title: Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study.
abstract: BACKGROUND
  Compared with traditional photon radiotherapy, proton radiotherapy irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue. We did a trial to assess late complications, acute side-effects, and survival associated with proton radiotherapy in children with medulloblastoma.
  
  
  METHODS
  In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients aged 3-21 years who had medulloblastoma. Patients had craniospinal irradiation of 18-36 Gy radiobiological equivalents (GyRBE) delivered at 1·8 GyRBE per fraction followed by a boost dose. The primary outcome was cumulative incidence of ototoxicity at 3 years, graded with the Pediatric Oncology Group ototoxicity scale (0-4), in the intention-to-treat population. Secondary outcomes were neuroendocrine toxic effects and neurocognitive toxic effects, assessed by intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00105560.
  
  
  RESULTS
  We enrolled 59 patients from May 20, 2003, to Dec 10, 2009: 39 with standard-risk disease, six with intermediate-risk disease, and 14 with high-risk disease. 59 patients received chemotherapy. Median follow-up of survivors was 7·0 years (IQR 5·2-8·6). All patients received the intended doses of proton radiotherapy. The median craniospinal irradiation dose was 23·4 GyRBE (IQR 23·4-27·0) and median boost dose was 54·0 GyRBE (IQR 54·0-54·0). Four (9%) of 45 evaluable patients had grade 3-4 ototoxicity according to Pediatric Oncology Group ototoxicity scale in both ears at follow-up, and three (7%) of 45 patients developed grade 3-4 ototoxicity in one ear, although one later reverted to grade 2. The cumulative incidence of grade 3-4 hearing loss at 3 years was 12% (95% CI 4-25). At 5 years, it was 16% (95% CI 6-29). Pediatric Oncology Group hearing ototoxicity score at a follow-up of 5·0 years (IQR 2·9-6·4) was the same as at baseline or improved by 1 point in 34 (35%) of 98 ears, worsened by 1 point in 21 (21%), worsened by 2 points in 35 (36%), worsened by 3 points in six (6%), and worsened by 4 points in two (2%). Full Scale Intelligence Quotient decreased by 1·5 points (95% CI 0·9-2·1) per year after median follow-up up of 5·2 years (IQR 2·6-6·4), driven by decrements in processing speed and verbal comprehension index. Perceptual reasoning index and working memory did not change significantly. Cumulative incidence of any neuroendocrine deficit at 5 years was 55% (95% CI 41-67), with growth hormone deficit being most common. We recorded no cardiac, pulmonary, or gastrointestinal late toxic effects. 3-year progression-free survival was 83% (95% CI 71-90) for all patients. In post-hoc analyses, 5-year progression-free survival was 80% (95% CI 67-88) and 5-year overall survival was 83% (95% CI 70-90).
  
  
  CONCLUSIONS
  Proton radiotherapy resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments.
  
  
  BACKGROUND
  US National Cancer Institute and Massachusetts General Hospital.
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: tyock@partners.org.
authors.forename: Torunn I
authors.initials: TI
authors.lastname: Yock
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.affiliation: Department of Pediatric Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Ebb
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Weyman
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Bree R
authors.initials: BR
authors.lastname: Eaton
authors.affiliation: Department of Pediatric Endocrinology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Sherry
authors.affiliation: Department of Pediatric Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Jones
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: MacDonald
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Margaret B
authors.initials: MB
authors.lastname: Pulsifer
authors.affiliation: Department of Pediatric Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Beverly
authors.initials: B
authors.lastname: Lavally
authors.affiliation: Department of Child Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Annah N
authors.initials: AN
authors.lastname: Abrams
authors.affiliation: Department of Pediatric Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Mary S
authors.initials: MS
authors.lastname: Huang
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Marcus
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Tarbell
mesh_terms: D000293:Adolescent; D000367:Age Factors; D002528:Cerebellar Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000532:radiotherapy*; D002648:Child; D002675:Child, Preschool; D016001:Confidence Intervals; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008527:Medulloblastoma / Q000175:diagnosis* / Q000401:mortality / Q000532:radiotherapy*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D061766:Proton Therapy; D011879:Radiotherapy Dosage; D018570:Risk Assessment; D012737:Sex Factors; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult; D011522:Protons
chemical_list: D011522:Protons