Waiting Is the Hardest Part

One of the more challenging conversations to have with a patient is one presenting a new diagnosis of an indolent and treatable type of cancer that is incurable but for which the plan is not to offer treatment but merely follow-up with the patient every few months to see what happens. This approach has been referred to as “watch and wait” (watchful waiting) or, by patients, as “watch and worry,” and has been a standard strategy for decades in the management of advanced-stage, asymptomatic follicular lymphoma (FL). To some patients, it is the relief of not needing intervention, allowing perhaps a bit of denial. But to others, it is as if the crescent blade in Edgar Allen Poe’s “The Pit and the Pendulum” is swinging overhead with its ominous descent “inch by inch, line by line, [. . .] at intervals that seemed like ages.” The rationalization is that all treatments have expense and adverse events, which might be worth it if cure is a realistic goal. However, FL is incurable and its progress slow but inexorable. The practice is supported by several retrospective and prospective studies comparing watchful waiting with early intervention ranging from regimens of only mild to moderate intensity to regimens of highly aggressive cytotoxic therapy with total lymphoid irradiation. In every instance, early intervention has failed to demonstrate a survival benefit compared with the anticipatory approach and with no suggestion that the likelihood of aggressive transformation is forestalled by therapy. Nevertheless, the argument has been made that these studies were conducted in the era before rituximab, the olden days before the anti-CD20 monoclonal antibody altered how we manage B-cell malignancies. Not only have complete and overall response rates improved with chemoimmunotherapy, but the incorporation of this antibody has provided the first evidence of a prolongation of survival in FL but again without any suggestion of cure. The controversy regarding watchful waiting was resurrected by Ardeshna et al in December 2010 at the American Society of Hematology meeting. The investigator presented a preliminary analysis of a trial in which 450 patients with asymptomatic, advanced-stage, nonbulky FL were randomly assigned to either watchful waiting or to four weekly doses of rituximab followed either by observation or by 2 years of maintenance rituximab. The time to initiation of chemotherapy or radiotherapy was significantly prolonged in the early intervention arms. For those opponents of watchful waiting, this study was taken as a validation of their practice. However, several valid criticisms of the study by Ardeshna et al have arisen. First, instead of comparing the time to initial treatment for the watchful waiting patients with the time to second-line therapy for the treated patients, the more appropriate comparison would have been time to second lymphoma therapy for each of the cohorts and their overall survival. Thus, it is important to note that there was no suggestion of a survival benefit for the patients treated initially. Additional data from the National LymphoCare Study also suggest that the progressionfree survival for patients who are managed first with watchful waiting and are treated at progression with rituximab is at least comparable with others treated with the antibody at diagnosis. The article by Solal-Celigny et al that accompanies this editorial adds additional fuel to this controversy. These investigators mined their database of 1,093 patients who had been registered onto the F2 study, a prospective collection of demographic and treatment data in the post-rituximab era, attempting to validate the Follicular Lymphoma International Prognostic Index (FLIPI), which was conducted before the use of rituximab. They identified 120 patients who were managed with watchful waiting, 80% of whom had advanced-stage disease and all had a low tumor burden. With a median follow-up of 64 months, half of the patients required therapy at a median of 14 months into the observation period, whereas the median time of observation without treatment was 55 months. Once treated, the response rate was 82%, including 60% complete remissions. The only predictor of a short time to lymphoma treatment was involvement of more than four nodal areas; however, whether early treatment in that population had an impact on outcome cannot be determined. The time to treatment failure was comparable with 242 patients from the data set with good prognostic features but who were started on initial rituximab therapy. However, the watchful waiting patients were less likely to have an increased lactate dehydrogenase, bulky disease, anemia, and a lower FLIPI score (although the difference in F-2 scores was only of borderline significance). With a 5-year overall survival of 87%, the conclusion was that watchful waiting remains a valid option. Nonetheless, the concept of merely observing the natural history of a lethal malignancy, even one that is usually indolent, is not intellectually satisfying. What would it take to move beyond watchful waiting? A treatment would not only have to be efficacious but also well-tolerated and compatible with a good quality of life, unlike what occurs with most chemotherapy. Of course, it would preferably be curative as well. To reach such an objective, the focus of clinical research must be away from nonspecific chemotherapy regimens and toward combinations of noncytotoxic agents. Cancer and Leukemia Group B investigators have been studying doublets of biologic agents in untreated, low FLIPI FL—first rituximab plus galiximab, then rituximab plus epratuzumab, and most recently, rituximab plus lenalidomide as has also been reported by Fowler et al. All of these regimens achieved response rates around 90%, which is far greater than expected from either agent alone and comparable with what has JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 31 NOVEMBER 1 2012