stimulating factor (G-CSF). However, if infectious complications have occurred during chemotherapy, prophylactic administration of G-CSF is recommended for the following cycles (165, 168). The ‘intermediate prognosis’ group in the IGCCCG has been defined as patients with a 5- year survival rate of about 80%. The available data support four cycles of PEB as standard treatment (146, 169). Due to the generally less favourable prognosis of patients in this group compared with those with a ‘good prognosis’, they may be treated in prospective trials such as, for example, the EORTC Genitourinary Tract Cancer Cooperative Group trial with PEB vs PEB + paclitaxel (169).

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For patients with a ‘poor prognosis’, standard treatment consists of four cycles of PEB. Four cycles of cisplatin, etoposide and ifosfamide (PEI) have the same effect, but are more toxic (170, 171). The 5-year progression-free survival is between 45% and 50%. A randomised study has shown no advantage in high-dose chemotherapy for the overall group of ‘poor prognosis’ patients. However, patients with a slow marker decline may represent a prognostically inferior subgroup (172). Since a matched-pair analysis resulted in a better survival rate (173175), poor prognosis patients should still be treated in ongoing prospective randomised trials, investigating the value of high-dose chemotherapy. Patients meeting ‘poor-prognosis’ criteria should therefore be transferred to a reference centre. There are no general recommendations for treatment modifications for patients with a poor general condition (Karnofsky < 50%), extended liver infiltration (> 50%), or extended pulmonary infiltration.

8.3 Restaging and further treatment 8.3.1 Restaging Restaging is performed by imaging investigations and re-evaluation of tumour markers. At marker decline and stable or regressive tumour manifestation, chemotherapy will be completed (three or four cycles, depending on the initial stage) (146, 176, 177). In the case of marker decline but growing metastases, resection of the tumour is obligatory after termination of induction therapy, other than in an emergency, according to local tumour growth (178). Only with documented marker growth after two courses of chemotherapy is an early crossover of therapy indicated. These patients are usually candidates for new drugs trials (173, 179). Patients with a low-level marker plateau post-treatment should be observed to see whether complete normalisation occurs. Salvage chemotherapy is indicated for documented marker rise only (180, 181). 8.3.2 Residual tumour resection A residual mass of seminoma should not be resected, irrespective of the size, but controlled by imaging investigations and tumour markers (182-188). FDG-PET has a high prognostic value in patients with residual masses after treatment of seminoma. In patients with residuals of > 3 cm, FDG-PET should be performed in order to gain more information on the viability of these residuals. In patients with residuals of < 3 cm, the use of FDG-PET is optional (189). On progression, salvage therapy is indicated (chemotherapy, salvage surgery, radiotherapy) (190-194). In the case of non-seminoma and complete remission after chemotherapy (no tumour visible), residual tumour resection is not indicated (195-200). In the case of any visible residual mass and marker normalisation, surgical resection is indicated. In patients with lesions < 1 cm, there still is an increased risk of residual cancer or teratoma (201). In persistent retroperitoneal disease, all areas of primary metastatic sites must be completely resected within 4-6 weeks of completion of chemotherapy. If technically feasible, a nerve-sparing procedure should be performed (195, 202-209). Overall, following PEB induction chemotherapy, only 10% of residual masses contain viable cancer, 50% contain mature teratoma, and 40% contain necrotic-fibrotic tissue. As yet, no imaging investigations, including PET or a prognosis model, are able to predict histological differentiation of the non-seminomatous residual tumour. Thus, residual tumour resection is mandatory (196-198, 208-218). The extent of surgery should be based on the risk of relapse of an individual patient and quality of life issues (203). If possible, all the masses should be resected, because a complete resection, in the setting of viable malignant cells, is more critical than recourse to post-operative chemotherapy (219). The histology may diverge in different organ sites (211). Resection of contralateral pulmonary lesions is not mandatory in case pathologic examination of the lesions from the first lung shows complete necrosis (220). 8.3.3 Consolidation chemotherapy after secondary surgery After resection of necrosis or mature teratoma, no further treatment is required. In the case of incomplete resection of vital carcinoma or immature teratoma, two adjuvant cycles of conventionally dosed cisplatinbased chemotherapy may be given in certain subgroups (e.g. ‘poor prognosis’ patients) (219, 221) (caution: cumulative doses of bleomycin). After complete resection of vital tumour < 10% of the total volume, adjuvant chemotherapy is not beneficial for preventing further relapse. The prognosis will definitely deteriorate if vital carcinoma is found in resection specimens after second- and third-line chemotherapy. In this latter situation, post-operative chemotherapy is not indicated and is unable to improve the prognosis (207, 212).

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8.4

Systemic salvage treatment for relapse or refractory disease

8.4.1 Seminoma Cisplatin-based combination salvage chemotherapy will result in long-term remissions for about 50% of the patients who relapse after first-line chemotherapy (222). The regimens of choice are four cycles of PEI/ VIP (etoposide, ifosfamide, cisplatin), four cycles of TIP (paclitaxel, ifosfamide, cisplatin) or four cycles of VeIP (vinblastine, ifosfamide, cisplatin). At present, it is impossible to determine whether conventionally dosed cisplatin-based combination chemotherapy is sufficient as first-salvage treatment or whether early intensification of first-salvage treatment with high-dose chemotherapy should be attempted (223). It is therefore of the utmost importance that these rare patients are treated within clinical trials and at experienced centres. 8.4.2 Non-seminoma Standard salvage treatment after first-line chemotherapy consists of either four cycles of PEI/VIP, four courses of TIP, or four cycles of VeIP, respectively (Table 7). Table 7: Standard PEI/VIP, TIP and VeIP chemotherapy (interval 21 days) Chemotherapy agents Dosage Duration of cycles PEI/VIP Cisplatin* 20 mg/m2 Days 1-5 Etoposide 75-100 mg/m2 Days 1-5 Ifosfamide† 1.2 g/m2 Days 1-5 TIP Paclitaxel Ifosfamide† Cisplatin*

250 mg/m2 1.5 g/ m2 25 mg/m2

24 hour continuous infusion day 1 Days 2-5 Days 2-5

VeIP Vinblastin 0.11 mg/kg Days 1 + 2 Ifosfamide† 1.2 g/m2 Days 1-5 Cisplatin* 20 mg/m2 Days 1-5 PEI/VIP = cisplatin, etoposide, ifosfamide; TIP = paclitaxel, ifosfamide, cisplatin; VelP = vinblastine, ifosfamide, cisplatin. *Plus hydration. †Plus mesna protection. Conventionally dosed salvage chemotherapy may achieve long-term remissions in 15-40% of patients, depending on individual risk factors (181, 224). Prognostic indicators of response to salvage therapy are (181, 224-226): • the location and histology of the primary tumour • the response to first-line treatment • the duration of remissions • the level of AFP and hCG at relapse. Salvage therapy with VeIP is probably not superior to other conventionally dosed cisplatin-based combination regimens (220-222). The use of conventionally dosed combination regimens with more than three agents will increase toxicity without improving the treatment outcome (227). Depending on the presence of adverse prognostic factors, the results of salvage therapy after first-line cisplatin based treatment are unsatisfactory (181, 228). Although some phase II trials indicate a 10% improvement in survival with early intensification of first-salvage treatment using high-dose chemotherapy, others fail to demonstrate such improvement (229-233). High dose chemotherapy offered no advantage as first salvage treatment according to the results of the randomised IT 94 trial in good prognosis patients (234). Patients with good prognostic features should therefore be offered conventional-dose first salvage treatment. Several phase II trials, as well as one retrospectively matched pair-analysis, have shown an improvement in survival in poor-prognosis patients with early intensification of first-salvage treatment using high-dose chemotherapy (225, 235-237) (EBM: 2B).

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Recently, paclitaxel and gemcitabine have proved to be active in the treatment of refractory germ cell tumours; both drugs are synergistic with cisplatin (238-240). However, all of these patients should be entered into ongoing multicentre studies to define the optimal approach to salvage treatment, and should be referred to centres experienced in caring for relapse and/or refractory patients (223). 8.4.3 Late relapse (≥ 2 years after end of first-line treatment) Late relapse is defined as any patient relapsing more than 2 years following chemotherapy for metastatic disease. If technically feasible, all patients with late relapse should undergo immediate radical surgery of all lesions, irrespective of the level of their tumour markers to resect completely all undifferentiated germ-cell tumour, mature teratoma or secondary non-germ cell cancer (120, 241). If the lesions are not completely resectable, biopsies should be obtained for histological assessment, and salvage chemotherapy should be initiated according to the histological results. If the patient responds to salvage chemotherapy, secondary surgery should be conducted whenever possible. In the case of unresectable, but localised, refractory disease, radiotherapy can be considered. To avoid excess mortality, late relapses should be treated only at centres experienced in managing such patients (242).

8.5

Salvage surgery

Residual tumours after salvage chemotherapy should be resected within 4-6 weeks after marker normalisation or when a marker plateau is reached. In the case of marker progression after salvage treatment and a lack of other chemotherapeutic options, resection of residual tumours (‘desperation surgery’) should be considered if complete resection of all tumour seems feasible (about 25% long-term survival may be achieved) (181, 205, 213, 216, 243-252).

8.6

Treatment of brain metastases

Brain metastases occur in the frame of a systemic relapse and rarely as an isolated relapse. The long-term survival of patients presenting with brain metastases at initial diagnosis is poor (30-40%), but even poorer is the development of a brain metastasis as a recurrent disease (the 5-year survival-rate is 2-5%) (253, 254). Chemotherapy is the initial treatment in this case, and some data support the use of consolidation radiotherapy, even in the case of a total response after chemotherapy (255). Surgery can be considered in the case of a persistent solitary metastasis, depending on the systemic state, the histology of the primary tumour and the location of the metastasis.

8.7 Guidelines for the treatment of metastatic germ cell tumours GR 1. L  ow volume NSGCT stage IIA/B with elevated markers should be treated like ‘good or intermediate prognosis’ advanced NSGCT, with three or four cycles of PEB. Stage IIA/B without marker elevation can be treated by RPLND or close surveillance. 2. In metastatic NSGCT (> stage IIC) with a good prognosis, three courses of PEB is the primary A treatment of choice 3. In metastatic NSGCT with an intermediate or poor prognosis, the primary treatment of choice is A four courses of standard PEB 4. S  urgical resection of residual masses after chemotherapy in NSGCT is indicated in the case of B visible residual masses and when serum levels of tumour markers are normal or normalising 5. S  eminoma CSII A/B can initially be treated with radiotherapy. When necessary, chemotherapy can A be used as a salvage treatment with the same schedule as for the corresponding prognostic groups of NSGCT 6. In stage CS IIB, chemotherapy (4 x EP or 3 x PEB, in good prognosis) is an alternative to B radiotherapy. Although more toxic in the short term, it appears that 4 x EP or 3 x PEB achieve a similar level of disease control. 7. S  eminoma stage IIC and higher should be treated with primary chemotherapy according to the A same principles used for NSGCT GR = grade of recommendation

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9. FOLLOW-UP AFTER CURATIVE THERAPY 9.1 General considerations The selection of the test to be performed in follow-up should adhere to the following principles (256). • The interval between examination and duration of testing should be consistent with the time of maximal risk of recurrence and the natural history of the tumour. • The tests should be directed at the most likely sites of recurrence and should have a high predictive value, both positive and negative. • Therapy should be available that will result in cure of the recurrence, significant prolongation of life or palliation of symptoms. The initiation of earlier therapy should improve the outcome compared with therapy given when the patient becomes symptomatic from the tumour recurrence. • The increased risk of second malignancy, both in the primary site and in other tissues that may have been exposed to the same carcinogens, or in which there is epidemiological evidence of increased risk, should also guide the ordering tests. Malignant and non-malignant complications of therapy must also be considered. Such testing should also be performed with a frequency and duration consistent with the nature of the risk, and include only tests with high positive- and negative-predictive values. The following considerations apply in a general manner for the selection of an appropriate schedule and testing in the follow-up of all stages of testis tumour. • Most recurrences after curative therapy will occur in the first 2 years; surveillance should therefore be most frequent and intensive during this time. • Late relapses can occur beyond 5 years, and therefore yearly follow-up for life may be advocated. • After RPLND, relapse in the retroperitoneum is rare, the most likely site of recurrence being the chest. • The value of chest X-ray has been recently questioned in the follow-up of patients with disseminated disease after complete remission (257, 258). • CT of the chest has a higher predictive value than chest X-ray (258). • The results of therapy are dependent on the bulk of disease; thus an intensive strategy to detect asymptomatic disease may be justifiable. • After chemotherapy or radiotherapy, there is a long-term risk of the development of secondary malignancies.

9.2

Follow-up: stage I non-seminoma

Approximately 5% of patients with CS1 NSGCT present with elevated levels of tumour markers after orchidectomy, and up to 25-30% relapse during the first 2 years (5, 113, 131, 134, 155, 259-262). The follow-up schedule will differ depending on which of the three possible treatment strategies was chosen: • surveillance • nerve-sparing RPLND • adjuvant chemotherapy. 9.2.1 Follow-up investigations during surveillance The results of a surveillance policy depend upon a careful pre-operative staging procedure and follow-up management. In a ‘wait and see’ policy, relapses will occur in 30% of cases. Of these relapses, 80% will occur in the first 12 months after orchidectomy, and approximately 12% during the second year. The median time to relapse is 6 months (range 1-62 months), but relapses after 3-5 years, and even later, can still occur, with an annual rate of 4% (108, 109). Relapse occurs mainly in the retroperitoneum: approximately 20% of patients have evident metastases in the retroperitoneum, and 10% in the mediastinum and lungs (263). Sometimes the only indication is an elevated level of tumour markers. A randomised trial of two versus five CT scans has been published by the MRC recommending the reduction of imaging during surveillance in this stage to one CT scan at 3 months after orchidectomy, and another at 12 months. The trial, with a cohort of 414 patients, was powered to exclude a 3% probability of detecting a patient during surveillance only, with a relapse presenting already-metastatic disease with ‘intermediate’ or ‘poor’ prognosis features. Relapses were detected in 15% with two CTs, and 20% with five CTs; 1.6% of these patients had ‘intermediate’ or ‘poor’ prognosis features. Only 10% of patients had high-risk features (vascular invasion). In summary, this first randomised trial yielded level 1 evidence for a minimum follow-up in patients with CS1 non-seminoma (122). The recommended follow-up schedule (Table 8) includes the minimum requirements for imaging, and adds recommendations for other surveillance tests.

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Table 8: Recommended minimum follow-up schedule in a surveillance policy: stage I non-seminoma Procedure Year 1 Physical examination 4 times Tumour markers 4 times Chest X-ray Twice Abdominopelvic CT scan Twice (at 3 and 12 months) CT= computed tomography scan.

2 3-5 4 times Twice per year 4 times Twice per year Twice

6-10 Once per year Once per year

During the initial post-treatment phase, follow-up consists of regular clinical examinations, the monitoring of serum tumour markers, and imaging investigations. The frequency and type of the examinations depend on the estimated risk of relapse, the chosen treatment strategy, and the time that has elapsed since completion of therapy, and should be modified according to these risks. However, only limited information about the optimal follow-up strategy exists, and currently recommendations can only be given for seminoma (264). For low-risk stage I non-seminoma, two abdominopelvic CT scans during the first year seem sufficient to detect relapses at an early stage (122). The significance of additional CT scans remains uncertain. No studies are available that address the optimal monitoring of such patients by serum tumour markers (AFP, beta-hCG). 9.2.2 Follow-up after nerve-sparing RPLND Retroperitoneal relapse after a properly performed nerve-sparing RPLND is rare. RPLND should eliminate the retroperitoneal nodes as a site of relapse and thus the need for repeated abdominal CT scans. The US Testicular Cancer Intergroup study data show retroperitoneal relapse in 7/264 patients with pathological stage I disease (and 20 pulmonary relapses); four of these seven had no marker elevation (265). In the Indiana series, only one relapse in 559 cases was reported (266). If a relapse occurs, it is generally in the chest, neck or at the margins of the surgical field. Pulmonary relapses occur in 10-12% of patients, and more than 90% of those relapses occur within 2 years of RPLND (74, 267). However, the low rate of retroperitoneal relapse after RPLND can only be achieved by surgery in specialised centres, as shown by the high in-field relapse rate (7/13 relapses) in the German randomised trial of RPLND versus one course of PEB (143). The recommended minimum follow-up schedule is shown in Table 9. Table 9: Recommended minimum follow-up schedule after retroperitoneal lymphadenectomy or adjuvant chemotherapy: stage I non-seminoma Procedure Year 1 Physical examination 4 times Tumour markers 4 times Chest X-ray Twice Abdominopelvic CT scan Once CT = computed tomography scan.

2 3-5 4 times Twice/year 4 times Twice/year Twice Once

6-10 Once/year Once/year

9.2.3 Follow-up after adjuvant chemotherapy Prospective reports with long-term follow-up after adjuvant chemotherapy have shown a low relapse rate (113, 114, 259, 260) of about 3%. In a randomised trial with one course of PEB versus RPLND, the relapse rate with adjuvant chemotherapy was 1% (2/174 patients, one with marker relapse, one with mature teratoma in the retroperitoneum) (143). The need for repeated and long-term assessment of the retroperitoneum is still not clear. Owing to the risk of developing a late, slow-growing teratoma in the retroperitoneum after adjuvant chemotherapy, an abdominal CT should still be performed (see Table 9).

9.3

Follow-up: stage I seminoma

The majority of patients with seminoma (70-80%) present with clinical stage I disease at diagnosis (89). In - 20% of cases, there is nodal radiological involvement at the level of the retroperitoneum, and only 5% of 15¬-20% patients present with distant metastasis (89). The relapse rate varies between 1% and 20%, depending on the post-orchidectomy therapy chosen. Only up to 30% of seminomas present with elevation of hCG at diagnosis or in the course of the disease.

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Consequently, in most cases, measurement of blood markers will not be a reliable test for follow-up (268). The treatment options post-orchidectomy in stage I seminoma are retroperitoneal radiotherapy, surveillance and adjuvant chemotherapy. Due to extreme radio- and chemosensitivity, high cure rates of almost 100% are reached with each of the approaches, even in cases of relapse. The costs of the different therapies vary, as do the expected side-effects (91, 269, 270). 9.3.1 Follow-up after radiotherapy Low doses of radiotherapy (20-24 Gy) limited to the retroperitoneal or the hockey-stick field achieve an overall survival rate of approximately 99% at 5-10 years (97-99, 271, 272). The rate of relapse is 1-2% and the most common time of presentation is within 18 months of treatment (97, 100, 270, 273, 274), although late relapses have also been described (275). The site of relapse is mainly at the supradiaphragmatic lymph nodes, mediastinum, lungs or bones. In a small proportion of cases, the tumour will relapse in the inguinal or external iliac nodes (89). The side-effects of radiotherapy include impaired spermatogenesis, GI symptoms (peptic ulceration), and induction of second malignancies (270, 276, 277). Up to 50% of patients can develop moderate toxicity grade I-II (268). The schedule of follow-up is described in Table 10. Table 10: Recommended minimum follow-up schedule for post-orchidectomy surveillance, radiotherapy or chemotherapy: stage I seminoma Procedure Year 1 2 3-4 Physical 3 times 3 times Twice/year examination Tumour markers 3 times 3 times Twice/year Chest X-ray Twice/year Twice/year Once/year Abdominopelvic CT scan Twice/year Twice/year Once/year CT = computed tomography scan.

5-10 Once/year Once/year Once/year Once/year

9.3.2 Follow-up during surveillance The actuarial risk of relapse at 5 years ranges between 6% (low risk) and 20% (106, 278-282). There is no increased risk of death. The median time to relapse ranges from 12-18 months, but up to 29% of relapses can develop later than this (87, 283). The sites of relapse are the PA lymph nodes in up to 82% of cases; the pelvic lymph nodes, inguinal nodes and lungs can also be affected (87, 284-288). Due to the high and often late rate of relapse, close and active follow-up is mandatory for at least 5 years (289) (see Table 10). 9.3.3 Follow-up after adjuvant chemotherapy One or two courses of carboplatin-based chemotherapy is an effective alternative treatment in stage I seminoma. The relapse rate is 1.9-4.5%. In general, this treatment is well tolerated, with only mild, acute and intermediate-term toxicity (289, 290). Long-term data on late relapses and survival are missing (see Table 10).

9.4

Follow-up: stage II and advanced (metastatic) disease

The more advanced the nodal stage of the disease, the higher the likelihood of recurrence (138). In general, the primary tumour bulk governs the outcome for patients with NSGCT (291). In stage II NSGCT, regardless of the treatment policy adopted, excellent survival rates of 97% are reached provided that relapse is identified as soon as possible (149, 150, 156). In advanced metastatic germ cell tumours, the extent of the disease is correlated with the response to therapy and with survival. The combination of cisplatin-based chemotherapy and surgery (aggressive multimodality) achieves cure rates of between 65% and 85%, depending on the initial extent of disease (292, 293). Complete response rates to chemotherapy are in the order of 50-60% (292); another 20-30% of patients could be rendered disease-free with post-chemotherapy surgery (294). The main reasons for failure of therapy in advanced NSGCT are (291, 295, 296): • the presence of bulky disease not responding completely to chemotherapy • unresectable residual teratoma after chemotherapy • the presence or development of chemoresistant non-germ elements, which account for 8.2% of cases.

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Table 11 gives the recommended minimum follow-up schedule in advanced NSGCT and seminoma. Table 11: Recommended minimum follow-up schedule in advanced NSGCT and seminoma Procedure Year 1 2 3-5 Thereafter Physical examination 4 times 4 times Twice per year Once per year Tumour markers 4 times 4 times Twice per year Once per year Chest X-ray 4 times 4 times Twice per year Once per year Abdominopelvic CT scan*† Twice Twice Once per year Once per year Chest CT scan†‡ As indicated As indicated As indicated As indicated Brain CT scan§ As indicated As indicated As indicated As indicated CT = computed tomography scan. *Abdominal CT scanning must be performed at least annually if teratoma is found in the retroperitoneum. †If the post-chemotherapy evaluation in a seminoma patient shows any mass > 3 cm, the appropriate CT scan should be repeated 2 and 4 months later to ensure that the mass is continuing to regress. If available, FDG-PET scanning can be performed. ‡A chest CT scan is indicated if abnormality is detected on chest X-ray and after pulmonary resection. §In patients with headaches, focal neurological findings, or any central nervous system symptoms.

10. TESTICULAR STROMAL TUMOURS 10.1

Background

Testicular stromal tumours are rare and account for only 2-4% of adult testicular tumours. However, only Leydig cell and Sertoli cell tumours are of clinical relevance. As no general recommendations have been published to date, the Testicular Cancer Working Group of the European Association of Urology (EAU) has decided to include these tumours in the EAU Germ Cell Tumour Guidelines. Recommendations for diagnosis and treatment are given only for Leydig and Sertoli cell tumours.

10.2

Methods

A Medline search for Leydig cell tumours (synonym: interstitial cell tumour) and Sertoli cell tumours (synonym: androblastoma) was performed. Approximately 850 papers were found. After excluding pure laboratory work without clinical data, female and paediatric tumours and animal cases, 371 papers and abstracts were reviewed. Double publications and papers with unclear histology or missing data on clinical course were excluded. The majority of the remaining 285 publications are case reports, with only a few papers reporting series of more than 10 cases, most of them published in the pathology literature. The true incidence of stromal tumours therefore remains uncertain, and the proportion of metastatic tumours can only be given approximately. Nevertheless, the symptoms for pre-operative suspicion of testicular stromal tumours and the characteristics of tumours at high risk for metastases are sufficiently well established (EBM: IIA and IIB) to enable recommendations to be made regarding diagnosis and surgical approach. However, no recommendations for appropriate follow-up can be given due to the absence of follow-up data in most reported cases, and the fatal outcome of metastatic tumours, irrespective of the therapy chosen. The individual publications have been rated according to EBM categories (see above). The literature research for clinical data on Leydig cell tumours resulted in 193 publications dealing with more than 480 tumours in adults, including three publications (1-3) reporting larger series on a total of 90 patients. Follow-up data of more than 2 years are available for about 80 patients. The literature research for clinical data on Sertoli cell tumours resulted in 93 publications dealing with more than 260 tumours in adults, including three publications (from the same group) (4-6) reporting on a total of 80 patients. Follow-up data of more than 2 years are available in fewer than 40 patients.

10.3

Classification

The non-germ cell tumours of the testicle include the sex cord/gonadal stromal tumours and the miscellaneous non-specific stromal tumours. The different histological subtypes of testicular tumours are defined according to the WHO classification 2004 (adapted) (7).

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10.4

Leydig cell tumours

10.4.1 Epidemiology Leydig cell tumours constitute about 1-3% of adult testicular tumours (2, 8) and 3% of testicular tumours in infants and children (8). The tumour is most common in the third to sixth decade in adults, with a similar incidence observed in every decade. Another peak incidence is seen in children aged between 3 and 9 years. Only 3% of Leydig cell tumours are bilateral (2). Occasionally, they occur in patients with Klinefelter’s syndrome (8). 10.4.2 Pathology of Leydig cell tumours Leydig cell tumours are the most common type of sex cord/gonadal stromal tumours. Histopathologically, they are well outlined and usually up to 5 cm in diameter. They are also solid, coloured yellow to tan, with haemorrhage and/or necrosis present in 30% of cases. Microscopically, the cells are polygonal, with eosinophilic cytoplasm with occasional Reinke crystals, regular nucleus, solid arrangement and capillary stroma. The cells express vimentin, inhibin, protein S-100, steroid hormones, calretinin and cytokeratin (focally) (7). About 10% of Leydig cell tumours are malignant tumours, which present with the following parameters: • large size (> 5 cm) • cytological atypia • increased mitotic activity (> 3 per 10 high-power field [HPF]) • increased MIB-1 expression (18.6% vs 1.2% in benign) • necrosis • vascular invasion (9) • infiltrative margins • extension beyond the testicular parenchyma • DNA aneuploidy (1,10). 10.4.3 Diagnosis Patients either present with a painless enlarged testis or the tumour is an incidental ultrasound finding. In up to 80% of cases, hormonal disorders with high oestrogen and oestradiol levels and low testosterone, increased levels of LH and FSH are reported (11, 12), while negative results are always obtained for the testicular germ cell tumour-markers AFP, hCG, LDH and PLAP. Approximately 30% of patients present with gynaecomastia (13, 14). Only 3% of tumours are bilateral (2). Leydig cell tumours must be distinguished from the multinodular tumour-like and often bilaterally occurring lesions of the androgenital syndrome (15). Diagnostic work-up must include markers, hormones (at least testosterone, LH and FSH; if not conclusive, additionally oestrogen, oestradiol, progesterone and cortisol), ultrasound of both testes, and CT scan of chest and abdomen. On ultrasound, it may be possible to observe well-defined, small, hypoechoic lesions with hypervascularisation, but the appearance is variable and is indistinguishable from germ cell tumours (16, 17). The proportion of metastatic tumours in all published case reports is only 10%. Within three larger series with longer follow-up, 18 metastatic tumours were found in a total of 83 cases (21.7%) (1-3). Histopathological signs of malignancy have been depicted above (see 4.2) (1, 10). In addition, patients of older age have a greater risk of harbouring a tumour of malignant potential. 10.4.4 Treatment Asymptomatic testicular tumours of small volume are often misinterpreted as germ cell tumours, and inguinal orchidectomy is performed. It is highly recommended to perform an organ-sparing procedure in every small intraparenchymal lesion in order to obtain the histological diagnosis. Especially in patients with symptoms of gynaecomastia or hormonal disorders, a non germ-cell tumour should be considered and immediate orchidectomy avoided (18). In cases of germ cell tumour in either frozen section or paraffin histology, orchidectomy is recommended as long as a contralateral normal testicle is present. In stromal tumours with histological signs of malignancy, especially in patients of older age, orchidectomy and retroperitoneal lymphadenectomy is recommended to prevent metastases (19). Without histological signs of malignancy, an individualised surveillance strategy after orchidectomy is recommended (CT follow-up may be most appropriate since specific tumour markers are not available). Tumours that have metastasised to lymph nodes, lung, liver or bone respond poorly to chemotherapy or radiation and survival is poor (19).

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10.4.5 Follow-up Recommendations for appropriate follow-up cannot be given because of the lack of follow-up data in most reported cases and the lethal outcome of metastatic tumours, irrespective of the therapy chosen.

10.5

Sertoli cell tumour

10.5.1 Epidemiology Sertoli cell tumours account for fewer than 1% of testicular tumours, and the mean age at diagnosis is around 45 years, with rare cases under 20 years of age (4, 20). On rare occasions, these tumours may develop in patients with androgen insensitivity syndrome and Peutz-Jeghers syndrome. 10.5.2 Pathology of Sertoli cell tumours The tumour is well circumscribed, yellow, tan or white, with an average diameter of 3.5 cm (4). Microscopically, the cells are eosinophilic to pale with vacuolated cytoplasm. The nuclei are regular with grooves and there may be inclusions. The arrangement of the cells is tubular or solid; a cord-like or retiform pattern is possible. The stroma is fine and capillary, but in some cases a sclerosing aspect predominates. The cells express vimentin, cytokeratins, inhibin (40%) and protein S-100 (30%) (4). The rate of malignant tumours ranges between 10% and 22%, and fewer than 50 cases have been reported (21-23). Signs of a malignant Sertoli tumour are: • large size (> 5 cm) • pleomorphic nuclei with nucleoli • increased mitotic activity (> 5 per 10 HPF) • necrosis • vascular invasion. 10.5.2.1 Classification Three subtypes have been described (20): • the classic Sertoli cell tumour (4) • the large cell calcifying form with characteristic calcifications (5, 24) • the rare sclerosing form (6, 25). 10.5.3 Diagnosis Patients present either with an enlarged testis or the tumour is an incidental ultrasound finding (26). Most classic Sertoli tumours are unilateral and unifocal. Hormonal disorders are infrequent, although gynaecomastia is sometimes seen (4). The testicular tumour-markers AFP, hCG, LDH and PLAP are always negative. Diagnostic work-up must include tumour markers, hormones (at least testosterone, LH and FSH; if not conclusive, additionally oestrogen, oestradiol, progesterone and cortisol), ultrasound of both testes and CT scan of chest and abdomen. Sertoli cell tumours are generally hypoechoic on ultrasound, but they can be of variant appearance and therefore cannot be safely distinguished from germ cell tumours (20). Only the large cell calcifying form has a characteristic image with brightly echogenic foci due to calcification (27, 28). The large cell calcifying form is diagnosed in younger men and is associated with genetic syndromes (Carney’s complex [29] and Peutz-Jeghers syndrome [30]) or, in about 40% of cases, endocrine disorders. A total of 44% of cases are bilateral, either synchronous or metachronous, and 28% show multifocality (24). The characteristics of metastatic tumours have been depicted above (24, 25). However, among patients whose tumours have been histopathologically classified as ‘malignant’ using these or similar characteristics (i.e. 18.8% of tumours in all reported cases), only 7% showed metastatic disease during follow-up. In the largest series with the longest follow-up, 7.5% of patients had been classified as ‘malignant’ at primary diagnosis and 11.7% showed metastatic disease long-term (4). In general, affected patients are of higher age, tumours are nearly always palpable, and show more than one sign of malignancy (4). Up to 20% of the large cell sclerosing form are malignant. There are some hints that discrimination between an early and late onset type may define a different risk for metastatic disease (5.5% compared with 23%) (20). Metastases in the infrequent sclerosing subtype are rare.

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10.5.4 Treatment Testicular tumours of small volume, otherwise asymptomatic, are often misinterpreted as germ cell tumours and inguinal orchidectomy is performed. It is highly recommended to proceed with an organ-sparing approach in small intraparenchymal testicular lesions until final histology is available. Especially in patients with symptoms of gynaecomastia or hormonal disorders or typical imaging on ultrasound (calcifications, small circumscribed tumours), organ-sparing surgery should be considered. Secondary orchidectomy can be performed if final pathology reveals a non-stromal (e.g. germ cell) tumour. Organ-sparing surgical approaches are justified as long as the remaining testicular parenchyma is sufficient for endocrine (and in stromal tumours also exocrine) function. In tumours with histological signs of malignancy, especially in patients of older age, orchidectomy and retroperitoneal lymphadenectomy are recommended to prevent metastases (19). Without signs of malignancy, an individualised surveillance strategy after orchidectomy is recommended (CT scans may be most appropriate since specific tumour-markers are not available). Tumours metastasising to lymph nodes, lung or bone respond poorly to chemotherapy or radiation, and survival is poor. 10.5.5 Follow-up Recommendations for appropriate follow-up cannot be given because of the lack of follow-up data in most reported cases and the lethal outcome of metastatic tumours, irrespective of the therapy chosen.

10.6 Granulosa cell tumour This is a rare tumour, with two variants: juvenile and adult. • The juvenile type is benign. It is the most frequent congenital testicle tumour and represents 6.6% of all prepubertal testicular neoplasms. The cystic appearance is characteristic of this tumour type (31). • With the adult type, the average age at presentation is 44 years. The typical morphology is of a homogeneous, yellow-grey tumour, with elongated cells with grooves in microfollicular and Call-Exner body arrangements. Malignant tumours represent around 20% of cases. They are usually > 7 cm diameter. Vascular invasion and necrosis are features suggestive of malignant biology (32).

10.7

Thecoma/fibroma group of tumours

These tumours are very rare and benign (7).

10.8

Other sex cord/gonadal stromal tumours

Sex cord/gonadal stromal tumours may be incompletely differentiated or mixed forms. There is limited experience with incompletely differentiated sex cord/gonadal stromal tumours and no cases of reported metastasis (7). In mixed tumour forms, all the histological components should be reported. However, the clinical behaviour is most likely to reflect the predominant pattern or the most aggressive component of the tumour (33)

10.9

Tumours containing germ cell and sex cord/gonadal stromal (gonadoblastoma)

If the arrangement of the germ cells are in a nested pattern and the rest of the tumour is composed of sex cord/gonadal stroma, the term gonadoblastoma is used. It is most frequent in gonadal dysgenesis with ambiguous genitalia. Bilateral tumours are present in 40% of cases. The prognosis is correlated with the invasive growth of the germinal component (34). In the case of a diffuse arrangement of the different components, there are some doubts about the neoplastic nature of the germinal cells and some authors consider them to be entrapped rather than neoplastic (35).

10.10 Miscellaneous tumours of the testis 10.10.1 Tumours of ovarian epithelial types These tumours resemble the epithelial tumours of the ovary. A cystic appearance with occasional mucinous material can be observed. Microscopically, the aspect is identical to their ovarian counterparts, and their evolution is similar to that of the different epithelial ovarian subtypes. Some Brenner types can be malignant (7). 10.10.2 Tumours of the collecting ducts and rete testis These tumours are very rare. Benign (adenoma) and malignant (adenocarcinoma) have been reported, with malignant tumours showing local growth with a mortality rate of 56% (18).

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10.10.3 Tumours (benign and malignant) of non-specific stroma These are very uncommon and have a similar criteria, prognosis and treatment as do the soft tissue sarcomas.

11 REFERENCES 11.1 Germ cell tumours 1. 2.

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5. 6.

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19.

20.

21. 22.

23. 24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34. 35.

Mosharafa AA, Foster RS, Bihrle R, Koch MO, Ulbright TM, Einhorn LH, Donohue JP. Does retroperitoneal lymph node dissection have a curative role for patients with sex cord-stromal testicular tumours? Cancer 2003;98(4):753-7. http://www.ncbi.nlm.nih.gov/pubmed/9428434 Giglio M, Medica M, De Rose AF, Germinale F, Ravetti JL, Carmignani G. Testicular Sertoli cell tumours and relative sub-types. Analysis of clinical and prognostic features. Urol Int 2003;70(3): 205-10. http://www.ncbi.nlm.nih.gov/pubmed/12660458 Jacobsen GK. Malignant Sertoli cell tumours of the testis. J Urol Pathol 1993;1:233-55. Kratzer SS, Ulbright TM, Talerman A, Srigley JR, Roth LM, Wahle GR, Moussa M, Stephens JK, Millos A, Young RH. Large cell calcifying Sertoli cell tumour of the testis: contrasting features of six malignant and six benign tumours and a review of the literature. Am J Surg Pathol 1997;21(11): 1271-80. http://www.ncbi.nlm.nih.gov/pubmed/9351565 Henley JD, Young RH, Ulbright TM. Malignant Sertoli cell tumours of the testis: a study of 13 examples of a neoplasm frequently misinterpreted as seminoma. Am J Surg Pathol 2002;26:541-50. Plata C, Algaba F, Andujar M, Nistal M, Stocks P, Martinez JL, Nogales FF. Large cell calcifying Sertoli cell tumour of the testis. Histopathology 1995;26(3):255-9. http://www.ncbi.nlm.nih.gov/pubmed/7541015 Anderson GA. Sclerosing Sertoli cell tumour of the testis: a distinct histological subtype. J Urol 1995;154(5):1756-8. Review. http://www.ncbi.nlm.nih.gov/pubmed/7563340 Grabrilove JL, Freiberg EK, Leiter E, Nicolis GL. Feminizing and non-feminizing Sertoli cell tumour. J Urol 1980;124(6):757-67. http://www.ncbi.nlm.nih.gov/pubmed/7003168 Gierke CL, King BF, Bostwick DG, Choyke PL, Hattery RR. Large-cell calcifying Sertoli cell tumour of the testis: appearance at sonography. AJR Am J Roentgenol 1994;163(2):373-5. http://www.ncbi.nlm.nih.gov/pubmed/8037034 Chang B, Borer JG, Tan PE, Diamond DA. Large-cell calcifying Sertoli cell tumour of the testis: case report and review of the literature. Urology 1998;52(3):520-2. http://www.ncbi.nlm.nih.gov/pubmed/9730477 Washecka R, Dresner MI, Honda SA. Testicular tumours in Carney’s complex. J Urol 2002;167(3):1299-302. http://www.ncbi.nlm.nih.gov/pubmed/11832717 Young S, Gooneratne S, Straus FH, Zeller WP, Bulun SE, Rosenthal IM. Feminizing Sertoli cell tumours in boys with Peutz-Jeghers syndrome. Am J Surg Pathol 1995;19(1):50-8. http://www.ncbi.nlm.nih.gov/pubmed/7802138 Kaplan GW, Cromie WJ, Kelalis PP, Silber I, Tank ES Jr. Gonadal stromal tumours: a report of theprepuberal testicular tumours registry. J Urol 1986;136(1Pt2):300-2. http://www.ncbi.nlm.nih.gov/pubmed/3723681 Al-Bozom IA, El-Faqih SR, Hassan SH, El-Tiraifi AE, Talic RF. Granulosa cell tumour of the adult type. A case report and review of the literature of a very rare testicular tumour. Arch Pathol Lab Med 2000;124(10):1525-8. http://www.ncbi.nlm.nih.gov/pubmed/11035589 Perito PE, Ciancio G, Civantos F, Politano VA. Sertoli-Leydig cell testicular tumour. case report and review of sex cord/gonadal stromal tumour histogenesis. J Urol 1992;148(3):883-5. http://www.ncbi.nlm.nih.gov/pubmed/1512847 Scully RE. Gonadoblastoma. A review of 74 cases. Cancer 1970;25(6):1340-56. http://www.ncbi.nlm.nih.gov/pubmed/4193741 Ulbright TM, Srigley JR, Reuter VE, Wojno K, Roth LM, Young RH. Sex-cord-stromal tumours of the testis with entrapped germ cells: a lesion mimicking unclassified mixed germ cell sex cord-stromal tumours. Am J Surg Pathol 2000;24(4):535-42. http://www.ncbi.nlm.nih.gov/pubmed/10757400

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12. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations.

AFP AUC hCG Cg A CI CS CT EAU EBM EP EORTC FDG-PET FSH GI G-CSF GR HPF IGCCCG LE LH LDH MRC MRI NSGCT PA PEB PEI PET PFS PS PLAP PVB RPLND SWENOTECA Tin TIP TNM UICC ULN VelP WHO VIP (VP-16)

alpha-fetoprotein area under curve human chorionic gonadotrophin chromogranine A confidence interval clinical stage computed tomography European Association of Urology evidence-based medicine etoposide, cisplatin European Organisation for Research and Treatment of Cancer fluorodeoxyglucose-positron emission tomography follicle-stimulating hormone gastrointestinal granulocyte colony-stimulating factor grade of recommendation high-power field International Germ Cell Cancer Collaborative Group level of evidence luteinising hormone lactate dehydrogenase Medical Research Council magnetic resonance imaging non-seminomatous germ cell tumour para-aortic cisplatin, etoposide, bleomycin cisplatin, etoposide, ifosfamide positron emission tomography progression-free survival pathological stage placental alkaline phosphatase cisplatin, vinblastine, bleomycin retroperitoneal lymph node dissection Swedish-Norwegian Testicular Cancer Project carcinoma in situ pathological definition: undifferentiated intratubular germ cell carcinoma paclitaxel, ifosfamide, cisplatin Tumour Node Metastasis International Union Against Cancer upper limit of normal vinblastine, ifosfamide, cisplatin World Health Organization etoposide, ifosfamide, cisplatin

Conflict of interest All members of the Testicular Cancer Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Benign Prostatic Hyperplasia J. de la Rosette, G. Alivizatos, S. Madersbacher, C. Rioja Sanz, J. Nordling, M. Emberton, S. Gravas, M.C. Michel, M. Oelke

© European Association of Urology 2009

TABLE OF CONTENTS 1. Background 1.1 Prevalence 1.2 Is BPH a progressive disorder? 1.2.1 Indicators of progression 1.2.2 Conclusions 1.2.3 References

page 5 5 5 6 7 7

2. RISK FACTORS 2.1 For developing the disease 2.2 For surgical treatment 2.3 References

9 9 9 10

3. ASSESSMENT 3.1 Symptom scores 3.1.1 International Prostate Symptom Score (I-PPS) 3.1.2 Quality-of-life assessment 3.1.3 Symptom score as decision tool for treatment 3.1.4 Symptom score as outcome predictor 3.1.5 Conclusions 3.1.6 Recommendations 3.1.7 References 3.2 Prostate specific antigen (PSA) measurement 3.2.1 Factors influencing the serum levels of PSA 3.2.2 PSA and prediction of prostatic volume 3.2.3 PSA and probability of having prostate cancer 3.2.4 PSA and prediction of BPH-related outcomes 3.2.5 Conclusions 3.2.6 Recommendation 3.2.7 References 3.3 Creatinine measurement 3.3.1 Conclusions 3.3.2 References 3.4 Urinalysis 3.4.1 Recommendation 3.5 Digital rectal examination (DRE) 3.5.1 DRE and cancer detection 3.5.2 DRE and prostate size evaluation 3.5.3 Conclusions and recommendations 3.5.4 References 3.6 Imaging of the urinary tract 3.6.1 Upper urinary tract 3.6.2 Lower urinary tract 3.6.3 Urethra 3.6.4 Prostate 3.6.5 References 3.7 Voiding charts (diaries) 3.7.1 Conclusions 3.7.2 References 3.8 Uroflowmetry 3.8.1 References 3.9 Post-void residual volume (PVR) 3.10 Urodynamic studies 3.10.1 Outcome 3.10.2 Conclusions 3.10.3 References 3.11 Endoscopy 3.11.1 LUTS caused by bladder outlet obstruction 3.11.2 Morbidity of urethrocystoscopy

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3.11.3 Relationship between trabeculation and peak flow rate 3.11.4 Relationship between trabeculation and symptoms 3.11.5 Relationship between trabeculation and prostate size 3.11.6 Relationship between trabeculation and obstruction 3.11.7 Bladder diverticula and obstruction 3.11.8 Bladder stones and obstruction 3.11.9 Intravesical pathology 3.11.10 Conclusions 3.11.11 References 3.12 Recommendations for assessment

23 23 23 23 24 24 24 24 24 25

4. TREATMENT 4.1 Watchful waiting (WW) 4.1.1 Patient selection 4.1.2 Education, reassurance and periodic monitoring 4.1.3 Lifestyle advice 4.1.4 Conclusions 4.1.5 References 4.2 Medical treatment 4.2.1 5-Alpha reductase inhibitors 4.2.1.1 Finasteride (type 2, 5-Alpha reductase inhibitor) 4.2.1.1.1 Efficacy and clinical endpoints 4.2.1.1.2 Haematuria and finasteride 4.2.1.1.3 Side-effects 4.2.1.1.4 Effect on PSA 4.2.1.2 Dutasteride 4.2.1.3 Combination therapy 4.2.1.4 Conclusions 4.2.1.5 References 4.2.2 Alpha-blockers 4.2.2.1 Uroselectivity 4.2.2.2 Mechanism of action 4.2.2.3 Pharmacokinetics 4.2.2.4 Assessment 4.2.2.5 Clinical efficacy 4.2.2.6 Durability 4.2.2.7 Adverse effects 4.2.2.8 Acute urinary retention 4.2.2.9 Conclusions 4.2.2.10 References 4.2.3 Phytotherapeutic agents 4.2.3.1 Conclusions 4.2.3.2 References 4.3 Surgical management 4.3.1 Indications for surgery 4.3.2 Choice of surgical technique 4.3.3 Perioperative antibiotics 4.3.4 Treatment outcome 4.3.5 Complications 4.3.6 Long-term outcome 4.3.7 Conclusions and recommendations 4.3.8 References 4.4 Lasers 4.4.1 Laser types 4.4.2 Right-angle fibres 4.4.3 Interstitial Laser Coagulation (ILC) 4.4.4 Holmium laser resection of the prostate (HoLRP) 4.4.5 Conclusions 4.4.6 References

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4.5 Transrectal high-intensity focused ultrasound (HIFU) 4.5.1 Assessment 4.5.2 Procedure 4.5.3 Morbidity/complications 4.5.4 Outcome 4.5.5 Urodynamics 4.5.6 Quality of life and sexual function 4.5.7 Durability 4.5.8 Patient selection 4.5.9 Conclusions 4.5.10 References 4.6 Transurethral needle ablation (TUNA®) 4.6.1 Assessment 4.6.2 Procedure 4.6.3 Morbidity/complications 4.6.4 Outcome 4.6.5 Randomized clinical trials 4.6.6 Impact on bladder outflow obstruction 4.6.7 Durability 4.6.8 Patient selection 4.6.9 Conclusions 4.6.10 References 4.7 Transurethral microwave therapy (TUMT) 4.7.1 Assessment 4.7.2 Procedure 4.7.3 The microwave thermotherapy principle 4.7.4 Morbidity 4.7.5 High-intensity-dose-protocol 4.7.6 Prostatic temperature feedback treatment 4.7.7 Durability 4.7.8 Patient selection 4.7.9 Conclusions 4.7.10 References 4.8 Recommendations for treatment

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5.

FOLLOW-UP 5.1 Watchful waiting 5.2 Alpha-blocker therapy 5.3 5-Alpha-reductase inhibitors 5.4 Surgical management 5.5 Alternative therapies

52 52 52 52 52 52

6. ABBREVIATIONS USED IN THE TEXT

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1. BACKGROUND Benign prostatic hyperplasia (BPH) is a condition intimately related to ageing (1). Although it is not lifethreatening, its clinical manifestation as lower urinary tract symptoms (LUTS) reduces the patient’s quality of life (2). Troublesome LUTS can occur in up to 30% of men older than 65 years (3).

1.1 Prevalence Although many epidemiological clinical studies have been conducted worldwide over the last 20 years, the prevalence of clinical BPH remains difficult to determine. A standardized clinical definition of BPH is lacking, which makes it intrinsically difficult to perform adequate epidemiological studies. Among the published epidemiological studies, some include probability samples from an entire country, while others represent agestratified random samples or enroll participants from general practice, hospital populations or responders to selective screening programmes. There is also a lack of homogeneity among these studies in the way in which BPH is assessed, with different questionnaires and methods of administration. Barry et al. have provided the histological prevalence of BPH, based on a review of five studies relating age to histological findings in human male prostate glands (4). Histological BPH was not found in men under the age of 30 years but its incidence rose with age, reaching a peak in the ninth decade. At that age, BPH was found in 88% of histological samples (4). A palpable enlargement of the prostate has been found in up to 20% of males in their 60s and in 43% in their 80s (5); however, prostate enlargement is not always related to clinical symptoms (2). Clinical BPH is a highly prevalent disease. By the age of 60 years, nearly 60% of the cohort of the Baltimore Longitudinal Study of Aging had some degree of clinical BPH (6). In the USA, results of the Olmstead County survey, in a sample of unselected Caucasian men aged 40-79 years, showed that moderate-to-severe symptoms can occur among 13% of men aged 40-49 years and among 28% of those older than 70 years (1). In Canada, 23% of the cohort studied presented with moderate-to-severe symptoms (7). The findings for prevalence of LUTS in Europe are similar to those in the USA. In Scotland and in the area of Maastricht, the Netherlands, the prevalence of symptoms increased from 14% of men in their 40s to 43% in their 60s (8,9). Depending on the sample, the prevalence of moderate-to-severe symptoms varies from 14% in France to 30% in the Netherlands (10,11). The proportion of men with moderate-to-severe symptoms doubles with each decade of life (10). Preliminary results of one of the most recent European epidemiological studies on the prevalence of LUTS show that approximately 30% of German males aged 50-80 years present with moderateto-severe symptoms according to the International Prostate Symptom Score (i.e. I-PSS > 7) (12). A multicentre study performed in different countries in Asia showed that the age-specific percentages of men with moderate-to-severe symptoms were higher than those in America (13,14). The prevalence increases from 18% for men in their 40s to 56% for those in their 70s (13). Curiously, the average weight of Japanese glands seemed to be smaller than those of their American counterparts (15). Despite methodological differences, some conclusions can be drawn from the studies mentioned above: • Mild urinary symptoms are very common among men aged 50 years and older • Mild symptoms are associated with little bother, while moderate and severe symptoms are associated with increasingly higher levels of inconvenience and interference with living activities (16) • The same symptoms can cause different troublesome and daily living interference (17) • The correlation between symptoms, prostate size and urinary flow rate is relatively low (18). It must be stressed that there is still a need for an epidemiological definition of BPH and its true incidence has yet to be determined (19).

1.2

Is BPH a progressive disorder?

As it is almost impossible to obtain agreement on what it is that defines a man with LUTS/BPH, it seems logical to say that progression cannot be defined in terms of a transition from non-cases to cases. Instead, progression must be measured by documenting deterioration in any number of physiological variables that we associate with the LUTS/BPH syndrome. Traditionally these have included the following: • decrease in maximum flow rate • increase in residual volume • increase in prostate size • deterioration (increase) in symptom score. In addition, definable events, such as the occurrence of acute urinary retention or prostate surgery, have been used. Less commonly, changes in urodynamic variables and deterioration in disease-specific quality of life have been advocated. Considerable interest currently rests with PSA. It appears to be as good a predictor of progression as any of the variables mentioned above.

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1.2.1 Indicators of progression The strongest evidence to support progression comes from the Olmsted County (20) community-based study and the PLESS placebo group (21). The strength of evidence for individual parameters as indicators of progression is summarised in Table 1 and is categorised as strong, weak, or none. The actual rates of progression of the individual parameters as determined from the papers reviewed is shown in Table 2. These parameters could potentially be used in decisions about treatment management. Patients who show signs of more pronounced disease progression could be targeted for preventative strategies. The same strategy could be applied to patients who are at increased risk of progression based on recognised risk factors. Risk factors for progression were found to be age (Olmsted County), PSA (PLESS) and prostate volume (combined 2-year placebo analysis). Other baseline risk factors can be identified, such as symptom severity and decreased urinary flow rate, but current data are not as convincing as those for age, PSA level and prostate volume. Several other complications, such as renal impairment and bladder dysfunction, have been associated with progression of BPH. Although these are important, they are very rare and therefore could not be evaluated accurately in community-based and clinical studies. The evidence for the progression of BPH has been summarised previously (22). Table 1: Strength of evidence for specific parameters as indicators of progression of benign prostatic hyperplasia (BPH) Parameter Community- based studies Clinical trials LUTS I-PSS S N/W* BII S N/N QoL N W/S* BPE DRE N N TRUS S S MRI N S/S* BOO Qmax S W/S* BPH Histology N/A N/A Miscellaneous AUR S S/S* Surgery S W/S* Crossover/treatment S N *Conditional risk factors: age and prostate-specific antigen (PSA); S = strong; W = weak; N = no evidence; N/A = not available. AUR = acute urinary retention; BOO = bladder outlet obstruction; BPE = benign prostatic enlargement; BII = BPH Impact Index; DRE = digital rectal examination; I-PSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; MRI = magnetic resonance imaging; Qmax = maximum flow rate; QoL = quality of life; TRUS = transrectal ultrasonography. Table 2: Rates of progression of individual parameters in BPH Study Rate of progression LUTS Flow rate Prostate Acute urinary retentiona Surgerya (points) size (Incidence/1000 (Incidence/1000 person years) person years) 40-49 > 70 40-49 > 70 years years years years Olmsted 0.18 -2% 1.9% 3.0 34.7 0.3 10.9 (20, 23-26) per year per year per year Health Pro- NR NR NR 3.3 11.3 NR NR fessional (27) PLESS (28) -1.3 in +0.2 mL/s +14% 7% over 4 years 10% over 4 years 4 yearsb in 4 yearsb in 4 years 2-year studies NR NR NR 1.6-4.2%c NR (22, 29-32) 0.5-3.9%d North Ame- NR NR NR NR 10-39%e rican (33) a Men with moderate to severe symptoms. b Flow rate and LUTS responded to placebo treatment by showing an initial improvement, which deteriorated

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baseline during the course of the placebo-controlled trial. According to baseline prostate volume. d According to baseline prostate-specific antigen (PSA) level. LUTS = lower urinary tract symptoms; NR = not reported. c

1.2.2 Conclusions Based on published data on consequences and complications of the disease, BPH can be considered a progressive disease. There are limited published data on longitudinal studies and the key pieces of evidence that support this notion are the Olmsted County and PLESS studies. A group of patients at increased risk of progression can be identified based on specific risk factors, i.e. age, PSA level and prostate volume. It might be appropriate to identify these patients at risk of progression and initiate early preventative treatment. 1.2.3 References 1. Chute CG, Panser LA, Girman CJ, Oesterling JE, Guess HA, Jacobsen SJ, Lieber MM. The prevalence of prostatism: a population based survey of urinary symptoms. J Urol 1993;150(1):85-9. http://www.ncbi.nlm.nih.gov/pubmed/7685427 2. Donovan JL, Kay HE, Peters TJ, Abrama P, Coast J, Matos-Ferreira A, Rentzhog L, Bosch JL, Nordling J, Gajewski JB, Barbalias G, Schick E, Silva MM, Nissenkorn I, de la Rosette JJ. Using the ICSQoL to measure the impact of lower urinary tract symptoms on quality of life: evidence from the ICS-‘BPH’ study. International Continence Society - Benign Prostatic Hyperplasia. Br J Urol 1997;80(5):712-21. http://www.ncbi.nlm.nih.gov/pubmed/9393291 3. Chapple CR. BPH disease management. Eur Urol 1999; 36(Suppl 3):1-6. http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ArtikelNr=52342&Ausgab e=227835&ProduktNr=224083 4. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984;132(3):474-9. http://www.ncbi.nlm.nih.gov/pubmed/6206240 5. Lytton B, Emery JM, Harvard BM. The incidence of benign prostatic obstruction. J Urol 1968;99(5):639-45. http://www.ncbi.nlm.nih.gov/pubmed/4171950 6. Arrighi HM, Metter EJ, Guess HA, Fozzard JL. Natural history of benign prostatic hyperplasia and risk of prostatectomy, the Baltimore Longitudinal Study of Aging. Urology 1991;35(Suppl):4-8. http://www.ncbi.nlm.nih.gov/pubmed/1714657 7. Norman RW, Nickel JC, Fish D, Pickett SN. Prostate-related symptoms in Canadian men 50 years of age or older: prevalence and relationships among symptoms. Br J Urol 1994;74(5):542-50. http://www.ncbi.nlm.nih.gov/pubmed/7530115 8. Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991;338(8765):469-71. http://www.ncbi.nlm.nih.gov/pubmed/1714529 9. Wolfs GG, Knottnerus JA, Janknegt RA. Prevalence and detection of micturition problems among 2,734 elderly men. J Urol 1994;152(5 Pt 1):1467-70. http://www.ncbi.nlm.nih.gov/pubmed/7933185 10. Sagnier PP, McFarlane G, Teillac P, Botto H, Richard F, Boyle P. Impact of symptoms of prostatism on level of bother and quality of life of men in the French community. J Urol 1995;153(3 Pt 1):669-73. http://www.ncbi.nlm.nih.gov/pubmed/7532230 11. Bosch JL, Hop WC, Kirkels WJ, Schröder FH. The international prostate symptom score in a community-based sample of men between fifty-five and seventy-four years of age. Prevalence and correlation of symptoms with age, prostate volume, flow rate and residual urine volume. Br J Urol 1995;75(5):622-30. http://www.ncbi.nlm.nih.gov/pubmed/7542132 12. Berges RR, Pientka L. Management of the BPH syndrome in Germany: who is treated and how? Eur Urol 1999; 36(Suppl 3):21-7. http://www.ncbi.nlm.nih.gov/pubmed/10559627 13. Homma Y, Kawabe K, Tsukamoto T, Yamanaka H, Okada K, Okajima E, Yoshida O, Kumazawa J, Gu FL, Lee C, Hsu TC, dela Cruz RC, Tantiwang A, Lim PH, Sheikh MA, Bapat SD, Marshall VR, Tajima K, Aso Y. Epidemiologic survey of lower urinary tract symptoms in Asia and Australia using the International Prostate Symptom Score. Int Urol 1997;4(4):40-6. http://www.ncbi.nlm.nih.gov/pubmed/9179665

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14.

Tsukamoto T, Kumamoto Y, Masumori N, Miyakr H, Rhodes T, Girman GJ, Guess HA, Jacobsen SJ, Lieber MM. Prevalence of prostatism in Japanese men in a community-based study with comparison to a similar American study. J Urol 1995;154(2 Pt 1):391-5. http://www.ncbi.nlm.nih.gov/pubmed/7541852 15. Masumori N, Tsukamoto T, Kumamoto Y, Miyake H, Rhodes T, Girman CJ, Guess HA, Jacobsen SJ, Lieber MM. Japanese men have smaller prostate volumes but comparable urinary flow rates relative to American men: results of community based studies in 2 countries. J Urol 1996;155(4):1324-7. http://www.ncbi.nlm.nih.gov/pubmed/8632564 16. Guess HA. Population-based studies of benign prostatic hyperplasia. In: Kirby R et al. eds. Textbook of Benign Prostatic Hyperplasia. Oxford: Isis Medical Media,1996, pp. 117-124. http://www.isismedical.com/ 17. Guess HA, Chute CG, Garraway WM, Girman CJ, Panser LA, Lee RJ, Jacobsen SJ, McKelvie GB, Oesterling JE, Lieber MM. Similar levels of urological symptoms have similar impact on Scottish and American men although Scots report less symptoms. J Urol 1993;150(5 Pt 2):1701-5. http://www.ncbi.nlm.nih.gov/pubmed/7692105 18. Girman CJ, Jacobsen SJ, Guess HA, Oesterling JE, Chute CG, Panser LA, Lieber MM. Natural history of prostatism: relationship among symptoms, prostate volume and peak urinary flow. J Urol 1995;153(5):1510-5. http://www.ncbi.nlm.nih.gov/pubmed/7536258 19. Oishi K, Boyle P, Barry JM, et al. Epidemiology and natural history of benign prostatic hyperplasia. In: Denis L, Griffiths K, Khoury S et al, eds. Fourth International Consultation on BPH, Paris, July 1997. Plymouth: Health Publications, 1998, pp. 25-59. http://www.congress-urology.org/ 20. Jacobsen SJ, Girman CJ, Guess HA, Rhodes T, Oesterling JE, Lieber MM. Natural history of prostatism: longitudinal changes in voiding symptoms in community dwelling men. J Urol 1996;155(2):595-600. http://www.ncbi.nlm.nih.gov/pubmed/8558668 21. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P, Roehrborn CG, Nickel JC, Wang DZ, Taylor AM, Waldstreicher J. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. New Engl J Med 1998;338(9):557-63. http://www.ncbi.nlm.nih.gov/pubmed/9475762 22. Anderson JB, Roehrborn CG, Schalken JA, Emberton M. The progression of benign prostatic hyperplasia: examining the evidence and determining the risk. Eur Urol 2001; 39(4):390-9. http://www.ncbi.nlm.nih.gov/pubmed/11306876 23. Jacobsen SJ, Jacobson DJ, Girman CJ, Roberts RO, Rhodes T, Guess HA, Lieber MM. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997;158(2):481-7. http://www.ncbi.nlm.nih.gov/pubmed/9224329 24. Jacobsen SJ, Jacobson DJ, Girman CJ, Roberts RO, Rhodes T, Guess HA, Lieber MM. Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County Study of urinary symptoms and health status. J Urol 1999;162(4):1301-6. http://www.ncbi.nlm.nih.gov/pubmed/10492184 25. Rhodes T, Girman CJ, Jacobsen DJ, Roberts RO, Lieber MM, Jacobsen SJ. Longitudinal prostate volume in a community-based sample: 7 year followup in the Olmsted County Study of urinary symptoms and health status among men. J Urol 2000;163(Suppl 4):249 abstr 1105. 26. Roberts RO, Jacobsen SJ, Jacobson DJ, Rhodes T, Girman CJ, Lieber MM. Longitudinal changes in peak urinary flow rates in a community-based cohort. J Urol 2000;163(1):107-13. http://www.ncbi.nlm.nih.gov/pubmed/10604326 27. Meigs JB, Barry MJ, Giovannucci E, Rimm EB, Stampfer MJ, Kawachi I. Incidence rates and risk factors for acute urinary retention: the Health Professional Followup Study. J Urol 1999;162(2):376-82. http://www.ncbi.nlm.nih.gov/pubmed/10411042 28. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P, Roehrborn CG, Nickel JC, Wang DZ, Taylor AM, Waldstreicher J. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. New Engl J Med 1998;338(9):557-63. http://www.ncbi.nlm.nih.gov/pubmed/9475762 29. Arrighi HM, Guess HA, Metter EJ, Fozard JL. Symptoms and signs of prostatism as risk factors for prostatectomy. Prostate 1990;16(3):253-61. http://www.ncbi.nlm.nih.gov/pubmed/1691843

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30. Roehrborn CG, Boyle P, Bergner D, Gray T, Gittelman M, Shown T, Melman A, Bracken RB, deVere White R, Taylor A, Wang D, Waldstreicher J. PLESS Study Group. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a fouryear, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology 1999;54(4): 662-9. http://www.ncbi.nlm.nih.gov/pubmed/10510925 31. Roehrborn CG, McConnell JD, Lieber M, Kaplan S, Geller J, Malek GH, Castellanos R, Coffield S, Saltzman B, Resnick M, Cook TJ, Waldstreicher J. PLESS Study Group. Serum prostate-specific antigen is a powerful predictor of acute urinary retention and the need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group. Urology 1999;53(3):473-80. http://www.ncbi.nlm.nih.gov/pubmed/10096369 32. Roehrborn CG, McConnell JD, Bonilla J Rosenblatt S, Hudson PB, Malek GH, Schellhammer PF, Bruskewitz R, Matsumoto AM, Harrison LH, Fuselier HA, Walsh P, Roy J, Andriole G, Resnick M, Waldstreicher J. PROSCAR long term efficacy and safety group. Serum prostate-specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR longterm efficacy and safety study. J Urol 2000;163(1):13-20. http://www.ncbi.nlm.nih.gov/pubmed/10604304 33. Gormley GJ, Stoner E, Bruskowitz RC, Imperato-McKinley J, Walsh PC, McConnell JD, Adriole GL, Geller J, Bracken BR, Tenover JS et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. New Engl J Med 1992 Oct 22;327(17):1185-91. http://www.ncbi.nlm.nih.gov/pubmed/1383816

2. RISK FACTORS 2.1

For developing the disease

The aetiology of BPH is multifactorial. Currently, there is no strong evidence that smoking, vasectomy, obesity or high alcohol intake are risk factors in the development of clinical BPH. Results of the different epidemiolo­ gical studies are controversial, probably because of differences in sampling and methods of analysis. In most cases only insufficient marginal differences can be established (1). Chronic conditions, such as hypertension or diabetes, have been related to clinical BPH, but given the frequent occurrence of these conditions in ageing men a large proportion of patients can be expected to suffer from such an association (2,3). Recently, it has been stated that diabetes and clinical BPH are associated more frequently than would be expected based on chance alone. Although more severe BPH symptoms (increased I-PSS and post-void residual) seem to be found in diabetic males even after age adjustment, the fact that both conditions increase with age and can cause partially similar voiding symptoms, produces a considerable bias (3). The only true factors related to the development of the disease are age and hormonal status (4). The crucial role of the testis has been recognized for more than a century and current research has extended into the field of molecular biology (5). Both of these risk factors are currently beyond prevention.

2.2

For surgical treatment

Although the number of surgical procedures for BPH has declined in the USA and Europe over the last decade (6), they still represent the second most common major operation in aged men (7). Ultimately, three in 10 men may undergo surgery for this condition (2). Surgical risk depends on age and the presence of clinical symptoms. In the absence of clinical symptoms, the likelihood of being treated surgically is about 3% (8,9). The need for surgery increases with symptoms and is twice as high in men with a high baseline-symptom score than for those with a low score (10). For men presenting with urinary retention, the cumulative incidence for prostatectomy is 60% at 1 year and 80% at 7 years (11). Multivariate analysis carried out on a sample of 16,219 men, aged at least 40 years, with a mean follow-up of 12 years, showed a positive association with surgery for age, low body mass index, nonsmokers, urine pH greater than 5, and a history of kidney X-ray and/or tuberculosis, for each of the five clinical urinary symptoms studied (12). In the Veterans Normative Aging Study, in a cohort of 2,280 men, the main predictor for surgery was the presence of urinary symptoms. The risk of requiring subsequent surgery also varied with age, the odds ratio being 1.8 for nocturia and 4.3 for hesitancy in young men (aged < 65 years). Among older men, only nocturia (odds ratio 2.4) was predictive of surgery (13). In the Baltimore study, the three predictive symptoms for surgery were change in size and force of the urinary stream, sensation of incomplete voiding and digital rectal

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enlargement of the prostate. Men with one factor had a cumulative incidence of surgery of 9%, those with two factors of 16%, and those with three factors of 37%. Nevertheless, the same study showed that increasing age was the predominant risk factor for surgery (8). From the above, it can be concluded that the risk of needing surgery for BPH increases with age and with the degree of clinical symptoms at baseline. Nocturia and changes in urinary stream seem to be the most important predictive symptoms.

2.3

REFERENCES

1. Oishi K, Boyle P, Barry JM et al. Epidemiology and natural history of benign prostatic hyperplasia. In: Denis L, Griffiths K, Khoury S et al. eds. Fourth International Consultation on BPH, Paris, July 1997. Plymouth: Health Publications, 1998, pp. 25-59. http://www.congress-urology.org/ 2. Boyle P. Epidemiology of benign prostatic hyperplasia: risk factors and concomitance with hypertension. Br J Clin Pract Suppl 1994;74:18-22. http://www.ncbi.nlm.nih.gov/pubmed/7519437 3. Michel MC, Mehlburger L, Schumacher H, Bressel HU, Goepel M. Effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. J Urol 2000;163(6):1725-9. http://www.ncbi.nlm.nih.gov/pubmed/10799169 4. Isaacs JT, Coffey DS. Etiology and disease process of benign prostatic hyperplasia. Prostate 1989;(Suppl 2):33-50. http://www.ncbi.nlm.nih.gov/pubmed/2482772 5. Voller MC, Schalken JA. Molecular genetics of benign prostatic hyperplasia. In: Kirby R et al, eds. Textbook of Benign Prostatic Hyperplasia. Oxford: Isis Medical Media, 1996, pp. 109-113. http://www.isismedical.com/ 6. Holtgrewe HL, Ackermann R, Bay-Nielsen H et al. Report from the Committee on the Economics of BPH. In: Cockett ATK et al, eds. Third international consultation on benign prostatic hyperplasia (BPH). Jersey: Scientific Communication International, 1996, pp. 51-70. http://www.congress-urology.org/ 7. Meigs JB, Barry MJ. Natural history of benign prostatic hyperplasia. In: Kirby R et al, eds. Textbook of benign prostatic hyperplasia. Oxford: Isis Medical Media, 1996, pp. 125-135. http://www.isismedical.com/ 8. Arrighi HM, Metter EJ, Guess HA, Fozzard JL. Natural history of benign prostatic hyperplasia and risk of prostatectomy, the Baltimore Longitudinal Study of Aging. Urology 1991;38(1 Suppl):4-8. http://www.ncbi.nlm.nih.gov/pubmed/1714657 9. Diokno AC, Brown MB, Goldstein N, Herzog AR. Epidemiology of bladder emptying symptoms in elderly men. J Urol 1992;148(6):1817-21. http://www.ncbi.nlm.nih.gov/pubmed/1279223 10. Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM, Henderson WG. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995;332(2):75-9. http://www.ncbi.nlm.nih.gov/pubmed/7527493 11. Craigen AA, Hickling JD, Saunders CR, Carpenter RS. Natural history of prostatic obstruction: a prospective survey. J R Coll Gen Pract 1969;18(87):226-32. http://www.ncbi.nlm.nih.gov/pubmed/4186545 12. Sidney S, Quesenberry C Jr, Sadler MC, Lydick EG, Guess HA, Cattolica EV. Risk factors for surgically treated benign prostatic hyperplasia in a prepaid health care plan. Urology 1991;38(Suppl 1):13-9. http://www.ncbi.nlm.nih.gov/pubmed/1714653 13. Epstein RS, Lydick E, deLabry L, Vokonas PS. Age-related differences in risk factors for prostatectomy for benign prostatic hyperplasia: the VA Normative Aging Study. Urology 1991; 38(Suppl 1):9-12. http://www.ncbi.nlm.nih.gov/pubmed/1714659

3. ASSESSMENT Diagnostic investigations have been classified as: • recommended: there is evidence to support the use of this test

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• •

optional: this test is done at the discretion of the clinician not recommended: there is no evidence to support the use of this test.

3.1

Symptom scores

Probably the best way to assess symptom severity is with a validated symptom score. A number of instruments exist that can measure symptom severity, bother and quality of life (Table 3) (1). Most instruments in current use conform to acceptable standards of validity, reliability and responsiveness; in other words they measure what they purport to measure, are stable over time and are able to reflect clinically important changes (2). 3.1.1 International Prostate Symptom Score (I-PSS) The I-PSS has become the international standard. It is derived from the American Urological Association (AUA) 7 score described by Barry and his colleagues in the early 1990s (3). By adding the scores (with equal weighting) to its constituent questions, a summary or index score is generated which has been shown to be an accurate reflection of a man’s overall symptoms over the preceding month (4). The extent to which the self-reported scores reflect actual events has been questioned. Men report nocturia with accuracy but tend to overstate daytime frequency. Correlation of the self-reported score to intermittency or to the strength of stream was poor (5). Age and cultural factors may be important. The I-PSS appears less reliable in men over 65 years old (6) and careful linguistic validation needs to be undertaken prior to its use in non-North American cultures (7). Numerous authors have reported and commented upon the poor correlations between I-PSS and other physiological variables. For example, there are numerous reports of symptom severity (as expressed by I-PSS) correlating poorly with peak urinary flow rate, average flow rate, post-void residual volume, prostate size or pressure-flow relationships (1, 8-10). This lack of correlation has troubled many investigators and has led to some questions raised about the validity of the I-PSS. Correlations of similar magnitude have been seen in many other disease areas, e.g. peak respiratory flow correlates poorly with patient’s own reports of the severity of their asthma. The lack of correlation can be explained in two ways. Firstly, I-PSS and physiological measures measure different things. Secondly, there are statistical issues related to the clustering of values or data points, which will also result in poor correlation. A validated symptom score assesses symptom severity. It can be used to monitor change in symptoms over time or following an intervention. 3.1.2 Quality-of-life assessment The impact of urinary symptoms on the quality of life is generally evaluated by means of question 8 of the I-PSS. However, this question measures the extent to which patients tolerate their symptoms rather than evaluating their quality of life. A number of health-related, quality-of-life instruments have been used for clinical research. One of the best known is the generic measure, the Medical Outcomes Study, a 36-item short-form health survey (SF36) (14). It is a self-completed questionnaire used to measure general health status and quality of life. It has been used in a number of studies addressing men with lower urinary tract symptoms. Using this score, a postal population survey among 217 men aged 55 years and over with LUTS showed that, depending on the respondent’s activity, 9-49% of those with moderate or severe urinary symptoms reported interference with some of their daily activities. Increasing symptom severity was associated with worsening physical condition, social functioning, vitality, mental health and perception of general health. Increasing ‘bothersome­ ness’ was associated with a worsening of all dimensions of general health status and quality of life. The association between the outcome of this population survey and the degree of ‘bothersomeness’ was stronger than that with the I-PSS symptom score. 3.1.3 Symptom score as decision tool for treatment Can symptom severity alone be used to allocate treatment? The US Agency for Health Care Policy and Research Guidelines (1) tried to do this. Three categories of symptom severity were described: mild (0-7), moderate (8-19) and severe (20-35). The authors suggested that patients with mild symptoms were most appropriately managed by a watchful waiting approach. Patient with moderate symptoms might benefit from pharmacotherapy, while patients with severe symptoms may derive most benefit from prostatectomy. Although notions of appropriateness have not been well-studied, the proposed policy appears to hold true for patients with mild symptoms but is less reliable for men with moderate or severe symptoms (15). 3.1.4 Symptom score as outcome predictor Symptom score may be one of the more powerful predictors of symptomatic outcome (16). As men with mild symptoms have little room for improvement it is of little surprise that they do not experience high levels of symptom reduction following surgery. A man with a pre-operative I-PSS of 17, or more, has an 87% chance of experiencing a substantial symptom reduction (17). There is little evidence that physiological measures improve

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the chances of predicting a favourable symptomatic outcome. 3.1.5 Conclusions Evaluating symptom severity with a symptom score is an important part of the initial assessment of a man. It is helpful in allocating treatment, and in both predicting and monitoring the response to therapy. 3.1.6 Recommendations Recommended investigations: • Clinical history • Symptom assessment • Physical examination • Validated symptom score, e.g. I-PSS.

3.2 Prostate-specific antigen (PSA) measurement Before selecting the proper treatment for men with LUTS, every urologist will perform a DRE and most will measure the serum value of PSA. 3.2.1 Factors influencing the serum levels of PSA In cases where the architecture of the prostatic gland is disrupted, PSA will ‘leak’ into the circulation. This occurs when prostatic carcinoma is present but also in BPH, prostatitis and after urinary retention. This is why PSA is not considered as being cancer-specific, but organ-specific. Other known causes of PSA serum elevations are biopsy of the prostate gland and ejaculation (1). In addition, small and clinically insignificant changes occur after DRE. Two other important factors, age and race, must also be considered when evaluating PSA values in men with LUTS (2,3). African-Americans with no evidence of prostate carcinoma have higher PSA values after their fourth decade of life, and therefore age-specific reference ranges must be adapted and interpreted according to race and ethnicity (4). A recent community-based study of African-American men contradicts the beliefs of racial PSA differences, since only minor variations in PSA reference ranges were found (5). 3.2.2 PSA and prediction of prostatic volume Stamey et al. were the first to correlate PSA serum values and volume of prostatic tissue (6). In their studies in the late 1980s, they found that the serum PSA contribution from BPH was 0.30 ng/mL per gram of tissue and 3.5 ng/mL per cm3 of cancer tissue. Roehrborn et al, have shown that PSA and prostate volume have an agedependent, log-linear relationship and that PSA has a good predictive value for assessing prostatic volume (7). Vesely et al, also found that prostate volume and serum PSA are significantly correlated and increase with advanced age (8). Prediction of prostate volume can also be based on total and free PSA. Both PSA forms were found to be able to predict the TRUS prostate volume (± 20%) in more than 90% of the cases (9). 3.2.3 PSA and probability of having prostate cancer The chance of having prostate cancer is strongly related with the serum value of PSA. For many years the value of 4ng/mL was considered as the upper normal limit of PSA (10) but lately a lower threshold of PSA for recommending prostate biopsy in younger men has shown to improve the clinical value of this test (11). In order to avoid unnecessary biopsies, Potter et al, (12) have used three clinical parameters - age, PSA and DRE - and have calculated the likelihood of detecting prostate cancer on sextant TRUS-guided biopsies among 2,054 men. At the same time, predictive nomograms have been developed by various groups. These nomograms are being constructed from variables such as age, race, family history, DRE, PSA, PSA density and TRUS findings (13,14). 3.2.4 PSA and prediction of BPH-related outcomes In a series of studies, Roehrborn et al. (15,16) have shown that PSA and prostatic volume can be used to evaluate the risks of either needing surgery or developing acute urinary retention. These parameters were also related with long-term changes in symptom scores and flow rates. In a recent epidemiological study, elevated free PSA levels could predict clinical BPH, independent of total PSA levels (17). 3.2.5 • • • •

12

Conclusions various factors (cancer, BPH, infection, trauma, age, may influence serum PSA levels the level of PSA correlates with the volume of the prostate gland the higher the PSA level, the greater is the probability of having prostate cancer the PSA level might predict the natural history of BPH.

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3.2.6 Recommendation The measurement of PSA is recommended when a diagnosis of prostatic carcinoma will change the decision made about which therapeutic option to use. 3.2.7 1.

References Herschman JD, Smith DS, Catalona WJ. Effect of ejaculation on serum total and free prostate specific antigen concentrations. Urology 1997;50(2):239-43. http://www.ncbi.nlm.nih.gov/pubmed/9255295 2. Oesterling JE, Jacobsen SJ, Chute CG, Guess HA, Girman CJ, Panser LA, Lieber MM. Serum prostate specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860-4. http://www.ncbi.nlm.nih.gov/pubmed/7688054 3. Laguna P, Alivizatos G. Prostate specific antigen and benign prostatic hyperplasia. Curr Opin Urol 2000;10(1):3-8. http://www.ncbi.nlm.nih.gov/pubmed/10650506 4. Eastham JA, Sartor O, Richey W, Moparty B, Sullivan J. Racial variation in prostate specific antigen in a large cohort of men without prostate cancer. J La State Med Soc 2001;153(4):184-9. http://www.ncbi.nlm.nih.gov/pubmed/11394329 5. Cooney KA, Strawderman MS, Wojno KJ, Doerr KM, Taylor A, Alcser KH, Heeringa SG, Taylor JM, Wei JT, Montie JE, Schottenfeld D. Age-specific distribution of serum prostate-specific antigen in a community-based study of African-American men. Urology 2001;57(1):91-6. http://www.ncbi.nlm.nih.gov/pubmed/11164150 6. Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317(15):909-16. http://www.ncbi.nlm.nih.gov/pubmed/2442609 7. Roehrborn CG, Boyle P, Gould AL, Waldstreicher J. Serum prostate specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 1999;53(3):581-9. http://www.ncbi.nlm.nih.gov/pubmed/10096388 8. Vesely S, Knutson T, Damber JE, Dicuio M, Dahlstrand C. Relationship between age, prostate volume, prostate-specific antigen, symptom score and uroflowmetry in men with lower urinary tract symptoms. Scand J Urol Nephrol. 2003,37(4):322-8. http://www.ncbi.nlm.nih.gov/pubmed/12944191 9. Morote J, Encabo G, López M, de Torres IM. Prediction of prostate volume based on total and free serum prostate specific antigen: is it reliable? Eur Urol 2000;38(1):91-5. http://www.ncbi.nlm.nih.gov/pubmed/10859448 10. Barry MJ. Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med 2001;344(18):1373-7. http://www.ncbi.nlm.nih.gov/pubmed/11333995 11. Punglia RS, D’ Amico AV, Catalona WJ, Roehl KA, Kuntz KM. Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen. N Engl J Med. 2003,349(3):335-42. http://www.ncbi.nlm.nih.gov/pubmed/12878740 12. Potter SR, Horniger W, Tinzl M, Bartsch G, Partin AW. Age, prostate specific antigen and digital rectal examination as determinants of the probability of having prostate cancer. Urology 2001;157(6):1100-4. http://www.ncbi.nlm.nih.gov/pubmed/11377318 13. Kalra P, Togami J, Bansal BSG, Partin AW, Brawer MK, Babaian RJ, Ross LS, Niederberger CS. A neurocomputational model for prostate carcinoma detection. Cancer 2003;98(9):1849-54. http://www.ncbi.nlm.nih.gov/pubmed/14584066 14. Garzotto M, Hudson RG, Peters L, Hsieh YC, Barrera E, Mori M, Beer TM, Klein T. Predictive modelling for the presence of prostate carcinoma using clinical, laboratory, and ultrasound parameters in patients with prostate specific antigen levels
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17.

Meigs JB, Mohr B, Barry MJ, Collins MM, McKinlay JB. Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men. J Clin Epidemiol 2001;54(9): 935-44. http://www.ncbi.nlm.nih.gov/pubmed/11520654

3.3

Creatinine measurement

It is well-accepted today that bladder outlet obstruction due to BPH might cause hydronephrosis and renal failure (1). Ten years ago, it was shown that patients with BPH and renal insufficiency had a 25% risk of developing post-operative complications compared with the 17% risk in patients with normal renal function (2). Earlier studies also showed a much higher mortality among BPH patients who underwent surgical treatment when renal insufficiency was present at the same time (3,4). Most studies have found that the incidence of azotaemia in men with BPH varies from 15-30% (5,6). However, these figures might be overestimates as these studies involved patients undergoing surgical treatment (i.e. those with severe symptoms and with urinary retention). A recent study evaluated 246 men presenting with BPH symptoms and found that approximately one in 10 (11%) had renal insufficiency (7). It was also shown that neither the symptom score nor the quality-of-life assessment was associated with serum creatinine levels in patients with BPH. When renal dysfunction was present, diabetes and hypertension were the most probable causes of the elevated creatinine level among this group of patients. This study also noted that it was rather rare to find patients with high creatinine levels due to bladder outlet obstruction only. Comiter et al. (8) reported a study in which voiding dysfunction of a non-neurogenic aetiology did not appear to be a risk factor for elevated BUN (blood urea/nitrogen) and creatinine levels. Bruskewitz et al. (9) also found that an isolated serum creatinine level could not predict the outcome after TURP, as measured by an improvement in quality of life. Despite all of the above, it is p