Ototoxicity After Intensity-Modulated Radiation Therapy and Cisplatin-Based Chemotherapy in Children With Medulloblastoma

Int. J. Radiation Oncology Biol. Phys., Vol. 78, No. 5, pp. 1445–1450, 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter

doi:10.1016/j.ijrobp.2009.09.031

CLINICAL INVESTIGATION

Central Nervous System

OTOTOXICITY AFTER INTENSITY-MODULATED RADIATION THERAPY AND CISPLATIN-BASED CHEMOTHERAPY IN CHILDREN WITH MEDULLOBLASTOMA ARNOLD C. PAULINO, M.D.,*yz MARK LOBO, M.D.,z BIN S. TEH, M.D.,*z M. FATIH OKCU, M.D., M.P.H.,yz MICHAEL SOUTH, C.M.D.,* E. BRIAN BUTLER, M.D.,* JACK SU, M.D.,yz AND MURALI CHINTAGUMPALA, M.D.yz *Department of Radiation Oncology, The Methodist Hospital and The Methodist Hospital Research Institute, and yDepartment of Pediatrics, Division of Hematology/Oncology, Texas Children’s Hospital, and zBaylor College of Medicine, Houston, TX Purpose: To report the incidence of Pediatric Oncology Group (POG) Grade 3 or 4 ototoxicity in a cohort of patients treated with craniospinal irradiation (CSI) followed by posterior fossa (PF) and/or tumor bed (TB) boost using intensity-modulated radiation therapy (IMRT). Methods and Materials: From 1998 to 2006, 44 patients with medulloblastoma were treated with CSI followed by IMRT to the PF and/or TB and cisplatin-based chemotherapy. Patients with standard-risk disease were treated with 18 to 23.4 Gy CSI followed by either a (1) PF boost to 36 Gy and TB boost to 54 to 55.8 Gy or (2) TB boost to 55.8 Gy. Patients with high-risk disease received 36 to 39.6 Gy CSI followed by a (1) PF boost to 54 to 55.8 Gy, (2) PF boost to 45 Gy and TB boost to 55.8 Gy, or (3) TB boost to 55.8 Gy. Median audiogram follow-up was 41 months (range, 11–92.4 months). Results: POG Grade Ototoxicity 0, 1, 2, 3. and 4 was found in 29, 32, 11, 13. and 3 ears. respectively, with POG Grade 3 or 4 accounting for 18.2% of cases. There was a statistically significant difference in mean radiation dose (Dmean) cochlea according to degree of ototoxicity, with Dmean cochlea increasing with severity of hearing loss (p = 0.027). Conclusions: Severe ototoxicity was seen in 18.2% of ears in children treated with IMRT boost and cisplatin-based chemotherapy. Increasing dose to the cochlea was associated with increasing severity of hearing loss. Ó 2010 Elsevier Inc. Medulloblastoma, Children, Ototoxicity, Cochlea, Radiation dose.

dulloblastoma is limited. A previous report from our institution of 15 children treated with CSI followed by PF and/or TB boost using IMRT showed that only 13% of patients experienced Pediatric Oncology Group (POG) Grade 3 or 4 ototoxicity compared with 64% of patients treated with conventional RT. Two criticisms of the above study included a short median follow-up of 18 months and a small number of patients treated with IMRT. This report summarizes an extended follow-up of a larger cohort of medulloblastoma patients treated with an IMRT boost.

INTRODUCTION Current treatment strategies, which include maximal safe resection, craniospinal irradiation (CSI) followed by a boost to the posterior fossa (PF), and/or tumor bed (TB)–based and cisplatin-based chemotherapy have resulted in approximately 80% and 70% 5-year survival rates in standard-risk and highrisk medulloblastoma (1, 2). As survival rates in children with medulloblastoma improve, the issue of late effects of treatment becomes more important. One possible consequence of treatment with cisplatin-based chemotherapy and radiotherapy (RT) is sensorineural hearing loss. To reduce the incidence of ototoxicity in children, several methods of reducing radiation dose to the cochlea have been investigated, including the use of three-dimensional (conformal) RT, intensity-modulated radiation therapy (IMRT), and more recently proton therapy (3–5). Information regarding ototoxicity and cochlear dose reduction using IMRT in me-

METHODS AND MATERIALS Patient, tumor, and treatment characteristics From 1998 to 2006, 44 patients with medulloblastoma were treated at The Methodist Hospital and Texas Children’s Hospital, Baylor College of Medicine, and had audiometric evaluation before RT and during the follow-up period. The medical and RT records of Society for Therapeutic Radiology and Oncology, September 21– 25, 2008, Boston, Massachusetts. Conflict of interest: none. Received June 20, 2009, and in revised form Sept 21, 2009. Accepted for publication Sept 26, 2009.

Reprint requests to: Arnold C. Paulino, M.D., Department of Radiation Oncology, The Methodist Hospital, 6565 Fannin St., DB1-077, Houston, TX 77030. Tel: (713) 441-4844; Fax: (713) 441-4493; E-mail: [email protected] Presented in part at the 50th Annual Meeting of the American 1445

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Fig. Example of case treated with tumor bed intensity-modulated radiation therapy (IMRT) boost. The patient initially received 2,340 cGy craniospinal irradiation for standard-risk medulloblastoma. Prescription dose was 3,240 cGy to the planning target volume (PTV) and clinical target volume. Shaded areas: tumor bed (red), CTV (yellow), PTV (purple), brainstem (aqua), non–tumor bed posterior fossa (orange), right cochlea (olive), left cochlea (lavender). Isodose curves: 3,400 cGy (dark blue), 3,240 cGy (pink), 2,945 cGy (orange), 2,520 cGy (yellow), 1,080 cGy (aqua). (a) Axial slice. (b) Sagittal slice. these patients were retrospectively reviewed after internal review board approval at both The Methodist Hospital and Baylor College of Medicine. There were 30 male and 14 female patients, with a median age at the time of RT of 9 years (range, 33 months to 18 years). Risk category was standard in 33 patients and high in 11. Patients were treated with maximal safe resection, CSI and IMRT to the PF, and/or TB followed by cisplatin-based chemotherapy. Patients with standard-risk disease were treated with 18 to 23.4 Gy CSI followed by either a (1) PF boost to 36 Gy and TB boost to 54 to 55.8 Gy (n = 29) or (2) TB boost to 55.8 Gy (n = 4). Patients with high-risk disease received 36 to 39.6 Gy CSI followed by a (1) PF boost to 54 to 55.8 Gy (n = 8), (2) PF boost to 45 Gy and TB boost to 55.8 Gy (n = 2), or (3) TB boost to 55.8 Gy (n = 1). The CSI was delivered with the patient in the prone position until 2004, when patients were treated in the supine position (6). For standard- and high-risk patients receiving PF followed by TB boost, the clinical target volume (CTV) was defined as the primary tumor bed and residual tumor with a 2-cm margin. For standard- and high-risk patients receiving only a TB boost, the CTV was defined as the primary tumor bed and residual tumor with a 1-cm margin. The planning target volume (PTV) was defined as the CTV with a 3-mm margin. The entire PTV was covered by at least 95% of the prescription dose. No more than 10% of the PTV received more than 110% of the prescribed dose. The figure shows an example of a case treated using IMRT to minimize dose to the cochlea. The technique for immobilization has been previously described in our earlier reports (4, 6). Dose constraints for various structures in the brain and head and neck were as follows: optic chiasm 45 Gy, optic nerves 45 Gy, brainstem 54 Gy, and lenses 8 Gy. For the temporal lobes, the dose constraint was generally 50% of the IMRT boost dose. In patients receiving 23.4 Gy and 36 Gy CSI, dose constraints for the temporal lobe were approximately 40 Gy and 46 Gy, respectively. For the cochlea, the dose constraint was generally 40% of the IMRT boost dose. In patients receiving 23.4 Gy and 36 Gy CSI, dose constraints for the cochlea were approximately 37 Gy and 45 Gy, respectively. The maximum, minimum, and mean (Dmean) right and left cochlear doses were recorded for each patient. Chemotherapy was cisplatinbased according to SJMB96 (n = 28) or Children’s Oncology Group A9961 (n = 16) protocols (1, 7). The median cisplatin dose was 300 mg/m2 (75–562.5 mg/m2). Cisplatin dose was decreased by 50% for

a hearing loss of 40 dB loss or more at 4,000 to 8,000 Hz (POG Grade 3 ototoxicity). Eleven patients (25%) had a reduction in cisplatin doses. Nineteen patients treated on or according to the SJMB96 protocol also received amifostine. The details of amifostine dose and administration have been previously reported (8).

Audiometric evaluation Hearing thresholds were assessed by pure tone audiograms at Texas Children’s Hospital. Hearing thresholds were determined for each ear at stimulus frequencies of 0.25, 0.5, 1, 2, 4, 6, and 8 KHz. In all, 270 pure tone audiograms were analyzed and graded according to the POG objective ototoxicity scale: Grade 0 = normal, Grade 1 = 20 to 40 dB loss at >4 KHz, Grade 2 = >40 dB loss at 4 KHz, Grade 3 = >40 dB loss at >2 KHz, Grade 4 = 40 dB loss at <2 KHz. Audiograms were scheduled before and 6 weeks after RT; after each cycle of chemotherapy; and 6 months, 1 year, and thereafter annually after completion of therapy. Median audiogram follow-up was 41 months (range, 11–92.4 months) from the initiation of RT.

Statistical analysis The unpaired t-test was used to determine differences in Dmean cochlea and cisplatin dose according to risk category (standard- vs. high-risk) and to determine whether age at time of RT and cisplatin dose were related to degree of ototoxicity (POG Grade #2 vs. Grade >2). For categoric variables such as gender, risk category, and use of amifostine, the Fisher exact test was used to detect differences in degree of ototoxicity (POG Grade #2 vs. Grade >2). Because it is possible that the right and left cochleae will have different grades of hearing loss, the worse grade for the patient was counted in determination of relationship with age, cisplatin dose, gender, risk category, and use of amifostine. The one-way analysis of variance was used to test for differences in Dmean cochlea among the different POG ototoxicity grade categories.

RESULTS The Dmean cochlea was higher in high-risk patients than in standard-risk patients (p < 0.0001). The median Dmean

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Table 1. Treatment characteristics and timing of hearing loss in children with POG Grade 3 and 4 ototoxicity Patient

Dmean Cochlea Use of POG ototoxicity Timing of Age (y)/ gender/ Cisplatin dose Ear (Gy) amifostine grade hearing loss (mo) risk category (mg/m2)

1 2 3

9.8/M/HR 7.6/M/HR 12/F/HR

450 300 225

4 5 6 7

3/F/HR 4.2/M/SR 9/M/SR 6.8/M/SR

525 300 300 300

8

10/M/SR

262.5

9

6.5/M/SR

300

10

5/M/SR

225

11

4.3/M/SR

300

L R R L L R L R L R L R L R L R

51.8 46.0 50.4 50.4 47.9 35.4 33.1 32.1 32.0 35.2 35.2 38.7 39.7 38.5 36.5 37.9

No No No

4 3 3 3 4 3 3 3 3 3 3 3 3 3 4 3

No No Yes Yes Yes Yes No No

12 10 3 3 7 53 66 77 57 47 47 5 4 5 5 17

Comments Hearing aid Hearing aid Hearing aids Hearing aid FM assisted listening device Hearing aids FM assisted listening device Hearing aids Hearing aid

Abbreviations: M = male; F = female; SR = standard-risk; HR = high-risk; R = right; L = left; POG = Pediatric Oncology Group.

cochlea was 35.3 Gy (range, 25.2–55.0 Gy) for standard-risk patients and 43.0 Gy (range, 40.6–51.8 Gy) for high-risk patients. There was no difference in cisplatin dose according to risk group category (p = 0.36). A total of 11 (25.0%) of 44 patients did not have any hearing loss in either ear. POG Grade 3 and/or 4 ototoxicity was found in 11 (25.0%) patients; 6 had unilateral and 5 had bilateral Grade 3 and/or 4 ototoxicity. POG Grade 0, 1, 2, 3, and 4 ototoxicity was found in 29, 32, 11, 13, and 3 ears respectively, with POG Grade 3 or 4 accounting for 18.2% of the 88 ears. No patient developed hearing loss after the RT course and before initiation of cisplatin chemotherapy. The 16 ears with Grade 3 or 4 hearing loss are presented in Table 1 with respect to timing of ototoxicity. Median time to develop Grade 3 or 4 ototoxicity was 8.5 months (range, 3–77 months) from the initiation of RT. For the 6 patients who developed unilateral Grade 3 or 4 hearing loss, the ear developing a Grade 3 or 4 ototoxicity had a median Dmean cochlea dose of 2.7 Gy (range, 0.6–8.2 Gy) higher than the contralateral ear with less than Grade 3 hearing loss. The median Dmean cochlea and cisplatin dose according to POG ototoxicity grade are presented in Table 2. There was a statistically significant difference in Dmean cochlea according to degree of ototoxicity, with Dmean cochlea increasing with severity of hearing loss (p = 0.027). Cochlear dose did not exceed 43 Gy in the 29 ears without ototoxicity. Gender

(p = 0.46), age of the child (p = 0.13), risk group (p = 0.42), cisplatin dose (p = 0.20), and use of amifostine (p = 0.73) were not related to the degree of ototoxicity. Of the 19 patients who received amifostine, 4 (21.1%) developed Grade 3 or 4 ototoxicity. In the remainder of patients who did not receive amifostine, 7 (28%) developed Grade 3 or 4 ototoxicity. For patients receiving amifostine, 1 of 4 developed Grade 3 or 4 ototoxicity at 12 months after initiation of RT, whereas of those not receiving amifostine, 5 of 7 developed Grade 3 or 4 ototoxicity (p = 0.24). DISCUSSION In our institution, IMRT has been used for the past 13 years to treat pediatric brain tumors. Its main advantage is increased conformality around the target volume, thus decreasing the high-dose region in surrounding normal tissue. The use of an IMRT boost in medulloblastoma is particularly attractive because the cochlea is usually in the high-dose region when compared to conventional RT techniques (9). Furthermore, most patients with medulloblastoma receive cisplatin chemotherapy, a known ototoxic drug, which causes hearing loss at higher frequencies and with continued exposure affects the lower frequencies that are used for communication. Our initial report of 15 patients with an 18-month median follow-up showed that 13% of children who received an IMRT

Table 2. Median Dmean cochlea and median cisplatin dose according to POG ototoxicity grade POG grade 0 1 2 3 4

No. of cases

Median Dmean cochlea (Gy)

29 32 11 13 3

34.3 35.6 36.8 37.0 47.9

Abbreviation: POG = Pediatric Oncology Group.

Range Dmean cochlea (Gy) 25.2–43.0 31.6–55.0 33.9–45.4 28.7–50.4 36.5–51.8

Median cisplatin dose (mg/m2) 300 300 300 300 450

Range cisplatin dose (mg/m2) 103.6–562.5 75–450 75–562.5 225–460 225–525

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Table 3. Review of ototoxicity literature in patients with medulloblastoma and other tumors treated with radiotherapy and cisplatinbased chemotherapy Study (Ref)

n

Fouladi et al. (8)

97

Huang et al. (4) 15 Polkinghom et al. (12) 16

Estimated cisplatin dose (mg/m2)

Estimated cochlear RT dose (Gy)

Median audiogram follow-up (mo)

No. of patients with ototoxicity

MB

300

49 (median)

19

MB MB

300 Not stated

36.7 (mean) 53% of prescription boost dose (mean) 59.5–76.5

18 12

22/97 (22.7%) Grade 3–4 ototoxicity 13% Grade 3–4 ototoxicity 13% Grade 3–4 ototoxicity

24

48.5 (median)

29

64.4–69.6

24 (minimum)

48.9 (median)

24

13 (median)

7.5 weeks

35.3 standard-risk, 43.0 high-risk (median)

41

Tumor

Kwong et al. (13)

132 NP

Chen et al. (14)

22

NP

100–185 (52/132 pts received cisplatin) 200–500

Oh et al. (15)

30

NP

229 (mean)

Chan et al. (16)

140 NP

Zuur et al. (17)

146 HN

Current study

44

MB

160–240 (median for concurrent and sequential chemo/RT) 263 (intra-arterial) 300

24.2% persistent hearing loss At 4 KHz, 61% for >48 Gy and 24% for #48 Gy 29.2% of ears with hearing loss 55% at high frequency and 7.9% at low frequency 23% of ears considered for hearing aids 25% Grade 3–4 ototoxicity (18.2% of ears)

Abbreviations: RT = radiation therapy; Ref = reference; MB = medulloblastoma; NP = nasopharyngeal carcinoma; HN = head-and-neck cancer.

boost had Grade 3 or 4 ototoxicity (4). The study has been criticized not only because of the small number of patients but also because ototoxicity can occur more than 18 months after the initiation of RT and cisplatin chemotherapy. A study from Parma showed that 44% of patients developed hearing loss 2 years or more after the initiation of cisplatin chemotherapy (10). None of the patients received RT to the cochlea, and 15% of patients developed Grade 3 or 4 ototoxicity. A study from St. Jude Children’s Hospital showed that hearing loss after conformal RT does not usually occur before 18 months; the median time to develop hearing loss was 3.4 years in 11% of cochleae receiving RT without cisplatin chemotherapy (11). With longer median follow-up at 41 months and a larger number of patients, we found that 11 (25%) of 44 patients developed POG Grade 3 or 4 ototoxicity. In particular, 16 (18.2%) of 88 ears tested had Grade 3 or 4 ototoxicity. Six of the 11 patients had unilateral Grade 3 or 4 hearing loss. Inasmuch as cisplatin-related ototoxicity is usually bilateral, it is possible that the differential Dmean cochlea between the right and left cochlea using IMRT may be partly responsible. A limited number of studies have reported the outcomes of minimizing dose to the cochlea and hearing loss in medulloblastoma. At Memorial Sloan-Kettering Cancer Center, 16 patients underwent audiometric testing after IMRT boost and cisplatin-based chemotherapy for medulloblastoma (12). At a median follow-up of 12 months, 13% of patients had Grade 3 or 4 ototoxicity. A recent multi-institutional study of 97 children who underwent cisplatin-based chemotherapy and three-dimensional conformal RT boost showed that 22 (22.7%) patients had Grade 3 or 4 ototoxicity (8). Table 3 summarizes the existing literature on ototoxicity with RT and cisplatin-based chemotherapy and also selected series in nasopharyngeal and other head-and-neck carcinoma (4, 8, 12–17). Our results are in agreement with what is

published in the literature, with about 25% of patients have severe hearing loss after cochlear-sparing RT and cisplatinbased chemotherapy (8, 14, 15). One of the interesting findings in our study is the relationship of Dmean cochlea to the degree of severity of hearing loss. As Dmean cochlea increased, the severity of POG ototoxicity grade increased. For ears that did not have any hearing loss, the Dmean cochlea was 43 Gy or less. In another study, the Dmean cochlea was predictive of hearing loss with the threshold at 48 Gy (14). Hua et al. also found that an increase in cochlear dose correlated positively with hearing loss in children treated with conformal RT but without ototoxic chemotherapy. Hearing loss was rare below 30 Gy and increased at doses of 40 to 45 Gy (11). Chan et al. found that a Dmean cochlea of below 47 Gy resulted in fewer than 15% of patients developing severe high-frequency sensorineural hearing loss (16). Investigators from the University of Utah found that the threshold for hearing loss with cisplatin-based chemotherapy and RT was 10 Gy based on a mathematical model; for cochlea receiving 10 Gy, hearing loss at 8 KHz was 21.5  9.5 dB, whereas for 40 Gy, it was 38.4 dB  18.9 dB (18). Amifostine has been reported to protect against cisplatininduced ototoxicity. In a previous study by Fouladi et al., amifostine before and during cisplatin infusion reduced the risk of severe ototoxicity in patients with average-risk medulloblastoma (8). Nineteen of the patients in our study were treated in or according to the multi-institutional protocol SJMB96 and received amifostine. Our findings are different in that we did not find cytoprotection with the use of amifostine. There are some possible explanations for this discrepancy. First is our sample size. Only 19 patients in our study received amifostine, compared with 62 in the study by Fouladi et al. Second, the endpoint in the study by Fouladi et al. was the need for hearing aids (defined as $Grade 3

IMRT and ototoxicity in medulloblastoma d A. C. PAULINO et al.

ototoxicity in one ear) at 1 year from the initiation of treatment. The 1-year endpoint is not long enough, as is seen in Table 1, where only 1 of the 4 patients who received amifostine in our series developed Grade 3 or 4 ototoxicity during this time; the rest of 3 patients developed ototoxicity 47 to 77 months after RT. The median follow-up of our patients is greater than those in the study by Fouladi et al. (41 vs. 19 months). A study from Children’s Hospital of Philadelphia did not show any benefit for amifostine in medulloblastoma patients, where 78% had severe ototoxicity after cisplatin-based chemotherapy (18). Total cisplatin dose was not found in this study to correlate with degree of ototoxicity. One reason why cisplatin dose did not correlate with ototoxicity is that cisplatin dose was lowered when Grade 3 ototoxicity was encountered. Hence, patients who had less than Grade 3 ototoxicity had full doses of cisplatin and higher cumulative cisplatin doses. Children with tumor dissemination received higher cochlear doses because of the higher craniospinal dose. The question whether the degree of tumor spread or higher cochlear dose was responsible for ototoxicity is difficult to assess because both variables are interconnected. Although tumor dissemination rather than higher dose to the cochlea may have contributed to worse ototoxicity, none of our patients had radiographic evidence of auditory apparatus involvement. We also did not find a statistically significant difference in degree of ototoxicity according to risk group category, making it more likely that the higher Dmean cochlea was responsible for the greater degree of hearing loss, rather than tumor spread itself. Some investigators have noted that IMRT may have a detrimental impact on local control and survival as the high-dose

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region becomes more conformal, resulting in a marginal miss of the target (19). The study by Merchant et al. of standardrisk patients does not support this notion because the 5-year event-free survival rate was 83% and the posterior fossa failure rate was only 4.9% with the use of conformal RT, including IMRT (2). Polkinghom et al. reported a 5-year progression-free survival of 84% with no isolated posterior fossa failures outside the tumor bed (12). More studies are needed, however, to substantiate these findings. There is also concern that because the low-dose region in the supratentorial brain with IMRT is greater in comparison with conventional RT, one may be trading hearing preservation with more neurocognitive toxicity (20). A recent study from our institution showed that IMRT was not associated with greater decline in nonverbal intellectual ability, visual-spatial skills, processing speed, or fine motor dexterity compared with conventional RT (21). The other potential complication of IMRT is a higher risk of secondary tumors because of a larger volume of tissue receiving low-dose radiation (22). Currently, we are unaware of any clinical reports documenting increased risk of secondary tumors with this method of RT delivery. Others have investigated proton therapy to minimize the risk of secondary neoplasms (23). CONCLUSIONS With a larger cohort of patients and longer follow-up, our findings indicate that POG Grade 3 and 4 ototoxicity was found in 25% of children and 18.2% of ears receiving cochlear-sparing IMRT and cisplatin-based chemotherapy. Furthermore, the Dmean cochlea was found to increase with severity of hearing loss.

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14. Chen WC, Jackson A, Budnick AS, et al. Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma. Cancer 2006;106:820–829. 15. Oh YT, Kim CH, Choi JH, et al. Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma. Radiother Oncol 2004;72:79–82. 16. Chan SH, Ng WT, Kam KL, et al. Sensorineural hearing loss after treatment of nasopharyngeal carcinoma: A longitudinal analysis. Int J Radiat Oncol Biol Phys 2009;73:1335–1342. 17. Zuur CL, Simis YJ, Lansdaal PE, et al. Risk factors of ototoxicity after cisplatin-based chemo-irradiation in patients with locally advanced head-and-neck cancer: A multivariate analysis. Int J Radiat Oncol Biol Phys 2007;68: 1320–1325. 18. Hitchcock YJ, Tward JD, Szabo A, et al. Relative contributions of radiation and cisplatin-based chemotherapy to sensorineural hearing loss in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 2009;73:779–788.

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19. Fisher MJ, Lange BJ, Needle MN, et al. Amifostine for children with medulloblastoma treated with cisplatin-based chemotherapy. Pediatr Blood Cancer 2004;43:780–784. 20. Soomal R, Saran F, Brada M. In regard to Huang et al: Intensitymodulated radiation therapy for pediatric medulloblastoma: Early report on the reduction of ototoxicity. IJROBP 2002;52:599–605. Int J Radiat Oncol Biol Phys 2003;55:853. 21. Jain N, Krull KR, Brouwers P, et al. Neuropsychological outcome following intensity-modulated radiation therapy for pediatric medulloblastoma. Pediatr Blood Cancer 2008;51: 275–279. 22. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006;65:1–7. 23. Miralbell R, Lomax A, Cella L, et al. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol Phys 2002;54:824–829.