In a French study, Brice et al randomized 193 newly diagnosed follicular lymphoma patients with a low tumor burden to no initial treatment, prednimustine, or interferon alfa-2b(Drug information on interferon alfa-2b) (Intron A) and found no difference in the overall survival rate at 5 years among the three groups. In the Stanford study described above, Advani et al found that at a median follow-up of 86 months, 27 patients (63%) had not yet required treatment. Radiation Therapy
Radiation therapy has been the mainstay of treatment for limited-stage grade 1 and 2 follicular lymphoma. Table 2 presents an overview of the clinical trials that have used RT as the major modality for treatment.[38-49] The results of these studies uniformly show that involved-field RT confers a 10-year failure-free survival of approximately 45% in patients presenting with early-stage disease. Chemotherapy
The role of chemotherapy alone in the treatment of early-stage follicular lymphoma is not exactly clear. Jeffery et al treated 30 patients with nonbulky stage I, nodal, intermediate-grade NHL with RT. They then compared the outcomes in 11 patients with bulky stage I disease treated with combination chemotherapy. They found that the 5-year actuarial survival for the 30 patients treated with RT was 86%, as compared to a 60% 4-year actuarial survival in the 11 patients treated with chemotherapy. In contrast, Teczan et al evaluated 40 patients with previously untreated follicular lymphoma and found that stage IA patients treated with chemotherapy (with or without RT) showed a better trend for 10-year event-free survival as compared to RT alone. There was, however, no difference in the estimated 10-year overall survival. Combined Chemoradiation
In a study conducted at Memorial Sloan-Kettering Cancer Center, Yahalom et al randomized 44 patients with clinical or pathologic stage I intermediate-grade or low-grade NHL to receive regional RT alone or regional RT followed by six cycles of CHOP chemotherapy (cyclophosphamide [Cytoxan, Neosar]/doxorubicin HCl/vincristine [Oncovin]/prednisone). They found an 83% actuarial relapse-free survival rate for the RT-plus-CHOP group at 7 years, compared with 47% for the RT-alone group. The overall survival for the two groups was 88% and 66%, respectively. However, in patients with low-grade NHL, the addition of adjuvant CHOP did not improve outcomes. McLaughlin et al prospectively treated 44 patients with stage I/II lowgrade lymphoma with sequential chemotherapy and involved-field RT. At a median follow-up of 32 months, they had 5-year overall and failurefree survival rates of 89% and 74%, respectively. Seymour et al studied 102 eligible patients with stage I/II low-grade lymphoma (85 patients with follicular lymphoma) treated with chemotherapy and involved-field RT. They found that the 10-year time to treatment failure and overall survival rates in patients with follicular lymphoma were 72% and 80%, respectively.[ 54] These results constitute a marked improvement in the 10-year disease-free survival of 41% to 64% reported by the various studies involving RT alone described above. Richards et al retrospectively studied 202 patients with clinical stage I/II NHL between 1972 and 1985. They found that although the duration of remission was better in patients who received adjuvant chemotherapy than in those treated with RT alone, there was no difference in overall survival between the two groups of patients. Since neither of these were randomized trials, it is unclear whether the addition of chemotherapy would improve the outcomes obtained by RT alone. Treatment of Advanced Disease No Initial Treatment
The exact time to initiate treatment in this setting is controversial, since these patients have a prolonged survival despite frequent relapses. In an effort to answer the question of whether early aggressive therapy is superior to watchful waiting, the National Cancer Institute (NCI) conducted a study in 104 patients with advanced indolent lymphomas. They randomly assigned 44 patients to the watchful waiting group, in which only carefully defined, limited RT was administered if necessary; 45 were randomly assigned to aggressive combinedmodality treatment with ProMACEMOPP (prednisone, methotrexate(Drug information on methotrexate), doxorubicin, cyclophosphamide(Drug information on cyclophosphamide), etoposide(Drug information on etoposide), mechlorethamine [Mustargen], vincristine, procarbazine(Drug information on procarbazine) [Matulane], prednisone(Drug information on prednisone)), followed by total nodal irradiation. They found no difference in overall survival at 5 years (> 75% in each group), but diseasefree survival was better in the group that received initial therapy. In a recently published British study, Ardeshna et al randomized 309 patients with asymptomatic, advancedstage, low-grade NHL (204 patients with follicular lymphoma) to immediate systemic chemotherapy with chlorambucil(Drug information on chlorambucil) (Leukeran), 10 mg/d continuously, vs an initial policy of observation with systemic therapy delayed until disease progression. However, in contrast to the above study, they found that overall survival and cause-specific survival did not differ between the two groups. Chemotherapy
- CVP-Systemic chemotherapy is the mainstay of treatment in patients with advanced-stage follicular lymphoma. Hoppe et al randomized 51 patients with favorable-histology NHL (pathologic stage III/IV disease) to single-alkylating agent chemotherapy, combination chemotherapy with CVP (cyclophosphamide, vincristine, prednisone), or fractionated wholebody irradiation followed by low-dose involved-field irradiation. They found an actuarial survival of 84% at 4 years, with similar survival observed for each of the three treatment options. Kennedy et al randomized 58 patients with advanced lymphoma to the CVP combination or these same three agents given separately in succession. They demonstrated a complete remission rate of 81% with the combination and 46% with sequential use of the three agents. Portlock et al randomized 63 previously untreated patients with stage IV NHL with favorable histologies to three groups: CVP alone, split-course CVP and total lymphoid irradiation, or single- alkylating agent therapy. The actuarial probability of obtaining a complete remission was greater than 80% in all three groups. In contrast to the above findings of Kennedy et al, they found no statistically significant differences among the groups in terms of the probability of disease-free or overall survival.
- CHOP-Peterson et al randomized 228 patients with stage III/IV follicular lymphoma to cyclophosphamide or the CHOP-B combination (cyclophosphamide, doxorubicin(Drug information on doxorubicin), vincristine, prednisone, bleomycin(Drug information on bleomycin) [Blenoxane]). These investigators observed complete responses in 66% of those treated with cyclophosphamide and in 60% of those treated with CHOP-B. They found no difference in overall survival between the two groups. However, in an unplanned subgroup analysis, patients with follicular mixed lymphoma who received the combination experienced improved disease control and survival. Jones et al compared two CHOP regimens (CHOP with either low-dose bleomycin or bacille Calmette-Guérin [BCG] by scarification) to COP-Bleo (cyclophosphamide/vincristine/prednisone, with low-dose bleomycin). In patients with follicular lymphoma, they found no difference in complete response rates, relapse-free survival, and overall survival among the three groups.
- Other Combinations-In an effort to improve outcomes in this setting, other regimens have been tried. Ezdinli and associates analyzed 252 patients with advanced-stage favorable NHL treated with moderate-CP (cyclophosphamide, prednisone)-vs intensive- BCVP (carmustine [BCNU, Gliadel], cyclophosphamide, vincristine, prednisone) or COPP (cyclophosphamide, vincristine, procarbazine, prednisone)-chemotherapy regimens. They found an overall complete response rate of 57% and a median duration of remission of 88 weeks. There was no difference in the response rate, response duration, or survival rate among the various groups. In a recent Italian study, Zinzani et al performed a comparative trial of FM (fludarabine [Fludara], mitoxantrone(Drug information on mitoxantrone) [Novantrone]) with CHOP as front-line chemotherapy, with and without sequential rituximab(Drug information on rituximab) (Rituxan). They randomized 140 previously untreated patients with grades 1 and 2 follicular lymphoma to either CHOP or FM. The overall clinical response was the same in both groups (FM: 96%; CHOP: 98%). However, the complete response rate was higher in the FM arm (68% vs 42%; P = .003). They also found that the percentage of patients with a negative bcl-2/immunoglobulin heavy chain (IgH) status by qualitative polymerase chain reaction was higher in the FM group (47% vs 29%; P = .03). These results seem to indicate that FM may be superior to CHOP for front-line therapy of follicular lymphoma. However, it is unclear whether this superiority translate into superior progression-free or overall survival.
- Interferon-Interferon has been tried alone and in combination with cytotoxic chemotherapy for the treatment of advanced follicular lymphoma. The individual studies are summarized in Table 3.[37,65-72] Rohatiner et al performed a meta-analysis of these clinical trials involving interferon. Their initial meta-analysis showed an overall survival difference in favor of interferon, but a significant heterogeneity effect suggested significant differences between trials. The investigators then divided the trials based on the interferon dose used and found that trials using a more intensive therapy showed a large and significant survival advantage in favor of interferon, with a 14% survival difference at 5 years (74% vs 60%) and a 19% survival difference at 8 years (57% vs 38%). However, trials that used a low-intensity interferon regimen showed no survival difference.[ 73] The results with the use of interferon are mixed, thereby leading to controversy about the exact role of interferon in the treatment of advanced follicular lymphoma.