Induction Chemotherapy Using Cyclophosphamide and Topotecan in Treating Patients Who Are Undergoing Autologous Peripheral Stem Cell Transplantation for Newly Diagnosed or Progressive Neuroblastoma

OBJECTIVES:

Primary

• Determine the toxicity and feasibility of adding cyclophosphamide and topotecan to induction therapy in patients with newly diagnosed or progressive high-risk neuroblastoma undergoing autologous peripheral blood stem cell (PBSC) transplantation.
• Determine the feasibility of PBSC mobilization and in vivo PBSC tumor purging in these patients after treatment with this regimen.

Secondary

• Determine tumor response rate in patients treated with this regimen.
• Determine the pharmacokinetics of this regimen in these patients.
• Determine whether topotecan affects cyclophosphamide pharmacokinetics in these patients.
• Correlate host DNA with toxicity and cyclophosphamide and topotecan pharmacokinetics in patients treated with this regimen.
• Determine toxicity in patients treated with this regimen.

OUTLINE: This is a pilot, multicenter study. Patients are stratified according to diagnosis (newly diagnosed vs initially stage 1, 2, or 4S that progressed to stage 4 without interval chemotherapy).

• Induction therapy: Patients receive 6 courses of induction therapy.

• Courses 1 and 2: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 6 and continuing until blood counts recover.
• Course 3: Patients receive etoposide IV over 2 hours on days 1-3, cisplatin IV over 1 hour on days 1-4, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover.
• Course 4: Patients receive cyclophosphamide IV over 6 hours on day 1 and doxorubicin IV and vincristine IV continuously over 24 hours on days 1-3. Patients also receive G-CSF SC or IV beginning on day 4 and continuing until blood counts recover.
• Course 5: Patients receive etoposide, cisplatin, and G-CSF as in course 3.
• Course 6: Patients receive cyclophosphamide, doxorubicin, vincristine, and G-CSF as in course 4.

Treatment repeats every 21 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity.

• Consolidation therapy: Within 4-6 weeks after completing induction therapy, patients receive melphalan IV on days -7 to -5 and etoposide IV and carboplatin IV continuously over 24 hours on days -7 to -4.
• Stem cell transplantation: Peripheral blood stem cells are collected after course 2 of induction therapy and infused on day 0. Patients receive G-CSF IV beginning on day 0 and continuing until blood counts recover.
• Surgery: After course 5 of induction therapy, patients undergo surgery.
• Radiotherapy: Beginning 28-42 days after transplantation, patients receive 12 fractions of local radiotherapy to all areas of residual soft tissue disease and the primary tumor site, even if completely resected.
• Maintenance therapy: Beginning 66 days after transplantation, patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for a total of 6 courses.

Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 10-29 patients will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed neuroblastoma or ganglioneuroblastoma meeting 1 of the following staging criteria:

• Newly diagnosed disease, at least 1 year of age, and meets criteria for 1 of the following:

• International Neuroblastoma Staging System (INSS) stage 2a/2b with MYCN amplification (greater than 10) AND unfavorable pathology
• INSS stage 3 with MYCN amplification OR unfavorable pathology
• Newly diagnosed INSS stage 4 disease meeting criteria for 1 of the following:

• Over 18 months of age
• Age 12 to 18 months with any unfavorable biologic feature (MYCN amplification, unfavorable pathology, and/or DNA index=1) or any biologic feature that is indeterminant, unsatisfactory, or unknown

• No INSS stage 4 disease and age 12 to 18 months with all 3 favorable biologic features (i.e., nonamplified MYCN, favorable pathology, and DNA index greater than 1)
• Newly diagnosed INSS stage 3, 4, or 4S disease AND under 1 year of age with MYCN amplification
• At least 1 year of age and initially diagnosed with INSS stage 1, 2, or 4S disease that progressed to stage 4 without interval chemotherapy

• Must have been enrolled on COG-ANBL00B1 at initial diagnosis

PATIENT CHARACTERISTICS:

Age

• 30 and under at initial diagnosis

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,000/mm^3*
• Platelet count at least 100,000/mm^3* (transfusion independent)
• Hemoglobin at least 10.0 g/dL* (red blood cell transfusions allowed) NOTE: *Granulocytopenia, anemia, and/or thrombocytopenia allowed for patients with tumor metastatic to the bone marrow

Hepatic

• Bilirubin no greater than 1.5 mg/dL
• ALT less than 300 IU/L

Renal

• Creatinine no greater than 1.5 mg/dL
• Creatinine clearance or radioisotope glomerular filtration rate at least 60 mL/min

Cardiovascular

• ECG normal
• Shortening fraction at least 27% by echocardiogram OR
• Ejection fraction at least 50% by MUGA

Other

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

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics
• No more than 1 prior chemotherapy course on the low- or intermediate-risk neuroblastoma studies (COG-P9641, COG-A3961) prior to determination of MYCN amplification and Shimada histology

Endocrine therapy

• Not specified

Radiotherapy

• Prior localized emergency radiotherapy to sites of life-threatening or function-threatening disease allowed

Surgery

• Not specified

Other

• No other prior systemic therapy