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Detroit, MI
Dr. Ruckdeschel is President and CEO, Karmanos Cancer Institute, Detroit, MI.
Correspondence to: John C. Ruckdeschel, MD, FCCP, 4100 John R, Executive Offices 2nd Floor, Detroit, MI 48201; e-mail: ruckdeschel{at}karmanos.org
The article by Chen et al1 (see page 1031) is highly instructive from a number of perspectives. First and foremost, the authors (and the reviewers) failed to emphasize that this is a randomized phase II trial and not a randomized phase III trial. Phase III trials are true comparison trials and are sized so that clear inferences can be made about the superiority (or lack thereof) of any of the study arms tested. Randomized phase II trials are designed to choose the best option from among several with similar expected outcomes and to test the feasibility of randomizing across different modalities. They are, in reality, parallel phase II trials. The required numbers for these trials are far smaller than phase III trials. Their major use is in eliminating the problems inherent in interpreting the outcome of multiple phase II trials done at separate institutions. It is not statistically valid to draw conclusions based on comparisons between the study arms.23 Consequently, the inter-arm comparisons in this trial are invalid, although an actual phase III trial confirmed these findings.4 Despite that, there are several useful lessons from this trial.
The major lesson for pulmonologists from this article is that second-line (and even third- and fourth-line) therapy for metastatic non-small cell lung cancer is common and reasonable for patients who remain in "good" condition and who desire further treatment.567 This is an important change in clinical perspective. A decade ago, there were essentially no active regimens for patients who failed first-line chemotherapy. Indeed, up to the mid 1990s, the response rate for first-line chemotherapy was only on the order of 20 to 25%, and only 25% of patients with metastatic disease survived > 1 year.8 Following the introduction of the taxanes, gemcitabine and navelbine, in the mid-1990s, the response rates have climbed and 1-year survival is closer to 50%, with 20 to 30% of patients with metastatic disease surviving 
2 years.910 The later introduction of the epidermal growth factor receptor (EGFR)-targeted agents, gefitinib and erlotinib,11 has added another level of response and disease control that has served to prolong survival in the second-line setting. Most recently the addition of bevacizumab, an angiogenesis inhibitor, to paclitaxel plus carboplatin resulted in a significant improvement in survival, although there is a small subset of patients with severe and even fatal hemorrhage.12 When I first joined the American College of Chest Physicians in 1993, there were still debates about whether patients should receive any chemotherapy for metastatic lung cancer. We are, thankfully, well beyond those discussions as demonstrated by the appearance of this article in CHEST (see page 1031).
Docetaxel was, for a period, the only agent approved by the US Food and Drug Administration (FDA) for this indication, and that is a lesson in itself. The FDA approval process bears no relationship to the actual utility of any regimen compared to another. The company need only show that the outcome is superior to no treatment or to some other inferior therapy. Several other agents are now approved for use in this setting, including pemetrexed (an antifol13) and erlotinib (an EGFR inhibitor11). Pemetrexed has been shown to have equal efficacy with lower toxicity in a phase III randomized trial.13 In practice, oncologists try to choose a regimen that is non–cross-resistant with the regimen that just failed and which the patient can tolerate. The data on weekly therapy have been a bit confusing. There are no reports that it is superior to traditional every 3-week therapy, only that in some settings that it may be less toxic.
A second lesson from this trial is the importance of pharmacogenomics. It is clear that Asian patients have very different response rates and toxicities to several common chemotherapy regimens including docetaxel14 and other taxanes.15 In addition, the response rate to the EGFR inhibitors, gefitinib or erlotinib, is significantly higher in Asian patients, especially young, female patients who have lung cancer despite a negative smoking history.16 This has now been correlated with a much higher rate of EGFR mutations in this group of patients.16 This is not an issue of racial profiling; it is a matter of what works and doesn’t work in patients, and needs to be factored in to studies and day-to-day clinical decision making.
It is frustrating that this article was not the randomized study that we need but rather another tidbit of information that suggests benefit. Despite at least one true randomized trial4 suggesting equal efficacy and lower toxicity, the type II error is large enough that significant differences may still exist that favor more intensive doses every 3 weeks. It is not yet time to leap to the conclusion that weekly therapy is better. The only certainty we have to date is that the reimbursement for weekly therapy is superior.
References
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