To the Editor: Recently, Eaton and Martins (JNCCN 2010;8:815–821) nicely reviewed pivotal studies of maintenance therapy for non–small cell lung cancer (NSCLC). They note that, in the study by Fidias et al.,1 “only 63% of patients randomized to delayed docetaxel after evidence of disease progression underwent this therapy” and that in other studies in which subsequent crossover was not part of the design, even fewer patients crossed over. They concluded that “current clinical trials do not preclude the equivalence or superiority of the paradigm of watchful waiting between first- and second-line treatments.”
Although their conclusion is true, the fact that in the docetaxel study—in which the patients were randomized to receive delayed docetaxel—only 63% actually did, underscores a very common theme. Despite the recent addition of multiple FDA-approved drugs and other non-approved drugs for second- and even third-line NSCLC treatments, the number of patients who actually receive these drugs decreases with each subsequent line of therapy (i.e., many fewer patients receive second-line therapy as receive first, and again fewer receive third-line compared with second). This pattern suggests that a window of opportunity for patients to be exposed to these modestly active drugs will commonly be missed under a plan for observation with the expectation of treatment at progression.
One might speculate that with closer follow-up, more patients would receive these agents at progression, but I know of no evidence suggesting that close observation changes this well-established pattern of “drop-off” between lines of therapy. As still more active agents become available, it is important to recognize that watchful waiting could likely result in lost opportunities for patients to be exposed to active therapies.
Steven Sorscher, MD
Washington University in St. Louis
The Authors Reply: Dr. Sorscher raises a very important point regarding the data of “maintenance chemotherapy.” What percentage of patients are not able to be treated with second-line therapy at disease progression if a strategy of “watchful waiting” is chosen? No population-based data are available on the rates of second-line chemotherapy in patients with documented partial response or stable disease after 4 cycles of platinum doublet chemotherapy, the population investigated in the trials discussed. Consequently, we do not know if the 63% seen in the trial investigating delayed docetaxel1 is in line with what happens in the community.
A number of factors influence the administration of chemotherapy. For example, younger age and having private insurance are associated with higher rates.2 The very low rates of crossover to the maintenance therapy in the trials involving pemetrexed and erlotinib may not reflect a decline in performance status but rather the lack of availability of these agents due to economic or regulatory constraints.
Dr. Sorcher's letter also raises the question of how to define “close follow-up.” In the docetaxel trial, patients assigned to delayed therapy were seen every 3 weeks and underwent imaging evaluation every 3 months. With this schedule of follow up, the authors note that “additional patient review revealed that many of these patients (not treated on the delayed arm) experienced significant symptomatic deterioration by the time they reached PD and were unable to receive docetaxel therapy.” Notably, this trial does not say if the patients not treated with docetaxel received other second-line therapy. This trial accrued between February 2000 and October 2005. Pemetrexed was approved for second line therapy of non–small cell lung cancer in August 2004, and erlotinib was approved for the same indication in November 2004. Consequently, the “drop off” rate described is for docetaxel use but may not be for all second-line options. One can only speculate if the use of other second-line therapies may have influenced the lack of statistically significant survival benefit observed.
At the University of Washington, we explain to patients that “delayed second-line therapy” includes: 1) immediately reporting new or worsening symptoms impacting quality of life; 2) monthly visits; and 3) radiologic evaluation with approximately the frequency (every other visit) that they would have if they were receiving chemotherapy. We believe that patient education regarding symptom reporting and access to the medical oncologist are paramount for the safety of a “watchful waiting” strategy.
Keith D. Eaton, MD, PhD Renato G. Martins, MD, MPH
University of Washington in Seattle
Call for Correspondence
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FidiasPMDakhilSRLyssAP. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell-lung. J Clin Oncol2009;27:591–598.
RascoDWYanJXieY. Looking beyond Surveillance, Epidemiology, and End Results: patterns of chemotherapy administration for advanced non-small cell lung cancer in a contemporary, diverse population. J Thorac Oncol2010;5:1529–1535.