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Amifostine Protects Against Cisplatin-Induced Ototoxicity in Children With Average-Risk Medulloblastoma

Maryam Fouladi, Murali Chintagumpala, David Ashley, Stewart Kellie, Sridharan Gururangan, Tim Hassall, Lindsey Gronewold, Clinton F. Stewart, Dana Wallace, Alberto Broniscer, Gregory A. Hale, Kimberly A. Kasow, Thomas E. Merchant, Brannon Morris, Matthew Krasin, Larry E. Kun, James M. Boyett, Amar Gajjar

From the Departments of Oncology, Biostatistics, Pharmaceutical Sciences, Radiological Sciences, St Jude Children's Research Hospital, Memphis, TN; Baylor College of Medicine, Houston, TX, Royal Children's Hospital, Melbourne, Australia; Children's Hospital at Westmead, Sydney, Australia; Royal Children's Hospital, Brisbane, Australia; and The Preston Robert Tisch Brain Tumor Center and Departments of Pediatrics and Surgery, Duke University Medical Center, Durham, NC

Corresponding author: Maryam Fouladi, MD, Department of Oncology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794; e-mail: maryam.fouladi{at}stjude.org

	ABSTRACT

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Purpose To determine the role of amifostine as a protectant against cisplatin-induced ototoxicity in patients with average-risk (AR) medulloblastoma treated with craniospinal radiotherapy and four cycles of cisplatin-based, dose-intense chemotherapy and stem-cell rescue.

Patients and Methods The primary objective was to determine whether, in patients with AR medulloblastoma (n = 62), amifostine would decrease the need for hearing aids (defined as grade 3 ototoxicity in one ear) compared with a control group (n = 35), 1 year from initiating treatment. Ninety-seven patients received craniospinal irradiation (23.4 Gy) followed by 55.8 Gy to the primary tumor bed using three-dimensional conformal technique, and four cycles of high-dose cyclophosphamide (4,000 mg/m²/cycle), cisplatin (75 mg/m²/cycle), and vincristine (two 1.5 mg/m² doses/cycle) and stem-cell rescue. When used, amifostine (600 mg/m²/dose) was administered as a bolus immediately before and 3 hours into the cisplatin infusion.

Results The median age of the 97 patients was 8.7 years (range, 3.2 to 20.2 years). The study and control groups were similar in age and sex distribution. Amifostine was well-tolerated. One year after treatment initiation, 13 patients (37.1%) in the control group versus nine (14.5%; one-sided ² test P = .005) of the amifostine-treated patients had at least grade 3 ototoxicity, requiring hearing aid in at least one ear.

Conclusion Amifostine administered before and during the cisplatin infusion can significantly reduce the risk of severe ototoxicity in patients with AR medulloblastoma receiving dose-intense chemotherapy.

	INTRODUCTION

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Medulloblastoma is the most common malignant brain tumor of childhood. The addition of platinum-based chemotherapy to postoperative craniospinal irradiation (CSI) has increased cure rates for patients with localized, resected medulloblastoma to more than 80% and permitted reductions in the dose of CSI.^1,2 However, 23% to 50% of patients experience cisplatin-associated ototoxicity.^2-4

When administered before chemotherapy or radiation, amifostine provides broad-spectrum cytoprotection of hematologic, renal, neural, and mucosal tissues without attenuating antitumor effect.^5,6 Amifostine is rapidly converted by alkaline phosphatase to its active metabolite WR-1065.^7,8 The much greater concentration of membrane-bound alkaline phosphatase in normal compared with neoplastic tissue accounts for the differential protection.⁹

The recommended adult single daily amifostine dose is 910 mg/m², with hypotension as the dose-limiting toxicity.^10-12 Evidence suggests that multiple daily doses of amifostine may improve its cytoprotective effects, especially with drugs such as cisplatin.^13-15 A phase I pediatric study established the recommended pediatric dose of amifostine for a twice-daily dose regimen as 600 mg/m² per dose.¹⁶

Studies of amifostine's protective effect against cisplatin-induced ototoxicity have yielded conflicting preclinical^17,18 and clinical^5,19-25 results. The use of other agents including sodium thiosulfate,^26,27 sodium salicylate²⁸ and n-acetylcysteine²⁷ have also been explored to protect against cisplatin-induced ototoxicity.

We prospectively investigated whether amifostine, administered before and during cisplatin infusion, would protect children with average-risk (AR) medulloblastoma, who received CSI followed by four cycles of platinum-based, dose-intense chemotherapy, from developing grade 3 or 4 ototoxicity (requiring a hearing aid in at least one ear) 1 year after initiation of therapy.

	PATIENTS AND METHODS

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Patients
Between October 1996 and May 2005, 113 patients ranging in age from 3 to 21 years with newly diagnosed, previously untreated AR medulloblastoma received protocol-prescribed therapy at participating institutions. AR was classified according to a modified Chang staging system,²⁹ and as previously described.¹ Eligibility criteria for enrollment onto this treatment protocol have been previously described.¹ The protocol was reviewed and approved by the institutional review boards of all participating institutions, and informed consent for treatment was obtained from all patients, parents, or legal guardians as appropriate.

Figure 1 summarizes the treatment groups. The control arm comprised 36 patients with medulloblastoma treated on a prospective trial (St Jude Medulloblastoma [SJMB] 96) described in the Treatment section herein. One patient died within 1 year of starting treatment. Hence, 35 patients with audiology exams approximately 1 year from starting therapy were included in the control group. In August 1999, the protocol was amended to include amifostine. Fifty-one patients with AR medulloblastoma were enrolled onto the amended study (SJMB 96). The follow-up study (SJMB 03) expanded the biology components into primary objectives, while retaining the same dose-intense, cisplatin-based chemotherapy regimen with amifostine. The first 26 assessable patients enrolled onto SJMB 03 were also included in the amifostine-treatment cohort.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Distribution of average-risk (AR) medulloblastoma patients by amifostine administration and treatment protocol. SJMB, St Jude Medulloblastoma; PFRT, posterior fossa irradiation; TBRT, tumor-bed irradiation; TX, treatment.

After completing the initial analysis, we noted that six of the amifostine-treated patients who did not receive all four courses of cisplatin did not experience severe ototoxicity. To ensure that the inclusion of these patients did not compromise the study findings, we reanalyzed the data after replacing these patients with six consecutive patients on the ongoing SJMB 03 protocol who had received all courses of cisplatin and amifostine and had 1-year audiology follow-up.

Treatment
Maximal resection of the tumor was attempted in all patients. All patients received 23.4 Gy of CSI and 55.8 Gy to the primary tumor bed using the three-dimensional, conformal (3D-CRT) technique. Seventy-five patients on SJMB 96 (35 without and 40 with amifostine, respectively) received an initial 12.6-Gy 3D-CRT boost to the posterior fossa (cumulatively 36 Gy), followed by primary site irradiation to 55.8 Gy using a 2-cm clinical target volume margin; 22 patients enrolled onto the SJMB 03 study (all treated with amifostine) received primary-site irradiation to 55.8 Gy using a 1-cm clinical target margin. After a 6-week rest, all patients began four cycles of high-dose chemotherapy as previously described.^1,30

When administered, amifostine, 600 mg/m²/dose, was administered intravenously over 1 minute, immediately before and 3 hours into the cisplatin infusion. Supportive care guidelines for amifostine included (1) adequate prehydration; (2) withholding antihypertensive medication for 24 hours before infusion; (3) placing patients supine and monitoring blood pressure every 5 to 10 minutes for 25 minutes after amifostine infusion, administering a 20-mL/kg normal saline bolus over 1 hour with decreases of 20 mm systolic; and (4) monitoring of serum total and ionized calcium for 24 hours after amifostine administration and, if ionized calcium was less than 1.0 mmol/L, administration of intravenous calcium chloride (10 to 20 mg/kg/dose).

After observing mild to moderate hypocalcemia in several patients, we began prophylactic administration of continuous intravenous calcium chloride infusion (20 mg/kg) concurrently with the 6-hour cisplatin infusion and then again 6 hours after the completion of the cisplatin infusion, while monitoring ionized serum calcium for 24 hours. Additional supportive care and stem-cell collection procedures have been described previously.^1,30

Patient Monitoring and Follow-Up
During protocol therapy, patients’ disease status and toxicities (graded using the National Cancer Institute's Common Toxicity Criteria) were monitored with appropriate laboratory assessments and imaging studies. After completion of therapy, follow-up examinations and imaging were performed every 3 months for the first 18 months, every 6 months until 5 years, and yearly thereafter.

Hearing Evaluations
Audiograms were obtained at diagnosis, after radiotherapy (RT) completion, after each cycle of chemotherapy, and 6 weeks, 6 months, 1 year and thereafter annually after the completion of all therapy. Evaluation of hearing depended on the patient's age, development, and cooperation. Conventional audiometry was generally performed on patients age 5 years and older: the patient would sit in a sound-booth and indicate when a pure tone stimulus was heard by raising his or hand or by pressing a button. Conditioned play was typically performed on children aged 3 to 5 years: Patients would sit in a sound-booth and indicate when a pure tone stimulus was heard by playing a simple game (ie, throwing blocks into a bucket). Conventional pure-tone audiometry and conditioned play audiometry were obtained using a GSI-61 audiometer (Grason-Stadler Inc, Milford, NH) with ER-3A/5A insert earphones and TDH-50 headphones. Air conduction thresholds were measured at 2.5, 5, 1, 2, 3, 4, 6, and 8 kHz.

The ototoxicity criteria were similar to criteria used in the recently completed phase III intergroup AR medulloblastoma protocol (A9961; Table 1). Any patients with at least grade 3 ototoxicity (> 25-dB HL loss at 2,000 Hz) required hearing aids. We obtained the thresholds from 2,000 to 8,000 HZ and the audiologist-determined toxicity grades for all exams. The audiology exam obtained closest to 1 year from study enrollment was selected for analysis. Grades were assigned by audiologists who performed exams as part of their routine clinical responsibilities. Grades were confirmed by plotting the thresholds and grades over time for each patient, ensuring that the thresholds were consistent with the grade assigned by the audiologist.

The left and right cochlea were defined systematically on the treatment-planning computed tomography scan, and the mean radiation dose for each cochlea was computed.

Dose Modifications for Ototoxicity
If patients experienced grade 3 ototoxicity, the cisplatin dose was reduced by 50%. For grade 4 ototoxicity, cisplatin was held and not restarted unless follow-up audiograms demonstrated improved hearing.

Statistical Design
The study objective was to investigate amifostine's ability to protect children receiving a dose-intense cisplatin-based regimen from severe ototoxicity, defined as at least grade 3 ototoxicity requiring hearing aids in at least one ear 1 year after treatment initiation. We estimated³¹ that 62 patients receiving amifostine would be required for 80% power (one-sided ² test = .05) to detect a 20% reduction from the observed rate of 37% in the 35 AR patients treated on the protocol without amifostine. Two interim analyses³² were performed, after 24 patients and 32 patients, both resulting in continuation of the trial.

To investigate the effect of cochlear radiotherapy (RT) dose and treatment with amifostine on the occurrence of a grade 3 or 4 ototoxicity at 1 year from treatment initiation, a method utilizing generalized estimating equations (GEE),³³ as implemented in PROC GENMOD of the SAS/STAT software (SAS Institute, Cary, NC), was used. PROC MIXED of the SAS/STAT software was used to investigate differences in the RT dose to the cochlea between the control group and those patients receiving amifostine. These repeated-measures models analyze the cochlear doses from each ear while taking into consideration that the outcomes within a patient may be correlated.

	RESULTS

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Characteristics for the control (n = 35) and amifostine (n = 62) groups are summarized in Table 2. Among the 35 patients in the control group, four (11%) did not receive all four courses of cisplatin because of development of grade 3 ototoxicity before completing four courses (n = 3), and grade 1 ototoxicity in a blind patient (n = 1; at physician's discretion).

Hearing Loss
One year from study enrollment, nine (14.5%) of 62 patients in the amifostine group had grade 3 or 4 ototoxicity requiring hearing aids, compared with 13 (37.1%) of 35 in the control group (P = .005; Table 3).

Among the eight amifostine-treated patients who received fewer than four courses of cisplatin, six did not experience severe ototoxicity 1 year after treatment initiation. Thus, we reanalyzed the data replacing those six patients in the amifostine group with six consecutive patients on the ongoing SJMB 03 study who received all four courses of cisplatin. Even with this new cohort, amifostine significantly decreased the percentage of patients experiencing severe ototoxicity: 10 (16%) of 62 versus 13 (37.1%) of 35 (P = .010).

Cochlear radiation doses were available in 56 patients. Fourteen patients had at least grade 3 ototoxicity in at least one ear. The mean cochlear radiation dose with at least grade 3 ototoxicity was 49.4 Gy (range, 34.6 to 47.5Gy) compared with 49 Gy (range, 31.0 to 60 Gy) in ears with less than grade 3 ototoxicity (P = .94).

In a univariate GEE model, no amifostine use was the only factor significantly associated with severe ( grade 3) ototoxicity (P = .042); cochlear radiation dose was not (P = .80). In a multivariate GEE model including both cochlear dose and amifostine, only the absence of amifostine remained significantly associated with severe ototoxicity (P = .047).

Eighty-two patients had hearing assessments 2 years after treatment initiation. The incidence of severe ototoxicity in the control group (n = 34) was 35%, compared with 17% in the amifostine group (n = 48; P = .048). Although the number of amifostine-treated patients with 3-year follow-up was too small for adequate statistical analysis, amifostine continued to demonstrate a protective trend (data not shown).

Toxicities Related to Amifostine
Given the short half-life and toxicity profile of amifostine, we reviewed all adverse events that occurred within 48 hours of the amifostine infusion for all cycles. Table 4 includes grade 3 or 4 adverse events at least possibly attributable to amifostine.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Event-free survival with or without amifostine.

	DISCUSSION

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Cisplatin ototoxicity, typically bilateral and high frequency in nature, is caused by damage to the outer hair cells in the organ of corti,^34,35 the spiral ganglion and stria vascularis.^36,37 The mechanism of cisplatin ototoxicity involves the formation of reactive oxygen species, generated in cells by cellular metabolism, inflammation, and chemotherapy.³¹ Amifostine's active metabolite, WR-1065, has been reported to attenuate cisplatin-induced toxicity by acting as a scavenger of oxygen free radicals³⁸ and binding to the active species of platinum agents, to prevent^38,39and reverse DNA platination.⁴⁰

Few prospective studies have documented amifostine protection against cisplatin-induced ototoxicity. Although Kemp et al's⁵ randomized phase III trial reported that pretreatment with amifostine resulted in a 43% reduction in the incidence of ototoxicity, other adult^22,41 and pediatric^23-25 trials have failed to show any protection.

Marina et al²³ reported the lack of protection of amifostine against cisplatin ototoxicity in children with extracranial, extragonadal germ cell tumors. Twenty-five children (15 assessable for ototoxicity) received amifostine, 825 mg/m² as a 15-minute infusion 30 minutes before cisplatin 40 mg/m²/d on days 1 through 5; 75% of patients had grade 2 to 4 ototoxicity, similar to historical controls. The lack of activity in Marina et al's study may reflect the schedule of amifostine and cisplatin administration, the higher total cisplatin dose, and the small sample size, which had only 80% statistical power to detect a 35% reduction in ototoxicity (74% v 39%), had all 25 patients been assessable for ototoxicity. Given the very short half-life of amifostine and its metabolite, WR-1065, a single 15-minute infusion of amifostine 30 minutes before cisplatin infusion may not be optimal. In the current nonrandomized study, amifostine was administered as a bolus over 1 minute, immediately before the cisplatin infusion and again 3 hours into the cisplatin infusion, based on evidence that WR-1065 can reverse DNA platination and that multiple daily dosing may improve cytoprotection.^13-15

Katzenstein et al²⁵ reported the results of an unplanned interim analysis of amifostine's effect on cisplatin-induced ototoxicity in a randomized trial of patients with hepatoblastoma. Patients received cisplatin 100 mg/m² on day 1 with or without amifostine 740 mg/m² over 15 minutes before cisplatin. Analysis of 82 patients revealed significant hearing loss in 14% (five of 37) of patients receiving amifostine versus 9% (four of 45) of controls (P = .72). Younger age, different dose, and schedule and length of infusion of amifostine and cisplatin may have contributed to the lack of protection reported. Further studies are needed to delineate the importance of these factors for amifostine-related protection against cisplatin-induced ototoxicity. However, this abstract reports on only 82 randomly assigned patients, approximately 33% of the planned sample size. Furthermore, only 40% of the 203 eligible patients had sufficient data to be included in the analysis.

Fisher et al²⁴ reported that seven of nine assessable patients with newly diagnosed high-risk and AR medulloblastoma or primitive neuroectodermal tumor treated with RT, cisplatin-based chemotherapy, and amifostine developed grade 2 to 3 hearing loss 1 to 3 years after treatment. Amifostine 1,000 mg/m² was administered over 15 minutes before cisplatin and 4 hours into the 8-hour cisplatin infusion. However, study limitations include the small cohort, the inclusion of AR and high-risk patients who received significantly different doses of CSI, combining patients with posterior fossa and supratentorial disease types, and the variability of the time points at which hearing was evaluated.

Amifostine was well tolerated in the current study. Although mild to severe hypocalcemia has been reported in the literature in up to 80% of patients, our supportive care guidelines minimized the frequency and severity of hypocalcemia.

Long-term hearing deterioration after platinum therapy has been reported in the literature.^4,42,44 We have also reported late, often unilateral hearing loss as radiation-related ototoxicity in up to 27% of patients after more than 50 Gy to the cochlea by the 5th year after RT,⁴³ with a lower but dose-related incidence after 3D-CRT, as was used in the current report.⁴² A suggested dose threshold of 32 Gy in patients receiving chemotherapy was noted in the latter setting. In a report of cisplatin-treated patients followed for a median of 20.6 months after therapy, only those receiving CSI experienced mild progression of ototoxicity.⁴ In contrast, Bertolini et al⁴⁴ reported continued deterioration of hearing in platinum-treated patients followed for more than 2 years. To address the sustainability of amifostine's protection against cisplatin ototoxicity over time, we demonstrated a continued trend towards otoprotection by amifostine at 2 and 3 years after initiation of therapy.

Amifostine did not confer tumor protection, as evidenced by similar progression-free survival in the control and amifostine-treated patients. Although the median follow-up for the amifostine cohort was shorter (3.4 years) than that for controls (7.6 years), median time to progression was comparable (2.7 years [controls] v 2.9 years [amifostine group]).

In summary, in patients with AR medulloblastoma treated prospectively with cisplatin-based, dose-intense chemotherapy, twice-daily doses of amifostine 600 mg/m²/dose before and during the cisplatin infusion significantly decreased the need for hearing aids.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

	AUTHOR CONTRIBUTIONS

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Conception and design: Maryam Fouladi, Murali Chintagumpala, Stewart Kellie, Dana Wallace, Gregory A. Hale, Thomas E. Merchant, Larry E. Kun, James M. Boyett, Amar Gajjar

Provision of study materials or patients: Maryam Fouladi, Murali Chintagumpala, David Ashley, Stewart Kellie, Sridharan Gururangan, Tim Hassall, Clinton F. Stewart, Alberto Broniscer, Gregory A. Hale, Kimberly A. Kasow, Thomas E. Merchant, Brannon Morris, Matthew Krasin, Larry E. Kun, Amar Gajjar

Collection and assembly of data: Maryam Fouladi, David Ashley, Stewart Kellie, Sridharan Gururangan, Tim Hassall, Lindsey Gronewold, Clinton F. Stewart, Dana Wallace, Brannon Morris, Matthew Krasin, Larry E. Kun, Amar Gajjar

Data analysis and interpretation: Maryam Fouladi, Murali Chintagumpala, David Ashley, Stewart Kellie, Sridharan Gururangan, Lindsey Gronewold, Clinton F. Stewart, Dana Wallace, Thomas E. Merchant, Larry E. Kun, James M. Boyett, Amar Gajjar

Manuscript writing: Maryam Fouladi, Dana Wallace, Thomas E. Merchant, Larry E. Kun, James M. Boyett, Amar Gajjar

Final approval of manuscript: Maryam Fouladi, Murali Chintagumpala, David Ashley, Stewart Kellie, Sridharan Gururangan, Tim Hassall, Lindsey Gronewold, Clinton F. Stewart, Dana Wallace, Alberto Broniscer, Gregory A. Hale, Kimberly A. Kasow, Thomas E. Merchant, Brannon Morris, Matthew Krasin, Larry E. Kun, James M. Boyett, Amar Gajjar

	NOTES

 
Supported in part by National Cancer Institute Grant No. P30 CA21765, the Pediatric Brain Tumor Foundation, the Noyes Brain Tumor Foundation, Musicians Against Childhood Cancer, the Ryan McGhee Foundation, and the American Lebanese Syrian Associated Charities.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on www.JCO.org.

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Submitted September 10, 2007; accepted April 23, 2008.

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