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Chapter 29 Chemical Modifiers of Radiation Response

measurements in head and neck cancer have demonstrated that anemic patients are significantly more likely to have poorly oxy- genated tumors than nonanemic patients, but significant tumor hypoxia has also been detected in patients who are not ane- mic. 6,38 Whether correction or prevention of anemia with blood transfusions or erythropoiesis-stimulating agents can improve treatment outcomes has been investigated in multiple studies. The use of blood transfusions in cervical cancer patients gained traction after an initial publication from Princess Margaret Hospital showing an improvement in pelvic control and cure rates associated with correction of anemia. 39 However, subsequent publications from the same group showed no sur- vival benefit to transfusion when the data were critically re- examined and analyzed on an intent-to-treat basis. 40 In head and neck cancer patients, studies suggest that blood transfu- sions may have a negative effect on survival. 41,42 Correction of anemia via erythropoietin (EPO) administration was evaluated in a double-blind, placebo-controlled randomized trial in 351 head and neck patients treated with RT. 43 The primary end point was local-regional progression-free survival. Eighty-two percent of patients (54) who received EPO maintained > 14 g/dL (women) or 15 g/dL (men), while only 15% of the patients in the placebo arm attained this benchmark. The relative risk of locoregional progression, however, was 1.62 in the EPO arm, compared to placebo ( P = .0008) with a similar, detriment seen for survival in those patients who received EPO (relative risk 1.39; P = .02). A systematic review pooling data from five ran- domized studies with a total of 1,397 patients showed signifi- cantly worse overall survival in head and neck cancer patients with the addition of EPO to radiotherapy (odds ratio 0.73; P = .005). 44 These poorer outcomes may have been the result of overcorrection of hemoglobin levels with increased thrombo- embolic events. 45 Tumor cells have also been found to express EPO receptors, with stimulation of downstream signaling path- ways that may promote a more invasive phenotype. 46,47 Sensitization of Hypoxic Cells Electron-affinic compounds can oxidize radiation-induced free radical damage in the cell to produce increased kill. 48 The use of these agents would be particularly attractive in the hypoxic tumor microenvironment, where low oxygen concentrations impair the effectiveness of RT. The 2-nitroimidazoles are one such class of compounds that are metabolized into their active form under hypoxic conditions. Misonidazole, the pro- totype 2-nitroimidazole, was tested in two randomized trials. The Danish Head and Neck Cancer Study-2 (DAHANCA-2) per- formed a double-blind randomized trial evaluating the effect of misonidazole given in two drug schedules with split-course irradiation in the treatment of carcinoma of the larynx and pharynx. 49 Patients were stratified according to tumor site (lar- ynx vs. pharynx), nodal status, and institution. The total miso- nidazole dose was 11 g/m 2 . The study assessed 626 patients. Overall, the misonidazole group did not have significantly better local tumor control than the placebo group. Serious peripheral neuropathy, the dose-limiting toxicity of all nitroimidazole com- pounds, occurred in 26% of misonidazole-treated patients. The European Organisation for Research and Treatment of Cancer conducted a randomized study of conventional fractionation RT versus modified fractionation RT (three fractions per day) with or without misonidazole in 523 advanced head and neck cancer patients. No differences were seen in treatment outcome. 50 Etanidazole (SR2508) is an analog of misonidazole with lower lipid solubility and less neurotoxicity in phase II studies in head and neck cancer. 51 A Radiation Therapy Oncology Group (RTOG) phase III study with etanidazole in head and neck tumors entered 521 patients who received conventionally fractionated irradiation with or without etanidazole 2 mg/m 2 3 times per week. 52 Of those on the etanidazole arm, 77% received at least 14 doses of the drug. No grade III or IV central nervous system or peripheral neuropathy was observed. The

2-year actuarial local tumor control was 40% in each arm, and the survival was 41% and 43%, respectively, in the irradiation alone and the irradiation plus etanidazole arms. A similar study of 374 patients performed in Europe did not show any overall benefit to treatment with etanidazole but did demonstrate increased neurotoxicity in the patients who received the drug. 53 Nimorazole is a 5-nitroimidazole of the same structural class as metronidazole. 54 Its dose-limiting toxicity is nausea and vomiting; however, the drug can be administered with each radiation treatment. DAHANCA conducted a phase III trial of nimorazole (1.2 g/m 2 vs. placebo) for squamous cell cancer of the supraglottic larynx and pharynx. 55 There was a statistically significant improvement in locoregional tumor control (49% vs. 33% at 5 years; P = .002) but not for survival, which is consistent with the DAHANCA misonidazole trial. The use of nimorazole has become the standard of care in Denmark but has not been adopted in other countries. Pharmacologic Targeting of Hypoxic Cells Mitomycin C (MMC) is an alkylating agent metabolized in regions of low oxygen concentration and preferentially cytotoxic to hypoxic cells. MMC plays an integral role in con- junction with RT and 5-FU (fluorouracil) in the definitive nonsurgical management of squamous cell carcinomas of the anus. 56 Yale University investigators examined the concurrent use of MMC in 195 head and neck cancer patients treated on two randomized trials. 57 Their treatment program consisted of 68 Gy with or without MMC on days 1 and 43 of RT. Local regional recurrence-free survival was improved with the addi- tion of MMC from 54% to 76% ( P = .003). Overall survival improved from 42% to 48%, but this was not statistically sig- nificant. The majority of patients in these trials received adju- vant postoperative or preoperative irradiation. Only 74 (38%) received definitive primary RT, and the benefit from the addi- tion of MMC in this subset is unclear. A three-armed randomized trial conducted by the University of Vienna compared conventionally fractionated (CF) RT (2 Gy daily to 70 Gy) against variation of continuous hyperfraction- ated accelerated RT with or without MMC (V-CHART + MMC and V-CHART, respectively). 58 RT was given as an initial 2.5-Gy fraction followed by 1.65 Gy twice a day to a total dose of 55.3 Gy in 17 days. MMC was given as a 20 mg/m 2 bolus on day 5 of RT. Of the 239 patients enrolled, 85% had T3 or T4 primaries and 79% had nodal involvement. Three-year actu- arial locoregional control was 48% for V-CHART plus MMC versus 32% for V-CHART and 31% for CF ( P = .05 and .03, respectively). Survival including death from all causes was also improved to 41% in the V-CHART plus MMC arm as compared with 31% for V-CHART and 24% for CF ( P = .03). The incidence of confluent mucositis was 90% in both experimental arms as compared with 33% in the CF arm. The median time to com- plete resolution of mucositis was 6 to 7 weeks in all three arms. Grade 3 or 4 hematologic toxicity, primarily thrombocytopenia, developed in 18% of the V-CHART plus MMC patients. Porfiromycin, a derivative of MMC, provides greater differ- ential cytotoxicity between hypoxic and oxygenated cells in vitro. 59 The Yale investigators also conducted a phase III study that compared patients treated with conventionally frac- tionated radiation plus MMC versus radiation plus porfiromy- cin. 60 Hematologic and nonhematologic toxicity was equivalent in the two treatment arms. With a median follow-up > 6 years, MMC was superior to porfiromycin with respect to 5-year local relapse-free survival (91.6% vs. 72.7%; P = .01), local-regional relapse-free survival (82% vs. 65.3%; P = .05), and disease-free survival (72.8% vs. 52.9%; P = .03). There were no significant differences between the two arms with respect to overall sur- vival (49% vs. 54%) or distant metastasis-free rate (80% vs. 76%). Their data supported the continued use of MMC as an adjunct to radiation therapy in advanced head and neck cancer and will become the control arm for future studies.

Techniques, Modalities, and Modifiers in Radiation Oncology