In this issue of ONCOLOGY, David Maloney presents the evidence for rituximab (Rituxan) maintenance in patients with follicular lymphoma. Rituximab maintenance refers to the use of prolonged treatment with rituximab alone after a response to initial therapy. However, it includes many types of administration (for example, one injection every 2 or 3 months, or four infusions every 6 months) for different durations (most frequently 2 years) in different settings (first-line or relapse), and after different treatments have induced the initial response (rituximab alone, chemotherapy without rituximab, rituximab/chemotherapy combination, or autologous transplant).

Studies exist in all these settings, and all such investigations are designed differently; none may be considered confirmatory. However, all studies have shown the same results: a statistically lower relapse rate in patients receiving rituximab maintenance therapy and, thus, a prolongation of progression-free and overall survival.

Unconfirmed Benefit

Although these studies have shown a statistically significant advantage in terms of survival, most of them are not relevant to the current treatment of follicular lymphoma. Most patients are now treated with R-CHOP, a combination of rituximab and CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone), allowing high complete response rates and longer progression-free survival than any other available treatment (even if the superiority of R-CHOP over R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] was not proven in a prospective randomized study).

None of the studies presented in the article by Dr. Maloney have looked at the benefit of rituximab maintenance in patients treated with first-line R-CHOP. This is precisely the objective of the European Primary Rituximab and Maintenance (PRIMA) study, which is closed for accrual with 1,200 patients given R-CHOP or R-CVP and more than 1,000 of them randomized between observation and rituximab maintenance for 2 years. However, the median follow-up after randomization is currently too short, and no analysis has yet been presented.

In his review, Dr. Maloney writes, "Given the above data [showing a statistically significant benefit in relapsing patients treated with R-CHOP] it would seem reasonable to conclude that the results should be similar [in first-line patients treated with R-CHOP]." This has not been demonstrated. We may assume that patients achieving a complete response with R-CHOP in the first-line setting have less refractory disease and a deeper response than relapsing patients, as demonstrated by a much longer median progression-free survival than the one observed after R-CHOP at time of relapse. Because of this deeper response, the demonstration of the benefit of rituximab maintenance may require a longer period of observation or may never be seen in the whole population of patients.

A benefit in patients with more aggressive disease or in those who did not reach a complete response after induction also seems probable but has not been demonstrated. In fact, only one study has been presented in first-line patients treated with R-CHOP and then randomized between observation and rituximab maintenance, and that study was conducted in patients with diffuse large B-cell lymphoma. These investigators concluded that there was no benefit from rituximab maintenance.

Magnitude of Benefit

Thus, while it may seem logical that rituximab maintenance benefits follicular lymphoma patients treated with first-line R-CHOP, the magnitude of this benefit is totally unknown. Based on these assumptions, Dr. Maloney recommends that rituximab maintenance "should be considered," especially in high-risk patients. Even if this strategy is associated with a benefit during the first years after treatment, I am not certain that we may consider it standard treatment—that is, treatment implemented by several randomized studies.

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