Amifostine in the Treatment of Head and Neck Cancer: Intravenous Administration, Subcutaneous Administration, or None of the Above

Radiotherapy (RT) exerts most of its effect through ionization of water, which results in the formation of highly reactive free radicals that can damage the DNA. Oxygen binds to short-lived free radical sites in the DNA and fixes the damage, whereas molecules such as sulfhydryl compounds compete with oxygen and reduce free radical activity to exert a protective effect. However, sulfhydryl compounds such as cysteine do not have a preference for protecting normal cells as compared with tumor cells. Amifostine was formed by the addition of a phosphate group to the sulfhydryl compound, resulting in a prodrug activated by membrane-bound alkaline phosphatase, which dephosphorylates the prodrug to its active sulfhydryl molecule. The cellular concentration of alkaline phosphatase is low in tumors, given that the pH of tumors is often lower than that of normal tissues, and this provides a selective mechanism for normal tissue protection in preference to protection of the tumor. Other mechanisms for preferential protection of the normal tissues include increased

uptake of the compound by certain organs such as the salivary glands and kidneys.1 The primary adverse effects of combined chemotherapy and RT for the treatment of head and neck cancer include acute mucositis and dermatitis and late xerostomia and dysphagia. Multiple protecting agents have been developed to ameliorate these effects, although amifostine has the longest track record and largest body of controlled studies that assess its effectiveness. Notably, the landmark study by Brizel et al2 of patients who were administered postoperative RT demonstrated reduced xerostomia in the amifostine arm. This study gained the drug approval by the US Food and Drug Administration, which was followed by an intensive marketing effort by the drug manufacturer. The main barriers to the widespread use of amifostine have been the logistics of its use and its toxicity. Because of rapid clearance from the blood and tissue, the drug needs to be delivered shortly before RT, preferably before each RT fraction. Intravenous bolus drug administration, used as a standard, causes high rates of adverse effects, including hypotension and nausea, which require close observation. These adverse effects may occur in addition to similar adverse effects that result from concurrent chemotherapy, which is frequently administered to patients with

head and neck cancer, and cause a substantial drop in patient compliance. In recent years, the subcutaneous (SC) route of amifostine administration has been promoted as a way to simplify logistics, reduce toxicity, and improve drug bioavailability.3 In this issue of Journal of Clinical Oncology, Bardet et al4 report the results of a controlled study of patients with head and neck cancer who received conventional radiotherapy without concurrent

chemotherapy and who were randomly assigned to receive amifostine intravenously, 200 mg/m2 daily before each RT fraction, or subcutaneously, 500 mg before each fraction. The authors reported no difference in compliance; 70% of the patients in each arm received the full amifostine dose, and the remainder discontinued amifostine treatment because of toxicity or logistic issues. No significant difference in xerostomia, the study's primary end point, was observed between the two arms when all time points were considered, or in other end points relating to RT toxicity, or in tumor control rates. The primary difference between the arms was the nature of amifostine toxicity: higher rates of grade 1 to 2 hypotension were observed in the group that received amifostine intravenously, and higher rates of skin rash and pain at injection sites were observed in the group that received SC amifostine, but no differences were observed in the

rates of nausea/vomiting. Given that no overall difference in compliance was found, the authors recommended that the intravenous route should remain the standard mode of amifostine administration. Is this recommendation reasonable? One could argue that if efficacy and patient compliance are equal, the preferred administration route should be the one that offers the most convenience and demands the least personnel, time, and resources. The impression of previous investigators was that SC administration was simpler, did not require blood pressure monitoring throughout the infusion period or the presence of a specialized nurse, resolved logistic problems that had previously limited the number of patients who could be treated daily with amifostine, and was likely to reduce the costs of administering the drug.3 It is unlikely, therefore, that the study by Bardet et al4 will change practice patterns, which in recent years have tended to favor the SC route. A more important question related to amifostine is whether we should use it at all in the treatment of advanced head and neck cancer. If controlled studies do show that it substantially reduces acute and late sequelae of therapy without protecting the cancer cells, its use may not only improve patients' well-being but may also, by improving the tolerance to therapy, reduce treatment

breaks, as suggested in one study.3 Reduced treatment breaks may improve tumor-related outcomes, and reduced toxicity may allow better-tolerated would treatment the intensification. expenses Reducing with

sequelae

decrease

associated

supportive care and treatment-related hospitalizations, which would counter the cost of the drug. Thus far, the substantial body of controlled studies that have compared amifostine versus no amifostine during RT alone, or during RT concurrent with chemotherapy, has produced few firm conclusions. The first conclusion is that amifostine does not seem to protect cancer cells from treatment, given that reduced tumor-related outcomes have not been observed in patients receiving the drug.5 The second conclusion is that amifostine is likely effective in reducing xerostomia in patients who are receiving conventional RT alone. This outcome, observed in three randomized studies, prompted the American Society of Clinical Oncology to recommend in its 2008 clinical practice guideline update that amifostine be considered for the treatment of these patients.5 Surprisingly, an advantage of amifostine in reducing xerostomia has not been clearly demonstrated in controlled studies of patients receiving a combination of chemotherapy and RT; two studies suggested a benefit,6,7 and two studies demonstrated no benefit.8,9 The reasons for the equivocal effectiveness of amifostine in patients

who are receiving a combination of chemotherapy and RT might result from uncertainties in scoring and assessing xerostomia, as well as the lack of a placebo and blinding in most of these studies, or the possible worsening of xerostomia by cisplatin,10which is hard to overcome by treatment with amifostine. All of the randomized studies of amifostine involved patients who were receiving conventional RT, which delivers high doses to the majority of the salivary glands. New technology that provides highly conformal radiation dose distributions, such as intensitymodulated radiotherapy (IMRT), can achieve a significant sparing of the major salivary glands, as well as the minor glands within the oral cavity, which results in mild xerostomia that continues to improve with time.11 In a retrospective study, the effect of IMRT in sparing saliva seemed to be much greater than the effect of amifostine.12 It is not clear whether adding amifostine to IMRT is worthwhile; however, the potential benefit in reducing xerostomia is likely less than the benefit observed when the drug is given to patients who are receiving conventional RT. In the management of advanced head and neck cancer with intensive, combined chemotherapy and RT, severe acute mucositis and consequential late dysphagia have emerged as the primary and dose-limiting toxicities. If amifostine could protect against these effects, it would be the most important contribution

of the drug to a reduction in the morbidity of combined chemotherapy and RT. The results thus far are mixed; some studies have suggested an improvement in severe mucositis,1 but the majority have demonstrated no improvement.79,13 However, almost all of these studies lacked a placebo in the control patients as well as blinding in the randomized arms. Amifostine also failed to demonstrate a clear advantage with respect to the incidence of esophagitis in patients being treated for lung cancer.5 It can be concluded that, after more than a decade of numerous clinical studies, there is no evidence as of yet that the potential benefits of amifostine outweigh its toxicity and cost in the setting of combined chemotherapy and RT for the treatment of patients with head and neck cancer. Numerous other candidates for selective protection of normal tissue, especially the mucosa, have been proposed in recent years. Keratinocyte growth factor (palifermin) stimulates

differentiation of mucosal cells and was found to be effective in reducing mucositis after intensive therapy of hematologic malignancies, which prompted a recent initiation of clinical trials in patients receiving combined chemotherapy and RT for head and neck cancer.14 Because some solid cancers contain receptors for keratinocyte growth factor, the issue of potential tumor protection by the drug requires a high degree of scrutiny.15 Other potential

protectants are being studied, but no drug has yet been proven to be effective without the associated risk of action as a tumor protectant. IMRT may reduce the extent of mucositis if avoidance of the noninvolved oral cavity is included in the planning goals, and long-term dysphagia was found to be mild after combined chemotherapy and IMRT for the treatment of oropharyngeal cancer in which the swallowing-related structures (pharyngeal constrictor muscles, glottic and supraglottic larynx, and

esophagus) were spared.16 Thus, highly conformal radiotherapy, aimed specifically at reducing mucositis and dysphagia, may help reduce these toxicities compared with conventional combined chemotherapy and RT. Replacing concurrent chemotherapy with cancer-specific targeted therapy has the greatest potential to reduce adverse effects and complications of treatment. A randomized study of RT alone versus RT concurrent with cetuximab showed improved tumor control rates without increased mucositis in the combined arm,17 which suggested that this combination may compare favorably with combined chemotherapy and RT. However, the observer-based assessment of mucositis in that study was prone to inaccuracies. Indeed, some reports suggest that the rate of adverse effects during treatment with cetuximab and RT, including severe mucositis, may be higher than the rate reported

in the randomized study.18 Obviously, a randomized study of combined chemotherapy and RT versus cetuximab and RT is required before we can assume that the latter provides similar tumor control rates with less severe adverse effects. Lastly, if we can safely reduce treatment intensity in patients with excellent prognoses, such as nonsmokers with oropharyngeal cancer related to human papillomavirus,19 we may achieve reduced mucositis and dysphagia in these patients. Although none of the strategies to reduce toxicity have been adequately tested in controlled studies, there is an ample body of evidence regarding amifostine, and the bottom line is that this evidence does not justify its routine use in patients receiving combined

chemotherapy and RT for head and neck cancer.