Erin Gourley Reid, MD
Watchful waiting can often be a psychological double-edged sword for cancer patients. On the one hand, it can be a relief not to face immediate risks of chemotherapy; on the other hand, it can be difficult to live with cancer and not be doing anything about it — the “watch and worry” perspective. For asymptomatic advanced-stage follicular lymphoma, early treatment has yet to be proven beneficial to long-term outcomes. Given that the disease remains incurable, a major principle of management is to maximize the time before initiation of chemotherapy with its attendant risks.
Data presented yesterday in the plenary talk by Dr. Kirit M. Ardeshna and colleagues from London challenge the watchful-waiting approach for those patients with asymptomatic advanced-stage follicular lymphoma. Citing the relative tolerability of rituximab, the team designed a randomized, controlled prospective trial to determine whether initial treatment with rituximab resulted in improvement in the median time to initiation of therapy by at least 18 months compared with the standard watchful-waiting strategy. Subjects were randomly assigned to one of three arms:
Arm A: watchful waiting
Arm B: rituximab 375mg/m2 weekly for 4 weeks
Arm C: rituximab 375mg/m2 weekly for 4 weeks followed by rituximab maintenance every 2 months for 2 years (starting at month 3 until month 25)
The five-year study was modified mid-way in 2007 to discontinue Arm B based on accumulating reports regarding the efficacy of maintenance rituximab. Subjects were monitored for response at month 7, 13, and 25 with required CT imaging at months 7 and 25 and bone marrow required to confirm complete response suggested by clinical and radiographic criteria.
Aware that patients were still receiving protocol therapy, the data-monitoring committee recommended full analysis of the data in March of this year. This demonstrated that time to initiation of new therapy was similar to previous studies at 34 months in the watchful-waiting arm while the median time was not yet reached in the rituximab arms at four years. At three years, the percentage of patients not having started new treatment was 48 percent in the watchful-waiting arm, 80 percent in the rituximab-induction arm, and 91 percent in the rituximab-maintenance arm. Furthermore, there was a highly significant difference in progression-free survival between all three arms. Thirty-one of the 45 observed serious adverse events occurred in the rituximab-containing arms and included infections, allergic reactions, and four cases of neutropenia.
Updates to the data were presented at the session. Currently, there is no difference in overall survival between the three arms with 95 percent of all patients remaining alive.
Dr. Ardeshna concluded, “It is too early to make definitive treatment recommendations as we need to analyze the quality-of-life data. However, if these do not demonstrate a detriment to quality of life in the rituximab arm, this option is likely to be a popular one for patients and their doctors.”
The discussion following the abstract involved several members of the audience challenging change to the standard practice of watchful waiting outside of demonstrating overall survival benefit. Dr. Ardeshna conceded that, while upfront rituximab may not replace watchful waiting, favorable quality-of-life data would support its use as an alternative option.
It looks like we will be watchfully waiting for an answer along with our patients.
Dr. Reid receives research funding from Millennium for an investigator-initiated study and is a PI for pharma-sponsored trials from BMS, Millennium, and Novartis.