Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	under 18	NCI	CCG-3881

Objectives

I.  Evaluate in patients with favorable stages (Stages I, II, and IV-S) of 
neuroblastoma the prognostic significance of a number of biological and 
clinical factors, including serum ferritin, serum neuron-specific enolase, the 
number of copies of the N-myc oncogene and N-myc protein expression in the 
primary tumor and in bone marrow metastases, tumor histopathology, the 
presence of subclinical involvement of the bone marrow as detected with 
immunohistologic techniques, and regional lymph node involvement.

II.  Determine whether "good-prognosis" neuroblastoma patients (i.e., patients 
with Stage I disease and those with Stage II disease with fewer than 3 copies 
of N-myc) have a 3-year progression-free survival (PFS) in excess of 90% 
following surgery alone.

III.  Determine whether "intermediate-prognosis" neuroblastoma patients (i.e., 
patients of any age with Stage III disease, favorable histopathology, fewer 
than 3 copies of N-myc, and normal serum ferritin and patients under the age 
of 1 year with Stage IV disease and neuron-specific enolase less than 100 
ng/ml) have a 3-year PFS in excess of 70% with combination chemotherapy 
together with surgery and radiotherapy for residual disease.

IV.  Determine the PFS of selected "poor-prognosis" neuroblastoma patients 
(i.e., Stage II patients under the age of 1 year with at least 3 copies of 
N-myc, Stage III patients under the age of 1 year with unfavorable 
histopathology, at least 3 copies of N-myc, or elevated serum ferritin, and 
Stage IV patients under the age of 1 year with neuron-specific enolase of at 
least 100 ng/ml) following treatment with combination chemotherapy together 
with surgery and radiotherapy for residual disease.

V.  Determine whether patients with Stage IV-S neuroblastoma have a 3-year PFS 
in excess of 90% with standardized supportive care alone and whether those 
requiring additional therapy can be identified at diagnosis.

Entry Criteria

Disease Characteristics:

Newly diagnosed neuroblastoma in one of the following groups:

  Stage I and less than 18 years of age

  Stage II and less than 18 years of age

     Children age 1 to 18 years found to have 10 or more copies of N-myc are
     transferred to CCG-3891; transfer must occur within 6 weeks of diagnosis

  Stage III and less than 18 years of age

     Children age 1 to 18 years found to have unfavorable histology, 10 or
     more copies of N-myc, or elevated ferritin are transferred to CCG-3891

     Children under age 1 with unfavorable characteristics remain on this
     study

  Stage IV/IV-S and under 1 year

     Infants subsequently found to have 10 or more copies of N-myc are
     transferred to CCG-3891

Entry within 4 weeks of diagnosis or, as applicable, 96 hours of starting
induction chemotherapy required

Final determination of N-myc must be obtained from the Neuroblastoma Reference
Laboratory

Prior/Concurrent Therapy:

Biologic therapy:
  No prior therapy

Chemotherapy:
  No prior therapy (except as noted above for patients transferring from
  CCG-3891)

Endocrine therapy:
  No prior therapy

Radiotherapy:
  No prior therapy

Surgery:
  No prior therapy

Patient Characteristics:

Age:
  Under 18 (see Disease Characteristics)

Performance status:
  Not specified

Hematopoietic:
  Not specified

Hepatic:
  Not specified

Renal:
  Not specified

Expected Enrollment

171 patients will be entered over approximately 3 years.

Outline

All Stage I patients and Stage II patients with fewer than 10 copies of N-myc 
are treated on Regimen A.  Stage II patients under the age of 1 year with 10 
or more copies of N-myc and all Stage III and Stage IV patients are treated on 
Regimen B, and patients with Stage IV-S disease are managed on Regimen C.

Regimen A:  Surgery plus (if indicated) Radiotherapy.  Primary tumor 
resection; plus (in selected cases of cord compression) irradiation of the 
site of cord compression using megavoltage equipment.

Regimen B:

Dose-Intense Induction followed by Standard Induction.  4-Drug Combination 
Chemotherapy.  Cyclophosphamide, CTX, NSC-26271; Cisplatin, CDDP, NSC-119875; 
Doxorubicin, DOX, NSC-123127; Etoposide, VP-16, NSC-141540; followed by the 
same drugs at standard doses.

Consolidation:  Surgery followed by 2-Drug Combination Chemotherapy plus 
Radiotherapy.  Total resection of residual disease or debulking as 
appropriate; followed by a single course of CTX/VP-16; plus irradiation of 
residual disease using Co60 or 4-10 MV photons (electron beams may be used for 
appropriately superficial lesions).

Maintenance:  4-Drug Combination Chemotherapy followed by Surgery.  CTX; DOX; 
CDDP; VP-16; followed by resection of residual disease if appropriate.

Regimen C:  Standardized supportive care with surgical intervention, 
radiotherapy, and/or treatment with CTX as dictated by individual clinical 
circumstances.

Matthay K, Lukens J, Stram D, et al.: Prognosis for stage IV neuroblastoma less than one year at diagnosis: a prospective Childrens Cancer Group study. [Abstract] Proceedings of the American Society of Clinical Oncology 14: A-1425, 446, 1995.

Matthay KK, Stram D, Seeger RC, et al.: A prospective Childrens Cancer Group study of stage II neuroblastoma treated with surgery alone. [Abstract] Proceedings of the American Society of Clinical Oncology 12: A-1420, 414, 1993.

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]

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 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.

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]

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]

Haase GM, Atkinson JB, Stram DO, et al.: Surgical management and outcome of locoregional neuroblastoma: comparison of the Childrens Cancer Group and the international staging systems. J Pediatr Surg 30 (2): 289-94; discussion 295, 1995.[PUBMED Abstract]

Matthay KK, Sather HN, Seeger RC, et al.: Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol 7 (2): 236-44, 1989.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Children's Cancer Group

John Lukens, MD, Protocol chair(Contact information may not be current)		Ph: 615-936-1782; 800-811-8480