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Manhasset, NY
Great Neck, NY
Dr. Fein is Professor of Medicine, Dr. Ost is Assistant Professor of Medicine, and Dr. Glassman is Assistant Professor of Surgery, New York University School of Medicine. Dr. Philip Marcus is Clinical Professor, Department of Medicine, New York College of Osteopathic Medicine.
Correspondence to: Alan M. Fein, MD, FCCP, Center for Pulmonary, Critical Care and Sleep Medicine, North Shore-Long Island Jewish Health System, 300 Community Dr, Manhasset, NY 11030; e-mail: afein{at}nshs.edu
Everybody loves previews, and this issue of CHEST provides a great one. Like the early silent movies, lung volume reduction surgery (LVRS) has proven effective in gaining an audience, but has limited mass-market appeal. We are entering a great new age of therapeutics, in which medicine will harness the fruits of scientific advances in physiology, biochemistry, and molecular biology to improve the quality of life for many patients. Among the diseases proven most recalcitrant to treatment has been COPD, which has increased in prevalence and mortality to the point at which it is expected to be the third-leading cause of death by 2020.12 Recent reviews3 have highlighted new medical options now available for COPD management, particularly enhanced bronchodilator therapy (long-acting ßagonists and anticholinergics) and anti-inflammatory medications such as inhaled corticosteroids. Despite this improving therapeutic landscape, COPD remains a progressive degenerative disease, accompanied by declining functional status with enormous costs to the individual and society.
To address the limitations of medical therapy, surgeons over the years have devised many innovative interventions, including bullectomy, lung transplantation, and LVRS. LVRS has been the focus of multiple observational and at least two randomized clinical trials.4567 Despite the generally favorable findings reported by the investigators, there is only muted enthusiasm for this procedure, and it has not penetrated into most standard treatment paradigms. In fact, a recent systematic review3 concluded that "for most patients with COPD, LVRS cannot be recommended at this time." To understand the ambivalence in the medical community with respect to LVRS, it is useful to briefly review the development of surgical interventions for COPD and the significant barriers limiting its more widespread acceptance in medical practice.
Brantigan et al8 first proposed multiple wedge resections of emphysematous tissue > 40 years ago. He hypothesized that this would "resize" the lung, improving elastic recoil, airflow, and lung mechanics. This "resizing" hypothesis has been largely integrated into our current paradigm of emphysema physiology. Using the limited outcome methodologies available at the time, these pioneers reported overall clinical benefit. Despite these positive opinions, extremely high perioperative mortality, in the 25% range, limited its acceptance as part of the medical armamentarium for management of advanced emphysema. Cooper et al,9 utilizing advances in modern anesthesia and surgical practice, revisited these techniques and reported improved spirometry, dyspnea, and 6-min walk results after his "bilateral pneumectomy." In addition, mortality in these studies was < 5%, which was a significant improvement compared with historical controls. Multiple other groups subsequently reported their observational results, which have consistently demonstrated benefit despite variability in surgical strategy, technique, and selection. Gains in FEV1, exercise tolerance, reduced need for oxygen supplementation, decreased steroid use, and improved quality of life were all reported with benefits persisting up to 5 years after surgery. So what is the problem?
Mortality remained unacceptably high, especially when performed outside of the environment of a clinical trial. Death rates up to 17% within 6 months in a Medicare claims database were reported.10 These concerns lead to the recently completed National Emphysema Treatment Trial.7 In this study, short-term mortality was increased fourfold in those patients with a preoperative FEV1 or diffusion capacity < 20%.11 In addition, even within the context of a clinical research trial with leading academic centers, LVRS failed to modify all-cause mortality.7 However, certain subsets of patients accrued remarkable benefits, most notably those with heterogeneous, upper-lobe emphysema that failed to improve after a program of pulmonary rehabilitation. This emphasizes the pivotal role of patient selection, since different patient subsets, even in a carefully controlled clinical trial, had remarkably different outcomes. Thus, the skill of the selectors may be as important as the hands of the surgeon.11121314
Other factors have also contributed to the less than enthusiastic response to LVRS. Perioperative morbidity, most notably prolonged air leaks, and requirements for extended high-level nursing care, remain significant problems. Costs are enormous, and based on cost-effectiveness studies, LVRS make sense only if the physiologic benefits are sustainable, a hypothesis that has yet to be proven by long-term follow-up studies. The proportion of patients with COPD who meet these criteria and are willing to take the substantial short-term risks is unknown, but based on our own experience, is likely to be small.
What if there were another way to achieve the same physiologic outcomes while significantly reducing the risks from anesthesia, infection, and respiratory failure? What if even only part of the physiologic and quality-of-life benefit to patients with COPD afforded by LVRS could be produced at a fraction of the cost as well? The lung volume reduction approaches outlined in the review by Brenner et al in this issue of CHEST (see page 238) have the potential to do just that. These new technologies are just now becoming available and need to be tested.
What is on the preview channel? New innovations in bronchoscopic and surgical techniques offer an intriguing alternative to "traditional" LVRS. Brenner and his colleagues provide a useful overview of some of these novel techniques, bronchoscopic and otherwise, for us to consider. Most of the bronchoscopic techniques revolve around a simple premise: collapse rather than remove segmental zones by allowing gas to exit while preventing its reentry. Plugs, valves, and endobronchial glues and sealants have been evaluated in animals and to a limited extent in humans.14151617181920 Such approaches could theoretically provide equivalent efficacy without the risks of death and prolonged recovery often attendant in the "pneumectomy" surgical approach. Unfortunately, currently this is just a preview, with data just now being collected from a number of international clinical trials.18 Outcomes even in animal models are limited. Preliminary work using endobronchial glues and sealants, one-way valves, and spigots have resulted in improvements in measures of air trapping and therapeutic atelectasis. In addition, the one-way valves and spigots offer the important additional benefit of being removable. The potential reversibility of some of these techniques is important, since this would make the problem of proper patient selection more manageable, with wider margins for error. This will significantly effect how well these techniques are accepted and implemented in general clinical practice.
Surgical innovations have targeted methods to reduce the invasiveness of the procedure while limiting complications. Recent work has suggested that creating fenestrations using radio frequency ablation results in improved expiratory resistance and airflow in lung preparations. Alternatively surgical compression banding, while still invasive, could potentially reduce the high rates of air leak that plague current surgical LVRS.
These innovations challenge our system of technology assessment and clinical trial design. Because reports are limited, we do not know what potential morbidities described in animal models will prove to be the most clinically significant when these techniques are employed in patients with advanced emphysema. Risk/benefit assessment will require consideration of therapeutic efficacy against the likelihood of anesthetic risks, foreign body reactions, pneumothorax, and pneumonia.1518 Our estimates of these risks are imprecise at this time because of the small populations studied so far.
How future clinical trials should be designed is an important issue in resolving these risk/benefit questions. Specifically, what should these interventions be compared to? Should they be compared to surgical LVRS or programs of pulmonary rehabilitation? What about patients who are not surgical candidates or do not want to have surgery?
Because many patients who are candidates for these less invasive techniques would not be surgical candidates, such comparisons may not be valid and might prove to be both impractical and costly. The ease of implantation and reversibility if "things do not go well" make bronchoscopic LVRS particularly attractive for these patients. In particular, five major questions come to mind as we design the clinical trials that will determine whether and how LVRS can be more generally applied to the management of COPD: (1) Can benefits equivalent to those of surgical LVRS for patients with heterogeneous emphysema be achieved by less invasive means? (2) How much improvement in pulmonary function, exercise capacity, and quality of life would be sufficient for clinicians to integrate bronchoscopic LVRS into the management of COPD? (3) Do patients with severe disease who are not acceptable surgical candidates become candidates for LVRS by other means? (4) Are there other groups of patients in whom LVRS is not as effective, such as those with emphysema that is not predominantly upper lobe, who would benefit from these innovative approaches? (5) As medical therapy, including pulmonary rehabilitation, becomes more generally available, what will be the marginal benefit derived from any modality of LVRS?
The previews are over. The scripts have been written, and the theater is darkened. Will LVRS prove to be a technologic turning point in COPD management or just another dead end? The main event is about to begin.
References
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