Rituximab and Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With B-Cell Non-Hodgkin's Lymphoma
Rituximab and Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With B-Cell Non-Hodgkin's Lymphoma
RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different
 ways. Some find cancer cells and kill them or carry cancer-killing substances to them. Others
 interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy,
 such as cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone, work in
 different ways to stop the growth of cancer cells, either by killing the cells or by stopping
 them from dividing. Radiation therapy uses high-energy x-rays to kill cancer cells. Giving
 rituximab and combination chemotherapy together with radiation therapy may kill more cancer
 cells. It is not yet known which schedule of rituximab and combination chemotherapy is more
 effective when given with or without radiation therapy in treating non-Hodgkin's lymphoma.

 PURPOSE: This randomized phase III trial is studying two different schedules of rituximab and
 combination chemotherapy with or without radiation therapy to compare how well they work in
 treating patients with aggressive B-cell non-Hodgkin's lymphoma.
OBJECTIVES:

 Primary

 -  Compare the time to treatment failure in patients with previously untreated, low-risk,
 aggressive, B-cell non-Hodgkin's lymphoma treated with 2 different schedules of
 immunochemotherapy comprising rituximab, cyclophosphamide, doxorubicin hydrochloride,
 vincristine, and prednisone with vs without radiotherapy.

 Secondary

 -  Compare the time to progression in patients treated with these regimens.

 -  Compare the overall and disease-free/relapse-free survival of patients treated with
 these regimens.

 -  Compare the complete response rate in patients treated with these regimens.

 -  Compare the tumor control in patients treated with these regimens.

 -  Compare the safety of these regimens in these patients.

 -  Compare the pharmacoeconomics of these regimens.

 -  Compare patient adherence to these regimens.

 OUTLINE: This is an open-label, randomized, multicenter study. Patients are stratified
 according to study center, serum lactic dehydrogenase level (≤ upper limit of normal [ULN] vs
 > ULN), disease stage (I or II vs III or IV), ECOG performance status (0-1 vs 2-3), bulky
 disease, and extranodal involvement. Patients with initial bulky disease and/or qualifying
 extranodal involvement are randomized to 1 of 4 treatment arms. Patients with non-bulky
 disease are randomized to treatment arms I or III.

 All patients will be given the option of receiving a 1-week course of pretreatment therapy
 comprising vincristine IV once on day -6 and oral prednisone once daily on days -6 to 0.

 -  Arm I (R-CHOP-21): Patients receive R-CHOP immunochemotherapy comprising rituximab IV,
 cyclophosphamide IV over 15 minutes, doxorubicin IV, and vincristine IV on day 1 and
 oral prednisone once daily on days 1-5. Treatment repeats every 21 days for up to 6
 courses in the absence of disease progression or unacceptable toxicity.

 -  Arm II (R-CHOP-21 and radiotherapy): Patients receive R-CHOP as in arm I. Treatment
 repeats every 21 days for up to 6 courses in the absence of disease progression or
 unacceptable toxicity. Beginning 2-6 weeks after the last course of R-CHOP, patients who
 achieve a complete remission (CR) undergo radiotherapy 5 days a week for approximately
 5½ weeks.

 -  Arm III (R-CHOP-14): Patients receive R-CHOP as in arm I. Patients also receive
 filgrastim (G-CSF) subcutaneously once daily on days 4-13 or until blood counts recover.
 Treatment repeats every 14 days for up to 6 courses in the absence of disease
 progression or unacceptable toxicity.

 -  Arm IV (R-CHOP-14 and radiotherapy): Patients receive R-CHOP as in arm I. Patients also
 receive G-CSF an in arm III. Treatment repeats every 14 days for up to 6 courses in the
 absence of disease progression or unacceptable toxicity. Beginning 2-6 weeks after the
 last course of R-CHOP, patients who achieve CR undergo radiotherapy as in arm II.

 Patients in all arms undergo restaging of their disease after courses 3 and 6 of R-CHOP.
 Patients with stable disease after 6 courses or disease progression after courses 3 or 6
 proceed to salvage chemotherapy off study. Patients achieving a partial remission or an
 unconfirmed CR after 6 courses undergo additional restaging 4 weeks later. Patients with
 disease progression proceed to salvage chemotherapy off study. Patients who achieve CR after
 6 courses of R-CHOP or have a confirmed CR after the additional restaging undergo
 radiotherapy according to randomization (as above).

 After completion of study treatment, patients are followed periodically for 5 years and then
 annually thereafter.

 PROJECTED ACCRUAL: A total of 1,072 patients will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed aggressive B-cell non-Hodgkin's lymphoma, including the
 following subtypes:

 -  Grade 3 follicular lymphoma

 -  Diffuse B-cell lymphoma, including diffuse large cell lymphoma with the following
 variants:

 -  Centroblastic

 -  Immunoblastic

 -  Plasmablastic

 -  Anaplastic large cell

 -  T-cell-rich B-cell lymphoma

 -  Primary effusion lymphoma

 -  Intravascular B-cell lymphoma

 -  Primary mediastinal B-cell lymphoma

 -  Burkitt's or Burkitt-like lymphoma

 -  Mantle cell lymphoma (blastoid)

 -  Aggressive marginal zone lymphoma (monocytoid)

 -  Previously untreated disease

 -  CD20-positive disease

 -  International prognostic index (IPI) score 0 or 1 (age-adjusted)

 -  Only patients with bulky disease, as defined by largest single or conglomerate
 tumor ≥ 7.5 cm in diameter, are allowed to have an IPI score of 0

 -  No mucosa-associated lymphoid tissue (MALT) lymphoma

 -  No CNS involvement of lymphoma (intracerebral, meningeal, or intraspinal)

 PATIENT CHARACTERISTICS:

 -  ECOG performance status 0-2

 -  Platelet count ≥ 100,000/mm³

 -  WBC ≥ 2,500/mm³

 -  No known hypersensitivity to the study medications

 -  No known HIV-positivity

 -  No active hepatitis infection

 -  Not pregnant or lactating

 -  Negative pregnancy test

 -  No other malignancy within the past 5 years except carcinoma in situ or basal cell
 skin cancer

 -  No impaired left ventricular function

 -  No severe cardiac arrhythmias

 -  No other impaired organ function

 -  No other serious disorder

 PRIOR CONCURRENT THERAPY:

 -  No prior chemotherapy or radiotherapy

 -  No prior immunosuppressive treatment with cytostatics

 -  No concurrent participation in other treatment studies