Non-Hodgkin's Lymphoma

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.)

Optimal treatment of advanced stages of low-grade lymphoma is controversial because of low cure rates with the current therapeutic options. Numerous clinical trials are in progress to settle treatment issues, and patients should be urged to participate. The rate of relapse is fairly constant over time, even in patients who have achieved complete responses to treatment. Indeed, relapse may occur many years after treatment. In this category, deferred treatment (i.e., watchful waiting until the patient becomes symptomatic before initiating treatment) should be given consideration.[1,2,3] Three randomized trials compared watchful waiting to immediate chemotherapy. All three trials showed no difference in cause-specific or overall survival (OS). For patients randomly assigned to watchful waiting, the median time to require therapy was 2 to 3 years and one-third of patients never required treatment with watchful waiting (half died of other causes and half remained progression-free after 10 y).[2,4];[5][Level of evidence: 1iiA] The PRIMA trial compared watchful waiting to immediate rituximab, the anti-CD20 monoclonal antibody, with or without maintenance doses. Numerous prospective clinical trials of interferon-alpha, including SWOG-8809, have shown no consistent benefit; the role of interferon in patients with indolent lymphoma remains controversial.[6,7,8,9,10,11,12,13,14,15,16,17]

Standard therapy includes rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with purine nucleoside analogs such as fludarabine or 2-chlorodeoxyadenosine, oral alkylating agents (with or without steroids), or combination chemotherapy. Since none of these therapies are curative for advanced-stage disease, innovative approaches are under clinical evaluation. The approaches include intensive therapy with chemotherapy and total-body irradiation (TBI) followed by autologous or allogeneic bone marrow transplantation (BMT) or peripheral stem cell transplantation, and the use of idiotype vaccines and radiolabeled monoclonal antibodies. Currently, no randomized trials guide clinicians about the initial choice of watchful waiting, rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options.[18];[3] [Level of evidence: 1iiDiii]

However, four randomized prospective studies of previously untreated patients (involving more than 1,300 patients) and one Cochrane meta-analysis including both untreated and previously treated patients (involving almost 1,000 patients) have compared rituximab plus combination chemotherapy with chemotherapy alone. Rituximab plus chemotherapy was superior in terms of event-free or progression-free survival (ranging from 2-3 years) in all of the studies and in terms of OS in all but one study (absolute benefit ranging from 6%-13% at 4 years, P < .04 and hazard ratio = 0.63 [0.51-0.79] for the meta-analysis).[19,20,21,22];[23][Level of evidence: 1iiA] All of these trials were performed in symptomatic patients who required therapy. These results do not negate watchful waiting when appropriate. In a prospective randomized trial of 465 patients with relapsed follicular lymphoma, responders to R-CHOP or CHOP were further randomly assigned to rituximab maintenance (one dose every 3 months for 2 years) or no maintenance. At 6 years' median follow-up, rituximab maintenance was better for median progression-free survival (44 months vs. 16 months, P < .001) and borderline for 5-year OS (74% vs. 64%, P = .07).[24][Level of evidence: 1iiDiii] This benefit for maintenance was evident even for patients who received rituximab during induction therapy. Most patients in both arms received extensive rituximab during post-protocol salvage treatment.