Source: Journal of Clinical Oncology, 10.1200/JCO.2008.20.1160
Authors: David R. Freyer et al.

To The Editor:
Fouladi et al1 are to be congratulated for the recent publication of their study demonstrating that amifostine protects against cisplatin-induced ototoxicity in children with average risk medulloblastoma. Despite limitations imposed by the study design (eg, use of a nonrandomized control group and heterogenous cranial irradiation techniques), the investigators nonetheless have made a valuable contribution to the growing field of pediatric cancer control research and to prevention of hearing loss in particular. First, they persisted in completing this study despite others that failed to demonstrate otoprotection by amifostine.2-4 Second, as the authors discuss, their positive results may be attributable to their use of a more dose-intensive schedule of amifostine, illustrating the critical need for cancer-control trials, like their disease-directed counterparts, to incorporate the most current and complete pharmacologic data for the drug under investigation. Finally, this study provides good evidence for adding amifostine to the growing list of agents used to prevent specific chemotherapeutic toxicities in pediatric oncology practice, including calcium leucovorin, mesna, cytokine growth factors, and, more recently, dexrazoxane. In so doing, the study strengthens the case for active development of other forms of chemoprotection as a useful supportive care strategy.

At the same time, important questions remain, owing to the study’s focus on patients with medulloblastoma and selection of amifostine as the drug of interest. The cisplatin dose and schedule are somewhat different in this study (a lower cisplatin dose being given on a single day) than regimens commonly used for other pediatric malignancies (eg, hepatoblastoma, osteosarcoma, neuroblastoma, and germ cell tumor). Would amifostine be protective in those settings? This study is an important step in establishing a role for amifostine, but follow-up studies will be necessary to know whether the agent is active in other tumor systems treated with more dose-intensive cisplatin regimens. In addition, amifostine, although apparently effective, is neither simple to administer nor necessarily well-tolerated. What is the therapeutic burden associated with administering amifostine? Sentinal grade 3 and 4 adverse events (hypocalcemia, hypotension, and nausea/vomiting) were relativelyuncommon,being noted in only 3%, 3%, and 13% of patients, respectively; but achieving this necessitated a somewhat complex amifostine administration protocol that required providing adequate prehydration, withholding antihypertensive medication for 24 hours before treatment, placing patients supine and monitoring serial blood pressures frequently after drug administration, administering boluses of normal saline for moderate decreases in blood pressure, monitoring of serum total and ionized calcium levels for 24 hours after treatment, and correcting measured deficits. The incidences of less severe (grades 1 and 2) toxicities were not reported, but their frequency is implied by the addition to the protocol of prophylactic continuous infusions of calcium chloride for 6 hours during and 6 hours after the cisplatin infusion, which was prompted by observing mild to moderate episodes of hypocalcemia in several patients.1 While these requirements are not insurmountable and certainly attest to the careful medical attention given to study participants, they also serve as strong incentive to continue the search for other otoprotectants that are at least equally effective against other cisplatin regimens and ideally are simpler to administer with less potential for clinically significant adverse effects.

To that end, the Children’s Oncology Group has recently activated ACCL0431, a randomized, phase III clinical trial evaluating the efficacy of sodium thiosulfate (STS) for preventing cisplatin-induced hearing loss in children aged 1 to 18 years newly diagnosed with hepatoblastoma, germ cell tumor, medulloblastoma, neuroblastoma, or osteosarcoma.5 Access to this study is available internationally through all 212 current Children’s Oncology Group institutions. The primary study aim is to compare the proportion of subjects who develop hearing loss, which in this study is defined using the more sensitive grading system of the American Speech-Language-Hearing Association.6 Secondary aims will measure change in hearing thresholds and the incidences of hematological and renal toxicities that might also be ameliorated by STS. Subjects will receive cisplatin according to their disease-specific regimens, and their audiometry data will be pooled for statistical analysis. STS is a reducing agent whose efficacy in preventing ototoxicity has been demonstrated in extensive preclinical,7-11 some adult,12,13 and limited pediatric7 studies. Evidence also suggests STS may permit maintaining dose-intensity of cisplatin by preventing myelosuppression and renal toxicity.14-16 The medication is administered as a single fifteen minute infusion intravenously and has a favorable toxicity profile in children.7 In the quest to reduce the devastating impact of hearing loss inyoungchildren treated with cisplatin, it is hoped that ACCL0431 will demonstrate that STS is effective across a variety of cisplatin regimens and pediatric age groups, as well as being safe and simple to administer.

Authors and Affiliations:
David R. Freyer Childrens Center for Cancer and Blood Diseases, Childrens Hospital Los Angeles; Keck School of Medicine, University of Southern California, Los Angeles; Children’s Oncology Group Study ACCL0431, Arcadia, CA

Lillian Sung Division of Paediatric Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; Cancer Control and Survivorship Committee, Children’s Oncology Group, Arcadia, CA

Gregory H. Reaman The George Washington University School of Medicine and Health Sciences, Washington, DC; Children’s Oncology Group, Arcadia, CA AUTHORS’

Note:
The author(s) indicated no potential conflicts of interest.

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. Marina N, Chang KW, Malogolowkin M, et al: Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ cell tumors: A Children’s Oncology Group study. Cancer 104:841-847, 2005

3. Fisher MJ, Lange BJ, Needle MN, et al: Amifostine for children with medulloblastoma treated with cisplatin-based chemotherapy. Pediatr Blood Cancer 43:780-784, 2004

4. Katzenstein HM, Chang K, Krailo M, et al: A randomized study of platinum-based chemotherapy with or without amifostine for the treatment of children with hepatoblastoma: A report of the Intergroup Hepatoblastoma Study P9645. Proc Am Soc Clin Oncol 22:799s, 2004 (suppl; abstr 8518)

5. National Cancer Institute: Phase III randomized study of sodium thiosulfate in preventing ototoxicity in young patients receiving cisplatin chemotherapy for newly diagnosed germ cell tumor, hepatoblastoma, medulloblastoma, neuroblastoma, or osteosarcoma. http://www.cancer.gov/search/ViewClinicalTrials.aspx? cdrid_588655&version_HealthProfessional&protocolsearchid_5079860

6. Knight KRG, Kraemer DR, Neuwelt EA: Ototoxicity in children receiving platinum chemotherapy: Underestimating a commonly occuring toxicity that may influence academic and social development. J Clin Oncol 23:8588-8596, 2005

7. Neuwelt EA, Gilmer-Knight K, Lacy C, et al: Toxicity profile of delayed high-dose sodium thiosulfate in children treated with carboplatin in conjunction with blood-brain barrier disruption. Pediatr Blood Cancer 47:174-182, 2006

8. Leitao DJ, Blakely BW: Quantification of sodium thiosulphate protection on CDDP-induced toxicities. J Otolaryngol 32:146-150, 2003

9. Muldoon LL, Pagel MA, Kroll RA, et al: Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity. Clin Cancer Res 6:309-315, 2000

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11. Harned TM, Kalous O, Neuwelt A, et al: Sodium thiosulfate administered six hours after cisplatin does not compromise antineuroblastoma activity. Clin Cancer Res 14:533-540, 2008

12. Neuwelt EA, Brummet RE, Doolittle ND, et al: First evidence of otoprotection against carboplatin-induced hearing loss with a two-compartment system in patients with central nervous system malignancy using sodium thiosulfate. J Pharmacol Exp Ther 286:77-84, 1998

13. Doolittle ND, Muldoon LL, Brummett RE, et al: Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors. Clin Cancer Res 7:493-500, 2001

14. Doolittle ND, Tyson RM, Lacy C, et al: Potential role of delayed sodium thiosulfate as protectant against severe carboplatin-induced thrombocytopenia in patients with malignant brain tumors. Blood 98:37a-38a, 2001 (abstr 149)

15. Kumar P, Robbins KT: Treatment of advanced head and neck cancer with intra-arterial CDDP and concurrent radiation therapy: The RADPLAT protocol. Curr Oncol Rep 3:59-65, 2001

16. Robbins KT, Fontanesi J, Wong F, et al: A novel organ preservation protocol for advanced carcinoma of the larynx and pharynx. Arch Otolaryng Head Neck Surg 122:853-857, 1996 DOI: 10.1200/JCO.2008.20.1160; published online ahead of print at www.jco.org on December 8, 2008