The results of the ECOG E4402/RESORT trial recently reported by Kahl and colleagues,¹ and reviewed in this issue of The ASCO Post, provide interesting new information on the use of maintenance rituximab (Rituxan) vs retreatment with rituximab at progression in patients with low–tumor burden indolent lymphoma initially treated with single-agent rituximab. The authors conclude that the retreatment strategy provides comparable results while using less rituximab.

Study Design Raises Questions

Many of the controversial issues with this study relate to how the actual study design and choice of endpoints influence the conclusions the reader can make today. Rituximab maintenance was scheduled to continue indefinitely until treatment failure occurred. It is now relatively well established that continuing rituximab maintenance for an indefinite duration is not desirable and has been associated with increased infectious complications. Thus, most current studies limit the length of maintenance therapy to 2 years.

The endpoints of the study are also problematic. What was the definition of treatment failure? Patients whose lymph nodes went from 1 cm to 2 cm had progressive disease by definition but clearly did not always need additional therapy. This problem is also exaggerated by the use of computed tomography scans every 6 months for the duration of the study. This approach will undoubtedly detect these types of small progressions that do not require therapy, leaving questions about the use of time to treatment failure as an appropriate endpoint. It is stated, but not widely appreciated, that patients on retreatment could be treated multiple times before being called a treatment failure. The difference between this strategy and maintenance can certainly blur in specific patients.

What Determines Treatment Failure?

Most problematic, however, is the study definition that “inability to complete planned therapy for any reason” is part of the definition of treatment failure. Since maintenance went on forever, a patient who remained in remission and decided to stop maintenance, say after 2 to 5 years, was called a treatment failure. In fact, every patient on the maintenance arm who remains in remission will either continue maintenance forever or ultimately be labeled a treatment failure when they decide they have had enough maintenance therapy and stop the proposed schedule.

The concept that everyone on maintenance will ultimately become a treatment failure while those on retreatment may stay in remission is certainly problematic. The authors have tried to answer this question by censoring the patients who chose to stop treatment voluntarily on the maintenance arm from the primary analysis. When they do that, the curves for time to treatment failure separate some, with 65% in the retreatment arm and 73% in the maintenance arm free of treatment failure at 3 years (P = .16 in article’s appendix).

Finally, although there was no protocol-based definition of when to institute chemotherapy, there was a significant difference in time to next chemotherapy favoring the maintenance arm (P = .03). This should also impact the cost analysis, which focused on the doses of rituximab administered but not the increased cost of chemotherapy caused by its earlier and therefore perhaps more frequent usage in the retreatment arm. Recall also that the cost of rituximab is estimated to decrease by 25% to 35% as biosimilar molecules enter the market.

Thus, what conclusions can be reached with some certainty? First, a retreatment strategy does appear to provide comparable disease control using less rituximab based on the definitions employed in this study. For some patients, this is clearly a viable option. However, maintenance rituximab does produce a major prolongation of progression-free survival and freedom from cytotoxic therapy. For some patients, this also may be a viable option.

In the end, a knowledgeable physician and an informed patient will need to explore their particular treatment goals. Why should we be surprised? Absolute statements about how to treat follicular lymphoma have never been easy to achieve.  ■

Disclosure: Dr. Fisher reorted no potential conflicts of interest.

Reference

1. Kahl BS, Hong F, Williams ME, et al: Rituximab extended schedule or re-treatment trial for low–tumor burden follicular lymphoma: Eastern Cooperative Oncology Group Protocol E4402. J Clin Oncol. August 25, 2014 (early release online).

Dr. Fisher is President and CEO, Fox Chase Cancer Center – Temple Health, and Senior Associate Dean, Temple University School of Medicine.