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

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Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase III, Phase IITreatmentClosed0 to 18NCICCG-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 

Entry Criteria

Disease Characteristics:

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

  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)

Prior/Concurrent Therapy:

Biologic therapy:
  No prior therapy

  No prior chemotherapy except as noted above

Endocrine therapy:
  No prior therapy

  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

  Prior surgery allowed

Patient Characteristics:

  No more than 18

Performance status:
  Not specified

  Not specified

  Bilirubin no more than 3.0

  Creatinine no more than 1.5 mg/dl OR
  Creatinine clearance at least 60 ml/min/1.73 sqm

  Ejection fraction at least 55%
  Shortening fraction below normal

  Any significant organ dysfunction due to bulky disease should be discussed
  with the study chairman prior to entry

Expected Enrollment

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).


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.


Arm III:  Biological Response Modifier Therapy.  Isotretinoin, 13-CRA, 

Arm IV:  Observation.

Published Results

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]

Haas-kogan DA, Swift PS: Radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1562, 2002.

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.

Related Publications

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

Katherine Matthay, MD, Protocol chair
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.