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Adult Non-Hodgkin Lymphoma Treatment (Professional) (cont.)

Treatment for Indolent, Noncontiguous Stage II/III/IV Adult NHL

Optimal treatment of advanced stages of low-grade non-Hodgkin 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 response to treatment. Indeed, relapse may occur many years after treatment. 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.[1]; [2][Level of evidence: 1iiDiii]

For patients with indolent, noncontiguous stage II and stage III non-Hodgkin lymphoma, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.[3,4]

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.[5,6,7,8,9,10,11,12,13,14,15,16]

Standard Treatment Options for Indolent, Noncontiguous Stage II/III/IV Adult NHL

Standard treatment options for indolent, noncontiguous stage II/III/IV adult NHL include the following:

  1. Watchful waiting for asymptomatic patients.
  2. Rituximab.
  3. Purine nucleoside analogs.
  4. Alkylating agents (with or without steroids).
  5. Combination chemotherapy.
  6. Yttrium-90-labeled ibritumomab tiuxetan and iodine-131-labeled tositumomab.
  7. Maintenance rituximab.

Watchful waiting for asymptomatic patients

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 considered.[2,17,18,19]

Evidence (watchful waiting):

  1. Three randomized trials compared watchful waiting to immediate chemotherapy.[18,20]; [21][Level of evidence: 1iiA]
    • 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 years).
  2. The PRIMA trial compared watchful waiting to immediate rituximab, the anti-CD20 monoclonal antibody, with or without maintenance doses.


Rituximab may be considered as first-line therapy, either alone or in combination with other agents.

  • Rituximab alone, as was shown in the ECOG-E4402 (NCT00075946) trial, for example.[22,23,24,25,26]
  • R-Bendamustine: rituximab plus bendamustine.[27]
  • R-F: rituximab plus fludarabine.[28]
  • R-CVP: rituximab plus cyclophosphamide plus vincristine plus prednisone.[29,30]
  • R-CHOP: rituximab plus cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[31,32,33]
  • R-FM: rituximab plus fludarabine plus mitoxantrone.[34]
  • R-FCM: rituximab plus fludarabine plus cyclophosphamide plus mitoxantrone.[35]

Standard therapy includes rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with purine nucleoside analogs such as fludarabine or 2-chlorodeoxyadenosine, alkylating agents (with or without steroids), or combination chemotherapy.

Evidence (rituximab):

  • 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.[30,33,36]; [37,38][Level of evidence: 1iiA]
    • Rituximab plus chemotherapy was superior in terms of event-free survival or progression-free survival (PFS) (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 [HR] = 0.63 [0.51–0.79] for the meta-analysis).
    • All of these trials were performed in symptomatic patients who required therapy. These results do not negate watchful waiting when appropriate.

Purine nucleoside analogs

  • Fludarabine.[1,39,40]
  • 2-chlorodeoxyadenosine.[41,42]

Alkylating agents (with or without steroids)

  • Cyclophosphamide (oral or intravenous).[43]
  • Chlorambucil (oral).

Combination chemotherapy

  • CVP: cyclophosphamide + vincristine + prednisone.[1,44]
  • CVP followed by rituximab maintenance.[45]
  • C-MOPP: cyclophosphamide + vincristine + procarbazine + prednisone.[46,47]
  • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone.[43,48]
  • FND: fludarabine + mitoxantrone +/- dexamethasone, as evidenced in the SWOG-9501 trial, for example.[49,50]

Yttrium-90-labeled ibritumomab tiuxetan and iodine-131-labeled tositumomab

Yttrium-90-labeled ibritumomab tiuxetan and iodine-131-labeled tositumomab are available for previously untreated and relapsing patients with minimal (<25%) or no marrow involvement with lymphoma, as was shown in the SWOG-9911 trial, for example.[51,52] Randomized prospective studies are required to determine the optimal utilization of this modality.[53]

Maintenance rituximab

Evidence (maintenance rituximab):

  1. 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.[54][Level of evidence: 1iiDiii]
    • At 6 years' median follow-up, rituximab maintenance was better for median PFS (44 months vs. 16 months, P < .001) and borderline for 5-year OS (74% vs. 64%, P = .07).
    • 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.
  2. In the PRIMA study, 1,019 high-risk patients who required treatment achieved complete or partial response after induction therapy with immunochemotherapy (usually R-CHOP) and were then randomly assigned to 2 years of maintenance rituximab versus no maintenance.[55]
    • With a median follow-up of 36 months, PFS favored rituximab maintenance 74.9% to 57.6% (HR 0.56, 95% confidence interval 0.44–0.68, P <.0001) but with no difference in OS.
  3. A meta-analysis of 2,586 patients with follicular lymphoma in nine randomized clinical trials that compared rituximab maintenance with no maintenance showed improved OS for rituximab maintenance in previously treated patients (HR of death, 0.72; 95% CI, 0.57–0.91).[56][Level of evidence: 1iiA]

Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. The most salient question is whether a strategy of observation after induction with rituximab therapy at time of symptomatic progression is equivalent or superior to mandated rituximab maintenance.[57]

Treatment Options Under Clinical Evaluation for Indolent, Noncontiguous Stage II/III/IV Adult NHL

Since none of the standard therapies listed above 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.

  1. Intensive therapy with chemotherapy with or without TBI or high-dose radioimmunotherapy followed by autologous or allogeneic BMT or peripheral stem cell transplantation is under clinical evaluation.[58,59,60,61,62,63,64,65,66]
  2. Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[67,68,69]
  3. Extended-field radiation therapy (stage III patients only).[70]
  4. Ofatumumab—human anti-CD20 monoclonal antibody.[71]
  5. Short-course low-dose, palliative radiation therapy (2 × 2 Gy).[72,73]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, noncontiguous stage II adult non-Hodgkin lymphoma, indolent, stage III adult non-Hodgkin lymphoma and indolent, stage IV adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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