Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Drug combinations described in this section:

• ACVBP: doxorubicin plus cyclophosphamide plus vindesine plus bleomycin plus prednisone.
• CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.
• CNOP: cyclophosphamide plus mitoxantrone plus vincristine plus prednisone.
• m-BACOD: methotrexate plus bleomycin plus doxorubicin plus cyclophosphamide plus vincristine plus dexamethasone plus leucovorin.
• MACOP-B: methotrexate plus doxorubicin plus cyclophosphamide plus vincristine plus prednisone fixed dose plus bleomycin plus leucovorin.
• ProMACE CytaBOM: prednisone plus doxorubicin plus cyclophosphamide plus etoposide plus cytarabine plus bleomycin plus vincristine plus methotrexate plus leucovorin.
• R-CHOP: Rituximab, an anti-CD20 monoclonal antibody, plus cyclophosphamide plus doxorubicin plus vincristine plus prednisone.

The treatment of choice for patients with advanced stages of aggressive non-Hodgkin lymphoma (NHL) is combination chemotherapy, either alone or supplemented by local-field radiation therapy. [1]

Doxorubicin-based combination chemotherapy produces long-term disease-free survival in 35% to 45% of patients. [2] [3] [4] Higher cure rates have been reported in single-institution studies than in cooperative group trials.

A prospective randomized trial of four regimens (CHOP, ProMACE CytaBOM, m-BACOD, and MACOP-B) for patients with diffuse large B-cell lymphoma showed no difference in overall survival (OS) or time-to-treatment failure (TTF) at 3 years. [4] [ Level of evidence: 1iiA] Other randomized trials have confirmed no advantage among the standard doxorubicin-based combinations versus CHOP. [5] [6] [ Level of evidence: 1iiA] A randomized clinical trial failed to demonstrate a beneficial effect of adjuvant radiation therapy in advanced-stage aggressive NHL. [7]

The combination of rituximab and CHOP (R-CHOP) showed improvement in event-free survival (EFS) and OS compared with CHOP alone in 399 advanced-stage patients with diffuse large B-cell lymphoma older than 60 years (EFS = 57% vs. 38%, P=.002, and OS = 70% vs. 57%, P=.007 at 2 years). [8] [ Level of evidence: 1iiA] At 5-years’ median follow-up, the OS of patients who received R-CHOP compared with patients who received CHOP was 58% vs. 45%, P<.007. [9] Similarly, for 326 evaluable patients younger than 61 years, R-CHOP showed improvement in EFS and OS compared to CHOP alone (EFS = 79% vs. 59%, P=.001, and OS = 93% vs. 84%, P=.001 at 3 years). [10] [Level of evidence: 1iiA]These two studies established R-CHOP as the standard regimen for newly diagnosed patients with diffuse large B-cell lymphoma. [11]

A trial of 635 patients, aged 61 to 69 years, with stage III and stage IV disease, elevated lactate dehydrogenase (LDH), or performance status of 2 to 4, randomized patients to receive CHOP or ACVBP. With a median follow-up of 68 months, patients who received ACVBP had superior EFS and OS (EFS = 39% vs. 29% at 5 years, P=.005 and OS = 46% vs. 38% at 5 years, P=.036). [12] [ Level of evidence: 1iiA] Two prospective randomized trials that compared CHOP with CNOP for patients aged 60 years and older with diffuse large cell lymphoma showed a significant advantage for CHOP in terms of disease-free survival and OS. [13] [14] [ Level of evidence: 1iiA] Two other randomized trials of patients aged 70 years and older confirm the superiority of CHOP over other less toxic regimens in progression-free survival and OS. [15] [16] [ Level of evidence: 1iiA] Although infusion regimens have been proposed, a randomized trial of infusional CHOP versus standard CHOP therapy showed no improvement in relapse-free survival or OS. [17] [ Level of evidence: 1iiA] Clinical trials such as SWOG-9349, for example, continue to explore modifications of CHOP and rituximab with CHOP by increasing doses, reducing intervals between cycles, and combining new drugs with new mechanisms of action. [12] [18] [19] [20]

An International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS: [21]

1. Age (≤60 years vs. >60 years).
2. Serum LDH (normal vs. elevated).
3. Performance status (0 or 1 vs. 2 – 4).
4. Stage (stage I or stage II vs. stage III or stage IV).
5. Extranodal site involvement (0 or 1 vs. 2 – 4).

Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. This study also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system (CNS), liver, lung, and spleen. Patients at high risk of relapse may be considered for clinical trials. [22] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy. [23] [24]

Several randomized prospective trials evaluated the role of autologous bone marrow transplantation (BMT) or stem cell transplantation consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma. [25] [26] [27] [28] [29] [30] [31] [32] [33] [ Level of evidence: 1iiA] Although some of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series. Retrospective analyses of high-intermediate (two risk factors) or high-risk patients (more than three risk factors) as defined by IPI suggest improved survival with BMT in two of the trials. [26] [32] These studies do not establish that high-dose consolidation is of value to patients with aggressive lymphoma who are truly at high risk of relapse, and they also demonstrate that EFS may be a poor surrogate for OS for these patients. [34] Whether autologous BMT, or peripheral stem cell transplantation, or allogeneic BMT have definitive roles in the treatment of high-risk patients in first remission awaits the results of ongoing randomized trials such as SWOG-S0016, for example, employing R-CHOP or other rituximab-based chemotherapy regimens.

CNS prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with paranasal sinus or testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased. [35] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, and others do not. [4] A retrospective analysis of 605 patients with diffuse large cell lymphoma who did not receive prophylactic intrathecal therapy identified an elevated serum LDH and more than one extranodal site as independent risk factors for CNS recurrence. Patients with both risk factors have a 17% probability of CNS recurrence at 1 year after diagnosis (95% confidence interval [CI], 7% – 28%) versus 2.8% (95% CI, 2.7% – 2.9%) for the remaining patients. [36] [ Level of evidence: 3iiiDiii] Patients with diffuse small noncleaved-cell/Burkitt’s lymphoma or lymphoblastic lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis is recommended for these histologies.

Standard treatment options:

1. CHOP plus rituximab. [8]
2. Combination chemotherapy alone:
   • CHOP. [4] [5] [6]
3. Autologous BMT or peripheral stem cell transplantation or allogeneic BMT for patients at high risk of relapse is under clinical evaluation.