Proton Beam Radiation Therapy in Treating Young Patients Who Have Undergone Biopsy or Surgery for Medulloblastoma or Pineoblastoma

Phase II Study of Craniospinal and Posterior Fossa Irradiation Using Proton Beam Radiotherapy for Medulloblastoma and Pineoblastoma: Assessment of Acute and Long Term Sequelae

RATIONALE: Specialized radiation therapy that delivers radiation directly to the area where a tumor was surgically removed may kill any remaining tumor cells and cause less damage to normal tissue.

PURPOSE: This phase II trial is studying how well proton beam radiation therapy works in treating young patients who have undergone biopsy or surgery for medulloblastoma or pineoblastoma.

Study Overview

• Status: Completed
• Conditions: Brain and Central Nervous System Tumors; Long-term Effects Secondary to Cancer Therapy in Children
• Intervention / Treatment: Radiation: radiation therapy

Detailed Description

OBJECTIVES:

• Determine the 3-year incidence and severity of ototoxicity in young patients with medulloblastoma or pineoblastoma treated with adjuvant proton beam craniospinal and posterior fossa radiotherapy.
• Determine the incidence of primary hypothyroidism and other endocrine dysfunction (neuroendocrine and end organ) in patients treated with this regimen.
• Determine the incidence and severity of neurocognitive abnormalities in patients treated with this regimen.
• Determine the acute side effects of this regimen, including esophagitis, upper and lower gastrointestinal tract disease, and weight loss, in these patients.
• Determine the 3-year progression-free survival rate of patients treated with this regimen.

OUTLINE: Patients are stratified according to risk (standard vs high).

Patients receive proton beam craniospinal and posterior fossa radiotherapy once daily 5 days a week for 6-8 weeks*.

NOTE: *Unless otherwise specified by a co-existing protocol.

Patients undergo neurocognitive evaluation at baseline or within 3 months after completion of radiotherapy and then at 1, 3, and 5 years. Patients also undergo endocrine evaluation at baseline and then annually for 5 years; and audiology evaluation at baseline, before each course of cisplatin-based chemotherapy (if receiving this), and then annually for 5 years.

After completion of study treatment, patients are followed every 3-6 months for 2-5 years.

PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed medulloblastoma or pineoblastoma

  • Standard-risk or high-risk disease
• Must have undergone biopsy or attempted surgical resection of the tumor within the past 35 days
• Requires craniospinal irradiation

PATIENT CHARACTERISTICS:

Age

• 3 to 21

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No more than 1 prior chemotherapy regimen
• No prior IV or intrathecal methotrexate
• No prior intrathecal thiotepa
• Concurrent cisplatin-based chemotherapy, including chemotherapy administered on another study, allowed

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• See Disease Characteristics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Radiation therapy; This is a single arm study of radiation therapy with protons to standard doses.	Radiation: radiation therapy; Radiation therapy with proton beam to standard doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Incidence of Ototoxicity	Percentage participants who experienced ototoxicity as measured by Common Toxicity Criteria for Adverse Events (CTCAE) v3.0 after the completion of radiation therapy in the overall participant population and by baseline measure subgroups. Incidence is shown after follow-up of 3 years, 5 years, 7 years, and 10 years.	3 Years, 5 years, 7 years, 10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 3 Years	Percentage of participants who experienced endocrine dysfunction (neuroendocrine and end organ defects) after 3 years of follow-up (as determined by CTCAE 3.0). Incidence is grouped by hormone type and risk group	3 years
Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 5 Years	Percentage of participants who experienced endocrine dysfunction (neuroendocrine and end organ defects) after 5 years of follow-up (as determined by CTCAE 3.0). Incidence is shown by hormone type and risk group.	5 years
Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 7 Years	Percentage of participants who experienced endocrine dysfunction (neuroendocrine and end organ defects) after 7 years of follow-up, as determined by CTCAE 3.0. Incidence is shown by hormone type and risk group	7 years
Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 7 Years	percentage of participants who experienced endocrine dysfunction (neuroendocrine and end organ defects) as determined by CTCAE 3.0) at year 3, year 5, and year 7 of follow-up.	3 years, 5 years, 7 years
Mean Change Per-Year in Neurocognitive Outcomes	The mean change per-year in neurocognitive outcomes as assessed by Wechsler Intelligence Scale for Children version 4 (WISC-IV). The test measures the Full Scale Intelligence Quotient (FSIQ) of children with the use of four indices; the Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), working memory test, and a processing speed test. FSIQ and the four indices are all assessed on a bell curve scale that has an average score of 100 and standard deviation of 15 points in the general population, meaning on average 68% of test takers would be within +/- 15 points of 100 and 95% within +/- 30 points. Higher scores represent higher intelligence and lower score represent reduced intelligence. Participants were assessed for changes in score with the use of repeated testing during a median follow-up time of 5.2 years. Repeated measures were taken at baseline, 1, 3, 5, and 7 years or until the participant was not available for evaluation (whichever comes first).	Baseline, 1, 3, 5, 7 years
Progression Free Survival	The percentage of participants with progression free survival after five, seven, and ten years in the overall population and by risk and histological group.	5 years, 7 years, 10 years
Overall Survival	the percentage of participants surviving after five and seven years and at the end of follow-up in the overall population. Survival is shown by risk and histological group.	5 years, 7 years, 10 years

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Nancy J. Tarbell, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Yock TI, Yeap BY, Ebb DH, Weyman E, Eaton BR, Sherry NA, Jones RM, MacDonald SM, Pulsifer MB, Lavally B, Abrams AN, Huang MS, Marcus KJ, Tarbell NJ. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol. 2016 Mar;17(3):287-298. doi: 10.1016/S1470-2045(15)00167-9. Epub 2016 Jan 30. Erratum In: Lancet Oncol. 2020 Mar;21(3):e132.
• Vatner RE, Niemierko A, Misra M, Weyman EA, Goebel CP, Ebb DH, Jones RM, Huang MS, Mahajan A, Grosshans DR, Paulino AC, Stanley T, MacDonald SM, Tarbell NJ, Yock TI. Endocrine Deficiency As a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors. J Clin Oncol. 2018 Oct 1;36(28):2854-2862. doi: 10.1200/JCO.2018.78.1492. Epub 2018 Aug 17.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2002
• Primary Completion (ACTUAL): December 1, 2012
• Study Completion (ACTUAL): December 1, 2020

Study Registration Dates

• First Submitted: March 15, 2005
• First Submitted That Met QC Criteria: March 15, 2005
• First Posted (ESTIMATE): March 16, 2005

Study Record Updates

• Last Update Posted (ACTUAL): December 28, 2021
• Last Update Submitted That Met QC Criteria: December 3, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: long-term effects secondary to cancer therapy in children; untreated childhood medulloblastoma; untreated childhood pineoblastoma
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Brain Neoplasms; Neuroectodermal Tumors, Primitive; Nervous System Neoplasms; Central Nervous System Neoplasms; Medulloblastoma; Pinealoma
• Other Study ID Numbers: CDR0000415841; P01CA021239 (U.S. NIH Grant/Contract); MGH-99-271 (OTHER: Massachusetts General Hospital)