Adult Non-Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]-Treatment for Indolent, Noncontiguous Stage II / III / IV Adult NHL Optimal treatment of advanced stages of low-grade non-Hodgkin lymphoma (NHL) 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]

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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. Obinutuzumab.
4. Purine nucleoside analogs.
5. Alkylating agents (with or without steroids).
6. Bendamustine.
7. Combination chemotherapy.
8. Yttrium-90-labeled ibritumomab tiuxetan and iodine-131-labeled tositumomab.
9. 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 with 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. A selected group of 107 patients with advanced stage follicular lymphoma were managed with initial watchful waiting; with a median delay of 55 months, subsequent therapy resulted in equivalent freedom from treatment failure and OS compared to a similar cohort treated immediately with rituximab.[22][Level of evidence: 3iiiDiii] This implies that watchful waiting remains a relevant approach even in the rituximab era.

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