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Originally published as JCO Early Release 10.1200/JCO.2008.20.1632 on December 8 2008 © 2009 American Society of Clinical Oncology.
In Reply
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN We appreciate the comments of Freyer et al. We share their view that our study demonstrating the otoprotective effective of amifostine in patients with average-risk medulloblastoma may not be extrapolatable to other diseases in which protocols use significantly different schedules and doses of cisplatin.1 In the current study, cisplatin was administered at 75 mg/m2 over 6 hours on day –4, followed by cyclophosphamide 2 g/m2 on days –3 and –2, before peripheral-blood stem-cell transplantation on day 0.2 Most pediatric solid tumor protocols include daily cisplatin for 3 to 5 days with higher cumulative doses of cisplatin. Furthermore, such protocols do not generally use a 6-hour infusion of cisplatin. Both these considerations are important in addressing the second question appropriately raised by Freyer et al: What is the therapeutic burden associated with giving amifostine? The reported study is a multi-institutional, international study that was conducted at six centers in the United States and Australia and has recently expanded to eight centers including Canada. Although the supportive care guidelines are extensive, they have been implemented successfully in these institutions with the provision of appropriate education and clear guidelines. Although we did not capture the incidence of grades 1 and 2 toxicities in this protocol, we do not have concerns regarding the ability to export this therapy to other institutions. However, we concur with Freyer et al that administering multiple daily doses of amifostine to patients with other solid tumors receiving cisplatin daily for 3 to 5 days may require new supportive guidelines and close monitoring. A previous study has shown that amifostine leads to rapid, transient suppression of parathyroid hormone, and hence, transient hypocalcaemia.3 In that study, amifostine was administered at 600 mg/m2/dose twice daily for 3 days with ifosfamide, carboplatin and etoposide to six patients. Grade 3 hypocalcemia was documented in two patients.3 Thus, administration of amifostine twice daily with each cisplatin dose for 3 to 5 days will likely lead to more profound hypocalcemia, requiring prolonged prophylactic calcium infusions and modifications of our supportive guidelines. In addition, although the prescribing information for amifostine recommends administration over 15 minutes, 15 to 30 minutes before radiotherapy or chemotherapy, Wagner et al4 reported the significantly lower incidents of toxicities such as hypotension with bolus administration of amifostine, a strategy which we adopted in the reported study. Finally, we concur with Freyer et al that other otoprotectants such as sodium thiosulfate also deserve investigation. It is important to point out that both sodium thiosulfate and amifostine are thiol drugs that have similar mechanisms of action, in part acting as scavengers of oxygen-free radicals and binding to the active species of platinum agents.5 However, we believe that given the extensive experience with amifostine, this agent may deserve further study in children with other solid tumors with more careful attention to dosing and scheduling issues. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on December 8, 2008 REFERENCES
1. Fouladi M, Chintagumpala M, Ashley D, et al: Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma. J Clin Oncol 26:3749-3755, 2008 2. Gajjar A, Chintagumpala M, Ashley D, et al: Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): Long-term results from a prospective, multicentre trial. Lancet Oncol 7:813-820, 2006[Medline] 3. Fouladi M, Stempak D, Gammon J, et al: Phase I trial of a twice-daily regimen of amifostine with ifosfamide, carboplatin, and etoposide chemotherapy in children with refractory carcinoma. Cancer 92:914-923, 2001[CrossRef][Medline] 4. Wagner W, Radmard A, Schonekaes KG: A new administration schedule for amifostine as a radioprotector in cancer therapy. Anticancer Res 19:2281-2283, 1999[Medline] 5. Blakley BW, Cohen JI, Doolittle ND, et al: Strategies for prevention of toxicity caused by platinum-based chemotherapy: Review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001. Laryngoscope 112:1997-2001, 2002[CrossRef][Medline]
Related Correspondence
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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