Phase II/III Randomized Comparison of Consolidation with Intensive Chemotherapy Using CDDP/VP-16/DOX/IFF vs Myeloablative Chemoradiotherapy and Autologous Marrow Rescue and of Continuation Therapy with Isotretinoin vs No Further Therapy in High-Risk Neuroblastoma
Basic Trial Information
|Phase III, Phase II||Treatment||Closed||0 to 18||NCI||CCG-3891|
I. Determine the efficacy and toxicity of an intensive induction chemotherapy regimen consisting of cisplatin/etoposide/doxorubicin/cyclophosphamide in children with high-risk neuroblastoma. II. Compare, in a randomized Phase III setting, the efficacy and toxicity of intensive consolidation chemotherapy using cisplatin/etoposide/doxorubicin/ifosfamide vs. myeloablative chemoradiotherapy using carboplatin/etoposide/melphalan and fractionated TBI with autologous bone marrow rescue. III. Compare, by prospective randomization, the effects of the biological response modifier isotretinoin vs. no further therapy on minimal residual disease (i.e., bone marrow micrometastases) and on relapse-free survival. IV. Determine whether the following parameters are predictive of response to intensive therapy with or without bone marrow therapy: immunocytologic detection of marrow metastases; N-myc amplification and/or expression in tumor and/or marrow; histopathology; serum ferritin and other tumor markers; and retinoic acid receptors in tumor cells. V. Determine whether there is a correlation between relapse sites and sites of disease at diagnosis and at the completion of induction therapy. VI. Determine the relative power of prognostic indicators by multivariate analysis.
Previously untreated high-risk neuroblastoma diagnosed histologically or by elevated urinary catacholamines and tumor cell clumps in the bone marrow High-risk defined as any of the following groups: Stage II, at least 10 copies of N-myc, and age greater than 1 year (register on CCG-3881 while awaiting results) Stage III, age greater than 1 year, and at least one of the following: At least 10 copies of N-myc (register on CCG-3881 while awaiting results) Unfavorable histopathology by Shimada classification Elevated serum ferritin (more than 142 ng/ml by RIA or positive by counterimmunoelectrophoresis) Stage IV/IVS, at least 10 copies of N-myc, and age less than 12 months (register on CCG-3881 while awaiting results) Stage IV and age 1 to 18 years Stage I, II, or IVS and age greater than 1 year at presentation with subsequent development of disseminated disease (including bony metastases) without interval chemotherapy or radiotherapy Staging evaluation completed within 2 weeks prior to entry Bone scan or MIBG scan may be obtained, if logistics require, up to the completion of the first week of Induction chemotherapy No more than 2 weeks between diagnosis and entry, except: Stage II patients found to have more than 10 copies of N-myc eligible for entry for up to 6 weeks Stage IVS patients found to have more than 10 copies of N-myc eligible for entry for up to 6 weeks provided no more than 2 courses of low-dose cyclophosphamide as prescribed on CCG-3881 (study now closed) administered in the interim Stage IV patients less than 12 months of age and Stage III patients may receive up to one 28-day course of therapy as described in CCG-3881 while awaiting results of N-myc analysis; if a second course is required prior to obtaining results, treatment should conform to the second course of induction on the high-risk protocol (CCG-3891)
Biologic therapy: No prior therapy Chemotherapy: No prior chemotherapy except as noted above Endocrine therapy: No prior therapy Radiotherapy: No prior radiotherapy except as emergency dose of no more than 600 cGy given no more than 96 hours prior to the start of chemotherapy Surgery: Prior surgery allowed
Age: No more than 18 Performance status: Not specified Hematopoietic: Not specified Hepatic: Bilirubin no more than 3.0 Renal: Creatinine no more than 1.5 mg/dl OR Creatinine clearance at least 60 ml/min/1.73 sqm Cardiovascular: Ejection fraction at least 55% Shortening fraction below normal Other: Any significant organ dysfunction due to bulky disease should be discussed with the study chairman prior to entry
It is anticipated that 420 patients will be entered over about 4 years and that 183 patients per arm will be randomized for Consolidation.
Study randomized for Consolidation and Continuation. Eligible patients (no medical, psychosocial, insurance contraindication) are randomized for Consolidation on Arms I and II; patients less than 6 months old at entry, those not eligible for randomization, and those refusing randomization to bone marrow therapy are assigned nonrandomly to Arm I and will be analyzed separately. Following Consolidation, eligible patients are randomized for Continuation on Arms III and IV; those with histologic evidence of residual disease are nonrandomly assigned to treatment on Arm III. Regimen A: Surgery. Gross resection of primary tumor. Induction: 4-Drug Combination Chemotherapy plus Surgery followed, if indicated, by Radiotherapy. Cisplatin, CDDP, NSC-119875; Etoposide, VP-16, NSC-141540; Doxorubicin, DOX, NSC-123127; Cyclophosphamide, CTX, NSC-26271; plus debulking of residual primary tumor; followed by local irradiation of gross residual tumor using Co60 machines or accelerator beams of 2 MeV or greater (suitable electron beams may be used for superficial lesions). Consolidation: Arm I: 4-Drug Combination Chemotherapy with Urothelial Protection and Hematologic Toxicity Attenuation. CDDP; VP-16; DOX; Ifosfamide, IFF, NSC-109724; with Mesna, NSC-113891; and Granulocyte Colony Stimulating Factor (Amgen), G-CSF, NSC-614629. Arm II: 3-Drug Combination Myeloablative Chemotherapy plus Radiotherapy followed by Autologous Bone Marrow Therapy (BMT) with Growth Factor Therapy. Carboplatin, CBDCA, NSC-241240; VP-16; Melphalan, L-PAM, NSC-8806; plus Fractionated Total Body Irradiation (TBI) using Co60 machines or accelerator beams of 4 MeV; followed by infusion of purged autologous bone marrow; with Granulocyte-Macrophage Colony Stimulating Factor (Immunex), GM-CSF, NSC-613795. Continuation: Arm III: Biological Response Modifier Therapy. Isotretinoin, 13-CRA, NSC-329481. Arm IV: Observation.
Matthay KK, Reynolds CP, Seeger RC, et al.: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 27 (7): 1007-13, 2009.[PUBMED Abstract]
Park JR, Villablanca JG, London WB, et al.: Outcome of high-risk stage 3 neuroblastoma with myeloablative therapy and 13-cis-retinoic acid: a report from the Children's Oncology Group. Pediatr Blood Cancer 52 (1): 44-50, 2009.[PUBMED Abstract]
London WB, Castleberry RP, Matthay KK, et al.: Evidence for an age cut-off greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group (COG). [Abstract] J Clin Oncol 23 (Suppl 16): A-8500, 800s, 2005.
Adkins ES, Sawin R, Gerbing RB, et al.: Efficacy of complete resection for high-risk neuroblastoma: a Children's Cancer Group study. J Pediatr Surg 39 (6): 931-6, 2004.[PUBMED Abstract]
Haas-Kogan DA, Swift PS, Selch M, et al.: Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study. Int J Radiat Oncol Biol Phys 56 (1): 28-39, 2003.[PUBMED Abstract]
Reynolds CP, Villablanca JG, Gerbing RB, et al.: 13-cis-retinoic acid improves overall survival following myeloablative therapy for high-risk neuroblastoma: a randomized Children's Cancer Group (CCG) study. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1564, 2002.
Gurney JG, Tersak JM, Ness KK, et al.: Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group. Pediatrics 120 (5): e1229-36, 2007.[PUBMED Abstract]
Cantos MF, Gerstle JT, Irwin MS, et al.: Surgical challenges associated with intensive treatment protocols for high-risk neuroblastoma. J Pediatr Surg 41 (5): 960-5, 2006.[PUBMED Abstract]
Kobayashi C, Monforte-Munoz HL, Gerbing RB, et al.: Enlarged and prominent nucleoli may be indicative of MYCN amplification: a study of neuroblastoma (Schwannian stroma-poor), undifferentiated/poorly differentiated subtype with high mitosis-karyorrhexis index. Cancer 103 (1): 174-80, 2005.[PUBMED Abstract]
London WB, Castleberry RP, Matthay KK, et al.: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23 (27): 6459-65, 2005.[PUBMED Abstract]
Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80, 2005.[PUBMED Abstract]
Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 92 (9): 2451-61, 2001.[PUBMED Abstract]
Umehara S, Nakagawa A, Matthay K, et al.: Ganglioneuroblastoma, nodular - prognostic subsets determined by histopathologic evaluation: a report from the Children's Cancer Group. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A-2307, 2000.
Matthay KK, Perez C, Seeger RC, et al.: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. J Clin Oncol 16 (4): 1256-64, 1998.[PUBMED Abstract]
Trial Contact Information
Trial Lead Organizations
Children's Cancer Group
Ph: 415-476-0603; 800-888-8664
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.