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Individualized first-line management of FL
line treatment options in clinical trials needs to be under- stood. If maintenance rituximab is provided, a short schema (M3, M5, M7 and M9) is preferred because these give similar results to those of a prolonged schedule.50 Because such a recommendation results in complete response in 50 to 70%, without significant side effects, it allows “time without disease and chemotherapy” (option preferred by the patient) instead of “time to wait for treat- ment” (option preferred by the physician). With rituximab treatment, approximately 25% of patients will need re- treatment within 5 years1. In patients for whom “wait and watch” has been chosen, close clinical monitoring (every 3 months) should be carried out during the first year of sur- veillance, before moving to less intensive observation (every 6 months) in the absence of early signs of progres- sion. Patients must be assured that they will be seen promptly in the event of any concerns about progression. Annual CT scanning may be appropriate to offer and reas- sure the patient with isolated abdominal disease. The fre- quency of scanning is ultimately often reduced by those concerned about radiation exposure but for many with stable or only very slowly progressive disease annual imaging provides reassurance that they can continue with work or other life plans without expectation of interrup- tion. The use of PET to monitor FL during the “watch and wait” period is discouraged.
Advanced stage follicular lymphoma with treatment initiation criteria (high-tumor burden)
Immunochemotherapy improves overall survival
For disseminated FL that meets criteria for treatment ini- tiation, the benefit of combining rituximab with chemotherapy has been clearly demonstrated in four prospective randomized trials51-54 (Table 5.). A Cochrane analysis55 including these studies showed a 37% reduction in the risk of death (HR=0.63, 95% CI: 0.51 - 0.79) when rituximab is used in combination with chemotherapy as first-line treatment. Because of the significant decrease of toxicity, rituximab alone has been proposed. This approach cannot, however, be considered as standard treatment for symptomatic patients with FL considering the reduced PFS and TTNT compared to those achieved with immunochemotherapy.56
Rituximab maintenance improves progression-free survival but not overall survival
The PFS benefit of maintenance treatment using ritux- imab was demonstrated in the PRIMA trial.2 After induc- tion using immunochemotherapy, with R-CHOP, R-CVP (rituximab plus cyclophosphamide. vincristine, pred- nisone) or R-FCM (rituximab plus fludarabine, cyclophos-
phamide, mitoxantrone), responding patients were ran- domized to observation or maintenance treatment with rituximab every 2 months for 2 years. With 10 years of fol- low-up, this trial showed a significant increase in PFS for patients receiving maintenance treatment with a median PFS of 10.5 years versus 4.1 years for those not given main- tenance. The median time to the next treatment was not reached in patients receiving maintenance treatment com- pared to 6.6 years in the control arm. However, this trial did not show an OS benefit for maintenance, with 10-year OS being 80% in both arms, raising questions about the merits of maintenance, especially in elderly patients or those with respiratory problems in whom toxicity may be less acceptable. The PFS benefit of maintenance treatment with rituximab after immunochemotherapy with ben- damustine-rituximab was suggested in an ad hoc analysis in the BRIGHT study.57
The best chemotherapy regimen is likely patient-specific
A number of chemotherapy regimens have been enhanced by their combination with an anti-CD20 anti- body (Table 5). One study (Foll05) prospectively compared three different chemotherapy regimens,58 R-CVP, R-CHOP and R-FC (rituximab plus fludarabine and cyclophos- phamide), showing that while both R-CHOP and R-FC produced superior PFS and TTNT, in the long-term, the immunosuppressive toxicity of fludarabine precluded it as a first-line therapy. In two other studies R-CHOP was compared with rituximab-bendamustine.59,60 Although both studies suffered from methodological issues (non- exclusively FL population, abnormally low results of the R- CHOP arm, R-CHOP/R-CVP aggregation) they showed a superior PFS of the rituximab-bendamustine combination. The recent GALLIUM study,61 albeit with a non-random- ized choice of chemotherapy, was arguably the only study to systematically collect comprehensive toxicity data after bendamustine use. As a counterpoint to an emphasis on PFS as the key consideration when choosing bendamus- tine as the chemotherapy backbone, the rate of fatal adverse events in GALLIUM was 5.3% (36/676) in patients assigned to bendamustine as part of induction compared to 1.8% (9/513) in those who received CHOP or CVP after a median follow-up of 41 months. The difference was par- ticularly notable in older patients. The choice of chemotherapy backbone for a given patient is strongly influenced by the patient’s age, co-morbidities and treat- ment preferences (Table 6). Notwithstanding the debate over the potential trade-offs between toxicity and efficacy of CHOP and bendamustine, in patients with a contraindi- cation to anthracyclines, the preference may be for ben- damustine in younger patients while the CVP combination may be preferred in elderly patients because of its lower
Table 5. Randomized trials demonstrating the benefit of chemo-immunotherapy on overall survival.
Trial Treatment N. of patients Follow-up OS (%)
Rituximab P M390251 8xCVPvs8xR-CVP 318 53mo 77 83 0.029
(months) Control
GLSG54
M3902353
FL200052
6-8 x CHOP vs 6-8 x R-CHOP 428 8 x MCP vs 8 x R-MCP 201 6 x CHVP-I vs 6 x R-CHVP-I 360
60 mo 47 mo 100 mo
84 90 74 87 70 78
0.016 0.0096 0.076
OS: overall aurvival; CVP: 750 mg/m2 cyclophosphamide 750 mg/m2 intravenously (iv) day 1; vincristine 1.4 mg/m2 (maximum 2 mg) iv day 1; prednisone 40 mg/m2
days 1-5. CHOP: cyclophosphamide 750 mg/m2 iv day 1; doxorubicin 50 mg/m2 iv day 1; vincristine 1.4 mg/m2 (max, 2.0 mg) iv day 1; prednisone 100 mg/m2 po days 1-5. MCP : mitoxantrone8mg/m2 ivday1;chlorambucil3x3mg/m2 podays1-5;prednisolone25mg/m2 podays1-5.CHVP:cyclophosphamide600mg/m2 ivday1;doxorubicin25mg/m2 iv day 1; etoposide 100 mg/m2 iv day 1; prednisolone 40 mg/m2 po days 1-5. I: interferon-a: 3 x/week for 18 months, 4.5 MUI < 70 years ; 3 MUI > 70 years. R: rituximab: 375 mg/m2 iv
orally (po)
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