• Time to engrafment [ Designated as safety issue: No ]
• CD34 content [ Designated as safety issue: No ]
• Tumor content as measured by reverse transcriptase polymerase chain reaction [ Designated as safety issue: No ]

• Time to engrafment
• CD34 content
• Tumor content as measured by reverse transcriptase polymerase chain reaction

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.

PURPOSE: This randomized phase III trial is studying peripheral stem cell transplantation with treated peripheral stem cells following combination chemotherapy to see how well it works compared to peripheral stem cell transplantation with untreated peripheral stem cells following combination chemotherapy in treating patients with neuroblastoma.

OBJECTIVES:

Primary

• Compare the event-free survival in patients with newly diagnosed high risk neuroblastoma or ganglioneuroblastoma treated with myeloablative consolidation chemotherapy and autologous purged versus unpurged peripheral blood stem cells (PBSC).
• Compare the time to engraftment and CD34 content and tumor content by reverse transcriptase polymerase chain reaction (RT-PCR) of purged versus unpurged PBSC in patients treated with these regimens.
• Determine event-free survival of patients treated with dose intensive induction chemotherapy comprising cyclophosphamide, doxorubicin, and vincristine alternating with cisplatin and etoposide.
• Determine the toxicity of this dose-intensive induction chemotherapy regimen in these patients.
• Evaluate tumor resectability at second look or delayed surgery, response (complete response and very good partial response) at completion of induction therapy, tumor content of peripheral blood and bone marrow, and the comparison of historical data from CCG-3891 induction therapy in these patients.

Secondary

• Compare the toxicity of this myeloablative consolidation regimen using purged vs unpurged PBSC in these patients.
• Determine if event-free survival is predictable by RT-PCR positivity of the stem cell, minimal residual disease in bone marrow and peripheral blood after transplantation by immunocytology, and extent of disease as measured by MIBG after transplantation in patients treated with these regimens.
• Evaluate the prognostic impact of tumor biology on event free survival in patients treated with these regimens.
• Determine the incidence of relapse in the primary site after radiotherapy and in irradiated versus unirradiated metastatic sites in these patients.
• Assess the toxicity and tolerability of maintenance therapy with topotecan and cyclophosphamide after intensive induction therapy in patients who decline or are unable to receive myeloablative therapy.
• Determine the health-related quality of life of patients treated with these regimens.
• Compare late effects of these regimens on the growth, endocrine, pulmonary, and cardiac function of these patients vs general population standards.
• Determine the incidence of second malignant neoplasms in patients treated with these regimens.
• Determine the variability of isotretinoin pharmacokinetics and relationship to pharmacogenomic parameters in these patients.
• Correlate the isotretinoin pharmacokinetics and pharmacogenomic parameters and/or genetic variations in isotretinoin metabolic enzymes with event-free survival or systemic toxicity in these patients.

OUTLINE: This is a randomized study. Patients are randomized to one of two treatment arms for peripheral blood stem cell (PBSC) collection.

All patients receive induction chemotherapy comprising cyclophosphamide IV over 6 hours on days 0 and 1, doxorubicin IV and vincristine IV continuously over 72 hours on days 0-2, and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 3 and continuing until blood counts recover for courses 1, 2, 4, and 6. Treatment alternates with courses 3 and 5 comprising etoposide IV over 2 hours on days 0-2, cisplatin IV over 1 hour on days 0-3, and G-CSF SC or IV beginning on day 4 and continuing until blood counts recover. Induction chemotherapy repeats every 3 weeks or when blood counts recover in the absence of disease progression or unacceptable toxicity.

After course 2 or 3 of induction chemotherapy, patients undergo PBSC collection, either purged or unpurged, depending on randomization. Patients continue on daily G-CSF until cell collection is complete.

• Arm I: Patients undergo unpurged PBSC collection until the target cell count is reached.
• Arm II: Patients undergo purged PBSC collection until the target cell count is reached.

Patients with immunocytology positive PBSC undergo purged autologous bone marrow collection or repeat purged or unpurged PBSC collection depending on individual patient characteristics.

All patients undergo delayed surgical resection of the residual tumor after course 5 of induction chemotherapy.

After induction therapy, patients achieving complete response, very good partial response, or partial response receive consolidation therapy comprising melphalan IV on days -7 to -5 followed by carboplatin IV and etoposide IV continuously over days -7 to -4. Patients receive purged or unpurged PBSC infusion or purged autologous bone marrow transplantation on day 0 followed by G-CSF SC or IV beginning 4 hours after completion of transplantation and continuing until blood counts recover. Beginning on day 66, patients receive oral isotretinoin twice daily for 14 days. Isotretinoin therapy repeats every 4 weeks for 6 courses.

After completion of consolidation (at least 28 days from stem cell infusion), all patients receive local radiotherapy daily over 7 days.

Patients not undergoing transplantation or who are ineligible for consolidation therapy receive maintenance therapy comprising cyclophosphamide IV over 30 minutes followed by topotecan IV over 30 minutes on days 0-4. Patients receive G-CSF SC or IV beginning on day 5 and continuing until blood counts recover. Maintenance therapy repeats every 3 weeks for 3 courses. After completion of maintenance therapy, patients receive radiotherapy as outlined above. Patients then receive oral isotretinoin twice daily for 14 days. Isotretinoin therapy repeats every 4 weeks for 6 courses.

Quality of life is assessed at 1* and 5 years.

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

NOTE: * Patients under 5 years of age at 1 year are not assessed until 5 years.

PROJECTED ACCRUAL: A total of 486 patients will be accrued for this study within 4 years.

• Biological: filgrastim
• Drug: carboplatin
• Drug: cisplatin
• Drug: cyclophosphamide
• Drug: doxorubicin hydrochloride
• Drug: etoposide
• Drug: isotretinoin
• Drug: melphalan
• Drug: topotecan hydrochloride
• Drug: vincristine sulfate
• Procedure: autologous bone marrow transplantation
• Procedure: bone marrow ablation with stem cell support
• Procedure: conventional surgery
• Procedure: peripheral blood stem cell transplantation
• Radiation: radiation therapy

• Cantos MF, Gerstle JT, Irwin MS, Pappo A, Farley S, Cheang T, Kim PC. Surgical challenges associated with intensive treatment protocols for high-risk neuroblastoma. J Pediatr Surg. 2006 May;41(5):960-5.
• Kushner BH, Budnick A, Kramer K, Modak S, Cheung NK. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer. 2006 Jul 15;107(2):417-22.

DISEASE CHARACTERISTICS:

• Histologically confirmed newly diagnosed neuroblastoma OR ganglioneuroblastoma, and/or evidence of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites, meeting 1 of the following criteria:

  • Age greater than 18 months with stage IV disease, regardless of biologic factors

  • Age 12-18 months with stage IV disease meeting one of the following criteria:

    • Any unfavorable biologic feature (e.g., MYCN amplification, unfavorable pathology, and/or DNA index = 1)
    • Any biologic feature that is indeterminate, unsatisfactory, or unknown

• At least 1 year old with the following:

  • Stage IIa/IIb with MYCN amplification (> 10) AND unfavorable pathology
  • Stage III with MYCN amplification (> 10) OR unfavorable pathology

  • Stage I, II, or IVS with disease progression to stage IV without interval chemotherapy

    • No more than 3 weeks since progression
    • Must have been enrolled on protocol CCG-B973, COG-ANBL00B1, or POG-9047

• Less than 1 year old with the following:

  • Stage III, IV, or IVS disease with MYCN amplification (> 10)
• Registration on protocol COG-ANBL00B1 required within 14 days of diagnosis

PATIENT CHARACTERISTICS:

Age:

• See Disease Characteristics
• 30 and under at time of diagnosis

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3
• Inadequate hematopoiesis secondary to bone marrow involvement with > 10% tumor infiltration allowed

Hepatic:

• Bilirubin ≤ 1.5 mg/dL
• ALT ≤ 300 units/L

Renal:

• Creatinine ≤ 1.5 mg/dL
• Creatinine clearance or glomerular filtration rate ≥ 60 mL/min

Cardiovascular:

• ECG normal
• Ejection fraction ≥ 55% by echocardiogram or MUGA OR
• Fractional shortening ≥ 28% by echocardiogram

Other:

• Able to tolerate peripheral blood stem cell collection
• HIV negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for at least 1 month prior to, during, and for 1 month after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• See Disease Characteristics
• No more than 1 prior course of chemotherapy on the Intergroup low/intermediate risk neuroblastoma study (P9641, A3961)

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