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Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 7233-7235 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.3572
In Reply:
Henry Ford Health System, Detroit, MI It is always challenging to interpret the results of multiple trials testing the same hypothesis, but yielding conflicting results. As pointed out in our discussion of Radiation Therapy Oncology Group (RTOG) trial 98-01, we agree that the scheduling of amifostine is an important issue.1 While animal data suggest that amifostine should optimally be administered before each radiation (RT) dose,2 this finding is not fully consistent with the clinical evidence. Indeed, in the only other non–small-cell lung cancer trial testing the role of amifostine in the setting of hyperfractionated RT (N = 62 patients), Komaki et al reported a significant reduction in severe esophagitis by utilizing amifostine only two mornings per week.3 If the limited amifostine scheduling did not seem to hamper the results of this clinical trial, why would limiting the schedule have a negative effect on the results of the much larger trial (N = 243 patients) performed by RTOG? Similarly, the optimal time interval between amifostine administration and RT is not known. Whereas the plasma levels of intravenous (IV) WR-1065, the active metabolite of amifostine, peak rapidly (in minutes) and show a biexponential decline, the normal tissue levels in primates (including the esophagus) generally increase or stabilize at 60 minutes (compared with 30 minutes) after IV infusion.4 Similarly, the maximum concentration of WR-1065 in a variety of normal tissues studied (parotid gland, small intestine, and spleen) in the rat model occurred approximately 30 to 90 minutes after either IV or subcutaneous injection.5 Moreover, it is possible that other mechanisms of protection, such as activation of manganese superoxide dismutase, are longer lasting than WR-1065 itself.6 Nevertheless, in RTOG 98-01, RT was administered 15 to 30 (maximally 60) minutes from the start of the amifostine on RT-only days, which comprised the majority of treatment days.1 As pointed out, the amifostine dose and scheduling used in RTOG 98-01 was largely based on the randomized trial by Buntzel et al.7 In that positive trial, the amifostine was also administered before chemotherapy, but only 1/3 of all RT fractions were preceeded by amifostine. It is reasonable, though, for future studies to test the role of amifostine before each session of RT (or chemotherapy) in order to maximize the potential benefit.
Similar to other clinical trials of amifostine in lung cancer, RTOG-9801 defined the rate of grade We fully agree that the results of the clinical trials to date testing amifostine in lung cancer have been mixed (Table 6 in RTOG 98-01). Despite its potential limitations, RTOG-9801 remains the largest trial to date of amifostine in lung cancer and, unlike many other efforts, was performed in the setting of a multi-institutional, cooperative group. Clinicians should certainly consider these strengths when interpreting the results. Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Movsas B, Scott C, Langer C, et al: Randomized trial of amifostine in locally advanced non-small cell lung cancer (NSCLC) patients receiving chemotherapy and hyperfractionated radiation: Radiation Therapy Oncology Group (RTOG) 98-01. J Clin Oncol 23:2145-2154, 2005 2. Bachy CM, Fazenbaker CA, Kifle G, et al: Daily dosing with amifostine is necessary for full protection against oral mucositis caused by fractionated radiation in rats: Protection and pharmacokinetics. Proc Am Soc Clin Oncol 22:517, 2003 (abstr 2081) 3. Komaki R, Lee JS, Milas L, et al: Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell-lung cancer: Report of a randomized comparative trial. Int J Radiat Oncol Biol Phys 58:1369-1377, 2004[CrossRef][Medline] 4. Bachy C, Fazenbaker C, Kifle G, et al: Tissue levels of WR-1065, the active metabolite of Amifostine (Ethyol), are equivalent following intravenous or subcutaneous administration in cynomolgus monkeys. Oncology 67:187-193, 2004[CrossRef][Medline] 5. Cassatt D, Fazenbaker C, Kifle G, et al: Subcutaneous administration of amifostine (Ethyol) is equivalent to intravenous administration in a rat mucositis model. Int J Radiat Oncol Biol Phys 57:794-802, 2003[CrossRef][Medline] 6. Murley JS, Kataoka Y, Weydert CJ, et al: Delayed cytoprotection after enhancement of Sod2 (mnSOD) gene expression in SA-NH mouse sarcoma cells exposed to WR-1065, the active metabolite of amifostine. Radiat Res 158:101-109, 2002[CrossRef][Medline]
7. Buntzel J, Frohlich D, Kuttner K, et al: Selective cytoprotection with amifostine in simultaneous radiochemotherapy of head and neck cancer. Ann Oncol 9:505-509, 1998
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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3 acute esophagitis (as defined by the National Cancer Institute Common Toxicity Criteria version 2.0) as the primary end point.
