The Video-Assisted Thoracoscopic or Open Lobectomy (VIOLET) trial: The final chapter to this epic

Central MessageThe publication of innovative clinical trials is surging, including VIOLET. The availability of trials and technology beckons thoracic surgeons to immerse themselves in this wave of transformation.This Invited Expert Opinion provides a perspective on the following paper: NEJM Evid. 2022;1(3). https://doi.org/10.1056/EVIDoa2100016.Feature Editor’s Introduction—Thoracic surgeons have long considered thoracoscopic lobectomy to be superior compared with open lobectomy based on several propensity score-matched studies from large national databases (eg, STS, NSQIP, NIS, SEER, and NCDB) that uniformly show thoracoscopic lobectomy results in fewer complications and shorter hospital stay, but no oncologic compromise. However, propensity score-matched studies are not substitutes for well-designed randomized controlled trials (if they can be completed). This is perhaps among the main reasons why adoption of the thoracoscopic approach to lobectomy has been slow. Hence, the importance of the recently published randomized Video-Assisted Thoracoscopic or Open Lobectomy (VIOLET) trial, a trial that not only sets thoracoscopic approach as the standard for surgical treatment of early-stage lung cancer, but also shows the medical and surgical community that thoracic surgeons can come together and complete a surgical trial that was once thought not possible. These and other important implications of the VIOLET trial are eloquently discussed in the following Invited Expert Opinion article by our world-renowned expert in thoracoscopic surgery, Dr. Thomas D'Amico.Thomas Ng, MD, FRCSC, FACS The publication of innovative clinical trials is surging, including VIOLET. The availability of trials and technology beckons thoracic surgeons to immerse themselves in this wave of transformation. This Invited Expert Opinion provides a perspective on the following paper: NEJM Evid. 2022;1(3). https://doi.org/10.1056/EVIDoa2100016. The evolution of thoracoscopic lobectomy suffered a slow start. When first introduced, the technique varied widely, with surgeons essentially teaching themselves based on techniques developed for laparoscopic surgery with instruments designed for laparoscopic surgery (or worse). Perhaps it should not be surprising to learn that early results were disappointing. In fact, as of 2005, a decade into the evolution, there wasn't even a consistently accepted definition of the procedure. Nor was there agreement that the procedure should be considered oncologically acceptable. In 2007, the results of a clinical trial were published, a multi-institutional cooperative group registry sponsored by the Cancer and Leukemia Group B (CALGB), that established the definition of video-assisted thoracoscopic (VATS) lobectomy, provided evidence of safety and feasibility, and documented patient-related (short-term) clinical outcomes that were superior to those published for open lobectomy.1Swanson S.J. Herndon J.E. D'Amico T.A. Demmy T.L. McKenna Jr., R.J. Green M.R. et al.Video-assisted thoracic surgery (VATS) lobectomy—report of CALGB 39802: a prospective, multi-institutional feasibility study.J Clin Oncol. 2007; 25: 4993-4997Crossref PubMed Scopus (462) Google Scholar That trial, CALGB 39802, led to increased interest in learning the procedure and various thoracoscopic techniques were developed successfully. VATS lobectomy made its way into training programs, and eventually the American Board of Thoracic Surgery recognized VATS lobectomy as an essential component of its qualification requirements. Over the next decade, the first clinical results of VATS lobectomy were published—patient-related outcomes (quality of life), short-term outcomes (complications), oncologic outcomes (lymph node upstaging), long-term outcomes (survival), and cost. The studies came from single-institution series, multi-institution series, large data sets (such as the National Cancer Database), and meta-analyses. In general, although not all studies were in agreement, taken as a whole they demonstrated that VATS lobectomy, compared with open lobectomy, was associated with better quality of life, preservation of pulmonary function, fewer complications, and at least equivalent oncologic outcomes and survival at a lower cost. Nevertheless, adoption rates even for patients with early-stage lung cancer lagged behind expectations, and some surgeons remained unconvinced of the advantages of VATS lobectomy, preferring to wait for a prospective randomized controlled trial. Such a trial was proposed after the completion of the CALGB registry trial, but it did not achieve funding from the National Cancer Institute. Since then, a great deal of data have been collected, including results from the application of VATS resections for more complex lung cancer, including lobectomy for locally advanced disease and following induction therapy, sleeve lobectomy, and pneumonectomy. Although safety, feasibility, and oncologic efficacy were demonstrated, adoption rates were disappointing. A prospective, randomized trial (funded by the UK National Health Service) has now been completed, presented at the World Congress of Lung Cancer, and recently published: The Video-Assisted Thoracoscopic or Open Lobectomy (VIOLET) trial.2Lim E. Batchelor T.J.P. Dunning J. Shackcloth M. Anikin V. Naidu B. et al.Video-assisted thoracoscopic or open lobectomy in early stage lung cancer.NEJM Evid. 2022; 1https://doi.org/10.1056/EVIDoa2100016Crossref Google Scholar In this study, 503 patients were randomized to VATS (n = 247) or open (n = 256) lobectomy. Surgeons were required to have performed at least 40 VATS lobectomies to qualify for the trial, which was conducted across 9 institutions and included 25 surgeons. The primary outcome of the study was physical function over the first 5 weeks after randomization, and secondary outcomes included clinical efficacy, safety, and oncologic outcome to 1 year. The authors are to be commended for the design of the trial, for accomplishing full and rapid accrual of patients, and for outstanding technical results. To establish objectivity in postoperative assessments, a wound dressing large enough to conceal a thoracotomy incision was applied at the end of the operation, regardless of if VATS or open lobectomy had been performed. At discharge, patients were informed of the surgery they had received (after they had been asked to indicate to which group they believed they had been assigned). The conversion rate from VATS to open lobectomy was only 6.1%, and the postlobectomy operative mortality was only 1.5%. Regarding the primary outcome (physical function as the global measure of recovery), VATS patients had significantly better physical functioning at 5 weeks, with a median score of 73 versus 67 in the open surgery group (mean difference, 4.65; 95% CI, 1.69-7.61; P = .009). Regarding pain, analgesic consumption in the 2 groups had a mean ratio (VATS:open) of 0.90 (95% CI, 0.80-1.01), favoring VATS. In addition, prolonged incision-related pain was experienced by 59.6% of participants in the VATS group and by 72.3% of participants in the open group. Of VATS patients, 30.7% had serious adverse events after discharge compared with 37.8% of those allocated to open surgery (risk ratio, 0.81; 95% CI, 0.66-1.00). Finally, at 52 weeks, there were no differences in cancer progression-free survival (hazard ratio, 0.74; 95% CI, 0.43-1.27) or overall survival (hazard ratio, 0.67; 95% CI, 0.32-1.40). There was more bleeding and there were more patients with air leaks in the VATS group, but these events did not have a major influence on patient outcomes. Is this the final chapter in the epic story of the transformation of pulmonary resection from a predominately open procedure (performed by many) to a nearly entirely minimally invasive procedure (performed by general thoracic surgeons)? I think it does represent an important transformation in the body of knowledge regarding VATS lobectomy and provides an ability to use benchmarks regarding outcomes that were generated from a modern, prospective randomized trial, without influence from selection bias. However, the information that we have about minimally invasive lung resection with even more complex resections than standard lobectomy—VATS or robotic—from nonrandomized studies is also still valid. This should be used in conjunction with VIOLET outcomes to influence the trajectory of minimally invasive resection and should be incorporated into the design of future studies, randomized or not.3Norris S.L. Atkins D. Challenges in using nonrandomized studies in systematic reviews of treatment interventions.Ann Int Med. 2005; 142: 1112-1119Crossref PubMed Google Scholar The magnitude of potential benefit of having designed and completed a study such as VIOLET a decade earlier, when it was originally conceived, is unknown. Would a randomized trial published in 2010 have changed the arc of the adoption curve of minimally invasive resection? Would it have convinced reluctant surgeons to learn and subsequently teach the procedure? Would it have accelerated its requirement in training programs? Would it have brought VATS technology to patients in health systems that are resource-limited and in which VATS adoption was even slower than average? Would it have stimulated even more technical innovation than the nonrandomized evidence? Would VIOLET have stimulated more research on enhanced recovery protocols and other applications of minimally invasive thoracic surgery? How many patients would have benefited? Another lesson from VIOLET relates to our ability as thoracic surgeons to design, conduct, complete, and publish randomized trials. Landmark prospective randomized trials have recently been successfully completed, including CheckMate 8164Forde P.M. Spicer J. Lu S. Provencio M. Mitsudomi T. Awad M.M. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (390) Google Scholar and Japanese Clinical Oncology Group 0802,5Saji H. Okada M. Tsuboi M. Nakajima R. Suzuki K. Aokage K. et al.Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.Lancet. 2022; 399: 1607-1617Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar each published this year, and CALGB 140503, which was recently presented. There are many other avenues of innovation in lung cancer surgery alone, technical and oncologic, for which clinical trials will be necessary to determine the ultimate value of the innovation, including induction immunotherapy for early-stage disease, use of circulating tumor DNA to determine prognosis and therapy, new robotic platforms, use of artificial intelligence and other adjuncts to screening, and use of fluorescence in resection among others. In addition to the numerous ongoing trials focused on the use of immunotherapy and biologic therapy in the induction setting, the American Association for Thoracic Surgery Thoracic Surgical Oncology Group has a portfolio of trials that are currently recruiting and require the enthusiastic support of surgeons to answer questions that only surgeons can answer. So, if the question is, Have we reached the final chapter? The answer is, Whereas studying VATS lobectomy has reached its denouement, other epics continue. The author reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.