Induction Therapy Including 131 I-MIBG and Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma Undergoing Stem Cell Transplant, Radiation Therapy, and Maintenance Therapy With Isotretinoin

• Proportion of patients treated with iodine I 131 meta-iodobenzylguanidine (131 I-MIBG), carboplatin, etoposide phosphate, and melphalan [ Designated as safety issue: No ]
  
• 1-year event-free survival rate [ Designated as safety issue: No ]
  

• Response rate [ Designated as safety issue: No ]
  
• Tumor burden [ Designated as safety issue: No ]
  
• Toxicity [ Designated as safety issue: Yes ]
  
• Relationship of sinusoidal obstruction syndrome to dosages of myeloablative consolidation therapy and autologous stem cell rescue, and whole-body radiation dose or delay of radiation clearance due to 131 I-MIBG [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• To assess the feasibility of treating high-risk neuroblastoma patients, age 365 days to 30 years, with an induction block of meta-iodobenzylguanidine labeled with iodine-131 (^131I-MIBG)/irinotecan/vincristine delivered after multi-agent chemotherapy, and post-Induction busulfan/melphalan consolidation therapy.

Secondary

• To assess the tolerability of these regimens in these patients.
• To assess the response rate of patients treated with these regimens.
• To describe the relationship of tumor norepinephrine transporter (hNET) expression with ^131I-MIBG uptake at diagnosis and immediately after ^131I-MIBG therapy, and tumor response.
• To assess the relative reliability of ^123 I-MIBG and 18FDG-PET imaging in assessment of tumor activity at diagnosis, after 2 courses of induction chemotherapy, before surgical resection and ^131I-MIBG.
• To compare detectable tumor burden before and immediate after therapy on the ^123I-MIBG diagnostic scan.
• To test for the relationship of occurrence of sinusoidal obstruction syndrome (SOS) to dosages of myeloablative consolidation therapy with busulfan/melphalan and whole-body radiation dose or delay of radiation clearance due to^131I-MIBG.
• To analyze busulfan first-dose pharmacokinetics as measured by area under the curve (AUC) and to relate exposure to SOS incidence.
• To describe the toxicity of ^131I-MIBG combined with vincristine and irinotecan given on a 5-day schedule.

OUTLINE: This is a pilot, multicenter study.

• Induction chemotherapy: Patients receive 5 courses of induction therapy.

  • Courses 1-2: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5.

Patients undergo peripheral blood stem cell (PBSC) collection after course 2.

• Course 3 and 5: Patients receive cisplatin IV over 1 hour on days 1-4 and etoposide phosphate IV over 1-2 hours on days 1-3.

Patients undergo surgery to remove remaining tumor following course 5.

• Course 4: Patients receive cyclophosphamide IV over 1-6 hours on days 1-2 and vincristine sulfate IV and doxorubicin hydrochloride IV over 24 hours on days 1-3.

Treatment repeats every 21 days for a total of 5 courses in the absence of disease progression or unacceptable toxicity. Patients without progressive disease proceed to iobenguane I 131 (^131I-MIBG) induction therapy beginning 3-6 weeks after course 5.

• Patients receive vincristine IV on day 0, irinotecan IV over 90 minutes on day 0-4, and iobenguane I 131 IV over 90-120 minutes on day 1.

  • Surgery: Patients ùundergo surgery after course 4 or before consolidation therapy.
  • Consolidation therapy: Within 4-6 weeks after completion of induction therapy, patients receive busulfan IV over 2 hours every 6 hours on days -6 to -3 and melphalan IV on day -1.

Patients also complete a questionnaire regarding costs for travel and accommodations during therapy.

Blood samples maybe collected after the first dose of busulfan for pharmacokinetic assays.

• Autologous stem cell rescue: Patients undergo infusion of PBSC on day 0.
• Radiotherapy: Beginning 28-42 days after peripheral blood stem cell infusion, patients undergo 12 fractions of external-beam radiotherapy (2D, 3D-conformal, or intensity-modulated) to all areas of residual disease, primary tumor site, and involved nodal disease.
• Maintenance therapy: Beginning 66 days after transplantation, patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses.

After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually for 5 years.