Surgery in Treating Children With Neuroblastoma

Study Overview
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Brief Summary
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RATIONALE: Surgery alone may be effective in treating children with neuroblastoma. PURPOSE: Phase III trial to study the effectiveness of surgery alone in treating children who have neuroblastoma.

Detailed Description
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OBJECTIVES: To determine if asymptomatic patients with low-risk neuroblastoma treated with surgery alone will have a 3-year survival rate of 95%. Estimate the response and 3-year event-free survival rates of symptomatic patients treated with chemotherapy. Estimate the event-free survival and overall survival rates in patients who relapse or progress after initial treatment with surgery alone. Determine the acute and chronic toxic effects associated with treating low-risk neuroblastoma with surgery alone or surgery and chemotherapy. OUTLINE: This is a multicenter study. Patients are stratified according to disease stage, MYCN status, age, and histology. Patients undergo primary tumor resection and biopsy of regional nodes. Patients with at least 50% of the tumor resected are followed monthly for 3 months, every 3 months for 9 months, every 6 months for one year, and then annually thereafter. Regimen I Patients with clinically symptomatic (e.g., respiratory distress, spinal cord compromise with or without neurologic deficit, inferior vena cava compression with renal or bowel ischemia, intractable vomiting due to gastrointestinal obstruction, genitourinary obstruction, or coagulopathy) low-risk neuroblastoma or who have less than 50% of the primary tumor resected receive 4 different courses of chemotherapy. Course 1: Patients receive carboplatin IV over 1 hour followed by etoposide IV over 2 hours on day 0 and etoposide only on days 1 and 2. Course 2: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1 hour, and doxorubicin IV over 15-60 minutes on day 1. Course 3: Patients receive cyclophosphamide IV over 1 hour followed by etoposide IV over 2 hours on day 0 and etoposide only on days 1 and 2. Course 4: Patients receive carboplatin IV over 1 hour and etoposide IV over 2 hours followed by doxorubicin IV over 15-60 minutes on day 0 and etoposide only on days 1 and 2. Regimen II Patients who progress to or recur with unfavorable biology intermediate-risk disease receive an additional 4 courses of chemotherapy. Course 5: Patients receive treatment as in course 3 above. Course 6: Patients receive treatment as in course 2 above. Course 7: Patients receive treatment as in course 1 above. Course 8: Patients receive cyclophosphamide IV over 1 hour followed by doxorubicin IV over 15-60 minutes on day 1. All infants under 60 days of age receive filgrastim (G-CSF) or sargramostim (GM-CSF) subcutaneously beginning 24 to 36 hours after chemotherapy and continuing until blood counts recover. Courses in both regimens repeat every 3 weeks in the absence of unacceptable toxicity. Patients at risk for symptomatic spinal cord compression may also receive chemotherapy. Patients experiencing progressive or recurrent disease after observation undergo repeat surgery and/or chemotherapy as above. Patients with clinically symptomatic disease may also undergo radiotherapy if response to chemotherapy is not rapid. Patients are followed every 2 months for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: A total of 820 patients will be accrued for this study within 4 years.

Official Title
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Primary Surgical Therapy for Biologically Defined Low-Risk Neuroblastoma: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study

Conditions
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Neuroblastoma

Intervention / Treatment
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* Biological: filgrastim
* Biological: sargramostim
* Drug: carboplatin
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: etoposide
* Procedure: adjuvant therapy
* Procedure: conventional surgery
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven low-risk neuroblastoma (excluding ganglioneuroma) International Neuroblastoma Staging System (INSS) stage 1 in all patients INSS stage 2A or 2B in patients less than 365 days of age INSS stage 2A or 2B tumor with nonamplified MYCN with any Shimada histology in patients ages 1 to 20 years INSS stage 2A or 2B tumor with amplified MYCN with Shimada favorable histology in patients ages 1 to 20 years INSS stage 4S tumors with nonamplified MYCN, Shimada favorable histology, and a DNA index not equal to 1 in patients less than 365 days of age Immediate chemotherapy allowed prior to biopsy for patients with intradural extension and/or emergent paresis if biopsy performed within 96 hours Must have no abnormal organ function unless due to neuroblastoma Concurrent registration on companion biology study (protocol COG-ANBL00B1) or its successor PATIENT CHARACTERISTICS: Age: Under 21 Performance status: Not specified Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Bilirubin less than 1.5 times normal SGOT or SGPT less than 2.5 times normal Renal: Creatinine less than 1.5 times normal Cardiovascular: Shortening fraction greater than 27% by echocardiogram OR Ejection fraction greater than 47% by radionuclide angiogram PRIOR CONCURRENT THERAPY: Biologic therapy: No prior immunotherapy Chemotherapy: See Disease Characteristics Endocrine therapy: No prior hormonal therapy Radiotherapy: No prior radiotherapy Surgery: Prior surgery allowed Other: No other prior therapy

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment 1 - Asymptomatic - no immediate chemotherapy<br> | Procedure: conventional surgery<br> <br> Radiation: radiation therapy<br> <br> |
| Experimental: Symptomatic - immediate chemotherapy<br> | Biological: filgrastim<br> <br> Biological: sargramostim<br> <br> Drug: carboplatin<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: etoposide<br> <br> Procedure: adjuvant therapy<br> <br> Procedure: conventional surgery<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the 3 year survival rate for low risk asymptomatic stage 2A/2B patients who are treated with surgery alone | The primary objective is to estimate the 3 year survival rate for low risk asymptomatic stage 2A/2B patients who are treated with surgery alone. Under the assumption that about 90% of the low risk 2A/2B patients will be asymptomatic, and 10% of these will be lost to follow up, the projected sample size will enable estimation of the survival rate with a standard error less than .03. This sample size will also provide sufficient power for the sequential monitoring plan (see below) for this subgroup of patients. |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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localized resectable neuroblastoma, stage 4S neuroblastoma