RATIONALE: Drugs used in chemotherapy, such as carboplatin, thiotepa, and etoposide, work in
different ways to stop tumor cells from dividing so they stop growing or die. Combining
chemotherapy with autologous stem cell transplantation may allow the doctor to give higher
doses of chemotherapy drugs and kill more tumor cells. Isotretinoin may be effective in
preventing recurrence of glioma. It is not yet known which regimen of chemotherapy plus
autologous stem cell transplantation with or without isotretinoin is more effective in
treating recurrent high-grade glioma.
PURPOSE: This randomized phase III trial is studying high-dose chemotherapy or
intermediate-dose chemotherapy followed by autologous stem cell transplantation to see how
well it works compared to high-dose chemotherapy or intermediate-dose chemotherapy followed
by autologous stem cell transplantation and isotretinoin in treating young patients with
recurrent high-grade glioma.
- Compare the event-free survival and overall survival of pediatric patients with
recurrent high-grade gliomas treated with a single course of high-dose carboplatin,
etoposide, and thiotepa and autologous stem cell transplantation vs multiple courses of
intermediate-dose carboplatin and thiotepa and autologous stem cell transplantation with
or without isotretinoin.
- Compare the number of hospital days and time to engraftment in patients treated with
- Compare the toxic death rate in patients treated with these regimens.
- Compare the tolerability of isotretinoin in patients treated with these regimens.
OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
pathologic diagnosis (glioblastoma multiforme vs anaplastic astrocytoma vs other high-grade
glioma).
- Chemotherapy and autologous stem cell reinfusion (ASCR): Patients are randomized to 1 of
- Arm I (high-dose chemotherapy and ASCR): Patients receive high-dose chemotherapy
comprising carboplatin IV over 4 hours on days - 8 to -6; thiotepa IV over 3 hours
and etoposide IV over 3 hours on days - 5 to -3; and filgrastim (G-CSF) IV or
subcutaneously (SC) once daily beginning on day 1 and continuing until blood counts
recover. Autologous peripheral blood stem cells (PBSC) or bone marrow are reinfused
on day 0.
intermediate-dose chemotherapy comprising carboplatin IV over 4 hours and thiotepa
IV over 3 hours on days 1-2 and G-CSF IV or SC once daily beginning on day 4 and
continuing until blood counts recover. Autologous PBSC or bone marrow are reinfused
on day 3. Treatment repeats every 28 days for a total of 3 courses.
post-transplantation), all patients are further randomized to 1 of 2 maintenance arms.
- Arm I: Patients receive oral isotretinoin twice daily on days 1-14. Treatment
- Arm II: Patients do not receive maintenance therapy. In all arms, treatment
Patients are followed every 3 months for 1 year, every 6 months for 3 years, and then
annually thereafter.
PROJECTED ACCRUAL: A total of 80-150 patients (40-75 per treatment arm) will be accrued for
this study within 5 years.
DISEASE CHARACTERISTICS:
- Histologically confirmed diagnosis of 1 of the following high-grade gliomas:
- Glioblastoma multiforme
- Anaplastic astrocytoma
- Gliosarcoma
- Disease in first relapse
- No primary brainstem or spinal cord gliomas
- No secondary glioblastomas arising after prior treatment for a non-glial tumor
- Prior local radiotherapy of 5,000-6,000 cGy required
- Less than 1. 5 cm of residual gadolinium-enhancing tumor in maximal cross-sectional
diameter by MRI
- No metastatic tumor by spinal MRI
PATIENT CHARACTERISTICS:
Age
- Under 21 at diagnosis
Performance status
- Lansky 50-100% OR
- Karnofsky 50-100%
Life expectancy
- Not specified
Hematopoietic
- Absolute neutrophil count ≥ 500/mm^3
- Platelet count ≥ 100,000/mm^3 (transfusion independent)
Hepatic
- Bilirubin ≤ 1. 5 times upper limit of normal (ULN)
- AST or ALT < 2. 5 times ULN
Renal
- Glomerular filtration rate ≥ 60 mL/min AND/OR
- Creatinine clearance ≥ 60 mL/min
Cardiovascular
- Shortening fraction ≥ 27% by echocardiogram OR
- Ejection fraction ≥ 50% by MUGA
Pulmonary
- No dyspnea at rest
- No exercise intolerance
- Pulse oximetry > 94%
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
PRIOR CONCURRENT THERAPY:
Biologic therapy
- Not specified
Chemotherapy
- More than 4 weeks since prior chemotherapy
- No prior thiotepa
- No prior myeloablative chemotherapy
Endocrine therapy
- No concurrent corticosteroids
Radiotherapy
- See Disease Characteristics
- More than 8 weeks since prior radiotherapy
- No prior craniospinal radiotherapy
Surgery
- Not specified
Arkansas Cancer Research Center at University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States
Children's & Women's Hospital of British Columbia, Vancouver, British Columbia V6H 3V4, Canada
Children's Hospital and Health Center - San Diego, San Diego, California 92123-4282, United States
Children's Hospital and Research Center - Oakland, Oakland, California 94609-1809, United States
University of California Davis Cancer Center, Sacramento, California 95817, United States
Children's Hospital Cancer Center, Denver, Colorado 80218-1088, United States
Children's National Medical Center, Washington, District of Columbia 20010-2970, United States
All Children's Hospital, St. Petersburg, Florida 33701, United States
Kaplan Cancer Center at St. Mary's Medical Center, West Palm Beach, Florida 33407, United States
Miami Children's Hospital, Miami, Florida 33155, United States
Nemours Children's Clinic, Jacksonville, Florida 32207, United States
St. Joseph's Cancer Institute at St. Joseph's Hospital, Tampa, Florida 33607, United States
University of Florida Shands Cancer Center, Gainesville, Florida 32610-0232, United States
University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida 33136, United States
Emory University Hospital - Atlanta, Atlanta, Georgia 30322, United States
Cancer Research Center of Hawaii, Honolulu, Hawaii 95813, United States
Indiana University Cancer Center, Indianapolis, Indiana 46202-5289, United States
St. Vincent Indianapolis Hospital, Indianapolis, Indiana 46260, United States
Kosair Children's Hospital, Louisville, Kentucky 40232, United States
CancerCare of Maine at Eastern Maine Medial Center, Bangor, Maine 04401, United States
Floating Hospital for Children at Tufts - New England Medical Center, Boston, Massachusetts 02111, United States
Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201-1379, United States
Spectrum Health Cancer Care - Butterworth Campus, Grand Rapids, Michigan 49503-2560, United States
Van Elslander Cancer Center at St. John Hospital and Medical Center, Grosse Pointe Woods, Michigan 48236, United States
Children's Hospital of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States
Fairview University Medical Center - University Campus, Minneapolis, Minnesota 55455, United States
University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, United States
Children's Mercy Hospital, Kansas City, Missouri 64108, United States
Siteman Cancer Center at Barnes-Jewish Hospital, St. Louis, Missouri 63110, United States
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, United States
Herbert Irving Comprehensive Cancer Center at Columbia University, New York, New York 10032, United States
James P. Wilmot Cancer Center at University of Rochester Medical Center, Rochester, New York 14642, United States
New York Medical College, Valhalla, New York 10595, United States
NYU Cancer Institute at New York University Medical Center, New York, New York 10016, United States
Roswell Park Cancer Institute, Buffalo, New York 14263-0001, United States
SUNY Upstate Medical University Hospital, Syracuse, New York 13210, United States
Children's Hospital Medical Center of Akron, Akron, Ohio 44308-1062, United States
Children's Medical Center - Dayton, Dayton, Ohio 45404-1815, United States
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, United States
Columbus Children's Hospital, Columbus, Ohio 43205-2696, United States
Rainbow Babies and Children's Hospital, Cleveland, Ohio 44106-5000, United States
Oklahoma University Medical Center, Oklahoma City, Oklahoma 73104, United States
Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
McMaster Children's Hospital at Hamilton Health Sciences, Hamilton, Ontario L8N 3Z5, Canada
Penn State Cancer Institute at Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033-0850, United States
Centre Hospitalier Universitaire de Quebec, Ste-Foy, Quebec G1V 4G2, Canada
Hopital Sainte Justine, Montreal, Quebec H3T 1C5, Canada
Montreal Children's Hospital at McGill University Health Center, Montreal, Quebec H3H 1P3, Canada
Hollings Cancer Center at Medical University of South Carolina, Charleston, South Carolina 29425, United States
Sioux Valley Hospital and University of South Dakota Medical Center, Sioux Falls, South Dakota 57117-5039, United States
Cook Children's Medical Center - Fort Worth, Fort Worth, Texas 76104-9958, United States
Covenant Children's Hospital, Lubbock, Texas 79410, United States
Primary Children's Medical Center, Salt Lake City, Utah 84113-1100, United States
Children's Hospital of the King's Daughters, Norfolk, Virginia 23507-1971, United States
INOVA Fairfax Hospital, Fairfax, Virginia 22031, United States
Massey Cancer Center at Virginia Commonwealth University, Richmond, Virginia 23298-0037, United States
Princess Margaret Hospital for Children, Perth, Western Australia 6001, Australia
Marshfield Clinic - Marshfield Center, Marshfield, Wisconsin 54449, United States
University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792-6164, United States
