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St. Louis, MO
Dr. Yusen is an Assistant Professor of Medicine, Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences, Washington University School of Medicine. Dr. Littenberg is the Henry and Carleen Tufo Professor of Medicine, Division of General Internal Medicine, University of Vermont.
Burlington, VT
Dr. Yusen is a consultant for Spiration, Inc. Spiration is developing and testing an intrabronchial valve for endoscopic lung volume reduction surgery, and a lung volume reduction surgery lung capturing device. Dr. Yusen also serves on a clinical events committee for two related studies.
Correspondence to: Dr. Roger D. Yusen, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, Campus Box 8052, 660 S. Euclid Ave, St. Louis, MO 63110; e-mail: ryusen{at}im.wustl.edu
Most patients with severe COPD remain significantly symptomatic despite medical therapy, and they have a disturbingly high short-term mortality. Many patients desperately seek symptomatic relief, and they would consider undergoing a major procedure such as lung volume reduction surgery (LVRS) to improve quality of life, whether or not the treatment produces a survival benefit.
In this issue of CHEST (see page 1108), Miller et al describe the combined results of two modestly sized randomized controlled trials of LVRS. The four-center Canadian Lung Volume Reduction (CLVR) study and the six-center US Overholt Blue Cross Emphysema Surgery Trial (OBEST) compared the effects of bilateral LVRS to medical therapy in patients with COPD due to emphysema. Almost all of the patients had heterogeneously distributed emphysema demonstrated by chest CT scan, with a predominance of disease in the upper lobes. The CLVR trial excluded patients with 
1-antitrypsin deficiency, and OBEST excluded patients with a lower lobe predominance of emphysema. Each patient completed a required pulmonary rehabilitation program of 6 to 8 weeks duration prior to randomization. Of the combined 93 enrolled patients, 54 were randomized to LVRS and 39 were randomized to medical therapy alone (OBEST used a 2:1 allocation ratio).
The primary outcome of CLVR was the Health Utility Index score. For OBEST, the primary outcomes were the 6-min walk distance and the interviewer-administered Chronic Respiratory Disease Questionnaire (CRQ). Both studies evaluated patients with the CRQ, the 6-min walk test, the Medical Outcomes Study 36-item Short Form (SF-36) questionnaire, and pulmonary function tests. Miller and colleagues combined the individual patient results of the overlapping outcomes assessments from the two studies and presented the 6-month postrandomization findings; they did not report the primary outcome data from CLVR.
The combined data from the two studies demonstrated similar mortality in the LVRS cohort (5.6%) and the medical cohort (5.1%) at 6 months after randomization. However, among the survivors, the LVRS group experienced improvement in pulmonary function, exercise capacity, dyspnea, and physical functioning, and the medical therapy group experienced either no change or deterioration. The authors concluded that LVRS produced better palliation than medical therapy.
Both studies were initiated prior to completion of the National Emphysema Treatment Trial (NETT),1 the largest prospective randomized controlled trial of LVRS vs medical therapy ever conducted. The NETT and these two smaller trials used somewhat similar eligibility criteria, though the NETT allowed enrollment of patients with a wider range of lung function and emphysema distribution as depicted on imaging studies. Over an average of 2.4 years of follow-up, the NETT did not show a difference in survival between patients randomized to LVRS and patients randomized to medical therapy. However, lung function, exercise tolerance, dyspnea, and quality of life were better in survivors of LVRS compared to survivors of medical therapy. Post hoc analyses suggested the following: (1) the subgroup of patients with heterogeneous upper lobe predominant emphysema and with low postrehabilitation exercise capacity experience a survival benefit from LVRS compared to medical therapy; and (2) the subgroup of patients without heterogeneous upper lobe predominant emphysema and with high postrehabilitation exercise capacity experience a higher mortality from LVRS compared to medical therapy.
After a decade of publications involving thousands of patients in cohort studies, hundreds of patients in small randomized controlled trials, and over a thousand patients in the NETT, many questions remain unanswered. Do the benefits of LVRS outweigh the harms? The NETT, the CLVR study, the OBEST, and the other published randomized controlled trials of LVRS have all demonstrated a low but significant early postoperative mortality (approximately 5%) from LVRS. The NETT has been the only published randomized controlled trial that assessed the impact of LVRS on mortality past 1 year after randomization, and a survival benefit from LVRS has not been demonstrated over a few years of follow-up. Although the NETT results suggest that a subgroup might improve its survival with LVRS, bias may have led to erroneous conclusions in this post hoc analysis.2 Likewise, one cohort study3 with concomitant controls of patients with heterogeneous emphysema suggested that LVRS prolongs life after 2 to 4 years of follow-up, but the comparison of nonrandomized groups may have introduced significant bias. Overall, the impact of LVRS on survival seem clear: The surgery causes low but significant early mortality, and we lack the data to strongly support that it improves longevity.
Judging the success or failure of LVRS based only on survival is inadequate, especially since LVRS appears to provide significant palliation. Every published randomized controlled trial has shown that LVRS improves symptoms and functioning in survivors.145678 However, the follow-up duration in these studies has typically been measured in months and not years. Long-term quality-of-life data from randomized controlled trials have not been published, though a few nonrandomized studies have suggested that LVRS improves quality of life for at least 2 to 5 years.9101112131415
Unfortunately, most studies that have assessed quality of life and survival have not provided a formal mechanism for weighing the risks vs the benefits. Patients who die are often censored from quality-of-life assessments as if their outcomes were neither good nor bad. This practice tends to inflate the apparent benefits of interventions with increased mortality, an issue that becomes more important during long-term follow-up as the death rates rise. When studying the overall effects of a treatment, it is insufficient to measure survival or quality of life; Survival and quality of life need to be measured, and the results need to be presented as a package. Some studies have tried to address this issue by focusing on success rates and by reporting proportions of patients improved within treatment groups.1 In this scenario, all patients are included, and transplanted patients (presumably transplanted for poor quality of life after LVRS), missing patients, and the dead are considered treatment failures.
Formal mechanisms for combining quantity and quality of life information exist. One approach adjusts the observed length of survival by a numeric factor that represents quality of life. For example, investigators may use certain types of quality-of-life data to generate quality scores for all patients. Investigators use quality scores added up over time to estimate quality-adjusted life years (QALYs). QALYs take into consideration quantity as well as quality-of-life consequences of illnesses and their testing and treatments. The group with more QALYs has a better quality-adjusted survival. For example, if an LVRS cohort and a medical therapy cohort have equal survival rates, then the group with better quality of life will generate more QALYS. Alternatively, a relatively high mortality could be offset by excellent quality of life within a cohort of LVRS patients, while a relatively low mortality and low quality of life in a cohort of medical patients might produce fewer QALYS than in the LVRS cohort. Using QALY and cost data, researchers can estimate the cost-effectiveness of LVRS.16
A few studies assessing LVRS have used instruments that incorporate quality of life and survival into one measure.1816 The NETT did not detect a difference in survival between the treatment arms at the end of the study period, but it did show a clinically and statistically significant higher quality-adjusted survival in patients undergoing LVRS.116 Although the surgical and medical groups both showed declines in quality of life during follow-up, the medical group declined more rapidly. Interestingly, if similar findings would have occurred in a cohort study of LVRS without a non-LVRS control arm, this finding would have not been detected and LVRS would have been considered a failure. Even in a subgroup of NETT "high-risk patients," where the LVRS group had a markedly higher death rate than the medical group, the two treatment groups had similar quality-adjusted survival during follow-up, demonstrating that the higher mortality associated with LVRS was offset with gains in quality of life.17
For those who hoped that LVRS would be a panacea for patients with severe COPD due to emphysema, these data are disappointing. LVRS does not appear to extend life in most patients. However, LVRS does offer the hope of significant improvement in quality of life. Patients, clinicians, researchers, policy makers, and payors face many challenges in making decisions about LVRS. Clinicians need to help patients to balance the considerable risks and costs of LVRS against the likely impacts on longevity, symptoms, functioning, and other aspects of quality of life. Investigators need better tools for measuring quality of life, and for negotiating these trade-offs with patients. Policy makers and payors need robust methods for evaluating the outcomes (and costs) of interventions designed to improve health, so they may make informed judgments. We propose that future studies of LVRS and other technologies assess patients with tools that integrate both survival and quality-of-life information.
References
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