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Clinical Trials and Future Prospects for Lung Volume Reduction Surgery
Clinical Trials and Future, Prospects for Lung Volume Reduction Surgery Joel D. Cooper Copyright 2002, Elsevier Science (USA). All rights reserved. Key words: Emphysema, lung volume reduction surgery, clinical trials.
F
ew new surgical procedures have generated as much controversy as lung volume reduction surgery (LVRS) for the palliative treatment of selected patients with end-stage emphysema. ~[ost of the controversy has centered not on the procedure, or on the results, but on the issue as to how new surgical procedures should be introduced and scientifically evaluated, and how they should be funded by health care providers. There are perhaps specific reasons why this particular procedure has been the subject of so much debate. Throughout the last century, numerous procedures were introduced for the treatment of end stage emphysema, most without a physiologic rationale, objective assessment, or more than transient acceptance. Perhaps the reintroduction of LVRS occurred at a time when "e'\idence-based medicine" was the watchword of the day. Perhaps unsubstantiated and unfounded predictions that "surgery for emphysema has the potential to bankrupt the medical care system in this country"l panicked the ~[edicare system and bears some responsibility. At the heart of the matter is how should new surgical procedures be introduced in a responsible fashion, one which does not stifle innovation, protects the interest of patients, and recognizes the need for managing the limited resources available for healthcare in general.
From tM DiVISIon ofCardiothoraclC Surgery, Washington UniverSchool oj Medicine, Barnes-]ewish Hospital, St. Louis, MO. Addrm rrprint regutsls loloel D. Coop"_ MD. Chiif, Division 0/ Cardiothoracic Surgf7)', Washington UnivtTSiry School of Medicine, Barnes-]ewish I/ospital, One Barne.s-]nuish /lospital Pla~a, Suite 3108 Q,J«ny Town', St. Louis, AlO 63110. Co/!}'Tight 2002, Elseui" Snence (USA). All rights reserved. 1013-0679/02//101-0000135.00/0 doi: 10.1 053/ stc$.2oo2.35302 si~)'
In the late 1950s, Brantigan and coworkers proposed that excision of the most functionally useless regions of the lung in patients with severe emphysema, might favorably alter respiratory mechanics and alleviate some of the more distressing limitations imposed by end-stage emphysema. 2,1 They recognized that the loss of lung elastic recoil left these patients trapped in a state of permanent hyperinflation and that the collapse of small airways on attempted forced expiration further contributed to distension of the lungs and hyperexpansion of the chest wall and diaphragm. However, the notion of excising lung to improve respiratory mechanics appears counterintuitive on the surface. Furthermore, Brantigan's failure to undertake objective assessment of his procedure contributed to its lack of acceptance. In addition, his incorporation of radical pulmonary denervation-a procedure that generally fell into disrepute-did not help matters. Based on Brantigan's earlier proposals, we reintroduced LVRS in 1994, using a median sternotomy for bilateral resection with gratifying early results. 4 We consider the procedure a palliative one, to be used not as an alternative to medical management, but rather as the last resort when the patient remains significantly disabled in spite of all known alternative therapy (other than lung transplantation). The goal of LVRS is to palliate some of the distressing symptoms and limitations imposed by end-stage emphysema, especially dyspnea and the inability to conduct routine activities of daily living. Ideal candidates for the procedure are those patients with marked hyperinflation and significant regions of severe destruction with other areas of more well-preserved lung parenchyma. The areas to be removed, often referred to as "target areas," have little if any perfusion as demonstrated on quantitative lung perfusion
366
Joel D. Cooper
scans. Elimination of these areas, which in most candidates are in the upper lobes, improves overall respiratory mechanics and the function of the remaining lung. The anticipated benefits include lessened dyspnea, improved exercise tolerance, a measurable increase in forced expiratory volume in 1 minute (FEVd and reduced residual volume. These theoretical goals have indeed been confirmed not only in our own series,5 but also in more than 200 scientific publications to date. Sciurba and colleagues,6 among others, documented a significant reduction in dyspnea index, improved lung elastic recoil, decrease in residual volume, improved 6-minute walk distance, and increased FEV I . Although publication bias favoring publication of positive results must be considered, there has been a striking absence of reports on negative outcome. Almost all of the evaluation of LVRS has been done by means of prospective observational data, using the patient as his or her own control and comparing preoperative and postoperative subjective and objective parameters. Indeed, most surgical procedures currently in use have been evaluated over the years through analysis of observational data. It is recognized that this method may fail to deal with confounding bias and may, for a time, foster the use of procedures subsequently proven of questionable value. In the case of end-stage emphysema, however, the natural history has been well documented and is one of progressive and unrelenting decline in function. Several studies have demonstrated that once the FEV I falls below 30% of the predicted value, 3-year mortality rises to 40% and 50%.1. 10 Based upon observational data, it is generally accepted that a bilateral procedure gives results superior to a unilateral procedure, II and that a heterogeneous pattern of emphysema is more favorable than a homogeneous pattern. 12 We have recently reported on our initial 250 consecutive patients undergoing bilateral LVRS with a mean follow-up of 4.4 ± 1.9 years'" As has been reported in many series, there is an initial improvement in FEV I (55%) and a reduction in residual volume (31 %). As would be anticipated, subjective assessment in terms of dyspnea and quality of life show parallel improvement. In keeping with the known natural history of emphysema, there is a progressive decline in function over time after the initial improvement seen after LVRS. In our own series, actuarial
5-year survival is 67%, and most survivors at 5 years are both objectively and subjectively improved compared to their preoperative status. In addition to individual observational reports on outcomes following LVRS, several systematic epidemiologic reviews of reported results have been conducted. Young and coworkersl-l in the Department of Public Health and Epidemiology at the University of Birmingham, U.K., conducted a systematic review of the evidence on the effects of LVRS. Of 75 manuscripts reviewed, 19 were selected as meeting the methodologic criteria for critical evaluation. On the basis of their review, the authors concluded that "significant short-term benefits occurred across a range of outcomes which appeared to continue into the longer term. Physiological improvements were matched by functional and subjective improvements. Early mortality rates were low, and late mortality rates compared favorably with those of the general COPD population." The authors noted, however, that a rigorous assessment, especially in terms of cost-effectiveness, requires further research, "particularly randomized controlled trials." It has been suggested in recent years that new operations, like new drugs, should be routinely evaluated through randomized clinical trials (RCTs).I 5- 17 The role of clinical trials in the evaluation of new surgical procedures has indeed been a subject of controversy and debate for many years. But there are inherent differences between the evaluation of a new drug and the evaluation of surgical procedures. In RCTs for drugs, the nature of the intervention does not change over time. The results are unrelated to the skill of the prescribing physician. The biologic response may be variable, requiring that the trial contain large numbers of patients. Unforeseen late toxic side effects may occur_ Surgical procedures, on the other hand, are in a state of constant evolution. The nature of the intervention changes over time as experience is gained, techniques are refined, patient selection clarified, and preoperative and postoperative management improved. Both the intervention and the associated risk change over time. Reeves, III in his article on the subject, noted that "what makes a surgical technique new is not always easier to define because surgical procedures generally evolve in small steps, which make it difficult to decide when a procedure has changed sufficient Iy to jus-
Clinical Trials and Future Prospects for LVRS
tify formal evaluation." He furthermore noted that "at the very start of the process, it is difficult to know \"hen to give a new procedure priority for evaluation. If an assessment is done too early, before surgeons have mastered the technique, there is a risk of rejection of an effective procedure. If too late, the technique may have diffused and become established, at which time surgeons will consider it unethical to withhold the procedure."'8 It is generally acknowledged that when the effect of a surgical intervention is great and the natural history of the disease is well established, randomized trials may be unnecessary or inappropriate. 18,19 In addition, long randomization periods in RCT protocols designed to evaluate operations with known benefits may expose control patients to serious risk. This is especially true with end-stage emphysema, which has a projected annual mortality rate of 10% to 15%.1·\0 l\'"otwithstanding these issues, RCTs remain the gold standard. In the case of LVRS, the true magnitude of benefit can be obtained only by comparing identical groups of patients who have been randomized to either the surgical procedure or continued observation. If the goal is to determine the eITect of the procedure on long-term mortality, then a control group must be observed for a number of years without access to the procedure by cross-over or companionate provision. Meyers and coworkers 20 reported on a group of Medicare patients accepted for LVRS, but subsequently split into surgical and nonsurgical arms by Medicare's subsequent decision to deny funding for the procedure. Those who received the operation before the deadline became the LVRS group and those not receiving the operation by the deadline became the control group.20 Both groups had identical physiologic and demographic parameters. Patients denied operation experienced a progressive worsening of their function, whereas the patient who underwent volume reduction experienced sustained improvements when measured at 2 years. In a follow-up report, actuarial 4-year survival for the operated group was 72%, versus 41 % for the control group.21 To date, at least five randomized clinical trials comparing LVRS "ith ongoing medical management have been either published or reported. 22 -26 These trials have many similarities. Patients were enrolled voluntarily and had the option of receiving the surgery outside of the trial if they
367
did not wish to participate. All of the trials were designed to measure the short-term physiologic and functional benefits achieved by LVRS and permitted patients in the control arm to cross over to surgery after a period ranging from 3 to 24 months, or if interim analysis showed significant benefit for the surgical group. All five studies reported better outcomes in the surgical arms. Importantly, all five trials confirmed the progressive decline in function in the patients in the medical arm, even with optimum medical management. None of the studies was designed to maintain the control arm for a long period (greater than 2 years) as a means of documenting the effect of LVRS on long-term survival. Additional RCTs ofLVRS similar to the aforementioned trials are currently underway and are soon expected to report their results. These include the Overholt-Blue Cross Emphysema Surgery Trial (OBEST), the Canadian Lung Volume Reduction Trial, and the University of Toronto Lung Volume Reduction Trial. These trials are also designed to evaluate the short-term effectiveness of LVRS, provide cross-over to surgery on a compassionate basis, and allow patients in the medical arm to cross over to surgery within 6 to 24 months. As in the previously noted RCTs, patients enroll voluntarily and are given provision for LVRS outside of the trial if they so chose. On January 1, 1996, with only several weeks notice, Medicare suddenly discontinued reimbursement for LVRS, citing insufficient evidence for effectiveness. Subsequently, the Health Care Finance Administration and the National Institutes of Health organized a clinical trial on LVRS, now known as the National Emphysema Treatment Trial (NETT). This trial has several distinct and significant differences from all other LVRS RCTs. The trial is available to all qualified Medicare patients, and those randomized to nonsurgical treatment must remain in the control arm for the duration of the study (which currently is in its seventh year). No provision is made for compassionate cross over to surgery, nor for funding of the procedure for Medicare patients outside of the trial for those ineligible or unwilling to enroll. The primary outcome, in terms of statistical design, is long-term mortality, with secondary outcomes related to quality of life and functional improvement. Clearly the interest of the National Institutes of Health is to conduct a rigorous, scientific evaluation of LVRS. Medi-
368
Joel D. Cooper
care's stated objective, however, is to use the trial as a means for determining whether or not coverage for the LVRS procedure will be provided by the Medicare system. The NETT trial was initially designed to randomize 4,700 patients between LVRS and ongoing medical management. However, because of disappointing recruitment, the original enrollment goal was cut back from 4,700 to 2,500 patients. n Recent reports indicate that approximately 1,100 patients have been randomized as of January 2002. A recent initial report from the NETT identified patients in the trial found to be at high risk for death after LVRS. Two such groups of patients were identified, one group with an FEV. no more than 20% of their predicted value and a homogeneous distribution of emphysema, and the other with both an FEV. and a carbon monoxide diffusing capacity no more than 20% of their predicted value. Together these two groups, totaling 140 patients, represented 14% of patients enrolled in the trial. Of this number, 69 were randomized to surgery. Of these, 45 had a homogeneous pattern of emphysema with severe functional impairment (FEV I ~20% of predicted) and a 30-day mortality post-LVRS of 18%. The remaining 24 operative patients had a heterogeneous pattern of emphysema, with both diffusing capacity and FEV. S20% of predicted. In this group, 30-day mortality was 12.5%. It is of significance that the patients with homogeneous severe emphysema were initially excluded from participation in the NETT trial. Subsequently, however, the exclusionary criteria were dropped, allowing these patients to be enrolled. It is not known when the results of the NETT trial will be available. Enrollment is scheduled to end sometime in the year 2002, well short of the reduced recruitment goal. Results will presumably be reported after a certain period of follow-up has been achieved. Berger and colleagues 2H have published an excellent review of the evidence to date supporting the value of LVRS. They also address the ethical problems associated with RCTs for evaluating emerging operations. Regardless of the outcome of the NETT trial, LVRS will continue to have a role in the treatment of selected patients with end-stage emphysema. As a result of the NETT trial, guidelines for selection of appropriate candidates may be refined, and the true "value" of the procedure for
these patients will be better defined. Whether or not the results of the trial will be generalizable remains to be seen. \Vhat has been demonstrated is that for selected patients, LVRS can produce significant improvements in pulmonary physiology and function. This in turn has led to research for less-invasive means of accomplishing the same goal, to reduce the risk of the procedure and extend its application. Most of these proposals are technology-driven and are being developed through collaboration by investigators and startup biodevice companies. Brenner and colleagues,29 working with Spiration Incorporated (Redman, 'VA), are evaluating a silicone elastomer sleeve to compress lung tissue and reduce lung volume without surgical resection. This device has been applied in a rabbit model of emphysema. Ingenit030 has proposed a bronchoscopic means of lung volume reduction. The target region of the lung is flooded with an antisurfactant to help induce collapse when the ventilation to that region of the lung is suspended. Following collapse, a biologic glue is instilled with the goal of fusing the collapsed portions of the lung together, to prevent subsequent reinflation. It has been proposed that obstructing the air passages to a portion of the lung targeted for volume reduction could achieve such reduction by creating atelectasis distal to the point of obstruction. However, the extensive collateral ventilation present in patients with severe emphysema might lead to continued expansion of the target areas despite central airway blockade. This not only might prevent volume reduction of the obstructed region, but also might conceivably lead to further gas trapping and overexpansion. Devices to obviate this problem are being evaluated to blockade central airways with a one-way valve, which would allow air to exit the lung on expiration but prevent inspiratory air flow through the bronchi. Such an approach has been proposed by Pulmonx (Palo Alto, CA), Spiration, and Emphysys (Mountain View, CA). All of the aforementioned proposals are designed to reduce the volume of certain regions of the lung to accomplish benefits similar to that produced by LVRS. Presumably their application would be most appropriate for patients who ha\'e a heterogeneous distribution of emphysema. providing target areas for collapse similar to the
Clinical Trials and Future Prospectsjor LVRS
target areas removed at lung volume reduction surgery. \Ve have been exploring an alternate bronchoscopic approach to reduce hyperinflation in patients with homogeneous severe emphysematous destruction of the lungs. Such patients do not have target areas for removal or decompression but are severely disabled, in part by the persistent hyperinflation of the chest with its attendant effects on dyspnea, work at breathing, and diaphragmatic and chest wall mechanics. We have proposed creating transbronchial communications between segmental bronchi in adjacent lung parenchyma. These channels could theoretically improve expired volume by taking advantage of the collateral ventilation in the lung parenchyma by which gas otherwise trapped in the lung by collapse of the small airways could exit to the central airways. Inspiratory flow would be through the usual airways, but on expiration, once small airway closure occurred, persistent expiration could continue through these new exits. Studies in freshly excised emphysematous lungs from lung transplant recipients have been used to demonstrate the improved expiratory flow that can be achieved by this method. 31 LVRS has focused increased attention on the treatment of patients with end-stage emphysema. The importance of an exercise program is increasingly accepted, as has been the important role of altered respiratory mechanics in the disability produced by severe emphysema. This has become particularly apparent from the ability of LVRS to significantly reduce dyspnea, improve exercise tolerance, and favorably affect the overall quality of life of these patients. This in turn has stimulated interest in the development of less-invasive and more broadly applicable techniques for achieving similar goals.
References I. Make 8J. Fein AM; Is volume reduction surgery appropriate in the treatment of emphysema? N Am j Respir Crit Care ~Ied 153:1205-1207, 1996 2. 8rantigan OC, Mueller E: Surgical treatment of pulmonary emphysema. Am Surg 23:789-804, 1957 3. Brantigan OCt ~Iueller E. Kress 1I.1B: A surgical approach to pulmonaf)' emphysema. Am Rev Respir Dis 80: 194202, 1959 4. Cooper jD. Trulock EP, Triantafillou Al'l, et al: Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 109:106119,1995
369
5. Cooper JD, Patterson GA, Sundaresan RD, et al: Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 112:1319-1330, 1996 6. Sciurba FC, Rogers RM, Keenan RJ. et al; Improvement in pulmonary function and elastic recoil after lung reduction surgery for diffuse emphysema. N Engl J Med 334: 1095-1099, 1996 7. Diener CF, Burrows B: Further observations on the course and prognosis of chronic obstructive lung disease. Am Rev Respir Dis 111:719-724, 1975 8. Traver GA. Cline MG, Burrows 8: Predictors of mortality in chronic obstructive pulmonary disease. Am Rev Respir Dis 119:895-902, 1979 9. 8urrows B, Earle RII: Course and prognosis of chronic obstructive lung disease: A prospective study of 200 patients. N Engl J Med 280:397.404, 1969 10. Nocturnal Oxygen Therapy Trial Group: Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. Ann Int Med 93:391-39H, 1980 II. McKenna RJ, Brenner M, Fischel I\J, et al: Should volume reduction for emphysema be unilateral or bilateral. J Thorac Cardiovasc Surg 112: 1331-1339. 1996 12. Hamacherj, 8Ioch KE, Stammberger U, et at: Two years' outcome of lung volume reduction surgery in different morphologic emphysema types. Ann Thorac Surg 68: 1792-1798, 1999 13. Rendina EA, DeGiacomo T, Venuta F, et al: Feasibility and safety of extra anatomic transbronchial decompression for emphysema. Submitted as an abstract at the American Association for Thoracic Surgery meeting, May 2002 14. Young j, Fry-Smith A, Hyde C: Lung volume reduction surgery (LVRS) for chronic obstructive pulmonary disease (COPD) with underlying severe emphysema. Thorax 54:779-789, 1999 15. Spodick DH: Numerators without denominators: There is no FDA for the surgeon.jAMA 232:35-36, 1975 16. Spodick DB, Aronow W, Barber 8, et al: Standards for surgical trials. Ann Thorac Surg 27:284, 1979 17. Horton R: Surgical research or comic opera: Questions but few answers. Lancet 347:984-985, 1996 18. Reeves B: Health-technology assessment in surgery. lancet 353(suppl 1):3-5, 1999 19. Baum M: Reflections on randomised controlled trials in surgery. Lancet 353(suppl 1):6-8, 1999 20. Meyers 8F, Yusen RD, Lefrak SS, et al: Outcome of medicare patients with emphysema selected for, but denied, a lung volume reduction operation. Ann Thorac Surg 66:331-336. 1998 21. Meyers BF, Yusen RD, Lefrak SS, et al: Improved longterm survival seen after lung volume reduction surgery compared to continued medical therapy for emphysema [letter]. Ann Thorac Surg 71:2081, 2001 22. Geddes D. Davies 1\1, Koyama II, et al: Effects of lung volume reduction surgery in patients with severe emphysema. N Engl J Med 343:239-245, 2000 23. Criner GJ, Cordova SC, Furukawa S, et al: Prospective randomized trial comparing bilateral lung volume reduction surgery to pulmonary rehabilitation in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160:2021-2027, 1999
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24. Pompeo E, Marino M, Nofroni I, et al: Reduction pneumoplasty versus respiratory rehabilitation in severe emphysema: a randomized study. Ann Thorac Surg 70:948954,2000 25. Goodnight-White S, Jones \\1, Baaklini J, et a1: Prospective randomized controlled trial comparing bilateral lung volume reduction surgery (LVRS) to medical therapy alone in patients with severe emphysema. Chest 118(suppI4):I02S, 2000 26. Lofdahl CG, lIi11erdal G, Strom K: Randomized controlled trial of volume reduction surgery-preliminary results up to 12 months [abstract]. AmJ Respir Crit Care Med 161:A585, 2000 27. The National Emphysema Treatment Trial Research Group: Rationale and design of the National Emphysema Treatment Trial (NETT): a prospective randomized trial of lung volume reduction surgery. J Thorac Cardiovasc Surg 118:518-528, 1999
28. Berger RL, Celli BR, Meneghetti AI., et al: Limitations of randomized clinical trials for evaluating emerging operations: the case of lung volume reduction surgery. Ann Thorac Surg 72:649-657, 2001 29. Brenner M, Gonzalez X,Jones B, et al: Effects of a nOl'el implantable elastomer device for lung volume reduction surgery in a rabbit model of elastase-induced emphysema. Chest 121:20)-209,2002 30. Ingenito EP, Reilly 11, Mentzer SJ, et al: Bronchoscopic volume reduction-A safe and effective alternative to surgical therapy for emphysema. Am J Respir Crit Care Med 164:295-301,2001 31. Lausberg HF, Chino K, Patterson GA, et al: BronchIal fenestration improves expiratory flow in emphysematous human lungs. Submitted as an abstract at the Society of Thoracic Surgeons meeting, January 2002
F
ew new surgical procedures have generated as much controversy as lung volume reduction surgery (LVRS) for the palliative treatment of selected patients with end-stage emphysema. ~[ost of the controversy has centered not on the procedure, or on the results, but on the issue as to how new surgical procedures should be introduced and scientifically evaluated, and how they should be funded by health care providers. There are perhaps specific reasons why this particular procedure has been the subject of so much debate. Throughout the last century, numerous procedures were introduced for the treatment of end stage emphysema, most without a physiologic rationale, objective assessment, or more than transient acceptance. Perhaps the reintroduction of LVRS occurred at a time when "e'\idence-based medicine" was the watchword of the day. Perhaps unsubstantiated and unfounded predictions that "surgery for emphysema has the potential to bankrupt the medical care system in this country"l panicked the ~[edicare system and bears some responsibility. At the heart of the matter is how should new surgical procedures be introduced in a responsible fashion, one which does not stifle innovation, protects the interest of patients, and recognizes the need for managing the limited resources available for healthcare in general.
From tM DiVISIon ofCardiothoraclC Surgery, Washington UniverSchool oj Medicine, Barnes-]ewish Hospital, St. Louis, MO. Addrm rrprint regutsls loloel D. Coop"_ MD. Chiif, Division 0/ Cardiothoracic Surgf7)', Washington UnivtTSiry School of Medicine, Barnes-]ewish I/ospital, One Barne.s-]nuish /lospital Pla~a, Suite 3108 Q,J«ny Town', St. Louis, AlO 63110. Co/!}'Tight 2002, Elseui" Snence (USA). All rights reserved. 1013-0679/02//101-0000135.00/0 doi: 10.1 053/ stc$.2oo2.35302 si~)'
In the late 1950s, Brantigan and coworkers proposed that excision of the most functionally useless regions of the lung in patients with severe emphysema, might favorably alter respiratory mechanics and alleviate some of the more distressing limitations imposed by end-stage emphysema. 2,1 They recognized that the loss of lung elastic recoil left these patients trapped in a state of permanent hyperinflation and that the collapse of small airways on attempted forced expiration further contributed to distension of the lungs and hyperexpansion of the chest wall and diaphragm. However, the notion of excising lung to improve respiratory mechanics appears counterintuitive on the surface. Furthermore, Brantigan's failure to undertake objective assessment of his procedure contributed to its lack of acceptance. In addition, his incorporation of radical pulmonary denervation-a procedure that generally fell into disrepute-did not help matters. Based on Brantigan's earlier proposals, we reintroduced LVRS in 1994, using a median sternotomy for bilateral resection with gratifying early results. 4 We consider the procedure a palliative one, to be used not as an alternative to medical management, but rather as the last resort when the patient remains significantly disabled in spite of all known alternative therapy (other than lung transplantation). The goal of LVRS is to palliate some of the distressing symptoms and limitations imposed by end-stage emphysema, especially dyspnea and the inability to conduct routine activities of daily living. Ideal candidates for the procedure are those patients with marked hyperinflation and significant regions of severe destruction with other areas of more well-preserved lung parenchyma. The areas to be removed, often referred to as "target areas," have little if any perfusion as demonstrated on quantitative lung perfusion
366
Joel D. Cooper
scans. Elimination of these areas, which in most candidates are in the upper lobes, improves overall respiratory mechanics and the function of the remaining lung. The anticipated benefits include lessened dyspnea, improved exercise tolerance, a measurable increase in forced expiratory volume in 1 minute (FEVd and reduced residual volume. These theoretical goals have indeed been confirmed not only in our own series,5 but also in more than 200 scientific publications to date. Sciurba and colleagues,6 among others, documented a significant reduction in dyspnea index, improved lung elastic recoil, decrease in residual volume, improved 6-minute walk distance, and increased FEV I . Although publication bias favoring publication of positive results must be considered, there has been a striking absence of reports on negative outcome. Almost all of the evaluation of LVRS has been done by means of prospective observational data, using the patient as his or her own control and comparing preoperative and postoperative subjective and objective parameters. Indeed, most surgical procedures currently in use have been evaluated over the years through analysis of observational data. It is recognized that this method may fail to deal with confounding bias and may, for a time, foster the use of procedures subsequently proven of questionable value. In the case of end-stage emphysema, however, the natural history has been well documented and is one of progressive and unrelenting decline in function. Several studies have demonstrated that once the FEV I falls below 30% of the predicted value, 3-year mortality rises to 40% and 50%.1. 10 Based upon observational data, it is generally accepted that a bilateral procedure gives results superior to a unilateral procedure, II and that a heterogeneous pattern of emphysema is more favorable than a homogeneous pattern. 12 We have recently reported on our initial 250 consecutive patients undergoing bilateral LVRS with a mean follow-up of 4.4 ± 1.9 years'" As has been reported in many series, there is an initial improvement in FEV I (55%) and a reduction in residual volume (31 %). As would be anticipated, subjective assessment in terms of dyspnea and quality of life show parallel improvement. In keeping with the known natural history of emphysema, there is a progressive decline in function over time after the initial improvement seen after LVRS. In our own series, actuarial
5-year survival is 67%, and most survivors at 5 years are both objectively and subjectively improved compared to their preoperative status. In addition to individual observational reports on outcomes following LVRS, several systematic epidemiologic reviews of reported results have been conducted. Young and coworkersl-l in the Department of Public Health and Epidemiology at the University of Birmingham, U.K., conducted a systematic review of the evidence on the effects of LVRS. Of 75 manuscripts reviewed, 19 were selected as meeting the methodologic criteria for critical evaluation. On the basis of their review, the authors concluded that "significant short-term benefits occurred across a range of outcomes which appeared to continue into the longer term. Physiological improvements were matched by functional and subjective improvements. Early mortality rates were low, and late mortality rates compared favorably with those of the general COPD population." The authors noted, however, that a rigorous assessment, especially in terms of cost-effectiveness, requires further research, "particularly randomized controlled trials." It has been suggested in recent years that new operations, like new drugs, should be routinely evaluated through randomized clinical trials (RCTs).I 5- 17 The role of clinical trials in the evaluation of new surgical procedures has indeed been a subject of controversy and debate for many years. But there are inherent differences between the evaluation of a new drug and the evaluation of surgical procedures. In RCTs for drugs, the nature of the intervention does not change over time. The results are unrelated to the skill of the prescribing physician. The biologic response may be variable, requiring that the trial contain large numbers of patients. Unforeseen late toxic side effects may occur_ Surgical procedures, on the other hand, are in a state of constant evolution. The nature of the intervention changes over time as experience is gained, techniques are refined, patient selection clarified, and preoperative and postoperative management improved. Both the intervention and the associated risk change over time. Reeves, III in his article on the subject, noted that "what makes a surgical technique new is not always easier to define because surgical procedures generally evolve in small steps, which make it difficult to decide when a procedure has changed sufficient Iy to jus-
Clinical Trials and Future Prospects for LVRS
tify formal evaluation." He furthermore noted that "at the very start of the process, it is difficult to know \"hen to give a new procedure priority for evaluation. If an assessment is done too early, before surgeons have mastered the technique, there is a risk of rejection of an effective procedure. If too late, the technique may have diffused and become established, at which time surgeons will consider it unethical to withhold the procedure."'8 It is generally acknowledged that when the effect of a surgical intervention is great and the natural history of the disease is well established, randomized trials may be unnecessary or inappropriate. 18,19 In addition, long randomization periods in RCT protocols designed to evaluate operations with known benefits may expose control patients to serious risk. This is especially true with end-stage emphysema, which has a projected annual mortality rate of 10% to 15%.1·\0 l\'"otwithstanding these issues, RCTs remain the gold standard. In the case of LVRS, the true magnitude of benefit can be obtained only by comparing identical groups of patients who have been randomized to either the surgical procedure or continued observation. If the goal is to determine the eITect of the procedure on long-term mortality, then a control group must be observed for a number of years without access to the procedure by cross-over or companionate provision. Meyers and coworkers 20 reported on a group of Medicare patients accepted for LVRS, but subsequently split into surgical and nonsurgical arms by Medicare's subsequent decision to deny funding for the procedure. Those who received the operation before the deadline became the LVRS group and those not receiving the operation by the deadline became the control group.20 Both groups had identical physiologic and demographic parameters. Patients denied operation experienced a progressive worsening of their function, whereas the patient who underwent volume reduction experienced sustained improvements when measured at 2 years. In a follow-up report, actuarial 4-year survival for the operated group was 72%, versus 41 % for the control group.21 To date, at least five randomized clinical trials comparing LVRS "ith ongoing medical management have been either published or reported. 22 -26 These trials have many similarities. Patients were enrolled voluntarily and had the option of receiving the surgery outside of the trial if they
367
did not wish to participate. All of the trials were designed to measure the short-term physiologic and functional benefits achieved by LVRS and permitted patients in the control arm to cross over to surgery after a period ranging from 3 to 24 months, or if interim analysis showed significant benefit for the surgical group. All five studies reported better outcomes in the surgical arms. Importantly, all five trials confirmed the progressive decline in function in the patients in the medical arm, even with optimum medical management. None of the studies was designed to maintain the control arm for a long period (greater than 2 years) as a means of documenting the effect of LVRS on long-term survival. Additional RCTs ofLVRS similar to the aforementioned trials are currently underway and are soon expected to report their results. These include the Overholt-Blue Cross Emphysema Surgery Trial (OBEST), the Canadian Lung Volume Reduction Trial, and the University of Toronto Lung Volume Reduction Trial. These trials are also designed to evaluate the short-term effectiveness of LVRS, provide cross-over to surgery on a compassionate basis, and allow patients in the medical arm to cross over to surgery within 6 to 24 months. As in the previously noted RCTs, patients enroll voluntarily and are given provision for LVRS outside of the trial if they so chose. On January 1, 1996, with only several weeks notice, Medicare suddenly discontinued reimbursement for LVRS, citing insufficient evidence for effectiveness. Subsequently, the Health Care Finance Administration and the National Institutes of Health organized a clinical trial on LVRS, now known as the National Emphysema Treatment Trial (NETT). This trial has several distinct and significant differences from all other LVRS RCTs. The trial is available to all qualified Medicare patients, and those randomized to nonsurgical treatment must remain in the control arm for the duration of the study (which currently is in its seventh year). No provision is made for compassionate cross over to surgery, nor for funding of the procedure for Medicare patients outside of the trial for those ineligible or unwilling to enroll. The primary outcome, in terms of statistical design, is long-term mortality, with secondary outcomes related to quality of life and functional improvement. Clearly the interest of the National Institutes of Health is to conduct a rigorous, scientific evaluation of LVRS. Medi-
368
Joel D. Cooper
care's stated objective, however, is to use the trial as a means for determining whether or not coverage for the LVRS procedure will be provided by the Medicare system. The NETT trial was initially designed to randomize 4,700 patients between LVRS and ongoing medical management. However, because of disappointing recruitment, the original enrollment goal was cut back from 4,700 to 2,500 patients. n Recent reports indicate that approximately 1,100 patients have been randomized as of January 2002. A recent initial report from the NETT identified patients in the trial found to be at high risk for death after LVRS. Two such groups of patients were identified, one group with an FEV. no more than 20% of their predicted value and a homogeneous distribution of emphysema, and the other with both an FEV. and a carbon monoxide diffusing capacity no more than 20% of their predicted value. Together these two groups, totaling 140 patients, represented 14% of patients enrolled in the trial. Of this number, 69 were randomized to surgery. Of these, 45 had a homogeneous pattern of emphysema with severe functional impairment (FEV I ~20% of predicted) and a 30-day mortality post-LVRS of 18%. The remaining 24 operative patients had a heterogeneous pattern of emphysema, with both diffusing capacity and FEV. S20% of predicted. In this group, 30-day mortality was 12.5%. It is of significance that the patients with homogeneous severe emphysema were initially excluded from participation in the NETT trial. Subsequently, however, the exclusionary criteria were dropped, allowing these patients to be enrolled. It is not known when the results of the NETT trial will be available. Enrollment is scheduled to end sometime in the year 2002, well short of the reduced recruitment goal. Results will presumably be reported after a certain period of follow-up has been achieved. Berger and colleagues 2H have published an excellent review of the evidence to date supporting the value of LVRS. They also address the ethical problems associated with RCTs for evaluating emerging operations. Regardless of the outcome of the NETT trial, LVRS will continue to have a role in the treatment of selected patients with end-stage emphysema. As a result of the NETT trial, guidelines for selection of appropriate candidates may be refined, and the true "value" of the procedure for
these patients will be better defined. Whether or not the results of the trial will be generalizable remains to be seen. \Vhat has been demonstrated is that for selected patients, LVRS can produce significant improvements in pulmonary physiology and function. This in turn has led to research for less-invasive means of accomplishing the same goal, to reduce the risk of the procedure and extend its application. Most of these proposals are technology-driven and are being developed through collaboration by investigators and startup biodevice companies. Brenner and colleagues,29 working with Spiration Incorporated (Redman, 'VA), are evaluating a silicone elastomer sleeve to compress lung tissue and reduce lung volume without surgical resection. This device has been applied in a rabbit model of emphysema. Ingenit030 has proposed a bronchoscopic means of lung volume reduction. The target region of the lung is flooded with an antisurfactant to help induce collapse when the ventilation to that region of the lung is suspended. Following collapse, a biologic glue is instilled with the goal of fusing the collapsed portions of the lung together, to prevent subsequent reinflation. It has been proposed that obstructing the air passages to a portion of the lung targeted for volume reduction could achieve such reduction by creating atelectasis distal to the point of obstruction. However, the extensive collateral ventilation present in patients with severe emphysema might lead to continued expansion of the target areas despite central airway blockade. This not only might prevent volume reduction of the obstructed region, but also might conceivably lead to further gas trapping and overexpansion. Devices to obviate this problem are being evaluated to blockade central airways with a one-way valve, which would allow air to exit the lung on expiration but prevent inspiratory air flow through the bronchi. Such an approach has been proposed by Pulmonx (Palo Alto, CA), Spiration, and Emphysys (Mountain View, CA). All of the aforementioned proposals are designed to reduce the volume of certain regions of the lung to accomplish benefits similar to that produced by LVRS. Presumably their application would be most appropriate for patients who ha\'e a heterogeneous distribution of emphysema. providing target areas for collapse similar to the
Clinical Trials and Future Prospectsjor LVRS
target areas removed at lung volume reduction surgery. \Ve have been exploring an alternate bronchoscopic approach to reduce hyperinflation in patients with homogeneous severe emphysematous destruction of the lungs. Such patients do not have target areas for removal or decompression but are severely disabled, in part by the persistent hyperinflation of the chest with its attendant effects on dyspnea, work at breathing, and diaphragmatic and chest wall mechanics. We have proposed creating transbronchial communications between segmental bronchi in adjacent lung parenchyma. These channels could theoretically improve expired volume by taking advantage of the collateral ventilation in the lung parenchyma by which gas otherwise trapped in the lung by collapse of the small airways could exit to the central airways. Inspiratory flow would be through the usual airways, but on expiration, once small airway closure occurred, persistent expiration could continue through these new exits. Studies in freshly excised emphysematous lungs from lung transplant recipients have been used to demonstrate the improved expiratory flow that can be achieved by this method. 31 LVRS has focused increased attention on the treatment of patients with end-stage emphysema. The importance of an exercise program is increasingly accepted, as has been the important role of altered respiratory mechanics in the disability produced by severe emphysema. This has become particularly apparent from the ability of LVRS to significantly reduce dyspnea, improve exercise tolerance, and favorably affect the overall quality of life of these patients. This in turn has stimulated interest in the development of less-invasive and more broadly applicable techniques for achieving similar goals.
References I. Make 8J. Fein AM; Is volume reduction surgery appropriate in the treatment of emphysema? N Am j Respir Crit Care ~Ied 153:1205-1207, 1996 2. 8rantigan OC, Mueller E: Surgical treatment of pulmonary emphysema. Am Surg 23:789-804, 1957 3. Brantigan OCt ~Iueller E. Kress 1I.1B: A surgical approach to pulmonaf)' emphysema. Am Rev Respir Dis 80: 194202, 1959 4. Cooper jD. Trulock EP, Triantafillou Al'l, et al: Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 109:106119,1995
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5. Cooper JD, Patterson GA, Sundaresan RD, et al: Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 112:1319-1330, 1996 6. Sciurba FC, Rogers RM, Keenan RJ. et al; Improvement in pulmonary function and elastic recoil after lung reduction surgery for diffuse emphysema. N Engl J Med 334: 1095-1099, 1996 7. Diener CF, Burrows B: Further observations on the course and prognosis of chronic obstructive lung disease. Am Rev Respir Dis 111:719-724, 1975 8. Traver GA. Cline MG, Burrows 8: Predictors of mortality in chronic obstructive pulmonary disease. Am Rev Respir Dis 119:895-902, 1979 9. 8urrows B, Earle RII: Course and prognosis of chronic obstructive lung disease: A prospective study of 200 patients. N Engl J Med 280:397.404, 1969 10. Nocturnal Oxygen Therapy Trial Group: Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. Ann Int Med 93:391-39H, 1980 II. McKenna RJ, Brenner M, Fischel I\J, et al: Should volume reduction for emphysema be unilateral or bilateral. J Thorac Cardiovasc Surg 112: 1331-1339. 1996 12. Hamacherj, 8Ioch KE, Stammberger U, et at: Two years' outcome of lung volume reduction surgery in different morphologic emphysema types. Ann Thorac Surg 68: 1792-1798, 1999 13. Rendina EA, DeGiacomo T, Venuta F, et al: Feasibility and safety of extra anatomic transbronchial decompression for emphysema. Submitted as an abstract at the American Association for Thoracic Surgery meeting, May 2002 14. Young j, Fry-Smith A, Hyde C: Lung volume reduction surgery (LVRS) for chronic obstructive pulmonary disease (COPD) with underlying severe emphysema. Thorax 54:779-789, 1999 15. Spodick DH: Numerators without denominators: There is no FDA for the surgeon.jAMA 232:35-36, 1975 16. Spodick DB, Aronow W, Barber 8, et al: Standards for surgical trials. Ann Thorac Surg 27:284, 1979 17. Horton R: Surgical research or comic opera: Questions but few answers. Lancet 347:984-985, 1996 18. Reeves B: Health-technology assessment in surgery. lancet 353(suppl 1):3-5, 1999 19. Baum M: Reflections on randomised controlled trials in surgery. Lancet 353(suppl 1):6-8, 1999 20. Meyers 8F, Yusen RD, Lefrak SS, et al: Outcome of medicare patients with emphysema selected for, but denied, a lung volume reduction operation. Ann Thorac Surg 66:331-336. 1998 21. Meyers BF, Yusen RD, Lefrak SS, et al: Improved longterm survival seen after lung volume reduction surgery compared to continued medical therapy for emphysema [letter]. Ann Thorac Surg 71:2081, 2001 22. Geddes D. Davies 1\1, Koyama II, et al: Effects of lung volume reduction surgery in patients with severe emphysema. N Engl J Med 343:239-245, 2000 23. Criner GJ, Cordova SC, Furukawa S, et al: Prospective randomized trial comparing bilateral lung volume reduction surgery to pulmonary rehabilitation in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160:2021-2027, 1999
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24. Pompeo E, Marino M, Nofroni I, et al: Reduction pneumoplasty versus respiratory rehabilitation in severe emphysema: a randomized study. Ann Thorac Surg 70:948954,2000 25. Goodnight-White S, Jones \\1, Baaklini J, et a1: Prospective randomized controlled trial comparing bilateral lung volume reduction surgery (LVRS) to medical therapy alone in patients with severe emphysema. Chest 118(suppI4):I02S, 2000 26. Lofdahl CG, lIi11erdal G, Strom K: Randomized controlled trial of volume reduction surgery-preliminary results up to 12 months [abstract]. AmJ Respir Crit Care Med 161:A585, 2000 27. The National Emphysema Treatment Trial Research Group: Rationale and design of the National Emphysema Treatment Trial (NETT): a prospective randomized trial of lung volume reduction surgery. J Thorac Cardiovasc Surg 118:518-528, 1999
28. Berger RL, Celli BR, Meneghetti AI., et al: Limitations of randomized clinical trials for evaluating emerging operations: the case of lung volume reduction surgery. Ann Thorac Surg 72:649-657, 2001 29. Brenner M, Gonzalez X,Jones B, et al: Effects of a nOl'el implantable elastomer device for lung volume reduction surgery in a rabbit model of elastase-induced emphysema. Chest 121:20)-209,2002 30. Ingenito EP, Reilly 11, Mentzer SJ, et al: Bronchoscopic volume reduction-A safe and effective alternative to surgical therapy for emphysema. Am J Respir Crit Care Med 164:295-301,2001 31. Lausberg HF, Chino K, Patterson GA, et al: BronchIal fenestration improves expiratory flow in emphysematous human lungs. Submitted as an abstract at the Society of Thoracic Surgeons meeting, January 2002