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Chapel Hill, NC
Dr. Detterbeck is Professor of Surgery, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill.
Correspondence to: Frank C. Detterbeck, MD, FCCP, Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Medical School Wing C, Room 354, CB 7065, Chapel Hill, NC 27599-7065; e-mail: fdetter{at}med.unc.edu
In the past 15 years, there have been numerous publications of clinical trials demonstrating that chemotherapy has a palliative benefit for patients with advanced non-small cell lung cancer (NSCLC).1 These studies have indicated a prolongation of survival (1-year survival of 30 to 40% vs 10%), amelioration of symptoms, and better or at least stable quality of life (QOL), all at the price of either a small cost or in some cases even a cost savings.2 Nevertheless, skeptics argue that the benefits are modest and apply only to very selected patients enrolled in clinical trials.34 This argument suggests that little progress has been made for the majority of patients with advanced NSCLC who are treated outside of the context of a clinical trial. The skeptics assert that the apparent progress is really due merely to better staging (stage migration) and patient selection (the diminishing denominator).
The article by Waechter and colleagues in this issue of CHEST (see page 738) is an important study because it indicates that the gains noted in the randomized trial setting are in fact applicable to patients in general. They studied all consecutive patients presenting to the hospital clinics of University of Basel, Switzerland, for palliative treatment of NSCLC from 1990 to 2002. We are not informed of how many patients were treated in the context of a clinical trial, but only a small minority were treated with an experimental agent that was not part of mainstream therapy for these patients. All patients were included in the study whether they received active treatment or only supportive care. Their results clearly indicate an improvement in duration of survival during the course of the study. In addition, the outcomes of all patients treated with chemotherapy in the later years of the study (after 1997) parallel those of more strictly selected patients treated in the context of a clinical trial, as reported by others.1 Furthermore, better outcomes were also noted for patients treated in the later years only with best supportive care (BSC).
These results indicate that life in the real world has, in fact, gotten better for patients with advanced, incurable NSCLC. One-year and 2-year survivals of 40% and 23% are markedly better than the historical 1-year survival of 10%. The benefit does not seem to be related to better patient selection because it involves a consecutive unselected series of patients, and because there is no difference in patient and disease characteristics between those seen later and earlier in the study (before and after 1997). Although this is a retrospective study, data regarding such prognostic factors were obtained in a prospective standardized fashion. The better outcomes also do not seem to be related to stage migration, as the authors state that there has been no change in staging procedures throughout the course of the study. Specifically, positron emission tomography scanning was not generally used and did not result in a change of stage in these patients when it was used. However, details of staging procedures are not provided, and it remains possible that there were differences that were not apparent, even to the authors. Finally, it is possible that the improvement in outcomes represents a change in the type of patient referred to this center over time. The authors have stated that no change in referral practice in the region has occurred during the course of the study (Waechter, MD; personal communication; August 2004).
It is not clear from this study, however, what exactly does account for the better survival since 1997. Although outcomes are better for patients treated with "modern," third-generation chemotherapy regimens, outcomes were also better for patients receiving only BSC or for those receiving second-line chemotherapy. Although multivariate analysis was used to try to define this, the answer is not entirely clear. The use of modern chemotherapy agents loses independent prognostic value when treatment after 1997 is added to the model. This is corroborated by the improvement in survival since 1997 even for subsets of patients receiving only BSC, second-line chemotherapy, or only stage IV patients. The conclusion is that the improved results must be due to multiple factors, and improvement therefore occurred in all forms of treatment of these patients. Whatever the explanation, the fact that this is applicable broadly to patients is an important finding.
Very few patients were included in this study with a performance status of 3 or 4 (5%, compared with 20% in population-based series.5) Presumably, such patients were not referred to the University of Basel, and it is unclear whether the benefits of modern treatment (including BSC) extend to such patients.
The proportion of patients seen at the University of Basel with incurable lung cancer who were treated with chemotherapy is remarkably high (87%). This is in marked contrast to population-based studies in the United States (7 to 41%)67 and Europe (10 to 20%).8 This suggests that either the willingness to administer chemotherapy was much higher at the University of Basel than in other locales, or that many patients (not just those with a performance status of 3 or 4) were not referred to the University of Basel. The former hypothesis is supported by the consistent finding in other studies that the rate of chemotherapy use in patients with lung cancer is less dependent on comorbidities and is primarily due to differences in physician attitudes, and the level of sophistication of the institutions involved.679 Therefore, the results from the University of Basel indicate that therapeutic nihilism for patients with advanced NSCLC is no longer justified, and that the majority of such patients benefit from treatment (with the possible exception of patients with a performance status of 3 or 4).
Even most skeptics would have to agree that a difference in 1-year survival of 40% with aggressive treatment (either chemotherapy or BSC) vs 10% with the historical approach represents a clinically significant gain for patients with incurable NSCLC. The study by Waechter and colleagues shows that such outcomes can be achieved in the vast majority of patients. Advanced NSCLC has changed from a relatively hopeless situation to a disease that one can live with, at least for some time, with modern treatment approaches.
References
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