Brain Tumors, Central Nervous System Tumors, Medulloblastoma
Conditions
Keywords
average risk medulloblastoma, craniospinal radiotherapy, newly diagnosed
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells, but also damages normal cells in the developing brains of children. Combining low-dose radiation therapy in combination with chemotherapy should be effective in treating medulloblastoma while avoiding the long-term side effects of giving higher dose radiation to children with newly diagnosed average risk medulloblastoma.
Detailed description
OBJECTIVES: * By giving reduced dose craniospinal radiation followed by nine cycles of maintenance chemotherapy comprised of alternating cycles of lomustine, cisplatin, and vincristine alternating with cyclophosphamide and etoposide, we will reduce the late effects of higher dose radiation in children while maintaining the therapeutic efficacy (86% 3-year relapse-free survival) of current standard therapy * To evaluate the late neurotoxic effects of low-dose craniospinal radiotherapy, in terms of cognitive, endocrinologic, and auditory function, in these patients. OUTLINE: This is a multi center study of reduced dose craniospinal radiotherapy and chemotherapy in patients ages 3 - 30 years with newly diagnosed average risk medulloblastoma. * Induction chemoradiotherapy: Beginning within 28 days after complete surgical resection, patients undergo radiotherapy to the craniospinal axis (1800 centigray (cGy)) followed by conformal radiotherapy to the tumor bed (5400 cGy). Patients receive vincristine weekly for 6 weeks. * Maintenance chemotherapy: Beginning 4 weeks after the completion of craniospinal radiation therapy, patients receive two 6-week courses of regimen A as outlined below alternating with one 6-week course of regimen B for a total of 9 courses (AABAABAAB). * Regimen A: Patients receive oral lomustine and cisplatin on day 0 and vincristine on days 0, 7, and 14. * Regimen B: Patients receive cyclophosphamide on days 0 and 1 and etoposide intravenous (IV) on days 0 and 1, followed by oral etoposide on days 14-34. Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter with surveillance neuroimaging using Magnetic Resonance Imaging Scan (MRI scan) and clinical examination. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study within 3 years.
Interventions
DRUGCisplatin
Given at a dose of 70mg/m2 by intravenous (IV) infusion over 8 hours on day 0 of each cycle (Regimen A only).
DRUGCyclophosphamide
Given at a dose of 1g/m2/day by IV infusion on days 0 and 1 of a 6-week cycle. Administration of cyclophosphamide will always be preceded by prehydration and Mesna (Regimen B only).
DRUGEtoposide
Given at a dose of 150mg/m2/day by IV infusion on days 0 and 1 of a 6-week cycle. Given orally at a dose of 50mg/m2 as a single daily dose for 21 days beginning on day 14 of a cycle (Regimen B only).
DRUGLomustine
Given at a dose of 75mg/m2 taken orally on days 0 of each 6-week cycle with vincristine and cisplatin (Regimen A only).
DRUGVincristine
Given at a dose of 1.5mg/m2 given by IV infusion once a week for the first six weeks of treatment during radiation therapy. During maintenance therapy, it will be given as an IV push on days 0, 7 and 14 of each 6-week cycle (Regimen A only).
RADIATIONCraniospinal Radiation
Craniospinal radiation will begin within 28 days of surgery. Craniospinal Radiation therapy will last for 6 weeks, five days per week. Once a week during radiation, subjects will also be treated with chemotherapy (vincristine).
Sponsors
Stanford University
Emory University
Children's Hospital of Philadelphia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed medulloblastoma 2. Standard-risk disease 3. No residual tumor greater than 1.5 cm\^2 after resection by postoperative MRI * No tumor in the spinal or cerebral subarachnoid space by MRI * No tumor in the subarachnoid space by Cerebrospinal fluid (CSF) * No failure to perform staging studies (spine MRI and CSF cytology) preoperatively or postoperatively 4. Must begin radiotherapy on study within 28 days after surgery
Exclusion criteria
1. Prior radiotherapy and anti-tumor chemotherapy other than corticosteroids are not allowed. 2. Pregnant females will not be eligible 3. Patients must begin radiotherapy on protocol within 28 days of completion of surgery. Exceptions need to be approved by the Principal Investigator. 4. Patients with the following will not be eligible: * \> 1.5cm3 residual tumor following resection as indicated by post-operative MRI. * tumor in spinal or cerebral subarachnoid space either by MRI of brain and spine * tumor in subarachnoid space by CSF cytology * failure to perform staging studies (spine MRI, CSF cytology) either pre- or post- operatively
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate Rate of Late Neurotoxic Effects | 3 years | Evaluate the late neurotoxic effects of low dose craniospinal radiation, including neurocognitive decline as measured by serial neurocognitive testing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Long Term Survival | Up to 5 years from date of randomization until the date of first documented progression or date of death from any cause, whichever came first. | Survival Endpoints: Event free survival and overall survival were assessed at 5 years from time of study enrollment |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled at three participating institutions namely Childrens Hospital of Philadelphia, Stanford University and Emory University.
Pre-assignment details
Thirty subjects signed consent. One subject was deemed ineligible due to positive cerebrospinal fluid (CSF) and second subject was declared ineligible due to delayed start of radiation therapy (RT). Remaining 28 subjects continued on study.
Participants by arm
| Arm | Count |
|---|---|
| Study Treatment All subjects will undergo routine surgical staging of their tumor. Treatment must begin within 28 days of surgery. Craniospinal Radiation therapy will last for 6 weeks, five days per week. Once a week during radiation, subjects will also be treated with vincristine. 4 weeks after radiation and vincristine treatment is completed, all subjects will begin 9 cycles (each cycle lasts 6 weeks) of maintenance chemotherapy which will be given as 2 different drug combinations, Regimen A (Lomustine, Vincristine, and Cisplatin) and Regimen B (Cyclophosphamide, given with Mesna, and Etoposide) which will be given in the following order (total of 54 weeks):1st-Regimen A, 2nd-Regimen A, 3rd-Regimen B, 4th-Regimen A, 5th-Regimen A, 6th-Regimen B, 7th-Regimen A, 8th-Regimen A, 9th-Regimen B. Cisplatin: Given at a dose of 70mg/m2 by intravenous (IV) infusion over 8 hours on day 0 of each cycle (Regimen A only). Cyclophosphamide: Given at a dose of 1g/m2/day by IV infusion on days 0 and 1 of a 6 | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by parents | 2 |
Baseline characteristics
| Characteristic | Study Treatment |
|---|---|
| Age, Categorical <=18 years | 28 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Race/Ethnicity, Customized African american | 5 participants |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Hispanic | 5 participants |
| Race/Ethnicity, Customized Other | 0 participants |
| Race/Ethnicity, Customized White | 17 participants |
| Region of Enrollment United States | 28 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 28 / 28 |
| serious Total, serious adverse events | 0 / 28 |
Outcome results
Primary
Evaluate Rate of Late Neurotoxic Effects
Evaluate the late neurotoxic effects of low dose craniospinal radiation, including neurocognitive decline as measured by serial neurocognitive testing.
Time frame: 3 years
Population: The primary endpoint was not met due to lack of evaluable data from non-compliance with neurocognitive testing. Baseline neurocognitive testing was performed on 5 of 28 (18%) of study subjects. Of those 5 subjects with baseline testing, only 1 completed follow up neurocognitive testing at the protocol specified time points.
Secondary
Long Term Survival
Survival Endpoints: Event free survival and overall survival were assessed at 5 years from time of study enrollment
Time frame: Up to 5 years from date of randomization until the date of first documented progression or date of death from any cause, whichever came first.
Population: All subjects who received radiation and started chemotherapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Study Treatment | Long Term Survival | 5 year Event Free Survival (EFS) | 70 Percentage of participants |
| Study Treatment | Long Term Survival | 5 year Overall Survival (OS) | 87.5 Percentage of participants |