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.

PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy works in treating patients with stage II, stage III, or stage IV diffuse large B-cell non-Hodgkin's lymphoma.

OBJECTIVES:

Primary

• Determine the 2-year progression-free survival (PFS) rate after treatment with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in patients with bulky stage II or stage III or IV diffuse large B-cell non-Hodgkin's lymphoma who remain positron emission tomography (PET)-positive after 3 courses of rituximab, cyclophosphamide, vincristine, doxorubicin hydrochloride, and prednisone.

Secondary

• Determine the proportion of mid-treatment PET-positive patients who become PET-negative after 4 courses of R-ICE.
• Determine the PFS of mid-treatment PET-negative patients treated with these regimens.
• Determine the overall survival of patients treated with these regimens.
• Determine the toxicity of these regimens in these patients.

OUTLINE:

• Rituximab and Combination Chemotherapy (R-CHOP: R= Rituximab, C= Cyclophosphamide, H= Doxorubicin Hydrochloride (Hydroxydaunomycin), O= Vincristine Sulfate (Oncovin), P= Prednisone): Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine IV on day 1, and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients undergo fludeoxyglucose F18 positron emission tomography (PET) scanning and conventional restaging during course 3. Based on the PET results, patients are assigned to 1 of 2 treatment groups.

  • Group I (PET negative): Patients receive 2 more courses of R-CHOP as above in the absence of disease progression or unacceptable toxicity.
  • Group II (PET positive): Patients receive Rituximab 375 mg/m2 IV Day 1, Ifosfamide 5000 mg/m2 IV over 24 hours Day 2, Carboplatin AUC 5 (max: 800 mg) IV Day 2, Etoposide 100 mg/m2 IV Days 1, 2, 3 (R-ICE), Mesna 5000 mg/m2 IV over 24 hours Day 2, and Filgrastim 5 mcg/kg/day subcutaneous (SC) Day 4 until absolute neutrophil count (ANC) recovery every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 10 years from the date of study entry.

ACCRUAL: A total of 100 patients were accrued for this study.

INCLUSION CRITERIA:

• Diffuse large B-cell non-Hodgkin's lymphoma

  • Bulky stage II (bulk defined as any lesion ≥ 10 cm) or stage III or IV disease

  • The following lymphoma types are excluded:

    • Primary central nervous system lymphoma
    • Transformed low-grade lymphoma (prior history of low-grade lymphoma or clear presence of low-grade lymphoma on histologic sections)
    • Primary mediastinal B-cell lymphoma or testicular lymphoma (consolidative radiotherapy is usually indicated)
    • Immunodeficiency-related lymphoma (i.e., after organ or bone marrow transplant)

• Measurable disease

  • Patient must have at least one objective measurable disease site (i.e., measurable in at least 2 perpendicular parameters)
  • Measurable disease in the liver is required if the liver is the only site of lymphoma involvement
  • Abnormal positron emission tomography scans will not constitute evaluable disease, unless verified by CT scan or other appropriate imaging

• Eastern Cooperative Oncology Group (ECOG) performance status 0-3

• For patients > 50 years of age, a normal ejection fraction by ECHO or Multigated Acquisition Scan (MUGA) is required within 6 weeks prior to registration

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count > 100,000/mm^3

• Creatinine < 2.0 mg/dL

• Bilirubin < 2 mg/dL (may be up to 3.0 mg/dL if due to liver involvement by lymphoma)

EXCLUSION CRITERIA:

• Prior chemotherapy or radiation therapy for lymphoma
• Prior anthracyclines or platinum compounds used as systemic chemotherapy
• Prior radiation therapy to the mediastinum or to ≥ 25% of the bone marrow
• Concurrent pentostatin or trastuzumab (Herceptin®)
• Pregnant or nursing
• Prior malignancy within the past 5 years unless it was in situ OR was treated with curative intent AND the patient has remained relapse-free
• HIV positive