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

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00105560
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 59
• Location: 1
• Arm: 1
• Actual Duration (Months): 223
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors; Long-term Effects Secondary to Cancer Therapy in Children	Radiation: radiation therapy	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Craniospinal and Posterior Fossa Irradiation Using Proton Beam Radiotherapy for Medulloblastoma and Pineoblastoma: Assessment of Acute and Long Term Sequelae
• Actual Study Start Date: May 1, 2002
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Cumulative Incidence of Ototoxicity [3 Years, 5 years, 7 years, 10 years]

   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.

Secondary Outcome Measures

1. Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 3 Years [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

2. Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 5 Years [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.

3. Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 7 Years [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

4. Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 7 Years [3 years, 5 years, 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.

5. Mean Change Per-Year in Neurocognitive Outcomes [Baseline, 1, 3, 5, 7 years]

   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).

6. Progression Free Survival [5 years, 7 years, 10 years]

   The percentage of participants with progression free survival after five, seven, and ten years in the overall population and by risk and histological group.

7. Overall Survival [5 years, 7 years, 10 years]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Cancer Institute (NCI)

Investigators

• Study Chair: Nancy J. Tarbell, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nancy J. Tarbell, M.D., Attending Radiation Oncologist, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00105560
• Other Study ID Numbers: CDR0000415841; P01CA021239; MGH-99-271
• First Posted: Mar 16, 2005
• Last Update Posted: Dec 28, 2021
• Last Verified: Dec 1, 2021

• Keywords provided by Nancy J. Tarbell, M.D., Attending Radiation Oncologist, Massachusetts General Hospital: long-term effects secondary to cancer therapy in children; untreated childhood medulloblastoma; untreated childhood pineoblastoma
• Additional relevant MeSH terms: Nervous System Neoplasms; Central Nervous System Neoplasms; Medulloblastoma; Pinealoma

Study Results

Participant Flow

Arm/Group Title	Radiation Therapy
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses
Period Title: Overall Study
STARTED	59
COMPLETED	58
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Radiation Therapy
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses
Overall Participants	59
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	6.6
Age, Customized (Count of Participants)
< 8 Years	37 62.7%
≥ 8 Years	22 37.3%
Sex: Female, Male (Count of Participants)
Female	26 44.1%
Male	33 55.9%
Region of Enrollment (Count of Participants)
United States	59 100%
Histological Subtype (Dominant Pattern) (Count of Participants)
Classic	45 76.3%
Desmoplastic or Nodular Variant	6 10.2%
Anaplastic or Large Cell Variant	8 13.6%
Risk Group (Count of Participants)
Standard	39 66.1%
Intermediate	6 10.2%
High	14 23.7%
Posterior Fossa Syndrome (Count of Participants)
Yes	14 23.7%
No	45 76.3%
Ventriculoperitoneal Shunt (Count of Participants)
Yes	12 20.3%
No	47 79.7%
Enrolled on a Children's Oncology Group Protocol (participants) [Number]
Yes : ACNS0331	8 13.6%
Yes : ACNS0332	2 3.4%
Yes : ACNS0334	1 1.7%
Yes : A9961	1 1.7%
No	47 79.7%
Boost Field (Count of Participants)
Tumor Bed Involved Field	36 61%
Posterior Fossa	23 39%
Boost Dose (Count of Participants)
54 GyRBE	57 96.6%
>54 GyRBE	2 3.4%
Craniospinal Radiation Doses (Count of Participants)
18-27 GyRBE	45 76.3%
36 GyRBE	14 23.7%
Hypothalamus Mean Dose (D50) (Count of Participants)
<40 GyRBE	37 62.7%
≥40 GyRBE	22 37.3%
Cochlear Mean Dose to Each Ear (D50) (Ears) [Number]
<30 GyRBE	61
≥30 GyRBE	57
Cisplatin Cumulative Dose (participants) [Number]
≤300 mg/m2	17 28.8%
>300 mg/m2	34 57.6%
Use of Photons for <20% radiation dose (Count of Participants)
Yes	6 10.2%
No	53 89.8%

Outcome Measures

1. Primary Outcome

Title	Cumulative Incidence of Ototoxicity
Description	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.
Time Frame	3 Years, 5 years, 7 years, 10 years

Outcome Measure Data

Analysis Population Description

The overall study population after the stated durations of follow-up. Follow-up is ongoing and data is not yet available for the 10 year time point.

Arm/Group Title	Radiation Therapy - 3 Years Follow-up	Radiation Therapy - 5 Years Follow-up	Radiation Therapy - 7 Years Follow-up
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses
Measure Participants	59	59	59
All Participants	12 20.3%	16 NaN	16 NaN
Standard Risk	15 25.4%	20 NaN	20 NaN
Intermediate-high risk	7 11.9%	7 NaN	7 NaN
Male	4 6.8%	4 NaN	4 NaN
Female	20 33.9%	27 NaN	27 NaN
<8 years old	15 25.4%	20 NaN	20 NaN
≥8 years old	6 10.2%	6 NaN	6 NaN
Vetriculoperitoneal shunt	22 37.3%	22 NaN	22 NaN
No vetriculoperitoneal shunt	10 16.9%	14 NaN	14 NaN
Cisplatin total dose ≤300 mg/m2	18 30.5%	18 NaN	18 NaN
Cisplatin total dose >300 mg/m2	12 20.3%	17 NaN	17 NaN

2. Secondary Outcome

Title	Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 3 Years
Description	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
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Radiation Therapy - Overall Study Population	Radiation Therapy - Standard Risk Group	Radiation Therapy Intermediate-High Risk
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses
Measure Participants	59	39	20
Any hormone deficit	27 45.8%	28 NaN	25 NaN
Growth hormone deficit	22 37.3%	23 NaN	20 NaN
Thyroid deficiency	12 20.3%	10 NaN	15 NaN
Adrenal or cortisol deficit	5 8.5%	3 NaN	10 NaN
Sex hormone deficit	3 5.1%	3 NaN	5 NaN

3. Secondary Outcome

Title	Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 5 Years
Description	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.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Radiation Therapy - Overall Study Population	Radiation Therapy - Standard Risk Group	Radiation Therapy - Intermediate-High Risk
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses
Measure Participants	59	39	20
Any hormone deficit	55 93.2%	58 NaN	50 NaN
Growth hormone deficit	46 78%	50 NaN	40 NaN
Thyroid deficiency	21 35.6%	21 NaN	20 NaN
Adrenal or cortisol deficit	9 15.3%	3 NaN	20 NaN
Sex hormone deficit : Overall study population	3 5.1%	3 NaN	5 NaN

4. Secondary Outcome

Title	Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 7 Years
Description	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
Time Frame	7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Radiation Therapy - Overall Study Population	Radiation Therapy - Standard Risk Group	Radiation Therapy - Intermediate-High Risk
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses
Measure Participants	59	39	20
Any hormone deficit	63 106.8%	68 NaN	50 NaN
Growth hormone deficit	55 93.2%	62 NaN	40 NaN
Thyroid deficiency	26 44.1%	25 NaN	29 NaN
Adrenal or cortisol deficit	9 15.3%	3 NaN	20 NaN
Sex hormone deficit : Overall study population	3 5.1%	3 NaN	5 NaN

5. Secondary Outcome

Title	Cumulative Incidence of Endocrine Dysfunction (Neuroendocrine and End Organ Defects) at 7 Years
Description	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.
Time Frame	3 years, 5 years, 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Radiation Therapy - 3 Years Follow-up	Radiation Therapy - 5 Years Follow-up	Radiation Therapy - 7 Years Follow-up
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses
Measure Participants	59	59	59
Any hormone deficit	27 45.8%	55 NaN	63 NaN
Growth hormone deficit	22 37.3%	46 NaN	55 NaN
Thyroid deficiency	12 20.3%	21 NaN	26 NaN
Adrenal or cortisol deficit	5 8.5%	9 NaN	9 NaN
Sex hormone deficit	3 5.1%	3 NaN	3 NaN

6. Secondary Outcome

Title	Mean Change Per-Year in Neurocognitive Outcomes
Description	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).
Time Frame	Baseline, 1, 3, 5, 7 years

Outcome Measure Data

Analysis Population Description

The study participants that were evaluated for changes in neurocognitive outcomes

Arm/Group Title	Radiation Therapy
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses
Measure Participants	54
FSIQ	-1.5
VCI	-1.3
PRI	-.4
Working Memory	-0.8
Processing speed	-2.4

7. Secondary Outcome

Title	Progression Free Survival
Description	The percentage of participants with progression free survival after five, seven, and ten years in the overall population and by risk and histological group.
Time Frame	5 years, 7 years, 10 years

Outcome Measure Data

Analysis Population Description

Follow-up is ongoing and data is not yet available for the 10 year follow-up time point.

Arm/Group Title	Radiation Therapy - 5 Years Follow-up	Radiation Therapy - 7 Years Follow-up
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses
Measure Participants	59	59
All Participants	80 135.6%	75 NaN
Standard Risk	85 144.1%	81 NaN
Intermediate-high risk	70 118.6%	63 NaN
Classic or desmoplastic histological subtype	80 135.6%	75 NaN
Anaplastic or large cell histological subtype	75 127.1%	75 NaN

8. Secondary Outcome

Title	Overall Survival
Description	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.
Time Frame	5 years, 7 years, 10 years

Outcome Measure Data

Analysis Population Description

Follow-up for the 10 year follow-up is still ongoing and the data is not yet available.

Arm/Group Title	Radiation Therapy - 5 Years Follow-up	Radiation Therapy - 7 Years Follow-up
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses	radiation therapy: Radiation therapy with proton beam to standard doses
Measure Participants	59	59
All Participants	83 140.7%	81 NaN
Standard Risk	86 145.8%	86 NaN
Intermediate-high risk	75 127.1%	68 NaN
Classic or desmoplastic histological subtype	84 142.4%	82 NaN
Anaplastic or large cell histological subtype	75 127.1%	75 NaN

Adverse Events

Time Frame	Through study completion, median duration of 7 years
Adverse Event Reporting Description	Acute toxicity is assessed weekly during craniospinal irradiation (CSI) treatment and late side effects/complications are assessed during routine clinic visits starting at 90 days after the completion of radiation therapy. Participants were assessed for toxicity for the duration of followup, meaning until the patient withdraws from the study, is taken off the protocol, or dies.
Arm/Group Title	Radiation Therapy
Arm/Group Description	radiation therapy: Radiation therapy with proton beam to standard doses
All Cause Mortality
	Radiation Therapy
	Affected / at Risk (%)	# Events
Total	13/59 (22%)
Serious Adverse Events
	Radiation Therapy
	Affected / at Risk (%)	# Events
Total	13/59 (22%)
Gastrointestinal disorders
esophhagitis	1/59 (1.7%)
Investigations
Neutropenia	5/59 (8.5%)
Lymphopenia	7/59 (11.9%)
Nervous system disorders
Stroke	1/59 (1.7%)
Other (Not Including Serious) Adverse Events
	Radiation Therapy
	Affected / at Risk (%)	# Events
Total	59/59 (100%)
Blood and lymphatic system disorders
Neutropenia	42/59 (71.2%)
Lymphopenia	16/59 (27.1%)
Thrombocytopenia	13/59 (22%)
Eye disorders
Cataracts	16/59 (27.1%)
Gastrointestinal disorders
Nausea	34/59 (57.6%)
Vomiting	32/59 (54.2%)
General disorders
Fatigue	45/59 (76.3%)
Investigations
Weight Loss	10/59 (16.9%)
Metabolism and nutrition disorders
Anorexia	35/59 (59.3%)
Obesity	7/59 (11.9%)
Musculoskeletal and connective tissue disorders
Scoliosis	5/59 (8.5%)
Truncal muscle weakness	1/59 (1.7%)
Nervous system disorders
Headache	17/59 (28.8%)
CNS brainstem injury	1/59 (1.7%)
Ataxia	28/59 (47.5%)
Nystagmus	10/59 (16.9%)
Psychiatric disorders
Depression	4/59 (6.8%)
Skin and subcutaneous tissue disorders
Alopecia	59/59 (100%)
Radiation dermatitis (scalp or back)	21/59 (35.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.