Low-Dose Radiation and Combination Chemotherapy Following Surgery in Children With Newly Diagnosed Medulloblastoma
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
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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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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 [IV and oral]) which will be given in the following order: AABAABAAB (total of 54 weeks). |
Drug: Cisplatin
Given at a dose of 70mg/m2 by intravenous (IV) infusion over 8 hours on day 0 of each cycle (Regimen A only).
Other Names:
Drug: Cyclophosphamide
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).
Other Names:
Drug: Etoposide
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).
Other Names:
Drug: Lomustine
Given at a dose of 75mg/m2 taken orally on days 0 of each 6-week cycle with vincristine and cisplatin (Regimen A only).
Other Names:
Drug: Vincristine
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).
Other Names:
Radiation: Craniospinal 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).
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
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Histologically confirmed medulloblastoma
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Standard-risk disease
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No residual tumor greater than 1.5 cm^2 after resection by postoperative MRI
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No tumor in the spinal or cerebral subarachnoid space by MRI
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No tumor in the subarachnoid space by Cerebrospinal fluid (CSF)
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No failure to perform staging studies (spine MRI and CSF cytology) preoperatively or postoperatively
- Must begin radiotherapy on study within 28 days after surgery
Exclusion Criteria:
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Prior radiotherapy and anti-tumor chemotherapy other than corticosteroids are not allowed.
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Pregnant females will not be eligible
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Patients must begin radiotherapy on protocol within 28 days of completion of surgery. Exceptions need to be approved by the Principal Investigator.
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Patients with the following will not be eligible:
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1.5cm3 residual tumor following resection as indicated by post-operative MRI.
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tumor in spinal or cerebral subarachnoid space either by MRI of brain and spine
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tumor in subarachnoid space by CSF cytology
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failure to perform staging studies (spine MRI, CSF cytology) either pre- or post- operatively
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Lucile Packard Children's Hospital at Stanford University Medical Center | Palo Alto | California | United States | 94304 |
| 2 | Winship Cancer Institute of Emory University | Atlanta | Georgia | United States | 30322 |
| 3 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104-4318 |
Sponsors and Collaborators
- Children's Hospital of Philadelphia
- Stanford University
- Emory University
Investigators
- Principal Investigator: Peter C. Phillips, MD, Children's Hospital of Philadelphia
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 00-002301
- CHP-693
Study Results
Participant Flow
| Recruitment Details | Subjects were enrolled at three participating institutions namely Childrens Hospital of Philadelphia, Stanford University and Emory University. |
|---|---|
| Pre-assignment Detail | 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. |
| Arm/Group Title | Study Treatment |
|---|---|
| Arm/Group Description | 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 |
| Period Title: Overall Study | |
| STARTED | 28 |
| COMPLETED | 25 |
| NOT COMPLETED | 3 |
Baseline Characteristics
| Arm/Group Title | Study Treatment |
|---|---|
| Arm/Group Description | 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 |
| Overall Participants | 28 |
| Age (Count of Participants) | |
| <=18 years |
28
100%
|
| Between 18 and 65 years |
0
0%
|
| >=65 years |
0
0%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
9
32.1%
|
| Male |
19
67.9%
|
| Race/Ethnicity, Customized (participants) [Number] | |
| White |
17
60.7%
|
| African american |
5
17.9%
|
| Asian |
1
3.6%
|
| Hispanic |
5
17.9%
|
| Other |
0
0%
|
| Region of Enrollment (participants) [Number] | |
| United States |
28
100%
|
Outcome Measures
| Title | Evaluate Rate of Late Neurotoxic Effects |
|---|---|
| Description | Evaluate the late neurotoxic effects of low dose craniospinal radiation, including neurocognitive decline as measured by serial neurocognitive testing. |
| Time Frame | 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Study Treatment |
|---|---|
| Arm/Group Description | All subjects will undergo surgical resection and routine staging (MRI spine and LP for CSF cytology). Subjects aged 3-30 yrs with M0 disease are eligible. Treatment must begin within 28 days of surgery. Reduced dose craniospinal irradiation (CSI) (1800 centiGray (cGy) CSI + 3780 cGy tumor bed) will last for 6 weeks with concurrent, weekly vincristine. 4 weeks after radiation therapy is completed, all subjects will begin 9 cycles of maintenance chemotherapy: Regimen A (CCNU, Vincristine, and Cisplatin) and Regimen B (Cyclophosphamide, given with Mesna, and Etoposide). Cycles will be given as AABAABAAB Regimen A: Cisplatin: 70mg/m2/dose x 1 dose on day 0 Vincristine: 1.5 mg/m2/dose on days 0, 7, 14 CCNU: 75 mg/m2/dose x 1 dose on day 0 Regimen B: Cyclophosphamide: 1g/m2/dose on days 0 and 1 Etoposide: 150 mg/m2/dose (IV) on days 0 and 1 Etoposide: 50 mg/m2/day PO on days 14-34 (21 days total) |
| Measure Participants | 0 |
| Title | Long Term Survival |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received radiation and started chemotherapy. |
| Arm/Group Title | Study Treatment |
|---|---|
| Arm/Group Description | All subjects will undergo surgical resection and routine staging (Magnetic Resonance Imagine (MRI) spine and Lumbar Puncture (LP) for cerebrospinal fluid (CSF) cytology). Subjects aged 3-30 yrs with M0 disease are eligible. Treatment must begin within 28 days of surgery. Reduced dose craniospinal RT (1800 cGy CSI + 3780 cGy tumor bed) will last for 6 weeks with concurrent, weekly vincristine. 4 weeks after radiation therapy is completed, all subjects will begin 9 cycles of maintenance chemotherapy: Regimen A (Lomustine (CCNU), Vincristine, and Cisplatin) and Regimen B (Cyclophosphamide, given with Mesna, and Etoposide). Cycles will be given as AABAABAAB Regimen A: Cisplatin: 70mg/m2/dose x 1 dose on day 0 Vincristine: 1.5 mg/m2/dose on days 0, 7, 14 CCNU: 75 mg/m2/dose x 1 dose on day 0 Regimen B: Cyclophosphamide: 1g/m2/dose on days 0 and 1 Etoposide: 150 mg/m2/dose intravenous (IV) on days 0 and 1 Etoposide: 50 mg/m2/day oral (PO) on days 14-34 (21 days total) |
| Measure Participants | 28 |
| 5 year Overall Survival (OS) |
87.5
312.5%
|
| 5 year Event Free Survival (EFS) |
70
250%
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | Adverse events were recorded in the following categories: auditory toxicity, renal toxicity, and endocrinologic toxicity | |
| Arm/Group Title | Study Treatment | |
| Arm/Group Description | 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 | |
All Cause Mortality |
||
| Study Treatment | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Study Treatment | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/28 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| Study Treatment | ||
| Affected / at Risk (%) | # Events | |
| Total | 28/28 (100%) | |
| Ear and labyrinth disorders | ||
| hearing loss | 15/28 (53.6%) | |
| Endocrine disorders | ||
| thyroid dysfunction | 11/28 (39.3%) | |
| growth hormone deficiency | 6/28 (21.4%) | |
| Renal and urinary disorders | ||
| creatinine clearance | 5/28 (17.9%) | |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Peter Phillips |
|---|---|
| Organization | Childrens Hospital of Philadelphia |
| Phone | 215-590-1000 |
| phillipsp@email.chop.edu |
- 00-002301
- CHP-693