Creeping phase II-ism and the medical pharmaceutical complex: weapons of mass distraction in the war against lung cancer.

This issue reports the long-awaited Radiation Therapy Oncology Group (RTOG) phase II study that incorporated paclitaxel, the new drug of the 1990s, with standard twice-daily radiotherapy and cisplatin plus etoposide, which was presented initially at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO) in 2000. In that abstract, the authors addressed the following questions. Can the addition of paclitaxel to etoposide and cisplatin result in improved survival for patients with limited small-cell lung cancer (SCLC)? Can the addition of paclitaxel improve on the results (1-year survival of 70% and median survival of 23 months) of the best arm of the Intergroup study? They reported that the 1-year survival rate on their study was 83%, inferring an advantage at this unorthodox benchmark, but the median survival had not yet been reached. Ettinger et al have more carefully modified their prose in preparing this final report for the trial and parsed every phrase to diligently inform all and offend no one. At the end of the day, the addition of paclitaxel to etoposide plus cisplatin provides no advantage to standard treatment without paclitaxel, which is similar to the conclusion of the results of the extensive disease trial that incorporated these three drugs. Moreover, as in most lung cancer trials, the third drug adds toxicity without survival benefit. Unlike this sober and direct final report and the abstract on the phase III study in extensive-disease SCLC, the original abstract and preliminary presentation of these data perhaps over-optimistically forecast the survival benefit for this threedrug combination administered with concurrent twice-daily radiotherapy. We are all enthusiastic about our work and interested that the world should know about its promise. But, is it really useful news that the abstract proffered information that was ultimately misleading about the final outcome and importance of the study? This was a phase II cooperative group trial initially reported as a preliminary result. Although it may not be news, there are unintended consequences of the practice of magnifying the importance of such preliminary results at the Annual Meetings of ASCO and creating too much enthusiasm for phase II study results. A San Francisco newspaper expressed concern to ASCO that the data presented at these meetings and in the abstract book might “move the market” and represent “insider trading” (perhaps a concern for an entirely different editorial in the future). I am more concerned that such reports move the hearts and minds of the clinical practice community, perhaps too soon for these preliminary results. At the same time, such preliminary reports also throw clinical research into a state of uncertainty. Determining what is truly promising from what is hyperbole can be quite difficult with too early results. Sometimes, we as authors stretch to find a measure that makes results seem better or more important than they are. We have to be particularly cautious about phase II results, preliminary or otherwise, and downright dubious about fanciful claims and novel end points, such as 1-year survival, in lung cancer or any other disease. Paclitaxel promised great hope in lung cancer, but now that results of mature trials are available, it has produced some frankly disappointing results compared with our initial expectations. It is clearly not as good as the lung cancer pundits forecasted or preached at advisory boards. Obviously, paclitaxel has some activity, but despite a different mechanism of action and toxicity profile from cisplatin and etoposide, it does not seem to add significant benefit to those drugs in SCLC. Similarly, there is a real issue as to whether it is better, the same, or not as good in locally advanced or metastatic non–smallcell lung cancer (NSCLC). A final report at the ASCO Annual Meeting in 1998 of a randomized phase III study of paclitaxel has not, as yet, seen publication in a peer-reviewed journal. Are paclitaxel combinations really better than cisplatin plus etoposide for SCLC or NSCLC? I can ask this about paclitaxel JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 22 AUGUST 1 2005