Evolving Approaches to Improve Outcomes and Minimize Toxicities in Radiation Therapy (Oncology)

Evolving Approaches to Improve Outcomes and Minimize Toxicities in Radiation Therapy San Francisco, Calif., USA, November 4, 2001

Guest Editor

Gillian M. Thomas, Toronto, Canada

24 figures and 17 tables, 1999

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Vol. 63, Suppl. 2, 2002

Contents

1

Foreword Thomas, G.M. (Toronto)

2

Radioprotectants: Current Status and New Directions Grdina, D.J.; Murley, J.S.; Kataoka, Y. (Chicago, Ill.)

11

Prevalence of Anemia in Cancer Patients Undergoing Radiotherapy: Prognostic Significance and Treatment Harrison, L.B.; Shasha, D.; Homel, P. (New York, N.Y.)

19

Raising Hemoglobin: An Opportunity for Increasing Survival? Thomas, G.M. (Toronto)

29

New Chemotherapeutic Agents: Update of Major Chemoradiation Trials in Solid Tumors Curran, W.J. (Philadelphia, Pa.)

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Oncology 2002;63(suppl 2):1 DOI: 10.1159/00067144

Foreword

A variety of techniques are now available to radiation oncologists to optimize treatment of cancers, including altered fractionation schedules, enhanced image guidance, intensity modulation allowing radiation dose escalation and improved brachytherapy techniques. In recent years, there has been increasing interest in the concurrent or sequential use of chemotherapeutic agents with radiosensitizing ability to enhance the effectiveness of radiotherapy. These agents include cisplatin, 5-fluorouracil, taxanes, topotecan, gemcitabine, vinorelbine, and tirapazamine. In certain malignancies (e.g., non-small-cell lung cancer, head and neck cancers, esophageal cancer and cervical cancer), concurrent chemotherapy and radiotherapy protocols have resulted in better tumor control and/or patient survival than with radiotherapy alone. The review by Dr. Curran in this supplement provides an update of recent clinical trials in this area, and emphasizes that while much has been achieved in the quest for new combined modality regimens capable of improving the outcomes for patients with cancer, important questions concerning the selection of patients, and the optimal dosages and timing of sequential therapies remain to be answered in future studies. Other evolving approaches to optimizing radiotherapy include the use of radioprotectants to reduce radiotherapy-induced toxicity without affecting its antitumor efficacy, cytotoxic agents such as mitomycin C to specifically target hypoxic tumor cells, and strategies to counter anemia such as treatment with epoetin alfa (recombinant human erythropoietin). It is postulated that anemia in cancer patients may result in a poor treatment outcome because of an increased resistance to radiation or chemotherapy. Radioprotectants currently under investigation include amifostine (WR-1065), which has been shown in experimental studies to prevent both radiation-induced cell death and radiation-induced mutagenesis. Moreover, this agent reduced the incidence of early and late radiotherapy-induced xerostomia in a multicenter clinical

ABC

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study of patients with head and neck cancers. Other potential applications of amifostine are reviewed in the article by Dr. Grdina and colleagues, along with recent advances in the development of newer cytoprotectants to reduce the acute and chronic toxicities associated with high-dose treatment strategies and aggressive combined modality protocols. The occurrence of anemia in cancer patients is an often overlooked complicating factor that is associated with poorer outcome possibly by decreasing the response to radiotherapy, presumably via lowering the oxygen-carrying capacity of the blood and thus exacerbating intratumoral hypoxia. In addition, anemia has an adverse effect on the quality of life of cancer patients, as evidenced by the increased fatigue that has been associated with low hemoglobin levels. Studies in various types of cancers have indicated that a high proportion of patients are anemic prior to or during radiotherapy, and that low hemoglobin levels are associated with poor clinical outcomes with radiotherapy. As emphasized in other articles in this supplement, these findings underline the importance of early detection and treatment of anemia in cancer patients. Administration of epoetin alfa to correct anemia has been reported to enhance locoregional response rates to chemoradiation therapy in patients with certain types of cancers (e.g., oropharyngeal squamous cell carcinomas) and to improve quality of life. Whether epoetin alfa therapy will also increase long-term survival is currently being investigated. Other ongoing studies are investigating whether epoetin alfa may also be effective in protecting against radiotherapy-induced neurotoxicity. The challenge for the future is to utilize our present knowledge to optimize the management of cancer patients undergoing radiotherapy or combined modality protocols with the objective of improving both the outcome of treatment and quality of life. Gillian M. Thomas

Gillian M. Thomas Radiation Oncology, Obstetrics & Gynecology University of Toronto Toronto-Sunnybrook Regional Cancer Centre Toronto, Onta. (Canada)

Oncology 2002;63(suppl 2):2–10 DOI: 10.1159/000067146

Radioprotectants: Current Status and New Directions David J. Grdina Jeffrey S. Murley Yasushi Kataoka Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Ill., USA

Key Words Cytoprotection W Radiotherapy W Radiation-induced toxicity W Mutagenesis W Amifostine W Thiol compounds

Abstract The ability to prevent radiotherapy-induced toxicity without affecting antitumor efficacy has the potential to enhance the therapeutic benefit for cancer patients without increasing their risk of serious adverse effects. Among the currently available cytoprotective agents capable of protecting normal tissue against damage caused by either chemo- or radiotherapy, only amifostine has been shown in clinical trials to reduce radiationinduced toxicity. Most notably, it reduces the incidence of xerostomia, which is a clinically significant long-term toxicity arising in patients undergoing irradiation of head and neck cancers. In vitro studies with the active metabolite of amifostine (WR-1065) have shown it to prevent both radiation-induced cell death and radiation-induced mutagenesis. The potential of this agent to prevent secondary tumors, as well as other radiation-induced toxicities is now the focus of ongoing research. Among other novel approaches to radioprotection being explored are methods to increase levels of the antioxidant mitochondrial enzyme manganese superoxide dismutase

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(MnSOD). In addition, the use of epoetin alfa, alone or in combination with cytoprotectants (e.g., amifostine), to treat radiation-induced anemia is also being investigated. The objective of developing newer cytoprotective therapies is to improve the therapeutic ratio by reducing the acute and chronic toxicities associated with more intensive and more effective anticancer therapies. Copyright © 2002 S. Karger AG, Basel

Introduction

Radiotherapy is toxic not only toward cancer cells but also to healthy cells, particularly those with a high rate of proliferation, which may result in serious adverse effects for patients. The risk of cell toxicity is increased with the application of more intensive radiotherapy techniques intended to increase tumor cell kill. Radiation-induced adverse effects commonly include mucositis and/or dermatitis, and are usually managed symptomatically as they manifest. However, preventing these complications is clearly more desirable, and various approaches to reducing radiation-induced toxicities while maintaining antitumor efficacy have been investigated. These include altered radiation dose fractionation, the use of physical shielding or intensity modulated radiation therapy to

David J. Grdina Department of Radiation and Cellular Oncology University of Chicago Medical Center, MC 1105 5841 S. Maryland Avenue, Chicago, IL 60637 (USA) Tel. +1 773 702 5250, Fax +1 773 702 5940, E-Mail [email protected]

Pharmacologic Strategies for Cytoprotection of Normal Cells

In recent years, a number of cytoprotective agents capable of protecting normal tissue against damage caused by either chemo- or radiotherapy have been developed. As a result of studies implicating toxic metabolites of chemotherapeutic agents and/or the generation of highly reactive species or free radicals in the etiology of DNA damage [3–5], a number of different strategies have been proposed for cytoprotection of normal cells, including: E preventing the generation of toxic metabolites of chemotherapeutic agents; E enhancing the elimination of toxic metabolites of chemotherapeutic agents; E neutralizing DNA adduct-forming metabolites; E detoxifying free radicals. A number of compounds have been investigated with the objective of providing site-specific protection for normal tissues without compromising the antitumor efficacy of chemotherapeutic agents and/or radiotherapy, including amifostine (WR-2721), dexrazoxane, mesna, glutathione, and N-acetylcysteine. Among these, amifostine, dexrazoxane and mesna have FDA approval for use in cytoprotection. Amifostine Amifostine (WR-2721) is a nucleophilic sulfur prodrug that is dephosphorylated in vivo by membrane-bound alkaline phosphatase to the active, free thiol metabolite

Prevention of Radiation-Induced Toxicity

100

Probability of tumor control or normal tissue damage (%)

reduce the volume of exposure, and pharmacologic approaches. The latter can be divided into radiosensitizers which ideally differentially enhance the sensitivity of tumors rather than normal tissue, and radioprotectants to reduce the detrimental effects of radiation on normal tissue while maintaining tumor sensitivity [1, 2]. This article reviews the current status of radioprotectants in cancer therapy and provides an insight into some of the new directions that research in this area is taking. Typical response curves illustrating the probability of tumor control and normal tissue damage at varying radiation doses are shown in figure 1. The objective of radioprotection is to shift the response curve for normal tissue as far as possible to the right to achieve the highest probability of tumor control with the least amount of damage to normal tissue. The ideal radioprotectant is one that protects normal tissue while preserving antitumor effectiveness, and is itself without moderate or severe toxicity.

75

Tumor Normal tissue

50

25

0

A B Radiation dose

C

Fig. 1. Tumor and normal tissue response curves to radiotherapy, illustrating the probability of tumor control and normal tissue damage at varying radiation doses (reproduced with permission from Hall [12]).

WR-1065. This metabolite is then oxidized to the disulfide form WR-33278 [4–6]. Numerous preclinical studies have shown that amifostine protects normal cells against the adverse effects of both radiation and chemotherapeutic agents (e.g., alkylating agents, platinum compounds, anthracyclines and taxanes) without attenuating their cytotoxic effects on large solid tumors. This selective protection is due, in part, to the more efficient conversion and uptake of the active metabolite WR-1065 in normal tissue in comparison with neoplastic tissue, as a result of the higher alkaline phosphatase activity, greater vascularization, and higher pH of normal tissue [4–6]. Following intravenous administration, amifostine is rapidly and extensively taken up by normal tissue. Animal studies have indicated that maximal concentrations of the active metabolite WR-1065 occur 5–15 min after administration [7]. Uptake of WR-1065 in normal tissue is not uniform, and appears to be greatest in the kidney, salivary glands, intestinal mucosa, liver and lung [6]. Once inside the cell, WR-1065 protects against chemotherapy- and radiotherapy-induced DNA damage by (1) binding to and neutralizing the reactive species of organoplatinum and alkylating agents, thus preventing formation of adducts with DNA, and (2) scavenging free radicals [5–7].

Oncology 2002;63(suppl 2):2–10

3

Table 1. Net charges of thiol compounds with putative cytoprotec-

tive activity Compound

Net charge

WR-33278 (disulfide metabolite of amifostine) WR-1065 (free thiol metabolite of amifostine) Cystamine Cysteamine Captopril Dithiothreitol (DTT) 2-Mercaptoethanol (2-ME) N-Acetyl-L-cysteine (L-NAC) N-Acetyl-D-cysteine (D-NAC) Mesna Glutathione, reduced (GSH) Glutathione, oxidized (GSSG)

+4 +2 +2 +1 0 0 0 –1 –1 –1 –1 –2

The efficacy of amifostine in protecting cancer patients against radiotherapy-induced toxicity is discussed below. Currently, amifostine has FDA approval to reduce the incidence of xerostomia in patients undergoing radiation treatment for head and neck cancers. It is also approved to reduce cumulative renal toxicity associated with cisplatin treatment in patients with ovarian cancer or non-smallcell lung cancer. Dexrazoxane Dexrazoxane (ICRF-187) is a cyclic derivative of the metal-chelating agent ethylenediamine-tetraacetic acid (EDTA) that provides protection against the cardiotoxicity of anthracycline-based chemotherapeutic agents, such as doxorubicin. Although the risk of cardiotoxicity appears to be reduced with newer formulations, such as peglyated liposomal doxorubicin [8], cardiotoxicity is a well-recognized, serious, treatment-limiting adverse effect of these compounds. It occurs via the generation of reactive oxygen species, which are highly toxic to cardiac tissues, by the stable complexes formed between anthracycline drugs and iron [9]. The cardioprotective effect of dexrazoxane is believed to result from its intracellular metabolism to a ring-opened hydrolysis product (ICRF198), which is a strong chelator of free and bound intracellular iron in the myocardium. As a consequence, the amount of iron available to form complexes with anthracyclines is reduced and formation of the reactive oxygen species is blocked. Importantly, the protective effect of dexrazoxane against the cardiotoxicity of anthracycline drugs occurs without affecting their antitumor activity. This may be due, in part, to differences in the intracellular

4

Oncology 2002;63(suppl 2):2–10

metabolism of dexrazoxane and/or differences in its uptake between normal cardiac cells and tumor cells [5, 9–11]. Currently, dexrazoxane has FDA approval to reduce the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received cumulative doses 1300 mg/m2. Mesna Mesna (sodium 2-mercaptoethane sulfonate) was developed as a specific chemoprotectant against the toxicity of acrolein, a urotoxic metabolite of oxazaphosphorinebased alkylating agents (e.g., ifosfamide and cyclophosphamide), which produces hemorrhagic cystitis following its excretion into the urinary bladder. Following intravenous administration, mesna is converted into an inactive disulfide form in the blood and is then metabolized back to mesna in the urinary tract where its free sulfhydryl groups bind to and inactivate acrolein, forming a stable, non-toxic thioether that is rapidly excreted in the urine. Mesna also inhibits the further formation of acrolein in the bladder. Because its activity is restricted to the urinary tract, the systemic activity and non-urologic toxicity of oxazaphosphorine drugs are not affected [4, 5]. Currently, mesna has FDA approval for the prophylaxis of ifosfamide-induced hemorrhagic cystitis.

Relationship Between the Net Charge of Thiol Compounds and Their Ability to Protect Against Radiation-Induced DNA Damage

The mechanism by which radiation induces DNA damage is slightly different to that of chemotherapeutic agents. Radiation-induced damage is introduced into a genome by either a direct action, where the energy is deposited directly on the genome, or indirectly via the formation of free radicals which are responsible for the resultant cell killing, mutagenesis, transformation, and carcinogenesis. The latter mechanism, which accounts for about 75% of radiation-induced DNA damage by photons, can be abrogated with free radical scavengers present in the local microenvironment at the time the free radicals are formed. However, in the case of direct damage, there are no known radioprotectants as this process occurs too rapidly to be prevented by a pharmacologic agent [12]. Studies performed several years ago by Fahey et al. have shown that the net charge of thiol compounds with putative cytoprotective activity (table 1) markedly in-

Grdina/Murley/Kataoka

1.0

a

a Surviving fraction of cells

Surviving fraction of cells

1.0

0.1

60

0.1

60

Co g-radiation

Co γ - radiation

WR - 1065 after

WR-1065 before Co γ-radiation

60

Co γ - radiation

60

0.01 100 HPRT mutants per 106 survivors

HPRT mutants per 106 survivors

0.01 100

b

80 60 40 20

0

b

80

60

40

20

0

0

2

4 60

6

8

10

12

0

2

Co g dose (Gy)

4 60

6 8 Co γ dose (Gy)

10

12

Fig. 2. Response to varying doses of 60Co Á-radiation of V79 Chinese

Fig. 3. Response to varying doses of 60Co Á-radiation of V79 Chinese

hamster lung fibroblast cells in the absence or presence of WR-1065 4 mmol/l added to cell cultures 30 min before irradiation and allowed to remain until 3 h after irradiation. a Surviving fraction of cells. b Mutation induction at the HPRT (hypoxanthine-guanine phosphoribosyl transferase) locus among surviving cells that were grown in a non-selective medium for 6 days and then exposed to 6-thioguanine 5 Ìg/ml in ·-MEM-10 medium (containing hypoxanthine, aminopterin and thymidine) for 7 days and stained with 0.5% methylene blue. Bars indicate the standard errors of the mean of two or more replicate experiments (reproduced with permission from Grdina et al. [15]).

hamster lung fibroblast cells exposed immediately after irradiation to WR-1065 4 mmol/l added to cell cultures and allowed to remain for 3 h. a Surviving fraction of cells. b Mutation induction at the HPRT (hypoxanthine-guanine phosphoribosyl transferase) locus among surviving cells (assessed as described in fig. 2). The broken lines represent the radiation-only curves and are presented for comparison. Bars represent the standard errors of the mean of two or more replicate experiments (reproduced with permission from Grdina et al. [15]).

fluences the degree of protection that they provide against the DNA-damaging effects of radiation [13, 14]. Because WR-1065 has a net charge of +2, it will be attracted to DNA (which is negatively charged) and is therefore more likely to exert a protective effect against radiationinduced damage than a compound with a net charge of 0 or a negative net charge. Evidence in support of this hypothesis has come from studies with WR-1065, captopril, and N-acetylcysteine in Chinese hamster lung fibroblast and ovary cells.

Protective Effect of WR-1065 (Amifostine Metabolite) Studies in our institution using V79 Chinese hamster lung fibroblast cells have shown that WR-1065 in a concentration of 4 mmol/l protects against radiation-induced cell death when added to cell cultures 30 min before various doses of 60Co Á-radiation, but not when it is added immediately after irradiation (fig. 2a, 3a). This treatmentschedule dependence in the protective effect of WR-1065 is to be expected if it is acting as a free radical scavenger, since protection could only be expected to occur when the compound is present during irradiation [15].

Prevention of Radiation-Induced Toxicity

Oncology 2002;63(suppl 2):2–10

5

10 0

10 0

Co γ-radiation

60

Surviving fraction of cells

Surviving fraction of cells

60

10 -1

10 -1

Radiation only 10

Radiation + 4 mmol/l N-acetylcysteine Radiation + 0.04 mmol/l N-acetylcysteine

-2

Without captopril With 1 mmol/l captopril

10 -2

Co -radiation

10 - 3

0

200

400

600

800

1,000

60

Co γ dose (cGy)

0

200

400 600 Co γ dose (cGy)

800

1,000

60

Fig. 4. Surviving fractions of Chinese hamster ovary (CHO)-AA8 cells exposed to varying doses of 60Co Á-radiation in the absence or presence of captopril 1 mmol/l added to the cell cultures 30 min prior to irradiation (Grdina DJ, unpubl. data).

Fig. 5. Surviving fractions of Chinese hamster ovary (CHO)-AA8 cells exposed to varying doses of 60Co Á-radiation in the absence or presence of N-acetylcysteine 0.04 mmol/l and 4 mmol/l added to the cell cultures 30 min prior to irradiation (Grdina DJ, unpubl. data).

As well as increasing the surviving fraction of cells when administered before irradiation, WR-1065 has also been shown to reduce the degree of radiation-induced mutagenesis in V79 Chinese hamster lung fibroblast cells (expressed as the HPRT mutant frequency per 106 survivors exposed to 6-thioguanine 5 Ìg/ml) (fig. 2b). In contrast to the treatment-schedule dependence for the protective effect against cell killing, the antimutagenic effect of WR-1065 is also observed when it is administered after irradiation (fig. 3b), indicating that its post-irradiation action can effectively alter mutation induction in surviving cells [16].

of a protective effect against radiation-induced cell killing with either drug (fig. 4, 5) [Grdina DJ, unpubl. data]. Thus, key factors governing the radioprotective efficacy of a drug acting as free radical scavenger are: (1) an ability to concentrate within the nucleus or microenvironment of DNA (dependent on its net charge), and (2) the presence of the protectant at the radiation target at the time it is irradiated (important for prevention of cell death). No clinical advantage is achieved if the protector does not differentially protect normal tissues compared to tumor.

Lack of Protective Effect of Captopril and N-Acetylcysteine Because the net charges of captopril and N-acetylcysteine are 0 and –1, respectively, these thiol compounds would not be expected to concentrate within the negatively charged nucleus or the microenvironment of DNA to the same extent as those with positive net charges. Studies using Chinese hamster ovary (CHO)-AA8 cells exposed to various doses of 60Co Á-radiation in the absence or presence of captopril 1 mmol/l and N-acetylcysteine 0.04 mmol/l or 4 mmol/l have shown no evidence

6

Oncology 2002;63(suppl 2):2–10

Dose-Response Considerations with Amifostine: Prevention of Cell Death vs Prevention of Mutagenesis

The protection factor achievable with a radioprotectant is defined as the ratio of surviving cell fraction for treated cells as compared with untreated cells following radiation exposure. The clinical potential of a putative radioprotectant depends on the tolerability of the drug at a dosage required to achieve a particular protection factor. In studies conducted at our institution using CHO-

Grdina/Murley/Kataoka

8

Protection factor (cell survival)

AA8 cells, the protection factor for cell survival with the amifostine metabolite WR-1065 (i.e., the ratio of cell surviving fractions for WR-1065-treated versus untreated cells) was determined at various concentrations of WR1065 added to the incubation medium 30 minutes prior to exposure to a radiation dose of 750 cGy from a 60Co Á-ray source. As shown in figure 6, the protection factor fell sharply from 16 to around 3 as the concentration of WR-1065 was decreased from 4 to 1 mmol/l, and then declined further to essentially no protection at lower concentrations of 0.01–0.1 mmol/l. In contrast, the protection against mutagenesis (expressed as the HPRT mutant frequency per 106 survivors exposed to 6-thioguanine 5 Ìg/ml) remained largely constant over the same WR-1065 concentration range (0.01–4 mmol/l). This suggests that the mechanism by which WR-1065 provides protection against mutagenesis differs from that for protection against cell killing, and that the antimutagenic effect can be achieved at lower concentrations (as low as 0.01 mmol/l) [16]. Viewed in relation to therapeutic use of amifostine, the concentrations of WR-1065 achieved with dosages of amifostine used clinically are in the range 1.5–3.85 mmol/l [17], which suggests that the degree of cytoprotection provided at antimutagenic dosages are insufficient to increase survival of either normal or neoplastic cells. However, its effect in reducing the risk of radiation-induced mutagenesis, carcinogenesis, and secondary tumors is of considerable interest and this area is now an important focus for ongoing research into the protective effects of amifostine, particularly in view of increasing evidence that the risk of secondary tumors is increased as cancer therapies become more effective and, coincidentally, more damaging to normal tissues.

6

4

2

0 1 0.01 0.1 WR-1065 concentration (mmol/l)

4

Fig. 6. Protection factor for survival of Chinese hamster ovary (CHO)-AA8 cells (i.e., the ratio of cell surviving fractions for WR1065-treated to untreated cells) at varying concentrations of WR1065 added to the incubation medium 30 min prior to exposure to a radiation dose of 750 cGy from a 60Co Á-ray source. All plot points are the average of three separate experiments and the bars represent the standard errors of the mean (reproduced with permission from Grdina et al. [16]).

Clinical trials of the radioprotective effect of amifostine have been undertaken in patients receiving radiotherapy for head and neck, pelvic, and thoracic cancers [6]. Thus far, most studies have involved relatively small numbers of patients but have generally demonstrated significant reductions in the incidence of radiation-induced local toxicities. In the largest trial conducted to date, the efficacy of amifostine in ameliorating the adverse effects of radiotherapy and its influence on the clinical effectiveness of radiotherapy were evaluated in patients with previously untreated head and neck squamous cell carcino-

mas [18]. Patients in this multicenter study (n = 303) received radiotherapy in a dose of 1.8 to 2.0 Gy/day for 30 to 35 fractions (total dose 50–70 Gy), approximately half of whom (n = 153) were randomized to receive amifostine (200 mg/m2 intravenously over 3 min) 15 to 30 min before irradiation and half to receive radiotherapy alone (n = 150). As shown in table 2, amifostine significantly reduced the incidence of both early xerostomia within the first 90 days (as well as the cumulative radiotherapy dose required to cause this adverse effect) and late xerostomia at 1 year after initiation of radiotherapy, although it did not significantly reduce the incidence of acute mucositis. Patients who received amifostine were also found to produce more saliva than those treated with radiotherapy alone (median saliva production 0.26 vs 0.10 g; p = 0.04). When overall survival data for the two groups of patients were compared, there was a slight advantage for those receiving amifostine (fig. 7), but the difference was not statistically significant. Nor was there any significant dif-

Prevention of Radiation-Induced Toxicity

Oncology 2002;63(suppl 2):2–10

Clinical Studies of Amifostine as a Radioprotectant

7

100 (124) 90

(104)

80

(119)

Percent survival

70

Fig. 7. Percentages of survivors over a peri-

od of 27 months among patients with previously untreated head and neck squamous cell carcinomas who were randomized to receive either amifostine (200 mg/m2 i.v. over 3 min) 15–30 min before radiotherapy doses of 1.8–2 Gy/day for 30 to 35 fractions (total 54–70 Gy) or similar doses of radiotherapy alone. The numbers of patients at risk at 12 and 18 months are indicated in parentheses (reproduced with permission from Brizel et al. [18]).

Table 2. Incidence of acute and late

xerostomia 6grade 2 (RTOG acute/late morbidity scoring criteria) in patients with head and neck squamous cell carcinomas who received radiotherapy with or without amifostine (200 mg/m2 i.v. 15–30 min prior to irradiation) [18]

(98)

60 50 40

Amifostine + radiotherapy

30

Radiotherapy alone

Total No. Events of patients 34 153 45

180

Log-rank: p = 0.184 Hazard ratio: 1.351 (95% Cl 0.865 - 2.109)

20 10 0 0

6

3

Complication

Acute xerostomiaa Incidence (% of patients) Cumulative radiotherapy dose to onset

9

12

15 Months

18

21

24

27

Amifostine plus radiotherapy (n = 153)

Radiotherapy alone (n = 150)

p value

51%

78%

! 0.0001

60 Gy

42 Gy

! 0.0001

34%

57%

! 0.002

xerostomiab

Late Incidence (% of patients)

a b

RTOG = Radiation Therapy Oncology Group. Within 90 days of initiation of radiotherapy. At 1 year after initiation of radiotherapy.

ference between the two groups in locoregional tumor control rates. Thus, amifostine significantly reduced acute and chronic xerostomia in these patients without compromising the antitumor effectiveness of radiotherapy [18].

Potential Future Applications of Amifostine

Other potential roles for amifostine that are being explored include reducing renal toxicity associated with cisplatin treatment in ovarian cancer and non-small-cell

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Oncology 2002;63(suppl 2):2–10

lung cancer and reduction of toxicities associated with doxorubicin- and paclitaxel-containing regimens, highdose chemotherapies, and multimodality chemotherapy and radiotherapy for a variety of solid tumors. Possible prevention of secondary tumors (see above), is also being explored. In addition, the observation that amifostine may stimulate bone marrow progenitor cells has led to studies of its use as a potential treatment for patients with myelodysplastic syndrome. As yet, however, clinical data are limited and its value in this setting remains to be clarified [6].

Grdina/Murley/Kataoka

New Advances in Cytoprotection

A number of newer potential radioprotectants are currently undergoing preclinical research, including: (1) The amifostine analog S-[2-(3-methylaminopropyl) aminoethyl] phosphorothioate acid, which is orally bioavailable and less toxic than amifostine; (2) thiolamine compounds with thioglycoside-protecting groups; (3) covalent conjugates of thioamines and antioxidant vitamins, and (4) selenazolidine prodrugs. In addition, other approaches to radioprotection are also being explored. These include altering endogenous levels of antioxidant enzymes (specifically the mitochondrial enzyme manganese superoxide dismutase [MnSOD] which protects against oxidative stress induced by various agents including irradiation), and enhancement of erythropoiesis to treat the anemia that commonly occurs during irradiation (see review by Harrison in this supplement). Novel approaches that are currently being investigated include: E The use of MnSOD plasmid/liposome complex gene therapy to protect against radiation-induced esophagitis. Improved tolerance of the esophageal epithelium to fractionated radiation has recently been demonstrated with this approach in a mouse model [19, 20]. E The use of nonprotein thiol-containing compounds to activate MnSOD gene expression, e.g., the amifostine

metabolites WR-1065 and WR-33278, N-acetylcysteine, mesna, captopril, oltipraz, and dithiothreitol [21–23]. In human microvascular endothelial cells, exposure to WR-1065 0.04 mmol/l for 30 min has been shown to cause an increase in MnSOD gene expression that begins about 12 h after exposure to WR-1065, peaks at 16 to 18 h, and ends after about 22 h [21]. E The use of epoetin alfa (recombinant human erythropoietin; r-HuEPO) alone or in combination with cytoprotectants (e.g., amifostine) to treat radiation-induced anemia. The interaction of amifostine with epoetin alfa may produce a synergy in gene activation/expression (e.g., of the c-myb gene thereby leading to an increase in hematopoietic progenitor cells), as well as an increase in myeloproliferation and a reduction of genomic instability [24–26]. The objective of developing newer cytoprotective therapies is to be able to reduce the acute and cumulative toxicities associated with more intensive and more effective therapeutic anticancer regimens now being introduced into clinical practice, whether delivered as radiotherapy, chemotherapy, or combined modality regimens. The merging of these technologies will, it is hoped, enhance the therapeutic benefit for cancer patients without increasing their risk of serious adverse effects, and thus improving both their quality and duration of life.

References 1 Curran WJ: Radiation-induced toxicities: the role of radioprotectants. Semin Radiat Oncol 1998;8(4 suppl 1):2–4. 2 Brizel DM: Future directions in toxicity prevention. Semin Radiat Oncol 1998;8(4 suppl 1):17–20. 3 Schuchter LM: Current role of protective agents in cancer treatment. Oncology (Huntingt) 1997;11:505–512, 515–518. 4 Hoekman K, van der Vijgh WJF, Vermorken JB: Clinical and preclinical modulation of chemotherapy-induced toxicity in patients with cancer. Drugs 1999;57:133–155. 5 Links M, Lewis C: Chemoprotectants: A review of their clinical pharmacology and therapeutic efficacy. Drugs 1999;57:293–308. 6 Culy CR, Spencer CM: Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome. Drugs 2001;61:641–684. 7 Schuchter LM: Guidelines for the administration of amifostine. Semin Oncol 1996;23(4 suppl 8):40–43.

Prevention of Radiation-Induced Toxicity

8 Safra T, Muggia F, Jeffers S, Tsao-Wei DD, Groshen S, Lyass O, Henderson R, Berry G, Gabizon A: Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 2000;11:1029– 1033. 9 Wiseman LR, Spencer CM: Dexrazoxane: a review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy. Drugs 1998;56:385–403. 10 Hasinoff BB: The iron(III) and copper(II) complexes of adriamycin promote the hydrolysis of the cardioprotective agent ICRF-187 ((+)-1,2bis(3,5-dioxopiperazinyl-1-yl)propane). Agents Actions 1990;29:374–381. 11 Koning J, Palmer P, Franks CR, Mulder DE, Speyer JL, Green MD, Hellmann K: Cardioxane – ICRF-187 towards anticancer drug specificity through selective toxicity reduction. Cancer Treat Rev 1991;18:1–19.

12 Hall EJ: Radiobiology for the radiologist, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2000. 13 Zheng S, Newton GL, Gonick G, Fahey RC, Ward JF: Radioprotection of DNA by thiols: relationship between the net charge on a thiol and its ability to protect DNA. Radiat Res 1988;114:11–27. 14 Zheng S, Newton GL, Ward JF, Fahey RC: Aerobic radioprotection of pBR322 by thiols: effect of thiol net charge upon scavenging of hydroxyl radicals and repair of DNA radicals. Radiat Res 1992;130:183–193. 15 Grdina DJ, Nagy B, Hill CK, Wells RL, Peraino C: The radioprotector WR1065 reduces radiation-induced mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in V79 cells. Carcinogenesis 1985;6:929–931. 16 Grdina DJ, Shigematsu N, Dale P, Newton GL, Aguilera JA, Fahey RC: Thiol and disulfide metabolites of the radiation protector and potential chemopreventive agent WR-2721 are linked to both its anti-cytotoxic and anti-mutagenic mechanisms of action. Carcinogenesis 1995;16:767–774.

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17 Shaw LM, Bonner HS, Schuchter L, Schiller J, Lieberman R: Pharmacokinetics of amifostine: effects of dose and method of administration. Semin Oncol 1999;26(2 suppl 7):34–36. 18 Brizel DM, Wasserman TH, Henke M, Strnad V, Rudat V, Monnier A, Eschwege F, Zhang J, Russell L, Oster W, Sauer R: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000;18: 3339–3345. 19 Epperly MW, Gretton JA, DeFilippi SJ, Greenberger JS, Sikora CA, Liggitt D, Koe G: Modulation of radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutaseplasmid/liposome (SOD2-PL) gene therapy. Radiat Res 2001;155:2–14.

10

20 Epperly MW, Kagan VE, Sikora CA, Gretton JE, Defilippi SJ, Bar-Sagi D, Greenberger JS: Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) administration protects mice from esophagitis associated with fractionated radiation. Int J Cancer 2001;96:221–231. 21 Murley JS, Kataoka Y, Hallahan DE, Roberts JC, Grdina DJ: Activation of NFkappaB and MnSOD gene expression by free radical scavengers in human microvascular endothelial cells. Free Radic Biol Med 2001;30:1426– 1439. 22 Das KC, Lewis-Molock Y, White CW: Activation of NF-kappa B and elevation of MnSOD gene expression by thiol-reducing agents in lung adenocarcinoma (A549) cells. Am J Physiol 1995;269(5 Pt 1):L588–L602. 23 Antras-Ferry J, Maheo K, Chevanne M, Dubos MP, Morel F, Guillouzo A, Cillard P, Cillard J: Oltipraz stimulates the transcription of the manganese superoxide dismutase gene in rat hepatocytes. Carcinogenesis 1997;18:2113– 2117.

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24 List AF: Use of amifostine in hematologic malignancies, myelodysplastic syndrome, and acute leukemia. Semin Oncol 1999;26(2 suppl 7):61–65. 25 Jongen-Lavrencic M, Peeters HR, Vreugdenhil G, Swaak AJ: Interaction of inflammatory cytokines and erythropoietin in iron metabolism and erythropoiesis in anaemia of chronic disease. Clin Rheumatol 1995;14:519–525. 26 Zhu J, Heyworth CM, Glasow A, Huang QH, Petrie K, Lanotte M, Benoit G, Gallagher R, Waxman S, Enver T, Zelent A: Lineage restriction of the RARalpha gene expression in myeloid differentiation. Blood 2001;98:2563– 2567.

Grdina/Murley/Kataoka

Oncology 2002;63(suppl 2):11–18 DOI: 10.1159/000067147

Prevalence of Anemia in Cancer Patients Undergoing Radiotherapy: Prognostic Significance and Treatment Louis B. Harrison a Daniel Shasha a Peter Homel b a Department b Department

of Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt Hospital Center; of Grants and Research, Beth Israel Medical Center, New York, N.Y., USA

Key Words Radiotherapy W Anemia W Hypoxia W Radiation-induced toxicity W Epoetin alfa W Quality of life Abstract As the antitumor activity of radiation is mediated via its interaction with oxygen to form labile free radicals, the intratumoral oxygen level has an important influence on the ability of radiation therapy to kill malignant cells. By decreasing the oxygen-carrying capacity of the blood, anemia may result in tumor hypoxia and may have a negative influence on the outcome of radiotherapy for various malignancies, even for small tumors not normally assumed to be hypoxic. In addition, anemia also has a negative effect on the quality of life of cancer patients, as evidenced by worsening fatigue. As a high proportion (about 50%) of cancer patients undergoing radiotherapy are anemic prior to or during treatment, strategies to correct anemia and/or the resultant tumor hypoxia are increasingly being considered an important component of treatment. In particular, epoetin alfa (recombinant human erythropoietin), which has proved an effective and well-tolerated means of raising hemoglobin levels in anemic patients receiving radiotherapy, potentially could reverse the negative prognostic influence of a low

ABC

© 2002 S. Karger AG, Basel 0030–2414/02/0636–0011$18.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ocl

hemoglobin in patients with certain malignancies. Radiation oncologists need to be aware of the possibility of anemia in cancer patients undergoing radiotherapy so that timely intervention can be instituted whenever anemia is diagnosed. Copyright © 2002 S. Karger AG, Basel

Introduction

The objective of radiotherapy in cancer treatment is to maximize locoregional tumor control and patient survival. As the antitumor activity of radiation is known to be mediated via its interaction with oxygen to form labile free radicals, the intratumoral oxygen level has an important influence on the number of free radicals produced within a tumor and thus on the ability of radiation therapy to induce DNA damage in malignant cells. Consequently, the presence of acute or chronic anemia, which may decrease the oxygen-carrying capacity of the blood and results in tumor hypoxia, lowers the propensity of radiotherapy to produce DNA damage and is an obstacle to achieving maximal locoregional tumor control [1–3]. It has been estimated that the dose of radiation required to kill tumor cells under hypoxic conditions is 2 to 3 times

Louis B. Harrison, MD Department of Radiation Oncology, Beth Israel Medical Center 10 Union Square East, New York, NY 10003 (USA) Tel. +1 212 844-8087, Fax +1 212 844-8086 E-Mail [email protected]

Fraction of survivng cells

1

Hypoxic Normoxic

0.1

0.01

OER = 1,750 ⴜ 700 = 2.5

0.001 0 200

400

600

800 1,000 1,200 1,400 1,600 1,800 2,000

Radiation dose (cGy)

Fig. 1. Enhancement of radiation resistance by hypoxia. The oxygen enhancement ratio (OER) is the ratio of the radiation dose required to kill a given fraction of malignant cells in a hypoxic environment in relation to that in a normoxic environment.

the dose required in a normoxic environment (fig. 1). Hypoxia has also been found to produce mutations of the p53 suppressor gene, which results in an increase in angiogenesis and an increased tendency for the development of distant metastases. Thus, overcoming hypoxia may have positive effects on not only locoregional tumor control but also on decreasing the risk of developing metastatic disease [1, 3]. Hypoxia is a common characteristic of solid tumors. Athough the number and size of their hypoxic regions varies substantially [1], hypoxia may be present in even small tumors at an early stage of development. In the past, the prevalence of anemia and tumor hypoxia in cancer patients receiving radiotherapy has been an underappreciated problem that has frequently led to undertreatment. This article reviews the prevalence of anemia in patients undergoing radiotherapy, and emphasizes that effective reversal of anemia can be achieved. Until recently, little attention has been paid to hemoglobin levels in cancer patients.

Prognostic Significance of Anemia in Cancer Patients

Relationships between low hemoglobin levels and intratumoral hypoxia, and between intratumoral hypoxia and a less favorable prognosis in various cancers have been identified in studies in which oxygen partial pressures (pO2) were measured in tumor tissue [4–7]. In

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Oncology 2002;63(suppl 2):11–18

patients with head and neck cancers, a pretreatment hemoglobin level !11.0 g/dl was found to be a stronger predictor of poor tumor oxygenation than other factors such as tumor stage, tumor volume and smoking status [4]. Even prostate tumors, which are generally not considered to be hypoxic, have been reported to be associated with significantly lower pO2 levels in comparison with pathologically normal prostate tissue and muscles, particularly in patients with more advanced (T2/T3) prostatic tumors and in older individuals (662 years of age) [5]. Effect on Locoregional Tumor Control and Survival Recent studies have demonstrated an important relationship between anemia on locoregional tumor control and patient survival, principally in head and neck cancers. In patients with early stage glottic cancers, which are amongst the smallest tumors treated by oncologists, a clear relationship has been demonstrated between the pretreatment hemoglobin level and the hazard ratio for local relapse following radiotherapy (50 Gy in 20 fractions over 4 weeks) during a median follow-up period of 6.8 years [8]. Similarly, studies in patients with squamous cell carcinomas of the glottic larynx and head/neck who were treated with radiotherapy have noted significantly better 2-year locoregional tumor control rates and 2-year survival rates in those who presented with normal hemoglobin levels in comparison with those who presented with below-normal hemoglobin levels (!13 g/dl) (table 1) [9, 10]. In the patients with head/neck cancers, 5-year locoregional control and survival rates were also significantly better in those with normal hemoglobin levels (p ! 0.001 and p ! 0.01, respectively; table 1) [10]. Other studies have shown a relationship between the post-radiotherapy hemoglobin level and the outcome of treatment. Among patients with squamous cell carcinomas of either the glottic or supraglottic regions who received primary radiotherapy in doses ranging from 60 to 70 Gy over 6 to 7 weeks, disease-free survival rates were significantly better in those who had normal hemoglobin levels (defined as 12–16 g/dl in women, 13.7– 18 g/dl in men) at day 35 of treatment in comparison with those who had below-normal hemoglobin levels at this time (p = 0.0012 for glottic carcinoma; p = 0.05 for supraglottic carcinoma) (fig. 2) [11]. Effect on Fatigue In addition to locoregional tumor control and survival, other outcomes in patients undergoing radiotherapy may also be influenced by the presence of anemia. Fatigue is

Harrison/Shasha/Homel

Percentage of patients with a fatigue rating >5

40

Not anemic

37%

Anemic 28%]

29%

30

20 14% 10 4% 0

Pre-radiotherapy During radiotherapy Post-radiotherapy Time relative to radiotherapy

Fig. 2. Disease-free survival among patients with squamous cell carcinoma of the glottic and supraglottic regions treated with primary radiotherapy (60–70 Gy in 30–35 fractions over 6–7 weeks) in relation to their hemoglobin (Hb) levels at day 35 of treatment. p Values indicate differences between disease-free survival in each group for patients with normal vs below normal Hb levels. Normal Hb values were defined as 13.7–18 g/dl (8.5–11.0 mmol/l) for men and 12– 16 g/dl (7.5–10.0 mmol/l) for women (reproduced with permission from van Acht et al. [11]).

Fig. 3. Percentages of prostate cancer patients with fatigue ratings

greater than 5 (on a scale of 0–10) before, during and after radiotherapy in relation to whether they were anemic (Hb level ! 12 g/dl) or not anemic at the time (Harrison LB, unpublished data). * Statistically significant versus non-anemic patients (p = 0.015).

Table 1. Influence of anemia on locoregional tumor control rates and survival rates in two studies in patients with squamous cell carcinomas of the glottic larynx (n = 109) or head/neck region (n = 504) [9, 10]

Patient group

Locoregional control rates, %

Survival rates, %

2-year

5-year

2-year

5-year

Glottic squamous cell carcinomas [9] Normal hemoglobin levels Anemiaa

95* 66

NR NR

88** 46

NR NR

Head/neck squamous cell carcinomas [10] Normal hemoglobin levels Anemiab

52** 34

48** 32

51* 37

36* 22

a b

Hemoglobin ! 13 g/dl. Hemoglobin ! 13 g/dl (women) or ! 14.5 g/dl (men). * p ! 0.01 vs anemic patients; ** p ! 0.001 vs anemic patients; NR = not reported.

one such outcome that has been strongly associated with anemia [12–14]. In a group of patients with prostate cancer treated with radiotherapy at our institution, the percentage with a fatigue rating 15 (on a scale of 0–10) following radiotherapy was found to be significantly higher

in those who were anemic (hemoglobin !12 g/dl) than in those who were not anemic (fig. 3). This finding is of interest because fatigue is generally not considered a problem in prostate cancer patients receiving radiotherapy alone.

Prevalence and Treatment of Radiotherapy-Associated Anemia

Oncology 2002;63(suppl 2):11–18

13

100

Baseline

Fig. 4. The prevalence of anemia (Hb ! 12

g/dl) before and during radiotherapy in patients with different types of cancer treated at the Department of Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt Hospital Center, New York between December 1996 and June 1999. Baseline was defined as within 4 weeks prior to the first radiation dose. During therapy was defined as within 3 to 5 weeks of the first radiation dose.

Patients with anemia (%)

During radiotherapy 77%

80

Mean decrease in hemoglobin during radiotherapy (g/dl)

1.6

16% 26%

20

9%

0

Breast cancer (n = 81)

]

]

1.0 0.8 0.6 0.4 0.2 0

Breast Colorectal Lung Prostate Cervical cancer cancer cancer cancer cancer (n = 71) (n = 48) (n = 101) (n = 78) (n = 48)

Head/ neck cancer (n = 86)

Fig. 5. Mean decreases in hemoglobin (Hb) levels during radiotherapy versus preradiotherapy in patients treated at the Department of Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt Hospital Center, New York between December 1996 and June 1999. Data shown are for patients whose Hb levels decreased during treatment. * Statistically significant difference versus baseline (p ! 0.001).

Prevalence of Anemia in Patients Undergoing Radiotherapy for Various Cancers

Studies of patients presenting for radiotherapy at our institution between December 1996 and June 1999 (n = 574) have revealed a high prevalence of anemia (hemoglobin !12 g/dl) both before and during irradiation. Overall,

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Oncology 2002;63(suppl 2):11–18

44%

40

1.4 1.2

32%

55% 44% 45%

]

]

79%

63% 60

2.0 1.8

75%

Colorectal cancer (n = 64)

Lung/ bronchus cancer (n = 64)

Prostate cancer (n = 90)

Uterine/ cervical cancer (n = 53)

Head/ neck cancer (n = 68)

41% of patients were found to be anemic at baseline (within 4 weeks prior to radiotherapy) and 54% were anemic within 3 to 5 weeks after receiving the first dose of radiation [15]. The prevalence of anemia was higher in women than in men (54 vs 28% at baseline; 63 vs 43% during radiotherapy), and was higher in patients with certain types of cancer than others (fig. 4). In particular, high prevalences of anemia were noted in patients with colorectal, lung/bronchus and uterine/cervical cancers, and increases in prevalence from baseline to end of therapy were most notable for those with colorectal and lung/ bronchus cancers (fig. 4). Among patients who experienced a drop in their hemoglobin level during radiotherapy, the mean decreases ranged from 0.75 g/dl for those with breast cancer to 1.8 g/dl for those with head or neck cancers, and the decreases were statistically significant (p ! 0.001) in all groups except those with breast and cervical cancer (fig. 5). When the prevalence of anemia for each cancer type was stratified by the hemoglobin level measured at baseline and the lowest level recorded during radiotherapy, most patients in each group were found to have mild anemia (hemoglobin levels 610 g/dl), which should be easily correctable. These data, and the findings of studies reviewed previously in this article indicating that the presence of anemia is associated with poorer treatment outcomes, provide compelling evidence for employing strategies to correct anemia and/or the resultant tumor hypoxia in cancer patients undergoing radiotherapy.

Harrison/Shasha/Homel

HBO4 Air

Carbogen patients at 18 months (n = 36) Carbogen patients at 3 years (n = 36) [estimated probabilities]

80

Noncarbogen patients at 18 months (n = 36) 100

60 40

91% 91%

80

75% 75% 69%

20 0 0

1

2

3

4

5

Patients (%)

Local relapse-free rate (%)

100

62% 62% 60

55% 50%

40

Years 20

Fig. 6. Local relapse-free survival over 5 years in patients with locally

advanced squamous cell carcinomas of the head or neck who were randomized to treatment with either radiotherapy under hyperbaric oxygen at 4 atmospheres (HBO4) delivered in two fractions of 11.5 Gy over 21 days (n = 23), or radiotherapy delivered in air in two fractions of 12.65 Gy over 21 days (n = 25) (reproduced with permission from Haffty et al. [17]).

Strategies to Correct Anemia and/or Tumor Hypoxia

0

Local control

Cause-specific survival Overall survival

Fig. 7. Influence of carbogen breathing on local control, cause-specific survival and overall survival in patients with advanced head or neck cancers treated with a hyperfractionated chemoradiotherapy regimen. Patients received either carboplatin 5 mg/m2 administered 45 min before radiotherapy (115 cGy) with carbogen breathed 4 min prior to and during irradiation twice per day on 5 days a week for 7 weeks (n = 36), or the same chemoradiotherapy regimen without carbogen breathing (comparison group; n = 36). Data at 3 years for the carbogen breathing group are estimated probabilities [18].

Strategies that have been proposed to correct anemia and/or the resultant tumor hypoxia include the use of: E Hypoxic cell sensitizers (e.g., cytotoxic agents) E Fluosol infusion E Carbogen breathing E Hyperbaric oxygen E Blood transfusions E Epoetin alfa (recombinant human erythropoietin; r-HuEPO).

rate in comparison with the accelerated regimen alone (48 vs 34% and 39 vs 28%, respectively), indicating that hypoxia can, in part, be overcome by mitomycin C administration. Mitomycin C did not influence the local toxicity of radiotherapy as neither the intensity nor the duration of radiotherapy-induced mucositis was altered by its administration [16].

Hypoxic Cell Sensitizers In a study designed to evaluate the efficacy of the cytotoxic agent mitomycin C in sensitizing hypoxic tumor cells to the effects of radiotherapy, patients with squamous cell carcinomas of the head or neck were treated with either conventional fractionated radiotherapy (70 Gy/35 fractions/7 weeks) or continuous hyperfractionated accelerated radiotherapy (55.3 Gy/17 consecutive days/33 fractions) with or without mitomycin C (20 mg/m2) given on day 5 of treatment [16]. Local tumor control and survival rates over a median follow-up period of 148 months were similar with the two radiotherapy regimens given alone; however, the addition of mitomycin C to the accelerated regimen significantly reduced both the local tumor control rate and the overall survival

Hyperbaric Oxygen and Carbogen Breathing The use of hyperbaric oxygen to overcome tumor hypoxia has been reported to produce an improved response to hypofractionated radiotherapy in a randomized trial in patients with advanced squamous cell carcinoma of the head or neck. Patients who received radiotherapy under hyperbaric oxygen at 4 atmospheres showed a higher 5year local relapse-free rate than those who received a similar radiotherapy regimen delivered in air (29 vs 16%; fig. 6). However, there were no significant differences between the two groups in 5-year survival, distant metastasis, or second primary tumors [17]. Similarly, carbogen breathing has also been shown to improve the results of chemoradiotherapy (carboplatin 5 mg/m2 given before radiation doses of 115 cGy twice

Prevalence and Treatment of Radiotherapy-Associated Anemia

Oncology 2002;63(suppl 2):11–18

15

Table 2. Influence of the pretreatment hemoglobin level and epoetin alfa on the outcome of therapy in patients

undergoing chemoradiation plus surgical treatment for squamous cell carcinomas of the oral cavity or oropharynx [24] Patient group

Group 1: patients with Hb 614.5 g/dl not treated with epoetin alfa (n = 43) Group 2: patients with Hb ! 14.5 g/dl not treated with epoetin alfa (n = 87) Group 3: patients with Hb ! 14.5 g/dl treated with epoetin alfab (n = 57)

Overall complete response, %a

2-year locoregional tumor control, %

2-year survival, %

65*

88**

81**

17

72

60

61*

95*

88*

* p (0.001 compared with group 2; ** p ! 0.05 compared with group 2; Hb = hemoglobin; SC = subcutaneously. Complete responses were determined by histopathologic analysis of the en bloc resection of the primary tumor and regional cervical lymphatics performed 5 to 6 weeks after the completion of chemoradiotherapy. b Dosage: 10,000 IU/kg SC 3 to 6 times per week until week of surgery. a

daily on 5 days per week for 7 weeks) in patients with locally advanced head or neck cancer. Anemic patients also received either blood transfusions or epoetin alfa to correct the anemia. Patients who breathed carbogen 4 min before and during irradiation exhibited improved local control, cause-specific survival, and overall survival at 18 months in comparison with a similar number of patients who received the same chemoradiotherapy regimen without carbogen breathing (fig. 7). The high response rates achieved in this study appeared to persist as the estimated probabilities of local control, cause-specific survival, and overall survival at 3 years in the carbogen breathing group were similar to the rates observed at 18 months [18]. Epoetin Alfa (Recombinant Human Erythropoietin; r-HuEPO) The ability of epoetin alfa to correct anemia prior to and during radiotherapy has been evaluated in cancer patients to determine whether it produces clinically meaningful benefit. Studies in patients receiving radiotherapy for various malignancies have shown that the administration of epoetin alfa, with or without oral iron, is effective in increasing hemoglobin levels and is well tolerated [19–21]. A study in our institution in cancer patients receiving a variety of different chemotherapy regimens with concomitant or sequential radiotherapy has shown that weekly epoetin alfa administration improved the mean hemoglobin level by 1.8–3.4 g/dl [22] (fig. 5). Improvements of this magnitude are similar to or greater than the reductions in hemoglobin noted during radio-

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Oncology 2002;63(suppl 2):11–18

therapy in our earlier study of the prevalence of anemia in patients with various malignancies (fig. 5). The effects of epoetin alfa on the outcomes of therapy have been studied in anemic patients (Hb !14.5 g/dl) with squamous cell carcinomas of the oral cavity or oropharynx [23, 24]. All patients in this study received a regimen consisting of mitomycin C (15 mg/m2 on day 1), 5fluorouracil (750 mg/m2 on days 1–5) and radiotherapy (50 Gy in 25 fractions during weeks 1–5), followed by dissection of the primary tumor bed and a neck dissection. Epoetin alfa (10,000 IU/kg subcutaneously 3 to 6 times per week until the week of surgery) was administered to a group of patients (n = 57) who had a pretreatment hemoglobin level !14.5 g/dl. The outcome in this group of patients was compared with the outcomes in two other groups who did not receive epoetin alfa. One of these nonepoetin alfa groups had a pretreatment hemoglobin level !14.5 g/dl (n = 87) and the other had a pretreatment hemoglobin level 614.5 g/dl (n = 43). The results are summarized in table 2. In the two groups of patients who did not receive epoetin alfa, those with a low pretreatment hemoglobin level (!14.5 g/dl) (group 2) exhibited significantly lower complete response rates, 2-year locoregional control rates, and 2-year survival rates than those who had normal hemoglobin levels (614.5 g/dl) (group 1). However, in the patients with a low pretreatment hemoglobin level who received epoetin alfa (group 3), the rates of complete response, 2-year locoregional control and 2year survival were equivalent to or higher than those in patients with normal pretreatment hemoglobin levels (group 1) [24].

Harrison/Shasha/Homel

These findings suggest that epoetin alfa is an effective and well-tolerated means of achieving normal hemoglobin levels in patients undergoing radiotherapy, and may reverse the negative prognostic influence of a low pretreatment hemoglobin level. Improvements in quality-oflife parameters (linear analog scale assessment) have also been noted with epoetin alfa therapy in groups of patients receiving a variety of different chemotherapy regimens with concomitant or sequential radiotherapy [22].

Potential Benefit of Epoetin Alfa in Reducing Radiotherapy-Induced Neurotoxicity

In addition to studies of the efficacy of epoetin alfa in improving the clinical outcome of radiotherapy in patients with low hemoglobin levels, its potential to reduce radiation-induced neurotoxicity is also being investigated. Studies in experimental animals have revealed that endogenous erythropoietin (EPO) possesses other biological activities in addition to erythropoietic effects, and that many cells besides erythroid progenitors express the erythropoietin receptor, including brain cells. As in the periphery, erythropoietin production is known to be induced by hypoxia in the central nervous system (CNS), and it has been shown in animals to protect CNS neuronal cells from ischemic injury [25]. A recent study found that erythropoietin receptors are abundantly expressed in capillaries of the brain-periphery interface, suggesting that this may provide a route for circulating erythropoietin to enter the brain [26]. In support of this hypothesis, a study in mice showed that systemic administration of epoetin alfa (5,000 IU/kg intraperitoneally) 24 h before or up to 6 h after controlled blunt trauma to the frontal cortex and then continued once daily for 4 additional days (5 doses total) attenuated the resultant brain injury. Quantitative analysis of the cavitary injury volume showed that the concussive injury in mice treated with epoetin alfa was significantly less than in those treated with saline. In addition, epoetin alfa also ameliorated the damage caused by experimentally-induced focal ischemic stroke in rat brains, reduced the severity of experimental autoimmune encephalitis in Lewis rats, and delayed and lessened seizures induced in mice by the glutamate analog kainic acid. These findings in different models of neurologic injury suggest that epoetin alfa is able to cross the bloodbrain barrier and may provide protection against CNS neurologic damage [26]. Further evidence in support of a protective effect of erythropoietin against neurologic damage is provided by

Prevalence and Treatment of Radiotherapy-Associated Anemia

the results of studies in our institution in which visual evoked potentials (VEPs) were measured in animals receiving radiotherapy in the presence and absence of rHuEPO. Pretreatment of animals with epoetin alfa significantly prolonged VEPs as compared with those not receiving epoetin alfa, suggesting that it may protect visual pathways against radiation-induced damage (A. Evans, unpublished data). If confirmed clinically, this finding may have substantial implications for the use of radiotherapy in patients with malignancies of the head, paranasal sinuses and ocular regions because it suggests that epoetin alfa may provide biologic protection of the optic nerve against radiation-induced damage.

Conclusions

Anemia may result in tumor hypoxia by decreasing the oxygen-carrying capacity of the blood, resulting in radiation and, in some instances, chemotherapy resistance. Anemia is associated with a poorer prognosis in a variety of malignancies. It may be an important obstacle to achieving maximal locoregional tumor control and survival with radiotherapy, even for small tumors not normally assumed to be hypoxic. In addition, anemia negatively affects the quality of life of cancer patients, as evidenced by worsening fatigue. In view of the high prevalence of anemia recorded in cancer patients receiving radiotherapy (about 50% at our institution), it is evident that measures to reverse anemia and tumor hypoxia should be considered an important component of treatment for such patients. Indeed, a number of strategies, notably the administration of epoetin alfa, have been found to attenuate the negative prognostic influence of a low hemoglobin level in patients receiving radiotherapy with or without chemotherapy. These findings indicate the need for radiation oncologists to be aware of the possibility of anemia in cancer patients undergoing radiotherapy so that timely intervention with strategies to improve the outcome of treatment can be instituted whenever anemia is diagnosed. In view of the potential benefits of treating anemia, it is hoped that this aspect of cancer management will receive more attention in the future.

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References 1 Shasha D: The negative impact of anemia on radiotherapy and chemoradiation outcomes. Semin Hematol 2001;38(3 suppl 7):8–15. 2 Kumar P: Tumor hypoxia and anemia: impact on the efficacy of radiation therapy. Semin Hematol 2000;37(4 suppl 6):4–8. 3 Dunst J: Hemoglobin level and anemia in radiation oncology: prognostic impact and therapeutic implications. Semin Oncol 2000;27(2 suppl 4):4–8, 16–17. 4 Becker A, Stadler P, Lavey RS, Hansgen G, Kuhnt T, Lautenschlager C, Feldmann HJ, Molls M, Dunst J: Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 2000;46:459–466. 5 Movsas B, Chapman JD, Greenberg RE, Horwitz EM, Pinover WH, Hanlon AL, Stobbe C, Hanks GE: Increasing levels of hypoxia in human prostate carcinoma correlate significantly with increasing clinical stage and age: an Eppendorf pO2 study. Int J Radiat Oncol Biol Phys 1999;45(3 suppl):202. 6 Brizel DM, Dodge RK, Clough RW, Dewhirst MW: Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999;53: 113–117. 7 Höckel M, Vorndran B, Schlenger K, Baussmann E, Knapstein PG: Tumor oxygenation: a new predictive parameter in locally advanced cancer of the uterine cervix. Gynecol Oncol 1993;51:141–149. 8 Warde P, O’Sullivan B, Bristow RG, Panzarella T, Keane TJ, Gullane PJ, Witterick IP, Payne D, Liu FF, McLean M, Waldron J, Cummings BJ: T1/T2 glottic cancer managed by external beam radiotherapy: the influence of pretreatment hemoglobin on local control. Int J Radiat Oncol Biol Phys 1998;41:347–353. 9 Fein DA, Lee WR, Hanlon AL, Ridge JA, Langer CJ, Curran WJ Jr, Coia LR: Pretreatment hemoglobin level influences local control and survival of T1–T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 1995;13:2077– 2083.

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10 Lee WR, Berkey B, Marcial V, Fu KK, Cooper JS, Vikram B, Coia LR, Rotman M, Ortiz H: Anemia is associated with decreased survival and increased locoregional failure in patients with locally advanced head and neck carcinoma: a secondary analysis of RTOG 85-27. Int J Radiat Oncol Biol Phys 1998;42:1069–1075. 11 van Acht MJ, Hermans J, Boks DE, Leer JW: The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinoma. Radiother Oncol 1992; 23:229–235. 12 Groopman JE: Fatigue in cancer and HIV/ AIDS. Oncology (Huntingt) 1998;12:335–344. 13 Sabbatini P: Contribution of anemia to fatigue in the cancer patient. Oncology (Huntingt) 2000;14(11A):69–71. 14 Sobrero A, Puglisi F, Guglielmi A, Belvedere O, Aprile G, Ramello M, Grossi F: Fatigue: a main component of anemia symptomatology. Semin Oncol 2001;28(2 suppl 8):15–18. 15 Harrison LB, Shasha D, Shiaova L, et al: Prevalence of anemia in cancer patients undergoing radiotherapy (abstract). Proc Am Soc Clin Oncol 2000;19:471a. 16 Dobrowsky WH, Naudé J, Widder J, Dobrowsky E: Continuous hyperfractionated accelerated radiotherapy and mitomycin C in head and neck cancer. Int J Radiat Oncol Biol Phys 1999;45(3 suppl):148. 17 Haffty BG, Hurley R, Peters LJ: Radiation therapy with hyperbaric oxygen at 4 atmospheres pressure in the management of squamous cell carcinoma of the head and neck: results of a randomized clinical trial. Cancer J Sci Am 1999;5:341–347. 18 Martinez A, Cabezon M, Fuentes C, Espiñeira M, Perez M, Serdio J, Artazkoz J, Gil J, Borque C, Villar A: Hyperfractionated chemoradiotherapy with carbogen breathing for advanced cancer of the head and neck. Int J Radiat Oncol Biol Phys 1999;45(3 suppl):377. 19 Lavey RS, Dempsey WH: Erythropoietin increases hemoglobin in cancer patients during radiation therapy. Int J Radiat Oncol Biol Phys 1993;27:1147–1152.

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20 Dusenbery KE, McGuire WA, Holt PJ, Carson LF, Fowler JM, Twiggs LB, Potish RA: Erythropoietin increases hemoglobin during radiation therapy for cervical cancer. Int J Radiat Oncol Biol Phys 1994;29:1079–1084. 21 Sweeney PJ, Nicolae D, Ignacio L, Chen L, Roach M 3rd, Wara W, Marcus KC, Vijayakumar S: Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: final report of a randomised, open-labelled, phase II trial. Br J Cancer 1998; 77:1996–2002. 22 Shasha D, George M, Harrison LB: Onceweekly dosing of epoetin alfa increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concurrently or sequentially with chemotherapy. Presented at the 42nd Annual Meeting of the American Society of Hematology, San Francisco, CA, Dec 2000. 23 Glaser CM, Millesi W, Kornek GV, Lang S, Schüll B, Klug K, F, Wanschitz F, Lavey RS: Impact of hemoglobin (Hgb) level and use of recombinant human erythropoietin (r-HuEPO) on response to neoadjuvant chemoradiation therapy, tumor control, and survival in patients with oral or oropharyngeal squamous cell carcinoma (SCCA). Int J Radiat Oncol Biol Phys 1999;45(3 suppl):149. 24 Glaser CM, Millesi W, Kornek GV, Lang S, Schüll B, Watzinger F, Selzer E, Lavey RS: Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001;50:705– 715. 25 Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R: In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 1998;95:4635–4640. 26 Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A: Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000;97:10526– 10531.

Harrison/Shasha/Homel

Oncology 2002;63(suppl 2):19–28 DOI: 10.1159/000067148

Raising Hemoglobin: An Opportunity for Increasing Survival? Gillian M. Thomas Department of Radiation Oncology, Obstetrics & Gynecology, University of Toronto, Toronto-Sunnybrook Regional Cancer Centre, Toronto, Canada

Key Words Anemia W Hemoglobin W Hypoxia W Angiogenesis W Cancer W Radiotherapy W Chemotherapy W Surgery W Prognostic factor W Epoetin alfa

creased oxygen carrying capacity may lead to increased tumor hypoxia, radiation resistance and increased tumor angiogenesis. The interrelationship of low hemoglobin levels, hypoxia, tumor angiogenesis and survival is explored in this article. Copyright © 2002 S. Karger AG, Basel

Abstract Although the association between low hemoglobin levels and poorer outcomes in radiation oncology has long been recognized, anemia is often overlooked and untreated. However, a growing body of clinical evidence now indicates that low hemoglobin levels during radiation treatment are associated with decreased response and survival following radiotherapy. For example, a large Canadian retrospective study in patients receiving radical radiotherapy for cervical cancer showed that the 5-year survival rate was 19% higher in those whose hemoglobin during radiation treatment was =12 g/dl compared to those with levels ! 12 g/dl. The data suggest that clinical trials need to be performed to determine whether increasing hemoglobin levels leads to improved local control and survival. The mechanism by which low hemoglobin levels could cause poorer outcomes is not well understood and needs further elucidation. It is postulated that lower hemoglobin levels resulting in de-

ABC

© 2002 S. Karger AG, Basel 0030–2414/02/0636–0019$18.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ocl

Introduction

In radiation oncology, it is widely accepted that tumor hypoxia causes radiation resistance. Anemia is also associated with poorer outcomes to radiation. It has been inferred that there is a causal relationship between low hemoglobin levels, the resulting hypoxia and a poor outcome of radiotherapy in patients with cancer. Even though hemoglobin levels are monitored at most radiation oncology centers, anemia is often overlooked by radiation oncologists and is frequently only treated if severe. It has been suggested that oncologists do not routinely treat mild-to-moderate anemia as it is perceived to be clinically unimportant [1] and that patients are often not transfused unless hemoglobin levels fell below 10 g/dl or even 8 g/dl [1, 2]. For example, a US study in 1987 showed approximately two-thirds of academic radiation

Gillian M. Thomas, BSc, MD, FRCPC GlaxoSmithKline, 7333 Mississauge Road North Mississauge, Ont. L5N 8L4 (Canada) Tel. +1 905 814 2256, Fax +1 905 814 2100 E-Mail [email protected]

Table 1. Summary of studies which examined the relationship between anemia and outcome (local control B survival) of radiotherapy B chemotherapy in patients with cancer

Tumor site

Number of studies

Effect of anemia on outcome, number of studies Adverse

Bladder Bronchus Cervix Glioma Head and neck Prostate Total

6 5 22 1 17 1 52 (100%)

None

6 0 4 1 19 3 0 1 11 6 0 1 40 (76.9%) 12 (23.1%)

oncology departments transfusedpatients only if their hemoglobin levels were = 10 g/dl [3]. This reluctance to correct anemia was further increased in Canada in the late 1980s when the risk of contracting HIV or hepatitis from contaminated blood was first recognized. Although views are changing, there is still much uncertainty among radiation oncologists about the clinical importance of radiotherapy-associated anemia and the exact benefits of increasing hemoglobin levels. However, a growing body of clinical data is gathering in the medical literature which examines the relationship between hemoglobin levels and response to radiotherapy in patients with cancer. The present article reviews these data and also seeks to explore some of the downstream mechanisms, namely tumor hypoxia and angiogenesis, that may link low hemoglobin levels with clinical outcome in patients with cancer. It also poses questions for future study that may help to clarify treatment options for this patient group.

was no consistency in how it was defined (i.e., cut-off hemoglobin levels ranged from 10 to 12.5 g/dl). Nevertheless, 40 of the 52 (76.9%) studies showed that low hemoglobin levels were adversely related to local control and/or survival after radical adverse radiotherapy (table 1). There are two possible explanations, not mutually exclusive, for the observed relationship between low hemoglobin levels and impaired outcomes with radiotherapy. First, low hemoglobin levels may be a tumor-related marker for an aggressive cancer. In this scenario, it is unlikely that raising hemoglobin levels will improve the outcome of radiotherapy. The second, and more traditional, explanation is that there is a causal relationship between low hemoglobin levels and poor outcome of therapy. With a causal relationship, raising hemoglobin levels might therefore improve outcome following radiotherapy [4]. Until recently, clinical evidence to support a causal relationship between low hemoglobin levels and poor outcome was relatively limited. A single prospective, randomized trial, conducted over 30 years ago, was interpreted as demonstrating some benefit after correcting anemia during radiotherapy in patients with cervical cancer [5]. Pelvic recurrence occurred in 11 of 67 patients (16.4%) who received transfusions and maintained hemoglobin levels 112 g/dl compared with 21 of 68 patients (30.9%) who were given transfusions only if their hemoglobin levels dropped to !10 g/dl. No differences in survival were noted between the two treatment groups [5]. Although this study is widely quoted in the medical literature as proof that correcting hemoglobin levels improves outcomes following radiotherapy, the study was underpowered and had an inconclusive univariate analysis which did not assess the possible effect of other prognostic factors on patient outcome.

Studies in Patients with Cervical Cancer Effect of Hemoglobin Levels on Treatment Outcome

Historic Data More than 50 studies have investigated the effect of low hemoglobin levels at the start of radiotherapy B chemotherapy on outcomes in patients with various cancers [mostly of the cervix (42%) or head and neck (33%)] mainly using univariate analysis. A summary of these studies is provided in table 1. It should be noted that, although the term ‘anemia’ was used in all studies, there

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Radiotherapy Alone To examine the relationship between anemia and treatment outcome more rigorously, a large retrospective study using data from seven Canadian radiation oncology centers between 1989 and 1992 was performed [4]. The aim of the study was to examine the prevalence of anemia, its time course, and the effect of anemia and blood transfusions on the treatment outcome in 605 patients who had radical radiotherapy for cervical cancer. At presentation, approximately one-third of patients had hemoglobin levels of =12 g/dl (i.e., below the lower

Thomas

Table 2. Significance of prognostic factors on outcome of radiotherapy in 605 patients with cervical cancer: results of a multivariate analysis (with permission from Grogan et al. [4])

1.0 —– Hb =12.0 g/dl (n = 337) - - - Hb <12.0 g/dl (n = 172)

0.8

Significant Stage Average weekly nadir hemoglobin level Intracavitary treatment Squamous histology

p value

0.0001 0.0001 0.0004 0.0446

Nonsignificant Age Presenting hemoglobin level Radiation dose Center Transfusion Transfusion year Treatment volume Treatment time Chemotherapy

Survival

Prognostic factor

0.6 0.4 p <0.003

0.2 0.0

0

1

2

3

4

5

6

Year

Fig. 1. Survival in patients with carcinoma of the cervix receiving

radiotherapy stratified according to hemoglobin level (Hb) at presentation (reproduced with permission from Grogan et al. [4]).

1.0 0.8

Hemoglobin Levels and Outcome in Cancer Patients

— L – H (n = 25)

— H – H (n = 228)

Survival

limit of the normal range for women). Despite this, only 25% of patients received blood transfusions because clinicians were more likely to transfuse patients with nadir hemoglobin levels of !10 g/dl. This is demonstrated by the fact that most patients with hemoglobin levels of !9 g/dl (90%) and !10 g/dl (77%) were transfused, whereas much fewer patients (3–41%) with hemoglobin levels between 10 and 12 g/dl received transfusions. In all, four of the seven centers had policies for blood transfusion often not followed: two recommended transfusions for patients with hemoglobin levels of !10 g/dl, and one each for patients with hemoglobin levels of !11 and !12 g/dl [4]. The Canadian study showed that hemoglobin levels at baseline correlated with patient survival (fig. 1). This is consistent with earlier data indicating a correlation between anemia and poor prognosis in patients receiving radiotherapy B chemotherapy (table 1). Using a cut-off value for hemoglobin levels of 12 g/dl, the Canadian study reported a 12% greater 5-year survival rate in patients with baseline hemoglobin levels of 612 g/dl than in those with baseline levels of 612 g/dl (p ! 0.003; fig. 1). Hemoglobin levels at baseline also had a significant effect on disease-free survival (p = 0.005) and control of local pelvic disease (p = 0.002) according to univariate analysis [4]. Of note, however, are the results of the multivariate analysis from this study which considered patient-, tumor- and treatment-related factors, as well as hemoglobin

0.6 — L – L (n = 140) — H – L (n = 82)

0.4 p <0.0002

0.2 0.0

0

1

2

3 Year

4

5

6

Fig. 2. Survival in patients withcarcinoma of the cervix according to hemoglobin levels at baseline and during radiotherapy, where L indicates hemoglobin levels of ! 12 g/dl and H indicates hemoglobin levels of 612 g/dl. Results are adjusted for disease stage and for the use of intracavitary irradiation (reproduced with permission from Grogan et al. [4]).

levels (table 2). The multivariate analysis showed that hemoglobin levels during radiotherapy, rather than at presentation, were predictive of outcome of radiotherapy in terms of overall survival (p = 0.0001; table 2) [4] second in importance only to tumor stage. Average weekly hemoglobin nadir, which was calculated by averaging the weekly nadir hemoglobin levels for each patient, was taken as an estimate of hemoglobin levels during radiotherapy. Other significant prognostic factors for outcome were disease stage, intracavitary treatment, and squamous histology

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21

1.0 Hb

Survival

0.8

Fig. 3. Survival in patients with carcinoma of the cervix according to transfusion status and average weekly nadir hemoglobin levels (Hb) during radiotherapy, where T = transfused and NT = not transfused (reproduced with permission from Grogan et al. [4]).

NT T

0.6

NT T

0.4

NT

0.0

0

(table 2). Initial hemoglobin levels were not significant suggesting that the effect of low presenting hemoglobin levels could be overcome by raising the level during treatment. To further examine the differential impact of low hemoglobin levels during treatment versus those at presentation, the survival data were reanalyzed according to hemoglobin levels both at baseline and during radiotherapy (fig. 2; n = 475). The analysis showed that patients who had low hemoglobin levels during radiotherapy, regardless of their baseline hemoglobin levels, had a significantly poorer rate of survival than those whose hemoglobin levels were maintained greater than 12 g/dl during radiotherapy (fig. 2). The 5-year survival rates for those with low hemoglobin levels during radiotherapy were 51% or less compared with rates of at least 70% in patients who had high hemoglobin levels during radiotherapy (fig. 2). The relapse rates in patients with low hemoglobin levels during radiotherapy (56 and 60%) were almost double those of patients with high hemoglobin levels during therapy (32 and 33%). Interestingly, patients with high hemoglobin levels during radiotherapy also showed significant reductions in both pelvic (p ! 0.0001) and extrapelvic failure rates (p ! 0.0006) [4]. Finally, the study examined whether raising hemoglobin levels with blood transfusions influenced the outcome of radiotherapy (fig. 3). A significant stepwise increase in overall survival was observed with increasing hemoglobin levels during radiotherapy (fig. 3; p ! 0.0001). Survival rates were not significantly different between patients who attained a given hemoglobin level spontaneously and those who received blood transfusions (fig. 3). These data

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T

p <0.0001

0.2

1

2

3

4

5

12.0 g/dl 11.0–11.9 g/dl <11.0 g/dl

6

Year

show that it is the hemoglobin level attained, rather than the use of blood transfusions, that influenced outcome in these patients. It also confirmed the prognostic significance of hemoglobin levels during radiotherapy [4]. It was concluded from the Canadian study that the hemoglobin level during radiotherapy is an important prognostic factor, second only to disease stage, in patients with cervical cancer. The survival data from this study generate the hypothesis that maintaining hemoglobin levels above 12 g/dl in patients with cervical cancer can improve the response to radiotherapy. The study further showed that the mechanism by which hemoglobin levels are maintained (i.e., transfusion) is not important, but rather the hemoglobin level that is attained during radiotherapy. Concurrent Radiotherapy and Chemotherapy Since the study by Grogan et al. [4] was completed, concurrent cisplatin-based chemotherapy and radiotherapy has emerged as the treatment of choice for patients with advanced cancer of the cervix [6] as for many other epithelial cancers. A recent study by Pearcey et al. [7], however, showed no benefit for the addition of concurrent cisplatin to radiation. Contrary to the previous trials in patients with cervical cancer, which demonstrated a survival benefit for chemoradiotherapy versus radiotherapy alone [8–12], Pearcey et al. [7] observed similar 3- and 5-year survival rates with concurrent cisplatin and radiotherapy versus radiotherapy alone in patients with advanced cervical carcinoma. While there are many possible explanations for the lack of benefit observed with chemoradiotherapy in

Thomas

Fig. 4. Distribution of patients with ad-

vanced cervical cancer according to decrease in hemoglobin levels (Hb) during therapy. Patients were randomized to receive pelvic radiotherapy alone (n = 126) or radiotherapy plus cisplatin 40 mg/m2 weekly (n = 127) (reproduced with permission from Pearcey et al. [7]).

this trial, one reason may have been a differential drop in hemoglobin levels during therapy (fig. 4) between treatment groups. As would be expected, decreases in hemoglobin levels were found to be significantly greater in patients receiving chemotherapy plus radiotherapy versus those receiving radiotherapy alone (fig. 4). Thus, is it possible that the decreases in hemoglobin levels during therapy abrogated the beneficial effects of chemotherapy in this study.

therapy in a cancer type other than cervical cancer. Some have postulated that the poor results in anemic patients are a result of the association between anemia and large tumor volumes and development of distant metastases. Since laryngeal cancer does not have these characteristics, these data add weight to the suggestion that the relationship between anemia and outcome is not solely tumorrelated; the hypothesis generated is that some decrement in response to therapy may occur if the hemoglobin level is low during treatment.

Studies in Patients with Head and Neck Cancer Effect of Hypoxia on Treatment Outcome

Several studies have looked at the impact of anemia on clinical outcome following radiotherapy in patients with head and neck cancer (for review see Kumar 2001) [13]. As an example, van Acht et al. [14] observed that the 10-year rate of disease-free survival was significantly lower in patients with laryngeal cancer (n = 306) whose hemoglobin levels were below normal (!8.5 mmol/l in men and !7.5 mmol/l in women) after radiotherapy than in those with normal hemoglobin levels. Patients with glottic carcinoma and hemoglobin levels below normal at the start and/or the end of radiotherapy had significantly reduced 10-year disease-free survival rates (p = 0.009 and 0.0012, respectively), whereas below-normal hemoglobin levels at the end of therapy only were predictive of disease-free survival in those with supraglottic cancers (p = 0.05) [14]. These data are of interest because they confirm the negative association between low hemoglobin levels at the end of treatment and survival following definitive radio-

Hemoglobin Levels and Outcome in Cancer Patients

Hypoxia is a characteristic feature of solid tumors which is thought to occur when tumor growth exceeds the ability of the local microvasculature to supply oxygen. It is thought that approximately 60% of locally advanced squamous cell cervical carcinomas contain hypoxic and/ or anoxic areas of tissue [15]. Resistance to treatment and accelerated tumor growth and progression occur as a result of hypoxia. Hypoxia causes resistance to both radiotherapy and chemotherapy. It is now well established that intratumoral hypoxia has a negative effect on locoregional control in patients receiving definitive radiotherapy for head and neck or cervical cancer. Table 3 provides a summary of studies that measured tumor oxygenation levels directly and correlated tumor oxygenation status with locoregional control following radiotherapy [16–21]. Although the definitions assigned to hypoxia differed between studies, four of six studies showed a significant increase in local failure

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23

Table 3. Summary of studies investigating

locoregional control following radiotherapy according to tumor oxygenation status in patients with cervical or head and neck cancer

Study

Local failure rate (patients) nonhypoxic tumors

Fyles et al. [16] Höckel et al. [17] Kolstad [18] Brizel et al. [19] Gatenby et al. [20] Nordsmark et al. [21]

rate in patients who had hypoxic tumors compared with those whose tumors were oxygenated (table 3). It has long been recognized that hypoxia adversely affects the sensitivity of tumor cells to many chemotherapeutic agents. Although the precise mechanisms are unknown, oxygen is a radiosensitizer and impairs the ability to repair DNA damage caused by radiation-induced free radicals. More recently, attention has focused on the ability of tumor hypoxia to enhance malignant progression. This is based on the findings of Höckel et al. [17] who showed that, following tumor resection in 47 patients with cervical cancer, hypoxic tumors had larger extensions, more frequent parametrial spread and lymph-vascular involvement compared with oxygenated tumors. It is thought that hypoxia may drive disease progression through clonal selection and genome changes (for review see Höckel & Vaupel 2001) [22], which in turn produces a growth advantage for tumor cells that are resistant to apoptosis. Hypoxic tumors may overexpress the suppressor gene p53, a phenotype with a high malignant potential [23]. Hypoxia may also induce changes within the tumor cells for the expression of oxygen-dependent proteins, such as vascular endothelial growth factor (VEGF), which stimulate angiogenesis and increase the potential for tumor growth and metastases [24].

Effect of Angiogenesis on Treatment Outcome

Angiogenesis, the growth of new capillary vessels supporting tumor growth and progression, is stimulated by hypoxia. A summary of molecular events linking angiogenesis with intratumoral hypoxia is provided in table 4 [25]. Like hypoxia, angiogenesis has also been shown to influence outcome to surgery in patients with cancer,

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Tumor site

Oncology 2002;63(suppl 2):19–28

Cervix Cervix Cervix Head and neck Head and neck Head and neck

4/21 4/19 4/21 3/10 1/19 5/18

p value

hypoxic tumors 6/10 10/23 6/10 11/17 11/12 11/17

0.03 0.13 0.03 0.09 !0.001 0.03

Table 4. Molecular events linking hypoxia and angiogenesis [25]

Hypoxia-regulated genes (e.g., VEGF, EPO, LDHA, Glut-1) HIF-1· mediates transcriptional response by binding to the hypoxia responsive elements of genes HIF-1· induces VEGF and increases expression and half-life of mRNA Hypoxia leads to loss of p53, increases VEGF and decreases TSP-1 H-ras and V-src (oncoproteins) amplify response to hypoxia and lead to increased VEGF and decreased TSP-1 EPO = erythropoietin; HIF-1a = hypoxia-inducible factor 1a; LDHA = lactate dehydrogenase A; TSP-1 = thrombospondin-1; VEGF = vascular endothelial growth factor.

although the available data are limited. Obermair et al. [26] used microvessel density count as a measure of angiogenesis in patients with stage IB cervical cancer who underwent surgery. They found that the 5-year overall survival rate was significantly better in patients with a microvessel density of 20/field (n = 102) than in those with higher microvessel densities (n = 64) (80.7 versus 63.0%; p ! 0.0001). More recently, Birner et al. [27] showed that the expression of hypoxia-inducible factor 1a (HIF-1a), a transcriptional factor that promotes angiogenesis and regulates genes involved in the response to hypoxia, influenced prognosis in 91 surgically-treated patients with stage I cancer of the cervix. Once again, patients with strong expression of HIF-1a had a significantly poorer overall survival (p = 0.03) and disease-free survival (p ! 0.0001) compared with those with moderate or no expression of HIF-1a.

Thomas

Fig. 5. Possible management options to overcome the problems of anemia and hypoxia during radiotherapy. HCRS = Hypoxic cell radiation sensitizers; HT = hyperthermia; HBO = hyperbaric oxygen.

Anemia, Hypoxia and Angiogenesis: Are They Linked?

While there is evidence to suggest a direct association between hypoxia and angiogenesis, less is known about how anemia is linked to hypoxia and angiogenesis (fig. 5). Anemia may exacerbate intratumoral hypoxia by lowering the oxygen carrying capacity of the blood, although the link between the two and its relevance in the clinical setting remain controversial [1]. Nordsmark et al. [28] in Denmark recently showed that there was no relationship between hemoglobin levels and pretreatment tumor oxygen partial pressure in 263 patients with head and neck carcinoma. However, both hemoglobin levels and tumor oxygenation status (pO2 fraction !2.5 mm Hg) were independent prognostic factors for overall survival. Likewise Brizel et al. [29] noted only a weak association between low hemoglobin levels and poor tumor oxygenation status in patients with head and neck cancer receiving primary radiotherapy; many patients with higher hemoglobin levels (= 13 g/dl) also had hypoxic tumors. These data suggest that low hemoglobin levels and tumor hypoxia may be linked in a complex fashion but other factors, tumor

Hemoglobin Levels and Outcome in Cancer Patients

type and individual patient physiology, may also be involved. The relationship between anemia and angiogenesis remains poorly understood and data are sparse. A German group [30] showed that there was a trend towards higher serum VEGF levels in cancer patients with low hemoglobin levels undergoing radiotherapy, suggesting that anemia may stimulate angiogenesis via hypoxia. Patients had previously untreated, non-metastatic gynecologic cancer (n = 22), head and neck cancer (n = 14), gastrointestinal cancer (n = 13), lung cancer (n = 4) and prostate cancer (n = 1). In 26 patients with hemoglobin levels of !13 g/dl, mean serum VEGF levels were 805,656 pg/ml compared with levels of 438,360 pg/ml in 28 patients with hemoglobin levels of 113 g/dl (p = 0.016) [30].

Correcting Hemoglobin Levels

There are several potentially reversible causes of anemia (such as nutritional deficiencies, chronic blood loss, and subclinical disseminated intravascular coagulopathy), which should be sought and, if possible, corrected in

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25

patients presenting with anemia. A summary of management options for the prevention and treatment of hypoxia and anemia in patients with cancer in the radiation oncology setting, some of which are in the early stages of development, are summarized in figure 5. Transfusion of red blood cells is one readily available management option for patients with anemia (fig. 5), although it carries risks of unwanted transfusion reactions, infectious disease transmission, and possibly immunomodulation. Concerns about the risks of homologous blood transfusion, uncertainty about the benefits and inconvenience, mean that anemia is often undertreated in patients undergoing radiotherapy unless they are clearly symptomatic or have very low hemoglobin levels (!10 g/dl) [2]. Recombinant human erythropoietin is an alternative option that avoids the risks associated with transfusions. While several trials have already demonstrated that epoetin alfa (Procrit®; Ortho Biotech Products, LP, Bridgewater, NJ; Eprex®/Erypo®; Janssen-Cilag and Ortho Biotech outside the US) effectively corrects anemia and improves quality of life in patients with cancer receiving chemotherapy [31–35], it is only more recently that its use has been examined in patients receiving radiotherapy or combined chemoradiotherapy [36–42]. For example, a prospective, multicenter trial performed in Austria [40] showed that 84% of 143 patients with anemia responded to epoetin alfa, which was initiated approximately 10 days prior to radiotherapy or chemoradiotherapy. Hemoglobin levels increased at a median rate of 0.37 g/dl/week with epoetin alfa. These data are consistent with previous studies, which demonstrated the efficacy of epoetin alfa in cancer patients [36–39, 41, 42]. Furthermore, there are now data to support the use of epoetin alfa administered once weekly [41, 42], rather than the less convenient 3-times weekly regimen that is currently approved for use in anemic cancer patients receiving chemotherapy. In a multicenter study performed in the US, Shasha et al. [42] showed that overall patient quality of life, and energy and activity levels were significantly improved (p ! 0.05 versus baseline) after subcutaneous epoetin alfa 40,000 units was administered once weekly for 16 weeks. The size of effect observed with epoetin alfa (0.5–0.7) was judged to be representative of a medium to large improvement in patient quality of life [42].

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Future Research

Examining the impact of raising hemoglobin levels in cancer patients and finding ways of overcoming tumor hypoxia will be important areas of research over the next decade. The specific questions that need to be addressed include: E Does raising hemoglobin levels improve patient survival? E If so, by what mechanisms (i.e., does it improve the effectiveness of radiotherapy or chemotherapy or does it actually switch off the molecular events that lead to tumor growth, progression and metastases)? E What constitutes the ‘optimal’ hemoglobin level in patients with cancer? This may depend not only on tumor- and patient-related factors but also on the functional endpoint being studied. In an attempt to answer some of these questions, the Gynecologic Oncology Group (GOG) has initiated an international randomized trial in patients with stage IIB– IVA cervical cancer and hemoglobin levels of !13 g/dl. Patients will receive standard combination therapy of weekly cisplatin and radiotherapy with or without subcutaneous epoetin alfa 40,000 units administered once weekly. Blood transfusions are permitted in the control group if hemoglobin levels fall to !10 g/dl and in the epoetin alfa group if hemoglobin levels drop precipitously or are too low to raise to 112 g/dl before chemoradiotherapy begins. As well as survival, patient quality of life and economic outcomes will be evaluated in this trial. Ancillary studies will also be performed in an attempt to elucidate the underlying molecular mechanisms. These include monitoring cell markers of hypoxia (EF5 or 2-(2nitro-1-H-imidazol-I-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide) and angiogenesis [VEGF, thrombospondin-1 and platelet/endothelial cell adhesion molecule-1 (PECAM-1 or CD31)]. There will also be an assessment of the prognostic value of DNA-cisplatin adducts taken from buckle smears.

Conclusions

A growing body of literature now shows that there is a relationship between low hemoglobin levels and low rates of disease control and survival in the radiation oncology setting. Data suggest that correcting anemia with epoetin alfa improves quality of life, and we postulate, may improve response and thus impact survival following radiotherapy with or without concurrent chemotherapy.

Thomas

Although the long-term implications of correcting anemia have yet to be definitively established, collectively, these data suggest that it may be important to maintain adequate hemoglobin levels in patients receiving radiotherapy. At present, radiation oncologists are focused on whether or not it is possible to improve the control of local disease and survival, but it is important to consider patient

quality of life also. This is particularly relevant given the aggressive combined modality and high-dose treatment strategies commonly used in oncology today. Therefore, the challenge for the future will be to devise a unified approach to the management of anemia in patients with cancer, with the aim of improving both disease outcome and patient quality of life.

References 1 Shasha D, Harrison LB: Anemia treatment and the radiation oncologist: optimizing patient outcomes. Oncology (Huntingt) 2001;15:1486– 1496. 2 Littlewood TJ: The impact of hemoglobin levels on treatment outcomes in patients with cancer. Semin Oncol 2001;26(suppl 8):49–53. 3 Poskitt TR: Radiation therapy and the role of red blood cell transfusion. Cancer Invest 1987; 5:231–236. 4 Grogan M, Thomas GM, Melamed I, Wong FL, Pearcey RG, Joseph PK, Portelance L, Crook J, Jones KD: The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 1999;86:1528–1536. 5 Bush RS, Jenkin RD, Allt WE, Beale FA, Bean H, Dembo AJ, Pringle JF: Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer 1978;37(suppl):302–306. 6 Thomas GM: Improved treatment for cervical cancer – concurrent chemotherapy and radiotherapy. N Eng J Med 1999;340:1198–1200. 7 Pearcey RG, Brundage M, Drouin P, Jeffrey J, Johnston D, Lukka H, MacLean G, Souhami L, Stuart G, Tu D: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncology 2002;20:966–972. 8 Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC, Clarke-Pearson DL, Liao SY: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIBIVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999;17:1339–1348. 9 Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM, Mutch DG: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Eng J Med 1999;340:1137–1143. 10 Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL, Insalaco S: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Eng J Med 1999;340: 1144–1153.

Hemoglobin Levels and Outcome in Cancer Patients

11 Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL, Walker JL, Gersell D: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Eng J Med 1999;340:1154– 1161. 12 Peters WA, Liu PY, Barrett RJ, Stock RJ, Monk BJ, Souhami L, Grigsby P, Gordon W, Alberts DS: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18: 1606–1613. 13 Kumar P: Impact of anemia in patients with head and neck cancer. Oncologist 2000;5(suppl 2):13–18. 14 van Acht MJ, Hermans J, Boks DE, Leer JW: The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinoma. Radiother Oncol 1992; 23:229–235. 15 Vaupel P, Kelleher DK, Höckel M: Oxygenation status of malignant tumors: Pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol 2001;2(suppl 8):29–35. 16 Fyles AW, Milosevic M, Wong R, Kavanagh MC, Pintilie M, Sun A, Chapman W, Levin W, Manchul L, Keane TJ, Hill RP: Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 1998;48:149–156. 17 Höckel M, Schlenger K, Aral B, Mitze M, Schäffer U, Vaupel P: Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996;56:4509–4515. 18 Kolstad P: Intercapillary distance, oxygen tension and local recurrence in cervix cancer. Scand J Clin Lab Invest 1968;106(suppl):145– 157. 19 Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW: Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997; 38(2):285–289. 20 Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, Broder GJ: Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1988;14:831–838.

21 Nordsmark M, Overgaard M, Overgaard J: Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 1996; 41:31–39. 22 Höckel M, Vaupel P: Biological consequences of tumor hypoxia. Semin Oncol 2001;28(suppl 8):36–41. 23 Hlatky L, Tsionou C, Hahnfeldt P, Coleman CN: Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res 1994; 54:6083–6086. 24 Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF, Senger DR: Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 1993;143:1255–1262. 25 Blancher C, Harris AL: The molecular basis of the hypoxia response pathway: tumour hypoxia as a therapy target. Cancer Metastasis Rev 1998;17(2):187–194. 26 Obermair A, Wanner C, Bilgi S, Speiser P, Kaider A, Reinthaller A, Leodolter S, Gitsch G: Tumor angiogenesis in stage IB cervical cancer: correlation of microvessel density with survival. Am J Obstet Gynecol 1998;178:314–319. 27 Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G: Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000;60: 4693–4696. 28 Nordsmark M, Rudat V, Lartigau E, Stadler P, Becker A, Adam M, Molls M, Dunst J, Terris D, Overgaard J: Hypoxia and hemoglobin as prognostic markers of survival in head & neck carcinoma after primary radiation therapy. An international multi-center study (abstract 125). Eur J Cancer 2001;37(suppl 6):37. 29 Brizel DM, Dodge RK, Clough RW, Dewhirst MW: Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999;53: 113–117. 30 Dunst J, Pigorsch S, Hansgen G, Hintner I, Lautenschlager C, Becker A: Low hemoglobin is associated with increased serum levels of vascular endothelial growth factor (VEGF) in cancer patients. Does anemia stimulate angiogenesis? Strahlenther Onkol 1999;175:93–96.

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31 Littlewood TJ, Bajetta E, Nortier JWR, Vercammen E, Rapoport B: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, doubleblind, placebo-controlled trial. J Clin Oncol 2001;19:2865–2874. 32 Dammacco F, Silvestris F, Castoldi GL, Grassi B, Bernasconi C, Nadali G, Perona G, De Laurenzi A, Torelli U, Ascari E, Rossi Ferrini PL, Caligaris-Cappio F, Pileri A, Resegotti L: The effectiveness and tolerability of epoetin alfa in patients with multiple myeloma refractory to chemotherapy. Int J Clin Lab Res 1998;28: 127–134. 33 Garton JP, Gertz MA, Witzig TE, Greipp PR, Lust JA, Schroeder G, Kyle RA: Epoetin alfa for the treatment of the anemia of multiple myeloma. A prospective, randomized, placebocontrolled, double-blind trial. Arch Intern Med 1995;155:2069–2074. 34 Demetri GD, Kris J, Wade J, Degas L, Celia D: Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. J Clin Oncol 1998;16:3412–3425.

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35 Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedyian S, Vadhan-Raj S: Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997;15:1218– 1234. 36 Lavey RS: Clinical trial experience using erythropoietin during radiation therapy. Strahlenther Onkol 1998;174(suppl 4):24–30. 37 Dusenbery KE, McGuire WA, Holt PJ, et al: Erythropoietin increases hemoglobin during radiation therapy for cervical cancer. Int J Radiat Oncol Biol Phys 1994;29:1079–1084. 38 Antonadou D, Cardamakis E, Sarris G, et al: Effect of the administration of recombinant human erythropoietin in patients with pelvic malignancies during radiotherapy. Radiother Onol 1998;48:S122. 39 Glaser CM, Millesi W, Kornek GV, Lang S, Schull B, Watzinger F, Selzer E, Lavey RS: Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001;50(3):705– 715.

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40 Hawliczek R, Oismüller R: The effect of systematic rHu-erythropoietin (Epoietin alpha [sic]) treatment before and during radiotherapy (radio-chemotherapy) in unselected anemic cancer patients: results of an Austrian multicenter observation study (abstract 1465). Eur J Cancer Clin Oncol 1999;35(suppl 4):S361. 41 Gabrilove JL, Cleeland CS, Livingston RB, Sarokhan B, Winer E, Einhorn LH: Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001; 19:2875–2882. 42 Shasha D, George MJ, Harrison LB: Onceweekly dosing of epoetin alfa increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy (poster). Presented at the American Society of Hematology (ASH), 3 Dec 2000, San Francisco (CA).

Thomas

Oncology 2002;63(suppl 2):29–38 DOI: 10.1159/000067145

New Chemotherapeutic Agents: Update of Major Chemoradiation Trials in Solid Tumors Walter J. Curran Department of Radiation Oncology, Jefferson Medical College, Philadelphia, Pa., USA

Key Words Radiotherapy W Chemoradiation W Solid tumors W Locoregional control W Combined modality therapy

Abstract The institution of combined modality therapy for unresected solid tumors has resulted in significant improvements in tumor control and survival benefit compared with radiotherapy (RT) alone. A number of chemotherapy agents that can enhance the effectiveness of RT, such as cisplatin and 5-fluorouracil, are now considered standard treatment for patients with a number of cancer types. There is growing interest in a number of additional agents that have also been found to have radiosensitizing ability. These include paclitaxel, docetaxel, irinotecan, gemcitabine, and vinorelbine, as well as biologic agents. Other agents may be of value because they act to counter dose-limiting toxicities associated with RT. This article provides an update of some important, recently completed and ongoing clinical trials evaluating novel chemoradiation protocols, with examples taken primarily from studies conducted by the Radiation Therapy Oncology Group (RTOG). Theoretical approaches to the development of new agents and combined modality regimens are also discussed. Copyright © 2002 S. Karger AG, Basel

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Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ocl

Introduction

Combined modality therapy has been instituted for the treatment of several types of unresectable solid tumors, with various chemotherapeutic agents used either sequentially or concurrently with radiation. Some of these combination therapies have resulted in significant improvements in tumor control and survival benefit compared with radiotherapy (RT) alone. For example, Cancer and Leukemia Group B (CALGB) 8433 was the first major chemoradiotherapy trial to demonstrate a significant survival advantage with sequential chemotherapy and radiation in patients with inoperable stage III non-small-cell lung cancer (NSCLC) [1]. These results were subsequently confirmed in the same patient population in a phase III study carried out by the Radiation Therapy Oncology Group (RTOG) [2]. A number of chemotherapy agents, including radiosensitizing agents such as cisplatin and 5-fluorouracil (5-FU), that can be used in conjunction with RT have been identified and found to be effective in enhancing tumor control and/or improving survival rates in clinical trials. There has since been growing interest in a number of agents that have also been found to have radiosensitizing ability, including paclitaxel, docetaxel, irinotecan, gemcitabine, and vinorelbine, as well as agents with other antitumor activities, including the antiangiogenesis drugs [3–5]. Other agents, such as recombinant human erythropoietin

Walter J. Curran, Jr., MD Department of Radiation Oncology, Jefferson Medical College 111 S. 11th St. Philadelphia, PA 19107-5097 (USA) Tel. +1 215 955 6700, Fax +1 215 955 0412, E-Mail [email protected]

(rHuEPO, epoetin alfa), are of potential value because they may counter dose-limiting toxicities associated with RT [6–9], and they may potentially increase tumor oxygenation, and, therefore, the efficacy of RT. This article provides an update of some important recently completed and ongoing trials evaluating novel chemoradiation protocols. It also highlights methodologic changes in the way new agents and combined modality regimens are being developed.

Optimization of Radiotherapy Delivery

The quality and the mode of delivery of RT are of central importance to the success of combined modality therapy. An important hypothesis that underlies the development of new and more effective RT protocols is that improvement of radiotherapy delivery will reduce locoregional tumor failures. Consequently, this should lead to decreased mortality, and/or decreased treatment-related morbidity. Radiotherapy can be optimized in a number of ways. These include technical improvements in patient selection and staging, which involves the use of ever-improving imaging techniques, radiotherapy sequencing and fractionation, image guidance during RT procedures, brachytherapy, the provision of high radiation doses directly to a tumor through the implantation of small radioactive seeds or sources, radiation intensity modulation, and radiation dose escalation. Until 2000, standard treatment for stage III unresected non-small-cell lung cancer has been sequential chemotherapy and radiation. An example of this is the treatment protocol that was evaluated in the CALGB and RTOG studies in NSCLC mentioned previously [1, 2]. The combination regimen evaluated in both studies involved administration of cisplatin, 100 mg/m2 intravenously on days 1 and 29, and vinblastine, 5 mg/m2 on days 1, 8, 15, 22, and 29, followed by RT beginning on day 50 (60 Gy). This was compared with RT alone. Median survival times for patients treated with this regimen in the CALGB and RTOG studies were 13.7 and 13.2 months, respectively, versus 9.6 and 11.4 months for patients treated with RT alone. It was concluded by the authors of the CALGB study that the use of sequential chemoradiotherapy increases the projected proportion of 5-year survivors by a factor of 2.8 compared with standard RT [1]. Even with this improvement, however, approximately 80–85% of patients treated with sequential chemoradiotherapy will be expected to die within 5 years [1]. Therefore, there is a

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need for further improvements in the treatment of locally or regionally advanced unresectable tumors. Results from several, recent, prospective phase III trials provide convincing evidence that further optimization of RT delivery in the context of combined modality therapy, beyond that evaluated in the CALGB and RTOG trials, can result in better tumor control and/or patient survival. These studies are described below. Lung Cancer RTOG 9410 is a phase III study of 611 patients with unresected NSCLC, which compared a standard sequential protocol (chemotherapy followed by 60 Gy RT/7 weeks given once daily, initiated at day 50) with two concurrent chemoradiation protocols (RT initiated on day 1 of chemotherapy) [10]. Concurrent RT was administered either once daily (60 Gy RT/7 weeks) or as hyperfractionated RT (69.9 Gy/6 weeks, twice daily). Preliminary median survival times at a median follow-up time of 40 months for sequential, concurrent RT once daily, and concurrent hyperfractionated RT were 14.6, 17.1, and 15.6 months, respectively, from each patient’s registration. The concurrent RT/cisplatin/vinblastine arm had significantly better survival than the sequential arm with the same agents, with a p-value of 0.038. The rates of grade 3–4 nonhematologic toxicity were higher with concurrent vs. sequential chemotherapy, but late toxicity rates were similar and no differences in grade 5 toxicity rates were noted. A randomized intergroup study (RTOG 8815) carried out by Turrisi et al. [11] was aimed at optimizing RT delivery in patients (n = 417) with small-cell lung cancer (SCLC). After a follow-up of almost 8 years, patients who were given 45 Gy RT, concurrently with cisplatin and etoposide, twice daily for 3 weeks, had significantly improved median survival rates versus those who received 45 Gy RT given concurrently only once daily over 5 weeks (23 months vs. 19 months for patients receiving once-daily vs. twice-daily RT, respectively, p = 0.04). Survival rates at 5 years were 26 and 16% for patients receiving concurrent twice-daily or once-daily RT, respectively. However, patients receiving twice-daily RT experienced grade 3 esophagitis significantly more frequently than those receiving once-daily concurrent RT (27 vs. 11%, p ! 0.001). Head and Neck Cancer The randomized phase III trial RTOG 9111 compared concurrent chemoradiation (RT initiated on day 1 of chemotherapy) versus sequential chemoradiation (RT initiated on day 63 after chemotherapy) vs. RT alone, in 547

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patients with stage 3–4 potentially resectable cancer of the larynx [12]. The total RT dose was 70 Gy in 7 weeks (2 Gy/fraction), administered in the same regimen, for all of the study arms. The results showed that over a 2-year follow-up period, concurrent chemoradiation was statistically significantly better for laryngectomy-free survival time compared with RT alone (66 vs. 52%, respectively, p = 0.02). Similarly, concurrent chemoradiotherapy was statistically significantly better than sequential chemoradiation and RT alone for time to laryngectomy (p = 0.0094 and 0.00035 vs. sequential chemoradiation and RT alone, respectively) over the same follow-up period. In another phase III trial (RTOG 9003), Fu et al. [13] tested the efficacy of hyperfractionation in patients with locally advanced head and neck cancer, comparing two types of accelerated fractionation therapy with standard fractionated RT. A total of 1,113 patients were randomized into one of four treatment groups: (1) RT delivered with standard fractionation at 2 Gy/fraction/day, 5 days/ week, to 70 Gy/35 fractions/7 weeks; (2) hyperfractionation at 1.2 Gy/fraction, twice daily, 5 days/week, to 81.6 Gy/68 fractions/7 weeks; (3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or (4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/ 6 weeks. At a median follow-up time of 23 months for all assessable patients (n = 1,073), those treated with hyperfractionation (treatment 2) or accelerated fractionation with concomitant boost (treatment 4) had significantly better locoregional tumor control than those treated with standard fractionation (treatment 1) (54.4 and 54.5% for treatments 2 and 4, respectively, vs. 46.0% for treatment 1, p = 0.045 and 0.050, respectively) (fig. 1). A trend toward improved disease-free survival was also noted for the same comparisons (37.6 and 39.3% for treatments 2 and 4, respectively, vs. 31.7% for treatment 1), although these differences failed to achieve significance (p = 0.067 and 0.054, respectively). All three altered fractionation groups (treatments 2, 3, and 4) had increased grade 3 or worse acute adverse effects in skin, mucous membranes, pharynx/esophagus, and larynx compared with the standard RT group (treatment 1), but there was no difference in late toxicity (190 days after start of RT). The results of these studies clearly demonstrate that the quality of RT can be modified to improve tumor control and survival. In patients with NSCLC or laryngeal cancer, concurrent RT provided a clear benefit over

Update on Chemoradiation Trials in Solid Tumors

Fig. 1. RTOG 9003: Phase III trial comparing hyperfractionated RT

or accelerated fractionation RT with concomitant boost vs. standard RT in patients with advanced head and neck cancer. a Twice-daily (fractionated) RT resulted in significantly better locoregional control than did standard RT (p = 0.05). b Accelerated fractionation resulted in significantly better locoregional control than did standard, twicedaily fractionation (p = 0.05). Follow-up was from the time patients were randomized into the study (reproduced with permission from Fu et al. [13]).

sequential therapy, and in patients with SCLC, RT twice daily significantly improved survival rates vs. once-daily treatment. Clearly, it is important to keep in mind the value of modifying RT delivery when attempting to optimize established chemoradiation combinations, and when testing new systemic agents for use in combined modality regimens.

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Integration of New Systemic Therapies with Optimized Locoregional Therapy

A second important hypothesis that forms the basis for the development of novel combined modality therapies is the notion that the integration of new systemic therapies with optimized locoregional RT will decrease cancerrelated mortality. A number of recent trials were designed to compare the efficacy of RT with or without systemic therapy in patients with prostate cancer (RTOG 8531, 8610, 9202), stage III NSCLC (RTOG 8808), laryngeal cancer (RTOG 9111), esophageal cancer (RTOG 8501), and cervical cancer (RTOG 9001). Overall, the results from these trials, described in the following sections, indicate a significant clinical benefit from the addition of one or more systemic agents to RT regimens. Prostate Cancer The benefits of combined modality chemoradiotherapy were illustrated in the results of three phase III RTOG studies that evaluated the combination of RT with hormonal therapy for treatment of prostate cancer (RTOG 8531, RTOG 8610, RTOG 9202) [14–16]. A total of 977 patients with locally advanced prostate cancer (RTOG 8531) [14] were followed for a median period of 5.6 years. Results indicated that long-term administration of adjuvant goserelin (initiated at relapse and continued throughout the follow-up period) to induce androgen suppression, in addition to standard external-beam RT (n = 477 analyzable patients), significantly improved local tumor control (p ! 0.0001), freedom from distant metastases, and both absolute (p = 0.036) and cause-specific (p = 0.019) survival, as compared with patients who received standard externalbeam RT alone (n = 468 assessable patients). Another randomized, phase III trial (RTOG 8610) [15] investigated the effects of androgen ablation with goserelin before and during RT for patients with locally advanced prostate cancer vs. RT alone (n = 471). The results at an 8-year follow-up demonstrated that combined modality therapy was associated with a significant improvement in local tumor control (30 vs. 42% local failure rate; p = 0.016), reduction in disease progression (34 vs. 45% distant metastasis; p = 0.04), and improvement in survival (33 vs. 21% disease-free survival; p = 0.004) compared with RT alone. A subset analysis of patients with a Gleason score of 2 to 6 (indicating relatively less aggressive tumors) showed a highly significant improvement in all endpoints, including overall survival (p = 0.015) in patients treated with combined modality therapy compared with those treated with RT alone.

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In a prospective, randomized study conducted by Hanks et al. [16], a total of 1,554 patients with locally advanced prostate cancer received androgen suppression therapy (goserelin and flutamide) 2 months before and during RT. Patients were then randomized to either no further therapy or 24 months of additional goserelin alone; the groups were well matched for stratification and other baseline variables considered. The investigators found that disease-free survival (54 vs. 34%), local progression (6 vs. 13%), and reduction in distant metastasis (11 vs. 17%) were significantly better in patients receiving the longer-duration hormonal therapy compared with those receiving no further hormonal therapy after radiation. Patients with a Gleason score of 8–10 (more aggressive tumors) also showed a statistically significant advantage in overall survival compared with the same subset of patients who did not receive long-term hormone therapy (p = 0.017). It should be noted that long-term androgen ablation has hematologic toxicity, which may be detrimental to locoregional control with RT [17]. Given this possibility, these patients may benefit from additional systemic agents, such as epoetin alfa, to counter treatment-related anemias. The potential benefit of epoetin alfa for enhancing locoregional tumor control as well as improving patient quality of life has received support from recent clinical trials [6–9] and is currently under investigation in an RTOG phase III trial (9903). Stage III NSCLC The final results of an important randomized phase III trial involving 458 patients with unresectable NSCLC were published in 2000 (RTOG 88-08) [2]. This study compared sequential chemoradiation with either hyperfractionated or standard RT. Sause et al. evaluated the efficacy of three regimens: (1) chemoradiation, consisting of 2 months of cisplatin and vinblastine therapy, followed by either 60 Gy of radiation at 2.0 Gy per fraction of radiation delivered once daily (n = 152), (2) hyperfractionated RT, consisting of 1.2 Gy per fraction of radiation delivered twice daily to a total dose of 69.6 Gy (n = 152), and (3) standard RT alone (n = 154). Results indicated that overall survival was statistically significantly better in patients receiving chemoradiotherapy compared with the RT regimens (median survival of 13.2, 12, and 11.4 months for concurrent chemoradiotherapy, hyperfractionated RT, and standard RT, respectively, p = 0.04 for chemoradiotherapy vs. the RT regimens); the investigators did not find a statistically significant difference in survival between the two RT arms (standard vs. hyperfractionated) in this study.

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Laryngeal Cancer The objective of RTOG 9111, a randomized, phase III study described previously, was to compare the ability of sequential chemoradiation (cisplatin 100 mg/m2 plus 5FU 1,000 mg/m2/day ! 120 h for 3 cycles, followed by RT in responding patients) or concurrent chemoradiation (cisplatin 100 mg/m2 plus 5-FU on days 1, 22, 43 plus RT) with that of RT alone, to promote laryngectomy-free survival in patients with cancer of the larynx (n = 547) [12]. Although the study failed to establish a significant difference in survival between sequential chemoradiation and standard RT alone, concurrent chemoradiation resulted in significantly better survival than RT alone (66 vs. 52% after 2 years, respectively, p = 0.02). Moreover, concurrent chemoradiation was also significantly better than sequential chemoradiation (p = 0.0094) and RT alone (p = 0.00035) with regard to time to laryngectomy. These results not only demonstrate the benefit of concurrent chemoradiation over standard RT for treatment of laryngeal cancer, as assessed by either survival or time to laryngectomy, but also highlight the importance of optimizing RT delivery in the context of the specific combined modality therapy and the form of cancer involved. Esophageal Cancer Long-term follow-up results (of at least 5 years) from a randomized, controlled trial conducted from 1985 to 1990 (RTOG 8501) demonstrated that concurrent chemoradiotherapy (50 Gy/5 weeks plus cisplatin and 5-FU at weeks 1, 5, 8, and 11; n = 134) statistically significantly increased the survival of patients with squamous cell cancer or adenocarcinoma of the esophagus compared with RT alone (64 Gy/6.4 weeks; n = 62). The overall survival rate with combined therapy was 26% compared with 0% for RT alone [18]. Cervical Cancer RTOG 9001 was a randomized trial that examined the effects of adding chemotherapy with 5-FU and cisplatin to treatment with external beam and intracavitary radiation in women with locally advanced cervical cancer [19]. Of 403 patients followed for a mean duration of 43 months, estimated cumulative rates of overall survival were 73% among patients receiving combined modality therapy, compared with 58% for patients receiving RT alone (p = 0.004). Rates of disease-free survival at 5 years were also significantly higher among patients receiving chemoradiation (67 vs. 40%; p ! 0.001), and rates of distant metastases (14 vs. 33%) and locoregional recurrences (19 vs. 35%) were significantly lower in these patients (p !

Update on Chemoradiation Trials in Solid Tumors

0.001 for both parameters). These impressive results of disease-free survival and local control were corroborated in three important trials involving women with bulky stage IB cervical cancer [20] or locally advanced cervical cancer [21, 22], carried out by the Gynecologic Oncology Group. In both of these studies, chemoradiation regimens including cisplatin resulted in significantly improved survival and reduced risk of disease recurrence as compared with RT alone.

Unique Approaches to Testing Novel Systemic Therapies With Radiotherapy

A review of trials evaluating combined modality therapies illustrates some of the ways in which the approach to testing combined modality chemoradiation protocols may differ from traditional drug development strategies. It should always be kept in mind that the latest reports of new systemic agents undergoing testing, or the most recent modifications in RT delivery, may prove quite valuable for formulating novel combined modality regimens. It is possible that agents that exhibit only minimal efficacy when used alone may prove useful when combined with RT. Because of this, many new agents should be tested concurrently with RT after their safety has been established, rather than postpone concurrent testing until their efficacy when used alone has been demonstrated. In addition, because of the increasing numbers of potentially useful systemic agents, and the resultant exponential growth in the numbers of possible therapeutic drug combinations, the results of preclinical studies will likely play an increasing role in decisions on which new agents should be tested, and in what types of combinations. It is important to note that the maximum tolerated dose (MTD) of a systemic agent, or of a RT protocol, may be defined quite differently when these modalities are combined because of the potential interactions between the two forms of therapy. There may be quantitative differences, such as the dosages at which toxicity is seen, or there may be qualitative differences, such as in the types of adverse effects that occur. For example, the MTD may relate to organ-specific side effects, such as esophagitis, pneumonitis, or proctitis, rather than to hematologic parameters, when combined modality therapy is administered. Moreover, interactions between the treatment modalities render it likely that optimization of RT delivery will result in changes in optimal drug schedules, and vice versa.

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Optimization of Combined Modality Regimens The results of a phase I trial reported by Fossella et al. [23], aimed at identifying the MTD of gemcitabine in patients with NSCLC undergoing thoracic RT, provide an excellent illustration of how the optimization of RT delivery can play an important role when devising a combined modality regimen. These investigators found that doselimiting toxicity of gemcitabine occurred at 125 mg/m2 when used with a conventional RT regimen, whereas the MTD was 190 mg/m2 when gemcitabine was combined with 3-dimensional conformal RT. Thus, optimization of the RT protocol with reduction in the radiation volume allowed for the delivery of a substantially higher dose of chemotherapy. RTOG L-0017 is an ongoing phase I trial evaluating gemcitabine, paclitaxel, and RT vs. gemcitabine, carboplatin and RT in patients with NSCLC. The study design is an example of a technique that is being used within the RTOG to test more efficiently integrated treatment modalities. The design includes a first schema that involves administration of escalating doses of gemcitabine concurrently with a constant carboplatin dose, with the combination at each dose level of gemcitabine given to a group of 6 patients. A second schema involves an escalation of gemcitabine while also escalating paclitaxel in an alternating stepwise fashion, such that the dose of only one of the drugs is escalated at a time. In both schemata, chemotherapy is accompanied by adjuvant thoracic RT at a total dose of 63 Gy in 34 fractions in 7 weeks to affected areas, commencing on the first day of chemotherapy. Using this approach, it should be possible to efficiently establish a MTD for gemcitabine that is specific for its combination with either carboplatin or paclitaxel.

Novel Systemic Agents Undergoing Testing in Chemoradiotherapy Regimens

Substantial gains have been made over the past several years in the induction of remissions with the use of chemoradiation therapy. Despite these advances, patient survival rates are still unacceptably low and new treatment strategies are needed. Several promising, novel systemic agents are currently undergoing evaluation for use in conjunction with RT. Cyclooxygenase-2 Inhibitors Cyclooxygenase (COX) catalyzes the synthesis of prostaglandins from arachidonic acid. One form of the enzyme, COX-2, is overexpressed in a variety of different

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tumors, including colon, pancreatic, prostate, lung, and head and neck cancers, and is also observed in tumor neovasculature [24]. These and other data suggest that COX-2-mediated angiogenesis plays a major role in tumor growth. These findings have stimulated initiation of a number of trials evaluating COX-2 inhibitors used in conjunction with RT. A phase I/II RTOG trial (C-0128) is underway to determine treatment-related toxicity rates in patients with locally advanced carcinoma of the cervix who are being treated with a combination of celecoxib, cisplatin, and 5FU with concurrent pelvic radiation therapy. In addition, this study is designed to evaluate whether this regimen can improve locoregional control rates, distant control, and/or survival. Vascular Endothelial Growth Factor (VEGF) Blockade VEGF is thought to play an important role in tumor angiogenesis. Blockade of its function is, therefore, considered a treatment target for a number of tumor types, and is likely to be tested in conjunction with combined modality therapy. Sugen (SU) 5416 SU 5416 is a small molecule that exhibits potent inhibition of the fetal liver kinase (flk) receptor tyrosine kinase, which is the receptor for VEGF. Expression of flk is limited to endothelial cells and it appears to play a critical role in angiogenesis [25]. RTOG S-0120 and S-0121 are two ongoing phase I/II studies aimed at evaluating SU 5416 as part of a chemoradiotherapy protocol for treatment of low-to-intermediate grade (S-0120) or high-risk, high-grade (S-0121) soft tissue sarcoma. Angiostatin In a recent phase I trial at Jefferson Medical College in Philadelphia involving a small number of patients with advanced cancer of the head and neck, prostate, breast, and lung, it was determined that the combination of angiostatin (an antiangiogenesis drug that has antitumor activity) plus radiotherapy is well tolerated and partial local responses were observed. Studies are ongoing to evaluate longer-term treatment at higher doses [26]. Farnesyl Transferase Inhibitors Farnesyl transferase inhibitors target the protein encoded by the ras oncogene, blocking its membrane anchorage, and thereby inhibiting its cell transforming ability [27]. R11577 is a potent and selective farnesyl transferase inhibitor that has shown antitumor activity in animal models,

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and was found to have an acceptable tolerability profile in phase I trials (unpublished data). RTOG 0020 is an ongoing phase II trial in patients with locally advanced pancreatic cancer designed to evaluate the one-year survival rates of patients treated with paclitaxel, gemcitabine, and RT with or without farnesyl transferase inhibitor R115777. The above represents only a small number of the clinical trials and the novel agents currently being evaluated for use in combined modality therapies. Given the relatively recent understanding of the potential value of combining chemotherapeutic and RT regimens for patients with unresected solid tumors, this approach can be expected to further improve outcomes for patients with unresectable solid tumors.

New Therapeutic Strategies Based on Analyses of RTOG Clinical and Tissue Databases

The structure of the RTOG and other groups that are involved in evaluating new combined modality therapies encourages the development of such treatments from hypotheses-based analyses of clinical and tissue databases. Over the past few years, there has been a large expansion of knowledge concerning the biology of cancer. These advances include new information on the control of cancer cell growth and growth factor expression, regulation of necrotic and apoptotic cell death, regulation of angiogenesis and cell-cell communication, the influence of environmental factors, such as hypoxia, on tumor growth, and identification of markers that are over- or underexpressed on cancer cells. By maintaining centralized databases that make information on basic cancer biology widely available it will be possible to reassess archived information and utilize proteomic analysis on banked tissue and tumor specimens and apply this knowledge to the formulation of new combined modality clinical trials. An example of this process involves evaluation of cell markers, such as epidermal growth factor receptor (EGFR), on stored tumor tissue that had been obtained from patients with advanced head and neck cancer treated in study RTOG 9003. This was a phase III study that compared hyperfractionation and standard RT protocols [13]. Further analysis of the results of this trial revealed that there was a statistically significant increase in locoregional failure in cases where the tumor overexpressed EGFR vs. those without EGFR, resulting in a difference in survival. Interestingly, there was no difference in the development of distant metastases. This find-

Update on Chemoradiation Trials in Solid Tumors

ing, which was derived from archived material and information, suggests that the development of a strategy for EGFR blockade would be useful. Moreover, such a strategy would be most beneficial if used during radiotherapy, when locoregional failure can be targeted, rather than after radiotherapy, when attempts to influence distant metastases would probably be less useful.

New Standards of Care

Although there is still much work to be done, completed phase III trials carried out by the RTOG, GOG and other groups have made important contributions to defining new standards of care in locally advanced cervical cancer, stage III NSCLC, locally advanced head and neck and prostate cancer, localized prostate cancer, central nervous system lymphoma, and operable laryngeal cancer. Some of the RTOG studies are listed in table 1. A number of RTOG studies, also shown in table 1, have recently completed accrual, and should be providing data within the next few years. These trials include muchneeded prospective evaluations of radiosurgery. The results of two major phase III trials will be presented at the 2002 American Society for Therapeutic Radiology and Oncology (ASTRO) meeting. Concurrent Chemoradiotherapy Now the Standard The adoption of concurrent rather than sequential chemotherapy exemplifies how a meaningful improvement in outcome resulted from relatively subtle changes in therapy, including changes in the technique for delivering chemoradiotherapy. Using progress that has been made in the treatment of stage III NSCLC as an example, the survival of good performance status patients with unresected tumors progressively improved in a number of studies conducted over approximately 11 years (table 2) [12, 28]. This degree of improvement cannot be explained by stage migration alone (i.e., changes in staging due to a discrepancy between clinical and pathologic staging or other factors). As shown in table 3, the administration of concurrent rather than sequential chemoradiation, in a randomized RTOG study (9410) of patients with NSCLC, resulted in more than a 20% increase in median survival time, a statistically significant improvement [10]. A similar result was seen in a Japanese study reported by Furuse et al. [29]. These results support the positioning of concurrent chemoradiotherapy as the current standard of care. Although the ability to obtain positive results with consistency across studies is encouraging, it is important to note

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Table 1. Summary of some recently completed and ongoing major chemoradiation trials

Study

Treatment evaluated

Completed phase III RTOG studies 9001 Concurrent chemoradiation for locally advanced cervical cancer 9410 Sequential vs concurrent chemoradiotherapy for stage III NSCLC 9003 Hyperfractionated and accelerated fractionated RT vs standard RT for locally advanced head and neck cancer 9202, 8610 Long- vs short-term adjuvant hormone therapy for locally advanced prostate cancer 8531 Adjuvant hormone therapy plus RT for localized prostate cancer 9111 Sequential or concurrent chemoradiotherapy vs RT alone for operable laryngeal cancer Phase III studies with completed accrual 9305, 9508 Radiosurgery for glioma and brain metastases 9501 Chemotherapy for resected head and neck cancer 9408 Androgen ablation for localized prostate cancer 9413 Large-field RT for advanced prostate cancer 9802 Chemotherapy for low-grade glioma Unreported/active phase III trials for stage III NSCLC (RTOG and other groups) RTOG 9801 Amifostine as radioprotectant ECOG 2597 Role of 3 times daily RT CALGB 39801 Evaluation of induction chemotherapy R 9309/Intergroup Role of surgery in N2 disease ECOG Role of thalidomide SWOG/Intergroup Role of EGFR blockade CALGB = Cancer and Leukemia Group B; ECOG = Eastern Cooperative Oncology Group; EGFR = Epidermal growth factor receptor; N2 = mediastinal lymph node metastasis; NSCLC = non-small-cell lung cancer; RT = radiotherapy; RTOG = Radiation Therapy Oncology Group; SWOG = Southwest Oncology Group.

Table 2. Evidence for improvement over time in the treatment of unresected NSCLC

Table 3. Concurrent vs. sequential chemoradiotherapy for NSCLC –

Cooperative Group Trial

Study

CALGB 8433 RT [1] CALGB 8433 sequential CRT [1] RTOG 9104 concurrent CRT RTOG 9410 sequential CRT [2] RTOG 9410 concurrent CRT [2] SWOG 9504 concurrent CRT [28]

Median survival 3-year time (months) survival 9.6 13.7 19.6 14.6 17.0 27

10% 24% 40% 31% 37% 140%

CALGB = Cancer and Leukemia Group B; RT = radiotherapy; CRT = chemoradiotherapy; NSCLC = non-small-cell lung cancer; RTOG = Radiation Therapy Oncology Group; SWOG = Southwestern Oncology Group.

that there is much room for further improvement in outcomes. Moreover, with the concurrent protocols, there is substantially greater acute toxicity; work on the development of systemic agents to counter this is ongoing.

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impact on median survival time Median survival time (months)

Curran et al. [10] Furuse et al. [29]

concurrent sequential

p value

17.1 16.5

0.03998 0.038

14.6 13.3

NSCLC = Non-small-cell lung cancer.

Achieving Further Improvement Using Combined Modality Regimens

Based on the results of the most recent phase III trials in patients with stage III NSCLC treated with concurrent chemoradiation, there appears to be a plateau in median survival time of approximately a year and a half. It is likely that continued optimization of patient selection and the continued development, selection, and implementation

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of combined therapies will play important roles in any further improvements in survival times. One area of research that is contributing to improvements in both patient staging and treatment planning involves new uses of computed tomography (CT) and related techniques to provide more detailed information on target structures. For example, the use of metabolic imaging by means of F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) can improve tumor definition. This helps the clinician to delineate tumor extent and determine the areas that will require high-dose therapy, and to monitor the therapeutic response [30]. Recent work has also indicated that the use of FDG-PET staging for NSCLC, for example, is a powerful predictor of survival, and it should prove to be a valuable resource in treatment planning [31]. Continued improvements in radiotherapy delivery, including dose escalation, intensity modulation, development of fractionation techniques, enhanced image guidance, and exploitation of brachytherapy technology will be crucial to achieving further success; likewise, the ongoing search for novel systemic agents without heavy dependence on drugs that have undergone extensive testing without RT. Because of the possibility of unique interactions between agents with regard to both efficacy and toxicity profiles, aggressive concurrent testing, as already described, should also play a major role. The use of chemotherapy ‘doublets’ or ‘triplets’, in which novel interactions between chemotherapy agents and RT might be exploited, or in which novel biologic agents may be combined with other chemotherapy agents, is another promising area of research. For example, work carried out by Ang and others demonstrated that the combination of EGFR blockade using monoclonal antibody C225, radiosensitization with docetaxel, and RT resulted in a significantly greater delay in tumor growth than did any one or combination of two therapies (unpublished data). It is likely that in the next several years, what might be referred to as new trimodality therapy will be developed for a number of locally advanced malignancies.

Conclusions

Based on the studies described in this review, it is clear that much has been achieved in the quest for new combined modality regimens that improve outcomes in patients with cancer. One major problem, however, is the long duration of patient accrual, which sometimes results in trials that are inadequately powered. Moreover, there is very little information available from controlled trials involving low-performance status patients (based on the ECOG Performance Status Scale) [32]. Staging of patients has been variable across studies, which can lead to an uneven assessment of outcomes. Importantly, there has been too much reliance on the stage IV drug pipeline, rather than expending sufficient effort on developing drugs that might be of specific value when used in conjunction with RT. This last point relates to differences between the strategy for developing combined modality regimens testing concurrent regimens early in drug development rather than the approach used in standard drug development where single agent efficacy is the first process. Many factors will contribute to improving outcomes for patients with locally advanced lung cancer, as well as other solid tumors. Testing novel systemic agents with RT is critical, and should pave the way to substantial improvements in outcomes. Conducting large explanatory, proof of principle trials that address a single question, such as to determine the role of surgery or the optimum timing of sequential therapies, may prove more valuable than complicated studies that mask important principles. Clearly, improving radiation standards and quality assurance is also critical in this context. All of these approaches combined will slowly but surely contribute towards improving the survival of many patients with locally advanced solid tumors.

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Update on Chemoradiation Trials in Solid Tumors

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