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Chapter 29 Chemical Modifiers of Radiation Response

approximately 50% of the RT was delivered in the absence of the radioprotective drug in those patients who were random- ized to receive it. Preclinical study of amifostine delivered daily in conjunction with fractionated lung and esophageal irradia- tion has demonstrated morphologic and immunohistochemical evidence of radioprotection. 94–96 Amifostine is approved by the U.S. Food and Drug Administration for xerostomia in the setting of RT alone. The majority of both curative intent and adjuvant postoperative RT for head and neck cancer, with large target volumes that put the parotid glands at risk, is now delivered in conjunction with concurrent chemotherapy. Small phase II and III trials suggest that amifostine has a cytoprotective benefit in the chemoradia- tion setting, but level 1 evidence is lacking. 97,98 Moreover, the widespread adoption of IMRT with its ability to spare one or both parotid glands and reduce the incidence of xerostomia compared to conventional, non-IMRT techniques has further reduced the role for this drug. 99 The utility of amifostine in conjunction with IMRT has been investigated in small settings with inconclusive results. 100 Mitigation Administration of compounds that mitigate damage caused by previous radiation exposure constitutes a different approach to the management of radiation-induced toxicity. This strategy contrasts to the classical free radical scavenging radioprotec- tive mechanism of drugs such as amifostine. The leading drug under development in this category is palifermin. Palifermin is a recombinant human keratinocyte growth factor that belongs to the fibroblast growth factor (FGF-7) family of cytokines. It stimulates cellular proliferation and differentiation in a variety of epithelial tissues including mucosa throughout the alimentary tract, salivary glands, and type II pneumocytes. Palifermin also regulates intrinsic glutathione-mediated cytoprotective mecha- nisms. Administration of palifermin in preclinical rodent mod- els leads to a significant thickening of oral tongue mucosa. 101 Preclinical studies of fractionated RT have revealed that the administration of palifermin leads to increases in the dose of RT necessary to induce ulcerative mucositis and to reductions in the duration of this ulceration when it does occur. 102,103 Parotid gland production of saliva is also preserved when palifermin is administered in the setting of RT in preclinical systems. Preclinical evaluation of palifermin in a rodent model has also demonstrated that administration of a single dose of this drug after completion of a course of fractionated thoracic irradiation significantly reduces the severity and duration of pneumonitis and the severity of pulmonary fibrosis (Fig. 29.4). 104 The ability of palifermin to reduce mucositis in a clinical setting has been tested in a pivotal phase III double-blind placebo-controlled trial of patients with non-Hodgkin lym- phoma undergoing bone marrow transplantation. 105 The bone marrow ablative regimen consisted of 12 Gy of total-body irra- diation (TBI) given at 1.5 Gy twice a day. Thereafter, etoposide (VP-16) and cyclophosphamide were administered. Palifermin was delivered prior to the initiation of TBI and again after the completion of chemotherapy, which also corresponded to 5 days after the completion of TBI. The dose schedule of pali- fermin was 60 mcg/kg/d 3 times for both administrations. This trial enrolled 212 patients who were equally divided between the placebo and palifermin arms. The World Health Organization (WHO) scoring system was used. The incidence of grade 3 or 4 mucositis approached 90% in the placebo arm as opposed to approximately 60% in the palifermin arm. For those patients who developed this level of toxicity, the duration was significantly reduced from 10.4 days in the placebo arm to 3.7 days in the palifermin arm ( P < .001). Grade IV mucositis developed in 62% of the placebo arm patients and only 20% of the palifermin arm patients ( P > .001). Mean duration of grade IV mucositis was reduced from 6.2 days to 3.3 days with the use of this drug ( P < .001).

to 2.0 Gy. Curative intent delivery consisted of 66 to 70 Gy total dose, and postoperative irradiation was delivered at 50 to 60 Gy total dose depending on the patient’s assessed risk for recur- rence. IMRT was not utilized, and inclusion of > 75% of both parotid glands was required for inclusion in the study. Those patients who were randomized to receive amifostine were given a daily dose of 200 mg/m 2 intravenously for 15 to 30 minutes every day prior to each fraction of radiotherapy. Three hundred three patients were enrolled in this trial, and minimum follow-up was 2 years. Amifostine did not reduce the incidence of grade 3 mucositis but did significantly reduce the incidence of acute and long-term grade > 2 xerostomia. One-year post-RT, the incidence was 34% versus 56% for patients who had received amifostine versus those who had not ( P = .002). Unstimulated saliva production > 0.1 g was also more common in patients who had received amifostine (72% vs. 49%; P = .003). Two years post-RT, amifostine use was still associated with a significantly lower incidence of xerostomia, although the magni- tude of benefit was lower (19% vs. 36%; P = .05). The lower incidences in both groups of patients also suggest some late recovery of salivary function. Reinforcing this idea of late recov- ery of salivary function is the fact that the percentage of patients who did not receive amifostine but who could exceed the > 0.1 g of unstimulated saliva threshold had increased to 57%. 85 Severe toxicity (CTC grade > 3) attributable to amifostine occurred in < 10% of patients in this trial and consisted of nau- sea and vomiting and transient hypotension. Nearly two-thirds of the patients had less severe grades of these side effects. Drug-related toxicity did cause approximately 20% of patients to discontinue amifostine prior to completing radiotherapy. Subcutaneous administration of the drug causes less nausea, vomiting, and hypotension than intravenous dosing but is associated with an increased risk of cutaneous toxicity, which again causes 15% to 20% of patients to not complete a full course of amifostine in conjunction with their radiation. 86 The incidence of severe cutaneous toxicity, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, is 6 to 9 in 100,000. 87 Some have argued that the size of this trial made it under- powered to detect a very small compromise in survival caused by amifostine (tumor protection). 88 This argument is technically correct but overlooks the reality that absolute refutation of a small compromise of antitumor efficacy attributable to amifos- tine would have required an equivalence trial. Demonstration that amifostine reduced survival from a hypothetical 45% to 40% ( P = .05; 80% power) would have necessitated > 1,200 patients per study arm. 89 Such a large study cannot be per- formed in head and neck cancer, because patient resources are too scarce. The largest randomized head and neck trial ever conducted, RTOG-9003, required 8 years to enroll 1,113 patients into four treatment arms. 90 A meta-analysis with individual patient data from 12 trials and 1,119 patients examined the impact of amifostine on survival in patients treated with RT or CRT. The majority of patients (65%) had head and neck cancers, with 33% lung cancers and 2% pelvic carcinomas. The hazard ratio of death was 0.98 (95% confidence interval, 0.84 to 1.14; P = .78). 91 The potential of amifostine as a protector against radiation- induced esophagitis during the treatment of non–small cell lung cancer was studied in a randomized trial conducted by the RTOG. 92,93 No reduction in the incidence of grade 3 esopha- gitis was observed, although less swallowing dysfunction was observed in the patients who received amifostine. Part of the explanation for this absence may be attributable to the study design, which utilized a hyperfractionated radiation schedule 5 days per week (69.6 Gy total dose) and concurrent carboplatin/paclitaxel. Amifostine 500 mg intravenous was delivered 4 days per week prior to the afternoon fraction only. Moreover, 28% of the patients did not complete the full course of the drug either because of toxicity or refusal. Consequently,

Techniques, Modalities, and Modifiers in Radiation Oncology