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] Numerous prospective clinical trials, including SWOG-8809, of interferon-alpha have shown no consistent benefit; the role of interferon in patients with indolent lymphoma remains controversial.[3,4,5,6,7,8,9,10,11,12,13,14]

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 rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options.[15] Although the addition of rituximab to chemotherapy reproducibly improves response rates and failure-free survival in randomized clinical trials, as yet, no improvement in overall survival has been observed.[16,17][Level of evidence: 1iiDiii]

For patients with indolent, noncontiguous stage II and stage III lymphoma, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.[18,19]

STANDARD TREATMENT OPTIONS:

1. For asymptomatic patients, deferred therapy with careful observation.[2,20]
2. Rituximab may be considered as first-line therapy.
   • Rituximab alone, as evidenced in the ECOG-E4402 trial.[21,22,23,24,25]
   • R-F: rituximab + fludarabine.[26]
   • R-CVP: rituximab + cyclophosphamide + vincristine + prednisone.[16]
   • R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.[17,27]
   • R-FM: rituximab + fludarabine + mitoxantrone.[28]
   • R-FCM: rituximab + fludarabine + cyclophosphamide + mitoxantrone.[29]
3. Purine nucleoside analog:
   • Fludarabine.[15,30,31]
   • 2-chlorodeoxyadenosine.[32,33]
4. Oral alkylating agents (with or without steroids):
   • Cyclophosphamide.[34]
   • Chlorambucil.
5. Combination chemotherapy alone:
   • CVP: cyclophosphamide + vincristine + prednisone.[15,35]
   • C-MOPP: cyclophosphamide + vincristine + procarbazine + prednisone.[36,37]
   • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone.[34,38]
   • FND: fludarabine + mitoxantrone ± dexamethasone, as evidenced in the SWOG-9501 trial, for example.[39,40]
6. 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 evidenced in the SWOG S-9911 trial, for example.[41,42] Randomized prospective studies are required to determine the optimal utilization of this modality.
7. 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.[43,44,45,46,47,48,49,50]
8. Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[51,52,53]
9. Extended-field radiation therapy (stage III patients only).[54]