Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Drugs used in chemotherapy, such as vincristine, dactinomycin, cyclophosphamide, and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy together with radiation therapy may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective when given together with radiation therapy in treating patients with rhabdomyosarcoma.

PURPOSE: This randomized phase III trial is studying two different combination chemotherapy regimens to compare how well they work when given together with radiation therapy in treating patients with newly diagnosed rhabdomyosarcoma.

Further Study Information

OBJECTIVES:

Primary

• Compare the early response rates in patients with intermediate-risk rhabdomyosarcoma (RMS) treated with vincristine, dactinomycin, and cyclophosphamide (VAC) vs VAC alternating with vincristine and irinotecan hydrochloride (VI) in combination with radiotherapy.

• Compare failure-free survival (FFS) and overall survival of patients treated with these regimens.

Secondary

• Compare FFS, local control, and survival of patients with intermediate-risk RMS treated with VAC and early (week 4) radiotherapy vs delayed (week 10) radiotherapy, using data from IRS-IV for historic comparison.

• Compare the acute and late effects of VAC vs VAC alternating with VI, including the toxicity associated with concurrent VI and radiotherapy.

• Compare the acute and late effects of VAC as delivered on this study to that administered on COG-D9803.

• Correlate change in fludeoxyglucose F^18 positron emission tomography (FDG-PET) maximum standard uptake value from week 1 to week 4 and 15 with FFS.

• Correlate UGT1A1 genotype with VI toxicity in patients receiving VAC alternating with VI.

• Correlate CYP2B6, CYP2C9, and GSTA1 genotypes with VAC toxicity.

• Prospectively evaluate and validate gene expression values with the intent to define the best diagnostic predictors and more powerful prognostic classifiers.

OUTLINE: This is a prospective, historic control, randomized, multicenter study. Patients are stratified according to histology, disease stage, and clinical group (group III, stage 2 or 3 embryonal rhabdomyosarcoma [RMS] vs group I, stage 1 alveolar RMS vs group II or III, stage 2 or 3 alveolar RMS). Patients are randomized to 1 of 2 treatment arms. within 42 days of initial surgery or biopsy.

• Arm I (VAC): Patients receive VAC chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-13, 16, 19-25, 28, 31-37, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 4, 13, 16, 19, 22, 25, 28, 31, 34, 37,and 40; and cyclophosphamide IV over 1 hour on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40.

• Arm II (VAC/VI): Patients receive VAC chemotherapy alternating with VI chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-13, 16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 13, 22, 28, 34, and 40; cyclophosphamide IV over 1 hour on day 1 of weeks 1,10, 13, 22, 28, 34, and 40; and irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 4, 7, 16, 19, 25, 31, and 37.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients* in both arms also undergo radiotherapy 5 days a week for 4-6 weeks beginning in week 4 (except patients with alveolar RMS rendered group I by amputation OR patients needing week 1 emergency radiotherapy for symptomatic spinal cord compression).

NOTE: *Individualized local control plan that deviates from protocol-mandated radiotherapy allowed for patients ≤ 24 months of age

After completion of study treatment, patients are followed periodically for ≥ 10 years.

PROJECTED ACCRUAL: A total of 486 patients will be accrued for this study.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed rhabdomyosarcoma (RMS)

• Must be concurrently enrolled on COG-D9902 to confirm local histologic diagnosis

• Intermediate-risk disease, defined by 1 of the following surgicopathologic and staging criteria:

• Group III, stage 2 or 3 embryonal, botryoid, or spindle cell RMS

• Group III, stage 2 or 3 ectomesenchymoma

• Group I-III, stage 1-3 alveolar RMS

• Newly diagnosed disease

• Staging ipsilateral retroperitoneal lymph node dissection (SIRLND) required for patients ≥ 10 years of age with paratesticular tumors and for patients < 10 years with clinically or radiographically involved lymph nodes

• Patients with extensive lymph node involvement, defined as ≥ 2 lymph nodes > 2 cm in dimension, identified by imaging studies, are not required to undergo SIRLND

• Regional lymph node sampling or sentinel lymph node procedure is required for histologic evaluation in patients with extremity tumors

• Has undergone initial surgery or biopsy within the past 42 days

• Must be able to undergo radiotherapy

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 (Karnofsky PS 50-100% [≥ 16 years of age] or Lansky PS 50-100% [< 16 years of age])

• Absolute neutrophil count ≥ 750/mm^3

• Platelet count ≥ 75,000/mm^3 (transfusion independent)

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (40 mL/min for infants < 1 year of age)

• Patients with urinary tract obstruction by tumor must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for ≥ 1 month after completion of study treatment

• No evidence of uncontrolled infection

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy* (excluding steroids)

• No prior radiotherapy*

• No concurrent aprepitant during treatment with cyclophosphamide NOTE: *Patients who received prior radiotherapy or chemotherapy while enrolled on COG-ARST0331 allowed

Trial Contact Information

Trial Lead Organizations/Sponsors

Children's Oncology Group

Douglas Hawkins

Study Chair

Geoffrey McCowage

Leo Mascarenhas

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00354835
Information obtained from ClinicalTrials.gov on November 26, 2012

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