Vincristine, Dactinomycin, and Cyclophosphamide With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Low-Risk Rhabdomyosarcoma

Study Overview
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Brief Summary
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This phase III trial is studying how well combination chemotherapy and radiation therapy work in treating patients with newly diagnosed low-risk rhabdomyosarcoma. Drugs used in chemotherapy, such as vincristine, dactinomycin, and cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy with radiation therapy may kill more tumor cells. It is not yet known which treatment regimen is more effective in treating low-risk rhabdomyosarcoma.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the failure-free survival of patients with newly diagnosed low-risk rhabdomyosarcoma treated with vincristine (V), dactinomycin (A), cyclophosphamide (C), and radiotherapy. SECONDARY OBJECTIVES: I. Determine local control rates in patients treated with this regimen. II. Determine the rate of second-look surgery in patients with bulk residual tumor at diagnosis (clinical group III) and the proportion of second-look surgeries that render patients treated with this regimen tumor-free or with microscopic tumor only and evaluate the pathologic significance of that residual tumor. III. Determine the local control rates in patients with clinical group III disease treated with response-adjusted radiotherapy doses after second-look surgical resection. OUTLINE: This is a nonrandomized, multicenter study. Patients are assigned to 1 of 2 treatment regimens according to disease stage and clinical group. REGIMEN I (subset 1 patients) [closed to accrual as of 08/13/2010: Patients receive VAC chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-9 and dactinomycin IV over 1 minute and cyclophosphamide IV over 1 hour on day 1 of weeks 1, 4, 7, and 10; VA chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 13-21 and dactinomycin* IV over 1 minute on day 1 of weeks 13, 16, 19, and 22; and radiotherapy**, 5 days a week, beginning on week 13 and continuing for 4-7 weeks, depending on prescribed dose. REGIMEN II (subset 2 patients)[closed to accrual as of 9/23/2011]: Patients receive VAC chemotherapy and radiotherapy** as in regimen I and VA chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 13-21, 25-33, and 37-45 and dactinomycin* IV over 1 minute on day 1 of weeks 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, and 46. Patients with clinical group III disease may undergo second-look surgery at week 13 followed by response-adjusted radiotherapy, and continued VA* chemotherapy. In both regimens, treatment continues in the absence of disease progression or unacceptable toxicity. NOTE: *For both regimens, dactinomycin is omitted during radiotherapy. NOTE: **Clinical Group I tumors and those with Clinical Group III uterine/cervix primary disease with negative nodes who have undergone a complete resection (i.e. hysterectomy) at Week 13 do not receive radiotherapy at Week 13 Patients are followed up every 3 months for 1 year, every 4 months for 2 years, every 6 months for 1 year, and then annually thereafter.

Official Title
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Vincristine, Dactinomycin, and Lower Doses of Cyclophosphamide With or Without Radiation Therapy for Patients With Newly Diagnosed Low-Risk Embryonal/Botryoid/Spindle Cell Rhabdomyosarcoma

Conditions
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Adult Rhabdomyosarcoma, Embryonal Childhood Rhabdomyosarcoma, Embryonal-botryoid Childhood Rhabdomyosarcoma, Previously Untreated Childhood Rhabdomyosarcoma

Intervention / Treatment
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* Procedure: conventional surgery
* Drug: dactinomycin
* Drug: cyclophosphamide
* Drug: vincristine sulfate
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed newly diagnosed embryonal rhabdomyosarcoma (RMS), botryoid or spindle cell variants of embryonal RMS, or embryonal ectomesenchymoma, meeting criteria for 1 of the following subsets: Subset 1, defined by meeting 1 of the following criteria (closed to accrual as of 08/13/2010): Stage 1 and clinical group I (completely resected) or II (microscopic residual disease and/or regional lymph node involvement) disease Stage 1 and clinical group III (gross residual disease) disease arising in the orbit Stage 2 and clinical group I or II disease Subset 2, defined by meeting 1 of the following criteria (closed to accrual as of 09/23/2011): Stage 1 and clinical group III disease arising in a non-orbit site Stage 3 and clinical group I or II disease Prior staging ipsilateral retroperitoneal lymph node dissection required for all patients age 10 and over with paratesticular tumors and patients under 10 years of age with clinically or radiographically involved lymph nodes (except when extensive lymph node involvement is identified by imaging studies) If there is extensive gross node involvement only confirmatory node biopsy is recommended and the patient is classified as Clinical Group III Prior regional lymph node sampling required for patients with extremity tumors None of the following diagnoses: Intermediate-risk embryonal RMS Metastatic embryonal RMS Alveolar RMS Undifferentiated sarcoma RMS not otherwise specified (NOS) Other soft tissue sarcoma, including sarcoma NOS Prior enrollment on clinical trial COG-D9902 Performance status - ECOG 0-2 Performance status - Karnofsky 50-100% (≥ 16 years old) Performance status - Lansky 50-100% (< 16 years old) Absolute neutrophil count at least 750/mm^3 Platelet count at least 75,000/mm^3 (transfusion independent) Bilirubin no greater than 1.5 times upper limit of normal (ULN)* Creatinine* based on age/gender as follows: No greater than 0.8 mg/dL for patients age 5 and under No greater than 1.0 mg/dL for patients age 6 to 9 No greater than 1.2 mg/dL for patients age 10 to 12 No greater than 1.4 mg/dL for female patients age 13 and over No greater than 1.5 mg/dL for male patients age 13 to 15 No greater than 1.7 mg/dL for male patients age 16 and over Creatinine clearance* or radioisotope glomerular filtration rate at least 70 mL/min/1.73 m^2 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No uncontrolled infection No prior chemotherapy (except for patients treated on the related intermediate-risk study) Prior steroids allowed No prior radiotherapy

Ages Eligible for Study
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Maximum Age: 49 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen I (chemotherapy, radiotherapy)<br>Patients receive VAC chemotherapy comprising vincristine sulfate IV over 1 minute on day 1 of weeks 1-9 and dactinomycin IV over 1 minute and cyclophosphamide IV over 1 hour on day 1 of weeks 1, 4, 7, and 10; VA chemotherapy comprising vincristine sulfate IV over 1 minute on day 1 of weeks 13-21 and dactinomycin IV over 1 minute on day 1 of weeks 13, 16, 19, and 22 (dactinomycin is omitted during radiation therapy); and radiation therapy, 5 days a week, beginning on week 13 and continuing for 4-7 weeks, depending on prescribed dose. Some patients do not receive radiation therapy; some start it at week 24. (closed to accrual as of 08/13/2010) | Drug: dactinomycin<br>* Given IV<br>* Other names: DACT;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: vincristine sulfate<br>* Given IV<br>* Other names: Vincasar PFS;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;|
| Experimental: Regimen II (chemotherapy, radiotherapy, surgery)<br>Patients receive VAC chemotherapy and radiation therapy as in regimen I and VA chemotherapy comprising vincristine sulfate IV over 1 minute on day 1 of weeks 13-21, 25-33, and 37-45 and dactinomycin IV over 1 minute on day 1 of weeks 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, and 46 (dactinomycin is omitted during radiation therapy). Some patients do not receive radiation therapy; some start it at week 13 and some at week 24. Some patients have conventional surgery (second-look) at Week 13 (closed to accrual as of 9/23/2011). | Procedure: conventional surgery<br>* Some patients may undergo second-look surgery<br>* Other names: surgery, conventional;Drug: dactinomycin<br>* Given IV<br>* Other names: DACT;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: vincristine sulfate<br>* Given IV<br>* Other names: Vincasar PFS;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Low-risk Rhabdomyosarcoma in Subset 1 Failure Free at 5 Years Following Study Entry | Kaplan Meier estimate of failure free survival at 5 years, where failure free survival is defined as the time to relapse, progression, second malignancy, and death whichever occurs first. | From enrollment up to 5 years | 
| Percentage of Patients With Stage 1, Clinical Group IIB or C (Node Positive) or Stage 2 Failure Free at 5 Years Following Study Entry | Kaplan Meier estimate of failure free survival at 5 years, where failure free survival is defined as the time to relapse, progression, second malignancy, and death whichever occurs first. | From enrollment up to 5 years | 
| Percentage of Patients With Low-risk Rhabdomyosarcoma in Subset 2 Failure Free at 5 Years Following Study Entry | Kaplan Meier estimate of failure free survival at 5 years, where failure free survival is defined as the time to relapse, progression, second malignancy, and death whichever occurs first. | From enrollment up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Patients Who Receive Reduced Doses of Radiation Therapy | The local failure rate will be estimated using cumulative incidence curves. | From enrollment up to 5 years | 
| Percentage of Patients With Delayed Surgical Procedures | The decision to perform second-look surgery should be based on the physical examination and imaging studies at Week 12 and should only be considered if a reasonable functional and cosmetic result is anticipated. | At 13 weeks after induction | 
| Cumulative Incidence of Group III Patients Who Received With Reduced Radiotherapy Dose | The local failure rate will be estimated using cumulative incidence curves for Group III patients who received reduced doses of radiation therapy after second look surgical resection. | From enrollment up to 20 weeks |