Trial Information

PHASE III MULTICENTRE TRIAL OF TREATMENT OF NEUROBLASTOMA IN CHILDREN AND ADOLESCENTS

OBJECTIVES: I. Increase the survival rates and duration of survival in children and
adolescents with neuroblastoma by using stage- and risk group-appropriate therapy. II.
Determine whether using cisplatin/etoposide/vindesine and
vincristine/dacarbazine/ifosfamide/doxorubicin instead of cisplatin/teniposide and
vincristine/dacarbazine/cyclophosphamide/doxorubicin improves remission rate and lessens
toxicity in patients with stage 3C, 3D, or 4 neuroblastoma. III. Determine whether local
radiotherapy to the primary tumor and bone metastasis improves local tumor control in these
patients. IV. Compare the efficacy and survival associated with short-term, high-dose
conditioning chemotherapy plus autologous bone marrow transplantation vs. long-term,
low-dose cytostatic chemotherapy as consolidation therapy in these patients. V. Determine
whether early use of low-dose doxorubicin/vincristine plus hepatic irradiation slows disease
progression in patients with stage 4S-C neuroblastoma. VI. Determine whether 4 courses of
chemotherapy reduces the occurrence of local and systemic relapse in patients with stages 2,
3A, and 3B neuroblastoma. VII. Determine whether serum tumor markers (LDH, catecholamine
metabolites, and neuron-specific enolase) are predictive of remission behavior.

OUTLINE: Patients are staged according to the International Neuroblastoma Staging System and
are further defined by progressively less favorable risk groups based on age at diagnosis,
serum LDH, and tumor resectability (risk groups A, B, C, and D, representing presence of 0,
1, 2, or 3 risk factors, respectively). Patients who are unable to be resected at entry or
with incomplete resection are re-evaluated at 4-month intervals for the appropriateness of
tumor resection. STAGE 1 PATIENTS Patients undergo complete primary tumor resection and no
other therapy. STAGES 2, 3A, AND 3B PATIENTS Patients undergo primary tumor resection,
followed by cisplatin, etoposide, vindesine (PEV) alternating monthly with vincristine,
dacarbazine, ifosfamide, doxorubicin (VDIA). Patients in complete remission (CR) discontinue
therapy, while those with less than CR receive additional therapy as outlined below for
stages 3C, 3D, and 4 patients, except that these patients are not eligible for bone marrow
transplantation. STAGES 3C, 3D, AND 4 PATIENTS Patients receive PEV and VDIA as above, with
radiotherapy to sites of metastases during the third and fourth courses, following which
autologous bone marrow is collected. Following marrow harvest, patients receive up to 4 more
alternating courses of PEV/VDIA; those with no response or progressive disease after the
sixth chemotherapy course are referred for other therapy. Patients who complete PEV/VDIA
receive 3 weeks of radiotherapy to the primary tumor bed or residual tumor. Stage 4 patients
in complete or very good partial remission and with sufficient harvested marrow undergo ABMT
following radiotherapy. Myeloablation consists of high-dose MIBG radioisotope therapy
followed by high-dose melphalan, etoposide, and carboplatin. All other patients and those
who refuse ABMT receive 1 year of alternating, low-dose chemotherapy courses, beginning
concurrently with initiation of radiotherapy. One regimen consists of oral
melphalan/etoposide for 5 days and the other regimen consists of intravenous vincristine on
1 day and oral cyclophosphamide for 7 days. Therapy continues for 1 year. STAGE 4S PATIENTS
Patients in risk groups 4S-A and 4S-B receive no therapy. Patients in group 4S-C receive 4-8
weekly injections of doxorubicin and vincristine (AV). Patients with tumor progression may
receive low-dose radiotherapy. Primary tumor resection may be delayed up to 8 months after
diagnosis in these patients. Use of G-CSF is allowed but not recommended.

PROJECTED ACCRUAL: Approximately 500 patients will be accrued on this multicenter study.