Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining more than one drug with radiation therapy may kill more cancer cells. It is not yet known which combination chemotherapy regimen is most effective in treating Hodgkin's lymphoma. PURPOSE: This randomized phase III trial is studying two different combination chemotherapy regimens and comparing how well they work, with or without radiation therapy, in treating patients with Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Compare the failure-free survival of patients with locally extensive or advanced Hodgkin's lymphoma treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) vs doxorubicin, vinblastine, vincristine, bleomycin, mechlorethamine, etoposide, and prednisone (Stanford V) with or without radiotherapy. Compare the overall survival and freedom from progression in these patients at 5 and 10 years after treatment with these regimens. Compare pulmonary function, incidence of second cancers, reproductive function, and deaths from causes other than Hodgkin's lymphoma in patients treated with these regimens. OUTLINE: This is a randomized study. Patients are stratified according to number of adverse risk factors (0-2 vs 3-7), disease characteristics (locally extensive vs advanced) and time of entry (before addendum 6 vs. after addendum 6). Patients are randomized to 1 of 2 treatment arms. Arm A (ABVD): Patients receive doxorubicin (25 mg/m²), bleomycin (10 u/m²), vinblastine (6 mg/m²), and dacarbazine (375 mg/m²) IV on days 1 and 15. Courses repeat every 28 days. Patients are restaged after 4 courses. Patients who are in complete remission receive 2 additional courses. Patients with a partial response or less are evaluated after 6 courses, and if there is an ongoing response, patients may receive 2 additional courses for a total of 8. If no ongoing response is observed, patients are removed from the study. All patients with massive mediastinal disease, regardless of stage, receive radiotherapy 2-3 weeks after completion of chemotherapy. Arm B (Stanford V): Patients receive Stanford V chemotherapy comprising doxorubicin (25 mg/m²) and vinblastine (6 mg/m²) IV on day 1 of weeks 1, 3, 5, 7, 9, and 11; vincristine (1.4 mg/m²) and bleomycin (5 u/m²) IV on day 1 of weeks 2, 4, 6, 8, 10, and 12; mechlorethamine (6 mg/m²) IV on day 1 of weeks 1, 5, and 9 (if mechlorethamine is unavailable, may substitute with cyclophosphamide [375 mg/m²] IV); etoposide (60 mg/m²) IV on days 1 and 2 of weeks 3, 7, and 11; and oral prednisone (40 mg/m²) every other day of weeks 1-9 followed by a taper. All patients with bulky disease receive radiotherapy 2-3 weeks after completion of chemotherapy. Patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 850 patients will be accrued for this study within 4.3 years.

Official Title
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A Randomized Phase III Trial of ABVD Versus Stanford V (+/-) Radiation Therapy in Locally Extensive and Advanced Stage Hodgkin's Disease

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: Doxorubicin
* Drug: Bleomycin
* Drug: Vinblastine
* Drug: Dacarbazine
* Drug: Vincristine
* Drug: Mechlorethamine
* Drug: Etoposide
* Drug: Prednisone
* Drug: Cyclophosphamide
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically proven previously untreated classical Hodgkin's lymphoma The following stages are eligible: Locally extensive: Stage I-IIA/B with massive mediastinal adenopathy Advanced: Stage III or IV Measurable or evaluable disease Age of 16 and over ECOG Performance status 0-2 Disease-free of prior invasive malignancies for >5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix White blood cell (WBC) at least 4,000/mm³, (unless documented bone marrow involvement) Platelet count at least 100,000/mm³ (unless documented bone marrow involvement) Bilirubin no greater than 5.0 mg/dL Creatinine no greater than 2.0 mg/dL Ejection fraction determination recommended if over age 50 and/or have a history of cardiac disease Fertile patients must use effective contraception Prior corticosteroids allowed Prior surgery allowed Exclusion criteria: Pregnant or nursing Prior radiotherapy Prior chemotherapy Human immunodeficiency virus (HIV) positive

Ages Eligible for Study
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Minimum Age: 16 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (ABVD)<br>Arm A (ABVD): Patients receive doxorubicin (25 mg/m²), bleomycin (10 u/m²), vinblastine (6 mg/m²), and dacarbazine (375 mg/m²) intravenously (IV) on days 1 and 15. Courses repeat every 28 days. Patients are restaged after 4 courses. Patients who are in complete remission receive 2 additional courses. Patients with a partial response or less are evaluated after 6 courses, and if there is an ongoing response, patients may receive 2 additional courses for a total of 8. If no ongoing response is observed, patients are removed from the study. All patients with massive mediastinal disease, regardless of stage, receive radiotherapy 2-3 weeks after completion of chemotherapy. | Drug: Doxorubicin<br>* given IV<br>* Other names: ADR;Drug: Bleomycin<br>* given IV<br>* Other names: Bleo;Drug: Vinblastine<br>* given IV<br>* Other names: Alkaban AQ;Drug: Dacarbazine<br>* given IV<br>* Other names: dimethyl triazeno imidazole carboxamide;Radiation: Radiotherapy<br> <br> |
| Active Comparator: Arm B (Stanford V)<br>Arm B (Stanford V): Patients receive Stanford V chemotherapy comprising doxorubicin (25 mg/m²) and vinblastine (6 mg/m²) IV on day 1 of weeks 1, 3, 5, 7, 9, and 11; vincristine (1.4 mg/m²) and bleomycin (5 u/m²) IV on day 1 of weeks 2, 4, 6, 8, 10, and 12; mechlorethamine (6 mg/m²) IV on day 1 of weeks 1, 5, and 9 (if mechlorethamine is unavailable, may substitute with cyclophosphamide [375 mg/m²] IV); etoposide (60 mg/m²) IV on days 1 and 2 of weeks 3, 7, and 11; and oral prednisone (40 mg/m²) every other day of weeks 1-9 followed by a taper. All patients with bulky disease receive radiotherapy 2-3 weeks after completion of chemotherapy. | Drug: Doxorubicin<br>* given IV<br>* Other names: ADR;Drug: Bleomycin<br>* given IV<br>* Other names: Bleo;Drug: Vinblastine<br>* given IV<br>* Other names: Alkaban AQ;Drug: Vincristine<br>* given IV<br>* Other names: LCR;Drug: Mechlorethamine<br>* given IV<br>* Other names: nitrogen mustard;Drug: Etoposide<br>* given IV<br>* Other names: epipodophyllotoxin;Drug: Prednisone<br>* taken orally<br>* Other names: Liquid-Pred;Drug: Cyclophosphamide<br>* given IV<br>* Other names: CPM;Radiation: Radiotherapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure-free Survival at 5 Years | Failure-free survival is defined as the time from randomization to the earlier of progression/relapse or death. The 5-year failure-free survival is the probability a patient is failure-free and survives 5 years. Progression is defined as an increase in size of 25% of the sum of the products of the pretreatment measurements or appearance of new lesions. Significant enlargement of the liver or spleen is evidence of progression. A significant increase in size is defined as > 2.0 cm in distance between costal margin and the inferior margin of either organ. Relapse is defined as the re-appearance of any clinical evidence of Hodgkin's disease in a patient who has had a complete response. Relapse for partial responders is defined as progressive disease relative to disease status during the partial remission. | Assessed every 2 months if patient is < 1 year from study entry, every 3 months for the second year, every 4 months for the third year, every 6 months for years 4 and 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year Overall Survival | Overall survival is defined as the time from randomization to death or last known alive. The 5-year survival rate is the probability a patient survives 5 years. | Assessed every 2 months if patient is < 1 year from study entry, every 3 months for the second year, every 4 months for the third year, every 6 months for years 4 and 5, and yearly for 5 years | 
| Incidence of Second Cancers | Number of patients who developed second primary cancers | Assessed every 2 months if patient is < 1 year from study entry, every 3 months for the second year, every 4 months for the third year, every 6 months for years 4 and 5, and yearly for 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I adult Hodgkin lymphoma, stage II adult Hodgkin lymphoma, stage III adult Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, adult lymphocyte depletion Hodgkin lymphoma, adult nodular sclerosis Hodgkin lymphoma, adult mixed cellularity Hodgkin lymphoma