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Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy
Radiotherapy and Oncology xxx (2018) xxx–xxx
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Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy Arnold C. Paulino a,⇑, Anita Mahajan a, Rong Ye b, David R. Grosshans a, M. Fatih Okcu c, Jack Su c, Mary Frances McAleer a, Susan McGovern a, Victor A. Mangona a, Murali Chintagumpala c a Department of Radiation Oncology, MD Anderson Cancer Center; b Department of Biostatistics, MD Anderson Cancer Center; and c Texas Children’s Cancer Center and Baylor College of Medicine, Houston, USA
a r t i c l e
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Article history: Received 13 September 2017 Received in revised form 22 December 2017 Accepted 2 January 2018 Available online xxxx Keywords: Ototoxicity Medulloblastoma Proton therapy Intensity modulated radiation therapy
a b s t r a c t Purpose: To compare ototoxicity rates between medulloblastoma patients treated with protons vs. photons. Materials and methods: The study included 84 children diagnosed with medulloblastoma treated with either passively scattered protons (n = 38) or photons (n = 46). Patients underwent maximal safe resection followed by craniospinal irradiation, posterior fossa and/or tumor bed boost and chemotherapy according to one of 3 multi-institutional trials. Median audiogram follow-up was 56 months for protons and 66 months for photons. Results: Mean cochlear dose (Dmc) was lower in patients treated with protons for both standard (p < 0.0001) and high-risk disease (p < 0.001). Grade 3 and 4 ototoxicity was seen in 7 of 75 (9.3%) and 9 of 91 (9.9%) ears (Brock, p = 0.91), 13 of 75 (17.3%) and 19 of 91 (20.9%) ears (POG, p = 0.56), and 15 of 75 (20.0%) and 21 of 91 (23.1%) ears (SIOP Boston, p = 0.63) with protons and photons respectively. Conclusions: While cochlear doses were lower in the proton group, patients treated with either protons or photons had similar Grade 3 and 4 ototoxicity rates. Ó 2018 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2018) xxx–xxx
Hearing loss is an important treatment-related toxicity which may result in impairment of scholastic and social development in pediatric brain tumor patients [1]. In medulloblastoma, cisplatinbased chemotherapy is often given as part of the treatment regimen. Moreover, radiation therapy (RT) is routinely used in the treatment of medulloblastoma, and radiation exposure to the cochlea may exacerbate hearing loss. For decades, photon craniospinal irradiation (CSI) followed by a posterior fossa boost has been the standard radiotherapy (RT) treatment for medulloblastoma. Photon therapy has evolved dramatically. With the advent of intensity-modulated radiation therapy (IMRT) combined with the use of a tumor-bed boost, clinicians are better able to sculpt high dose regions away from critical structures in the posterior fossa, including the cochlea. A cochlear-sparing approach using IMRT in medulloblastoma patients receiving cisplatin has been shown to reduce Grade 3 and 4 ototoxicity [2]. Prior to IMRT, parallel opposed lateral fields to treat the posterior fossa delivered the prescribed dose to the tumor bed and neighboring cochleae with 64% developing Grade
⇑ Corresponding author at: Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 97, Houston, TX 77030, USA. E-mail address: [email protected] (A.C. Paulino).
3 and 4 ototoxicity [3]. More recently, proton therapy has been used in medulloblastoma. The obvious benefits of proton therapy when used for CSI include sparing anterior structures such as the heart, lungs and thyroid gland from the exit dose of the spine field [4]. Among proton therapy techniques, passive scattering proton therapy (PSPT) has been used for majority of CSI treatments. While during the CSI component of treatment PSPT does not spare the cochlea, for the tumor bed boost, protons deliver less dose to the cochlea compared to IMRT. A preliminary report from our institution showed a 5% Brock Grade 3 and 4 otoxicity at 1 year postradiotherapy with the use of protons in 19 patients [5]. With longer follow-up and more patients, an update on our proton experience with regard to ototoxicity was performed and compared to previous patients treated with photons using a cochlear-sparing IMRT approach. Patients and methods From 1997 to 2013, 107 children with medulloblastoma were diagnosed at Texas Children’s Hospital and treated with craniospinal RT (photons 63, protons 44) and cisplatin-based chemotherapy. For the 63 photon patients, 8 had audiogram follow-up <1 year from RT, 8 died in <1 year from RT, and 1 was
https://doi.org/10.1016/j.radonc.2018.01.002 0167-8140/Ó 2018 Elsevier B.V. All rights reserved.
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002
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Ototoxicity in medulloblastoma
treated with non-cochlear sparing RT, leaving 46 photon patients for analysis. For the 44 proton patients, 4 had audiogram followup <1 year from RT, 1 died in <1 year from RT and another had congenital hearing loss, leaving 38 proton patients for analysis. Therefore, the 84 patients (photons 46, protons 38) comprise the total number of patients analyzed in this study. Before 2007, all patients were treated with 3-dimensional (3-D) photons to the craniospinal axis followed by IMRT to the boost field (n = 46). Thereafter, patients were treated with passively scattered protons to the craniospinal axis and the tumor bed at the MD Anderson Proton Center (n = 38). There were 60 (71.4%) male and 24 (28.6%) female patients. Median age at diagnosis was 8.9 years (range, 35 months to 18 years). Twenty-six (31.0%) had high-risk disease. Patients underwent maximal safe resection followed by craniospinal irradiation (CSI), posterior fossa (PF) and/or tumor bed (TB) boost and cisplatin-based chemotherapy according to one of 3 multi-institutional trials. Standard-risk patients received 18–23.4 Gy/CGE while high-risk patients received 36–39.6 Gy/ CGE to the craniospinal axis. Dose to the tumor bed and any residual was 54–55.8 Gy/CGE. For photon therapy, the boost treatment was delivered using IMRT to the entire PF in 6, PF to 36 Gy followed by TB in 29, and TB alone in 11. For proton therapy, the boost was given to the tumor bed alone. Chemotherapy was delivered 4 weeks after RT. None of the children received concurrent chemotherapy during radiotherapy. All patients treated with protons had amifostine with the cisplatin chemotherapy, whereas only 19 (41.3%) of the patients treated with IMRT had amifostine. Contoured cochlear volumes were reviewed to make sure they were standardized. Cochlear volume delineation examples have been reported previously by our group [2,5]. Hearing thresholds were assessed by pure tone audiograms. Hearing thresholds were determined for each ear at stimulus frequencies of 0.25, 0.5, 1, 2, 4, 6 and 8 kHz. In all, 501 audiograms were reviewed, analyzed and graded according to the International Society of Pediatric Oncology (SIOP) Boston (Grade 0: 20 dB loss at all frequencies, Grade 1: >20 dB loss at >4 kHz, Grade 2: >20 dB loss at 4 kHz, Grade 3: >20 dB loss at 2 kHz, Grade 4: >40 dB loss at 2 kHz), Brock (Grade 0: <40 dB at all frequencies, Grade 1: 40 dB loss at 8 kHz, Grade 2: 40 dB loss at 4 kHz, Grade 3: 40 dB loss at 2 kHz, Grade 4: 40 dB loss at 1KHz) and Pediatric Oncology Group (POG) objective scale (Grade 0: normal, Grade 1: 20–40 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) [6,7]. Each patient’s hearing was also classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (Grade 1: threshold shift or loss of 15–25 dB relative to baseline, averaged at 2 or more contiguous test frequencies in at least 1 ear or subjective change in the absence of a Grade 1 threshold shift, Grade 2: threshold shift or loss of >25–90 dB, averaged at 2 contiguous test frequencies in at least 1 ear, Grade 3: hearing loss sufficient to indicate therapeutic intervention including hearing aids e.g., 20 dB bilateral hearing loss in the speech frequencies; 30 dB unilateral hearing loss; and requiring additional speechlanguage related services, Grade 4: audiologic indication for cochlear implant and requiring additional speech-language related services). Audiograms were scheduled before and 6 weeks after RT; after each cycle of chemotherapy; and 6 months, 1 year and thereafter. In a few cases, auditory brainstem response (ABR) was performed prior to radiotherapy because of young age or posterior fossa syndrome. Audiogram follow-up was calculated from the end of RT to the last audiogram. Median audiogram follow-up was 66 months (range, 13–163 months) for photons and 56 months (13–101 months) for protons. Wilcoxon rank sum test, Fisher’s exact test or Chi-square was used to evaluate the difference in the continuous variables and
the categorical variables between the photon and proton treatment groups. A two-side Wilcoxon rank sum test was performed to compare the mean cisplatin doses between the 2 groups. Likewise, the Wilcoxon rank sum test was used to compare the mean cochlear doses between grades 0–2 and 3–4 according to the SIOP Boston, POG, Brock ototoxicity scales and the CTCAE scale. The cumulative incidence rates of Grade 3 and 4 ototoxicity were estimated using Kaplan–Meier method. The log-rank test was adapted to evaluate the difference in time to event (Grade 3 or higher toxicity) between photon and proton therapy. Results Patient, tumor and treatment characteristics The patient, tumor, treatment and follow-up characteristics according to type of radiation delivered are presented in Table 1. There was no difference between the photon and proton patients with regard to gender, age, risk-category, posterior fossa syndrome and number of audiograms. Thirty-seven patients (44.0%) had a shunt; there was no difference in distribution of proton vs. photon patient with regard to shunt placement. Patients treated with photons were more likely to have the entire posterior fossa treated as part of the boost portion of RT (p < 0.0001). All patients treated
Table 1 Patient, tumor, treatment and follow-up characteristics in patients receiving photons and protons. Photons n = 46
Protons n = 38
Gender Male Female
32 (69.6%) 14 (30.4%)
28 (73.7%) 10 (26.3%)
Age, years Mean ± standard deviation Median (range)
9.0 ± 4.0 9.0 (3.0–18.0)
7.9 ± 3.4 7.6 (2.9–14.5)
Risk category Standard-risk High-risk
34 (73.9%) 12 (26.1%)
24 (63.2%) 14 (36.8%)
Shunt placement Yes No
24 (52.2%) 22 (47.8%)
13 (34.2%) 25 (65.8%)
Posterior fossa syndrome Yes No
7 (15.2%) 39 (84.8%)
5 (13.2%) 33 (86.8%)
6 (13.0%) 29 (63.0%)
0 (0) 0 (0)
11 (23.9%)
38 (100%)
3725.5 ± 543.3 3590.0 (2520.0– 5490.0)
3149.3 ± 785.5 2931.7 (1598.0– 5245.4)
350.5 ± 140.1 318.0 (55.0– 860.0)
281.3 ± 59.5 300.0 (135.0– 473.0)
Number of audiograms Mean ± std dev Median (range)
6.0 ± 3.6 5.5 (2–15)
6.2 ± 1.5 6 (4–9)
Audiogram follow-up, months Mean Median (range)
68.6 65.5 (13–163)
52.5 55.5 (17–101)
Amifostine use Yes No
19 (41.3%) 27 (58.7%)
38 (100%) 0 (0)
Radiotherapy boost Posterior fossa boost Posterior fossa followed by tumor bed boost Tumor bed boost Cochlear dose, cGy Mean ± standard deviation Median (range)
Cisplatin dose, mg/m2 Mean ± standard deviation Median (range)
P-value 0.678
0.262
0.289
0.099
0.788
<0.0001
<0.0001
0.004
0.388
0.105
<0.0001
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002
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A.C. Paulino et al. / Radiotherapy and Oncology xxx (2018) xxx–xxx
with protons received amifostine, whereas only 41.3% of patients in the photon group had amifostine. Mean cochlear dose The cochlear doses are reported with the standard deviations. The overall left Dmc was 34.8 ± 7.7 Gy, while the overall right Dmc was 34.5 ± 6.8 Gy. The mean cochlear dose or Dmc was lower for protons compared to photons. For photons, the mean left Dmc was 37.5 ± 5.8 Gy while for protons, it was 31.6 ± 8.5 CGE (p = 0.001). For photons, the mean right Dmc was 37.0 ± 5.1 Gy while for protons, it was 31.4 ± 7.3 CGE (p = 0.003). Dmc was lower in patients treated with protons for both standard (p < 0.0001) and high-risk disease (p < 0.001). Cisplatin dose The cisplatin doses are reported with the standard deviations. The mean cisplatin dose delivered for all patients was 319.2 ± 11 5.9 mg/m2. For patients treated with photons, it was 350.5 ± 140. 1 mg/m2, while for patients treated with protons, it was 281.3 ± 5 9.5 mg/m2 (p = 0.004). There was no correlation between the Dmc and cisplatin dose (Pearson correlation coefficient of 0.200, p = 0.069). Grade 3 and 4 hearing loss Table 2 shows the different grades of hearing loss according to the SIOP Boston, POG, Brock and CTCAE scales. There was no difference in proportion of patients developing Grade 3 and 4 ototoxicity score according RT modality. For the SIOP Boston scale, Grade 3 and 4 hearing loss was found in 21 of 91 (23.1%) treated with photons compared to 15 of 75 (20.0%) treated with protons (p = 0.63). For the Brock scale, Grade 3 and 4 hearing loss was found in 9 of 91 (9.9%) treated with photons and 7 of 75 (9.3%) treated with protons (p = 0.90). For the POG scale, Grade 3 and 4 hearing loss was found
in 19 of 91 (20.9%) treated with photons and 13 of 75 (17.3%) treated with protons (p = 0.56). For the CTCAE scale, Grade 3 and 4 hearing loss was found in 13 of 46 patients (28.3%) with photons and 11 of 38 (29.9%) with protons (p = 1.0). The Wilcoxon rank sum test was used to compare the mean cochlear dose between grade 0–2 and 3–4. For all patients, regardless of radiation modality, those who developed Grade 3 or 4 hearing loss in the left ear had a higher Dmc compared to those who had Grade 0 to Grade 2 hearing loss. This was significant when using the SIOP Boston (p = 0.0378), POG (p = 0.027) and Brock (p = 0.0023) ototoxicity scales. For the right ear, higher Dmc was only seen in Grade 3–4 ears according to the Brock but not SIOP Boston (p = 0.14) or POG (p = 0.089) scales. Table 3 shows the 3 and 5 year cumulative incidence of ototoxicity according to ear laterality and radiation modality. There was no difference in left Grade 3 or 4 otoxicity according to radiation modality in any of the ototoxicity scales: SIOP Boston (p = 0.696), POG (p = 0.588), and Brock (p = 0.987). There was also no difference in right Grade 3 and 4 ototoxicity according to radiation modality in any of the ototoxicity scales: SIOP Boston (p = 0.633), POG (p = 0.938), and Brock (p = 0.330). The difference in radiotherapy modality was then analyzed according to the patient’s worse hearing. In this case, any patient with Grade 3 or 4 hearing in any or both ears was scored as a Grade 3 and 4 toxicity. There was no difference in Grade 3 or 4 ototoxicity according to the SIOP Boston (p = 0.946), POG (p = 0.786), Brock (p = 0.803) or CTCAE (p = 0.672) scales. Fig. 1 shows the incidence of SIOP Boston Grade 3 and 4 ototoxicity according to radiotherapy modality.
Other factors associated with Grade 3 and 4 hearing loss On univariate analysis, Higher Dmc was found to be a prognostic factor for development of Grade 3 and 4 ototoxicity according to the SIOP Boston (p = 0.037), POG (p = 0.029) and Brock (p = 0.0003) scales. High risk category, a surrogate for craniospinal dose, was also found to be prognostic for Grade 3 and 4 ototoxicity
Table 2 Ototoxicity grade and type of radiation. Frequency Number of ears Photon N = 91
Number of patients (according to worse ear) Proton N = 75
Photon N = 46
Proton N = 38
International Society of Pediatric Oncology (SIOP) Boston 0 30 (33.0%) 1 33 (36.3%) 2 7 (7.7%) 3 15 (16.5%) 4 6 (6.6%)
28 (37.3%) 21 (28.0%) 11 (14.7%) 11 (14.7%) 4 (5.3%)
12 (26.1%) 16 (34.8%) 5 (10.9%) 8 (17.4%) 5 (10.9%)
12 (31.6%) 10 (26.3%) 7 (18.4%) 6 (15.8%) 3 (7.9%)
Brock 0 1 2 3 4
29 (31.9%) 35 (38.5%) 18(19.8%) 6 (6.6%) 3 (3.3%)
26 (34.7%) 24 (32.0%) 18 (24.0%) 4 (5.3%) 3 (4.0%)
12 (26.1%) 17 (37.0%) 10 (21.7%) 4 (8.7%) 3 (6.5%)
10 (26.3%) 12 (31.6%) 11 (28.9%) 3 (7.9%) 2 (5.3%)
Pediatric Oncology Group (POG) 0 24 (26.4%) 1 40 (44.0%) 2 8 (8.8%) 3 17 (18.7%) 4 2 (2.2%)
28 (37.3%) 23 (30.7%) 11 (14.7%) 10 (13.3%) 3 (4.0%)
10 (21.7%) 19 (41.3%) 6 (13.0%) 9 (19.6%) 2 (4.3%)
12 (31.6%) 12 (31.6%) 6 (15.8%) 6 (15.8%) 2 (5.3%)
CTCAE 0 1 2 3 4
NA NA NA NA NA
10 (21.7%) 18 (39.1%) 5 (10.9%) 10 (21.7%) 3 (6.5%)
13 (34.2%) 8 (21.1%) 6 (15.8%) 10 (26.3%) 1 (2.6%)
NA NA NA NA NA
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002
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Ototoxicity in medulloblastoma
Table 3 Three and five-year cumulative incidence of Grade 3 and 4 hearing loss according to ototoxicity scale, ear laterality and radiotherapy modality. SIOP Boston 3-Year
SIOP Boston 5-Year
Left ear Photon Proton
16.4% 11.5%
25.9% 18.9%
Right ear Photon Proton
11.6% 14.2%
18.3% 21.3%
P-value
POG 3-Year
POG 5-Year
16.4% 5.7%
23.0% 16.6%
11.6% 8.2%
18.3% 23.6%
0.696
P-value
Brock 3-Year
Brock 5-Year
12.2% 5.3%
15.6% 12.6%
9.3% 2.6%
12.7% 6.2%
0.588
0.633
according to the SIOP Boston (p = 0.019) and Brock (p = 0.003) scales. Gender, age at time of RT, type of boost field, presence of a shunt, posterior fossa syndrome and cisplatin dose did not have a significant effect on Grade 3 and 4 ototoxicity. Discussion Cochlear-sparing IMRT has been shown to reduce Grade 3 and 4 ototoxicity in children receiving cisplatin-based chemotherapy for medulloblastoma [2,3]. Because many of our patients receiving CSI are now treated with protons, we compared ototoxicity rates between patients previously treated with cochlear sparing IMRT and recent patients treated with protons. Amifostine, which has been shown previously to reduce the risk of cisplatin-induced severe ototoxicity in standard-risk medulloblastoma, was utilized in 41.3% of photon and 100% of proton patients [8]. The proportion of patients developing Grade 3 and 4 otoxicity were essentially the same with protons and photons. Despite lower mean cochlear doses, lower mean cisplatin doses, greater proportion of patients receiving a boost field to the tumor bed alone instead of the entire posterior fossa, and routine use of amifostine in the proton patients, there was no difference in Grade 3 and 4 ototoxicity rates according to SIOP Boston, Brock, POG and CTCAE scales. In one series, all medulloblastoma children without hearing loss had Dmc < 43 Gy. In the same report, a threshold of 37 Gy median Dmc was found to separate cochlea that had POG Grade 0–2 and Grade 3–4 otoxicity [2]. Perhaps the otoxicity attributed to RT cannot be significantly improved once the Dmc is below this threshold dose, and ototoxicity from cisplatin becomes the main contributing factor. It should be noted the median Dmc for protons and photons in the current study were 31.5 CGE and 37.3 Gy respectively, both at or below the 37 Gy threshold that has been associated with higher grade hearing loss [2]. While the 5% Grade 3 and 4 ototoxicity at 1 year with protons has been encouraging, it should be noted that the follow-up is short and the grading scale used by Moeller and colleagues was
CTCAE 3-Year
CTCAE 5-Year
16.4% 11.5%
25.9% 22.6%
11.6% 14.2%
21.3% 29.7%
0.987
0.938
Fig. 1. Comparison of International Society of Pediatric Oncology (SIOP) Boston Grade 3 and 4 hearing loss according to radiotherapy modality.
P-value
P-value 0.917
0.330
0.623
the Brock ototoxicity scale [4,5]. Others have reported Grade 3–4 hearing loss using the POG Ototoxicity scale with rates ranging from 16 to 19% [2,3,9,10]. At Massachusetts General Hospital, the 5-year POG Grade 3 and 4 ototoxicity rate was 16% with the use of protons [9]. At the Hospital Israelita Albert Einstein in Sao Paolo, 17% had POG Grade 3–4 ototoxicity with the use of IMRT and a mean follow-up of 44 months [10]. Our review revealed that even with longer follow-up, Brock Grade 3 and 4 ototoxicity was seen in only 9.3% and 9.9% treated with protons and photons. When the POG scale was used, the incidence of Grade 3 and 4 ototoxicity was higher at 17.3% and 20.9% with protons and photons. These results are consistent with the available literature with roughly the same follow-up time. At a median follow-up of 19 months, investigators from Memorial Sloan-Kettering Cancer Center have reported a 6% Grade 3 hearing loss according to the CTCAE, version 3; it is not clear from this report the length of audiogram follow-up time [11]. In the current report, the Grade 3 and 4 hearing loss according to CTCAE, version 3 was 29.9% with protons and 28.3% with photons. The most likely reason for the higher rate of hearing loss in the current report is the longer median audiogram follow-up of patients (66 months for photons and 56 months for protons). It has been previously reported that hearing loss secondary to radiotherapy is a late effect with a median onset at 3.6 years after RT [12]. In conclusion, the proportion of patients with severe hearing loss was found to be the same in patients treated with protons or photons, as assessed by four scoring systems. The Brock, POG and CTCAE ototoxicity scales were used as previous publications have reported radiation-induced ototoxicity rates using the same grading scales [2,3,5,9–11]. The SIOP Boston scale was also used because it was designed after an international workshop of experts on treatment-induced hearing loss [7]. While ototoxicity is not different between the two radiotherapy modalities, there may be a benefit for protons with respect to endocrine and cognitive function. Eaton et al. showed a lower risk of hypothyroidism, sex hormone deficiency and requirement for any endocrine replacement therapy with protons when compared to photons for children with medulloblastoma [13]. Kahalley et al. previously reported that protons were not associated with intelligence quotient (IQ) decline when compared to photons, but the IQ slopes over time did not differ between the 2 radiotherapy modalities. It remains unclear whether with longer follow-up, there may be a clinically meaningful cognitive sparing achieved with protons [14]. Lastly, similar to advances seen with photon therapies such as IMRT, proton therapy planning and delivery are advancing rapidly. All patients in the current study who received protons had passive scattering proton therapy in which there is no sparing of cochlea with the CSI component. As scanning beam proton therapy becomes more available and techniques such as intensity modulated proton therapy are used for the CSI component of treatment, additional cochlear sparing may be achieved which potentially can affect hearing outcome. Future studies and longer follow-up are needed to demonstrate the advantages of proton over photon radiotherapy in children with medulloblastoma.
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002
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Conflict of interest statement The authors have no conflict of interest to disclose with regard to this manuscript. References [1] Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 2005;23:8588–96. [2] Paulino AC, Lobo M, Teh BS, et al. Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with medulloblastoma. Int J Radiat Oncol Biol Phys 2010;78:1445–50. [3] Huang E, Teh BS, Strother DR, et al. Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 2002;52:599–605. [4] Eaton BR, Esiashvili N, Kim S, et al. Clinical outcomes among children with standard-risk medulloblastoma treated with proton and photon radiation therapy: a comparison of disease control and overall survival. Int J Radiat Oncol Biol Phys 2016;94:133–8. [5] Moeller BJ, Chintagumpala M, Philip JJ, et al. Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy. Radiat Oncol 2011;6:58. [6] Brock PR, Bellman SC, Yeomans EC, et al. Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol 1991;19:295–300.
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[7] Brock PR, Knight KR, Freyer DR, et al. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol 2012;30:2408–17. [8] Fouladi M, Chintagumpala M, Ashley D, et al. Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma. J Clin Oncol 2008;26:3749–55. [9] Yock TI, Yeap BY, Ebb DH, et al. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol 2016;17:287–98. [10] Vieira WA, Weltman E, Chen MJ, et al. Ototoxicity evaluation in medulloblastoma patients treated with involved field boost using intensitymodulated radiation therapy (IMRT): a retrospective review. Radiat Oncol 2014;9:158. [11] Polkinghorn WR, Dunkel IJ, Souweidane MM, et al. Disease control and ototoxicity using intensity-modulated radiation therapy tumor-bed boost for medulloblastoma. Int J Radiat Oncol Biol Phys 2011;81:e15–20. [12] Bass JK, Hua CH, Huang J, et al. Hearing loss in patients who received cranial radiation therapy for childhood cancer. J Clin Oncol 2016;34:1248–55. [13] Eaton BR, Esiashvili N, Kim S, et al. Endocrine outcomes with proton and photon radiotherapy for standard risk medulloblastoma. Neuro Oncol 2016;18:881–7. [14] Kahalley LS, Ris MD, Grosshans DR, et al. Comparing intelligence quotient change after treatment with proton versus photon radiation therapy for pediatric brain tumors. J Clin Oncol 2016;34:1043–9.
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002
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Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy Arnold C. Paulino a,⇑, Anita Mahajan a, Rong Ye b, David R. Grosshans a, M. Fatih Okcu c, Jack Su c, Mary Frances McAleer a, Susan McGovern a, Victor A. Mangona a, Murali Chintagumpala c a Department of Radiation Oncology, MD Anderson Cancer Center; b Department of Biostatistics, MD Anderson Cancer Center; and c Texas Children’s Cancer Center and Baylor College of Medicine, Houston, USA
a r t i c l e
i n f o
Article history: Received 13 September 2017 Received in revised form 22 December 2017 Accepted 2 January 2018 Available online xxxx Keywords: Ototoxicity Medulloblastoma Proton therapy Intensity modulated radiation therapy
a b s t r a c t Purpose: To compare ototoxicity rates between medulloblastoma patients treated with protons vs. photons. Materials and methods: The study included 84 children diagnosed with medulloblastoma treated with either passively scattered protons (n = 38) or photons (n = 46). Patients underwent maximal safe resection followed by craniospinal irradiation, posterior fossa and/or tumor bed boost and chemotherapy according to one of 3 multi-institutional trials. Median audiogram follow-up was 56 months for protons and 66 months for photons. Results: Mean cochlear dose (Dmc) was lower in patients treated with protons for both standard (p < 0.0001) and high-risk disease (p < 0.001). Grade 3 and 4 ototoxicity was seen in 7 of 75 (9.3%) and 9 of 91 (9.9%) ears (Brock, p = 0.91), 13 of 75 (17.3%) and 19 of 91 (20.9%) ears (POG, p = 0.56), and 15 of 75 (20.0%) and 21 of 91 (23.1%) ears (SIOP Boston, p = 0.63) with protons and photons respectively. Conclusions: While cochlear doses were lower in the proton group, patients treated with either protons or photons had similar Grade 3 and 4 ototoxicity rates. Ó 2018 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2018) xxx–xxx
Hearing loss is an important treatment-related toxicity which may result in impairment of scholastic and social development in pediatric brain tumor patients [1]. In medulloblastoma, cisplatinbased chemotherapy is often given as part of the treatment regimen. Moreover, radiation therapy (RT) is routinely used in the treatment of medulloblastoma, and radiation exposure to the cochlea may exacerbate hearing loss. For decades, photon craniospinal irradiation (CSI) followed by a posterior fossa boost has been the standard radiotherapy (RT) treatment for medulloblastoma. Photon therapy has evolved dramatically. With the advent of intensity-modulated radiation therapy (IMRT) combined with the use of a tumor-bed boost, clinicians are better able to sculpt high dose regions away from critical structures in the posterior fossa, including the cochlea. A cochlear-sparing approach using IMRT in medulloblastoma patients receiving cisplatin has been shown to reduce Grade 3 and 4 ototoxicity [2]. Prior to IMRT, parallel opposed lateral fields to treat the posterior fossa delivered the prescribed dose to the tumor bed and neighboring cochleae with 64% developing Grade
⇑ Corresponding author at: Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 97, Houston, TX 77030, USA. E-mail address: [email protected] (A.C. Paulino).
3 and 4 ototoxicity [3]. More recently, proton therapy has been used in medulloblastoma. The obvious benefits of proton therapy when used for CSI include sparing anterior structures such as the heart, lungs and thyroid gland from the exit dose of the spine field [4]. Among proton therapy techniques, passive scattering proton therapy (PSPT) has been used for majority of CSI treatments. While during the CSI component of treatment PSPT does not spare the cochlea, for the tumor bed boost, protons deliver less dose to the cochlea compared to IMRT. A preliminary report from our institution showed a 5% Brock Grade 3 and 4 otoxicity at 1 year postradiotherapy with the use of protons in 19 patients [5]. With longer follow-up and more patients, an update on our proton experience with regard to ototoxicity was performed and compared to previous patients treated with photons using a cochlear-sparing IMRT approach. Patients and methods From 1997 to 2013, 107 children with medulloblastoma were diagnosed at Texas Children’s Hospital and treated with craniospinal RT (photons 63, protons 44) and cisplatin-based chemotherapy. For the 63 photon patients, 8 had audiogram follow-up <1 year from RT, 8 died in <1 year from RT, and 1 was
https://doi.org/10.1016/j.radonc.2018.01.002 0167-8140/Ó 2018 Elsevier B.V. All rights reserved.
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002
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Ototoxicity in medulloblastoma
treated with non-cochlear sparing RT, leaving 46 photon patients for analysis. For the 44 proton patients, 4 had audiogram followup <1 year from RT, 1 died in <1 year from RT and another had congenital hearing loss, leaving 38 proton patients for analysis. Therefore, the 84 patients (photons 46, protons 38) comprise the total number of patients analyzed in this study. Before 2007, all patients were treated with 3-dimensional (3-D) photons to the craniospinal axis followed by IMRT to the boost field (n = 46). Thereafter, patients were treated with passively scattered protons to the craniospinal axis and the tumor bed at the MD Anderson Proton Center (n = 38). There were 60 (71.4%) male and 24 (28.6%) female patients. Median age at diagnosis was 8.9 years (range, 35 months to 18 years). Twenty-six (31.0%) had high-risk disease. Patients underwent maximal safe resection followed by craniospinal irradiation (CSI), posterior fossa (PF) and/or tumor bed (TB) boost and cisplatin-based chemotherapy according to one of 3 multi-institutional trials. Standard-risk patients received 18–23.4 Gy/CGE while high-risk patients received 36–39.6 Gy/ CGE to the craniospinal axis. Dose to the tumor bed and any residual was 54–55.8 Gy/CGE. For photon therapy, the boost treatment was delivered using IMRT to the entire PF in 6, PF to 36 Gy followed by TB in 29, and TB alone in 11. For proton therapy, the boost was given to the tumor bed alone. Chemotherapy was delivered 4 weeks after RT. None of the children received concurrent chemotherapy during radiotherapy. All patients treated with protons had amifostine with the cisplatin chemotherapy, whereas only 19 (41.3%) of the patients treated with IMRT had amifostine. Contoured cochlear volumes were reviewed to make sure they were standardized. Cochlear volume delineation examples have been reported previously by our group [2,5]. Hearing thresholds were assessed by pure tone audiograms. Hearing thresholds were determined for each ear at stimulus frequencies of 0.25, 0.5, 1, 2, 4, 6 and 8 kHz. In all, 501 audiograms were reviewed, analyzed and graded according to the International Society of Pediatric Oncology (SIOP) Boston (Grade 0: 20 dB loss at all frequencies, Grade 1: >20 dB loss at >4 kHz, Grade 2: >20 dB loss at 4 kHz, Grade 3: >20 dB loss at 2 kHz, Grade 4: >40 dB loss at 2 kHz), Brock (Grade 0: <40 dB at all frequencies, Grade 1: 40 dB loss at 8 kHz, Grade 2: 40 dB loss at 4 kHz, Grade 3: 40 dB loss at 2 kHz, Grade 4: 40 dB loss at 1KHz) and Pediatric Oncology Group (POG) objective scale (Grade 0: normal, Grade 1: 20–40 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) [6,7]. Each patient’s hearing was also classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (Grade 1: threshold shift or loss of 15–25 dB relative to baseline, averaged at 2 or more contiguous test frequencies in at least 1 ear or subjective change in the absence of a Grade 1 threshold shift, Grade 2: threshold shift or loss of >25–90 dB, averaged at 2 contiguous test frequencies in at least 1 ear, Grade 3: hearing loss sufficient to indicate therapeutic intervention including hearing aids e.g., 20 dB bilateral hearing loss in the speech frequencies; 30 dB unilateral hearing loss; and requiring additional speechlanguage related services, Grade 4: audiologic indication for cochlear implant and requiring additional speech-language related services). Audiograms were scheduled before and 6 weeks after RT; after each cycle of chemotherapy; and 6 months, 1 year and thereafter. In a few cases, auditory brainstem response (ABR) was performed prior to radiotherapy because of young age or posterior fossa syndrome. Audiogram follow-up was calculated from the end of RT to the last audiogram. Median audiogram follow-up was 66 months (range, 13–163 months) for photons and 56 months (13–101 months) for protons. Wilcoxon rank sum test, Fisher’s exact test or Chi-square was used to evaluate the difference in the continuous variables and
the categorical variables between the photon and proton treatment groups. A two-side Wilcoxon rank sum test was performed to compare the mean cisplatin doses between the 2 groups. Likewise, the Wilcoxon rank sum test was used to compare the mean cochlear doses between grades 0–2 and 3–4 according to the SIOP Boston, POG, Brock ototoxicity scales and the CTCAE scale. The cumulative incidence rates of Grade 3 and 4 ototoxicity were estimated using Kaplan–Meier method. The log-rank test was adapted to evaluate the difference in time to event (Grade 3 or higher toxicity) between photon and proton therapy. Results Patient, tumor and treatment characteristics The patient, tumor, treatment and follow-up characteristics according to type of radiation delivered are presented in Table 1. There was no difference between the photon and proton patients with regard to gender, age, risk-category, posterior fossa syndrome and number of audiograms. Thirty-seven patients (44.0%) had a shunt; there was no difference in distribution of proton vs. photon patient with regard to shunt placement. Patients treated with photons were more likely to have the entire posterior fossa treated as part of the boost portion of RT (p < 0.0001). All patients treated
Table 1 Patient, tumor, treatment and follow-up characteristics in patients receiving photons and protons. Photons n = 46
Protons n = 38
Gender Male Female
32 (69.6%) 14 (30.4%)
28 (73.7%) 10 (26.3%)
Age, years Mean ± standard deviation Median (range)
9.0 ± 4.0 9.0 (3.0–18.0)
7.9 ± 3.4 7.6 (2.9–14.5)
Risk category Standard-risk High-risk
34 (73.9%) 12 (26.1%)
24 (63.2%) 14 (36.8%)
Shunt placement Yes No
24 (52.2%) 22 (47.8%)
13 (34.2%) 25 (65.8%)
Posterior fossa syndrome Yes No
7 (15.2%) 39 (84.8%)
5 (13.2%) 33 (86.8%)
6 (13.0%) 29 (63.0%)
0 (0) 0 (0)
11 (23.9%)
38 (100%)
3725.5 ± 543.3 3590.0 (2520.0– 5490.0)
3149.3 ± 785.5 2931.7 (1598.0– 5245.4)
350.5 ± 140.1 318.0 (55.0– 860.0)
281.3 ± 59.5 300.0 (135.0– 473.0)
Number of audiograms Mean ± std dev Median (range)
6.0 ± 3.6 5.5 (2–15)
6.2 ± 1.5 6 (4–9)
Audiogram follow-up, months Mean Median (range)
68.6 65.5 (13–163)
52.5 55.5 (17–101)
Amifostine use Yes No
19 (41.3%) 27 (58.7%)
38 (100%) 0 (0)
Radiotherapy boost Posterior fossa boost Posterior fossa followed by tumor bed boost Tumor bed boost Cochlear dose, cGy Mean ± standard deviation Median (range)
Cisplatin dose, mg/m2 Mean ± standard deviation Median (range)
P-value 0.678
0.262
0.289
0.099
0.788
<0.0001
<0.0001
0.004
0.388
0.105
<0.0001
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002
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A.C. Paulino et al. / Radiotherapy and Oncology xxx (2018) xxx–xxx
with protons received amifostine, whereas only 41.3% of patients in the photon group had amifostine. Mean cochlear dose The cochlear doses are reported with the standard deviations. The overall left Dmc was 34.8 ± 7.7 Gy, while the overall right Dmc was 34.5 ± 6.8 Gy. The mean cochlear dose or Dmc was lower for protons compared to photons. For photons, the mean left Dmc was 37.5 ± 5.8 Gy while for protons, it was 31.6 ± 8.5 CGE (p = 0.001). For photons, the mean right Dmc was 37.0 ± 5.1 Gy while for protons, it was 31.4 ± 7.3 CGE (p = 0.003). Dmc was lower in patients treated with protons for both standard (p < 0.0001) and high-risk disease (p < 0.001). Cisplatin dose The cisplatin doses are reported with the standard deviations. The mean cisplatin dose delivered for all patients was 319.2 ± 11 5.9 mg/m2. For patients treated with photons, it was 350.5 ± 140. 1 mg/m2, while for patients treated with protons, it was 281.3 ± 5 9.5 mg/m2 (p = 0.004). There was no correlation between the Dmc and cisplatin dose (Pearson correlation coefficient of 0.200, p = 0.069). Grade 3 and 4 hearing loss Table 2 shows the different grades of hearing loss according to the SIOP Boston, POG, Brock and CTCAE scales. There was no difference in proportion of patients developing Grade 3 and 4 ototoxicity score according RT modality. For the SIOP Boston scale, Grade 3 and 4 hearing loss was found in 21 of 91 (23.1%) treated with photons compared to 15 of 75 (20.0%) treated with protons (p = 0.63). For the Brock scale, Grade 3 and 4 hearing loss was found in 9 of 91 (9.9%) treated with photons and 7 of 75 (9.3%) treated with protons (p = 0.90). For the POG scale, Grade 3 and 4 hearing loss was found
in 19 of 91 (20.9%) treated with photons and 13 of 75 (17.3%) treated with protons (p = 0.56). For the CTCAE scale, Grade 3 and 4 hearing loss was found in 13 of 46 patients (28.3%) with photons and 11 of 38 (29.9%) with protons (p = 1.0). The Wilcoxon rank sum test was used to compare the mean cochlear dose between grade 0–2 and 3–4. For all patients, regardless of radiation modality, those who developed Grade 3 or 4 hearing loss in the left ear had a higher Dmc compared to those who had Grade 0 to Grade 2 hearing loss. This was significant when using the SIOP Boston (p = 0.0378), POG (p = 0.027) and Brock (p = 0.0023) ototoxicity scales. For the right ear, higher Dmc was only seen in Grade 3–4 ears according to the Brock but not SIOP Boston (p = 0.14) or POG (p = 0.089) scales. Table 3 shows the 3 and 5 year cumulative incidence of ototoxicity according to ear laterality and radiation modality. There was no difference in left Grade 3 or 4 otoxicity according to radiation modality in any of the ototoxicity scales: SIOP Boston (p = 0.696), POG (p = 0.588), and Brock (p = 0.987). There was also no difference in right Grade 3 and 4 ototoxicity according to radiation modality in any of the ototoxicity scales: SIOP Boston (p = 0.633), POG (p = 0.938), and Brock (p = 0.330). The difference in radiotherapy modality was then analyzed according to the patient’s worse hearing. In this case, any patient with Grade 3 or 4 hearing in any or both ears was scored as a Grade 3 and 4 toxicity. There was no difference in Grade 3 or 4 ototoxicity according to the SIOP Boston (p = 0.946), POG (p = 0.786), Brock (p = 0.803) or CTCAE (p = 0.672) scales. Fig. 1 shows the incidence of SIOP Boston Grade 3 and 4 ototoxicity according to radiotherapy modality.
Other factors associated with Grade 3 and 4 hearing loss On univariate analysis, Higher Dmc was found to be a prognostic factor for development of Grade 3 and 4 ototoxicity according to the SIOP Boston (p = 0.037), POG (p = 0.029) and Brock (p = 0.0003) scales. High risk category, a surrogate for craniospinal dose, was also found to be prognostic for Grade 3 and 4 ototoxicity
Table 2 Ototoxicity grade and type of radiation. Frequency Number of ears Photon N = 91
Number of patients (according to worse ear) Proton N = 75
Photon N = 46
Proton N = 38
International Society of Pediatric Oncology (SIOP) Boston 0 30 (33.0%) 1 33 (36.3%) 2 7 (7.7%) 3 15 (16.5%) 4 6 (6.6%)
28 (37.3%) 21 (28.0%) 11 (14.7%) 11 (14.7%) 4 (5.3%)
12 (26.1%) 16 (34.8%) 5 (10.9%) 8 (17.4%) 5 (10.9%)
12 (31.6%) 10 (26.3%) 7 (18.4%) 6 (15.8%) 3 (7.9%)
Brock 0 1 2 3 4
29 (31.9%) 35 (38.5%) 18(19.8%) 6 (6.6%) 3 (3.3%)
26 (34.7%) 24 (32.0%) 18 (24.0%) 4 (5.3%) 3 (4.0%)
12 (26.1%) 17 (37.0%) 10 (21.7%) 4 (8.7%) 3 (6.5%)
10 (26.3%) 12 (31.6%) 11 (28.9%) 3 (7.9%) 2 (5.3%)
Pediatric Oncology Group (POG) 0 24 (26.4%) 1 40 (44.0%) 2 8 (8.8%) 3 17 (18.7%) 4 2 (2.2%)
28 (37.3%) 23 (30.7%) 11 (14.7%) 10 (13.3%) 3 (4.0%)
10 (21.7%) 19 (41.3%) 6 (13.0%) 9 (19.6%) 2 (4.3%)
12 (31.6%) 12 (31.6%) 6 (15.8%) 6 (15.8%) 2 (5.3%)
CTCAE 0 1 2 3 4
NA NA NA NA NA
10 (21.7%) 18 (39.1%) 5 (10.9%) 10 (21.7%) 3 (6.5%)
13 (34.2%) 8 (21.1%) 6 (15.8%) 10 (26.3%) 1 (2.6%)
NA NA NA NA NA
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002
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Table 3 Three and five-year cumulative incidence of Grade 3 and 4 hearing loss according to ototoxicity scale, ear laterality and radiotherapy modality. SIOP Boston 3-Year
SIOP Boston 5-Year
Left ear Photon Proton
16.4% 11.5%
25.9% 18.9%
Right ear Photon Proton
11.6% 14.2%
18.3% 21.3%
P-value
POG 3-Year
POG 5-Year
16.4% 5.7%
23.0% 16.6%
11.6% 8.2%
18.3% 23.6%
0.696
P-value
Brock 3-Year
Brock 5-Year
12.2% 5.3%
15.6% 12.6%
9.3% 2.6%
12.7% 6.2%
0.588
0.633
according to the SIOP Boston (p = 0.019) and Brock (p = 0.003) scales. Gender, age at time of RT, type of boost field, presence of a shunt, posterior fossa syndrome and cisplatin dose did not have a significant effect on Grade 3 and 4 ototoxicity. Discussion Cochlear-sparing IMRT has been shown to reduce Grade 3 and 4 ototoxicity in children receiving cisplatin-based chemotherapy for medulloblastoma [2,3]. Because many of our patients receiving CSI are now treated with protons, we compared ototoxicity rates between patients previously treated with cochlear sparing IMRT and recent patients treated with protons. Amifostine, which has been shown previously to reduce the risk of cisplatin-induced severe ototoxicity in standard-risk medulloblastoma, was utilized in 41.3% of photon and 100% of proton patients [8]. The proportion of patients developing Grade 3 and 4 otoxicity were essentially the same with protons and photons. Despite lower mean cochlear doses, lower mean cisplatin doses, greater proportion of patients receiving a boost field to the tumor bed alone instead of the entire posterior fossa, and routine use of amifostine in the proton patients, there was no difference in Grade 3 and 4 ototoxicity rates according to SIOP Boston, Brock, POG and CTCAE scales. In one series, all medulloblastoma children without hearing loss had Dmc < 43 Gy. In the same report, a threshold of 37 Gy median Dmc was found to separate cochlea that had POG Grade 0–2 and Grade 3–4 otoxicity [2]. Perhaps the otoxicity attributed to RT cannot be significantly improved once the Dmc is below this threshold dose, and ototoxicity from cisplatin becomes the main contributing factor. It should be noted the median Dmc for protons and photons in the current study were 31.5 CGE and 37.3 Gy respectively, both at or below the 37 Gy threshold that has been associated with higher grade hearing loss [2]. While the 5% Grade 3 and 4 ototoxicity at 1 year with protons has been encouraging, it should be noted that the follow-up is short and the grading scale used by Moeller and colleagues was
CTCAE 3-Year
CTCAE 5-Year
16.4% 11.5%
25.9% 22.6%
11.6% 14.2%
21.3% 29.7%
0.987
0.938
Fig. 1. Comparison of International Society of Pediatric Oncology (SIOP) Boston Grade 3 and 4 hearing loss according to radiotherapy modality.
P-value
P-value 0.917
0.330
0.623
the Brock ototoxicity scale [4,5]. Others have reported Grade 3–4 hearing loss using the POG Ototoxicity scale with rates ranging from 16 to 19% [2,3,9,10]. At Massachusetts General Hospital, the 5-year POG Grade 3 and 4 ototoxicity rate was 16% with the use of protons [9]. At the Hospital Israelita Albert Einstein in Sao Paolo, 17% had POG Grade 3–4 ototoxicity with the use of IMRT and a mean follow-up of 44 months [10]. Our review revealed that even with longer follow-up, Brock Grade 3 and 4 ototoxicity was seen in only 9.3% and 9.9% treated with protons and photons. When the POG scale was used, the incidence of Grade 3 and 4 ototoxicity was higher at 17.3% and 20.9% with protons and photons. These results are consistent with the available literature with roughly the same follow-up time. At a median follow-up of 19 months, investigators from Memorial Sloan-Kettering Cancer Center have reported a 6% Grade 3 hearing loss according to the CTCAE, version 3; it is not clear from this report the length of audiogram follow-up time [11]. In the current report, the Grade 3 and 4 hearing loss according to CTCAE, version 3 was 29.9% with protons and 28.3% with photons. The most likely reason for the higher rate of hearing loss in the current report is the longer median audiogram follow-up of patients (66 months for photons and 56 months for protons). It has been previously reported that hearing loss secondary to radiotherapy is a late effect with a median onset at 3.6 years after RT [12]. In conclusion, the proportion of patients with severe hearing loss was found to be the same in patients treated with protons or photons, as assessed by four scoring systems. The Brock, POG and CTCAE ototoxicity scales were used as previous publications have reported radiation-induced ototoxicity rates using the same grading scales [2,3,5,9–11]. The SIOP Boston scale was also used because it was designed after an international workshop of experts on treatment-induced hearing loss [7]. While ototoxicity is not different between the two radiotherapy modalities, there may be a benefit for protons with respect to endocrine and cognitive function. Eaton et al. showed a lower risk of hypothyroidism, sex hormone deficiency and requirement for any endocrine replacement therapy with protons when compared to photons for children with medulloblastoma [13]. Kahalley et al. previously reported that protons were not associated with intelligence quotient (IQ) decline when compared to photons, but the IQ slopes over time did not differ between the 2 radiotherapy modalities. It remains unclear whether with longer follow-up, there may be a clinically meaningful cognitive sparing achieved with protons [14]. Lastly, similar to advances seen with photon therapies such as IMRT, proton therapy planning and delivery are advancing rapidly. All patients in the current study who received protons had passive scattering proton therapy in which there is no sparing of cochlea with the CSI component. As scanning beam proton therapy becomes more available and techniques such as intensity modulated proton therapy are used for the CSI component of treatment, additional cochlear sparing may be achieved which potentially can affect hearing outcome. Future studies and longer follow-up are needed to demonstrate the advantages of proton over photon radiotherapy in children with medulloblastoma.
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002
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Conflict of interest statement The authors have no conflict of interest to disclose with regard to this manuscript. References [1] Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 2005;23:8588–96. [2] Paulino AC, Lobo M, Teh BS, et al. Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with medulloblastoma. Int J Radiat Oncol Biol Phys 2010;78:1445–50. [3] Huang E, Teh BS, Strother DR, et al. Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 2002;52:599–605. [4] Eaton BR, Esiashvili N, Kim S, et al. Clinical outcomes among children with standard-risk medulloblastoma treated with proton and photon radiation therapy: a comparison of disease control and overall survival. Int J Radiat Oncol Biol Phys 2016;94:133–8. [5] Moeller BJ, Chintagumpala M, Philip JJ, et al. Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy. Radiat Oncol 2011;6:58. [6] Brock PR, Bellman SC, Yeomans EC, et al. Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol 1991;19:295–300.
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[7] Brock PR, Knight KR, Freyer DR, et al. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol 2012;30:2408–17. [8] Fouladi M, Chintagumpala M, Ashley D, et al. Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma. J Clin Oncol 2008;26:3749–55. [9] Yock TI, Yeap BY, Ebb DH, et al. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol 2016;17:287–98. [10] Vieira WA, Weltman E, Chen MJ, et al. Ototoxicity evaluation in medulloblastoma patients treated with involved field boost using intensitymodulated radiation therapy (IMRT): a retrospective review. Radiat Oncol 2014;9:158. [11] Polkinghorn WR, Dunkel IJ, Souweidane MM, et al. Disease control and ototoxicity using intensity-modulated radiation therapy tumor-bed boost for medulloblastoma. Int J Radiat Oncol Biol Phys 2011;81:e15–20. [12] Bass JK, Hua CH, Huang J, et al. Hearing loss in patients who received cranial radiation therapy for childhood cancer. J Clin Oncol 2016;34:1248–55. [13] Eaton BR, Esiashvili N, Kim S, et al. Endocrine outcomes with proton and photon radiotherapy for standard risk medulloblastoma. Neuro Oncol 2016;18:881–7. [14] Kahalley LS, Ris MD, Grosshans DR, et al. Comparing intelligence quotient change after treatment with proton versus photon radiation therapy for pediatric brain tumors. J Clin Oncol 2016;34:1043–9.
Please cite this article in press as: Paulino AC et al. Ototoxicity and cochlear sparing in children with medulloblastoma: Proton vs. photon radiotherapy. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.01.002