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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

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

head and neck cancer. 70% of the patients in each arm received the full amifostine dose. the study's primary end point.3 In this issue of Journal of Clinical Oncology. or subcutaneously. No significant difference in xerostomia. or in tumor control rates. was observed between the two arms when all time points were considered. and higher rates of skin rash and pain at injection sites were observed in the group that received SC amifostine. 500 mg before each fraction. In recent years. the subcutaneous (SC) route of amifostine administration has been promoted as a way to simplify logistics. and the remainder discontinued amifostine treatment because of toxicity or logistic issues. but no differences were observed in the . reduce toxicity. and cause a substantial drop in patient compliance. 200 mg/m2 daily before each RT fraction. or in other end points relating to RT toxicity. The authors reported no difference in compliance. and improve drug bioavailability. 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. 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.

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

two studies suggested a benefit. 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. as suggested in one study. given that reduced tumor-related outcomes have not been observed in patients receiving the drug.6. which would counter the cost of the drug. or during RT concurrent with chemotherapy. Thus far.breaks. the substantial body of controlled studies that have compared amifostine versus no amifostine during RT alone.3 Reduced treatment breaks may improve tumor-related outcomes. expenses Reducing with sequelae decrease associated supportive care and treatment-related hospitalizations. observed in three randomized studies. The first conclusion is that amifostine does not seem to protect cancer cells from treatment. This outcome.9 The reasons for the equivocal effectiveness of amifostine in patients . an advantage of amifostine in reducing xerostomia has not been clearly demonstrated in controlled studies of patients receiving a combination of chemotherapy and RT. has produced few firm conclusions. and reduced toxicity may allow better-tolerated would treatment the intensification.5 Surprisingly.8.7 and two studies demonstrated no benefit.5 The second conclusion is that amifostine is likely effective in reducing xerostomia in patients who are receiving conventional RT alone.

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

5 It can be concluded that. Numerous other candidates for selective protection of normal tissue. some studies have suggested an improvement in severe mucositis. Keratinocyte growth factor (palifermin) stimulates differentiation of mucosal cells and was found to be effective in reducing mucositis after intensive therapy of hematologic malignancies. 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. Amifostine also failed to demonstrate a clear advantage with respect to the incidence of esophagitis in patients being treated for lung cancer.of the drug to a reduction in the morbidity of combined chemotherapy and RT.15 Other potential . have been proposed in recent years.14 Because some solid cancers contain receptors for keratinocyte growth factor. The results thus far are mixed.1 but the majority have demonstrated no improvement. especially the mucosa. which prompted a recent initiation of clinical trials in patients receiving combined chemotherapy and RT for head and neck cancer. after more than a decade of numerous clinical studies.13 However. almost all of these studies lacked a placebo in the control patients as well as blinding in the randomized arms. the issue of potential tumor protection by the drug requires a high degree of scrutiny.7–9.

the observer-based assessment of mucositis in that study was prone to inaccuracies. highly conformal radiotherapy.protectants are being studied. glottic and supraglottic larynx. aimed specifically at reducing mucositis and dysphagia. Replacing concurrent chemotherapy with cancer-specific targeted therapy has the greatest potential to reduce adverse effects and complications of treatment. including severe mucositis. may be higher than the rate reported . and esophagus) were spared. IMRT may reduce the extent of mucositis if avoidance of the noninvolved oral cavity is included in the planning goals. However.17 which suggested that this combination may compare favorably with combined chemotherapy and RT.16 Thus. may help reduce these toxicities compared with conventional combined chemotherapy and RT. 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. A randomized study of RT alone versus RT concurrent with cetuximab showed improved tumor control rates without increased mucositis in the combined arm. Indeed. some reports suggest that the rate of adverse effects during treatment with cetuximab and RT. but no drug has yet been proven to be effective without the associated risk of action as a tumor protectant.

there is an ample body of evidence regarding amifostine. Although none of the strategies to reduce toxicity have been adequately tested in controlled studies. .19 we may achieve reduced mucositis and dysphagia in these patients. 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. such as nonsmokers with oropharyngeal cancer related to human papillomavirus.18 Obviously.in the randomized study. if we can safely reduce treatment intensity in patients with excellent prognoses. 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. Lastly.