RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab together with combination chemotherapy may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective when given with rituximab in treating diffuse large B-cell non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying rituximab when given together with two different combination chemotherapy regimens to compare how well they work in treating patients with diffuse large B-cell non-Hodgkin's lymphoma.

OBJECTIVES:

Primary

• Compare the event-free survival of patients with previously untreated de novo diffuse large B-cell non-Hodgkin's lymphoma treated with R-CHOP comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone vs EPOCH-R comprising etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.
• Determine molecular predictors of outcome (using molecular profiling) in patients treated with these regimens.

Secondary

• Compare the response rate and overall survival of patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.
• Correlate the clinical parameters (i.e., toxicity, response, survival outcomes, and laboratory results) with molecular profiling in patients treated with these regimens.
• Determine the use of molecular profiling for pathological diagnosis in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to International Prognostic Index score. Patients are randomized to 1 of 2 treatment arms.

• Arm I (R-CHOP): Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV over 3-5 minutes, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• Arm II (EPOCH-R): Patients receive rituximab IV on day 1, doxorubicin IV, etoposide IV, and vincristine IV continuously over 96 hours on days 1-4, cyclophosphamide IV on day 5, and oral prednisone twice daily on days 1-5. Patients also receive filgrastim (G-CSF) once daily on days 2-11 or until blood counts recover. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for up to 3 years.

PROJECTED ACCRUAL: A total of 478 patients (239 per treatment arm) will be accrued for this study within 4.5 years.

• Biological: filgrastim
• Biological: rituximab
• Drug: cyclophosphamide
• Drug: doxorubicin hydrochloride
• Drug: etoposide
• Drug: prednisone
• Drug: vincristine sulfate

• Active Comparator: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV over 3-5 minutes, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• Experimental: Patients receive rituximab IV on day 1, doxorubicin IV, etoposide IV, and vincristine IV continuously over 96 hours on days 1-4, cyclophosphamide IV on day 5, and oral prednisone twice daily on days 1-5. Patients also receive filgrastim (G-CSF) once daily on days 2-11 or until blood counts recover. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

DISEASE CHARACTERISTICS:

• Histologically confirmed* de novo B-cell non-Hodgkin's lymphoma (NHL) of 1 of the following WHO histologic subtypes:

  • Diffuse large cell lymphoma, including any of the following morphologic variants:

    • Centroblastic
    • Immunoblastic
    • T-cell/histiocyte rich
    • Anaplastic
  • Mediastinal (thymic) large cell lymphoma
  • Intravascular large cell lymphoma NOTE: *Fine needle aspirates or core biopsies must not be the only diagnostic material
• Stage I primary mediastinal (thymic) OR stage II-IV disease
• CD20-positive disease
• No underlying low-grade lymphoma (e.g., transformed lymphoma or low-grade lymphoma in the bone marrow)

• No known lymphomatous CNS involvement

  • Lumbar puncture required unless there are no neurological symptoms NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3^*
• Platelet count ≥ 100,000/mm^3^*
• No active bleeding unrelated to NHL NOTE: *Unless due to NHL

Hepatic

• Bilirubin ≤ 2 mg/dL* NOTE: *Unless due to NHL or Gilbert's disease

Renal

• Creatinine ≤ 1.5 mg/dL^* OR
• Creatinine clearance ≥ 50 mL/min^* NOTE: *Unless due to NHL

Cardiovascular

• No active ischemic heart disease
• No congestive heart failure

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No active uncontrolled bacterial or viral infection unrelated to NHL
• No other active medical process unrelated to NHL

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior rituximab

Chemotherapy

• No prior chemotherapy for other malignancies
• No prior cytotoxic chemotherapy
• No other concurrent chemotherapy

Endocrine therapy

• Prior short course (< 10 days) glucocorticoids allowed for an urgent local disease complication (e.g., cord compression or superior vena cava syndrome) at diagnosis
• No concurrent hormonal therapy except steroids for adrenal failure or hormones for non-disease related conditions (e.g., insulin for diabetes)
• No concurrent dexamethasone or other steroidal antiemetics

Radiotherapy

• Prior limited field radiotherapy allowed for an urgent local disease complication (e.g., cord compression or superior vena cava syndrome) at diagnosis
• No concurrent radiotherapy except for isolated CNS lesions

Surgery

• Not specified

Other

• No other concurrent investigational or commercial agents or therapies for NHL