Seminars in RT: Current Controversies in Rectal Cancer

Volume 21, Number 3

July 2011

Introduction: Current Controversies in Rectal Cancer

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dvances in surgery, radiation therapy, and chemotherapy have contributed to the improvements in the contemporary management of rectal cancer. These advances have translated into improved rates of local control, survival, and quality of life. Historically, surgery alone was the treatment of choice for most patients. However, clinical experience and patterns of failure analyses suggested that pelvic failure was a common mode of recurrence, leading to profound morbidity and death.1,2 Subsequent adjuvant randomized trials rationally evaluated different combinations of radiation therapy and 5-fluorouracil– based chemotherapy. These studies showed that adjuvant chemoradiation improved survival and local control relative to surgery alone, leading to the standard implementation of these therapies by the 1990s.3-5 Because of potential and theoretic benefits associated with a preoperative therapy approach, interest evolved in adopting this approach in rectal cancer patients. Subsequent randomized trials from Europe and the United States proved that simply by altering the sequence of chemoradiotherapy, improved rates of local control, disease-free survival, sphincter preservation, and acute and late toxicity could be achieved, leading to a new paradigm of care.6,7 During this same period, British and other European investigators advocated that through a more complete dissection of the fatty “envelope” surrounding the rectum (ie, the mesorectum or total mesorectal excision), previously unrealized subclinical disease could be removed, thereby obviating the need for radiation therapy.8 However, a large randomized trial from the Netherlands evaluating patients with operable rectal cancer (including stage I disease) receiving preoperative radiation therapy versus surgery alone confirmed a statistical improvement in local control and recurrence-free survival with radiation despite more complete surgery, with potential survival improvement in stage III patients.9 These results were supported by an Medical Research Council (MRC) trial evaluating preoperative short-course radiotherapy versus selected postoperative combined modality therapy.10 Additionally, recent trials from the European Organisation for Research and Treatment of Cancer (EORTC), Fédération Francophone de la Cancérologie Digestive (FFCD), and Polish investigators have all supported the conclusions from older American trials that improved pathologic 1053-4296/11/$-see front matter © 2011 Published by Elsevier Inc. doi:10.1016/j.semradonc.2011.02.001

complete response rates and that local control can be achieved with the addition of chemotherapy to radiation therapy although the survival impact of concurrent chemotherapy in a neoadjuvant approach remains uncertain.11-13 In this issue of Seminars in Radiation Oncology, the ongoing evolution and increasingly complex treatment decision-making process surrounding rectal cancer therapy is highlighted by a series of articles examining newer staging and treatment strategies, including areas of controversy. The lead article describes the emerging role of magnetic resonance imaging in the initial staging and therapeutic algorithm in rectal cancer patients, followed by 2 articles describing the changing roles of surgery, including local excision as well as more contemporary radical resection approaches, with emphasis on sphincter-preservation techniques. The articles following detail newer roles of chemotherapy, including the use of chemotherapy alone (without radiation therapy) in the neoadjuvant setting as well as the use of newer, novel chemotherapeutic agents and targeted therapies in combination with radiation. The final series of articles focuses on controversial topics directly relating to the role of radiation therapy including the omission of radiation therapy in select stage II rectal cancer patients; point-counterpoint articles comparing the roles of short-course, accelerated radiation therapy alone with long-course chemoradiotherapy; and, finally, a review of the controversial (nonoperative) approach of chemoradiotherapy alone in highly selected patients. We would like to thank the authors for their contributions, which aid us in the understanding of this malignancy as well as the care of our patients, and our patients, whose willingness to undergo newer treatment strategies has allowed meaningful progress to occur in this disease. We hope you enjoy reviewing this work. Brian G. Czito, MD Christopher G. Willett, MD Guest Editors

References 1. Gunderson LL, Sosin H: Areas of failure found at reoperation (second or symptomatic look) following “curative surgery” for adenocarcinoma

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of the rectum. Clinicopathologic correlation and implications for adjuvant therapy. Cancer 34:1278-1292, 1974 Rich T, Gunderson LL, Lew R, et al: Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer 52:1317-1329, 1983 Gastrointestinal Tumor Study Group: Prolongation of the disease free interval in surgically treated rectal carcinoma. N Engl J Med 312:14651472, 1985 Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991 Wolmark N, Wieand HS, Hyams DM, et al: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project protocol R-02. J Natl Cancer Inst 92:388-396, 2000 Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:17311740, 2004 Roh MS, Colangelo LH, O’Connell MJ, et al: Preoperative multimodal-

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ity therapy improves disease free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 27:5124-5130, 2009 Heald RJ, Moran BJ, Ryall RD, et al: Rectal cancer: The Basingstoke Experience of total mesorectal excision, 1978-97. Arch Surg 133:894899, 1998 Marijnen CA, van Gijn W, Nagtegaal ID, et al: The TME trial after a median follow-up of 11 years (abstract 1). Presented at the 52nd Annual ASTRO Meeting, November 1, 2010 San Diego, OA Sebag-Montefiore D, Stephens, RJ, Steele R, et al: Preoperative radiotherapy vs selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicenter, randomized trial. Lancet 373:811-820, 2009 Bujko K, Nowacki M, Nasirowska-Guttmejer A, et al: Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomized trial comparing short-term radiotherapy vs conventionally fractionated radiochemotherapy. Radiother Oncol 75:15-24, 2004 Bosset JF, Collette L, Calais G, et al: Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114-1123, 2006 Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leukovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 24:4620-4625, 2006

Rectal Cancer: Primary Staging and Assessment After Chemoradiotherapy Jessica Evans, MBBS, MRCS, Uday Patel, FRCR, and Gina Brown, MD, FRCR Rectal cancer staging is based on 2 principles. The first is an anatomic definition of the tumor allowing for surgical planning. The second is prognostic stage grouping. A given prognostic stage carries different risks of both local and distant recurrence, a selective and tailored approach to preoperative therapy is appropriate. Increasingly, selective approaches enable an overall reduction in morbidity from overtreatment, while allowing aggressive treatment of high-risk patients. Therefore, the aim of preoperative staging is to accurately and reproducibly differentiate between good and poor prognosis tumors. In the preoperative setting, superficial and flat rectal cancers are probably best initially staged using endoscopic ultrasound, and where available magnetic resonance imaging is used for all other rectal cancers because of its proven high sensitivity and specificity in identifying poor-risk patients based on circumferential margin status, the depth of extramural spread, extramural venous invasion, and nodal status. Restaging after neoadjuvant therapy is a challenge to all modalities because of radiation-induced changes, namely fibrosis, edema, inflammation, and necrosis. However, emerging data suggest that reassessment using a combination of high-resolution magnetic resonance imaging, diffusion-weighted imaging, and positron emission tomography/computed tomography scanning may help to provide valuable prognostic information before definitive surgery. Semin Radiat Oncol 21:169-177 © 2011 Elsevier Inc. All rights reserved.

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ectal cancer staging is based on 2 principles. The first is defining the pertinent anatomy, allowing for surgical planning. The second is to allow prognostic stage grouping. Because a given prognostic stage carries different risks of both local and distant recurrence, a selective and tailored approach to preoperative therapy is appropriate. Increasingly, selective approaches enable an overall reduction in morbidity from potential overtreatment, while allowing aggressive treatment of high-risk patients. Therefore, the aim of preoperative staging is to accurately and reproducibly differentiate between good and poor prognosis tumors. This article focuses on local staging before and after treatment.

Royal Marsden Hospital, Surrey, England. Gina Brown is supported by the Royal Marsden NIHR Biomedical Research Centre. Jessica Evans is supported by the Royal College of Surgeons Fellowship and Croydon Colorectal Charity. Address reprint requests to Gina Brown, MD, FRCR, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM7 2EX, UK. E-mail: gina. [email protected]

1053-4296/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2011.02.002

Selection of Patients for Preoperative Treatment Based on Prognostic Features The assessment of morphologic features by histopathologists in the resected rectal specimen remains the most robust method of prognostic stratification. These features include assessment of depth of spread, nodal status, extramural vascular invasion (EMVi), the circumferential resection margin (CRM), and peritoneal perforation.

Extramural Depth/T Stage A number of histopathological studies have shown that T3 tumors with ⬎5 mm of extramural invasion have a cancerspecific 5-year survival rate of approximately 54% but of over 85% when the depth is 5 mm or less.1 Therefore, it is not the distinction between T2 and T3 that may potentially govern treatment decisions but the identification of high risk patients with an extramural tumor spread of ⬎5-mm depth of extramural tumor invasion. It is also known that with increasing spread of tumor into the perirectal fat, there is an increase in nodal involvement.2 Therefore, the depth of ex169

170 tramural spread is a key factor in determining prognosis and aiding selection of patients for preoperative therapy.

Lymph Node Involvement Dukes’ original paper highlighted the strong relationship between the depth of spread through and beyond the muscularis propria and the risk of lymph node involvement.3 Lymph node involvement is an independent adverse prognostic factor, and the effect in total mesorectal excision (TME) specimens is more pronounced when 4 or more lymph nodes are involved.4 In the pre-TME era, any nodal involvement predicted for pelvis recurrence. However, there is now evidence suggesting that a low burden of nodal involvement (N1) with a TME procedure is not associated with an increased risk of pelvic recurrence.4

Circumferential Resection Margin CRM involvement is an important independent prognostic factor in the assessment of rectal cancer. This was first brought to light in 1986 following work by Quirke et al from Leeds in which after the examination of 52 resected rectal cancer specimens, they found that in 14 (27%) the tumor involved the lateral resection margin (defined as tumor within 1 mm), and, of these, 12 went on to develop a pelvic recurrence.5 A national audit of 686 patients in Norway showed that despite TME surgery 9% of patients had a positive CRM, and, of these, 22% developed local recurrence compared with only 5% of CRM-negative patients.6 This was independent of nodal status, and none of the patients received pelvic radiotherapy. CRM positivity is also a poor prognostic factor for survival, with 40% of patients going on to develop distant metastases, with double the risk of death.6-8 Therefore, the identification and aggressive treatment of potentially CRM-positive patients is a crucial factor in preventing unwanted pelvic recurrence in patients undergoing TME surgery.

Extramural Vascular Invasion In the 1980s, Talbot et al9 reported 5-year survival of only 33% in patients with invasion of extramural veins by tumor.9 Other studies have showed that venous invasion independently predicts for poor survival10-12 and local13 and distant metastases.14-16 In TME specimens, tumoral EMVi remains an important predictor of both local and distant failure.

Peritoneal Involvement Peritoneal involvement is defined as a tumor present at the peritoneal surface with inflammatory reaction/mesothelial hyperplasia/ulceration or tumor cells demonstrated free in the peritoneum and evidence of adjacent “ulceration.” Local peritoneal involvement in rectal cancer conveys considerable prognostic implications, predicting for local recurrence. In Shepherd et al’s study,17 approximately 26% of cases had histologic confirmation of peritoneal involvement, with a higher incidence in women and upper rectal cancers. Clearly, this is an important cause of pelvic failure, but the prevention and treatment of peritoneal perforation by the primary tumor have not been specifically addressed in clinical trials. Of note is that many centers will not offer preoperative therapy to patients with tumors at or

J. Evans, U. Patel, and G. Brown above the peritoneal reflection. Therefore, further clinical studies for this group of patients are needed. In terms of managing patients in the preoperative phase, the following features need to be assessed: (1) depth of extramural spread in mm (⬎5 mm vs not), (2) CRM status (tumor ⬍1 mm to mesorectal fascia), (3) EMVi (present or not), (4) lymph node status (N2 disease before TME surgery), and (5) peritoneal perforation by tumor.

Assessment of Known Prognostic Features by Imaging Available imaging modalities for the staging of rectal cancer include ultrasound, computed tomography (CT) scan, magnetic resonance imaging (MRI), and fluorodeoxyglucosepositron emission tomography (FDG-PET). When considering which test to use, diagnostic accuracy, reproducibility, cost-effectiveness, and availability need to be considered.

Modalities of Local Staging Intraluminal Endoscopic Ultrasound in Local Cancer Staging Intraluminal endoscopic ultrasound (EUS) is undertaken with a flexible or rigid ultrasound probe, which may be passed through a short rectoscope to assess higher lesions. The 5 layers of the bowel wall can be examined, and the depth of tumor invasion can be assessed for T staging. In studies excluding fixed tumors, tumors of the upper rectum, and patients with bulky or stenosing tumors, the accuracy of T staging has been reported to be 90% using EUS.18-20 A subsequent study of 1,184 patients with rectal cancer confirmed that EUS is very accurate for early-stage low tumors (T1 and T2), with a sensitivity of 94% and specificity of 86% but performs less well in cases of advanced rectal cancer.21 However, EUS should be used with caution when examining bulky villous adenomas because it is hard to visualize the layers deep to the polyp.22 High-frequency EUS (approximately 23 MHz) provides very detailed images of the mucosa and submusosa. Therefore, it is useful in the assessment of early noninvasive T1 tumors distinguishing between SM1, SM2, and SM3 lesions. This definition is important because it will help determine whether local excision is possible because the SM stage relates to the risk of nodal involvement (ie, 0% nodal involvement in SM1 and 25% nodal involvement SM3).23 EUS can detect lymph nodes that are 5 mm or greater in size. The overall accuracy of nodal staging by EUS has been reported to be 73% to 83%.24-27 However, Spinelli et al’s examination28 of 131 specimens showed a significant reduction in the accuracy of EUS according to the pathologic technique. The overall accuracy decreased from 76% to 43% and for metastatic lymph nodes ⬍5 mm in diameter, the sensitivity of EUS was significantly lower (P ⫽ .025). An estimated 50% of metastatic lymph nodes associated with rectal cancers are smaller than 5 mm. The mesorectum and peritoneum cannot be visualized by EUS, and, hence, the CRM status and degree of peritoneal involvement cannot be determined. Although large perirectal

Rectal cancer vessels may be visualized using EUS, there are very little published data on its ability to determine EMVi. Disadvantages in the EUS assessment of rectal tumors include its limited ability to examine stenosing, bulky lesions, or lesions of the upper rectum. It is also unable to reliably distinguish between fibrosis and tumor or whether the mesorectal fascia is involved. The procedure is operator dependent, with significantly lower performance with less experienced sonographers.21,29 EUS is invasive and potentially uncomfortable for the patient.30 However, it is relatively widely available and inexpensive. EUS is a valuable surgical assessment tool providing useful clinical information regarding the size and location of the tumor: (1) EUS is invaluable in identifying flat lesions suitable for local excision; (2) EUS lacks sufficient accuracy to determine prognosis of tumors that have breached the muscularis propria; (3) EUS cannot identify patients at an increased risk of local failure because of the inability to assess the CRM; and (4) other prognostic factors such as extramural venous invasion, nodal assessment of the mesorectum, and peritoneal perforation are not assessable.

CT Scanning CT scanning offers the opportunity in a single examination to stage rectal cancer both locally and distantly. It is readily available and relatively inexpensive and not prone to operator expertise. It also appears to be the most frequently used modality for local staging of primary rectal cancer in the United States.31 When examining advanced disease, CT scanning determines T stage with an accuracy of 79% to 94%; however, this falls to 52% to 74% when less advanced, smaller tumors are analyzed.32 This reduction in accuracy is caused by a lack of detailed spatial and contrast resolution. Lymph node involvement is assessed predominantly using size criteria when using CT scanning, with nodes ⬎1 cm being deemed abnormal and, to a lesser extent, morphology. This results in a very poor sensitivity of only 22% to 73%33 and overall poor accuracy because the vast majority of lymph node metastases occur in smaller nodes (⬍5 mm).34 Despite numerous attempts to determine CRM status using CT scanning, none have matched the accuracy shown using MRI, and, therefore, as a modality for detecting patients with potential CRM involvement, the sensitivity and specificity remains unacceptably poor.35,36 Other prognostic factors such as extramural venous invasion, nodal assessment of the mesorectum, and peritoneal perforation are not reliably assessed.37,38 CT scanning is a helpful modality for staging distant metastatic spread but provides only limited local staging information. However, CT scanning is not suitable for assessing early tumors because these are often not visualized, cannot reliably assess the depth of the extramural spread or nodal status, has insufficient sensitivity for the detection of EMVi and peritoneal disease, and is not recommended for assessing the potential CRM.

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MRI in Local Rectal Cancer Staging The use of the phase-array coil MRI (since the mid-1990s) and the development of T2-weighted fast-spin sequences have enabled thin-section MRI to delineate rectal tumors more accurately through an increase in spatial and contrast resolution. This allows accurate determination of prognostic features as well as anatomic assessment of the pelvis. Agreement between phase-array MRI and histopathology in predicting tumor stage was originally established by a number of single-center studies, including a prospective study by Brown et al39 that showed a 94% agreement between MRI and pathologic assessment of T stage. The multicenter MERCURY study directly compared the extramural depth of invasion measured by MRI and histopathology in 295 of 311 patients. The mean difference between MRI and histopathology was ⫺0.046 mm (standard deviation ⫽ 3.85 mm; 95% confidence interval, ⫺0.487 to 0.395 mm), thereby showing MRI to be equivalent to a histopathology assessment of depth to within 0.5 mm in terms of predicting depth of extramural tumor spread.40 Fifteen percent to 42% of patients with rectal cancer have small (⬍5 mm) mesorectal lymph nodes that contain a tumor.34 There is considerable overlap in size between normal, reactive nodes and those containing a tumor. Therefore, size is not advocated as a reliable way of assessing whether lymph nodes are involved. By determining mixed intranodal signal and/or irregularity of the border, MRI can determine lymph node involvement with 85% accuracy compared with the histopathology reference standard.39 However, a negative MRI scan of the lymph nodes is insufficient evidence to proceed with a local excision because imaging techniques cannot be expected to identify micrometastases within lymph nodes. Some promise in distinguishing between N0 and N1/2 disease has been shown by using MRI with lymph node–specific contrast enhancement; however, such agents only provide a modest improvement in accuracy compared with the morphologic assessment of border and signal-intensity characteristics. For example, the use of ultrasmall iron oxide particles had a higher diagnostic specificity than conventional high-resolution MRI but the same sensitivity as morphologic findings in pathologically matched mesorectal lymph nodes. This technique has another major advantage in displaying the anatomic distribution of nodes both within and outside the mesorectum and is, therefore, valuable as a tool for planning radiotherapy target volumes. The mesorectal fascia is the potential CRM in patients undergoing TME surgery. Its MRI appearance was first described in 1999, and in a subsequent article by Bissett et al,41 it was confirmed that the mesorectal fascia encompasses the entire mesorectum below the level of the peritoneal reflection. A retrospective study showed a high degree of correlation between the distance to the fascia and that of histopathology and hypothesized that a 5-mm cutoff could identify patients with involved CRM.42 The accuracy of high-resolution MRI scanning to detect involvement of the surgical CRM

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was prospectively investigated by the MERCURY Group from the Pelican Cancer Foundation.43 The definition of CRM involvement used by MERCURY radiologists was a tumor within 1 mm of the mesorectal fascia. The results of 408 consecutive patients from 12 colorectal units in 4 European countries showed the technique to be highly accurate and reproducible in the multicenter setting with 92% specificity for a clear CRM (confidence interval, 90%-95%). The ability to detect extramural venous invasion, which is a feature characterized by serpiginous tumor signal intensity extending beyond the muscularis and following the course of extramural vessels, was first described in 2003.39 Smith et al44 showed a 4-fold higher risk of distant metastases (52% vs 12%) and a 3-year relapse-free survival of only 35% when EMVi was present on preoperative MRI versus 74% for patients with no EMVi. Therefore, MRI prediction of EMVi is an important prognostic factor that identifies patients at risk of both local and distant failure. Peritoneal infiltration by a tumor has been described in a single prospective series and is identified by intermediate signal intensity protrusion through and beyond the peritonealized surface of the rectum (anteriorly).40 MRI may enable the visualization of gross perforation of the peritoneum by tumor but not of microscopic ulceration. The identification of the peritoneal attachment and distinction of the peritonealized surface from the surgical CRM is also an important one because involvement of the latter by tumor requires preoperative radiotherapy (Fig 1A and B). MRI has several advantages in the staging of the primary tumor and is considered the modality of choice for local staging of rectal cancer. MRI has the ability to accurately measure depth of extramural spread, is the best of available modalities for assessing nodal status, can accurately predict tumor involvement of the potential CRM in patients undergoing TME surgery, and is the only modality that can identify tumors with extramural venous invasion (an important biomarker for the development of metastatic disease).

PET/CT Scanning PET enables the measurement and visualization of metabolic changes within cancer cells. The poor spatial resolution and lack of detailed anatomy provided by FDG-PET make the determination of the degree of local tumor spread, EMVi, CRM status, or relationship to the sphincter complex difficult. Studies have shown that PET/CT scanning can reliably detect colorectal cancer but not its depth of invasion and, hence, T stage.45 Existing data have shown that FDG-PET is disappointing at predicting lymph node involvement with a reported sensitivity of only 29%.46 Therefore, it is not recommended for local staging of the primary tumor. Overall, there is currently limited evidence in regards to the specificity and sensitivity of FDG-PET in the initial staging of rectal cancer. The combination of anatomic imaging, provided by CT scanning, and metabolic data from FDG-PET may provide more detailed information. However, PET/CT scanning remains unproven in the setting of initial staging. It may, however, be useful in detecting occult synchronous

Figure 1 (A) Example of tumor extending to potential circumferential resection margin before treatment (white arrow-extensive extramural spread, black arrow-infiltrating mesorectal fascia). (B) After treatment, showing substantial regression of extramural spread (white arrow).

tumors or metastases at the time of initial presentation, but the detection rate is too low to justify the costs and radiation exposure for its routine use. At present, PET is reserved for the staging of patients before surgery for recurrence or distant metastases and the localization of recurrence in patients with an unexplained rise in serum carcinoembryonic antigen (CEA). PET-CT can be a helpful modality for staging distant metastatic spread, particularly if radical surgery is considered but provides no local staging information. Table 1 shows the relative strengths of varying preoperative staging modalities.

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Table 1 Preoperative Staging: Modality Strengths CRM T Stage N Stage EMVi Peritoneum EUS NA CT ⴙ MRI ⴙⴙⴙ PET/CT NA

ⴙⴙⴙ ⴙⴙ ⴙⴙⴙ NA

ⴙⴙ ⴚ ⴙⴙⴙ ⴙ

NA ⴙ ⴙⴙⴙ NA

NA ⴙ ⴙⴙ NA

NA, not applicable.

The Assessment of Response to Treatment Surgical Planning The identification of excellent versus poor responders before definitive surgery is an important goal. For example, excellent responders may be offered less radical treatment,47 and poor responders could be considered for more radical surgery or second-line chemotherapy/radiotherapy. Downstaging, including complete response and partial response, has been found to be associated with a better prognosis in most series, and histopathologists have reported that in up to 25% of patients, no residual tumor (pathological complete response [pCR]) is seen on pathologic examination (ie, a complete response of a locally advanced tumor to neoadjuvant combined modality therapy).48 There has been growing interest in selecting those patients who are likely to have achieved pCR. This is of particular relevance for patients with low rectal cancers who would otherwise require an abdominoperineal resection. Although the identification of these patients is impossible with a single scan, it is reasonable to adopt a policy of stringent monitoring with serial imaging, clinical examination, and CEA, especially in individuals who refuse a stoma and those with significant comorbidities (ie, high risk for surgery). This strategy of monitoring and the deferral of surgery in such patients is being investigated in an ongoing clinical trial.49 In patients with low rectal cancer, chemotherapy/radiotherapy may shrink the tumor away from the anal verge. This craniocaudal regression could potentially facilitate a change in surgical strategy, from that requiring a permanent stoma to a sphincter-preserving operation. Although much debate continues regarding the safety of such an approach, reliable imaging is important in this decision-making process. The assessment of response is vital in all cases of rectal cancer after the completion of preoperative therapy to determine the timing/deferral of surgery and the type of operation. There is little evidence for other modalities apart from MRI for surgical planning because it reliably shows the status of the CRM and the anatomy of the pelvic floor.

How Is Response Assessed? Standardized criteria (response evaluation criteria in solid tumors [RECIST]) have been developed to determine the response with a tumor classified as responding if the largest diameter of tumor has decreased by at least 30%.50 However, this is an arbitrary figure that is not based on outcome data, and nontumoral masses may persist. Therefore, the assess-

ment of response is not only by the reduction in size but the reduction or absence of the pretherapy prognostic factors including the extramural depth of invasion, nodal status, CRM, EMVi, and peritoneal involvement. EUS studies comparing the sonographic appearance and histopathology have shown that EUS cannot reliably differentiate between fibrosis and tumor51,52 and, hence, the degree of downstaging. In Rau et al’s study51 of 84 patients with locally advanced rectal cancer, EUS was performed 4 to 6 weeks after the completion of chemoradiotherapy (CRT). The T stage was correctly determined in 15 of the 51 responders (29%) and in 27 of 33 nonresponders (82%), whereas misinterpretation occurred in 36 of the responders (71%) and in 6 of the nonresponders (18%) (P ⬍ .001). The distance of the tumor from the anal verge and tumor location on EUS did not correlate with the staging accuracy. Lymph node involvement was correctly assessed in 48 patients (57%). This supported previous work in which an accuracy of only 47% in determining T stage has been reported.53 Neither pre- nor postchemoradiotherapy EUS can visualize the CRM or peritoneum and therefore is unable to determine their status. Therefore, EUS is not recommended for the assessment of patients after CRT or radiotherapy because its sensitivity and specificity for the reassessment of the primary tumor is too unreliable.

CT Scanning In a recent prospective study of 90 locally advanced rectal cancer patients, the accuracy of CT scanning in determining ypT stage was only 37% and nodal stage 62%. Over 90% of patients in this study had a negative CRM status postchemoradiotherapy, which was correctly predicted in 71%.54 The authors concluded that CT scanning, MRI, and EUS findings would have no impact on the therapeutic outcome of chemoradiation-treated patients with locally advanced rectal cancer because of poor agreement with histopathologic staging. Perfusion CT scanning in rectal cancer and its assessment of tumor vascularity and perfusion change as a means of determining response to CRT has not been assessed but may provide some information regarding response effects in the future. The main role for CT scanning in the management of rectal cancer is the initial identification and assessment of response of distant metastatic disease.

MRI Initial studies comparing post-therapy MRI and histopathology showed a relatively poor accuracy. In 2005, by Kuo et al55 (n ⫽ 36) and Chen et al56 (n ⫽ 50) found that MRI T stage had an accuracy of 47% and 52% when compared with pathologic T stage. Allen et al57 recorded similar results, with 18 of 30 (60%) tumors correctly T staged after treatment. Concordance between postchemoradiation therapy MRI and histologic stage was only fair to moderate (␬ ⫽ 0.40; 95% confidence interval, 0.10-0.66).57 The main reason for these poor results with early MRI was the inability to completely differentiate the changes of postchemoradiation fibrosis from residual tumor and the use of low-resolution scanning tech-

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174 niques.55,56 A greater appreciation of the reactive changes that occur in normal rectal tissue after CRT and a better understanding of the appearance of residual disease on MRI postchemoradiotherapy have since evolved. Combined with technological advancements enabling high-resolution (3 mm) slices to be oriented through the plane of the tumor, MRI accuracy has improved. Barbaro et al58 (n ⫽ 53) analyzed the correlation between pathologic T stage and MR T stage in 53 rectal cancer patients after CRT. This study grouped pathologic and radiologic T stage into T0-T2 (responders) and T3-T4 (nonresponders). Of the 36 MR T-stage responders, 30 were pathologic responders; of the 17 MR T-stage nonresponders, 12 were pathologic nonresponders. The overall accuracy of MR was 79%.58 Dresen et al,59 using the same radiologic and pathologic grouping between T0-T2 tumors versus T3-T4 tumors, found of the 11 yMR T0-T2 staged patients, 10 were pathologic ypT0-T2, whereas of the 56 yMR T3-4 staged patients, 42 were pathologically staged as yp3-4.59 The morphologic criteria (ie, irregular edge, signal inhomogeneity, and size) for MRI determination of lymph node status also apply after CRT. However changes in the morphologic appearance of lymph nodes, such as high-signal mucinous denegation, can also occur.60 MRI interpretation of lymph node status after CRT has been established as being reliable with reports of accuracy as high as 87%.58,60 A patient whose tumor is at or beyond the potential surgical margin (CRM) on baseline imaging may sustain regression to within the CRM after CRT, thus making him/her a candidate for TME excision. Similarly, continued involvement of the CRM after CRT is important because patients with resection margins that continue to be potentially involved could be offered either further neoadjuvant treatment or have more extensive radical resection.44 The accuracy of high-resolution MRI scanning to detect involvement of the surgical CRM after CRT was prospectively investigated by the MERCURY study group in 97 patients.43 The prediction of clear margins was correct in 59 of 60 patients with MRIdefined clear mesorectal fascia. Patients with involved margins were also identified correctly although just over half of the patients with MRI-predicted involved margins went on to have clear histopathology CRM. This was noted to be caused by a combination of extended surgery to clear the potentially involved margins and tumor signal at mesorectal margins not found to contain viable tumor on pathology assessment. Overall, MRI is considered helpful in the reassessment of tumors after CRT, particularly with respect to the assessment of the potential CRM.

MRI Diffusion-Weighted Imaging Diffusion-weighted imaging (DWI) explores the random motion of water molecules in the body. The degree of restriction of water diffusion in biological tissue is inversely correlated to the tissue cellularity and the integrity of cell membranes. Therefore, tissue contrast in DWI is derived from differences in the diffusion of water between tissues.

By applying a pair of strong magnetic field gradient pulses within the imaging sequence, imaging is sensitized to random-spin displacements of diffusing free-water molecules. The apparent diffusion coefficient (ADC) can be calculated from DWI measurements. The ADC is a measure of restriction to the diffusion of molecules by structures such as cell membranes, allowing inferences to be made about the microstructure of the cellular environment. Therefore, diffusionweighted MRI has been suggested as a tool to distinguish different tissue compartments and to detect changes in cellular tissue structure, which could be used to monitor effects of radiation in tumor tissue.61 The first study assessing the correlation of tumor ADC values with a response to chemoradiation was performed by Dzik-Jurasz et al62 in 2002. A significant difference between the mean ADC of responders and nonresponders was shown before (P ⫽ .03) and after chemotherapy (P ⫽ .03) but not after the end of chemoradiation (P ⫽ .20).62 Two larger more recent studies have had similar conclusions. Kim et al63 investigated the added value of DWI in the evaluation of the complete response to neoadjuvant-combined CRT in patients with locally advanced rectal cancer. The mean tumor ADC values in the pathologic complete response group were compared with those in the pathologic noncomplete response group. The mean ADC values in the responders (n ⫽ 11) was significantly higher than that of the noncomplete responders group (n ⫽ 29) (P ⬍ .0001).63 In a recent prospective study, the mean tumor ADC values in the downstaged patients (n ⫽ 17) before treatment were significantly lower than that of the nondownstaged group (n ⫽ 20) (P ⬍ .013). However, the authors failed to show a difference in ADC values at the end of the second week of CRT or on MRI immediately presurgery.64 In general, ADC values do appear to reflect tumor activity after treatment with persistent low values suggestive of poor response.

PET/CT Scanning PET is unable to evaluate anatomic tumor change or predict CRM status.65 It may, however, be used to assess the metabolic response of the tumor. A significant reduction of standardized uptake values (SUVs) on postradiation PET of responders compared with nonresponders has been noted by a number of studies.66-68 Capirci et al69 studied 44 patients with locally advanced rectal cancer who were imaged with FDG PET before and 5 to 6 weeks after the completion of CRT. The pretherapy SUV values were not predictive of pathologic response. However, the response index (SUVinitial ⫺ SUVfinal)/SUVinitial) showed a good correlation with the Mandard tumor regression grade (TRG). A cutoff of a 66% decrease in SUV allowed differentiation of responders (8 TRG1 ⫹ 15 TRG2) from nonresponders (9 TRG3 ⫹ 13TRG 4-5) with 80% overall accuracy. Kalff et al70 studied the use of PET before and 3 to 4 weeks after the completion of CRT. Response was graded as complete, partial, or absent. After a median follow-up of 3.1 years, all those with complete metabolic response were free of disease. Only 6 of 10 patients

Rectal cancer with a partial response were disease free, and all 3 patients who had not responded had died. Cascini et al71 found that a threshold of 52% decrease in the SUVmean resulted in an accuracy of 100% when distinguishing between histologic responders (TRG1-2) from nonresponders (TRG3-4). When using SUVmax values, a cutoff of a 42% decrease in SUVmax identified responders from nonresponders with an overall accuracy of 94%. These preliminary studies support the use of FDG PET in identifying the response to CRT for rectal cancer, but this needs to be validated in a prospective clinical trial. However, initially following the completion of CRT, an increased FDG uptake may be caused by inflammatory changes and not always associated with a residual tumor.72-74 PET is unable to distinguish viable tumor from scar tissue and is not sensitive in detecting mucin. There are a number of limitations in using PET for restaging of rectal cancers. The first is variation in definitions and parameters used for defining a good versus a poor response. The second is uncertainty regarding the timing of PET imaging after the completion of radiotherapy. The question of when to undertake PET after the completion of CRT to assess the response is currently unanswered, with initial studies suggesting an interval of only 6 weeks being too soon to confirm metabolic response.75 Therefore, at present, the role of PET in postchemoradiotherapy restaging is not well established. In the future, PET may provide additional information in assessing response; however, PET needs to be formally compared with existing methods.

Conclusions In the initial preoperative setting, superficial, low-lying rectal cancers are probably best initially staged using EUS, and, where available, MRI should be used for all other rectal cancers because of its proven high sensitivity and specificity in determining T-stage, EMVi, and CRM. Postchemoradiotherapy restaging is a challenge to all modalities because of radiation-induced changes, namely fibrosis, edema, inflammation, and necrosis. However, emerging data suggest that reassessment using a combination of high-resolution MRI, DWI, and PET/CT scanning may help to provide valuable prognostic information before definitive surgery.

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Local Excision: Is It an Adequate Substitute for Radical Resection in T1/T2 Patients? Y. Nancy You, MD, MHSc Local excision (LE) was historically developed to palliate patients with rectal adenocarcinoma who either are medically unfit or have adamantly refused to undergo transabdominal standard resection (SR) procedures. Over the years, the tradeoffs between the oncologic benefit and adverse functional sequelae associated with SR procedures have been increasingly recognized. In parallel, there has been growing interest in considering LE as an alternative to SR in select patients with early-stage disease. However, concerns regarding its oncologic adequacy remain. These concerns relate to the adequacy of tumor resection, the removal of mesorectal disease, the accuracy of preoperative selection, and the use of adjunctive treatment modalities. Evolving strategies that aim at improving the oncologic outcomes of LE for stage I T1/T2 rectal cancers include adoption of transanal endoscopic microsurgery and the addition of non-surgical modalities. Current evidence surrounding these approaches is examined to provide a basis for an informed discussion with patients. Key factors to be considered in formulating the treatment plan for an individual patient with T1/T2 rectal cancer are summarized. Semin Radiat Oncol 21:178-184 © 2011 Elsevier Inc. All rights reserved.

P

atients with rectal cancer often identify 3 major goals of therapy: maximizing survival benefit, minimizing disease recurrence, and preserving preoperative bowel function and health-related quality of life. In the current era of personalized medicine, treating physicians are challenged to formulate a treatment plan that achieves the best balance of these goals, given the individual patient and his/her disease. Fortunately, the contemporary armamentarium of the multidisciplinary treatment team includes a variety of surgical procedures that range from local excision (LE) to multivisceral pelvic exenteration as well as radiation (RT) and chemotherapy administered before or after surgical intervention. For patients with stage I T1/T2 rectal cancer, local management of rectal cancer has been increasingly considered as an alternative to traditional transabdominal resection. Given the increasing interest in organ and sphincter preservation, LE has rapidly gained appeal. However, its oncologic adequacy remains controversial. The aim of this article was to critically examine whether LE may be considered an adequate alternative to standard resection (SR) procedures in selected patients

with the earliest-stage rectal cancer. Factors that must be considered when formulating an individualized treatment plan for a given patient will be summarized.

Technical Aspects of LE and SR Local Excision The most commonly practiced local management option is transanal tumor excision. This can be accomplished either via a conventional transanal excision technique (TAE) or an operating microscope (transanal endoscopic microsurgery [TEMS]). Alternative approaches include the posterior proctotomy approach of Kraske et al,1 first described in 1885,1 and the posterior transsphincteric approach of Mason,2 first described in the early 1900s and reintroduced in the 1970s. In addition, transanal fulguration and electrocoagulation of rectal tumor are considered only for palliation.3 Because these latter approaches are rarely used today, this article mainly focuses on the transanal approaches.

Conventional TAE Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Y. Nancy You, MD, MHSc, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 444, Houston, TX 77030. E-mail: [email protected]

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The preoperative preparation for TAE is relatively uncumbersome. Depending on surgeon preference, distal enemas combined with intraoperative rectal irrigation typically constitute adequate preparation. General anesthetic is usually required, but exceptions can be made for those with severe comorbidi-

Local Excision ties. For anterior and lateral lesions, the patient is placed in a prone jackknife position for the procedure, whereas the lithotomy position is used for posterior lesions. Exposure and instrumentation of TAE limit its application to only rectal cancers with certain physical characteristics. Currently, there is general agreement that the ideal tumors for TAE are ⬍4 cm in greatest diameter, located below the middle rectal valve or within 8 cm of the dentate line, and comprising no more than 40% of the rectal circumference. The technical feasibility of TAE is challenged when these parameters are exceeded. Several technical aspects of TAE can directly influence its outcome. TAE aims to completely excise the tumor-containing bowel wall. After achieving adequate exposure and visualization, the planned resection margin should be marked before the tumor-containing bowel is handled. Adequate resection margin should consist of at least 1 cm of normal tissue circumferentially. Care must be taken to avoid fragmenting the specimen. The excised specimen should be full thickness, and this can be confirmed by visualization of the mesorectal fat after excision. TAE does not aim to remove nodal tissue in the mesorectum; however, mesorectal fat and even lymph nodes can be found occasionally in a TAE specimen if the full-thickness excision was carried deep into the mesorectum. For very distal tumors, full-thickness excision with an adequate margin may require partial excision of the internal sphincter and may lead to adverse functional consequences. Finally, the specimen should be diligently oriented for proper pathologic assessment of margins.

Transanal Endoscopic Microsurgery TEMS is a minimally invasive technique that was developed to overcome some of the limitations of TAE. Using carbon dioxide insufflation and a lighted rectoscope, it offers a magnified, stereoscopic view of the tumor. The rectoscope has a length of either 12 or 20 cm. Therefore, lesions in the upper rectum, up to 18 cm from the anal verge, are technically accessible by TEMS; however, caution needs to be exercised when obtaining a full-thickness excision of a high anterior lesion because of the risk of intraperitoneal perforation.4,5 In contrast, TEMS may not be most suited for low-lying rectal lesions within 4 cm of the anal verge. The principles of adequate resection margin, nonfragmentation, full-thickness excision remain similar to those for TAE, but TEMS is thought to provide superior technical conditions, thereby affording the operating surgeon a better chance to achieve on oncologically sound operation when compared with TAE.6-8 However, TEMS is being slowly adopted at select centers only and is limited by the steep learning curve as well as the specialized equipment required.

Standard Resection Procedures In contrast to the LE procedures described previously, SR removes the primary tumor, draining lymphatic tissue, and any other involved pelvic structures in an en bloc fashion. Depending on the distance of the tumor from the anal verge,

179 SR procedures include low anterior resection (LAR), coloanal anastomosis, and abdominoperineal resection (APR). Although the rates of perioperative morbidity and mortality associated with these procedures used to be significant, recent developments in minimally invasive surgery has significantly improved perioperative outcomes.9 Technical aspects of SR also have direct implications for its oncologic outcome. Popularized by Heald et al,10,11 total mesorectal excision (TME) involves sharp dissection of the avascular plane between the visceral covering of the mesorectum and the parietal fascia of the pelvis. The excised package is thought to include the draining nodal basin and tumor deposits. Clearance of the proximal, distal, and radial margin is best achieved with TME.10,11 By contrast, because of the close proximity of the dissection planes to pelvic nerves, postoperative bladder dysfunction and sexual dysfunction are known complications of SR.

Controversies Regarding Oncologic Adequacy of LE Versus SR The significant differences between LE and SR as described earlier constitute the fundamental consideration when assessing the oncologic adequacy of LE versus SR in T1/T2 tumors. Several questions arise. First, does LE adequately manage the local tumor bed within the bowel wall? Although a detailed study of patterns of local recurrence after LE is not available, there is evidence that tumor extension in the bowel wall distal to the palpable tumor edge is relatively uncommon.12 Therefore, there is general agreement that if fullthickness excision with adequate margin without intraoperative tumor fragmentation or spillage can be achieved, either TAE or TEMS can sufficiently manage the local tumor bed for stage I T1/T2 lesions. Second, does LE adequately manage the nodal basin draining the rectal cancer? LE does not aim to remove the mesorectum, whereas SR aims to remove the entire mesorectal package. Therefore, the oncologic adequacy of LE versus SR hinges on whether there is malignant nodal disease in the mesorectum. The general incidence of occult nodal involvement in T1 tumors ranges from 10% to 13%. The rate increases to at least 17% to 22% for T2 tumors.13-15 Recently, the St Mark’s Lymph Node Positivity Model was developed to predict nodal involvement based on T stage and other factors including patient age, tumor histology, degree of differentiation, lymphocytic infiltration, and evidence of vascular or perineural invasion.16 This model has yet to be externally validated. To date, although the incidence of malignant nodal disease in T1/T2 tumors is well documented, no method can predict the nodal status of a patient with complete accuracy. Because LE does not remove nodal tissue, there is a significant risk of understaging and undertreatment of nodal disease when LE rather than SR is chosen as the sole therapy for T1/T2 rectal cancer. Third, how accurate is the clinical staging of patients with T1N0 or T2N0 disease? Preoperative selection of patients for TAE/TEMS or SR depends on the accuracy of clinical staging

Y.N. You

180 by preoperative imaging. Reviewed in detail elsewhere, the preoperative staging of rectal adenocarcinoma has significantly improved but remains imperfect. The most commonly used imaging modalities include endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI). The reported stage-specific sensitivities and specificities of EUS are T1 (88% and 98%), T2 (81% and 96%), T3 (96% and 91%), and T4 (95% and 98%); corresponding sensitivity and specificity for nodal staging are 73% (95% confidence interval, 71%76%) and 76% (95% confidence interval, 74%-78%), respectively.17,18 EUS is operator dependent and is of limited value when severe anorectal pain or luminal stenosis is present or when performed in the post-RT setting because inflammatory changes of the soft tissues reduce the accuracy of EUS.17,18 For pelvic MRI, the accuracy of T staging and N stage ranges between 66% and 91% and 65% to 88%, respectively.19 Therefore, at present, uncertainties in clinical staging exist, and it is not possible to identify patients with T1N0 or T2N0 rectal cancer with precision. Although a full discussion of the use of LE procedures in the setting of rectal cancers downstaged to ypT0-2 after neoadjuvant treatment is beyond the scope of this article, it should be noted that the inaccuracy of imaging tools is magnified in the postneoadjuvant treatment setting. Finally, how effective is salvage therapy for local failure after LE? For patients who undergo LE but later develop a recurrence in the pelvis, salvage operations typically involve multivisceral pelvic resections, with morbidity rates of 34% and R0 resection rates between 79% and 94%. The 5-year disease-free survival after salvage surgery ranges between 53% and 59% at best.20,21 By contrast, for patients who undergo LE but were found to have either a T3 lesion, evidence of lymphovascular invasion, or gross residual disease on pathology, proceeding to immediate salvage resection does not appear to compromise long-term outcomes, with reported 5-year overall survival rates of 79%.22 Thus, the risk of delayed failure after LE may be costly and the importance of vigilant tumor surveillance after resection underscored.

Current Evidence Regarding Oncologic Outcomes of LE Versus SR T1 Tumors Level III Evidence (Single-Institutional Cohort Studies) The oncologic outcomes associated with LE have been most commonly reported in institutional case series. Only a few studies contain a comparison arm of contemporaneous patients treated by SR. Because these studies are retrospective, inherent biases that influenced the selection of patients for TAE versus SR are not accounted for, and reported results must be interpreted in light of this caveat. Willett et al23 compared the oncologic outcomes of 56 patients treated with TAE versus 69 patients treated with APR and reported a favorable 5-year recurrence-free survival of 87% and a local control rate of 96% after TAE. The corresponding rates after APR were 91% and 91%, respectively. The authors further identified that tumors with poor differentiation or evidence of venous and lymphovascular invasion exhibited poor longterm oncologic outcome when treated with TAE. Therefore, this study first suggested that TAE may be an acceptable alternative SR but only when tumors with favorable histology were selected for TAE. Additional contemporary series that have compared oncologic outcomes of TAE versus SR are summarized in Table 1. These studies contain patients treated at institutions with established surgical experience in TAE and practice SR with TME technique. All have highlighted substantially higher rates of local failure after TAE (7%-18%) versus after SR (0%-3%).6,24-28 These higher rates have also translated into inferior 5-year overall survival (OS) in most cases. In the most recent study from the Memorial Sloan-Kettering Cancer Center with a prolonged median follow-up of 5.6 years, statistically significant differences in 5-year disease-specific and overall survival were shown.29 Given these alarming findings, many have cautioned against the universal application of TAE for T1 tumors and have emphasized the need for select-

Table 1 Oncologic Outcomes after LE and SR for T1 Rectal Tumors: Summary of Single-Institutional Retrospective Case Series

Author, Year Mellgren (2000)27 Nascimbeni (2004)28 Bentrem (2005)24 Nash (2009)29 Winde (1996)32 Lee (2003)33 De Graaf (2009)34

Number of Patients TAE 69 70 152 137 TEMS 24 52 80

*Denotes statistically significant difference. †Denotes 5-year disease-specific survival.

SR 30 74 168 145 SR 26 From 100 T1/T2 pts 75

5-Year Overall Survival (%) TAE

SR

5-Year Local Recurrence (%) TAE

SR

Follow-up (y)

72 72 89 87† TEMS 96 96†

80* 90* 93 96* SR 96 94†

18 6.6 15 13.2 TEMS 4.1 4.0

0* 2.8* 3* 2.7* SR 0 0

4.4-4.8, mean 8.1, median 4.3, median 5.6, median TEMS/SR 3.8/3.4, mean 2.6/2.9

75

77

0*

3.5/7

24

Local Excision

181

ing only very low-risk T1 tumors, as initially suggested by Willett et al.23 Since the emergence of TEMS, single-institutional case series have reported significantly lower rates of local failure after TEMS when compared with those historically reported for TAE.30,31 When stage I (T1/T2) tumors located at least 5 cm from the anal verge treated by either TAE (n ⫽ 69) or TEMS (n ⫽ 38) were compared, the 5-year local failure rates were 24.0% versus 15.9% (TAE vs TEMS), but the difference did not reach statistical significance (P ⫽ .47).8 Few studies have compared TEMS with SR (Table 1). In a small prospective single-institutional study that was underpowered to compare oncologic outcomes, 50 patients with T1 cancer underwent either TEM or LAR. This study showed a 5-year local recurrence rate of 4.1% after TEM and 0% after LAR with a median follow-up of approximately 3.5 years. There was no difference in 5-year OS (96 vs 96%, Table 1).32 These results were similar to those found in another small series.33 However, a larger series found an elevated risk for local failure after TEMS when comparing 80 patients treated with TEMS with 75 patients enrolled in the Dutch TME trial, even after excluding patients with margin-positive resection from the analyses34 (Table 1). These studies highlight the potential technical advantages offered by TEM; however, prudent patient selection is still required. Level IIb Evidence (Large Multi-institutional Cohort Studies) Recently, several national cancer registries have reported oncologic outcomes of substantially larger sample sizes of patients treated with TAE versus SR (Table 2). The data contained in these national cancer registries were typically collected through well-described methodologies and qualityvalidation measures. However, they may lack some of the pathologic details available in single-institutional series, and the reported outcomes reflect wide ranges of surgical techniques, selection biases, and surveillance practices. These series substantiate the higher rates of local failure observed after LE in single-institutional studies (5%-13% after LE vs 1%-7% after SR) (Table 2). Based on data from the US National Cancer Database (NCDB), TAE was an independent predictor of local failure, after excluding patients with positive resection margin.35 By contrast, whether the observed

difference in rates of local control translated to differences in 5-year OS remain unclear. These large studies showed 5-year OS rates of 70% to 87% after TAE and 80% to 93% after SR, with differences reaching statistical significance in only 1 study.35-38 In the NCDB, after adjusting for patient and tumor variables, the estimated OS did not significantly diverge even at 8 years after LE versus SR (62% vs 66%, P ⫽ .09).35 In multivariate analyses, OS was not influenced by the type of procedure (LE vs SR) but was predicted by patient-related factors, including age,35,36,38 sex,36 American Society of Anesthesiology class,38 and number of comorbidities.35 These findings confirm that the main oncologic risk for patients with T1 tumors treated by LE rather than SR is local failure. Whether this ultimately translates into a detriment in OS remains to be elucidated. Level IIa Evidence (Prospective Nonrandomized Single-Arm Clinical Trial) To date, two multi-institutional prospective trials of local management for rectal cancer have been published: Radiation Oncology Therapy Group (RTOG) 89-02 and CALBG 8984.39-41 In the RTOG trial, 27 patients with T1 rectal cancer were followed, and a local failure rate of 4% was found.40 Similarly, the CALBG 8984 trial enrolled 59 patients with T1 tumors resected with TAE. The inclusion criteria were tumors within 10 cm of the anal verge, measuring ⱕ4 cm in diameter and involving ⱕ40% of the circumference, and resection with negative margins. After a median follow-up of 7.1 years, the 6- and 10-year local failure rates were 6.8% and 8%, whereas the corresponding OS rates were 87% and 84%, respectively.39,41 The authors suggest that these outcomes compared favorably with historic controls of patients treated by abdominal perineal resection, citing a 5-year OS of 94% according to data queried from the NCDB in 1997.39 These prospective clinical trial data provide benchmarks for oncologic outcomes when LE is performed in well-selected and carefully followed patients. Level I Evidence (Prospective Randomized Clinical Trial) Currently, there is no prospective randomized clinical trial comparing TAE/TEMS with SR for clinical T1N0 stage disease.

Table 2 Oncologic Outcomes After LE and SR for T1 Rectal Tumors: Summary of Large National Cancer Registries

Author, Year

Number of Patients LE

Endreseth, Norwegian Rectal Cancer Group, (2005)36 You, National Cancer Database, (2007)35 Ptok, German Colon/Rectal Cancer Study Group, (2007)38 Folkesson et al (2007) (Mix of T1 and T2)37 *Denotes statistically significant difference.

SR

5-Year Overall Survival (%) LE

SR

5-Year Local Recurrence (%) LE

35

256

70

80*

12

601

493

77

82

85

359

84

256

1141

87

SR

Follow-up (y)

6*

Not reported

12.5

6.9*

6.3, median

92

5.1

1.4*

3.5, mean

93

7

2*

Not reported

Y.N. You

182 Table 3 Factors to Consider When Formulating Treatment Plan for Patient With Clinical T1/T2N0 Rectal Cancer Disease-Related Factors

Patient-Related Factors

Treatment-Related Factors

Location of the tumor Size of the tumor Pathologic features on tumor biopsy Accuracy of clinical T staging with local expertise Accuracy of clinical N staging with local expertise

Comorbidities and life expectancy Relative value placed on oncologic cure Relative value placed on preservation of function and sphincter Willingness to undergo adjunctive treatments, such as radiation and/or chemotherapy Compliance with surveillance for disease recurrence Willingness to undergo salvage treatments for recurrent disease

Feasibility of TAE or TEMS Feasibility of sphincter preservation with SR Local surgical expertise

Summary Because of the fundamental differences in the extent of disease removal by TAE/TEMS versus SR, their oncologic equivalency is only possible in the few patients with confined low-risk disease. Based on our limited tools and knowledge at present, selection for LE should likely favor low-lying, small tumors with low-grade histology and no evidence of lymphovascular invasion. Patients considering local management of T1 disease must be counseled regarding their heightened risk for local failure, difficulty of salvage, and its uncertain impact on OS. Table 3 summarizes key factors to be considered when formulating an individualized treatment plan for these patients.

T2 Tumors TAE/TEMS Alone The significant rates of metastatic nodal disease in association with T2 rectal cancers have traditionally caused unease in treating T2 disease with LE alone. Alarmingly high rates of local failure and severe compromise in survival outcomes were highlighted by a study from the University of Minnesota. Outcomes of 39 patients treated with TAE were compared with those of 123 who underwent SR. The 5-year local recurrence rate was as high as 47% after TAE compared with 6% after SR. Similarly, the 5-year OS was only 65% after TAE, which is significantly worse than the 81% rate seen after SR.27 The NCDB was recently queried to identify 164 patients treated with TAE and 866 who underwent SR. Data from the NCDB found similar trends, showing significantly higher rates of local failure (22% vs 15% TAE vs SR, P ⫽ .01) and lower 5-year OS (68% vs 77% TAE vs SR, P ⫽ .02).35 In 1 small study reporting the use of TEMS, 22 T2 patients were followed. A local failure rate of 22% was observed, which is significantly higher than the 9% found after SR (P ⫽ .04).33 Taken together, these results suggest that LE should not be considered oncologically adequate for T2 tumors when compared with SR and should be reserved for patients who have multiple comorbidities, are elderly, or otherwise carry a compromised life expectancy. Strategies to Improve Oncologic Outcomes of TAE/TEMS Alone The use of multimodality adjuvant therapy to improve local control has been applied to advanced-stage rectal cancer. In

Perioperative mortality and morbidity with local expertise Feasibility of adjunctive treatments, such as radiation and/or chemotherapy

an attempt to improve on the unacceptably poor results from LE alone, this approach was borrowed for T2 rectal cancer after local surgical management. Minsky et al42 reported an encouraging 14% local failure rate among 7 patients with locally excised T2 tumors treated with 5-fluorouracil (5-FU) and RT. Additional authors have reported 5-year local failure rates of 20% to 24% using a similar treatment regimen.43-46 In a retrospective comparison, Chakravarti et al47 reported that 5-year actuarial local control rates were 33% in 8 patients treated with TAE but 85% in 33 patients treated with TAE plus postoperative RT (P ⫽ .004), suggesting that the addition of postoperative adjuvant RT may indeed improve local control. The only prospective data are available from the CALGB 8984 trial, which enrolled 51 T2 patients who underwent TAE followed by postoperative RT (5400 cGy in 30 fractions) with concomitant 5-FU. The 10-year estimated local recurrence was 18%, and the 10-year survival was 66%. The only independent predictor of recurrence was lymphovascular invasion.39 Thus, although adjuvant chemoradiation has been used to improve oncologic outcomes of LE alone, the degree of benefit, added morbidity, and potential functional sequelae have not been examined in a prospective comparative trial. Neoadjuvant chemoradiation, when added to SR for patients with locally advanced rectal cancer, has been shown to improve local control and survival.19 This approach has also been extended to T2 rectal tumors.48 A prospective phase II clinical trial sponsored by the American College of Surgeons Oncology Group (ACOSOG Z6041)49 enrolled 90 patients with T2N0 rectal cancer as defined by pretreatment EUS or pelvic MRI. Patients received neoadjuvant treatment consisting of RT, capecitabine, and oxaliplatin followed by either TAE or TEMS. Short-term results showed that 81% of the patients completed neoadjuvant chemoradiation, and a complete pathologic response at the local tumor bed was achieved in 44% of the patients. Patients are expected to complete follow-up for the primary endpoint of 3-year disease-free survival in 2013.50 One prospective randomized control trial has focused on T2N0 rectal cancers. Lezoche et al51 treated 70 patients with T2N0 tumor with neoadjuvant radiation (5,040 cGy) with 5-FU and then randomized them to either TEMS or laparoscopic TME (either LAR or abdominal perineal resection). After a median of 7 years of follow-up, no statistically signif-

Local Excision icant difference was seen in either the 5-year local failure rate (TEMS vs laparoscopic resection: 5.7% vs 2.8%) or the OS rate (94 vs 94%). The observed results in the TEMS arm are highly favorable and await further confirmation by studies with larger sample sizes. Summary When compared with SR, the use of LE alone for T2 tumors leads to disappointing oncologic outcomes and should be reserved for patients who are unfit for SR. The benefit of adjuvant therapy in this group has not been definitively shown in a comparative study; a novel neoadjuvant approach is under investigation through prospective clinical trials. The application of TAE or TEMS for T2 tumors should be limited to the clinical trial setting at present.

Conclusions Current evidence suggest that local surgical excision may be considered as an alternative to SR only in very select few patients whose disease is confined and tumor biology is highly favorable. In the current era of personalized medicine, the optimal treatment plan for an individual patient requires a well-informed discussion. A careful consideration of multiple key factors (Table 3) would inform an individualized analysis of benefits and risks of LE versus SR. New approaches in multimodality therapy aimed at improving oncologic outcome after LE alone have emerged but remain in the setting of clinical trials.

References 1. Kraske P, Perry EG, Hinrichs B: A new translation of professor Dr P. Kraske’s zur Exstirpation Hochsitzender Mastdarmkrebse. Aust N Z J Surg 59:421-424, 1885 2. Mason AY: Transsphincteric approach to rectal lesions. Surg Annu 9:171-194, 1977 3. Madden JL, Kandalaft S: Electrocoagulation. A primary and preferred method of treatment for cancer of the rectum. Ann Surg 166:413-419, 1967 4. Touzios J, Ludwig KA: Local management of rectal neoplasia. Clin Colon Rect Surg 21:291-299, 2008 5. Tytherleigh MG, Warren BF, Mortensen NJ: Management of early rectal cancer. Br J Surg 95:409-423, 2008 6. Paty PB, Nash GM, Baron P, et al: Long-term results of local excision for rectal cancer. Ann Surg 236:522-529, 2002 7. Moore JS, Cataldo PA, Osler T, et al: Transanal endoscopic microsurgery is more effective than traditional transanal excision for resection of rectal masses. Dis Colon Rectum 51:1026-1030, 2008 8. Christoforidis D, Cho HM, Dixon MR, et al: Transanal endoscopic microsurgery versus conventional transanal excision for patients with early rectal cancer. Ann Surg 249:776-782, 2009 9. Row D, Weiser MR: An update on laparoscopic resection for rectal cancer. Cancer Control 17:16-24, 2010 10. Heald RJ: Total mesorectal excision. The new European gold standard. G Chir 19:253-255, 1998 11. Heald RJ: Total mesorectal exsicion (TME). Acta Chir Iugosl 47:17-18, 2000 12. Smith AJ, Driman DK, Spithoff K, et al: Guideline for optimization of colorectal cancer surgery and pathology. J Surg Oncol 101:5-12, 2010 13. Nascimbeni R, Burgart LJ, Nivatvongs S, et al: Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum 45:200-206, 2002 14. Blumberg D, Paty PB, Guillem JG, et al: All patients with small intra-

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mural rectal cancers are at risk for lymph node metastasis. Dis Colon Rectum 42:881-885, 1999 Brodsky JT, Richard GK, Cohen AM, et al: Variables correlated with the risk of lymph node metastasis in early rectal cancer. Cancer 69:322326, 1992 St Mark’s L: Node positivity model. Available at: www.riskprediction. org. Accessed Feb 1st, 2010. Puli SR, Bechtold ML, Reddy JB, et al: How good is endoscopic ultrasound in differentiating various T stages of rectal cancer? Meta-analysis and systematic review. Ann Surg Oncol 16:254-265, 2009 Puli SR, Reddy JB, Bechtold ML, et al: Accuracy of endoscopic ultrasound to diagnose nodal invasion by rectal cancers: A meta-analysis and systematic review. Ann Surg Oncol 16:1255-1265, 2009 Guillem JG, Chessin DB, Jeong SY, et al: Contemporary applications of transanal endoscopic microsurgery: Technical innovations and limitations. Clin Colorectal Cancer 5:268-273, 2005 Friel CM, Cromwell JW, Marra C, et al: Salvage radical surgery after failed local excision for early rectal cancer. Dis Colon Rectum 45:875879, 2002 Weiser MR, Landmann RG, Wong WD, et al: Surgical salvage of recurrent rectal cancer after transanal excision. Dis Colon Rectum 48:11691175, 2005 Hahnloser D, Wolff BG, Larson DW, et al: Immediate radical resection after local excision of rectal cancer: An oncologic compromise? Dis Colon Rectum 48:429-437, 2005 Willett CG, Compton CC, Shellito PC, et al: Selection factors for local excision or abdominoperineal resection of early stage rectal cancer. Cancer 73:2716-2720, 1994 Bentrem DJ, Okabe S, Wong WD, et al: T1 adenocarcinoma of the rectum: Transanal excision or radical surgery? Ann Surg 242:472-477, 2005 Garcia-Aguilar J, Mellgren A, Sirivongs P, et al: Local excision of rectal cancer without adjuvant therapy: A word of caution. Ann Surg 231: 345-351, 2000 Madbouly KM, Remzi FH, Erkek BA, et al: Recurrence after transanal excision of T1 rectal cancer: Should we be concerned?. Dis Colon Rectum 48:711-719, 2005 Mellgren A, Sirivongs P, Rothenberger DA, et al: Is local excision adequate therapy for early rectal cancer? Dis Colon Rectum 43:1064-1071, 2000 Nascimbeni R, Nivatvongs S, Larson DR, et al: Long-term survival after local excision for T1 carcinoma of the rectum. Dis Colon Rectum 47: 1773-1779, 2004 Nash GM, Weiser MR, Guillem JG, et al: Long-term survival after transanal excision of T1 rectal cancer. Dis Colon Rectum 52:577-582, 2009 Suppiah A, Maslekar S, Alabi A, et al: Transanal endoscopic microsurgery in early rectal cancer: Time for a trial? Colorectal Dis 10:314-327, 2008 Zieren J, Paul M, Menenakos C: Transanal endoscopic microsurgery (TEM) vs. radical surgery (RS) in the treatment of rectal cancer: Indications, limitations, prospectives. A Rev Acta Gastroenterol Belg 70: 374-380, 2007 Winde G, Nottberg H, Keller R, et al: Surgical cure for early rectal carcinomas, vol T1. Transanal endoscopic microsurgery vs. anterior resection, Dis Colon Rectum 39:969-976, 1996 Lee W, Lee D, Choi S, et al: Transanal endoscopic microsurgery and radical surgery for T1 and T2 rectal cancer. Surg Endosc 17:12831287, 2003 De Graaf EJ, Doornebosch PG, Tollenaar RA, et al: Transanal endoscopic microsurgery versus total mesorectal excision of T1 rectal adenocarcinomas with curative intention. Eur J Surg Oncol 35:1280-1285, 2009 You YN, Baxter NN, Stewart A, et al: Is the increasing rate of local excision for stage I rectal cancer in the United States justified?: A nationwide cohort study from the National Cancer Database. Ann Surg 245:726-733, 2007

184 36. Endreseth BH, Myrvold HE, Romundstad P, et al: Transanal excision vs. major surgery for T1 rectal cancer. Dis Colon Rectum 48:13801388, 2005 37. Folkesson J, Johansson R, Pahlman L, et al: Population-based study of local surgery for rectal cancer. Br J Surg 94:1421-1426, 2007 38. Ptok H, Marusch F, Meyer F, et al: Oncological outcome of local vs radical resection of low-risk pT1 rectal cancer. Arch Surg 142:649-655, 2007 39. Greenberg JA, Shibata D, Herndon JE 2nd, et al: Local excision of distal rectal cancer: An update of cancer and leukemia group B 8984. Dis Colon Rectum 51:1185-1191, 2008 40. Russell AH, Harris J, Rosenberg PJ, et al: Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: Long-term results of radiation therapy oncology group protocol 89-02. Int J Radiat Oncol Biol Phys 46:313-322, 2000 41. Steele GD Jr, Herndon JE, Bleday R, et al: Sphincter-sparing treatment for distal rectal adenocarcinoma. Ann Surg Oncol 6:433-441, 1999 42. Minsky BD, Cohen AM, Enker WE, et al: Sphincter preservation in rectal cancer by local excision and postoperative radiation therapy. Cancer 67:908-914, 1991 43. Benson R, Wong CS, Cummings BJ, et al: Local excision and postoperative radiotherapy for distal rectal cancer. Int J Radiat Oncol Biol Phys 50:1309-1316, 2001

Y.N. You 44. Rich TA, Weiss DR, Mies C, et al: Sphincter preservation in patients with low rectal cancer treated with radiation therapy with or without local excision or fulguration. Radiology 156:527-531, 1985 45. Wagman R, Minsky BD, Cohen AM, et al: Conservative management of rectal cancer with local excision and postoperative adjuvant therapy. Int J Radiat Oncol Biol Phys 44:841-846, 1999 46. Bouvet M, Milas M, Giacco GG, et al: Predictors of recurrence after local excision and postoperative chemoradiation therapy of adenocarcinoma of the rectum. Ann Surg Oncol 6:26-32, 1999 47. Chakravarti A, Compton CC, Shellito PC, et al: Long-term follow-up of patients with rectal cancer managed by local excision with and without adjuvant irradiation. Ann Surg 230:49-54, 1999 48. Borschitz T, Wachtlin D, Mohler M, et al: Neoadjuvant chemoradiation and local excision for T2-3 rectal cancer. Ann Surg Oncol 15:712-720, 2008 49. American College of Surgeons Oncology Group Z 6041 50. Garcia-Aguilar J, Shi Q, Thomas CR, et al: Pathologic complete response to neoadjuvant chemoradiation of uT2N0 rectal cancer treated by local excision: Results of the ACOSOG Z6041 trial J Clin Oncol: suppl; abstr 3510, 2010 51. Lezoche G, Baldarelli M, Guerrieri M, et al: A prospective randomized study with a 5-year minimum follow-up evaluation of transanal endoscopic microsurgery versus laparoscopic total mesorectal excision after neoadjuvant therapy. Surg Endosc 22:352-358, 2008

How Low is Low? Evolving Approaches to Sphincter-Sparing Resection Techniques Kirk Ludwig, MD, and Lauren Kosinski, MD Although advances in rectal cancer staging may ultimately be accurate enough to reliably exclude disease outside the rectal wall (thereby allowing local approaches to be more widely and safely applied) and advances in the use of neoadjuvant chemo- and radiation therapy may ultimately produce more “complete responders” that can be accurately identified and spared surgery altogether, as it stands, radical resection forms the basis of curative treatment for rectal cancer. However, the concepts that guide the surgeon in choosing the optimal approach in radical resection are changing. In the past, the decision as to how to proceed surgically with radical resection was based primarily on the level of the tumor above the anal verge or anorectal ring. The issue was primarily “How low is the tumor?” and “Is the distal margin safe?” A more modern approach focuses attention on achieving a negative circumferential margin despite what historically may seem to be a very minimal distal margin, the current issue is not “How low is the tumor?” so much as it is “How deep does the tumor go?”. This shift in focus has been a major impetus in the evolution of sphincter sparing resection techniques. Semin Radiat Oncol 21:185-195 © 2011 Published by Elsevier Inc.

T

he abdominal perineal resection (APR), performed using blunt dissection in the pelvis, stood for decades as the gold standard operation for rectal cancer.1,2 This began to change in the middle part of the 20th century when Claude Dixon reported a 64% 5-year survival in over 400 patients treated with low anterior resection (LAR).3 Ultimately, although the choice of operation for any one patient with rectal cancer depends on multiple tumor and patient characteristics, there are data to suggest that higher surgeon or hospital caseload is associated with an increased use of sphinctersparing resections (SSRs).4-6 Despite data that suggest that APR rates in the United States are still above 50%,7,8 the permanent colostomy rate for rectal cancer patients treated by experienced rectal cancer surgeons should be well less than 30%.9,10 Although there remains a role for APR in the treatment of rectal cancer, it has diminished substantially. During the last 2 decades, major changes have taken place in the conduct of rectal cancer surgery and the results obtained using these techniques. Although there can be little doubt that the evolution toward SSR can be attributed to the use of multimodal neoadjuvant chemotherapy and radiation ther-

Department of Surgery, Division of Colorectal Surgery, Medical College of Wisconsin, Milwaukee, WI. Address reprint requests to Department of Surgery, Division of Colorectal Surgery, Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI 53226. E-mail: [email protected]

1053-4296/11/$-see front matter © 2011 Published by Elsevier Inc. doi:10.1016/j.semradonc.2011.02.004

apy to downstage locally advanced tumors and, therefore, alter the surgical approach,11 much of the change can be attributed to a better understanding of pelvic anatomy and the adoption of total mesorectal excision (TME) and to a better pathologic understanding of what most accurately predicts local recurrence (ie, the circumferential resection margin (CRM)12,13) and not the distal margin. Armed with a better understanding of how to properly remove the rectum and a better understanding of what is pathologically required to obtain good results, even for very low tumors in the distal rectum or the anal canal, a SSR can usually be offered with confidence that both an acceptable oncologic and functional outcome will be obtained.

The Evolution in SSRs What Is TME? TME, a concept introduced in 1982 by Bill Heald, from Basingstoke, England, has dramatically increased the implementation of SSRs. One of the best descriptions of the TME is still Heald’s Presidential Address to the Royal Society of Medicine, Surgery Section, in 1987, the publication of which has become known as the “Holy Plane” paper.14 In his address, Heald described the 3 basic principles that one must understand and follow to perform a TME. First, one must recognize that there is mobility at the interface between tissues of different embryologic origin. The rectum and its mesentery, 185

186 encased by the fascia propria of the mesorectum (Fig 1), are separate from those structures outside of this fascial envelope. The plane of dissection is just outside the fascia propria (the visceral endopelvic fascia) and just inside the parietal endopelvic fascia. This is the “Holy Plane.” Second, the dissection must be performed sharply (no ripping or tearing or blunt dissection), under direct vision, with good illumination. The sharp dissection is generally performed with either scissors or, more commonly, with the electrocautery. Good lighting can best be achieved by using fiberoptically illuminated pelvic retractors; these retractors cast the light directly where it is needed and provide excellent visualization even in the depths of the pelvis. An alternative is a headlight worn by the surgeon or assistant. To perform a precise dissection, one must both know and be able to see the anatomy. The field must be well lit. Third, there must be gentle opening of the plane by continuous traction and countertraction but not so much that the tissue tears or rips. Heald talks about what is encircled within the “Holy Plane” and what is outside the “Holy Plane.” Within the plane, one finds the rectum and its circumferential mesentery, the mesorectum. He described the rectum and the mesorectum as 1 distinct lymphovascular entity and noted “the tumor is more apt to spread initially along the field of active lymphatic and venous flow.” If one accepts that the vast majority of rectal cancers and their lymphatic metastases are confined to this envelope of tissue, one can understand how removing it intact might lead to very low rates of local failure (Fig 2). Outside the “Holy Plane,” one finds those structures that should be preserved: the sympathetic and parasympathetic pelvic nerves and the major vessels (of primary concern are the veins) of the pelvis. He notes that there are 2 bloodless planes of dissection in the pelvis: one just inside the inferior

Figure 1 The mesorectum is encased by the fascia propria of the mesorectum. Below the peritoneal reflection, this mesorectal fascia (white arrows) appears as a low signal line on this T2-weighted MRI. The proper plane of dissection for a TME is just outside this fascial plane. (Courtesy of Paul Knechtges, MD, Medical College of Wisconsin).

K. Ludwig and L. Kosinski

Figure 2 The concept with a total mesorectal excision is that most tumor spread takes place within the mesorectum and removal of the rectum and its mesentery as an intact unit should result in a very low rate of local recurrence.

hypogastric nerves, which is the proper plane, and one just outside the inferior hypogastric nerves, the wrong plane. With regard to the ultralow anastomosis that results after a TME, Heald points out that the rectum and mesorectum are attached to the pelvic floor by a clean tube of anorectal muscle. The mesorectum has a very definite end, just a centimeter or 2 above the anorectal angle. Beyond this point, there is no mesentery, just a muscular tube of bowel (Fig 3). During TME, it is in this area caudal to the mesorectum where the distal division of the bowel and construction of the “ultralow stapled anastomosis” occur. A stapled anastomosis in this location will put the circular staple line about 1.5 to 2 cm

Figure 3 The total mesorectal excision specimen. The mesorectum, encased by the fascia propria, has a smooth edge (white arrows) that ends just above the anorectal angle where the muscular tube of distal rectum is divided (dashed white arrows).

Sphincter-sparing resection above the dentate line. If one were to dissect this muscular tube more distally into the surgical anal canal, it would be found to be continuous with the intersphincteric space. Carried more distally, the line of dissection would exit at the anal verge in the intersphincteric groove. This anatomic understanding is critically important in conceptualizing and conducting an intersphincteric LAR. The use and application of TME in facilitating sphincter preservation has been aided tremendously by technical improvements. Heald’s imperatives for oncologic proctectomy included operating under direct vision in a well-lighted field. Several manufacturers responded to this need and now produce and market specially designed pelvic retractors that have a fiberoptic cord mounted on the retractor so the depths of the pelvis can be illuminated. This means that fascial planes, nerves, and other pertinent anatomy, which were once hidden in the depths of the dark pelvis, are now seen more clearly. Advances in stapling instruments that both secure and transect the rectum have made it possible to perform ultralow anastomoses. Narrow, low-profile staplers allow the surgeon to place a staple line across the rectum in the narrowest portion of the pelvis at the level of the anorectal ring or below. This, used in combination with a circular stapler, allows the surgeon to construct a quick and reliable “doublestapled” anastomosis even at the level of the anal canal, which is where TME takes the surgeon. These instruments have revolutionized low pelvic surgery. Why Use TME? Heald found that meticulous, sharp dissection, under direct vision, between the visceral and parietal pelvic fascia down to the level of the levator muscles (which define the upper aspect of the anal canal) enabled removal of the rectum and its mesentery as an intact unit and that this approach led to 3 very favorable outcomes. First, the lateral margin positivity rate was dramatically reduced and corresponded with astonishingly low local failure rates. Second, there was a sharp decline in the need for APR. Third, the incidence of bladder and sexual dysfunction after surgery also decreased because dissection in the proper planes helped avoid injury to the sympathetic and parasympathetic nerves in the pelvis.14 When Heald first described the technique of TME,15 he recognized that most local recurrences after rectal cancer resection were the result of inadequate resections using imprecise, blunt dissection. Local recurrence rates of from 15% to 50% were observed before the adoption of TME16,17 and, historically, for locally advanced T3 or node positive tumors,18 local failure rates of greater than 30% were observed. In contrast, Heald reported a local recurrence rate of just 6% in 519 patients with rectal cancer ⬍15 cm from the anal margin. In patients who had what he termed “curative” resections, the local failure rate was even better at only 3%. These results were achieved when only 49 patients (9.4%) were treated with neoadjuvant radiation therapy.19 Soon others reported superior local recurrence rates after TME. The multicenter, multisurgeon Dutch TME trial compared TME alone with TME combined with preoperative radiation; the

187 overall local failure rate for TME alone was only 8.2% (10% for tumors less than 10 cm from the anal verge and 15% for stage III cancers).20 Others have reported similarly impressive low local recurrence figures after the adoption of Heald’s exacting surgical technique.21-25 Likewise, the reduction in APR rates by surgeons skilled in TME mirrored Heald’s experience. Heald et al’s (1998) report included just 37 APRs (7.1%) after adopting TME; others have subsequently reported similarly low APR rates.6,26-28 Further evidence that adoption of the TME technique improves oncologic outcomes comes from Norway where decreased local recurrence rates and increased survival rates were found after a TME training program was introduced. A Norwegian national audit of rectal cancer resections performed between 1986 and 1988 identified a local recurrence rate of 28% and a survival rate of 55%. A TME training program was initiated in 1994, and by 1998, 96% of rectal cancer resections were conducted according to the principles of TME. The 1998 audit showed that even with a very low rate of neoadjuvant treatment (9% of patients underwent preoperative radiation therapy and only 2% with concurrent chemotherapy), the local recurrence rate had dropped to 8% and the survival rate had improved to 71%.16 The old-style proctectomy using blunt dissection showed little appreciation for the fine points of pelvic anatomy and too often failed to preserve autonomic functions supported by the sympathetic and parasympathetic pelvic nerves. Sexual dysfunction was seen in up to 75% of males and 40% of females. Similarly, bladder dysfunction was seen in up to 80% of patients. In the TME era, these rates have improved substantially, and, although a patient’s age, tumor location, and preoperative functional status influence outcomes, sexual dysfunction should be in the 10% to 30% range and bladder dysfunction should be 5% or less.29 The concept of TME has spread throughout Europe, Asia, and the United States. This technique of rectal dissection has been and can be taught on a broad scale. It is now clear that blunt dissection of the rectum should no longer be taught or practiced. TME has significantly influenced both the outcomes and surgical options for patients with rectal cancer.

The Margin Issue Distal Versus CRM In contradiction to longstanding dogma, it is now clear that 5-cm distal margins are not required to achieve good local control for rectal cancers. A 2-cm margin is quite adequate based on the fact that distal intramural spread and/or retrograde lymphatic extension are rare, and when they do occur, the prognosis is poor despite the surgery. Additionally, the distal resection margin does not appear to predict local recurrence. Williams et al30 showed that in a group of 50 rectal cancer specimens, there was no intramural spread distal to the tumor 75% of the time, distal spread ⬍1 cm was observed in 14% of the specimens, and in just 5 cases there was distal spread ⬎1 cm. All 5 of these patients had poorly differentiated stage III tumors and developed distant metastatic disease within 3 years. Pollett and Nicholls31 showed in a series of

K. Ludwig and L. Kosinski

188 over 300 rectal cancer specimens that the length of the distal margin did not correlate with the risk of local failure. Data from the Large Bowel Cancer Group Project corroborated these findings.32 More recent data suggest that an even narrower distal margin may be adequate for the very lowest of tumors, especially when resection follows neoadjuvant chemoradiation. Distal margins of 1 cm or less may be sufficient in radical attempts at sphincter preservation.33,34 It now appears that the CRM, previously referred to as the deep, lateral, or radial margin, is more critical to oncologic outcome than the length of the distal margin. The CRM is often measured in millimeters, and a positive CRM places the patient at a great risk for local failure. This has been shown nicely by Quirke et al35 who looked carefully at a group of 26 APR specimens and 26 LAR specimens. The margin was positive in 10 specimens from each group, and 75% of these margin-positive patients developed a local recurrence. In only 1 patient with a negative deep margin was there a local failure. Surprisingly, the lateral margin (measured microscopically from the deep edge of the tumor) was no different in LAR versus APR specimens. CRM involvement has also been shown to predict distant recurrence and overall survival.36 A CRM of ⬍1 mm, whether as direct tumor extension, lymph node metastasis, or intravascular growth, should be considered positive. In a report by Adam et al,37 the local failure rate was 74% with a margin of ⬍1 mm compared with 10% for a margin ⬎1 mm. Data from the North Central Cancer Treatment Group showed that if the CRM was 0 to 1 mm, the local failure rate was 25% compared with only 3% if the CRM was ⬎1 cm.38 Birbeck et al39 found a local failure rate of 58% when CRM was positive, 28% if CRM was ⬍1 mm, and 10% when CRM was 1 mm or more. Several authors have concluded that CRM is an acceptable rectal cancer oncologic endpoint that predicts both local recurrence and disease-free survival.35,37,39-42 A negative CRM is critical in achieving a good outcome. Precise consideration of the anatomy of proper rectal cancer resection leads one to the conclusion that the deep margin for all but the lowest and most advanced rectal tumor is not maximized by doing an APR. Unless a tumor has invaded the sphincter complex, one can legitimately ask why should this complex and the anus be removed? Although neoadjuvant treatment is not the focus of this article, one cannot minimize how the use of these therapies might alter the perception that a tumor is fixed or tethered to the pelvic floor, the external sphincter, or adjacent pelvic organs. Although the initial physical examination may suggest tumor fixation, a long course of neoadjuvant treatment may change things considerably such that the operative plan can be altered to a SSR. The final decision on what will be done is best made after neoadjuvant therapy has had an opportunity to shrink the tumor and minimize the edema and desmoplastic reaction that may have initially led the surgeon to think that the tumor was fixed and an APR required. Final judgment is usually reserved until at least 6 to 8 weeks have passed after the last radiation dose.

Sphincter-Sparing Resections The upper rectum is anatomically defined as the location where the tenia coli coalesce into a single longitudinal muscle layer. For the surgeon, landmarks in the abdomen that mark this location, such as the “peritoneal reflection” or the point at which the colon reaches the sacral promontory, are quite inaccurate. These landmarks may be variable depending on age, sex, and obstetric history. In general, the rectum measures approximately 12 to 15 cm in length and contains 3 valves that define the zones: the upper, the middle, and the lower or distal rectum. The middle rectal valve is a particularly valuable landmark. In an average-sized patient, it will be located 9 to 10.5 cm from the anal verge. The location of the middle rectal valve, in the average-sized adult, is at the anterior peritoneal reflection (ie, the anterior cul-de-sac). Lesions at or beneath the middle rectal valve are considered to lie in the extraperitoneal portion of the rectum. The upper rectal valve is located about 3 cm above the middle valve. The lower or distal rectal valve is located about 3 cm beneath the middle rectal valve. The 3 rectal zones (upper, middle, and lower or distal) are centered on their respective valves. The rectum, from a surgical standpoint, ends at the anorectal ring, which is defined by the puborectalis muscle not the dentate line. Thus, an anastomosis at or beneath the anorectal ring is considered a coloanal anastomosis. How Low Is Low? As stated previously, from a historic standpoint, the critical issue in rectal cancer surgery has been the distal margin. The classic question for patients with rectal cancer has been “at what level in the rectum does a patient go from being a candidate for sphincter preservation to APR?” If one accepts the historic 5-cm rule, then most patients with a low rectal tumor will be treated with an APR. If one accepts 2 cm as an adequate distal margin, then more patients will be treated with a LAR although most patients with tumors close to the anorectal ring would still not be treated with SSR. A more modern concept focuses on the deep margin rather than the distal margin. Therefore, the critical issue for tumors in the lower rectum, even those within the anal canal itself, is whether the tumor has invaded the external sphincter muscle. If the muscles of the pelvic floor/external sphincter are not involved by tumor, why remove them? Using modern surgical techniques and multimodality therapies, even for the very lowest of tumors, the anus and sphincters can often be preserved and an SSR can be offered.

Anterior Resection For tumors in the upper rectum, sphincter preservation, at least for oncologic reasons, should rarely be an issue. Surgery here involves an anterior resection, which, by definition, involves dissection and anastomosis confined to the extraperitoneal rectum (that portion of the rectum above the anterior peritoneal reflection). This operation results in a straight colorectal anastomosis, which is typically constructed with a circular stapler. These operations should be performed according to the principles of TME. Mobilization should take

Sphincter-sparing resection place in defined anatomic planes under direct vision using sharp dissection. The mesorectum is divided at a point approximately 5 cm below the distal edge of the tumor. It is at this point that the bowel is also divided. The surgeon must avoid the critical error of “coning in” on the rectum whereby the trajectory through the mesorectum achieves an adequate distal margin on the bowel, but potentially involved nodes or tumor deposits in the mesorectum are left behind. Tumor outside the bowel wall (in the mesorectum, deep to the tumor) can get left behind if the surgeon does not take the mesorectal dissection just behind the fascia propria of the mesorectum down to the point of the distal resection margin. The mesorectum is divided perpendicular to the distal rectal margin. LAR for Mid- and Low-Rectal Cancer Tumors in the mid- or low-rectum are treated with a LAR. For midrectal tumors, the bowel is divided distally, generally with a stapling gun, just past the lower edge of the mesorectum, at the upper aspect of the anal canal. At this point, the bowel is simply a muscular tube. Also, at this point, the rectal diameter diminishes significantly as it transitions into the anal canal. At this level, reconstruction is almost always performed using a colonic J-pouch (discussed later) to anal anastomosis using a circular stapling device. The anastomosis after a TME with stapled colonic J-pouch to anal anastomosis will be about 1.5 to 2.0 cm above the dentate line in very close proximity to the anorectal ring. This anastomosis is nearly always diverted temporarily with a loop ileostomy. For some tumors in the low rectum, the resection and the reconstruction can be managed as midrectal cancers are with a standard LAR, as described earlier. For the very low lesions, when a stapler cannot be applied between the tumor and the anorectal ring to achieve even a minimal distal margin or for tumors that actually extend into the anal canal itself but do not invade the external sphincter or pelvic floor, there are 2 techniques that allow for sphincter preservation. The first option is simply a reconstructive option, a transanal handsewn coloanal anastomosis, and the second is a resection and reconstruction technique known as an intersphincteric resection (ISR) with coloanal anastomosis. Transanal Hand-Sewn LAR The hand-sewn coloanal anastomosis is simply a technique for reconstruction used when there is simply not enough room to place a staple gun safely below a very distal tumor. This can happen in 2 circumstances. The first is when, in the fully mobilized rectum, there is adequate length distal to the tumor to apply a stapler well below the tumor, but the pelvic architecture (generally a deep and very narrow male pelvis) simply impedes stapler placement. The second is when the tumor is so close to (or even within) the anal canal that an adequate distal margin can be obtained from the abdominal approach but not enough margin for placing a distal staple line. In these cases, the TME is conducted in the standard fashion down to the anal canal. However, instead of placing a staple gun distally, as would be performed in a double-stapled anastomosis, the bowel is occluded just distal to the tumor. It is then simply divided sharply, from above, within

189 the anal canal, usually about 0.5 to 1.0 cm above the dentate line, and the specimen is passed off the table. Because this dissection has been carried down into the intersphincteric space, the uppermost portion of the internal anal sphincter is necessarily sacrificed to achieve an adequate full-thickness rectal wall margin. A colonic pouch is then fashioned, the patient is placed in a more exaggerated lithotomy position to expose the anus and perineum, and the surgeon then works from between the legs to construct a transanal, hand-sewn colonic pouch to anal anastomosis to reestablish gastrointestinal continuity. This anastomosis is diverted with a loop ileostomy. Intersphincteric Resection For the lowest of rectal cancers, the final and ultimate technique for sphincter-preserving resection is an ISR with colonic pouch to anal anastomosis. This operation is used when the tumor is located in proximity to the anorectal ring (either just above or just below) but has not invaded the external sphincter muscle or pelvic floor. The use of this operation for tumors in the lower third of the rectum can significantly increase SSR rates.43 These operations leave very little margin for error in terms of the deep and distal margins. Therefore, most tumors treated with this technique are managed with neoadjuvant chemoradiation therapy to maximize these narrow margins and to decrease the volume of intraluminal tumor to avoid intraoperative tumor seeding. However, there are data suggesting that for early-stage lower rectal tumors, ISR without preoperative treatments can also achieve good results.44 The validity of the ISR is again based on the concept that it is the deep margin on a tumor that is most critical. If the deep margin does not involve the skeletal muscle, then there is no reason to remove it. The ISR is based anatomically on the concept (described by Heald in his writings on the TME) that if one follows the muscular tube of anorectum distally, one eventually comes out on the anoderm in the intersphincteric groove at the anal verge (Fig 4). The ISR removes the upper aspect of the internal sphincter muscle (sometimes more), and, as such, there will be functional changes (Fig 5). Patients chosen for this type of operation must be motivated, have a well-functioning sphincter mechanism, and have normal premorbid continence. This operation is conducted in 2 phases: the first phase (the perineal phase) involves dissection within the anal canal and lower pelvis and is conducted with the patient in the prone-jackknife position to allow optimal visualization of the critical anatomy. Despite the inconvenience of repositioning for the abdominal phase of the operation, the first phase is more easily conducted in this position. The perineal portion of the operation involves incising the anal canal mucosa at the dentate line. The incision is circumferential, and it extends through the mucosa, the submucosa, and directly through the internal sphincter muscle into the intersphincteric groove and onto the external sphincter muscle, which is left intact. The critical issue with this part of the dissection is whether the external sphincter muscle is free of tumor. If the surgeon has judged incorrectly and this plane on the external sphincter muscle is not clean, the attempt at sphincter preservation

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shedding into the pelvis and soiling of the pelvis that can take place during the second phase of the operation. The patient is then repositioned for the second or abdominal phase of the operation. This takes place in the modified lithotomy position and involves an abdominal and pelvic dissection whereby the surgeon dissects from above to meet the dissection that has taken place during the perineal phase. The abdominal part of the operation is conducted according to the standard concepts of the TME. After the resection, a hand-sewn, transanal colonic pouch to anal anastomosis is constructed at the dentate line, and the anastomosis is diverted with a loop ileostomy.

Neorectal Construction After LAR

Figure 4 The specimen after an intersphincteric specimen includes the rectum (white dot), the mesorectum (white arrows), and the full-thickness upper portion of the anal canal (brackets).

should be aborted. The involved muscle will need to be resected with an APR. If not, dissection proceeds to a point well above the tumor onto the distal rectum. The transected anorectal tube is closed with a running stitch to avoid tumor cell

As LAR replaced APR, especially as the level of the anastomosis moved down to the anal canal, the bowel dysfunction that followed was appreciated and came to be known as LAR syndrome. It can be fairly stated that almost every patient treated with LAR, especially those who undergo a TME with an anastomosis constructed at the anorectal ring or below, will have some degree of functional difficulty. The symptoms of LAR syndrome are urgency, frequency, tenesmus, a feeling of incomplete evacuation, clustering of bowel movements (multiple small-volume stools over a period as if 1 bowel movement empties itself in “clusters” instead of all at once), and sometimes incontinence. The symptoms generally im-

Figure 5 The anatomy of an intersphincteric resection. (Reproduced with permission.86)

Sphincter-sparing resection prove over a period of 1 to 2 years. The etiology of this syndrome is not completely understood. Theories put forth include the impairment of internal anal sphincter function, a decrease in anal canal sensation, the disappearance of the rectoanal inhibitory reflex, and/or a disruption of local reflexes and communication between the rectum and the anus. The data that would support any of these concepts is somewhat inconsistent. The only consistent theme is that the neorectal reservoir lacks the type of compliance found in the native rectum. There are now data suggesting that the cause of the syndrome is extrinsic denervation of the neorectum that takes place as the result of the extensive efforts made to mobilize the left colon so that it will reach, without tension, to the anus.45 Recognizing the syndrome, in 1986, Lazorthes46 and Parc,47 both in the same volume of the British Journal of Surgery, described in separate studies their experience with reconstruction using, instead of a straight coloanal anastomosis, a colonic J-pouch to anal anastomosis. Both reported improved function after a low colorectal or coloanal anastomosis using a colonic pouch. Over the next decade, a number of studies clarified issues surrounding colonic J-pouch reconstruction. Initially, pouches were made too large and did not empty.47-49 The proper size of a colonic J-pouch is in the range of 5 to 7 cm.50-52 Pouches that were anastomosed to the rectum, too far from the anus, were found to be problematic. It became clear that a pouch should be used only for reconstruction at the lowest levels, within about 2 cm of the dentate line or 3 to 4 cm of the anal verge.53-55 If the anastomosis is performed above this level, the pouch may not empty well. A number of prospective randomized trials concluded that reconstruction using a colonic J-pouch to anal anastomosis was superior to a straight coloanal anastomosis.56,57 It was widely believed that the pouch reconstruction was primarily helpful in the first year or 2 after surgery. Thereafter, it was believed that even after a straight anastomosis, the neorectal compliance improved and the functional differences resolved. However, 2 long-term studies suggest that the functional superiority of pouch reconstruction is lasting. Dehni et al58 compared 47 pouch patients with 34 straight patients, with a mean follow-up of 5 years and found that for every variable measured (ie, frequency, clustering, use of antidiarrheal medications, need to restrict diet, and overall disruption of social or professional life because of bowel function), the pouch patients faired better.58 Hida et al59 also looked at long-term results (5year follow-up) of 46 pouch patients versus 48 straight patients, and, again, for every variable measured (ie, the number of bowel movements per day or night, urgency and soilage), the pouch patients did better.59 Meta-analysis of the multiple studies published on the colonic Jpouch support the functional superiority of this reconstruction over the straight coloanal anastomosis.60 For a variety of reasons, including perceived evacuation problems in some patients with colonic J-pouches and the technical difficulties of getting a bulky pouch into the depths of a narrow male pelvis, particularly when the anastomosis is at the dentate line, a different type of pouch, the transverse

191 coloplasty pouch, was described, first by Z’graggen et al in 199961,62 and then by Fazio et al in 2000.63 The concept was to duplicate J-pouch function without creating a pouch. From a technical standpoint, an 8- to 10-cm-long longitudinal colotomy is made starting about 4 to 5 cm from the end of the colon. The colotomy is then closed transversely. Because a “straight” anastomosis is constructed with the coloplasty pouch, the problems with getting a bulky pouch to reach to or down into the anal canal in a narrow deep pelvis are obviated. A large, multicenter, international trial was conducted to answer the question of whether this type of pouch works as well as a colonic J-pouch.64 Patients who could not have a colonic J-pouch were randomized to a straight coloanal or transverse coloplasty pouch. Patients in whom a colonic J-pouch was feasible were randomized to a J-pouch versus a transverse pouch. With 364 patients randomized, the authors found that the J-pouch was functionally superior to the transverse coloplasty pouch and that the transverse pouch was superior to a straight anastomosis.

Temporary Diversion After Coloanal Anastomosis An anastomosis at or beneath the anorectal ring, as one constructs after TME or ISR with coloanal anastomosis, is considered a high-risk anastomosis. This is based on a leak rate that is not insignificant and on the very significant consequences of a leak at this level. As such, they are typically diverted temporarily with a loop ileostomy. Leak rates as high as 40%, have been reported when there is routine radiographic evaluation. The true leak rate is probably somewhere in the 1% to 15% range. The leak rate appears to be lower among patients with a diverting stoma.65-67 In an early study by Heald et al’s group,67 clinically significant anastomotic complications were seen in 15% of 75 patients without an ostomy and in only 0.8% of 125 diverted patients. This is in the setting of diversion being used selectively for patients thought by the surgeon to be at high risk of anastomotic leak. Based on these results, Heald et al recommend temporary diversion for all patients undergoing TME. In the Dutch TME trial, TME was associated with an anastomotic leak rate of 12%, with absence of a protective stoma associated with an increased risk of anastomotic breakdown and a greater need for surgical intervention after the leak was diagnosed. The authors concluded that every patient undergoing TME should have a protective stoma.68,69 Eriksen et al69 studied leak rates in a prospective study of 1,958 patients undergoing anterior resection for rectal cancer with TME from 1993 to 1998. The overall leak rate was 11.6%, and multivariate analysis showed that the risk of leakage was significantly higher in men, in patients treated with neoadjuvant radiation therapy, and when the anastomosis was ⬍6 cm from the anal verge. The authors concluded that a low anastomosis after TME should be protected with a diverting stoma. Prospective and randomized trials support the concept that temporary diversion should accompany reconstruction with a low anastomosis after TME.70,71

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192 Table 1 Oncologic Results with Intersphincteric Resection

Rullier et al (2005) Schiessel et al (2005) Saito et al (2006) Braun (1992) Schiessel et al (1994)

n

Tumor Height (cm)

T-Stage

(ⴙ)Deep Margin (%)

(ⴙ)Distal Margin

F/U (mo)

LR (%)

Survival (%)

92 121 228 63 34

2-5 1-5 <5 3-9 4-7

T2-4 T1-3 T1-3 T1-3 T1-4

11 — 1 — —

2% — 1 — —

>24 (58 pts) 94 41 80 36

2 5.3 6.7 11 13

81 — 92 62 —

The consequences of a leak at this level in the pelvis can be very significant.72 Although some would argue that a diverting stoma does not reduce the anastomotic leak rate, few would disagree with the concept that the consequences of the leak are much reduced when a stoma is in place.65,73 In the diverted patient, pelvic sepsis can almost always be treated by simply placing a drain. In the nondiverted patient, drains may suffice, but a return to the operating room to construct a diversion may be in order. The consequences of a leak may entail significant fibrosis in and around the neorectum, which can adversely affect bowel function. In addition, pelvic sepsis can lead to a hard, static, and fibrotic pelvic floor that simply does not work very well. Combine these potential problems with the already problematic bowel function that can accompany these operations and one sees the obvious value in trying to avoid pelvic sepsis. Additionally, it is desirable to achieve a smooth postoperative recovery to facilitate timely delivery of adjuvant chemotherapy, as indicated in many of these patients. Finally, there are also data to suggest that pelvic sepsis after a rectal cancer operation puts the patient at an increased risk of a poor oncologic outcome.74,75 Temporary diversion after TME with reconstruction seems prudent.76 Oncologic Results With ISR There are abundant data indicating that local recurrence rates and survival figures are not adversely affected by aggressive attempts at sphincter preservation. There is no longer controversy on this point. Multiple reports have detailed good results with LAR. Other reports have detailed experiences with intersphincteric proctectomy with reconstruction.43,77-88 Local recurrence figures have been acceptably low, typically less than 10% to 13% (Table 1). In a series of 92 patients reported by Rullier et al83 using the ISR technique for tumors at from 1.5 to 4.5 cm from the anal verge, the rate of complete microscopic resection (R0) was 89%, with 98% negative distal margin and 89% negative circumferential margin. In 58 patients with a follow-up of greater than 24 months, the rate of local recurrence was 2%, and the 5-year overall and disease-free survival rates were 81% and 70%, respectively. Seventy-two of these patients had T3 disease, and 81 patients were treated with preoperative chemo/ radiotherapy.83 In another series of 121 patients undergoing ISR and coloanal anastomosis, the median distance of the inferior margin of the tumor to the anal margin was 3 (1-5 cm). One hundred seventeen of these patients had rectal cancer, and 113 patients underwent curative resection. With a median follow-up time of 93 (range, 24-185) months, the

local recurrence rate was 5.3% (6 patients), and 5 of these recurrences developed in the first 2 years.85 The largest series of ISRs comes from Japan. Saito et al86 reported on 228 patients undergoing this operation at 7 Japanese institutions. Curative operations were accomplished in 86% of patients, and complete microscopic curative surgery was achieved in 225 of the 228 patients. During the median observation time of 41 months, the rate of local recurrence was 5.8% at 3 years, and the 5-year overall and disease-free survival rates were 91.9% and 83.2%, respectively. Although not standard in Japan, 57 patients with T3 tumors were treated with neoadjuvant chemo/radiation therapy. One hundred three patients had T3 tumors, and 78 had T2 disease.86 Quality of Life After SSR Much effort has been extended toward sparing sphincter function with the thought that this would provide, for properly selected patients, the best quality of life. Although there are obvious body image issues that come with a permanent colostomy, there is a price to be paid in terms of disordered bowel function when a low anastomosis is constructed. Recent studies, using various instruments for measuring quality of life, suggest that the differences experienced by patients undergoing an APR versus a LAR are not as significant as one might predict. In a prospective study of 249 patients treated for rectal cancer (46 APRs and 203 LARs) using validated quality of life instruments, Schmidt et al89 found that quality of life for patients undergoing an LAR was not different from that of patients undergoing APR. APR patients had more sexual dysfunction, whereas LAR patients suffered more bowel dysfunction. Using data from the Norwegian Rectal Cancer Database, Guren et al90 found that in 319 rectal cancer patients (229 LARs and 90 APRs), LAR patients had better body image and better preserved male sexual function than APR patients; however, there were no differences in overall quality of life. Patients with a very low anastomosis (⬍3 cm from the anal verge) had worse bowel function than those with a higher anastomosis but still had a better overall quality of life than patients treated with an APR. This led the authors to conclude that impairment in functional outcome does not necessarily have a major impact on quality of life. They also found that radiation had an overall negative impact on quality of life. Using treatment tradeoff and time tradeoff methods, Bossema et al91 using patients participating in the Dutch TME trial found that most patients preferred LAR over APR even if LAR involved a risk of fecal incontinence. Seventy-one percent of LAR patients would chose LAR even if they would suffer monthly incontinence, and 32% would chose LAR

Sphincter-sparing resection even if the incontinence episodes were daily. However, APR patients would give up less remaining years of life to be without a stoma than LAR patients to be without monthly incontinence. Functional disturbances after almost any rectal cancer surgery are common, but a good quality of life can be achieved, even after intersphincteric proctectomy with coloanal anastomosis.53,92-98 Although ISR may have a negative impact on function, a good quality of life can be maintained.99 Comparing 37 patients with a conventional coloanal anastomosis with 40 patients with an ISR and coloanal anastomosis, Bretagnol et al94 found that there was no difference in stool frequency, fragmentation, urgency, dyschezia, and alimentary restriction between the 2 groups. However, the ISR patients had worse continence and needed more antidiarrheal drugs. The quality of life after ISR was altered based on the subscale of embarrassment in the Fecal Incontinence Quality of Life Score but not as measured by the SF-36 scale.94 It may be that increased frequency of defecation after an ISR is primarily a function of resecting the rectum and then reconstructing with a neorectum, whereas leakage is more an issue based on resection of part or all the internal anal sphincter. Although frequently used, preoperative radiotherapy with or without chemotherapy, may also negatively impact functional results in patients treated with an ISR.100,101 Reconstruction with a colonic J-pouch or a transverse coloplasty pouch (discussed earlier) can help minimize functional disturbances after ISR. In a report from Willis et al,53 looking specifically at the issue of the colonic pouch versus the straight coloanal anastomosis after ISR, the pouch patients had significantly better results in terms of stool frequency and urgency. On physiological testing, they faired better in terms of maximum tolerated volume, threshold volume, and compliance. Interestingly, continence was not different between groups.53 In addition, medical treatment with antidiarrheal agents, low residue diets, antispasmodic agents, enemas, and biofeedback can all help in this regard. Obviously, the intersphincteric operation removes at least the upper aspect of the internal sphincter, and this will lower the resting tone of the anus.102 The patient chosen for this type of operation must have a normal external sphincter and must understand that achieving normal continence may be a challenge. These authors’ experience has been that in properly chosen and motivated patients, conversion to a permanent colostomy is rarely requested. The patient is always given at least a year or more to adapt to the new anatomy before this type of conversion is even considered.

Conclusions The decision as to whether a rectal cancer is better treated with an SSR or an APR is a complex one based on multiple factors, including the exact location of the tumor, the stage and grade of the tumor, the patient’s baseline bowel and anal function and overall health status, and perhaps, most importantly, their personal desires in terms of how they would rather be treated once they have had honest counseling about the functional and oncological results associated with the

193 various treatment options. The decision is no longer simply a matter of “how low” in the pelvis the tumor is located. Whether operative treatment involves LAR, ISR, or APR, patients can achieve a good postoperative quality of life, and, preoperatively, they should be counseled as such. From a technical standpoint, the evolution of SSR for rectal cancer will likely involve a transition to performing these operations using laparoscopic and/or robotic techniques. Data comparing these minimally invasive approaches with conventional operations is being generated.

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44. Akasu T, Takawa M, Yamamoto S, et al: Incidence and patterns of recurrence after intersphincteric resection for very low rectal adenocarcinoma. J Am Coll Surg 205:642-647, 2007 45. Lee WY, Takahashi T, Pappas T, et al: Surgical autonomic denervation results in altered colonic motility: An explanation for low anterior resection syndrome? Surgery 143:778-783, 2008 46. Lazorthes F, Fages P, Chiotasso P, et al: Resection of the rectum with construction of a colonic reservoir and colo-anal anastomosis for carcinoma of the rectum. Br J Surg 73:136-138, 1986 47. Parc R, Tiret E, Frileux P, et al: Resection and colo-anal anastomosis with colonic reservoir for rectal carcinoma. Br J Surg 73:139-141, 1986 48. Mortensen NJ, Ramirez JM, Takeuchi N, et al: Pouch-anal anastomosis after rectal excision for carcinoma: Functional outcome. Br J Surg 82:611-613, 1995 49. Nicholls RJ, Lubowski DZ, Donaldson DR: Comparison of colonic reservoir and straight colo-anal reconstruction after rectal excision. Br J Surg 75:318-320, 1988 50. Hida J, Yasutomi M, Fujimoto K, et al: Functional outcome after low anterior resection with low anastomosis for rectal cancer using the colonic J-pouch. Prospective randomized study for determination of optimum pouch size. Dis Colon Rectum 39:986-991, 1996 51. Hida J, Yasutomi M, Maruyama T, et al: Enlargement of colonic pouch after proctectomy and coloanal anastomosis: Potential cause for evacuation difficulty. Dis Colon Rectum 42:1181-1188, 1999 52. Banerjee AK, Parc R: Prediction of optimum dimensions of colonic pouch reservoir. Dis Colon Rectum 39:1293-1295, 1996 53. Willis S, Kasperk R, Braun J, et al: Comparison of colonic J-pouch reconstruction and straight coloanal anastomosis after intersphincteric rectal resection. Langenbecks Arch Surg 386:193-199, 2001 54. Ikeuchi H, Kusunoki M, Shoji Y, et al: Functional results after “high” coloanal anastomosis and “low” coloanal anastomosis with a colonic J-pouch for rectal carcinoma. Surg Today 27:702-705, 1997 55. Hida J, Yasutomi M, Maruyama T, et al: Indications for colonic Jpouch reconstruction after anterior resection for rectal cancer: Determining the optimum level of anastomosis. Dis Colon Rectum 41:558563, 1998 56. Seow-Choen F, Goh HS: Prospective randomized trial comparing J colonic pouch-anal anastomosis and straight coloanal reconstruction. Br J Surg 82:608-610, 1995 57. Hallbook O, Pahlman L, Krog M, et al: Randomized comparison of straight and colonic J pouch anastomosis after low anterior resection. Ann Surg 224:58-65, 1996 58. Dehni N, Tiret E, Singland JD, et al: Long-term functional outcome after low anterior resection: Comparison of low colorectal anastomosis and colonic J-pouch-anal anastomosis. Dis Colon Rectum 41:817822, 1998 59. Hida J, Yoshifuji T, Tokoro T, et al: Comparison of long-term functional results of colonic J-pouch and straight anastomosis after low anterior resection for rectal cancer: A five-year follow-up. Dis Colon Rectum 47:1578-1585, 2004 60. Heriot AG, Tekkis PP, Constantinides V, et al: Meta-analysis of colonic reservoirs versus straight coloanal anastomosis after anterior resection. Br J Surg 93:19-32, 2006 61. Z’Graggen K, Maurer CA, Mettler D, et al: A novel colon pouch and its comparison with a straight coloanal and colon J-pouch—Anal anastomosis: Preliminary results in pigs. Surgery 125:105-112, 1999 62. Z’Graggen K, Maurer CA, Birrer S, et al: A new surgical concept for rectal replacement after low anterior resection: The transverse coloplasty pouch. Ann Surg 234:780-785, 2001 63. Fazio VW, Mantyh CR, Colonic HTL: “Coloplasty”: Novel technique to enhance low colorectal or coloanal anastomosis. Dis Colon Rectum 43:1448-1450, 2000 64. Fazio VW, Zutshi M, Remzi FH, et al: A randomized multicenter trial to compare long-term functional outcome, quality of life, and complications of surgical procedures for low rectal cancers. Ann Surg 246:481-488, 2007 65. Dehni N, Schlegel RD, Cunningham C, et al: Influence of a defunc-

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Neoadjuvant Chemotherapy Alone for Early-Stage Rectal Cancer: An Evolving Paradigm? Eliza A. Hawkes, MBBS, David Cunningham, MD, Diana Tait, MD, Gina Brown, MD, and Ian Chau, MD Current management of early-stage rectal cancer comprises combinations of surgery, radiotherapy, and chemotherapy, with the presence or absence of several validated highrisk features determining which treatment modalities will be used and the order of administration. In high-risk individuals, most centers have adopted neoadjuvant combined chemotherapy and radiotherapy followed by surgery as the initial approach. However, longterm toxicity, limited survival gains, and high rates of distant failure have called this approach into question, with early data suggesting that neoadjuvant chemotherapy alone may be feasible in selected patient groups. This review discusses the current data and feasibility of managing early stage rectal cancer with neoadjuvant chemotherapy before surgical resection. Semin Radiat Oncol 21:196-202 © 2011 Elsevier Inc. All rights reserved.

R

ectal cancer comprises approximately 25% of all primary colorectal cancers and follows a different natural disease course compared with tumors of the colon, yet many therapeutic trials, both in the metastatic and curative settings, evaluate the 2 diseases together. It is well established that the surgical approach required for early-stage rectal tumors, the associated complications, and local recurrence rates are distinct from that for colon cancers. This has led to the development of diagnostic and therapeutic interventions specific to rectal cancer being incorporated into routine care, including magnetic resonance imaging (MRI) staging, neoadjuvant or adjuvant radiotherapy, or chemoradiotherapy. However, data supporting these interventions are unsatisfactory and leave many questions unanswered, with improvements still required in the overall multidisciplinary management. Neoadjuvant or perioperative chemotherapy alone improves outcomes in other adenocarcinoma models, such as operable gastric cancer1 and colorectal liver metastases,2 and, therefore, may be an appropriate strategy for selected localized rectal tumors. However, direct comparison with the current

Royal Marsden Hospital, London & Surrey, United Kingdom. Supported by the National Health Service Funding to the National Institute for Health Research Biomedical Research Centre. David Cunningham received funding from Roche, Amgen, and Merck Serono and is on the Advisory Board for Roche and Amgen; and Ian Chau received funding from Novartis, Roche, and Merck Serono and is on the Advisory Boards of Imclone, Novartis and Merck. Address reprint requests to Ian Chau, MD, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. E-mail: [email protected]

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standards within a well-powered randomized study is needed.

Selection of Patients for Multimodality Therapy The universal implementation of total mesorectal excision (TME) and neoadjuvant hypofractionated (short-course) radiotherapy (SCRT) or long-course chemoradiation (CRT) have reduced local recurrence rates from 25% to 40% to under 10%.3-6 However, multimodality management increases toxicity and has not consistently translated to improved survival, with only the Swedish Rectal Cancer Trial showing a survival benefit after SCRT in the pre-TME era.7,8 With 5-year survival rates greater than 90% in TNM stage T1-T2N0 tumors, the addition of (neo)adjuvant treatment to surgery is generally reserved for patients with operable T3-4, N0-2 tumors as determined by MRI or endorectal ultrasound. Several identified prognostic features differentiate outcomes of T3 tumors. The involvement of the circumferential resection margin (CRM) was identified as a poor prognostic marker 2 decades ago. A recent meta-analysis of studies, including 17,000 patients by Nagtegaal and Quirke,9 showed a positive CRM strongly predicts for local recurrence, especially in patients who have received neoadjuvant CRT (hazard ratio [HR] ⫽ 6.3) but also distant metastases (HR ⫽ 2.8) and poor survival (HR for survival ⫽ 1.7). CRM involvement can be accurately predicted by high-resolution MRI at presentation10 with prognosis improving if neoadjuvant ther-

Neoadjuvant chemotherapy

197

Table 1 Prognostic Features of Stage T3-T4 Rectal Cancer That are Detectable on Baseline MRI Prognostic Feature

Definition of High Risk

Affect on Outcome

CRM involvement

<1 mm from mesorectal fascia

EMVI

Extension into perirectal vasculature

Extramural spread

Extramural tumor depth >5 mm

Nodal stage

Higher TNM nodal stage

Tumor location

Low-lying tumor requiring abdominoperineal resection

Local recurrence HR ⴝ 6.3; 95% CI, 3.7-16.7 Distant metastases HR ⴝ 2.8; 95% CI, 1.9-4.3 Overall survival HR ⴝ 1.7; 95% CI, 1.3-2.3 3-year relapse-free survival 35% vs 74.1%, P < .001 5-year disease-specific survival 54.1% vs 85.4%, P < .0001 5-year OS by stage T3N0 ⴝ 64%, T3N1 ⴝ 52.4%, T3N2 ⴝ 37.5% 5-year disease-specific survival 65.1% for APR vs 76.6% for low anterior resection P < .001

CRM, circumferential resection margin; EMVI, extramural venous invasion; HR, hazard ratio; TNM, tumour node metastases; OS, overall survival; APR, abdominoperineal resection.

apy renders the CRM free of disease by imaging criteria, thus avoiding incomplete surgical resection. Other prognosticators detectable on MRI (Table 1) that influence outcomes include the presence of extramural venous invasion (3-year relapse-free survival, 35% vs 74.1%; P ⬍ .001),11,12 extramural spread beyond 5 mm (5-year disease-specific survival, 54.1% vs 85.4%; P ⬍ .0001),13,14 increased nodal stage (5year overall survival [OS] by stage: T3N0, 64% vs T3N1, 52.4% vs T3N2, 37.5%),15 and a low rectal tumor requiring abdominoperineal resection (5-year cancer-specific survival 65.1% for APR vs 76.6% for low anterior resection, P ⬍ .001). The impact on survival of MRI detection of some of these pathologic features does, however, need prospective validation. The advent of targeted agents has driven research into prognostic and predictive biomarkers of locally advanced rectal cancer with preliminary data for gene polymorphisms16,17; intramural epidermal growth factor receptor (EGFR); and vascular endothelial growth factor (VEGF) messenger RNA expression, K-RAS,18 PIK3CA genetic mutations,19 among others. These features highlight the need for careful staging and individualized management based not only on tumor TNM stage but also on a combination of stage, MRI findings, and patient characteristics.

Neoadjuvant Radiotherapy The dominant pattern of local recurrence after rectal cancer surgery and its devastating impact have led to neoadjuvant radiotherapy becoming a standard of care. The treatment of local recurrence remains a management challenge, and outcomes are extremely poor. The neoadjuvant treatment strategy offers several advantages, allowing for preoperative downstaging of the primary tumor, thus increasing the likelihood of an R0 resection and/or sphincter-preserving surgery; improves radiosensitivity by delivering radiation to better oxygenated tissue; provides early relief from tumor-

related symptoms; and reduces acute and chronic toxicity rates compared with postoperative CRT. A large randomized phase III trial compared preoperative CRT with postoperative CRT showed a reduction in local relapse with neoadjuvant treatment (5-year local relapse 6% vs 13%, P ⫽ .006) with grade 3 or 4 acute toxicity in 27% of preoperative patients compared with 40% in the postoperative group (P ⫽ .001).20 A direct comparison of SCRT verses long-course chemoradiotherapy did not show superiority of either regimen,21,22 yet for high-risk patients long-course chemoradiotherapy is widely accepted as the standard of care.

Long-Term Impact of Radiotherapy The toxicity of pelvic radiotherapy for rectal cancer can be problematic. Although acute side effects and surgical complications are only marginally increased with the addition of preoperative radiotherapy to surgery,23 the impact of neoadjuvant SCRT on long-term toxicities has been established in large randomized trials. The Dutch Colorectal Cancer Group found that compared with those who underwent TME alone, irradiated patients experienced significantly higher rates of fecal incontinence (62% vs 38%, P ⬍ .001), including the need for incontinence pads, anal blood loss (11% vs 3%. P ⬍ .004) and mucous loss (27% vs 15%, P ⬍ .005), and increased bowel frequency.24 The long-term follow-up from the Swedish Rectal Cancer Trial reported higher hospital admission rates in irradiated patients within the first 6 months (relative risk ⫽ 1.64; 95% confidence interval [CI], 1.212.22). No difference was seen in late admissions overall, but irradiated patients had an increased likelihood of being admitted for bowel obstruction (P ⫽ .02), abdominal pain (P ⫽ .01), and nausea (P ⫽ .03) as late sequelae.25 Sexual dysfunction is also a major issue as shown by the same Dutch group

198 that evaluated 990 patients for quality of life and sexual function. The most notable deterioration was in the irradiated group in terms of sexual activity (males, P ⫽ .06; females, P ⫽ .01), and both erectile and ejaculatory problems were higher in irradiated males (P ⫽ .02).23 These trials relate to SCRT, which is generally given to patients with better prognosis tumors at a lower risk of recurrence, and, therefore, the acceptability of late sequelae is lower and use larger dose-perfraction radiation therapy, which increases the risk of late effects. However, radiotherapy techniques are evolving rapidly, and there is the potential for more focused delivery, with increased normal tissue sparing and reduced toxicity.

Adjuvant Chemotherapy Distant failure rates remain as high as 36% with neoadjuvant CRT alone,20 heavily contributing to the lack of survival benefit of this approach. Therefore, intensification of the systemic component of management is needed, and chemotherapy without radiotherapy has only been evaluated in the adjuvant setting. Several studies have shown a survival benefit with adjuvant chemotherapy.26-29 In a pooled analysis of 5 phase III trials, OS was significantly improved by adjuvant chemotherapy either alone, as part of a CRT regimen, or as maintenance in addition to CRT compared with surgery alone or surgery plus adjuvant radiotherapy (P ⬍ .0001).30 The QUASAR (Quick and Simple and Reliable)31 trial of adjuvant fluorouracil (5-FU) plus folinic acid in stage II colorectal cancer included 948 (29%) patients with resected rectal cancer, 21% of whom received neoadjuvant radiotherapy. Adjuvant chemotherapy provided a modest OS benefit for stage II colorectal cancer; in the subset analysis of rectal cancer patients who received neoadjuvant radiotherapy, chemotherapy significantly reduced the risk of recurrence (HR ⫽ 0.68; 95% CI, 0.48-0.96) but not death (HR ⫽ 0.77; 95% CI, 0.55-1.08). The European Organisation of Research and Treatment of Cancer (EORTC) Radiotherapy Group assessed the addition of bolus 5-FU plus leukovorin to radiotherapy plus surgery in a 4-arm design (EORTC 22,921),32 randomizing 1,011 patients to receive either preoperative radiotherapy alone or CRT with or without postoperative chemotherapy. No difference was seen with the addition of preoperative chemotherapy to radiotherapy, and although there was a trend toward improved OS with postoperative chemotherapy, it did not reach statistical significance (5-year OS, 67.2% vs 63.2%; P ⫽ .12). An exploratory subgroup analysis of those patients achieving an R0 resection showed that in the event of significant downstaging (ypT0-2 tumors) by preoperative treatment, adjuvant chemotherapy improved both disease-free survival (HR ⫽ 0.64; 95% CI, 0.45-0.91; P ⫽ .013), and OS (HR ⫽ 0.64; 95% CI, 0.42-0.96; P ⫽ .030). In the population without downstaging, no benefit was seen.33 Because of the modest benefit with single-agent chemotherapy, routine care has more recently incorporated combined fluoropyrimidine/oxaliplatin adjuvant chemotherapy for high-risk individuals, extrapolating data from the colon cancer adjuvant NSABP C0734 and MOSAIC35 studies. Seri-

E.A. Hawkes et al ous long-term toxicity from chemotherapy is rare. There is a theoretic risk of secondary malignancies; however, studies relating to this did not include drugs used in modern regimens for rectal cancer. The most problematic long-term side effect is peripheral neurotoxicity secondary to oxaliplatin.

Neoadjuvant Chemotherapy Plus Chemoradiotherapy Despite the efficacy of postoperative chemotherapy, only 40% to 60% is administered at full dose, most commonly because of toxicity.20,32,36 Thus, several phase II studies have incorporated chemotherapy into preoperative management in high-risk patients. At our institution in a single-arm phase II study, Chau et al37 administered 12 weeks of 5-FU plus mitomycin C (MMC) before CRT and postoperatively to 36 patients with locally advanced tumors (at least T3 disease on digital rectal examination and imaging). The overall response rate to neoadjuvant chemotherapy was 27.8%, increasing to 81% after CRT, with 65% of patients experiencing improved symptoms during neoadjuvant chemotherapy. R0 resections were achieved in 28 of 34 patients. Treatment was well tolerated, with 61% completing postoperative chemotherapy. The larger EXPERT trial38 enrolled 105 eligible MRIdefined poor-risk patients (defined as at least one of CRMpositive, T3 low-lying tumor at or below the levators, extension ⱖ5 mm into perirectal fat, T4N0-2 or T1-4N2 tumor) to a similar design, replacing 5-FU and MMC with capecitabine and oxaliplatin (CAPOX) showing considerably higher radiologic response rates with the neoadjuvant chemotherapy (74%) and CRT (89%). Ninety-three of 97 patients had R0 resections with 21 patients achieving a pathological complete response (pCR) with evidence of downstaging in 76% of tumors. Seventy-eight of the 97 patients (80%) who underwent surgery completed postoperative chemotherapy. Interestingly, distant recurrence occurred in only 19% of the intention-to-treat population. Eleven patients (10%) did not complete neoadjuvant because of toxicity, whereas 19% were unable to receive any adjuvant chemotherapy, predominantly because of postoperative complications. The Grupo Cancer de Recto 3 study39 randomized 108 patients to receive induction CAPOX or adjuvant CAPOX in combination with CRT and surgery and reported that R0 resection, pCR, and tumor downstaging rates were similar in both arms. Tumor downstaging was lower than reported in the EXPERT study (58% in induction arm vs 89% in the EXPERT study); however, this study included a lower proportion of cT4 or CRM-involved tumors than previous studies, and the radiotherapy dose was also slightly lower (50.4 vs 54 Gy). This study was not powered to detect a difference in relapse rates or survival, and superiority of either group was not seen. Nonetheless, these results still provide a strong argument for induction chemotherapy based on the toxicity profile. Only 2% of patients in the induction arm were unable to complete study treatment because of adverse events compared with 17% in the adjuvant arm, whereas rates of grade 3

Results Trial Chau, et al n ⴝ 36

EXPERT n ⴝ 105

EXPERT-C n ⴝ 163

Grupo Cancer de Recto 3 study n ⴝ 108

Marechal, et al n ⴝ 57

Avacross n ⴝ 47

DiPetrillo, et al n ⴝ 23

Design Phase 2 Single Arm 5FU ⴙ MMC ¡ CRT ¡ surgery¡ adjuvant 5FU ⴙ MMC Phase 2 single arm CAPOX ¡ CRT ¡ surgery¡ Adjuvant CAPOX

Phase 2 randomised ARM A: CAPOX - CRT-surgery adjuvant CAPOX ARM B: CAPOX ⴙC to CRTⴙC to surgery to adjuvant CAPOX ⴙC Phase 2 randomized Arm A CRT ¡ surgery¡ CAPOX ArmB: CAPOX¡ CRT¡ Surgery Phase 2 randomized ArmA: CRT¡ surgery Arm B FOLFOX6 (2 cycles)¡ CRT¡ surgery Phase 2 single arm Bev ⴙ CAPOX (4 cycles)¡ CRT ⴙ bev¡ surgery¡ CAPOX Phase 2 single arm Bev ⴙ FOLFOX6 (2 cycles)¡ CRT ⴙ bev¡ surgery¡ Bev ⴙ FOLFOX6 (6 cycles)

Population At Least T3N0 disease on DRE ⴙ imaging (CT or MRI)

Response to Chemotherapy

Pathologic Downstaging at Surgery (%)

R0 Resection (%)

27.8%

73.5%

82

3-year PFS: 47%

3-year OS: 67%

76%

98

3-year PFS: 68

3-year OS: 83

3-year PFS: 81

3-year OS: 81

MRI-defined high risk CRMⴙ Low-lying tumor >5 mm perirectal fat spread T4 or T1-4N2 MRI-defined high risk CRMⴙ Low-lying tumor >5 mm perirectal fat spread T4 or EMVI

74% (95% CI, 65-82)

MRI-defined high risk: ● CRMⴙ ● Low-lying tumor ● cT3-4 or cT3Nⴙ

Not reported

Arm a: 58 (95% CI, 43.271.3) Arm b: 43 (95% CI, 29.756.8) P ⴝ 0.13

Arm a: 87 Arm b: 86

cT2-4Nⴙ

Not reported

“No difference”

MRI-defined high risk: T3 low-lying tumor CRM ⴙ >cT4 or T3Nⴙ

Not reported

T stage Arm a: 48 Arm b: 46 P ⴝ .99 N stage Arm a: 55 Arm b: 43 P ⴝ .64 pCR rate: 38.6

Stage 2-3

Not reported

pCR rate: 25

Not reported

50%

Not reported

84

70%

Not reported

93

97

PFS (%)

OS (%)

80

96

18-mo failure-free survival Arm a: 82 (95% CI, 65-91) Arm b: 76 (95% CI, 61-86)

18 mo OS Arm a: 89 (95% CI 76-96) Arm b: 91 (95% CI 79-96)

Not yet reported

Not yet reported

Not reported

Not reported

Not reported

Not reported

Neoadjuvant chemotherapy

Table 2 Neoadjuvant Chemotherapy Plus Chemoradiation in Locally Advanced Rectal Cancer

DRE, digital rectal examination; FOLFOX6, 5FU, folinic acid ⴙoxaliplatin; Bev, bevacizumab; C, cetuximab.

199

E.A. Hawkes et al

200 or 4 toxicity were significantly different (19% induction arm vs 54% adjuvant arm, P ⫽ .0004). A small randomized phase II trial40 (n ⫽ 57) added 2 cycles of neoadjuvant 5-FU, leucovorin, and oxaliplatin (FOLFOX) to a CRT plus surgery regimen. No difference in pCR or downstaging was seen, and distant relapse rates were not reported; however, with only 4 weeks of additional chemotherapy and lower radiotherapy doses (45 Gy), conclusions are difficult to draw. From these trials (Table 2), it appears that the delivery of neoadjuvant chemotherapy is better tolerated than adjuvant treatment and may offer benefit over CRT alone; however, this approach needs to be evaluated in a phase III randomized control setting. Rationale for neoadjuvant chemotherapy without CRT includes the ability to commence antitumor therapy immediately, rather than delaying systemic therapy to administer local strategies and better surgical outcomes because of tumor downstaging. Omitting CRT would avoid important radiotherapy-associated toxicities, such as infertility and loss of sexual function, preoperative fibrosis, and tissue friability. Chemotherapy also provides the opportunity for the early identification of patients who do not benefit from standard regimens and may require intensified regimens. Sauer et al20 estimated that 18% of patients are overtreated by neoadjuvant CRT because of the failure of preoperative staging to detect early pathologic stage. Although endorectal ultrasound was mandatory, the study was performed before the introduction of routine MRI staging, which may explain these results. The EXPERT trial showed promising downstaging and symptom improvement after CAPOX

chemotherapy,38 suggesting that further assessment of neoadjuvant chemotherapy is warranted.

Targeted Therapy Blockade of both VEGF and EGFR with monoclonal antibodies has proven efficacy in advanced colorectal cancer.41-46 Bevacizumab, a VEGF antibody, has been incorporated into neoadjuvant CRT with variable toxicity and pCR rates (0%32%), but reports so far are limited to small numbers and no firm conclusions regarding its additional benefit can be made at present.47-49 Two recent studies have added bevacizumab to neoadjuvant chemotherapy, before CRT, again with small numbers. The Avacross single-arm study50 administered 4 cycles of CAPOX plus bevacizumab before CRT with capecitabine plus bevacizumab in 47 MRI-defined high risk patients with entry criteria similar to that of the EXPERT trial. Ninety-three percent underwent surgery with 38.6% achieving a pCR (95% CI, 24.7-54.5). DiPetrillo et al51 combined bevacizumab with FOLFOX6 for 2 cycles before CRT (delivered with bevacizumab, oxaliplatin, and capecitabine) and surgery with only 23 patients at the time of reporting. Five patients achieved a pCR, and toxicity was an issue during the CRT phase with 75% developing a grade 3 or higher toxicity. A further study recruited 31 patients with FOLFOX plus bevacizumab followed by surgery.52 No pre-operative RT was given. A pCR rate of 27% was observed. The incorporation of anti-EGFR monoclonal antibodies, such as cetuximab and panitumumab, into management of

Figure 1 Potential risk-adaptive treatment strategies in locally advanced rectal cancer.

Neoadjuvant chemotherapy rectal cancer has been evaluated in multiple phase I and II studies because of their proven efficacy in patients with advanced disease not harboring a Kirsten-RAS (K-RAS) gene mutation. Cetuximab is a known radiosensitizer, and its addition to neoadjuvant CRT is feasible; however, in phase I and II studies of unselected populations to date, no improvement in clinical outcomes have been proven.53,54 The EXPERT-C phase II trial randomized patients to the EXPERT treatment regimen plus or minus cetuximab, delivering the antibody therapy during both the neoadjuvant chemotherapy and CRT treatment phases, rather than using it purely as a radiosensitizer.55 Between 2005 and 2008, 164 patients were recruited. Among those with KRAS and B-RAF wild type tumours, radiological response rates were significantly improved with addition of cetuximab to neoadjuvant chemotherapy (50% vs 70%; P ⫽ 0.038) and CRT (72% vs 89%; P ⫽ 0.028). In addition, a significant improvement in overall survival was observed with the addition of cetuximab (HR: 0.27; P ⫽ 0.035).

Conclusions Three notions remain clear; first, all locally advanced rectal tumors do not behave in the same manner. Second, multimodality treatment, particularly neoadjuvant therapy, improves outcomes, and third, reductions in local recurrence do not obviously confer a survival benefit. Because of the strong prognostic value of CRM involvement, extramural spread, higher nodal stage, and low tumor position in T3-T4 tumors, along with the improved outcomes with an R0 resection in high-risk groups, patients should be stratified according to these risk factors. The authors suggest a possible treatment paradigm stratified according to risk in Figure 1. Those with a higher-risk profile should be selected to receive standard treatment, such as long-course CRT to increase the likelihood of complete resection plus adjuvant, and/or possibly neoadjuvant chemotherapy to minimize distant relapse. However, those with locally advanced tumors deemed to be “moderate” risk could be considered for neoadjuvant chemotherapy alone, followed by surgery and possible adjuvant radiotherapy or chemotherapy if required, based on pathologic stage, which would avoid unnecessary preoperative delays and postoperative toxicities. “Low-risk” patients (ie, absence of all high-risk features) could avoid neoadjuvant treatment altogether and receive adjuvant therapy if pathologic stage at time of surgery dictated a need. This approach needs to be evaluated in a clinical trial setting. Currently, there is no proven role for neoadjuvant chemotherapy alone except within the context of metastatic disease. A major need exists for randomized trials to assess the benefits of neoadjuvant chemotherapy over adjuvant chemotherapy and as an alternative to preoperative radiotherapy as treatment of locally advanced rectal cancer. When incorporating neoadjuvant chemotherapy into new trial designs, consideration should be given to validation of surrogate endpoints, such as pCR, and conducting adequately sized

201 randomized-control trials that are able detect a survival difference.

References 1. Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11-20, 2006 2. Nordlinger B, Sorbye H, Glimelius B, et al: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC InterGroup Trial 40983): A randomised controlled trial. Lancet 371:1007-1016, 2008 3. Havenga K, Enker WE, Norstein J, et al: Improved survival and local control after total mesorectal excision or D3 lymphadenectomy in the treatment of primary rectal cancer: An international analysis of 1411 patients. Eur J Surg Oncol 25:368-374, 1999 4. Nesbakken A, Nygaard K, Westerheim O, et al: Local recurrence after mesorectal excision for rectal cancer. Eur J Surg Oncol 28:126-134, 2002 5. Heald RJ, Moran BJ, Ryall RD, et al: Rectal cancer: The Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 133: 894-899, 1998 6. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001 7. Peeters KC, Marijnen CA, Nagtegaal ID, et al: The TME trial after a median follow-up of 6 years: Increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246:693-701, 2007 8. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-987, 1997 9. Nagtegaal ID, Quirke P: What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 26:303-312, 2008 10. Mercury Study Group: Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: Prospective observational study. BMJ 333:779, 2006 11. Smith NJ, Shihab O, Arnaout A, et al: MRI for detection of extramural vascular invasion in rectal cancer. AJR Am J Roentgenol 191:15171522, 2008 12. Smith NJ, Barbachano Y, Norman AR, et al: Prognostic significance of magnetic resonance imaging-detected extramural vascular invasion in rectal cancer. Br J Surg 95:229-236, 2008 13. Merkel S, Mansmann U, Siassi M, et al: The prognostic inhomogeneity in pT3 rectal carcinomas. Int J Colorectal Dis 16:298-304, 2001 14. Mercury Study Group: Extramural depth of tumor invasion at thinsection MR in patients with rectal cancer: Results of the mercury study. Radiology 243:132-139, 2007 15. Gunderson LL, Jessup JM, Sargent DJ, et al: Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes. J Clin Oncol 28:256-263, 2010 16. Hu-Lieskovan S, Yang D, Grimminger PP, et al: Use of EGF a⫹61G and TS-5’UTR 2R/3R polymorphisms to predict complete pathologic response in locally advanced rectal cancer patients undergoing preoperative cetuximab-based chemoradiation followed by surgery. J Clin Oncol 28:3641, 2010 (abstr) 17. Tanaka M, Bedrosian I, Chang GJ, et al: Correlation of single nucleotide polymorphisms (SNPs) of hypoxia-related genes with pathologic complete response (pCR) following neoadjuvant chemoradiation (chemoXRT) for locally advanced rectal cancer. J Clin Oncol 28, 2010 18. Vallbohmer D, Grimminger PP, Yang D, et al: Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in advanced rectal cancer. J Clin Oncol 28:276S, 2010 19. He Y, Lopez Yurda M, Mikolajewska-Hanclich I, et al: Effect of preoperative radiotherapy on local recurrences in rectal cancer patients with PIK3CA mutation. J Clin Oncol 28:3639, 2010 (abstr)

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202 20. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:17311740, 2004 21. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al: Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93:1215-1223, 2006 22. Ngan SFR, Goldstein D, Solomon M, et al: A randomized trial comparing local recurrence (LR) rates between short-course (SC) and longcourse (LC) preoperative radiotherapy (RT) for clinical T3 rectal cancer: An intergroup trial (TROG, AGITG, CSSANZ, RACS). J Clin Oncol 28:3509, 2010 (abstr) 23. Marijnen CA, van de Velde CJ, Putter H, et al: Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: Report of a multicenter randomized trial. J Clin Oncol 23:1847-1858, 2005 24. Peeters KC, van de Velde CJ, Leer JW, et al: Late side effects of shortcourse preoperative radiotherapy combined with total mesorectal excision for rectal cancer: Increased bowel dysfunction in irradiated patients—A Dutch colorectal cancer group study. J Clin Oncol 23:61996206, 2005 25. Birgisson H, Pahlman L, Gunnarsson U, et al: Adverse effects of preoperative radiation therapy for rectal cancer: Long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 23:8697-8705, 2005 26. Fisher B, Wolmark N, Rockette H, et al: Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: Results from NSABP protocol R-01. J Natl Cancer Inst 80:21-29, 1988 27. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991 28. Tepper JE, O’Connell M, Niedzwiecki D, et al: Adjuvant therapy in rectal cancer: Analysis of stage, sex, and local control—Final report of Intergroup 0114. J Clin Oncol 20:1744-1750, 2002 29. Wolmark N, Rockette H, Fisher B, et al: The benefit of leucovorinmodulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: Results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11:1879-1887, 1993 30. Gunderson LL, Sargent DJ, Tepper JE, et al: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: A pooled analysis. J Clin Oncol 22:1785-1796, 2004 31. Quasar Collaborative Group, Gray R, Barnwell J, et al: Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet 370:2020-2029, 2007 32. Bosset JF, Collette L, Calais G, et al: Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114-1123, 2006 33. Collette L, Bosset JF, den Dulk M, et al: Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: Does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organization for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 25: 4379-4386, 2007 34. Wolmark N, Wieand S, Kuebler PJ, et al: A phase III trial comparing FULV to FULV ⫹ oxaliplatin in stage II or III carcinoma of the colon: Survival results of NSABP Protocol C-07. J Clin Oncol 26, 2008 35. Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004 36. Rodel C, Liersch T, Hermann RM, et al: Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 25:110117, 2007 37. Chau I, Allen M, Cunningham D, et al: Neoadjuvant systemic fluorouracil and mitomycin C prior to synchronous chemoradiation is an effective strategy in locally advanced rectal cancer. Br J Cancer 88:10171024, 2003 38. Chua YJ, Barbachano Y, Cunningham D, et al: Neoadjuvant capecit-

39.

40.

41.

42.

43.

44.

45. 46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

abine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: A phase 2 trial. Lancet Oncol 11:241-248, 2010 Fernández-Martos C, Pericay C, Aparicio J, et al: Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol 28:859-865, 2010 Maréchal R, VB, Polus M, et al: Chemotherapy induction followed by preoperative chemoradiation versus preoperative chemoradiation alone in locally advanced rectal cancer (LARC): A randomized controlled phase II study. J Clin Oncol 28:295S, 2010 Van Cutsem E, Kohne CH, Hitre E, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360: 1408-1417, 2009 Bokemeyer C, Bondarenko I, Makhson A, et al: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663-671, 2009 Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007 Jonker DJ, O’Callaghan CJ, Karapetis CS, et al: Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040-2048, 2007 Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 Willett CG, Duda DG, di Tomaso E, et al: Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: A multidisciplinary phase II study. J Clin Oncol 27:30203026, 2009 Crane CH, Eng C, Feig BW, et al: Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 76:824-830, 2010 Resch G, de Vries A, Ofner D, et al: Preoperative treatment with capecitabine (C), bevacizumab (B) and radiotherapy (RT) for primary locally advanced rectal cancer (LARC): A two-stage phase II clinical trial. Proceedings of the 2010 ASCO Gastrointestinal Cancers Symposium. 2010 (abstr 496) Nogue M, Salud A, Vicente P, et al: Addition of bevacizumab to induction plus concominant capecitabine-oxaliplatin (XELOX) chemoradiotherapy (CRT) in MRI poor prognosis locally advanced rectal cancer: Avacross study. J Clin Oncol 27:4100, 2009 (abstr) DiPetrillo TA, Pricolo V, Sikov WM, et al: Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil and radiation in clinical stage II–III rectal cancer. J Clin Oncol 26, 2008 Schrag D, Weiser MR, Goodman KA, et al: Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer. J Clin Oncol 28: 15S-263S, 2010 (abstr 3511) McCollum AD, Kocs DM, Chada P, et al: A randomized phase II trial of preoperative chemoradiotherapy with or without cetuximab in locally advanced adenocarcinoma of the rectum. J Clin Oncol 28, 2010 Machiels JP, Sempoux C, Scalliet P, et al: Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol 18:738-744, 2007 Dewdney A, Cunningham D, Tabernero J, et al: EXPERT-C: A randomized phase II European multicenter trial of neoadjuvant chemotherapy (capecitabine/oxaliplatin) and chemoradiation (CRT) with or without cetuximab followed by total mesorectal excision (TME) in patients with MRI-defined high-risk rectal cancer. ASCO 2011 Gastrointestinal Cancers Symposium. J Clin Oncol 29:2011 (suppl 4; abstr 360)

Beyond 5-Fluorouracil: The Emerging Role of Newer Chemotherapeutics and Targeted Agents with Radiation Therapy Brian G. Czito, MD, and Christopher G. Willett, MD The management of rectal cancer has undergone significant evolution with advances in surgery, radiation therapy, and chemotherapy. These advances have translated into improved rates of local control, survival, and quality of life. More recently, the integration of newer chemotherapeutic and targeted agents in patients with advanced colorectal cancer have led to further improvements in disease-free and overall survival. These agents are now being studied with radiation therapy in the neoadjuvant therapy of rectal cancer. Semin Radiat Oncol 21:203-211 © 2011 Elsevier Inc. All rights reserved.

O

ver the past 30 years, the clinical management of rectal cancer has undergone significant change. Until the 1970s and 1980s, surgery was often the sole modality used in the treatment of rectal cancer patients. However, patterns of failure analyses showed that local recurrence was a frequent and clinically important pattern of relapse, resulting in significant morbidity and death.1,2 To reduce these high failure rates, phase III trials evaluated different strategies of adjuvant radiation therapy and 5-fluorouracil (5-FU)-based chemotherapy.3-5 Trial results showed that adjuvant radiation therapy with chemotherapy improved local control and survival compared with surgery alone, leading to the routine integration of adjuvant combined modality therapy into daily practice in the United States. More recently, significant innovations in the surgical technique of rectal cancer have taken place.6,7 Studies of surgery alone reported local failure rates of less than 10% through a more complete dissection of the enveloping rectal mesentery (ie, a total mesorectal excision [TME]). These impressive results led to questioning of the need for radiation therapy and prompted a Dutch study randomizing 1,805 eligible patients with operable (including stage I) rectal cancer to preoperative radiation therapy followed by TME versus TME alone.8 These study results showed that patients receiving preoperative radiation therapy had improved local control versus patients undergoing TME only. Furthermore, the magnitude of im-

Department of Radiation Oncology, Duke University Medical Center, Durham, NC. Address reprint requests to Brian G. Czito, MD, Duke University Medical Center, Radiation Oncology, Morris Bldg., Box 3085, Durham, NC 27710. E-mail: [email protected]

1053-4296/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2011.02.006

provement in local control with radiation therapy in this study was likely underestimated by the inclusion of stage I patients, who generally have excellent outcomes with surgery only. These findings have been supported by the results of a Medical Research Council Trial evaluating preoperative short-course radiation therapy versus selected postoperative combined modality therapy.9,10 In this phase III study, 1,350 patients with clinically resectable rectal cancer were randomized to short-course preoperative radiation therapy (25 Gy in 5 fractions) and TME versus TME followed by selective postoperative chemoradiation (45 Gy in 25 fractions with 5-FU) for patients with tumor invasion of the circumferential resection margin. In addition, patients with stage III disease received postoperative chemotherapy. In patients undergoing preoperative radiation therapy, compared with selective postoperative chemoradiotherapy, local recurrence was significantly reduced (4.4% vs 10.6%, respectively). Furthermore, 3-year disease-free survival was significantly improved in patients undergoing preoperative radiation versus selective postoperative chemoradiation (77.5% and 71.5%, respectively). Overall survival did not differ between the groups. These results suggest that even in the setting of TME and adjuvant chemotherapy, preoperative radiation improves outcomes over selective adjuvant postoperative chemoradiation in patients with high-risk disease. Because of the potential benefits of preoperative (vs postoperative) therapy, neoadjuvant trials have also been pursued. German investigators successfully completed the CAO/ ARO/AIO trial comparing neoadjuvant chemoradiation with adjuvant chemoradiation.11 This landmark study showed that simply by altering the sequence of chemoradiotherapy to 203

B.G. Czito and C.G. Willett

204 surgery, rates of compliance, local control, sphincter preservation, and acute/late toxicity were improved, validating the advantages of preoperative therapy. These findings led to a new standard of care in the United States and Europe in the treatment of rectal cancer. More recently, European trials have further evaluated the role of concurrent 5-FU– based chemotherapy with radiation therapy in the neoadjuvant treatment of rectal cancer. Results from the EORTC, FFCD, and Poland showed improved pathologic response rates and local control with the addition of chemotherapy; however, in contrast to adjuvant studies, these reports have not verified a survival advantage with the addition of concurrent 5-FU.12-14 Additionally, in patients with metastatic and locally advanced colorectal cancer, improved disease-free and overall survival rates have been achieved with the addition of newer chemotherapeutic (ie, capecitabine, oxaliplatin, irinotecan) agents and targeted (ie, bevacizumab, cetuximab, panitumumab) agents when compared to conventional chemotherapies. These agents are now being incorporated into testing of new strategies in the neoadjuvant therapy of rectal cancer. The goal of combining these agents with radiation therapy is to further enhance rates of tumor downstaging and possibly sphincter preservation, local control, survival, and to identify highly active regimens that could potentially obviate the need for radical surgery in selected patients. Herein, we review the background, rationale, and results of combining these agents with radiation therapy in the treatment of localized rectal cancer.

Table 1 Capecitabine-Based Combined–Modality Therapy Trials for Rectal Cancer-Selected Phase II Trials

Study Anderson101

MD University of Ulsan102 National Cancer Institute, Italy103 France104 Leeds Cancer Centre, UK105 Germany17

Patient #

Regimen

Pathologic Complete Response Rate (%)

51 95

Cape,* 52.5 Gy Cape,* 50 Gy

18 13

51

Cape,* 50.4 Gy

24

50 70

Cape,* 45 Gy Cape, 45 Gy

24 9

87

Cape, 50.455.8 Gy

7

Cape, capecitabine. *Continuously during radiation course.

with radiation therapy in the neoadjuvant treatment of rectal cancer appears tolerable with surgical outcomes similar to that of infusional 5-FU. Further evaluation of capecitabine delivered neoadjuvantly with radiation therapy in patients with stage II to III rectal cancer is being conducted in the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 and multiple European randomized trials (discussed later).

Oxaliplatin

Cytotoxic Chemotherapy Capecitabine Capecitabine (Xeloda, Hoffman-La Roche, Basel, Switzerland) is an oral 5-FU prodrug. The conversion of capecitabine to 5-FU is dependent on thymidine phosphorylase, an enzyme shown to be upregulated by radiotherapy in tumoral tissues relative to normal tissues.15 Additionally, there is a potential synergistic effect with the addition of capecitabine to radiation therapy, with improved tumorcidal effects relative to 5-FU– based radiation therapy.15 Clinically, similar disease-free and overall survival outcomes have been shown when adjuvant capecitabine was compared with bolus 5-FU and leucovorin chemotherapy in a randomized study of nearly 2,000 Dukes C colon cancer patients, with a trend toward improved disease-free and overall survival in the capecitabine arm.16 Multiple phase II studies have been conducted evaluating capecitabine combined with preoperative radiation therapy in patients with locally advanced rectal cancer (Table 1). Overall, pathologic complete response rates have ranged from 0% to 31%.17 More recently, a phase III German trial compared capecitabine versus 5-FU– based neoadjuvant chemoradiotherapy in 401 patients with locally advanced rectal cancer. Preliminary results of this study suggested that capecitabine has the potential to replace 5-FU as a perioperative treatment of locally advanced rectal cancer, with higher rates of tumor downstaging in the capecitabine arm.18 Therefore, to date, the combination of capecitabine

Oxaliplatin (Eloxatin, Sanofi-Aventis, Paris, France) is a newer-generation platinum analog that forms inter- and intrastrand DNA links, inhibiting cellular replication. In vitro and in vivo data in colon cancer cell lines have shown efficacy as well as an additive/synergistic effect with fluoropyrimidinebased cytotoxics.19 In metastatic colorectal cancer, oxaliplatin-containing regimens have been shown to improve survival.20 In the adjuvant treatment of stage III colon cancer, the addition of oxaliplatin to 5-FU– based chemotherapy has also been shown to improve disease-free and overall survival versus 5-FU– based regimens alone.21-24 Additionally, oxaliplatin has shown radiation-enhancing effects in vitro.25 Based on these data, investigators have evaluated the combination of oxaliplatin, fluoropyrimidines, and radiation therapy in the neoadjuvant treatment of rectal cancer. Phase II studies evaluating the addition of oxaliplatin to fluoropyrimidine-based chemoradiotherapy have shown good tolerability and encouraging response rates.26-33 More recently, however, 2 important European phase III trials have reported on the role of oxaliplatin in neoadjuvant 5-FU– based chemoradiation regimens. In the Italian Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial, 747 patients with locally advanced rectal cancer were randomized to 5-FU– based chemoradiation with and without concurrent weekly oxaliplatin. Preliminary results showed that the addition of weekly oxaliplatin to 5-FU– based preoperative chemoradiation significantly increased grade 3 to 4 toxicity without significantly impacting patho-

Combined therapy in rectal cancer

205

Table 2 Oxaliplatin-Based Combined–Modality Therapy Trials for Rectal Cancer-Phase III Trial Results

Study

Patient #

STAR-01106

741

ACCORD 12/0405 PRODIGE 2 35

598

Regimen RT vs RT RT vs RT

50.4 Gy ⴙ 5 - FU 50.4 Gy ⴙ 5 - FU ⴙ oxaliplatin 45 Gy ⴙ capecitabine 50 Gy ⴙ capecitabine ⴙ oxaliplatin

Pathologic Complete Response Rate (%)

Grade 3-4 Toxicity (%)

16 P ⴝ .98 15 14 P ⴝ .09 19

8 P < .001 24 11 P < .001 25

5-FU, 5-fluorouracil.

logic downstaging rates.34 Similarly, in the French ACCORD 12/0405 PRODIGE 2 study, 598 patients with locally advanced rectal cancer were randomized to receive concurrent radiation therapy and capecitabine versus concurrent radiation therapy, capecitabine, and oxaliplatin. Trial results showed higher grade 3 to 4 toxicity rates in patients receiving radiation therapy, capecitabine, and oxaliplatin versus radiation therapy and capecitabine, with no statistical differences in rates of pathologic complete response, although an improvement in circumferential radial margin involvement was seen (19% vs 10%, P ⫽ 0.02)35 (Table 2). Ongoing trials evaluating the role of oxaliplatin include the American NSABP R-04 study (a phase III trial comparing preoperative radiation therapy and capecitabine with or without oxaliplatin vs preoperative radiation therapy and continuous infusion of 5-FU with or without oxaliplatin), the German AIO/CAO/ARO-04 study (a phase III trial comparing preoperative radiation therapy and continuous infusion of 5-FU with or without oxaliplatin as well as adjuvant 5-FU with or without oxaliplatin), and the multinational PETACC-6 study (a phase III trial comparing preoperative radiation therapy and capecitabine with or without oxaliplatin as well as adjuvant capecitabine, with or without oxaliplatin). These trials should help further clarify the role of oxaliplatin when delivered with radiation therapy in the neoadjuvant therapy of rectal cancer.

Irinotecan Irinotecan (Camptosar, Pfizer, New York, NY) is a topoisomerase I inhibitor that interrupts DNA replication during transcription. In the setting of metastatic colorectal cancer, irinotecan has been shown to improve survival when combined with 5-FU and leucovorin (IFL) versus 5-FU/leucovorin alone.36 Additionally, preclinical and clinical data suggest that irinotecan is a potent radiation sensitizer.37 Multiple phase I/II studies combining irinotecan with neoadjuvant radiation therapy for rectal cancer have been completed, with pathologic complete response rates generally higher than that seen with fluoropyrimidine-based radiation therapy alone, although at the cost of higher acute toxicity rates (particularly diarrhea).38-44 The Radiation Therapy Oncology Group reported the results of a phase II randomized study comparing continuous infusion 5-FU with hyperfractionated radiation therapy versus continuous infusion 5-FU and irinotecan with radiation

therapy in patients with clinical T3/T4 rectal cancer. The pathologic complete response rate was 28% in each arm although grade 3 to 4 toxicity occurred in 45% of patients receiving irinotecan.45 A preliminary report from UK investigators described 135 patients with magnetic resonance imaging– defined poor risk rectal cancer (threatened margins and/or involved mesorectal fascia) who received neoadjuvant radiation therapy with concurrent capecitabine and weekly irinotecan. At final pathology, 23% showed T0 disease and 91% negative circumferential radial resection margins.46 A more recent Radiation Therapy Oncology Group randomized study compared oxaliplatin and capecitabine with radiation therapy versus irinotecan and capecitabine with radiation therapy. The pathologic complete response rates were 18% in the oxaliplatin arm and 10% in the irinotecan arm.47 Given these results along with the increased treatment-related toxicities in these studies, the role of irinotecan-based concurrent chemoradiotherapy remains investigational.

Targeted Agents With increasing knowledge of the biochemical cellular pathways of tumor growth and spread and the development of “targeted therapies” against these pathways, attention has turned to the use of these agents coupled with chemotherapy in the treatment of patients with metastatic colorectal cancer. For these patients, phase III trials have shown improved disease-free and overall survival rates using epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors when combined with conventional chemotherapy. These and other “targeted” agents are now being studied in the neoadjuvant therapy of rectal cancer and are discussed below.

EGFR Inhibitors The epidermal growth factor receptor (EGFR, HER-1, or ErbB1) is a transmembrane glycoprotein essential for tumor growth and division.48 Some colorectal cancers have been shown to overexpress EGFR,49-51 and overexpression of EGFR in colorectal cancers is associated with poorer prognosis. The overexpression of EGFR is regarded as a negative prognostic factor and is associated with resistance to radiation therapy. In retrospective analyses, patients

B.G. Czito and C.G. Willett

206 with EGFRexpressing rectal cancer undergoing neoadjuvant radiation therapy had a significantly lower diseasefree survival and lower chance of achieving pathologic complete response.52-58 Therefore, EGFR inhibition has emerged as a potential target in combination with radiation therapy. Two types of EGFR inhibitors have been evaluated in patients with colorectal cancer: small-molecule EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) and monoclonal antibodies to EGFR (cetuximab and panitumumab).

Small-Molecule EGFR Inhibitors Gefitinib (Iressa, AstraZeneca, London, United Kingdom) is a selective inhibitor of the EGFR tyrosine kinase, resulting in the interruption of mitogenic and antiapoptotic signals responsible for proliferation, growth, and angiogenesis. Preclinical studies in human colorectal and other cancer cell lines have shown enhanced cytotoxicity when gefitinib is combined with chemotherapy and radiation therapy.59-63 Gefitinib with 5-FU– based chemotherapy appears to be feasible in patients with advanced colorectal cancer without a significant increase in severity of side effects.64,65 Erlotinib (Tarceva, Genentech/OSI Pharmaceuticals, San Francisco, CA), another inhibitor of EGFR tyrosine kinase, has also been tested in patients with metastatic colorectal cancer.66,67 A small phase I trial from Duke University combining gefitinib, capecitabine, and radiation therapy in rectal cancer patients resulted in significant toxicity, and no recommended phase II dose could be determined.68 In contrast, an Italian study evaluating infusional 5-FU with gefitinib and radiation therapy showed good tolerability with a pathologic complete response rate of 30%69 (Table 3). Ongoing phase I to II studies are further evaluating the tolerability and efficacy of smallmolecule EGFR inhibitors with conventional neoadjuvant chemoradiotherapy regimens in patients with locally advanced rectal cancer.

Monoclonal Antibody EGFR Inhibitors Cetuximab (Erbitux, ImClone/Bristol-Myers Squibb, New York, NY) is an anti-EGFR monoclonal antibody that binds to the extracellular domain of human EGFR. Cetuximab has clinically significant activity when given alone or in combiTable 3 Small-Molecule EGFR-Based Combined-Modality Therapy Trials for Rectal Cancer-Selected Phase I/II Trials

Study

Patient No.

Duke68 Massachusetts General107 Catholic University of the Sacred Heart -Rome69

6 15 33

Regimen Cape, gefitinib, 50.4 Gy Bev, erlotinib, CI 5-FU, 50.4 Gy CI 5-FU, gefitinib, 50.4 Gy

Pathologic Complete Response Rate (%) 0 47 30

Bev, bevacizumab; Cape, capecitabine; CI, continuous infusion; 5-FU, 5-fluorouracil.

nation with irinotecan in patients with irinotecan-refractory colorectal cancer. This agent is used in the United States in combination with standard chemotherapeutic regimens for metastatic colorectal cancer in both the first- and second-line settings.70 Panitumumab (Vectibix, Amgen, Thousand Oaks, CA), a fully humanized monoclonal antibody that also targets the EGFR, has also been shown to improve progression-free survival in the first- and second-line settings as well as overall survival in the second-line therapy of metastatic colon cancer when added to standard chemotherapy regimens.71-73 Cetuximab can be safely administered with conventional or hyperfractionated radiation therapy in patients with head and neck cancer, and this combination improves survival in this group.74 Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy in preclinical models and in head and neck cancers, there is a strong rationale to combine these antibodies with neoadjuvant radiation therapy and chemotherapy in rectal cancer. Phase I and II studies have been undertaken to evaluate this combination and are discussed below. Investigators from Memorial Sloan-Kettering conducted a pilot trial to investigate the safety of cetuximab in combination with neoadjuvant protracted infusion 5-FU and radiation therapy in patients with rectal adenocarcinoma.75 Of patients undergoing surgery, the pathologic complete response rate was 12%. In a trial from Heidelberg, 20 patients with stage T2-4 or N⫹ rectal cancer received cetuximab and escalating doses of irinotecan and capecitabine with pelvic radiation therapy.76 Only 1 of 14 patients with T3/4 tumors and 4 of 5 patients with T2 tumors achieved a complete pathologic response. Investigators from Belgium reported on 40 patients with stage II/III rectal cancer receiving preoperative radiation therapy in combination with cetuximab and capecitabine.77 Only 2 patients (5%) had a pathologic complete response. In a phase I/II multicenter trial from Germany, 60 patients with clinical stage II to IV rectal cancer were treated with concurrent cetuximab, capecitabine, and oxaliplatin with pelvic irradiation.78 Pathologic complete response was observed in only 4 patients (9%). Preliminary results of a randomized phase II study evaluating continuous infusion 5-FU and radiation therapy, with or without cetuximab, were recently reported. Pathologic complete response was seen in 33% and 31% of patients, respectively. Of 98 assessable patients, grade 3 to 4 diarrhea was seen in 16% and 24%, respectively.79 Results from selected series are shown in Table 4. A recent pooled analysis of 316 patients receiving cetuximab-based chemoradiotherapy reported an overall pathologic complete response rate of 9.1%, with grade 3 to 4 diarrhea observed in 15% of patients. In comparison, an overall pathologic complete response rate of 13.1% was seen with fluoropyrimidinealone– based chemoradiation schedules in recently reported randomized trials.80 Therefore, compared with conventional neoadjuvant chemoradiotherapeutic regimens, the observed low rate of pathologic complete response rates in cetuximabbased studies should stimulate further preclinical investigations to establish the best sequence of EGFR inhibition combined with radiation therapy and contemporary cytotoxic

Combined therapy in rectal cancer

207

Table 4 Cetuximab-Based Combined-Modality Therapy Trials for Rectal Cancer-Selected Phase I/II Trials

Study

Patient No.

Memorial SloanKettering75 Modena108

20

Louvain77

40

German multisite78

60

Heidelberg109

50

38

Regimen Cetux, CI 5-FU, 50.4 Gy Cetux, CI 5-FU, 50.4 Gy Cetux, Cape, 45 Gy Cetux, Cape, ox, 50.4 Gy Cetux, Ir, Cape, 50.4 Gy

Pathologic Complete Response Rate (%) 12 8 5 9 8

Cetux, cetuximab; Ir, irinotecan; Cape, capecitabine; Ox, oxaliplatin.

agents as well as further study of EGFR inhibition on the expression of genes involved in tumor proliferation and inflammation.81 Additionally, the results of (1) a recently completed multinational randomized phase II Expert-C study (comparing neoadjuvant therapy with oxaliplatin, capecitabine and radiotherapy, with or without cetuximab); (2) additional phase II cetuximab-based chemoradiotherapy studies from Europe, Asia, and the United States; (3) the panitumumab-based Italian STAR-02 phase II chemoradiotherapy trial; and (4) additional phase II European-based panitumumab trials should help further define the role of concurrent anti-EGFR antibody-based chemoradiotherapy in the neoadjuvant therapy of locally advanced rectal cancer.80 In summary, it appears that cetuximab and panitumumab can be safely combined with radiation therapy and chemotherapy in the neoadjuvant treatment of rectal cancer. However, based on the results of current phase I and II studies, it is not clear that the addition of these agents to contemporary chemoradiation approaches in the neoadjuvant treatment of rectal cancer is of benefit. Further study is warranted, including further investigation in future studies of molecular markers (ie, KRAS, BRAF, and PIK3CA/PTEN genotypes) as predictors of response to EGFR inhibitor-based chemoradiotherapy.82,83

VEGF Inhibitors Increased levels of VEGF expression have been found in the tumors and sera of patients with localized as well as metastatic colon and rectal cancer.84-86 High VEGF expression has been associated with disease progression and inferior survival. In a study of patients with resected and adjuvantly treated (chemoradiation) rectal cancer, patients with tumors exhibiting VEGF overexpression were at a statistically higher risk for the development of local recurrence and metastases.87 Thus, the inhibition of VEGF is a logical target in the treatment of patients with rectal and colon cancer. A sentinel phase III trial randomized 813 patients with previously untreated metastatic colorectal cancer random-

ized patients to receive irinotecan, 5-FU, and IFL plus bevacizumab (Avastin, Genentech) (an antibody directed against VEGF) versus IFL plus placebo.88 The median duration of survival was 20.3 months in the group given IFL plus bevacizumab compared with 15.6 months in the group given IFL plus placebo (P ⬍ .001), leading the investigators to conclude that the addition of bevacizumab to FU-based combination chemotherapy resulted in a significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer. The use of bevacizumab in combination with other chemotherapy regimens for second-line treatment of metastatic colorectal cancer has also shown to be beneficial. The ECOG 3200 study evaluated previously treated metastatic colorectal cancer patients with (5-FU/irinotecan) who then received second-line therapy with an oxaliplatin-based regimen (FOLFOX4), with or without bevacizumab. Patients receiving bevacizumab had a survival benefit compared with patients who received FOLFOX4 alone (median survival 12.9 months vs 10.8 months, P ⬍ .001).89 Although VEGF inhibition has been shown to be beneficial for patients with metastatic colon and rectal cancer and enhanced their survival by several months, the magnitude of the effect of anti-VEGF therapy in patients with localized and nonmetastatic disease in the adjuvant setting is less clear. The randomized NSABP C-08 study compared a regimen of oxaliplatin 5-FU, with or without bevacizumab, in the adjuvant treatment of stage II to III colon cancer. Preliminary results showed that the addition of bevacizumab did not result in a significant prolongation in disease-free survival (75.5 vs 77.4%, P ⫽ .15).90 Further randomized studies are investigating the role of adjuvant bevacizumab in resected stage II to III colorectal cancer patients. In localized rectal cancer, this issue is under investigation in multiple phase I to II clinical trials that combine bevacizumab and radiation therapy with standard cytotoxic regimens. Recent experimental studies in human tumor xenografts as models of primary tumors have shown that VEGF blockade serves as a potent and nontoxic enhancer of radiation therapy and reduces tumor interstitial pressure, a known barrier to drug delivery to tumors, and in some cases, reduces tumor hypoxia, a known barrier to radiation therapy.91-94 This vascular “normalization” paradigm suggests antiangiogenic agents transiently normalize abnormal tumor vasculature (formed because of excessive local production of angiogenic factors).95,96 With structural and functional remodeling of the tumor blood vessels, the concentration of oxygen and penetration of cytotoxics are improved, and tumor’s response to chemotherapy and radiation therapy is potentially enhanced. To test this hypothesis, a neoadjuvant phase I/II trial with bevacizumab in combination with 5-FU and radiation therapy in patients with T3 or T4 rectal cancer was undertaken.97-99 Bevacizumab was delivered as an infusion once preceding and 3 times during radiation therapy. Infusional 5-FU was administered throughout each radiation treatment week. The primary objective of this study was to determine the maximum tolerated dose of bevacizumab when delivered concurrently with 5-FU and radiation therapy in patients with rectal cancer before sur-

B.G. Czito and C.G. Willett

208 gery as well as to clarify, through correlative studies, the mechanisms by which bevacizumab inhibits angiogenesis and improves outcomes. The results of 32 patients showed regression from a mean tumor size of 5 cm (range, 3-12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7-6.0 cm) in all patients, with no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site, resulting in a pathologic complete response rate of 16%. The actuarial 5-year local control and overall survival were both 100% and 5-year disease-free survival 75%, with 5 patients developing metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. The study also evaluated the effect/mechanism of action of bevacizumab alone (cycle 1) on rectal cancer before its concurrent administration (cycles 2-4) with radiation therapy and chemotherapy. Before and 12 days after the first bevacizumab infusion, patients underwent flexible sigmoidoscopy with tumor biopsy, tumor interstitial pressure measurement, perfusion computed tomography scan to measure blood flow, PET FDG scan, and analysis of blood and urine for a number of angiogenesis markers. Compared with prebevacizumab measurements, a number of antivascular effects after bevacizumab delivery were noted, including lower tumor interstitial pressure measurements, reduced tumor vascular density measurements, and increased pericyte coverage in tumor vessels while maintaining constant FDG uptake, thus supporting the normalization hypothesis.99 A phase I trial from Duke University evaluated the combination of capecitabine, oxaliplatin, and bevacizumab in patients with stage II to IV rectal cancer. Patients were treated with escalating doses of capecitabine and oxaliplatin, with a fixed dose of bevacizumab. Two patients (18%) achieved pathologic complete response and 3 patients microscopic disease only.100 These and other data have simulated further investigation of the combination of anti-VEGF therapy in conjunction with conventional radiation and chemotherapy in patients with rectal cancer, including trials using multiple targeted agents (Tables 3 and 5).

Targeted Agents Summary Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy seen in preclinical models, Table 5 Bevacizumab-Based Combined-Modality Therapy Trials for Rectal Cancer-Selected Phase I/II Trials

Study

Patient No.

Regimen

Pathologic Complete Response Rate (%)

MassachusettsGeneral and Duke97-99 Duke100

32

Bev, CI 5-FU, 50.4 Gy

16

11

18

Sarah Cannon110

35

Anderson111

25

Bev, Cape, Ox, 50.4 Gy Bev, CI 5-FU, 50.4 Gy Bev, Cape, 50.4 Gy

MD

Bev, bevacizumab; Cape, capecitabine; Ox, oxaliplatin.

29 32

there is a strong rationale to combine EGFR inhibitors with neoadjuvant radiation therapy and chemotherapy in rectal cancer. Phase I and II studies have recently been completed evaluating this approach. It appears that cetuximab can be safely combined with radiation therapy and chemotherapy in the neoadjuvant treatment of rectal cancer. However, it is not clear that the addition of these agents results in enhanced tumor responses or downstaging compared with contemporary chemoradiation approaches. Bevacizumab may lead to the indirect killing of cancer cells by damaging tumor blood vessels and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade may also “normalize” tumor vasculature, thereby leading to greater tumor oxygenation (a known radiosensitizer) and drug penetration. Phase I/II trials have shown that bevacizumab can be safely combined with neoadjuvant radiation therapy and chemotherapy in rectal cancer patients. In addition, bevacizumab has antivascular effects and supports the normalization hypothesis in this clinical setting. Ongoing phase II studies will further clarify the mechanisms of action and efficacy of this agent in locally advanced rectal cancer.

Conclusions For patients with clinical stage II and III rectal cancer, neoadjuvant treatment with radiation therapy and 5-FU– based chemotherapy is recommended. In the United States, radiation therapy treatment approaches usually use 3-dimensional conformal radiation therapy techniques delivering 45 Gy to the tumor and pelvic lymphatics followed by additional irradiation to gross tumor to a total dose of 50.4-54 Gy in 28 to 30 fractions over 5.5 to 6 weeks. 5-FU is usually administered as a continuous peripheral venous infusion during the entire course of radiation therapy although capecitabine may potentially replace 5-FU in this setting pending randomized trial results. Although the use of oxaliplatin in conjunction with conventional chemoradiotherapy approaches has shown promise in phase II studies, early results from randomized trials have not confirmed this benefit. Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy seen in preclinical models, there is a strong rationale to combine targeted agents with neoadjuvant radiation therapy in rectal cancer. Phase I and II studies have recently been completed evaluating this approach. It appears that these agents can be safely combined with radiation therapy in the neoadjuvant treatment of rectal cancer although, to date, the integration of antibody-based EGFR inhibitors has shown low-response rates compared with historical controls. Ongoing and planned trials will help further determine the tolerability and ultimate efficacy of these agents as well as VEGF inhibitors in the neoadjuvant treatment of this disease.

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74.

75.

dermal growth factor receptor promoter region. Int J Radiat Oncol Biol Phys 66:500-504, 2006 Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053-2063, 2000 Raben D, Phistery M, Helfrich B, et al: ZD 1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor enhances radiationinduced cytotoxicity in human pancreatic and cholangiocarcinoma cell lines in vitro: Gastrointestinal Cancer Research Conference, Orlando, FL, April 26, 2000 Raben D, Helfrich B, Chan D, et al: ZD 1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. Semin Oncol 29:37-46, 2002 Williams K, Telfer B, Stratford I, et al: ZD 1839 (“Iressa”), a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor, potentiates radiotherapy in a human colorectal cancer xenograft model. Br J Cancer 86:1157-1161, 2002 Magne N, Fischel J, Dubreuil A, et al: ZD 1839 (Iressa) modifies the activity of key enzymes linked to fluoropyrimidine activity: Rational basis for a new combination therapy with capecitabine. Clin Cancer Res 9:4735-4742, 2003 Fisher G, Kuo T, Cho C, et al: A phase II study of gefitnib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. J Clin Oncol 22:14S, 2004 Zeuli M, Gelibetr A, Nardoni C, et al: A feasibility study of getifinib in association with capecitabine (CAP) and oxaliplatin (OXA) as firstline treatment in patients with advanced colorectal cancer. J Clin Oncol 22:14S, 2004 Townsley C, Major P, Siu L, et al: Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 94:11361143, 2006 Meyerhardt J, Zhu A, Enzinger P, et al: Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastatic colorectal cancer. J Clin Oncol 24:1892-1897, 2006 Czito B, Willett C, Bendell J, et al: Increased toxicity with gefitinib, capecitabine and radiation therapy in pancreatic and rectal cancer: Phase I trial results. J Clin Oncol 24:656-662, 2006 Valentini V, De Paoli A, Gambacorta MA, et al: Infusional 5-fluorouracil and ZD 1839 (gefitinib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: A phase I and II Trial (1839IL/0092). Int J Radiat Oncol Biol Phys 72:644-649, 2008 Van Cutsem E, Kohne CH, Hitre E, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408-1417, 2009 Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007 Siena S, Cassidy J, Tabernero J, et al: Randomized phase III study of panitumumab (pmab) with FOLFOX4 compared to FOLFOX alone as first-line treatment for metastatic colorectal cancer (mcrc). Program and Abstracts of the 2010 ASCO Gastrointestinal Cancers Symposium, Orlando, FL, January 22-24, 2010 Peeters M, Price T, Hotko Y, et al: Randomized phase III study of panitumumab (pmab) with FOLFIRI versus FOLFIRI alone as secondline treatment in patients with metastatic colorectal cancer (mCRC): Patient-reported outcomes. Program and Abstracts of the 2010 ASCO Gastrointestinal Cancers Symposium, Orlando, FL, January 22-24, 2010 Bonner J, Harari P, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354: 567-578, 2006 Chung K, Minsky B, Schrag D, et al: Phase I trial of preoperative cetuximab with concurrent continuous infusion 5-fluorouracil and pelvic radiation in patients with local-regionally advanced rectal cancer. J Clin Oncol 24:18S, 2006

Combined therapy in rectal cancer 76. Hofheinz R, Horisberge K, Woernle C, et al: Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan and radiotherapy as neoadjuvant therapy for rectal cancer. Int J Radiat Oncol Biol Phys 66:1384-1390, 2006 77. Machiels J, Sempoux C, Scalliet P, et al: Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol 18:738-744, 2007 78. Rodel C, Hipp M, Liersch T, et al: Cetuximab, capecitabine, oxaliplatin and radiation therapy as preoperative treatment in rectal cancer. 48th Annual Meeting of Astro, Philadelphia, PA, November 5-9, 2006 79. McCollum AD, Kocs DM, Chada P: A randomized phase II trial of preoperative chemoradiotherapy with or without cetuximab in locally advanced adenocarcinoma of the rectum. J Clin Oncol 28:294s, 2010 80. Glynne-Jones R, Mawdsley S, Harrison M: Cetuximab and chemoradiation for rectal cancer—Is the water getting muddy? Acta Oncol 49:278-286, 2010 81. Debucquoy A, Haustermans K, Daemen A, et al: Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer. J Clin Oncol 27:2751-2757, 2009 82. Bengala C, Bettelli S, Bertolini F, et al: Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer. Ann Oncol 20:469-474, 2009 83. Machiels J, Debucquoy A, Gevaert O, et al: Prediction of pathological response to preoperative chemoradiotherapy with cetuximab in rectal cancer. J Clin Oncol 26:40S, 2008 84. Hyodo I, Doi T, Endo H, et al: Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer. Eur J Cancer 34: 2041-2045, 1998 85. Nanashima A, Ito M, Sekine I, et al: Significance of angiogenic factors in liver metastatic tumors originating from colorectal cancers. Dig Dis Sci 43:2634-2640, 1998 86. Chin K, Greenman J, Gardiner E, et al: Pre-operative serum vascular endothelial growth factor can select patients for adjuvant treatment after curative resection in colorectal cancer. Br J Cancer 83:14251431, 2000 87. Cascinus S, Garziano F, Catalano V, et al: Vascular endothelial growth factor (VEGF), p53, and BAX expression in node positive rectal cancer. ASCO Proc 20:595, 2001 88. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 89. Giantonio B, Levy D, O’Dwyer P, et al: A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group study. Ann Oncol 17:13991403, 2006 90. Wolmark N, Yothers G, O’Connell M, et al: A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08. J Clin Oncol 27, 2009 91. Lee C, Heijin M, di Tomaso E, et al: Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Caner Res 60:5565-5570, 2000 92. Kozin SV, Boucher Y, Hicklin DJ, et al: Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res 61:39-44, 2001 93. Tong R, Boucher Y, Kozin S, et al: Vascular normalization by vascular endothelial growth factor receptor 2 blockage induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64:373-376, 2004

211 94. Winkler F, Kozin SV, Tong RT, et al: Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553-563, 2004 95. Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 7:987-989, 2001 96. Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58-62, 2005 97. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004 98. Willett CG, Boucher Y, Duda DG, et al: Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: Continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 23:8136-8139, 2005 99. Willett C, Duda D, DiTomaso E, et al: Efficacy, safety, and biomakers of neoadjuvant bevacizumab, radiation therapy, and 5-fluorouracil in rectal cancer: A multidisciplinary phase II study. J Clin Oncol 27: 3020-3026, 2010 100. Czito BG, Bendell JC, Willett C, et al: Bevacizumab, oxaliplatin and capecitabine with radiation therapy in rectal cancer: Phase I trial results. Int J Radiat Oncol Biol Phys 68:472-478, 2007 101. Krishnan S, Janjan N, Skibber J, et al: Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 66:762-771, 2006 102. Kim JC, Kim TW, Kim JH, et al: Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 63:346-353, 2005 103. DePaoh A, Chiara S, Luppi G, et al: Capecitabine in combination with preoperative radiation therapy in locally advanced resectable, rectal cancer: A multicentric phase II study. Ann Oncol 17:246-251, 2006 104. Dupuis O, Vie B, Lledo G, et al: Capecitabine chemoradiation in the preoperative treatment of patients with rectal adenocarcinomas: A phase II GERCOR trial. 40th Annual Meeting of the American Society of Clinical Oncology Proceedings, New Orleans, LA, June 5-8, 2004 (poster 3538) 105. Craven I, Crellin A, Cooper R, et al: Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer. Br J Cancer 97:1333-1337, 2007 106. Aschele C, Pinto C, Cordio S, et al: Preoperative fluorouracil (FU)based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial. J Clin Oncol 27, 2009 107. Blaszkowsky LS, Hong TS, Zhu AX, et al: A phase I/II study of bevacizumab (Bev), erlotinib (Erl), and 5-fluorouracil (5-FU) with concurrent external beam radiation therapy (RT) in locally advanced rectal cancer (LARC). J Clin Oncol 27:194s, 2009 108. Bertolini F, Chiara S, Bengala C, et al: Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: A phase II study in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 73:466-472, 2009 109. Horisberger K, Treschl A, Mai S, et al: MARGIT (Mannheimer Arbeitsgruppe für Gastrointestinale Tumoren): Cetuximab in combination with capecitabine, irinotecan, and radiotherapy for patients with locally advanced rectal cancer: Results of a phase II MARGIT trial. Int J Radiat Oncol Biol Phys 74:1487-1493, 2009 110. Spigel D, Bendell J, McCleod M, et al: A phase II trial of neoadjuvant or adjuvant chemoradiotherapy and bevacizumab in patients with stage II/III rectal cancer. J Clin Oncol GI Symp 26, 2010 111. Crane CH, Eng C, Feig BW, et al: Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 76:824-830, 2010

T3N0 Rectal Cancer: Radiation for All? Jennifer Y. Wo, MD,* Harvey J. Mamon, MD, PhD,† David P. Ryan, MD,‡ and Theodore S. Hong, MD* The optimal oncologic management for patients with T3N0 rectal cancer is currently controversial. Patients with pathologic T3N0 disease may have an “intermediate” risk of disease recurrence, suggesting that perhaps trimodality therapy may not be indicated for all patients. Adverse prognostic features, including a greater depth of perirectal fat invasion, poor tumor differentiation, the presence of lymphovascular invasion, abnormally elevated pretreatment carcinoembryonic antigen levels (>5 ng/mL), circumferential margin involvement, and a low-lying position may identify T3N0 patients at high risk for local recurrence who may benefit from the addition of radiation therapy. However, recent randomized data suggest an improvement in local control and disease-free survival with preoperative radiation therapy compared with selective postoperative radiation therapy in all patient subgroups, arguing in favor of routine preoperative therapy. Additionally, rates of clinical understaging may exceed 20%, representing the percentage of patients who would require the delivery of postoperative radiotherapy with its associated sequelae. Future prospective randomized studies of T3N0 patients with upfront stratification by known prognostic factors and studies evaluating the molecular profile of rectal cancers hold the promise of better classifying patients at high risk of local and systemic recurrence, and thus, in need of adjuvant radiation and chemotherapy. Semin Radiat Oncol 21:212-219 Published by Elsevier Inc.

T

he role of radiation therapy in the management of T3N0 rectal cancer is currently unresolved. In the 1970s and 1980s, high rates of local failure after curative surgery for rectal cancer1-3 prompted the initiation of multiple large randomized cooperative group trials to evaluate the potential benefit of adjuvant (postoperative) chemotherapy and radiation4,5 to improve outcomes. The Gastrointestinal Study Group 7175 randomized 227 Stage II/III patients treated with curative surgery to receive no further therapy, adjuvant chemotherapy, adjuvant radiation therapy, or adjuvant chemoradiation. With an initial target accrual of 520 patients, the study was terminated early because of an overall survival benefit seen for patients treated with concurrent chemoradiation4. The North Central Cancer Treatment Group 79-47-51 confirmed the additional benefit of concurrent postoperative chemoradiation compared with radiation therapy alone, showing a 29% relative risk reduction in over*Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. †Department of Radiation Oncology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. ‡Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Address reprint requests to Jennifer Y. Wo, MD, Massachusetts General Hospital, 100 Blossom Street, Cox 3, Boston, MA 02114. E-mail: [email protected]

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1053-4296/11/$-see front matter Published by Elsevier Inc. doi:10.1016/j.semradonc.2011.02.007

all death compared with postoperative radiation therapy alone.5 On the basis of North Central Cancer Treatment Group 79-47-51 and Gastrointestinal Study Group 7175, the 1990 National Institutes for Health Consensus Statement recommended postoperative chemoradiotherapy as the standard treatment for all patients with completely resected stage II or III rectal cancer.6 Over the past 2 decades, major advances in imaging and surgical techniques have raised the question of whether the results of these earlier studies apply to current patients. Currently, the standard staging evaluation for patients with locally advanced rectal cancer includes a chest, abdomen, and pelvic computed tomography (CT) scan to assess for systemic disease and pelvic magnetic resonance imaging (MRI) to assess the extent of local disease. It is reasonable to assume that many patients on earlier studies had metastatic disease or pelvic sidewall involvement that was not appreciated preoperatively. Total mesorectal excision (TME), with or without routine preoperative radiotherapy, has improved rates of sphincter preservation, local control, and disease-specific survival in patients presenting with locally advanced disease.7-10 With the surgical standardization of TME resulting in lower recurrence rates, the additional benefit of radiation therapy, however, was subsequently called into question.11

T3N0 rectal cancer: radiation for all?

213

Table 1 Summary of Recent Phase III Preoperative Versus Postoperative Standard Fractionation Chemoradiotherapy Trials Trial

# of Patients

German Rectal Cancer Study Group10

823

NSABP R-0313

267

Stage

Study Arms

cT3-4, Nⴙ Preoperative CRT Postoperative CRT cT3-4, Nⴙ Preoperative CRT Postoperative CRT

RT Dose/Fx

P P P 5-Year 5-Year 5-Year LF (%) Value DFS (%) Value OS (%) Value

50.4 Gy/28 Fx

6

55.8 Gy/31 Fx

13

50.4 Gy/28 Fx

10.7

50.4 Gy/28 Fx

10.7

.006

68

.32

65 .69

64.7

76

.80

74 .01

53.4

74.5

.065

65.6

LF, local failure; DFS, disease-free survival; OS, overall survival; Fx, fractions.

The Dutch Colorectal Cancer Group performed a randomized controlled trial evaluating the benefit of preoperative shortcourse radiotherapy in the era of standardized TME. With a median follow-up of 6 years, preoperative radiation therapy reduced the rate of local recurrence compared with surgery alone (5-year local control: 5.6% vs 10.9%, P ⬍ .001), but there was no effect on overall survival.7,12 More recently, the German Rectal Cancer Study Group and National Surgical Adjuvant Breast and Bowel Project (NSABP) R-03, which are summarized in Table 1, have established the superiority of preoperative standard fractionation chemoradiotherapy compared with postoperative chemoradiotherapy with respect to local control, acute and late toxicity profiles, sphincter-preservation rates, and disease-free survival in patients with clinically staged T3/T4 or node-positive rectal cancer.10,13 The German Rectal Study Group, which randomized 823 patients with clinical T3/T4 (cT3/T4) or node-positive rectal cancer to receive either preoperative or postoperative chemoradiotherapy after TME, reported a reduction in 5-year local recurrence rate from 13% to 6% and an improvement in grade 3 or 4 late toxicity rates from 24% to 14% with preoperative chemoradiotherapy. Additionally, preoperative chemoradiotherapy was found to downstage approximately 30% of node-positive patients to pathologic node negativity. Because of the loss of prognostic information from pathologic nodal status, all patients treated with preoperative chemoradiotherapy received an additional 4 to 6 months of adjuvant chemotherapy after surgery.10 Subsequently, NSABP R-03 confirmed the superiority of preoperative chemoradiotherapy, showing an improvement in disease-free survival compared with postoperative chemoradiotherapy despite poor patient accrual.13 These published results have led to a paradigm shift for locally advanced rectal cancer in the United States away from postoperative chemoradiotherapy and have established the current standard of care as preoperative conventional fractionation chemoradiotherapy to a total dose of 50.4 Gy followed by TME 4 to 8 weeks after the completion of preoperative therapy and 4 to 6 months of adjuvant 5-fluorouracil (5-FU)-based chemotherapy. Despite this, some argue that these randomized controlled trials enrolled a heterogeneous group of stage II/III patients over long periods, making it difficult to tease out the additional benefits of chemoradiation for particular subgroups of patients. Specifically, patients with T3N0 disease have a more favorable prog-

nosis compared with T4 or node-positive patients,14 and subset analysis of these patients in the Dutch Colorectal Cancer Study did not show a statistically significant improvement in local control.12 Additionally, the value of adjuvant chemotherapy for stage II colon cancer patients is currently controversial,15 with published data suggesting that improved outcomes with the addition of adjuvant chemotherapy may be only realized among stage II patients with high-risk features.16 By extrapolating the existing published data from colon cancer and applying it to rectal cancer, it begs the question whether all patients with cT3N0 rectal cancer benefit from adjuvant chemotherapy. Because of the loss of prognostic information regarding upfront nodal status, all patients treated with preoperative chemoradiotherapy, regardless of their pathologic lymph node status at the time of surgery, are recommended to receive 4 to 6 months of adjuvant chemotherapy. Because 18% of patients in the German Rectal Study Group randomized to postoperative chemoradiotherapy were found to have pathologic stage I disease at the time of surgery, the routine use of preoperative chemoradiation for clinically stage T3 tumors results in a substantial rate of overtreatment.10 Finally, prolonging overall survival and improving cure rates are the primary motivation for the use of any therapy in the adjuvant setting. It is important to remember that we use disease-free survival and local control as surrogate endpoints. Only the Swedish Rectal Trial evaluating the use of short-course radiotherapy without any adjuvant chemotherapy showed an overall survival advantage for the use of adjuvant radiation therapy. There have been no other studies showing an overall survival benefit for the use of radiation therapy, which should give physicians pause, particularly when toxicities such as urinary dysfunction, sexual dysfunction, bowel dysfunction, and insufficiency fractures can adversely affect quality of life.17-21 Therefore, it is reasonable to question the benefit of adjuvant radiotherapy for patients with rectal cancer who otherwise have high rates of local control and cure. This review aims to provide an overview of the existing published literature regarding the optimal management of T3N0 patients.

Evidence Supporting Selective Radiotherapy Before the widespread adoption of preoperative chemoradiotherapy for locally advanced rectal cancer, postoperative

J.Y. Wo et al

214 Table 2 Summary of Retrospective Series of T3N0 Patients Treated with Surgery Alone Series MGH19

MSKCC18 MSKCC20 MSKCC26‡ Norwegian Rectal Cancer Group27‡

Number of Patients

High-Risk Features Identified

117 25 88 108 95 49

Tumor differentiation*, LVI*, extent of perirectal tumor invasion† None LVI* LVI*, age >70*, abnormal pretreatment CEA† Circumferential margin status

679 41 69 101

Patient Subgroup

Local Recurrence

Overall No high-risk features >1 high-risk features Overall Overall Overall

10 year: 24 10 year: 5 10 year: 29 5 year: 8 5 year: 12 Crude: 4.1

CRM >3 mm 2.1-3 1.1-2 CRM <1 mm

5 year: 11.1 5 year: 9.7 5 year: 16.8 5 year: 19.4

*Significant on univariate analysis. †Significant on multivariate analysis. ‡Only T3N0 patients included in the summary table.

chemoradiation was recommended for all patients with pathologic T3/T4 or node-positive disease.6 However, in the era of TME, among the subset of T3N0 patients, several retrospective series have reported low rates of local recurrence ranging from 2.8% to 9.0% and 5-year survival rates of 75% to 87% after surgery alone.11,17-20 Several of these studies have also failed to show an improvement in local control with the addition of radiation therapy,17,21 arguing that routine adjuvant radiation therapy may be potentially avoided. As a result, numerous studies have sought to identify subsets of T3N0 patients with favorable prognostic factors that may experience a low rate of local recurrence after surgery alone and, thus, may not benefit significantly from adjuvant radiation therapy.19,20 Several retrospective series, which are summarized in Table 2, have identified histopathological features, including the extent of mesorectal fat invasion, lymphovascular invasion (LVI), tumor differentiation, and distance to circumferential margin, as predictors of worse outcomes among T3N0 patients.19,20,22,23 Additionally, subgroup analyses of large randomized controlled trials, which have included T3N0 patients, have also identified lower-lying tumors and circumferential margin involvement, often defined as microscopic tumor present within 1 mm of the radial margin, as predictors of worse outcomes.12,24,25 The extent of mesorectal fat invasion was first recognized as a potential prognostic factor among T3N0 patients by Willett et al,19 who evaluated 117 patients with pT3N0 rectal cancer treated at Massachusetts General Hospital between 1968 and 1985. Although most patients were not treated with TME, this timeframe was chosen because it preceded the routine administration of preoperative or postoperative therapy. On univariate analysis, perirectal tumor invasion of ⱖ2 mm, vessel involvement, and poorly differentiated histology were significantly associated with worse local control, freedom from distant metastases, and recurrence-free survivals. On multivariate analysis, although all 3 pathologic features were predictive of distant metastases and recurrence-free survival, only the extent of perirectal tumor invasion remained a

significant predictor of local control. For tumors invading ⬍2 mm into the perirectal fat, they reported 10-year actuarial local control rates of 93% compared with 49% for tumors invading ⱖ8 mm. Moreover, among 25 patients with all favorable histologic features (well-differentiated histology, ⬍2 mm perirectal fat invasion, and absence of LVI), the 10-year actuarial rates of local recurrence was 5%. In contrast, among 88 patients with one or more poor histologic features, the 10-year actuarial rate of local recurrence was considerably higher at 29%. Based on these results, the authors concluded that the selection of patients for adjuvant therapy should reflect not only stage but also the extent of perirectal fat invasion, vessel involvement, tumor differentiation, and surgical resection by TME. In the era of routine TME, however, a recent study suggests that the prognostic significance of extent of perirectal fat invasion may be lost. Picon et al18 reviewed 108 prospectively collected patients with T3N0 rectal cancer treated with TME alone at Memorial Sloan-Kettering Cancer Center (MSKCC). None of the patients received adjuvant therapy at the physician’s preference, because of a lack of tumor bulk, adequate surgical margins, or a lack of adverse pathologic features. After pathologic review for pathologic stage confirmation and determination of the extent of perirectal fat invasion, the authors reported a cumulative 5-year disease-free survival of over 80% and local recurrence rate of 8%, which is comparable with previous reports.19 Neither gross T3 disease nor greater extent of perirectal fat invasion (dichotomized as ⬎3 mm vs ⱕ3 mm) was found to predict for disease-free survival or disease-specific survival.18 However, a small number of patients and events may have limited the ability to detect meaningful differences between patient subgroups. Looking at a similar cohort of patients treated at MSKCC, Merchant et al20 explored the prognostic significance of additional histopathologic and clinical features to determine whether TME alone yielded adequate local control for T3N0 patients. With a median follow-up of 53 months, 6 of 95 patients developed a local recurrence with a 5-year actuarial local recurrence rate of 12%. On univariate analysis, only the

T3N0 rectal cancer: radiation for all? presence of LVI was found to significantly predict for local recurrence (P ⬍ .04). Histologic tumor grade, perineural invasion, mucin production, pretreatment CEA levels, type of surgery, tumor location, and distal surgical margin, as defined by ⬍2 cm or ⱖ2 cm, were not significantly associated with local recurrence. However, as in the previous study, there were few events, thereby limiting the study’s power to detect meaningful between subgroups.20 More recently, Nissan et al26 focused on delineating the role of chemoradiotherapy for an even more favorable subset of patients with T2N0 (n ⫽ 45) and early T3N0 (n ⫽ 49) rectal cancer treated with surgery alone. With a median follow-up of 79.5 months, although the 5-year disease-free survival was 67.1%, only 2 patients (4.1%) developed local recurrences. On univariate analysis, the presence of LVI, abnormal preoperative CEA, and older age were significant predictors of worse recurrence-free survival; however, only abnormal preoperative CEA levels (⬎5 ng/mL) remained an independent predictor of disease-free survival (RR ⫽ 3.1; 95% confidence interval [CI], 1.2-8.1; P ⫽ .01) and diseasespecific survival (RR ⫽ 2.9, 95% CI: 1.1-7.6, P ⫽ 0.02) after adjusting for known confounders. Within the entire cohort, the authors noted that all pelvic recurrences were seen in patients with elevated preoperative CEA. Based on the results of this study, the authors concluded that the presence of LVI and elevated preoperative CEA may select patients who benefit from the addition of chemoradiotherapy.26 Most recently, in the largest published series to date, the Norwegian Rectal Cancer Group evaluated 1,676 prospectively registered patients with T3 rectal cancer treated with TME without preoperative radiotherapy. On multivariate analysis, circumferential margin status and lymph node staging were independent significant predictors of local recurrence, distant metastases, and overall mortality. Among 890 T3N0 patients, the cumulative rates of 5-year local recurrence were 19.4% for patients with circumferential margins of ⱕ1 mm compared with 11.1% for patients with circumferential margins of ⬎3 mm. Based on the results of this study, the Norwegian guidelines, which were previously restrictive for preoperative radiotherapy, were changed to include recommendations for preoperative MRI in initial staging assessment and preoperative chemoradiotherapy for all patients in whom the distance of the tumor to the mesorectal fascia is ⱕ3 mm. This study is limited by both treatment heterogeneity (with a small minority of patients receiving postoperative radiation therapy) and significant missing data regarding distance to circumferential margin, raising the question of suboptimal histopathologic review. Yet, these results support selective radiotherapy as a reasonable treatment approach.27 The results of the previously mentioned studies suggest that the routine administration of radiation therapy for all T3N0 rectal cancer may not be necessary to reduce the risk of local recurrence, particularly in the absence of negative prognostic factors.14,20 Although their prognostic significance have been inconsistently reported in the literature, greater depth of perirectal fat invasion, poor tumor differentiation, the presence of LVI, abnormally elevated pretreatment CEA

215 levels (⬎5 ng/mL), circumferential margin involvement, and low-lying tumors may predict for patient subgroups with poor disease outcomes and higher rates of local recurrence that may benefit from the addition of radiation therapy.19,20,26,27 To date, however, all the published data addressing outcomes for T3N0 patients are retrospective in nature and, therefore, should be viewed as hypothesisgenerating only. Moreover, it is important to note that all patients in the previously mentioned studies were surgically staged and underwent a thorough evaluation to determine the presence of adverse histopathologic features. In the era of routine preoperative radiotherapy, however, the decision to treat is made preoperatively without detailed histopathologic data available at the time of decision making. Consequently, the results of these studies may be most directly applicable in determining the benefit of adjuvant radiotherapy among patients with cT2N0 disease who are upstaged to pT3N0 at time of surgery.

Evidence Supporting Routine Preoperative Radiotherapy for Clinically Staged T3N0 In the first and only prospective trial to date attempting to indirectly address this issue, the MRC CR07/NCIC-CTG C016 launched a multi-institutional randomized controlled trial comparing preoperative radiotherapy with selective postoperative chemoradiotherapy. This study enrolled 1,350 patients between 1998 and 2005 with clinically operative adenocarcinoma of the rectum ⬍15 cm from the anal verge and randomized patients to receive either preoperative shortcourse radiotherapy (25 Gy in 5 fractions) (n ⫽ 674) or selective postoperative standard fractionation chemoradiotherapy for positive circumferential margins (defined as margins ⱕ1 mm) to a total dose of 45 Gy in 25 fractions given with concurrent 5-FU (n ⫽ 676).24 Patients randomized to selective postoperative chemoradiation not receiving chemoradiotherapy (because of negative circumferential margins) received adjuvant chemotherapy based on local institutional policy (with chemotherapy delivery contingent upon circumferential margin and lymph node status). In total, 88% of patients randomized to the selective postoperative radiotherapy arm had negative circumferential margins and only 12% (n ⫽ 77) positive circumferential margins. With a median follow-up of 4 years, the 5-year local recurrence was significantly improved with preoperative radiotherapy (5% vs 17%, P ⬍ .001) compared with selective postoperative radiotherapy. Preoperative radiotherapy offered a relative risk reduction of 61% in local recurrence (hazard ratio [HR] ⫽ 0.39; 95% CI, 0.27-0.58; P ⬍ .0001) and a 3-year absolute risk reduction of 6.2% (95% CI, 5.3%7.1%). Additionally, preoperative radiotherapy was found to confer a relative improvement in disease-free survival of 24% (HR ⫽ 0.76; 95% CI, 0.62-0.94; P ⫽ .013) and an absolute difference at 3 years of 6.0% (95% CI, 5.3-6.8) but no difference in overall survival.24 Notably, there was no significant interaction seen between treatment effect and circumferential

J.Y. Wo et al

216

Table 3 Summary of the 3-Year Local Recurrence Rates in MRC CR07/NCIC-CTG-CO16 Study of Preoperative Short-Course Radiotherapy Compared with Selective Postoperative CRT24

3-year local recurrence 3-year disease-free survival 3-year overall survival 3-year LR by CRM Involved Uninvolved 3-year LR by tumor position <10-15 cm >5-10 cm 0-5 cm 3-year LR by plane of dissection† Muscularis propria Intramesorectal Mesorectal

Preoperative RT (n ⴝ 674) (%)

Selective Postoperative CRT (n ⴝ 676) (%)

HR (95% CI)*

4.4 77.5 80.3

10.6 71.5 78.6

0.39 (0.27-0.58) 0.76 (0.62-0.94) 0.91 (0.73-1.13)

13.8 3.3

20.7 8.9

0.64 (0.25-1.64) 0.36 (0.23-0.57)

1.2 5.0 4.8

6.2 9.8 10.4

0.19 (0.07-0.47) 0.50 (0.28-0.90) 0.45 (0.23-0.88) P ⴝ .0039

10 4 1

16 10 7

RT, radiation therapy; CRT, chemoradiotherapy; HR, hazard ratio; CRM, circumferential margin; LR, local recurrence. *Compared with preoperative RT as baseline. †HRs not provided.

margin status, tumor location, or TNM stage, suggesting a benefit in all subgroups of patients.24 In a companion study, Quirke et al28 performed a secondary analysis of this trial to determine the effect of circumferential margin involvement and the plane of surgery achieved on local recurrence. The plane of surgery achieved was classified as within the mesorectal (good), intramesorectal (intermediate), and muscularis propria plane (poor) in 52%, 34%, and 13%, respectively. On univariate analysis, both circumferential margin and plane of surgery achieved were significantly associated with local recurrence; however, on multivariate analysis, only the plane of surgery achieved, in addition to T category, N category, treatment arm, and tumor involving the anterior quadrant, remained independently and significantly associated with local recurrence. With the muscularis propria plane of resection as a baseline, the HRs for the mesorectal plane and intramesorectal plane on local recurrence were 0.32 (95% CI, 0.16-0.64) and 0.48 (95% CI, 0.25-0.93), respectively. Importantly, the benefit of shortcourse preoperative radiotherapy was seen among all subgroups of the plane of surgery achieved, reducing the rate of local recurrence by more than 50% (Table 3). Finally, among patients treated with preoperative radiotherapy in which mesorectal plane of surgery was achieved, the 3-year local recurrence rate was exceeding low at 1%. Thus, the authors argue that the plane of surgery achieved and short-course preoperative radiotherapy may have additive effects and should be considered in all patient subgroups regardless of plane of surgery achieved.28 The MRC CR07/NCIC-CTG CO16 study has been criticized for the lack of formal surgical training for TME in participating centers and for treatment heterogeneity with respect to the administration of adjuvant chemotherapy depending on local institutional preference. Moreover, only a minority of patients included in this study were staged as cT3N0 or pT3N0, and the study was not powered to stratify

by poor prognostic factors, thereby decreasing statistical power to detect meaningful differences among this smaller subgroup of patients.24 Despite these limitations, however, this study provides the only prospective, randomized data to date evaluating the potential role of selective postoperative radiotherapy. The results suggest that regardless of circumferential margin status and the plane of surgery achieved, routine preoperative radiation therapy yields an improvement in local control and disease-free survival compared with selective postoperative chemoradiotherapy across all patient subgroups. Additionally, although retrospective series from the era of postoperative chemoradiotherapy have identified subsets of pT3N0 rectal cancer patients with low rates of local recurrence after TME alone,19,26 it is difficult to know how to effectively extrapolate these findings into the era of preoperative chemoradiotherapy. Most notably, using preoperative chemoradiotherapy, the ability to select patients for whom radiation therapy can be omitted is highly dependent on the accuracy of preoperative staging. In the German Rectal Study, 18% of patients with clinically staged T3 or nodepositive disease randomized to the surgery alone arm were found with pathologically staged stage I disease, representing the patients who were clinically “overstaged” and would be overtreated with preoperative therapy.10 More recently, several studies have attempted to address the rate of clinical “understaging” with modern staging techniques by determining of the frequency of regional lymph node involvement after preoperative chemoradiation among patients with clinically staged T3N0. The rate of node-positive patients detected at surgery would represent the percentage of “understaged” patients who would potentially undertreated by the omission of preoperative chemoradiation. In one of the first studies to address the question, Guillem et al29 retrospectively reviewed 188 patients with cT3N0 rectal cancer treated among an international consortium of aca-

T3N0 rectal cancer: radiation for all? demic institutions with high volumes of rectal cancer, staged either by endorectal ultrasound (ERUS) or MRI. All patients were treated with preoperative radiation prescribed to a total dose of 45 Gy to 50.4 Gy given concurrently with 5-FU chemotherapy, followed by surgical resection 4 to 8 weeks later. In total, 22% patients were found to have mesorectal lymph node involvement, representing the rate of “understaging.” Additionally, pathologic T stage after preoperative chemoradiation was significantly associated with the incidence of positive lymph node with rates of nodal positivity of 3%, 7%, 20%, and 36% for ypT0, ypT1, ypT2, and ypT3-4, respectively.29 More recently, Lombardi et al30 performed a similar study evaluating 32 patients with cT3N0 treated with preoperative chemoradiotherapy. Despite clinical staging with modern techniques, including ERUS, CT scans, positron emission tomography, and MRI, lymph node metastases were identified in 28% of patients at the time of surgery.30 Both of these studies confirm that rates of understaging with modern imaging modalities are at least 20% and may be as high as 30% to 40% after accounting for the effect of nodal downstaging with preoperative chemoradiation.10,29,30 In the absence of routine preoperative chemoradiation, these patients would require treatment with postoperative chemoradiotherapy, which is associated with increased acute and late toxicity and worse local control and disease-free survival compared with preoperative chemoradiotherapy.10,13 Given the current limitations in pretherapy imaging, a rate of “understaging” of at least 20% argues that patients with cT3N0 should continue to receive preoperative chemoradiotherapy and emphasizes the importance of optimizing pretherapy staging modalities for rectal cancer.29,30 However, these studies are retrospective in nature and, therefore, limited by inherent treatment selection bias, treatment heterogeneity among institutions, and a lack of central staging and pathologic review. Additionally, the accuracy and sensitivity of current imaging modalities in determining tumor and nodal category may vary between physicians depending on physician expertise. Maximizing the accuracy of pretreatment tumor and nodal assessment is essential to tailor patient therapy appropriately. To adopt a selective therapy approach, it is imperative that we improve upon preoperative radiographic estimation of postoperative high-risk pathologic features and lymph node positivity. Published literature reports a wide range of sensitivity and specificity in the detection of perirectal tissue invasion and lymph node involvement by current preoperative staging techniques, including ERUS, CT scan of the abdomen/pelvis, and MRI.31 Technical and technological advancements in imaging techniques, however, may lead to higher rates of accuracy in pretreatment staging and, therefore, more appropriate pretherapy treatment recommendations. Recent studies evaluating high-resolution MRI and MRI with phased-array coil have shown an improved accuracy in the determination of potentially involved circumferential margins.32,33 The MRI and Rectal Cancer European Equivalence (MERCURY) study also recently reported the equivalence of thin-section MRI and histopathologic assessment to within 0.5 mm with respect to the determination of tumor

217 maximal extramural depth.34 Other potential techniques to improve the accuracy of lymph node staging, including the use of superparamagnetic iron oxide nanoparticles with high-resolution MRI35 and ERUS-guided fine-needle aspiration of suspicious lymph nodes should be investigated in future studies.36 The incorporation of these imaging techniques may result in more adequate treatment planning; further decrease the number of positive resection margins at surgery; and, ultimately, improve patient outcomes.

Short-Course Preoperative Radiotherapy or Neoadjuvant Chemotherapy: Potential Middle Ground? Two preoperative treatment strategies, short-course preoperative radiotherapy (5 Gy ⫻ 5 fractions) and neoadjuvant chemotherapy alone, have recently been suggested as possible middle ground for patients with cT3N0 rectal cancer.37,38 With respect to preoperative short-course radiotherapy, emerging data from the Polish Rectal study and the TROG 01.04 study suggest that short-course radiotherapy and standard preoperative chemoradiotherapy may be equivalent with respect to local control, sphincter preservation, and overall survival.39,40 However, in contrast with standard fractionation chemoradiotherapy, short-course preoperative radiotherapy is typically followed by curative surgical resection within 1 week after treatment completion and, thus, has not been associated with tumor or nodal downstaging.7,41 As a result, the pathologic tumor and nodal assessment at the time of surgery more accurately represent pretreatment staging, and more appropriate adjuvant chemotherapy recommendations can be made. To date, in the United States, there has been reluctance to adopt short-course preoperative radiotherapy into standard practice given the concerns of potential increased long-term toxicity.42-44 Long-term toxicity data from randomized controlled trials comparing preoperative short-course and standard fractionation radiotherapy and future prospective quality of life comparison studies will be essential in establishing comparison toxicity profiles. In addition, there has been recent interest in defining the potential role of neoadjuvant chemotherapy alone for the treatment of favorable risk locally advanced rectal cancer. In a recent multi-institutional pilot feasibility trial of preoperative 5-Fluorouracil, Leukovorin, Oxaliplatin (FOLFOX)-bevacizumab, all 31 clinically staged II/III patients (excluding T4) were able to achieve a margin-negative resection with a pathologic complete response rate of 27%.38 The benefit of this approach is that exclusion of routine preoperative radiation can eliminate the risk of acute and late radiation-induced toxicities among patients who do not require selective postoperative radiation therapy. However, because of the potential risk of nodal downstaging, although postoperative chemotherapy was left to the investigator’s discretion, 6 cycles of adjuvant FOLFOX was generally recommended to all patients. Thus, this approach may still result in “overtreatment” with adjuvant chemotherapy for low risk cT3N0 pa-

J.Y. Wo et al

218 tients who may not benefit from additional chemotherapy. Future prospective cooperative group studies will hopefully further elucidate the role of preoperative chemotherapy.

Conclusions The optimal oncologic management for patients with T3N0 rectal cancer is currently controversial. Since the publication of the German Rectal Cancer Study, which included T3N0 patients, there has been a paradigm shift toward preoperative standard fractionation chemoradiotherapy in the treatment of locally advanced rectal cancer.10 However, patients with pT3N0 disease may have an “intermediate” risk of disease recurrence between localized stage I disease and more advanced stage II and III disease, suggesting that perhaps trimodality therapy may not be indicated for all patients. To adopt a selective therapy approach, it is imperative that we improve upon preoperative radiographic estimation of postoperative high-risk pathologic features and lymph node positivity. Although helpful, clinical features, such as extent of mesorectal extension, LVI, and preoperative CEA, are ultimately inadequate in guiding clinicians in determining who requires adjuvant therapy. Instead of additional studies evaluating known prognostic clinical features, we need to evaluate the molecular profile of rectal cancers, which holds the promise of better classifying patients at high risk of local and systemic recurrence and, thus, appropriate for the delivery of adjuvant radiation and chemotherapy. Until this promise is realized, in our institutions, we continue to treat T3N0 patients with conventional standard fractionation preoperative chemoradiotherapy using concurrent 5-FU followed by TME 4 to 6 weeks after the completion of preoperative therapy and 4 to 6 months of adjuvant 5-FU– based chemotherapy.

References 1. McDermott FT, Hughes ES, Pihl E, et al: Local recurrence after potentially curative resection for rectal cancer in a series of 1008 patients. Br J Surg 72:34-37, 1985 2. Rich T, Gunderson LL, Lew R, et al: Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer 52:1317-1329, 1983 3. Minsky BD, Mies C, Recht A, et al: Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival. Cancer 61:1408-1416, 1988 4. Gastrointestinal Tumor Study Group: Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. J Clin Oncol 10:549557, 1992 5. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991 6. NIH Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer. JAMA 264:1444-1450, 1990 7. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001 8. Kapiteijn E, van de Velde CJ: European trials with total mesorectal excision. Semin Surg Oncol 19:350-357, 2000 9. Heald RJ, Ryall RD: Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1:1479-1482, 1986 10. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postop-

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erative chemoradiotherapy for rectal cancer. N Engl J Med 351: 1731-1740, 2004 Enker WE, Thaler HT, Cranor ML, et al: Total mesorectal excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 181:335-346, 1995 Peeters KC, Marijnen CA, Nagtegaal ID, et al: The TME trial after a median follow-up of 6 years: Increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246:693-701, 2007 Roh MS, Colangelo LH, O’Connell MJ, et al: Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 27:5124-5130, 2009 Gunderson LL, Sargent DJ, Tepper JE, et al: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: A pooled analysis. J Clin Oncol 22:1785-1796, 2004 Andre T, Afchain P, Barrier A, et al: Current status of adjuvant therapy for colon cancer. Gastrointest Cancer Res 1:90-97, 2007 Andre T, Boni C, Navarro M, et al: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109-3116, 2009 Park IJ, Kim HC, Yu CS, et al: Effect of adjuvant radiotherapy on local recurrence in stage II rectal cancer. Ann Surg Oncol 15:519-525, 2008 Picon AI, Moore HG, Sternberg SS, et al: Prognostic significance of depth of gross or microscopic perirectal fat invasion in T3N0M0 rectal cancers following sharp mesorectal excision and no adjuvant therapy. Int J Colorectal Dis 18:487-492, 2003 Willett CG, Badizadegan K, Ancukiewicz M, et al: Prognostic factors in stage T3N0 rectal cancer: Do all patients require postoperative pelvic irradiation and chemotherapy? Dis Colon Rectum 42:167173, 1999 Merchant NB, Guillem JG, Paty PB, et al: T3N0 rectal cancer: Results following sharp mesorectal excision and no adjuvant therapy. J Gastrointest Surg 3:642-647, 1999 Kim JS, Kim NK, Min BS, et al: Adjuvant radiotherapy following total mesorectal excision for stage IIA rectal cancer: Is it beneficial? Int J Colorectal Dis 25:1103-1110, 2010 Cawthorn SJ, Parums DV, Gibbs NM, et al: Extent of mesorectal spread and involvement of lateral resection margin as prognostic factors after surgery for rectal cancer. Lancet 335:1055-1059, 1990 Merkel S, Mansmann U, Siassi M, et al: The prognostic inhomogeneity in pT3 rectal carcinomas. Int J Colorectal Dis 16:298-304, 2001 Sebag-Montefiore D, Stephens RJ, Steele R, et al: Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicentre, randomised trial. Lancet 373:811-820, 2009 Quirke P, Durdey P, Dixon MF, et al: Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet 2:996-999, 1986 Nissan A, Stojadinovic A, Shia J, et al: Predictors of recurrence in patients with T2 and early T3, N0 adenocarcinoma of the rectum treated by surgery alone. J Clin Oncol 24:4078-4084, 2006 Eriksen MT, Wibe A, Haffner J, et al: Prognostic groups in 1,676 patients with T3 rectal cancer treated without preoperative radiotherapy. Dis Colon Rectum 50:156-167, 2007 Quirke P, Steele R, Monson J, et al: Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: A prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet 373:821-828, 2009 Guillem JG, Diaz-Gonzalez JA, Minsky BD, et al: cT3N0 rectal cancer: Potential overtreatment with preoperative chemoradiotherapy is warranted. J Clin Oncol 26:368-373, 2008 Lombardi R, Cuicchi D, Pinto C, et al: Clinically staged T3N0 rectal cancer: Is preoperative chemoradiotherapy the optimal treatment? Ann Surg Oncol 17:838-845, 2010 Bipat S, Glas AS, Slors FJ, et al: Rectal cancer: Local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging—A meta-analysis. Radiology 232:773-783, 2004

T3N0 rectal cancer: radiation for all? 32. Beets-Tan RG, Beets GL, Vliegen RF, et al: Accuracy of magnetic resonance imaging in prediction of tumour-free resection margin in rectal cancer surgery. Lancet 357:497-504, 2001 33. Brown G, Radcliffe AG, Newcombe RG, et al: Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic resonance imaging. Br J Surg 90:355-364, 2003 34. Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: Results of the MERCURY study. Radiology 243:132-139, 2007 35. Harisinghani MG, Barentsz J, Hahn PF, et al: Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 348:2491-2499, 2003 36. Shami VM, Parmar KS, Waxman I: Clinical impact of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration in the management of rectal carcinoma. Dis Colon Rectum 47:59-65, 2004 37. Kachnic LA, Hong TS, Ryan DP: Rectal cancer at the crossroads: The dilemma of clinically staged T3, N0, M0 disease. J Clin Oncol 26:350351, 2008 38. Schrag D, Weiser MR, Goodman KA, et al: Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer. J Clin Oncol 28: 3511, 2010 (suppl) 39. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al: Long-term

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results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93:1215-1223, 2006 Ngan S, Fisher R, Goldstein D, et al: A randomized trial comparing local recurrence (LR) rates between short-course (SC) and long-course (LC) preoperative radiotherapy (RT) for clinical T3 rectal cancer: An intergroup trial (TROG, AGITG, CSSANZ, RACS).J Clin Oncol 28:15s, 2010 (suppl; abstr 3509) Marijnen CA, Nagtegaal ID, Klein-Kranenbarg E, et al: No downstaging after short-term preoperative radiotherapy in rectal cancer patients. J Clin Oncol 19:1976-1984, 2001 Marijnen CA, Kapiteijn E, van de Velde CJ, et al: Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: Report of a multicenter randomized trial. J Clin Oncol 20:817-825, 2002 Birgisson H, Pahlman L, Gunnarsson U, et al: Adverse effects of preoperative radiation therapy for rectal cancer: Long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 23:8697-8705, 2005 Peeters KC, van de Velde CJ, Leer JW, et al: Late side effects of shortcourse preoperative radiotherapy combined with total mesorectal excision for rectal cancer: Increased bowel dysfunction in irradiated patients—A Dutch colorectal cancer group study. J Clin Oncol 23:61996206, 2005

Point: Short-Course Radiation Therapy Is Preferable in the Neoadjuvant Treatment of Rectal Cancer Krzysztof Bujko, MD, PhD, and Magdalena Bujko, MD There are 2 types of neoadjuvant radiation regimens accepted as standard for resectable rectal cancer: short-course (5 ⴛ 5 Gy) radiation therapy alone with immediate surgery and long-course combined chemoradiation therapy with delayed surgery. A Polish randomized study (n ⴝ 312) and an Australian randomized study (n ⴝ 326) compared these 2 schedules. Both trials showed a lower rate of early adverse effects using a short-course radiation regimen and no differences in long-term oncologic outcomes and late toxicity rates between groups. The small number of fractions makes short-course radiation less expensive and more convenient than chemoradiation therapy. These facts indicate that short-course radiation is preferable to chemoradiation for resectable cancers. Additionally, short-course preoperative radiation with a long interval to surgery is a valuable option for patients unfit for chemotherapy, with unresectable cancer or with a small tumor that is amenable to local excision. Moreover, short-course radiation enables the intensification of both radiotherapy and chemotherapy in patients with metastatic rectal cancer with potentially resectable synchronous metastatic disease. Semin Radiat Oncol 21:220-227 © 2011 Elsevier Inc. All rights reserved.

I

n the treatment of rectal cancer, the delivery of preoperative radiation is generally preferable to postoperative radiation because it is more effective in preventing local relapse and is less toxic.1,2 There are 2 preoperative radiation regimens accepted as standard: short course (5 fractions of 5 Gy delivered over 1 week) with surgery performed within the next 5 days and conventionally fractionated chemoradiation (25-30 fractions of 1.8 or 2 Gy over 5-6 weeks) with surgery performed 4 to 8 weeks after treatment completion. The former schedule is preferred in Northern Europe and the latter schedule in Southern Europe and Americas. Cancer cells sterilized by radiation require time to undergo necrosis.3,4 Therefore, very limited tumor shrinkage5 and no downstaging6 occur after short-course radiation and immediate surgery, whereas in the long-course chemoradiation schedule the longer overall treatment time and interval to surgery results in the downsizing of virtually all cancers and in pathologic complete response in approximately 15% of patients (Fig. 1).7-11 Therefore, chemoradiation can make initially unresectable tumors resectable.9 Therefore, neoadjuvant chemoradiation is the treatment of choice for these can-

Department of Radiotherapy, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland. Address reprint requests to Krzysztof Bujko, MD, PhD, Maria SklodowskaCurie Memorial Cancer Centre, W. K. Roentgena 5, 02 781 Warsaw, Poland. E-mail: [email protected]

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1053-4296/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2011.02.008

cers. Short-course radiation with immediate surgery is an alternative option to chemoradiation for resectable clinically staged T3 cancers. Therefore, this article deals mainly with these categories of tumors. In the opinion of the authors of this article, short-course radiation therapy is preferable to chemoradiation in the neoadjuvant treatment of resectable rectal cancer. The next part of this work presents arguments supporting this view.

Randomized Trials Comparing Neoadjuvant Short-Course Radiation With Neoadjuvant Chemoradiation for cT3 Cancers There are 2 published randomized trials comparing neoadjuvant short-course radiation and neoadjuvant chemoradiation: the Polish study of 312 patients10,12-14 and the Australian study15,16 of 326 patients (Table 1). To date, the Australian study has been published only in abstract form. There is also a third study currently ongoing in Germany. The design of these trials is very similar, with slight differences. The Polish trial evaluated a hypothesized 15% difference in rates of sphincter-preserving surgery between the chemoradiation and short-course radiation group, and the Australian study evaluated a hypothesized 10% difference in local re-

Short-course radiation therapy

221

Figure 1 Morphologic manifestation of tumor response to radiation in relation to the duration of the interval between the beginning of rediation and surgery. Damage, which ceases unlimited cancer cell division, occurs at the time of irradiation. In some cancers, this eventually leads to a pathologic complete response. The manifestation of pathologic complete response is heavily dependent on the duration of the interval between the beginning of radiation and surgery.3,4 Within a few days after the start of radiation, nonviable cancer cells look morphologically intact (lower scenario) but undergo lysis within the next few weeks (upper and middle scenarios). This figure explains why in the Polish trial long-term outcomes were similar in the short-course radiation and chemoradiation groups despite more pathologic complete responses in the chemoradiation group (Table 1). Pathologic complete response is observed when surgery is delayed for a few weeks after 5 ⫻ 5 Gy even in unresectable cancers (middle scenario).20,39-41 This figure also shows why no downstaging occurs after short-course radiation and immediate surgery (lower scenario).6

currence rate. The median follow-up was 4 years in the Polish study and 5.9 years in the Australian trial. Both trials showed higher rates of early radiation toxicity in the chemoradiation group when compared with the 5 ⫻ 5 Gy group; grade III to IV acute toxicity rates were 18% versus 3% (P ⬍ .001) in the Polish trial and 28% versus 1.9% (P ⬍ .001) in the Australian study. In the Polish study, 2 toxic deaths (1.5%) were reported in the chemoradiation group and none in the short-course group. Lower early toxicity rates with short-course radiation translated into improved adherence to the protocol. In the Polish trial, the sphincter-preservation rate did not differ between groups at 61% in the short-course group and 58% in the chemoradiation group (P ⫽ .57). The incidence of postoperative complications was not statistically different between studies (Table 1). In the Polish trial, the local recurrence rate was slightly lower in the short-course group than in the chemoradiation group (10.6% vs 15.6% [P ⫽ .21]), whereas the opposite tendency was seen in the Australian study at 7.5% versus 4.4% (P ⫽ .24). There was no indication that chemoradiation had any advantage in terms of survival (Table 1). Additionally, no increase in late toxicity rates were seen in the short-course irradiation group compared with the chemoradiation group. In the Polish study, severe late toxicity was observed in 10.1% of patients after short-course radiation and in 7.1% of patients after chemo-

radiation (P ⫽ .36). The corresponding figures in the Australian study were 7.6% and 8.8% (P ⫽ .84). It should be acknowledged, however, that in both trials the follow-up was too short to draw definitive conclusions regarding late adverse effects. No significant differences were observed between the randomized groups regarding quality of life and anorectal and sexual functions13 (Table 1). It is interesting to note that despite more favorable postoperative pathology in the chemoradiation group (increased downstaging and fewer patients with positive circumferential margin) than in the short-course group, the long-term outcomes were similar (Table 1). A possible explanation for this phenomenon is depicted in Figure 1.

Other Evidence Supporting the Use of Short-Course Radiation With Immediate Surgery in Resectable Cancer Short-course radiation (5 ⫻ 5 Gy) has been the most extensively tested radiotherapy regimen in randomized trials of rectal cancer1,12,15,17-22 (Table 2). Approximately 6,000 patients have participated in varying studies.

K. Bujko and M. Bujko

222

Table 1 The Polish and Australian Randomized Trials10,12-16 Comparing Neoadjuvant Short-Course Radiation and Neoadjuvant Chemoradiation 5 ⴛ 5 Gy Grade III-IV acute toxicity (%) Polish study (PS) (N ⴝ 312) Australian study (AS) (N ⴝ 326) Overall acute toxicity (%) PS Adherence to the protocol (%) PS AS Severe surgical complications (%) PS AS Overall surgical complications (%) PS AS Sphincter preservation (%) PS Pathologic complete response (%) PS ypT0-2 (%) PS ypN0 (%) PS Positive circumferential margin (%) PS Local recurrence rate (%) PS at 4 years AS at 3 years Distant metastases (%) PS crude rates AS at 5 years Overall survival (%) PS at 4 years AS at 5 years Disease-free survival (%) PS at 4 years Grade III-IV late toxicity (%) PS crude rates AS crude rates Overall late toxicity (%) PS crude rates QLQ-C30 global health status* PS mean scores Poor anorectal function (%) PS Decline in sexual function (%) PS male PS female

Chemoradiation

3 1.9

P Value

18 28

<.001 <.001

24

85

<.001

98 100

69 77

10 7.1

11 3.5

0.85 0.26

27 51

21 49

0.27

61

58

0.57

1

15

<.001

40

62

<.001

52

68

0.007

13

4

0.017

10.6 7.5

15.6 4.4

0.21 0.24

31.4 28

34.6 31

0.54 0.85

67.2 74

66.2 70

0.96 0.56

58.4

55.6

0.82

10.1 7.6

7.1 8.8

0.36 0.84

28.3

27

0.81

57

61

0.22

59

64

0.52

80 41

69 52

0.56 0.1

Abbreviations: PS, Polish study; AS, Australian study; QLQ, quality of life questionnaire. Lack of data in the table indicates some data were not published. *The differences in the scores of all other scales or single items of QLQ were also insignificant.

Local Control and Survival Three large randomized Swedish trials compared shortcourse preoperative radiotherapy and immediate surgery with surgery alone.17,18,22 The relative reduction of local recurrence with radiation ranged from 52% to 65%. In the largest study (1168 patients), there was an 8% absolute ben-

efit in overall survival at 13 years.17 In the remaining 2 trials, benefits in disease-specific survival or in overall survival in the subgroup of curatively treated patients was shown18,22 (Table 2). One smaller Swedish randomized trial compared short-course preoperative radiotherapy and conventionally fractionated postoperative radiotherapy.1 Better local control

Short-course radiation therapy

223

Table 2 Randomized Trials (other than those presented in Table 1) Testing Short-Course Neoadjuvant Radiotherapy n

Median Follow-up (y)

5 ⴛ 5 Gy with immediate surgery vs surgery alone

849

4.5

5 ⴛ 5.1 Gy with immediate surgery vs postoperative radiotherapy, 60 Gy, 2 Gy per fraction 5 ⴛ 5 Gy with immediate surgery vs surgery alone

471

Minimum 5

557

9

Design Stockholm

122

Uppsala1

Stockholm 218

Swedish trial17

5 ⴛ 5 Gy with immediate surgery vs surgery alone

1168

13

Dutch TME trial19,34

5 ⴛ 5 Gy with immediate surgery vs surgery alone or postoperative radiotherapy for high risk patients (11%) 5 ⴛ 5 Gy with immediate surgery vs surgery alone or postoperative chemoradiation for high-risk patients (9%)

1861

6

1350

3

5 ⴛ 5 Gy with immediate surgery (group 1) vs 5 ⴛ 5 Gy with surgery after 4-8 wks (group 2) vs 25 ⴛ 2 Gy with surgery after 4-8 wks (group 3)

303

—

MRC CR0721

Stockholm III trial20

Results No difference in overall survival. Radiotherapy group had better disease-specific survival (RR ⴝ 0.76; 95% CI, 0.54-1.00; P ⴝ .05), less local recurrences (11% vs 23%, P < .01), and higher postoperative mortality (8% vs 2%, P < .01). No difference in overall survival. Preparative radiotherapy group at 5 years had less local recurrences (13% vs 22%, P ⴝ .02) and late small bowel obstructions (5% vs 11%, P < .01). No difference in overall survival. In the preoperative radiotherapy group at 5 years, there were less local recurrences (12% vs 25%, P < .001) and better overall survival for the subgroup of patients who underwent curative surgery (46% vs 39%, P ⴝ .03) In the preoperative radiotherapy group at 13 years, the overall survival was better (38% vs 30%, P ⴝ .008), and there were less local recurrences (9% vs 26%, P < .001). No difference in overall and disease-free survival. In the preoperative radiotherapy group at 5 years, there were less local recurrences (5.6% vs 10.9%, P < .001). No difference in overall survival. In the preoperative radiotherapy group at 3 years, disease-free survival was higher (77.5% vs 71.5%, P ⴝ .013), and there were less local recurrences (4.4% vs 10.6%, P < .001). Interim analysis. There were no differences between the 3 groups in postoperative complications. Pathologic complete response was 0.8% in group 1, 12.5% in group 2, and 5% in group 3 (P value not given).

Abbreviations: 5-FU, 5-fluorouracil; CRM, circumferential resection margin; LV, leucovorin; RR, relative risk; CI, confidence interval.

and a lower rate of late complications were reported in the preoperative radiotherapy group. Implementation of the total mesorectal excision (TME) technique has dramatically improved local control. Two recent large randomized studies, the Dutch TME trial19,23 and Medical Research Council (MRC) CR07 trial,21 used this technique. Both trials compared short-course preoperative radiotherapy with the selective use of postoperative radiochemotherapy or radiotherapy for the approximately 10% of patients with a positive circumferential resection margin (Table 2). Both trials showed an approximately 50% to 60% relative reduction of local recurrence after short-course preoperative radiotherapy although the absolute benefit was only about 5% to 6%. Both trials showed no benefit in overall

survival with radiation. In the MRC CR07 trial, however, disease-free survival was significantly better at 3 years in the preoperatively irradiated group. The reduction of local recurrence and survival benefit caused by preoperative chemoradiation is unknown because there have been no randomized studies comparing preoperative chemoradiation with surgery alone.

Acute Toxicity Acute toxicity after short-course radiation is usually mild when surgery is not delayed. Grade I to II gastrointestinal acute side effects were the most frequently observed complications in randomized trials.10,24 Sacral pain, usually of short

224 duration, was reported in 10% of patients; in 2.5% of patients, the pain was severe and required treatment interruption.24 Grade III to IV acute side effects were observed in 2% to 4% of patients after short-course radiation10,16,24 versus approximately 20% of patients after chemoradiation.2,8-10,16,25 No deaths from acute toxicity were reported after 5 ⫻ 5 Gy, whereas after chemoradiation such deaths were reported in approximately 1% of patients.10,25,26 Using modern radiotherapy techniques, there was no increase in postoperative mortality after short-course preoperative radiation compared with surgery alone.21,23,27

Late Toxicity The sensitivity of late toxicity to an increased dose per fraction is well known. Hence, there is concern regarding severe late adverse effects after using 5 Gy per fraction. This concern has not been validated by a recent report based on the Swedish Rectal Cancer Trial of 1.168 patients.28 The minimal follow-up time in this study was 11 years. The data were retrieved from the National Register, which included all hospital admissions. No difference in the risk for overall hospital admission was found between the group receiving 5 ⫻ 5 Gy preoperatively and the group treated with surgery alone; the relative risk was 1.07 with a 95% confidence interval ranging from 0.91 to 1.26. These data rule out a substantially increased risk of late toxicity resulting in hospital admission. This observation is in line with the prediction of the linearquadratic model, which suggests the biologically equivalent dose of the 5 ⫻ 5 Gy schedule to fractionation given at 2 Gy per fraction is 40 Gy, assuming that ␣/␤ equals 3 Gy for late damage.29 The incidence of anorectal and sexual dysfunction were more frequently observed after short-course radiation versus surgery alone.30,31 However, the rates of these dysfunctions after short-course radiation were similar to those observed after preoperative chemoradiation (Table 1).13 In the combined experience of the Stockholm I and II trials, 5.3% of irradiated patients and 2.4% of nonirradiated patients (P ⫽ .03) were hospitalized because of femoral or pelvic fractures.32 This may be caused by the fact that the posterior part of the sacrum was not shielded. No increase in femoral or pelvic fractures after the 5 ⫻ 5-Gy regimen was observed in other randomized trials.28,30 Late chronic neurotoxicity is another concern of shortcourse radiotherapy. During the follow-up period ranging from 3 to 14 years in a Swedish report, generally reversible sacral pain of long duration was reported in 7 of 503 patients (1.4%), with 3 (0.6%) of patients developing other neurologic symptoms, such as weakness, numbness, and parenthesis of the lower extremities.33 This neurotoxic effect, however, did not translate to a detectable difference in neurologic function between the preoperative short-course radiation group of this study and the selective postoperative radiation groups of the Dutch TME trial30 and the MRC CR07 trial.21 Similarly, in the Swedish Rectal Cancer Trial, there was no difference in hospital admissions between the groups because of neurologic disorders.28

K. Bujko and M. Bujko

Are There Any Subgroups of Patients Who May Benefit More From Chemoradiation Than From Short-Course Radiation? It is argued that preoperative chemoradiation is preferable to short-course radiation for patients with threatened circumferential resection margins detected on preoperative pelvic magnetic resonance imaging.34 It is also believed that preoperative chemoradiation is preferable to short-course radiation for patients with low-lying cancer to increase the chance for anterior resection.35 In the view of the authors of this article, the evidence presented below does not provide support for such convictions. It should be stressed that there are 2 types of cancers displaying threatened circumferential resection margins: (1) those deemed unresectable (ie, fixed lesions invading or abutting adjacent organs) and (2) those deemed resectable (ie, not fixed to the pelvis). Neoadjuvant chemoradiation is the treatment of choice for cancers deemed as unresectable. However, there is no evidence showing that preoperative chemoradiation is more effective than short-course radiation for resectable lesions with threatened circumferential resection margins. Patients with tumors deemed resectable but with involved circumferential resection margins participated in both the Dutch TME trial (18.2% of patients)34 and the MRC CR07 trial (10.8% of patients).21 In both trials, the rate of local recurrence in this subgroup of patients was lower in the short-course radiation group than in the selective postoperative radiation group: 9.3% versus 16.4% in the Dutch TME trial34 and 13.8% versus 20.7% in the MRC CR07 trial.21 These differences were rather small and statistically insignificant, which might be explained by the reduction of local recurrence in the selective postoperative radiation groups through postoperative radiation delivery in a substantial number of patients. The aforementioned data suggest that for patients with resectable cancer but with threatened circumferential resection margins, short-course preoperative radiation is more effective than selective postoperative conventionally fractionated radiation or chemoradiation. Because of the lack of relevant data, it is unknown whether conventionally fractionated preoperative chemoradiation is more beneficial than preoperative short-course radiation in these patients. Contrary to the belief that reduction in tumor bulk after radiation increases the likelihood of anterior resection,35 the Polish study did not confirm chemoradiation to have an advantage over short-course radiation in terms of sphincter preservation (Table 1). This finding is in line with the results of 2 meta-analyses showing that tumor shrinkage after preoperative radiation has no impact on the anterior resection rate.36,37

Preoperative Short-Course Radiation With Delayed Surgery The small randomized Stockholm III trial is comparing 3 preoperative radiotherapy schemes: short-course radiation

Short-course radiation therapy and immediate surgery, short-course radiation and delayed surgery, and conventionally fractionated radiation (without simultaneous chemotherapy) and delayed surgery.20 An interim analysis showed a pathologic complete response in 12.5% of patients in the short-course radiation and delayedsurgery group and only 0.8% in the short-course radiation and immediate-surgery group (Table 2). Other nonrandomized studies have confirmed that the rate of pathologic complete response seen after short-course radiation and delayed surgery38-41 is not much different from what is observed after conventionally fractionated chemoradiation. These data have suggested that short-course radiation with delayed surgery might be used when tumor shrinkage is needed. However, this treatment has a higher rate of acute toxicity than shortcourse radiation with immediate surgery. When surgery was delayed, grade I to II symptoms of acute radiation toxicity (such as proctitis, enteritis, cystitis, and dermatitis) occurred in approximately one third of patients around 1 week after radiation completion;38 severe acute toxicity was observed in 4.2% of patients.20 Another possible disadvantage of the delayed interval to surgery is the possibility of tumor clonogen repopulation during this interval.42 Preliminary results of the use of short-course radiation with delayed surgery are presented later. Small numbers of patients and short follow-up do not allow for definitive conclusions regarding the routine use of this schedule. However, it is a valuable option for elderly patients unfit for chemotherapy.

Preoperative Short-Course Radiation for Unresectable Primary Tumors in Patients Unfit for Chemotherapy Elderly patients with comorbidities are often unfit for chemotherapy. In addition, a 5- to 6-week hospital stay or the transportation required to undergo conventionally fractionated radiation treatments may be problematic for these patients. Because of these issues, short-course radiation with a 7- to 8-week interval to surgery can be a reasonable option. There are 2 retrospective reports showing promising results of such management.39,40 Among those patients who underwent surgery, the rate of resection with clear margins was approximately 85%, with a pathologic complete response observed in approximately 8% of patients. In the first report (n ⫽ 24) published by Radu et al,39 the follow-up ranged from 7 to 54 months. Local recurrence was observed in 1 patient. In the second series (n ⫽ 43) published by Hatfield et al,40 there were no local recurrences reported at a median follow-up of 18 months.

Preoperative Short-Course Radiation in Patients With Rectal Cancer and Synchronous Distant Metastases During conventionally fractionated chemoradiation, the dose of chemotherapy must be reduced by approximately 20% to keep the level of acute toxicity acceptable. In patients with a rectal cancer and potentially resectable synchronous metastatic disease, short-course radiotherapy and chemotherapy delivered in tight sequence may enable intensification of both

225 systemic treatment and radiation.39,41 In a series of 48 patients with rectal cancer and synchronous distant metastases reported by van Dijk et al,41 treatment was initiated with 5 ⫻ 5 Gy. Next, 6 courses of bevacizumab, capecitabine, and oxaliplatin were delivered in cycles of 3 weeks each. A complete pathologic response in the primary tumor was found in 22.5% of patients, with curative surgery possible in 85%. The previously described data show that the integration of 5 ⫻ 5 Gy with sequential consolidating chemotherapy during the interval to surgery is feasible and promising. Because the local efficacy of 5 ⫻ 5 Gy and chemoradiation is much the same (Table 1), it might be expected that the addition of consolidating chemotherapy after 5 ⫻ 5 Gy (during the interval to surgery) may produce higher antitumor activity than traditional chemoradiation. To test this hypothesis, a phase III study has been launched in Poland for patients with unresectable rectal cancer.

Short-Course Radiation Before Full-Thickness Local Excision Full-thickness local excision is an attractive treatment because of its low morbidity and promise of good anorectal function. Unfortunately, apart from selected T1 lesions, local excision is associated with a high rate of local failure. Preoperative radiation may expand the use of local excision for radiosensitive T2-3 tumors. Preliminary results of a prospective multicenter study using this approach have been published.38 Patients were treated with 5 ⫻ 5 Gy or with 5 ⫻ 5 Gy plus a 4-Gy boost (n ⫽ 31, including 13 patients unfit for chemotherapy) or with chemoradiation of 55.8 Gy delivered in 1.8 Gy per fraction (n ⫽ 13). The interval from radiation to full-thickness local excision was 6 weeks. If pathologic complete response of the primary tumor or downstaging to ypT1 with a clear surgical margin occurred after radiation, the local excision was considered the final treatment. For patients with more radioresistant cancers, immediate conversion to abdominal surgery was proposed. A complete pathologic response was recorded in 35% of patients from the shortcourse group and in 54% of patients from the chemoradiation group; the rates of patients who required conversion to transabdominal surgery were 39% and 23%, respectively. During the 14 months of median follow-up, local recurrence was detected in 7% of patients, and all underwent salvage surgery.

Why Is ShortCourse Radiation Therapy Preferable to Chemoradiation? The most striking difference between the short-course schedule and chemoradiation is a lower risk of early adverse effects in the former scheme (Table 1). This is caused by a lack of concomitant chemotherapy in the 5 ⫻ 5-Gy regimen. Immediate surgery is another factor that contributes to this low toxicity, primarily because the main organ at risk for early damage (the rectum) is removed before the occurrence of adverse effects.

226 A lower rate of early adverse effects with the short-course radiation regimen compared with a chemoradiation regimen, together with the lack of differences in the long-term outcomes between both treatments (Table 1), makes shortcourse radiation preferable to chemoradiation. The following question remains: Is there enough evidence indicating no difference in local control and survival exists between the two? Both the Polish trial and the Australian trial, when considered separately, are underpowered to detect small differences in these endpoints. However, considering both studies together, the power of evidence increases. There is no consistent tendency in local control or survival that would suggest the superiority of either schedule (Table 1). This makes the risk of a type II error (false-negative result) acceptable. However, because the Australian trial is published only as an abstract, peer review of the final report is necessary before making final recommendations. Apart from lower acute toxicity, there are other advantages of short-course radiation when compared with chemoradiation. Clearly, the delivery of 5 fractions of radiation is less expensive than the delivery of 25 to 28 fractions. By contrast, a smaller number of fractions makes the implementation of short-course radiation difficult in countries with a fee-forservice reimbursement system.43 This is because the fee-forservice reimbursement system provides an incentive to deliver many radiotherapy fractions because each of these fractions is reimbursed separately. A small number of fractions, however, makes short-course radiation more convenient than chemoradiation, both for patients and for radiotherapy departments, particularly for those with long waiting lists. Additionally, short-course preoperative radiation with a long interval to surgery is a valuable option for elderly highrisk patients with unresectable cancers or with small tumors that can be treated by local excision. In patients with a primary tumor and with potentially resectable synchronous metastatic disease, short-course radiation enables the intensification of treatment.

Acknowledgments The authors thank Ms Marta Michalska for linguistic assistance.

References 1. Frykholm GJ, Glimelius B, Pahlman L: Preoperative or postoperative irradiation in adenocarcinoma of the rectum: Final treatment results of a randomized trial and evaluation of late secondary effects. Dis Colon Rectum 36:564-572, 1993 2. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:17311740, 2004 3. Francois Y, Nemoz CJ, Bauliex J: Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: The Lyon R90-01 randomized trial. J Clin Oncol 17:2396-2402, 1999 4. Suit HD, Gallager HS: Intact tumor cells in irradiated tissue. Arch Pathol 78:648-651, 1964 5. Nagtegaal ID, Marijnen CA, Kranenbarg EK, et al: Short-term preoperative radiotherapy interferes with the determination of pathological parameters in rectal cancer. J Pathol 197:20-27, 2002

K. Bujko and M. Bujko 6. Marijnen CA, Nagtegaal ID, Klein-Kranenbarg E, et al: No downstaging after short-term preoperative radiotherapy in rectal cancer patients. J Clin Oncol 19:1976-1984, 2001 7. Yeo SG, Kim DY, Kim TH: Tumor volume reduction rate measured by magnetic resonance volumetry correlated with pathologic tumor response of preoperative chemoradiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys 78:164-171, 2010 8. Bosset JF, Collette L, Calais G, et al: Chemoradiotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114-1123, 2006 9. Braendengen M, Tveit KM, Berglund A, et al: Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol 26:3687-3694, 2008 10. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al: Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomized trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol 72:15-24, 2004 11. Gerard JP, Conroy T, Bonnetain F, et al: Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203. J Clin Oncol 24:4620-4625, 2006 12. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al: Long-term results of randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93:1215-1223, 2006 13. Pietrzak L, Bujko K, Nowacki MP, et al: Quality of life, anorectal and sexual functions after preoperative radiotherapy for rectal cancer: Report of a randomised trial. Radiother Oncol 84:217-225, 2007 14. Bujko K, Nowacki MP, Kepka L, et al: Postoperative complications in patients irradiated pre-operatively for rectal cancer: Report of a randomised trial comparing short-term radiotherapy vs chemoradiation. Colorectal Dis 7:410-416, 2005 15. Ngan S, Fisher R, Goldstein D: A randomized trial comparing local recurrence (LR) rates between short-course (SC) and long-course (LC) preoperative radiotherapy (RT) for clinical T3 rectal cancer: An intergroup trial (TROG, AGITG, CSSANZ, RACS). J Clin Oncol 28:15s, 2010 (suppl, abstr :3509) 16. Ngan S, Fisher R, Mackay J: Acute adverse events in a randomised trial of short course versus long course preoperative radiotherapy for T3 adenocarcinoma of rectum: A Trans-Tasman Radiation Oncology Group trial (TROG 01.04) Eur J Cancer 4:237, 2007 (suppl 5, abstr) 17. Folkesson J, Birgisson H, Pahlman L, et al: Swedish Rectal Cancer Trial: Long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 23:5644-5650, 2005 18. Martling AL, Holm T, Johansson H, et al: The Stockholm II trial on preoperative radiotherapy in rectal carcinoma. Long-term follow-up of a population-based study. Cancer 92:896-902, 2001 19. Peeters KC, Marijnen CA, Nagtegaal ID, et al: The TME trial after a median follow-up of 6 years: Increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246:693-701, 2007 20. Pettersson D, Cedermark B, Holm T, et al: Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer. Br J Surg 97:580-587, 2010 21. Sebag-Montefiore D, Stephens RJ, Steele R, et al: Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicentre, randomised trial. Lancet 373:811-820, 2009 22. Stockholm Colorectal Cancer Study Group: Preoperative short-term radiation therapy in operable rectal carcinoma. A prospective randomized trial. Cancer 66:49-55, 1990 23. Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001 24. Marijnen CA, Kapiteijn E, van de Velde CJ, et al: Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: Report of a multicenter randomized trial. J Clin Oncol 20:817-825, 2002

Short-course radiation therapy 25. Roh MS, Colangelo LH, O’Connell MJ, et al: Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 27:5124-5130, 2009 26. Cionini L, Manfredi B, Sainato A: Randomized study of postoperative chemotherapy (CT) after preoperative chemoradiation (CTRT) in locally advanced rectal cancer (LARC). Preliminary results. Eur J Cancer 37:S300, 2001 (abstr) 27. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-987, 1997 28. Birgisson H, Pahlman L, Gunnarsson U, et al: Adverse effects of preoperative radiation therapy for rectal cancer: Long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 23:8697-8705, 2005 29. Bujko K, Kolodziejczyk M: The 5x5Gy with delayed surgery in nonresectable rectal cancer: A new treatment option. Radiother Oncol 87: 311-313, 2008 30. Peeters KCMJ, van de Velde CJ, Leer JWH, et al: Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: Increased bowel dysfunction in irradiated patients—A Dutch Colorectal Cancer Group Study. J Clin Oncol 23: 6199-6206, 2005 31. Marijnen CAM, van de Velde CJ, Putter H, et al: Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: Report of multicenter randomized trial. J Clin Oncol 23:1847-1858, 2005 32. Holm T, Singnomklao T, Rutqvist LE, et al: Adjuvant preoperative radiotherapy in patients with rectal carcinoma. Adverse effects during long term follow-up in two randomised trials. Cancer 78:968-976, 1996 33. Frykholm JG, Sintorn K, Montelius A, et al: Acute lumbosacral plexopathy during and after preoperative radiotherapy of rectal adenocarcinoma. Radiother Oncol 38:121-130, 1996 34. Marijnen CA, Nagtegaal ID, Kapiteijn E, et al: Radiotherapy does not compensate for positive resection margins in rectal cancer patients:

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Report of a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55:1311-1320, 2003 Mohiuddin M, Marks J, Marks G: Management of rectal cancer: Shortvs. long-course preoperative radiation. Int J Radiat Oncol Biol Phys 72:636-643, 2008 Bujko K, Kepka L, Michalski W, et al: Does rectal cancer shrinkage induced by preoperative radio(chemo)therapy increase the likelihood of anterior resection? A systematic review of randomised trials. Radiother Oncol 80:4-12, 2006 Wong RKS, Tandan V, De Silva S: Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst Rev 2:CD002102, 2007 Bujko K, Richter P, Kołodziejczyk M, et al: Preoperative radiotherapy and local excision of rectal cancer with immediate radical re-operation for poor responders. Radiother Oncol 92:195-201, 2009 Radu C, Berglund A, Pahlman L, et al: Short course preoperative radiotherapy with delayed surgery in rectal cancer—A retrospective study. Radiother Oncol 87:343-349, 2008 Hatfield P, Hingorani M, Radhakrishna G, et al: Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity. Radiother Oncol 92:210-214, 2009 Van Dijk TH, Hospers GAP, Beukema JC: Short-course radiation therapy, neoadjuvant bevacizumab, capecitabine and oxaliplatin, and radical resection of primary tumour and metastases in primary stage IV rectal cancer: A phase II multicenter study of the Dutch colorectal cancer Group. Ann Oncol 21:i51, 2010 (suppl 1, abstr) Gasinska A, Skolyszewski J, Popiela T, et al: Bromodeoxyuridine labeling index as an indicator of early tumor response to preoperative radiotherapy in patients with rectal cancer. J Gastrointest Surg 11:520528, 2007 Lievens Y, Van den Bogaert W, Rijnders A, et al: Palliative radiotherapy practice within Western European countries: Impact of the radiotherapy financing system? Radiother Oncol 56:289-295, 2000

Counterpoint: Long-Course Chemoradiation Is Preferable in the Neoadjuvant Treatment of Rectal Cancer Bruce D. Minsky, MD There are 2 approaches to preoperative therapy. Short-course (25 Gy in 5 fractions) radiation and long-course (50.4 Gy in 28 fractions) radiation combined with chemotherapy (CMT). Although short-course radiation therapy is used in some European countries, it is not favored in all European countries or North America. Unlike long-course CMT, it cannot be safely combined with adequate doses of systemic concurrent chemotherapy, and, as currently designed, it does not increase sphincter preservation. Long-course CMT remains the preferred regimen for cT3 and/or node-positive disease. With parallel advances in staging, surgery, systemic therapy, and molecular markers, more selective approaches are being investigated. Semin Radiat Oncol 21:228-233 © 2011 Elsevier Inc. All rights reserved.

N

eoadjuvant (preoperative) therapy has become the most common adjunctive treatment for rectal cancer. There are 2 approaches to preoperative therapy: short-course (25 Gy in 5 fractions) radiation and long-course (50.4 Gy in 28 fractions) radiation combined with chemotherapy (CMT). As with most controversies, it is helpful to understand the historic context of their origins. Although there were trials of short-course radiation from the VA and Memorial Sloan-Kettering in the 1970s, most of the randomized trials have been performed in Scandinavia, the Netherlands, and the United Kingdom. Most physicians in those countries considered systemic chemotherapy for both colon and rectal cancers investigational. Therefore, long-course CMT programs for rectal cancer were not developed. Short-course radiation, a convenient and relatively inexpensive approach, became the standard adjuvant treatment for patients with cT1-3 rectal cancer. In contrast, in the 1980s, postoperative systemic chemotherapy was the standard of care for most T3 and/or nodepositive colon cancers in North America.1 It improved survival approximately 10% to 15% above surgery alone.

Department of Radiation and Cellular Oncology, University of Chicago Medical Center, Chicago, IL. Address reprint requests to Bruce D. Minsky, MD, Department of Radiation and Cellular Oncology, University of Chicago Medical Center, 5841 S Maryland Ave, MC-1000, Chicago, IL 60637. E-mail: bruce.minsky@ uchospitals.edu

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Because postoperative radiation alone was the common adjuvant treatment for rectal cancer, chemotherapy was added to postoperative radiation. The postoperative Intergroup adjuvant rectal trials revealed a similar 10% to 15% survival benefit when chemotherapy was added to radiation. By 1990, postoperative long-course CMT became the standard adjuvant treatment for cT3 and or node-positive rectal cancer.2 The significant improvement in local control, toxicity, and sphincter preservation reported with preoperative versus postoperative long-course CMT reported in the German CAO/ARO/AIO Rectal Cancer Trial changed the standard of care for patients with cT3 and/or node-positive rectal cancer to preoperative CMT in 2004.3 Short-course radiation was not pursued given its lack of sphincter preservation and the inability to safely combine it with adequate doses of systemic chemotherapy (Table 1).

Short-Course Radiation There are 11 modern randomized trials of short-course radiation therapy versus surgery alone for resectable rectal cancer. They use low to moderate doses of radiation, 500 cGy/ fraction for 1 to 5 fractions followed by surgery 1 week later. Most of the trials report a decrease in local recurrence. The only trial that revealed a significant improvement in survival by intent to treat was the Swedish Rectal Cancer Trial.4 With long-term follow-up (13 years), the benefits in local control (9% vs 26%, P ⬍ .001) and survival (38% vs 30% P ⫽ .008) were maintained.5 However, it must be emphasized that

Chemoradiation in the treatment of rectal cancer Table 1 Preoperative Treatment for Rectal Cancer: ShortCourse Versus Long-Course Chemoradiation

Eligible clinical stage In randomized trials Interval from radiation to surgery Radiation techniques Sphincter preservation Chemotherapy

Threatened margins seen on MRI Improved local control Improved survival vs surgery alone

Short Course

Long Course

CT1-3Nx

C3-4 and/or Nⴙ

5d Multiple field No

4-8 wk Multiple field Yes

No but sequential Is possible Exclusion criteria Yes

Concurrent

Only 1 of 11 positive Trials

Inclusion criteria Yes Yes (adjuvant)

none of the other 10 trials, including the Dutch CKVO trial,6 revealed a survival benefit. Although early trials of short-course radiation revealed a significant increase in mortality,7 it was not seen in the Swedish Rectal Cancer Trial, the Dutch CKVO, and other more modern trials. This may have been related to the change to the use of multiple-field techniques similar to those used in preoperative long-course CMT trials. Most short-course radiation trials reported a high incidence of perineal wound sepsis. It was as high as 33% in the Uppsala trial.8 However, this was likely related to the failure to exclude the perineum from the radiation field. The lack of sphincter preservation with short-course radiation may be related to the limited interval (5 days) between the completion of radiation and surgery. The results of the Lyon R90-01 trial support a longer interval (at least 4 weeks) between the completion of radiation and surgery.9 A total of 201 eligible patients were randomized to either a short interval (2 weeks) or a long interval (6-8 weeks). Patients randomized to the long interval had a significantly higher incidence of clinical complete response (pCR and/or a few residual foci of cells: 26% vs 10%, P ⫽ .0054) with no increase in operative morbidity. The Stockholm III trial will determine whether increasing this interval improves the incidence of sphincter preservation. In this 3-arm randomized trial, patients are randomized to 5 Gy ⫻ 5 followed by surgery 1 week later, 5 Gy ⫻ 5 followed by surgery 4 weeks later, and 2 Gy ⫻ 25 followed by surgery 4 weeks later. The results are pending. Although short-course radiation therapy is used in some European countries, it is not favored in all European countries or North America because it cannot be safely combined with adequate doses of systemic concurrent chemotherapy, and, as currently designed, it does not increase sphincter preservation.

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Randomized Trials of Short-Course Versus Long-Course CMT Intertrial comparisons of short-course radiation and longcourse CMT are not possible because the eligibility criteria vary. Patients with cT1-3 disease are eligible for short-course radiation trials, whereas long-course CMT trials are limited to patients with cT3 and/or node-positive disease. Two randomized trials of preoperative short-course radiation versus long-course CMT have been reported. Bujko et al10,11 randomized 316 patients with adenocarcinomas above the anorectal ring. TME was performed for distal tumors, and there was no radiation quality-control review. For the total group, there were no significant differences in local control or survival. The incidence of positive circumferential radial margins (circumferential radial margin [CRM]⫹) was lower after long-course CMT compared with short-course radiation (4% vs 13%, P ⫽ .017). A similar trial from Australia and New Zealand was reported by Ngan et al.12 A total of 326 patients with T3Nany rectal cancer (56% were N0) were randomized to shortcourse radiation versus long-course CMT. In contrast to the trial from Bujko et al10,11, patients were scheduled to receive postoperative adjuvant chemotherapy. There was no significant differences in 3-year local recurrence (8% vs 4%) or 5-year survival (74% vs 70%), respectively. The preliminary results of these trials challenge the role of long- course CMT in selected patients. However, they clearly need to be examined in perspective. Neither trial was limited to patients with N⫹ disease, and both require longer-term follow-up. Another key result that has not been presented is sphincter function. Because short-course radiation cannot be safely combined with systemic chemotherapy, some investigators have examined sequential treatment. In a series from the Netherlands, van Dijk et al13 enrolled 50 patients with primary rectal cancer and synchronous resectable metastasis in 1 or 2 organs (liver 42, lung 5, both 3) on a phase II trial of short-course radiation followed by 6 cycles of capecitabine/oxaliplatin (CAPOX) ⫹ bevacizumab (restaging after 2 cycles) and resection of the primary and resection and/or ablation of the metastasis.13 The median time between the completion of radiation and chemotherapy was 11 days (3-44 days). They reported “no toxicity” during radiation. Of the 41 patients brought to surgery, 44% achieved a tumor regression grade of 0 to 2. This approach needs to be prospectively tested in the adjuvant setting.

Experience and Emerging Controversies With Long-Course Chemoradiation Sphincter Preservation There is some debate as to the impact of preoperative longcourse CMT on sphincter preservation. The ideal method to

B.D. Minsky

230 determine if a treatment has an impact on sphincter preservation is for the operating surgeon to examine the patient before treatment and declare the type of operation which they predict will be necessary. The 2 randomized trials of preoperative versus postoperative CMT for clinically resectable rectal cancer used this pretreatment assessment and reported contradictory results. In the German rectal trial, there was a significant increase in sphincter preservation (39% vs 20%, P ⫽ .004).3 The trial was also stratified by surgeon, further increasing its strength in assessing sphincter preservation. In contrast, in the NSABP R-03 trial, there was no significant improvement in sphincter preservation (48% vs 39%).14 The difference in results between the NSABP and the German trial are likely because in the NSABP trial only 267 of the 900 planned patients were accrued, thereby limiting the statistical power to detect differences. Therefore, the German trial remains the definitive trial, and preoperative CMT for patients with cT3 and/or N⫹ disease is the standard of care.

Time to Recurrence In patients treated in the adjuvant setting for rectal cancer, local control and survival rates continue to decrease beyond 5 years.15 After postoperative long-course CMT, the 5-year rates of local recurrence and survival were 14% and 64%, respectively, and continued to increase at 7 years (17% and 56%, respectively).15 Results with preoperative long-course CMT are pending. These data underscore the importance of long follow-up in adjuvant rectal cancer trials.

Clinical Staging The most accurate tools in predicting T stage are transrectal ultrasound and high-resolution magnetic resonance imaging (MRI). Ultrasound is used commonly in the United States, whereas many European investigators prefer MRI. T stage is predicted accurately in approximately 50% to 90% of patients with ultrasound16 or high-resolution MRI17 and 50% to 70% with computed tomography scanning or conventional MRI.18 High-resolution MRI can identify patients likely to have close or positive (threatened) CRM before surgery. In some European centers, it is used to select patients for preoperative CMT.17 Those without threatened CRM may be selected to receive short-course radiation. The accurate identification of lymph nodes is more difficult. Overall, the accuracy in detecting positive pelvic lymph nodes with the previously described techniques is approximately 50% to 75%. MRI is similar to computed tomography scanning and is improved using external and/or endorectal coils. The ability to accurately predict the pathologic stage after preoperative CMT with MRI,19,20 ultrasound,21 FDGPET,22 or physical examination23 remains suboptimal. Overstaging can occur. Phased-array MRI is helpful in preoperatively predicting patients who will have ypT0-2 versus ypT3 disease.24 Both diffusion-weighted MRI and FDG-PET have been used to monitor therapeutic response and to predict outcome to preoperative therapy. There is a decrease in SUV on postradiation FDG-PET scans in responders when

compared with nonresponders, but the clinical value of this information remains to be determined.25

Is Pelvic Radiation Necessary for All Patients? Not all patients with T3 disease require CMT.26,27 Those who undergo a TME, have at least 12 nodes examined, and have stage pT3N0 disease likely do not need CMT. In this setting, the limited benefit in local control with radiation (3%-4%) may not be worth the toxicity. However, patients with pT3N0 tumors with either adverse pathologic features, resected without a TME, or who had fewer than 12 nodes examined should still receive postoperative CMT. The preoperative identification of patients with lymph node–positive disease remains a challenge. At the present time, neither imaging nor clinicopathologic factors can reproducibly identify lymph node–positive disease.28 The tumor regression grade may be helpful.29 The development of more accurate methods to identify lymph node–positive disease, including improved imaging techniques and/or molecular markers, are essential to reduce under- and overtreatment. For example, 18% of patients in the German trial clinically staged as cT3N0 undergoing initial surgery without preoperative therapy had pT1-2N0 disease. Those patients would have been overtreated had they received preoperative therapy. However, preoperative therapy is still preferred to performing surgery first given that even after preoperative CMT (which downstages tumors) in clinically staged T3N0 patients, Guillem et al30 reported that 22% will have ypN⫹ disease at the time of surgery. In patients who undergo surgery without preoperative CMT, this number is as high as 40%.31 These patients would then receive postoperative CMT, which, compared with preoperative CMT, has higher rates of local recurrence, acute and chronic toxicity, and, if a low anastomosis is performed, inferior functional results. Given the improvements in systemic chemotherapy, there may be an opportunity to use preoperative long-course CMT more selectively. Cercek et al32 treated 32 selected patients with uT2N1 or uT3N0-1 rectal cancer who did not require an APR by preoperative assessment with neoadjuvant FOLFOX ⫹ bevacizumab. Pelvic radiation was reserved for those patients who progressed preoperatively or postoperatively had T4, N2, or positive margins. Of 30 patients who underwent low anterior resection (LAR) none required radiation, the pCR rate was 27%, and 2 required postoperative radiation. This chemotherapy-alone approach remains investigational and requires validation in a larger study and long-term local control and survival outcomes.

Distance From the Anal Verge There are no prospective randomized data examining the impact of the distance from the anal verge on local recurrence.33 Most are subset analysis from randomized trials that were not stratified by distance. In addition, other variables such as the type of surgery, the definition of high rectal can-

Chemoradiation in the treatment of rectal cancer cer, and the technique of measurement may influence these outcomes. By univariate analysis, “high” tumors in both the Dutch CKVO6 and Swedish trial4 (defined as ⬎10.1 cm and 11 cm from the anal verge, respectively) had a lower incidence of local recurrence compared with mid and lower tumors. Short-course radiation did not significantly decrease local recurrence in these cohorts. In contrast, there was no significant difference between mid and upper tumors in the German trial.34 Although specific data were not provided, patients with tumors above 6 cm from the anal verge versus less than 6 cm had a lower local recurrence rate (Roedel C., personal communication 2010). Given the conflicting data combined with the data from Guillem et al confirming that the incidence of ypN⫹ disease after preoperative long-course CMT is similar from 0 to 12 cm from the anal verge,30 treatment decisions based on the current definitions of low versus mid versus high rectal cancers should not be used.

Positive Circumferential Margins The CRM also has an impact on local recurrence rates.35 In the Dutch CKVO trial, 17% of patients were CRM⫹. In a subset analysis by Nagtegaal et al,36 patients with CRM⫹ who underwent TME alone had local recurrence rate of 17% after an LAR and 30% after an APR. Unfortunately, few centers perform the necessary pathologic examination to appropriately identify CRM status.37 High-resolution MRI can help predict (preoperatively) patients who will have CRM⫹ as well as select those who may benefit from preoperative therapy.38-40 An involved CRM after any preoperative treatment is an unfavorable prognostic sign. In patients who receive longcourse CMT, Baik et al41 reported that patients with an involved CRM had higher local recurrence (35% vs 11%) and decreased survival rates (27% vs 73%). The series from Nagtegaal et al35 reported inferior survival in patients with an involved CRM after neoadjuvant treatment (with either short-course or long-course CMT) compared with immediate surgery (hazard ratio ⫽ 6.3; 95% confidence interval, 3.716.7 vs hazard ratio ⫽ 2.0; 95% confidence interval, 1.4-2.9, respectively). Postoperative treatment also has a limited ability to compensate for an involved CRM. In the MRC CR-07 trial, patients with a positive CRM who were selected to receive postoperative long-course CMT had an 11% local recurrence rate.42 Likewise, in a subset analysis of the Dutch CKVO trial, postoperative long-course radiation alone did not compensate for an involved CRM.43

Is Radical Surgery Necessary After Preoperative Therapy? One series has questioned the value of radical surgery in patients who had a biopsy-proven clinical complete response.44 However, it included patients with cT1-3 disease and has not been reproduced by other investigators. For patients with cT3-4 disease treated with preoperative long-

231 course CMT, radical surgery is still necessary to accurately identify the degree of pathologic downstaging. Neither posttreatment ultrasound45,21 nor physical examination46 are sufficient. Diffusion MRI47 is being investigated. A review of 218 phase II and 28 phase III trials of preoperative short-course radiation or long-course CMT confirmed that the clinical and/or radiologic response does not sufficiently correlate with pathologic response, with the authors recommending against a “wait and see” approach to surgery after preoperative therapy.48 Experience with preoperative long-course CMT followed by local excision is more limited. Most series select patients with cT3 disease who were either medically inoperable or refused radical surgery. Local recurrence rates range from 0% to 20%, and 5-year survival ranges from 78% to 90%. Borschitz et al49 reported local recurrence rates by pathologic stage as follows: ypT1: 2% and ypT2: 6% to 20% using this approach. Local recurrence rates were as high as 43% in ypT3 tumors that did not respond to CMT. The ACOSOG Z6041 phase II trial enrolled 77 patients with cT2N0 disease who were with treated with preoperative CAPOX-based longcourse CMT.50 The pCR rate was 43%. Local recurrence and survival results are pending. A similar trial (GRECCAR 2) will accrue 300 patients with cT2-3 disease.

Induction Chemotherapy The Spanish GCR-3 randomized phase II trial compared the use of induction chemotherapy with conventional preoperative long-course CMT followed by surgery and postoperative chemotherapy.51 A total of 108 patients received 50.4 Gy plus CAPOX preoperatively and were randomized to receive 4 months of CAPOX either by induction or adjuvantly (postoperative). Although the pCR rates were similar (14% vs 13%) with induction CAPOX, grade 3⫹ toxicity was lower (17% vs 51%, P ⫽ .00004), and the ability to deliver all 4 chemotherapy cycles was higher (93% vs 51%, P ⫽ .0001). This approach is now being investigated in a phase III trial.

Advances With Chemoradiation Regimens Standard long-course CMT regimens include either continuous infusion 5-FU or capecitabine. However, if the NSABP R-04 trial (which is comparing preoperative long-course CMT with continuous infusion 5-FU with capecitabine, with or without oxaliplatin) reveals capecitabine is inferior, this recommendation would need to be reevaluated. Both cytotoxic and targeted chemotherapeutic agents have been incorporated into long-course CMT programs, most commonly in the preoperative setting. Most of the regimens report higher pCR rates compared with 5-FU alone. However, for some, this is associated with an increase in acute toxicity. Despite promising phase I/II data, two-phase III adjuvant trials reported no benefit with the addition of oxaliplatin to preoperative long-course CMT. The STAR-01 trial (50.4 Gy ⫹ continuous infusion 5-FU, with or without oxaliplatin)52 and the ACCORD trial (50 Gy ⫹ CAPOX vs 45 Gy ⫹ capecitabine)53 reported similar increases in acute toxicity (24%

B.D. Minsky

232 vs 8%, P ⬍ .001, and 25% vs 11%, P ⬍ 0.001, respectively) with no corresponding increase in pCR rates. A similar question is being addressed in 3 ongoing phase III trials: NSABP04, CAO/ARO/AIO-04, and the PETACC-6. Although a study from Heidelberg with capecitabine/irinotecan reported a pCR rate of 25%,54 other trials with 5-FU, capecitabine, or CAPOX have more limited pCR rates of 5% to 12%.54,55 The data with cetuximab-based long-course CMT are disappointing.55,56 Whether selecting patients with wild-type KRAS will be helpful in the adjuvant rectal setting is unknown.57

Prediction of Tumor Response Although some series show no correlation,58 most series suggest that there is improved outcome with increasing pathologic response after preoperative long-course CMT.59,60 Capirici et al61 reported a retrospective review of 566 patients treated at multiple European centers who achieved a pCR after receiving a variety of long-course CMT regimens. With a median follow-up of 46 months, the local recurrence rate was only 1.6%, and the 5-year disease free and overall survival rates were 85% and 90%, respectively. Analysis of biopsies examining selected molecular markers have had varying success in helping to select patients who may best respond to preoperative therapy.62-64

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References 1. Minsky BD, Welton M, Venook A: Cancer of the rectum, in Hoppe RT, Phillips TL, Roche M (eds): Leibel and Phillips Textbook of Radiation Oncology. Philadelphia, PA Elsevier, 2010, 851-869 2. National Institutes of Health, Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer. JAMA 264:1444-1450, 1990 3. Sauer R, Becker H, Hohenberger P, et al: Preoperative chemoradiotherapy as compared with postoperative chemoradiotherapy for locally advanced rectal cancer. N Engl J Med 351:11-20, 2004 4. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-987, 1997 5. Folkesson J, Birgisson H, Pahlman L, et al: Swedish rectal cancer trial: Long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 23:5644-5650, 2005 6. Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001 7. Holm T, Rutqvist LE, Johansson H, et al: Postoperative mortality in rectal cancer treated with or without preoperative radiotherapy: Causes and risk factors. Br J Surg 83:964-968, 1996 8. Frykholm GJ, Glimelius B, Pahlman L: Preoperative or postoperative irradiation in adenocarcinoma of the rectum: Final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 36:564-572, 1993 9. Francois Y, Nemoz CJ, Baulieux J, et al: Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: The Lyon R90-01 randomized trial. J Clin Oncol 17:2396-2402, 1999 10. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al: Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomized trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol 72:15-24, 2004 11. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al: Long term results of a randomized trial comparing preoperative short-course radiotherapy

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with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93:1215-1223, 2006 Ngan S, Fischer R, Goldstein D, et al: A randomized trial comparing local recurrence (LR) rates between short course (SC) and long course (LC) radiotherapy (RT) for clinical T3 rectal cancer: An Intergroup (TROG, AGITG, CSSANZ, RACS). Proc Am Soc Clin Oncol 28:15s, 2010 van Dijk TH, Havenga K, Beukema J, et al: Short-course radiation therapy, neoadjuvant bevacizumab, capecitabine and oxaliplatin, and radical resection of primary tumor and metastasis in primary stage IV rectal cancer: A phase II multicenter study of the Dutch Colorectal Cancer Group. Proc Am Soc Clin Oncol 28:295s, 2010 Roh MS, Colangelo LH, O’Connell MJ, et al: Pre-operative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum (NSABP-R-03). J Clin Oncol 27:5124-5130, 2009 Tepper JE, O’Connell MJ, Niedzwiecki D, et al: Adjuvant therapy in rectal cancer: Analysis of stage, sex, and local control—Final report of Intergroup 0114. J Clin Oncol 20:1744-1750, 2002 Barbaro B, Valentini V, Coco C, et al: Tumor vascularity evaluated by transrectal color Doppler US in predicting therapy outcome for lowlying rectal cancer. Int J Radiat Oncol Biol Phys 63:1304-1308, 2005 Salerno GV, Daniels IR, Moran BJ, et al: Magnetic resonance imaging prediction of an involved surgical resection margin in low rectal cancer. Dis Colon Rectum 52:632-639, 2009 Kim NK, Kim MJ, Park JK, et al: Preoperative staging of rectal cancer with MRI: Accuracy and clinical usefulness. Ann Surg Oncol 7:732737, 2000 Kim YH, Kim DY, Kim TH, et al: Usefulness of magnetic resonance volumetric evaluation in predicting response to preoperative concurrent chemoradiotherapy in patients with resectable rectal cancer. Int J Radiat Oncol Biol Phys 62:761-768, 2005 Kuo LJ, Chern MC, Tsou MH, et al: Interpretation of magnetic resonance imaging for locally advanced rectal carcinoma after preoperative chemoradiation therapy. Dis Colon Rectum 48:23-28, 2005 Barbaro B, Schulsinger A, Valentini V, et al: The accuracy of transrectal ultrasound in predicting the pathological stage of low-lying rectal cancer after preoperative chemoradiation therapy. Int J Radiat Oncol Biol Phys 43:1043-1047, 1999 Kristiansen C, Loft A, Berthelsen AK, et al: PET/CT and histopathologic response to preoperative chemoradiation therapy in locally advanced rectal cancer. Dis Colon Rectum 51:21-25, 2008 Guillem JG, Chessin DB, Shia J, et al: Clinical examination following preoperative chemoradiation for rectal cancer is not a reliable surrogate endpoint. J Clin Oncol 23:3475-3479, 2005 Barbaro B, Fiorucci C, Tebala C, et al: Locally advanced rectal cancer: MR imaging in prediction of response after preoperative chemotherapy and radiation therapy. Radiology 250:730-739, 2009 Calvo FA, Domper M, Matute R, et al: 18F-FDG positron emission tomography staging and restaging in rectal cancer treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 58:528-535, 2004 Nissan A, Stojadinovic A, Shia J, et al: Predictors of recurrence in patients with T2 and early T3, N0 adenocarcinoma of the rectum treated with surgery alone. J Clin Oncol 24:4078-4084, 2006 Green FL, Stewart AK, Norton HJ: New tumor-node-metastasis staging system for node-positive (stage III) rectal cancer: An analysis. J Clin Oncol 22:1778-1784, 2004 Kim JH, Beets GL, Kim MJ, et al: High-resolution MR imaging for nodal staging in rectal cancer: Are there any criteria in addition to the size? Eur J Radiol 52:78-83, 2004 Rengan R, Paty P, Wong WD, et al: Distal cT2N0 rectal cancer: Is there an alternative to abdominoperineal resection? J Clin Oncol 23:49054912, 2005 Guillem JG, Diaz-Gonzalez J, Minsky BD, et al: cT3N0 rectal cancer: Potential overtreatment with preoperative chemoradiotherapy is warranted. J Clin Oncol 26:368-373, 2008 Mendenhall WM, Bland KI, Rout WR, et al: Clinically resectable adenocarcinoma of the rectum treated with preoperative irradiation and surgery. Dis Colon Rectum 31:287-290, 1988

Chemoradiation in the treatment of rectal cancer 32. Cercek A, Weiser MR, Goodman KA, et al: Complete pathologic response in the primary of rectal or colon cancer treated with FOLFOX without radiation. Proc Am Soc Clin Oncol 28:15s, 2010 33. Rosenberg R, Maak M, Schuster T, et al: Does a rectal cancer of the upper third behave more like a colon or a rectal cancer? Dis Colon Rectum 53:761-770, 2010 34. Sauer R, Roedel C: The author’s reply. N Engl J Med 352:510-511, 2005 35. Nagtegaal ID, Quirke P: What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 26:303-312, 2008 36. Nagtegaal ID, van de Velde CJH, Marijnen CAM, et al: Low rectal cancer: A call for a change of approach in abdominoperineal resection. J Clin Oncol 23:9257-9264, 2005 37. Guillem JG, Chessin DB, Shia J, et al: A prospective pathologic analysis using whole mount sections of rectal cancer following preoperative combined modality therapy. Implications for sphincter preservation. Ann Surg 245:88-93, 2007 38. Branagan G, Chave H, Fuller C, et al: Can magnetic resonance imaging predict circumferential margins and TNM stage in rectal cancer? Dis Colon Rectum 47:1317-1322, 2004 39. Burton S, Brown G, Daniels I, et al: MRI identified prognostic features of tumors in distal sigmoid, rectosigmoid, and upper rectum: Treatment with radiotherapy and chemotherapy. Int J Radiat Oncol Biol Phys 65:445-451, 2006 40. Rutten H, Sebag-Montefiore D, Glynne-Jones R, et al: Capecitabine, oxaliplatin, radiotherapy, and excision (CORE) in patients with MRIdefined locally advanced rectal adenocarcinoma: Results of an international multicenter phase II study. Proc Am Soc Clin Oncol 24:153s, 2006 41. Baik SH, Kim NK, Lee YC, et al: Prognostic significance of circumferential resection margin following total mesorectal excision and adjuvant chemoradiotherapy in patients with rectal cancer. Ann Surg Oncol 14:462-469, 2007 42. Sebag-Montefiore D, Stephens RJ, Steele R, et al: Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicenter, randomised trial. Lancet 373:811-820, 2009 43. Marijnen CAM, Nagtegaal ID, Kapiteijn E, et al: Radiotherapy does not compensate for positive resection margins in rectal cancer patients: Report of a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55:1311-1320, 2003 44. Habr-Gama A, Perez RO, Nadalin W, et al: Operative vs. nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long term results. Ann Surg 240:711-718, 2004 45. Gavioli M, Bagni A, Piccagli I, et al: Usefulness of endorectal ultrasound after preoperative radiotherapy in rectal cancer. Dis Colon Rectum 43:1075-1083, 2000 46. Hiotis SP, Weber SM, Cohen AM, et al: Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: An analysis of 488 patients. J Am Coll Surg 194:131-136, 2002 47. Dzik-Jurask A, Domenig C, George M, et al: Diffusion MRI for prediction of response of rectal cancer to chemoradiation. Lancet 360:307308, 2002 48. Glynne-Jones R, Wallace M, Livingstone JI, et al: Complete clinical response after preoperative chemoradiation in rectal cancer: Is a “wait and see” policy justified? Dis Colon Rectum 51:10-20, 2008 49. Borschitz T, Wachtlin D, Mohler M, et al: Neoadjuvant chemoradiation and local excision for T2-3 rectal cancer. Ann Surg Oncol 15:712-720, 2008

233 50. Garcia-Aguilar J, Shi Q, Thomas CR, et al: Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) of uT2UN0 rectal cancer (RC) treated by local excision (LE). Results of the ACOSOG Z6041 trial. Proc Am Soc Clin Oncol 28:15s, 2010 51. Fernandez-Martos C, Aparicio J, Salud A, et al: Multicenter randomized phase II study of chemoradiation (CRT) followed by surgery (S) and chemotherapy (CT) versus induction chemotherapy followed by CRT and S in high-risk rectal cancer: GCR-3 final efficacy and safety results. Proc Am Soc Clin Oncol 27:4103, 2009 52. Aschele C, Pinto C, Cordio S, et al: Preoperative fluorouracil (FU) based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adjuvante Retto (STAR)-01 randomized phase III trial. Proc Am Soc Clin Oncol 27:804s, 2009 53. Gerard JP, Azria D, Gourgou-Bourgade S, et al: Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: Results of the phase III Accord 12/0405 PRODIGE 2. J Clin Oncol 28:1638-1644, 2010 54. Hofheinz RD, von Gerstenberg-Helldorf B, Wenz F, et al: Phase I trial of capecitabine and weekly irinotecan in combination with radiotherapy for neoadjuvant therapy of rectal cancer. J Clin Oncol 23:1350-1357, 2005 55. Rodel C, Arnold D, Hipp M, et al: Phase I–II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys 70:1081-1086, 2008 56. Chung KY, Minsky B, Schrag D, et al: Phase I trial of preoperative cetuximab with concurrent contiuous infusion 5-fluorouracil and pelvic radiation in patients with local-regionally advanced rectal cancer. Proc Am Soc Clin Oncol 24:161s, 2006 57. van Cutsem E, Lang I, D’haens G, et al: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Proc Am Soc Clin Oncol 26:1006s, 2008 58. Stein DE, Mahmoud NN, Anne PR, et al: Longer time interval between completion of neoadjuvant chemoradiation and surgical resection does not improve downstaging of rectal carcinoma. Dis Colon Rectum 46: 448-453, 2003 59. Valentini V, Coco C, Picciocchi A, et al: Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long term analysis of 165 patients. Int J Radiat Oncol Biol Phys 53:664-674, 2002 60. Guillem JG, Chessin DB, Cohen AM, et al: Long term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 241:829838, 2005 61. Capirci C, Valentini V, Cionini L, et al: Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: Long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 72:99-107, 2008 62. Bertolini F, Bengala C, Losi L, et al: Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys 68:1455-1461, 2007 63. Unsal D, Under A, Akyuerk N, et al: Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 67:196-203, 2007 64. Johnston PG: Prognostic markers of local relapse in rectal cancer: Are we any further forward? J Clin Oncol 24:4049-4050, 2006

Nonoperative Approaches to Rectal Cancer: A Critical Evaluation Angelita Habr-Gama, MD, PhD,* Rodrigo O. Perez, MD, PhD,*,† Guilherme P. São Julião, MD,† Igor Proscurshim, MD,‡ and Joaquim Gama-Rodrigues, MD, PhD* A neoadjuvant multimodality approach with chemoradiation therapy (CRT) is the preferred treatment strategy for most distal rectal cancers. Significant downstaging and complete pathologic response may develop after this strategy, and there is still controversy regarding the management of these patients. In this setting, a nonoperative approach has been suggested in select patients with complete clinical response after thorough clinical, endoscopic, and radiologic assessment. However, the assessment of these patients is not straightforward and remains complex. Available data regarding this approach are limited to a single institution’s experience from retrospective analyses. Standardization of the assessment of tumor response and the development of radiological/molecular tools may clarify the role of no immediate surgery in patients with complete clinical response after neoadjuvant CRT. Advances in radiation and medical oncology could potentially lead to significant improvements in complete tumor regression rates, leading to an increase in importance of a minimally invasive approach in patients with rectal cancer. Semin Radiat Oncol 21:234-239 © 2011 Elsevier Inc. All rights reserved.

A

neoadjuvant multimodality approach has become the preferred treatment strategy for locally invasive rectal cancer. A significant improvement in local disease control, even after an optimal surgical technique using total mesorectal excision, has been observed after neoadjuvant therapy using a variety of chemoradiation or even radiation alone regimens.1-3 In addition to improvements in local disease control, neoadjuvant therapy may lead to significant tumor regression as reflected by decrease in tumor size (downsizing) as well as a shift toward earlier disease stage (downstaging) both in the primary tumor (T status) and perirectal nodes (N status).1-4 In a proportion of these patients, complete tumor regression may result, and radical surgery provides a specimen without any residual cancer cells (complete pathologic response). Considering the fact that total mesorectal excision and proctectomy are associated with significant morbidity and mortality rates in addition to disorders in urinary, fecal, and sexual function, alternative treatment *Angelita and Joaquim Gama Research Institute, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil. †Colorectal Surgery Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil. ‡Department of General Surgery, University of São Paulo School of Medicine, São Paulo, Brazil. Address reprint requests to Angelita Habr-Gama, MD, PhD, Rua Manuel da Nóbrega, 1564, São Paulo, SP 04001-005, Brazil. E-mail: [email protected]

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strategies have been suggested in patients with significant or complete tumor regression after neoadjuvant chemoradiation therapy (CRT).5,6

Complete Tumor Regression Several factors have been implicated in the prediction of complete pathologic response development after neoadjuvant CRT. A review of phase II and III studies using different regimens of neoadjuvant CRT for rectal cancer identified several predictive factors of a complete pathologic response, including the dose of radiation therapy delivered, the method of 5-fluorouracil (5-FU) infusion, and the use of additional drugs to standard 5-FU– based regimens. After reviewing 71 studies with over 4,000 patients treated with different regimens, the complete pathologic response ranged from 0% to 42% and was significantly associated with the delivery of ⬎45 Gy radiation therapy, continuous infusion of 5-FU regimens, and the use of a second drug, most frequently oxaliplatin.7 The addition of chemotherapy to radiation in the neoadjuvant setting has been shown not only to impact local disease control (ie, lower recurrence rates) but also to improve the effects of tumor downstaging.7 In a randomized trial of patients undergoing RT with or without 5-FU– based chemotherapy, patients in the CRT group more frequently achieved a complete pathologic response, had less risk of lymph node

Nonoperative approaches to rectal cancer

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metastases, and less risk of vascular invasion seen in the resected specimens. Additionally, patients treated by CRT also had fewer lymph nodes recovered in the resected specimens and decreased tumor size.8,9 Despite the suggestion that the use of additional drugs (other than 5-FU) could enhance tumor response to CRT, recently reported results from a prospective randomized trial showed that the addition of oxaliplatin to a 5-FU– based CRT regimen was not associated with improved rates of pathological complete response (pCR). In turn, patients treated with oxaliplatin experienced significantly more treatment-related toxicities.10 Finally, the downstaging effect of neoadjuvant CRT seems to be a time-dependent effect. Even though patients who undergo short-course radiation therapy followed by radical surgery 1 week after radiation therapy completion benefit in terms of improved local disease control, these patients develop very limited tumor downstaging and low rates of complete tumor response. Considering that the biological doses are roughly equivalent between short-course (5x5Gy) and long-course (50.4 Gy) strategies, a major difference between these 2 approaches is the interval between radiation therapy completion and surgery.11 In this setting, alternative treatment strategies using short-course RT regimens have been combined with “long” interval periods (6-8 weeks) to obtain downstaging of initially “unresectable” tumors.12 In fact, retrospective analysis of patients undergoing neoadjuvant CRT identified a longer interval between CRT completion and surgery as being associated with increased rates of complete pathologic response and improved oncologic outcomes.13-15

Tumor Response Assessment The efforts in identifying patients with tumors undergoing complete regression are important because the achievement of such is associated with excellent oncologic outcomes. Additionally, alternative treatment strategies, other than radical total mesorectal excision, may suffice in these patients.16 A major obstacle is that complete pathologic response can only be determined after full pathologic examination of the resected specimen after TME. In this setting, response assessment of tumors undergoing neoadjuvant CRT becomes crucial, and, ideally, clinical identification of patients with complete tumor regression would allow precise selection of patients in whom resection and total mesorectal excision could be avoided.17 Considering tumor response to CRT is a time-dependent effect, assessment should ideally be performed at least 8 weeks after RT completion. The assessment of the response at 4 to 6 weeks could potentially identify patients with residual disease who would eventually develop complete tumor regression at a later time point. There is no single test capable of identifying patients with complete tumor regression. However, a combination of clinical, endoscopic, and radiologic findings may provide sufficient information in identifying patients with a high suspicion for a complete pathologic response to neoadjuvant CRT (complete clinical response) (Fig 1). In such patients, available data suggest that there is

Figure 1 An endoscopic view of the (A) initial tumor before and (B) 8 weeks after chemoradiation completion showing a complete clinical response.

very little risk in performing no immediate surgery in terms of oncologic outcomes.18 The limitation to this approach is related to the potentially poor correlation between clinical and pathologic findings. In fact, one study analyzed the predictive value of clinical assessment in patients with rectal cancer after neoadjuvant CRT. A total of 488 patients with cT3/4 or N⫹ rectal cancer who underwent neoadjuvant CRT were assessed for tumor response within 1 week before surgical resection, usually performed at 6 weeks from CRT completion. Surprisingly, 75% of the patients thought to have a complete clinical response had incomplete pathologic response at the time of resection. However, several potential limitations of this study should be considered. First, tumor response assessment at 5 weeks from CRT completion could potentially be too early,

236 and some patients with incomplete response at this time point could have developed complete tumor regression if longer intervals had been used. Also, the number of surgeons assessing response result in for interobserver variability, a fact that could have been significant, considering the potential differences in expertise and previous experience of each attending surgeon involved in the study. Finally, the lack of a standardized definition of what constituted a complete clinical response between each attending physician could have contributed to discrepant results.19 Another study, with a limited number of patients, evaluated no immediate surgery in the presence of a “complete clinical response.” This study showed disappointing results, with a ⬎80% rate of recurrence or regrowth, leading to radical surgery. Again, the lack of standardization of a complete clinical response and interobserver variability could have accounted for such results.20 Given this, the recognition of a complete clinical response may be very challenging, even for the experienced colorectal surgeon. Even though there have been attempts for standardization of clinical, endoscopic, and other radiologic findings, recognition of this entity may require significant and specific training and expertise. It is likely that this complex process of assessing tumor response to neoadjuvant CRT may be associated with a learning curve, such as the one observed for many complex surgical procedures. Therefore, proficiency in this approach may require a significant amount of time, case volume, and practice. Interestingly, in a more recent study of patients with cT2N0 rectal cancer undergoing neoadjuvant therapy using oxaliplatin and capecitabine, 44% of patients showed a complete pathologic response after a full-thickness local excision. Of these patients with pCR in this study, 80% also had a complete clinical response, showing a significant improvement in the association between cCR and pCR.21 Another limitation in avoiding total mesorectal excision in patients with a complete clinical response is the risk of leaving lymph node metastases despite complete primary tumor regression. It has been shown that even in ypT0 rectal cancers treated by total mesorectal excision, the risk of lymph node metastases or mesorectal deposits may range from 0% to 12%.22-24 However, more contemporary studies using longer interval periods between CRT completion and surgery (usually more than 7-8 weeks from CRT) have reported such risk of metastatic disease to be under 5%.25-28 In this setting, assessing nodal response to neoadjuvant CRT is somewhat more complicated. The histologic absence of nodal disease (ypN0) in the presence of complete primary tumor regression is perhaps the best tool in assessing nodal disease. In the nonoperative setting, radiologic studies are crucial to rule out any obvious residual nodal disease, despite the finding of a complete clinical primary tumor response. However, the problem is that nodal accuracy of radiologic studies are somewhat disappointing, particularly in the setting of neoadjuvant CRT.29-31 Neoadjuvant CRT not only decreases the overall number of nodes but also leads to a significant decrease in their size,

A. Habr-Gama et al often rendering such nodes unevaluable by standard radiologic imaging techniques. In this setting, improvements in radiologic techniques for nodal assessment could potentially impact the risk of nodal recurrence/persistence in patients with complete clinical response.32 The observation that there is no survival benefit after radical surgery in patients with complete pathologic response when compared with patients achieving complete clinical response undergoing serial observation is striking.33 Even though it seems intuitive that there are few benefits in removing the rectum after clinical complete response after neoadjuvant CRT, accurate preoperative identification of such patients is still very challenging and complex. Also, even when patients were mistakenly diagnosed as achieving a complete clinical response and ultimately required surgery that was delayed, there did not seem to be a compromise in terms of outcomes.18 In fact, this concept has been suggested not only in patients who were considered to have a complete clinical response, but also in patients who were operated on at longer intervals because of other reasons, including institutions in which the watch and wait approach would never be considered.15 These patients may represent a distinct subgroup of patients with a probable near-complete response in whom there was difficulty in assessing the presence of residual cancer (or perhaps misdiagnosis) and ultimately underwent delayed radical surgery. Patients who do not sustain an arbitrary 12-month period free of local failure probably represent an inability to accurately assess gross tumor response. There is the possibility that this subgroup of patients who were mistakenly diagnosed as achieving a complete clinical response will decrease in frequency with experience and improvements in assessment of tumor response. Additionally, the use of very stringent criteria for the selection of patients who are candidates for a no immediate surgery approach will also help minimize such misdiagnoses. There is also another subgroup of patients managed by observation alone for a long period of time who ultimately develop disease recurrence and require salvage resection. In an effort to improve and increase complete tumor regression rates after neoadjuvant CRT, new regimens have been studied in the treatment of rectal cancer, including patients with earlier disease staging, such as T2N0 disease.34 This is the case of the American College of Surgeons Oncology Group trial that showed a surprising 44% complete pathologic response rate after full-thickness local excision after an oxaliplatin-capecitabine– based regimen.21 In another study, the use of additional chemotherapy cycles (5-FU and leucovorin) resulted in an improvement in the complete clinical response rate up to 65%. In this study, chemotherapy was used not only during radiation therapy but also during the interval between RT and surgery. A total of 6 cycles was given every 21 days throughout a period of 15 weeks (during the 6 weeks of RT and 9-week interval between CRT and surgery). This treatment strategy resulted in excellent complete response rates, 80% of which were assessed exclusively by clinical assessment alone with no immediate surgery,

Nonoperative approaches to rectal cancer whereas 20% underwent full-thickness transanal local excision with no residual cancer at final pathology (ypT0).35 One could argue that routine full-thickness local excision would be superior to observation alone in these patients, allowing confirmation of a complete pathologic response with little postoperative morbidity or functional disorders. However, the use of such procedures in the setting of neoadjuvant CRT seems to be associated with a higher risk of wound-related complications, possibly related to the suturing together of previously irradiated rectal tissue.36 In a recent report of patients undergoing transanal endoscopic microsurgery for rectal tumors with and without neoadjuvant CRT, the risk of wound breakdown was significantly higher among patients after neoadjuvant CRT (⬎30%). In fact, 10% of these patients required a stoma diversion, and 10% never healed their rectal wound dehiscence. In the light of these results, one could assume that even a minimally invasive surgical procedure may not heal after CRT. In addition, the follow-up of patients who undergo local excision may be challenging in terms of distinguishing postoperative scarring from recurrence, as opposed to patients without any previous resection. Finally, the performance of a salvage procedure in patients with local failure after full-thickness local excision and ypT0 may be significantly more difficult than a salvage resection for a recurrent cancer that has never been operated on.

237 program without immediate radical surgery and no adjuvant systemic chemotherapy. After a mean follow-up of 65 months in the nonoperative group, 52% of patients were followed at least 5 years, whereas 20% were followed at least 10 years. Overall survival and disease-free survival rates at 5 years were 96% and 72%, respectively (Fig 2). Deaths unrelated to rectal cancer occurred in 4% of patients, and 3% were lost to follow-up. Recurrences were observed in 15 patients (21%). Of these, 8 (11%) developed local recurrences (endorectal), 7 (10%) developed distant metastases, and none (0%) developed extrarectal pelvic recurrence. Median interval to recurrence was 38 months. Interestingly, median interval to recurrence was considerably longer for endorectal recurrences when compared with systemic relapses (39 months and 19 months, respectively). Additionally, the rates of systemic relapses (despite complete primary tumor regression) provides further support to the concept of using CRT regimens followed by additional chemotherapy cycles or even the use of induction chemotherapy regimens as suggested by others.35,37 All endorectal recurrences were amenable to salvage ther-

Authors’ Experience Between 1991 and 2009, 475 patients with distal rectal cancer were managed at 2 collaborating Institutions (University of São Paulo School of Medicine/Angelita and Joaquim Gama Institute). All patients were enrolled in this watch and wait strategy after achieving a complete clinical response. Here we present updated data from one of these instituions (Angelita and Joaquim Gama Institute and Hospital Alemão Oswaldo Cruz). In this experience, 173 patients with rectal cancers located no more than 7 cm from the anal verge were managed by neoadjuvant CRT. All patients received 50.4-54 Gy of radiation with concomitant 5-FU-based chemotherapy during the first and last three days of radiation therapy. All patients were assessed and staged before the initiation of treatment using physical examination, digital rectal examination, rigid proctoscopy, carcinoembryonic antigen (CEA) levels, endorectal ultrasound or magnetic resonance imaging, and abdominopelvic computed tomography scanning. At least 8 weeks from completion of therapy, patients were reassessed for tumor response using the same clinical, endoscopic, and radiologic studies used at initial assessment (described in more detail elsewhere).17 Initial staging studies revealed stage II disease (cT34N0M0) in 63% of patients, stage III disease (cTxN1-2M0) in 21% of patients, and stage I disease (cT2N0M0) in 16% of patients. The mean CEA level was 10.7 ng/dL. Overall, 67 (39%) of patients developed complete clinical response and did not undergo immediate radical surgery. Of the patients considered to have complete clinical response, 9 (13%) underwent full-excisional biopsy (full-thickness transanal excision) of the residual scar as a diagnostic procedure. The remaining patients (87%) were managed without any surgical procedure. All 67 patients were enrolled in a strict follow-up

Figure 2 (A) The overall survival of patients with cCR (complete clinical response with no immediate surgery). (B) Disease-free survival of patients with cCR (complete clinical response with no immediate surgery).

A. Habr-Gama et al

238 apy. Radical surgery was performed in 4 patients, 3 patients underwent transanal local excision, and 1 patient was managed by additional endorectal brachytherapy, experiencing a complete clinical response without additional surgical action. At a mean follow-up of 47 months from salvage procedure, only 1 patient developed rerecurrent disease, occurring 16 months after salvage APR.

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Conclusions The fact that a proportion of patients with distal rectal cancer may develop complete pathological and clinical response is one of the great advantages of a neoadjuvant CRT approach. The management of such patients remains highly controversial. The development of molecular and new radiologic tools may aid in the accurate clinical identification of such patients in the future. Currently, no immediate surgery may be considered as a safe alternative in highly selected patients using very stringent criteria in experienced hands. With the development of new CRT regimens with increased response rates and the inclusion of patients with earlier-stage disease may increasingly focus attention on this very relevant issue in rectal cancer management.

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