Japanese Oncology Group 0802: Another giant leap.

Central MessageA prospective randomized trial demonstrates comparable outcomes for segmentectomy compared with lobectomy for selected patients with early-stage lung cancer (T < 2 cm).Feature Editor Note—The momentum for pulmonary segmentectomy in patients with non–small cell lung cancer was brisk even before the recent publication of the practice-changing Japanese Oncology Group (JCOG) 0802 randomized trial, which demonstrated equivalency of segmentectomy and lobectomy for overall survival in patients treated for select non–small cell lung cancer tumors. Since publication of this trial and bolstered by the recent presentation of data from the international Cancer and Leukemia Group B/Alliance 140503 trial that randomized patients to sublobar resection or lobectomy, this momentum has only accelerated. We are privileged to work in a field that is enriched in surgical innovators, and publications and presentations on complex segmentectomies, segmentectomies for central tumors, and “sub-segmentectomies” are proliferating. Nevertheless, indications for patient selection for segmentectomy remain nuanced and personalized, and the sands continue to shift. For example, 59% of patients in the sublobar arm of the Cancer and Leukemia Group B trial were treated by wedge resection, and deciding between segmentectomy and wedge resection is an entirely additional layer of consideration. So where are reasonable “standards” for selecting patients for such a shift in surgical practice found? Logically, they are grounded in the eligibility criteria for enrollment into their respective landmark clinical trials; however, safe and thoughtful translation of trial results into the clinic requires a deep understanding of trial design that is enhanced by expert interpretation. In this Feature Expert Opinion article, a leader in this field distills the Japanese Oncology Group 0802 trial into its basic components and will prove useful to both the individual practices of our surgeon readership and for guiding the holistic direction of this rapidly progressing specialty.Bryan M. Burt, MD, FACS A prospective randomized trial demonstrates comparable outcomes for segmentectomy compared with lobectomy for selected patients with early-stage lung cancer (T < 2 cm). The decision to perform lobar or sublobar resection for early-stage non–small cell lung cancer has been the topic of debate and investigation for at least 5 decades. Proponents argue—with some evidence—that anatomic segmentectomy, in appropriately selected patients, will achieve equivalent oncologic outcomes while preserving pulmonary function. Regarding a priori oncologic equivalence, the development of appropriate patient selection criteria is critical, especially considering that the criteria and guidelines for converting segmentectomy to lobectomy are unclear as well. Regarding the ability to preserve pulmonary function, this potential advantage in part depends on the definition of segmentectomy: how many segments can be removed and still be considered only a segmentectomy. Critics will argue—with some evidence—that oncologic equivalence is limited to resection in patients with very small nodules (<1 cm), or with ground-glass opacities, or with nodules that are predominately ground glass, as quantified by consolidation to tumor ratios (CTR) <0.5. In addition, they will argue that evidence of the preservation of pulmonary function is not overwhelming. In summary, while there is consensus that anatomic segmentectomy has a role in the management of lung cancer in selected patients, there has not been consensus on how to select these patients to achieve oncologic equivalence. To address this issue definitively, the Japanese Oncology Group (JCOG) performed a multicenter, prospective, randomized trial (JCOG0802) at 70 institutions in Japan, recently published.1Saju 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 Patients with clinical stage IA non–small cell lung cancer (tumor diameter ≤2 cm; CTR >0.5; outer third of lung) were randomly assigned to lobectomy or segmentectomy. Furthermore, segmentectomy was defined as the anatomic resection of no more than 2 contiguous segments; however, left S1-S3 segmentectomy was permitted on the basis of the inclusion of the fused segments S1-S2. In this trial, 1319 patients were enrolled (2009-2014), and 1106 patients were randomized to receive lobectomy (n = 554) or segmentectomy (n = 552), using intent-to-treat methodology. The primary end point was overall survival, and secondary end points included postoperative pulmonary function, relapse-free survival, adverse events, length of hospital stay, chest tube duration, duration of surgery, amount of blood loss, and the number of automatic surgical staples used. The hypotheses, based on previously performed nonrandomized studies by the JCOG, was that segmentectomy would be noninferior to lobectomy for overall survival and that pulmonary function would be superior with segmentectomy. Regarding the primary outcome of overall survival, at a median follow-up of 7.3 years, both groups had outstanding survival: the 5-year overall survival was 94.3% for segmentectomy and 91.1% for lobectomy. Both superiority and noninferiority of segmentectomy in overall survival were confirmed using a stratified Cox regression model. Why would this be? How is segmentectomy even better than lobectomy in terms of survival? Interestingly, more patients died due to other diseases in the lobectomy group (63% of deaths) than in the segmentectomy group (47% deaths). Specifically, the number of patients who died of respiratory or cerebrovascular causes was greater in the lobectomy group than in the segmentectomy group. The timing of these deaths is not apparent from the study, whether these deaths were the immediately related to the surgery (death within 90 days) or more distant from the surgery. The authors offer no explanation for this finding and admit that “attribution of the increased number of deaths in the lobectomy group to non-malignant causes, including respiratory disease and cerebrovascular disease, is not directly supported by these data.” As well, other cancer-related deaths, including second primary lung cancer, were more frequent in patients who had a lobectomy. The authors found that additional “intensive resections and therapies” for treating relapse or second primary lung cancer were performed more frequently in patients after segmentectomy compared with lobectomy. Among the patients with relapse, 18 (49%) of 37 patients in the lobectomy group were alive at 5 years. However, in the segmentectomy group, 35 (68%) of 51 patients were alive. Furthermore, 80% (35 of 44) of patients with tumor relapse received treatment for relapse in the lobectomy group, whereas 93% (62 of 67) of patients in the segmentectomy group received intensive treatment of secondary primary lung cancer. In addition, additional intensive resections were performed in only 19 patients (63%) of 30 with second primary lung cancer in the lobectomy group, compared with 32 (89%) of 36 patients in the segmentectomy group. Regarding this disparity in aggressiveness of treating recurrences and new primary malignancies, the authors speculate that “segmentectomy, which preserves more lung parenchyma than does lobectomy, might have contributed to the more extensive treatment for not only relapse of the primary lung cancer and second primary lung cancer but also possibly for other cancers and other lethal disease that might be present, resulting in overall survival being significantly exceeded, despite the higher local relapse rate in this trial.” As will be discussed to follow, while it may preserve parenchyma, it is not clear from this study that segmentectomy does in fact significantly preserve lung function. At this point, I believe that the authors cannot adequately explain these results, and it is unclear whether this would be limited to this population of patients in Japan. It is possible that segmentectomy may prove to be a greater advantage in a population of patients with worse pulmonary function than in this trial. Before assuming that segmentectomy is oncologically equivalent to lobectomy, we must also consider the secondary outcomes. In this study, the 5-year relapse-free survival was similar in the 2 groups: 88.0% for segmentectomy and 87.9% for lobectomy (P = .9889). However, the proportions of patients with local relapse were 10.5% for segmentectomy and 5.4% for lobectomy (P = .0018). It is unclear whether this clinical and statistical difference in local relapse will influence relapse-free survival over time, or whether the degree of aggressiveness of treating relapses as discussed previously will eclipse the difference in local relapse. The patient selection criteria outlined in the methods section may be further assessed. The final iteration of the JCOG0802 protocol required that nodules have CTR >0.5; however, 11.4% in the lobectomy group and 13.2% in the segmentectomy group had nodules with CTR 0 to 0.5. Does this fraction of patients, in whom segmentectomy is generally agreed to be oncologically equivalent before to the study, inflate the value of segmentectomy in the final survival analysis? The publication does not specify the spectrum of adenocarcinoma that was found, but tumor having lepidic growth was found in 539 patients (48.7%) (K. Suzuki, MD, personal communication, June 19, 2022). It is uncertain whether this population, with a high proportion of never-smokers (44%) and nearly 50% with lepidic tumors, would be representative of North American or European patient populations. And, before assuming that segmentectomy preserves lung function, the authors found that there was a clinically insignificant difference in the reduction of median forced expiratory volume in 1 second between the 2 groups at 1 year, (2.7% at 6 months; 3.5% at 12 months), failing to meet the predefined threshold of 10%. The other secondary end points (adverse events, chest tube duration, duration of surgery, amount of blood loss, and the number of automatic surgical staples used) were reported previously.2Suzuki K. Saji H. Aokage K. Watanabe S.I. Okada M. Mizusawa J. et al.Comparison of pulmonary segmentectomy and lobectomy: safety results of a randomized trial.J Thorac Cardiovasc Surg. 2019; 158: 895-907Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar In summary, complications (grade ≥2) occurred in 26.2% and 27.4% in the lobectomy and segmentectomy arms (P = .68), respectively. Prolonged air leak was greater in patients who underwent lobectomy than segmentectomy, 21 (3.8%) and 36 (6.5%), respectively (P = .04). Multivariable analysis revealed that complex segmentectomy (vs lobectomy) was a significant predictor of pulmonary complications, including air leak and empyema. Although median postoperative duration of the chest tube placement was identical (4 days) in both arms, the frequency of reinsertion of the chest drain was significantly greater in the segmentectomy arm (P = .015). There was a statistically significant (but clinically not significant) greater intraoperative blood loss associated with segmentectomy (50 mL; range, 0-800 mL) versus lobectomy (44.5 mL; range, 0-900; P = .012). There was no difference in staple use. It does not appear that length of hospital stay was analyzed in either publication.1Saju 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,2Suzuki K. Saji H. Aokage K. Watanabe S.I. Okada M. Mizusawa J. et al.Comparison of pulmonary segmentectomy and lobectomy: safety results of a randomized trial.J Thorac Cardiovasc Surg. 2019; 158: 895-907Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar JCOG0802 is an important landmark trial, one of the most influential in the study of the surgical treatment of lung cancer ever published. Using objective criteria applied to other trials in thoracic surgery,3Robinson N.B. Fremes S. Hameed I. Rahouma M. Weidenmann V. Demetres M. et al.Characteristics of randomized clinical trials in surgery from 2008 to 2000. A systematic review.JAMA Netw Open. 2021; 4: e2114494https://doi.org/10.1001/jamanetworkopen.2021.14494Crossref PubMed Scopus (29) Google Scholar this trial does not appear to exhibit the flaws of inadequate size, incomplete or prolonged accrual, reporting bias, inadequate follow-up, or multiplicity. Given the size of the trial and experience of participating centers, I doubt that differential surgical experience is an issue. This multicenter, randomized trial affirms the role of segmentectomy in selected patients with lung cancer. Thoracic surgeons must employ segmentectomy in clinical situations in which it has been demonstrated to achieve outcomes equivalent to lobectomy. Despite the fact that this study did not demonstrate preservation of pulmonary function, parenchymal preservation is still an important goal, particularly valuable in patients who might need subsequent resections. In addition, JCOG0802 provides landmarks for the primary and secondary outcomes from the study that can be used for quality improvement among surgical programs that perform segmentectomy commonly. Is the study perfect? No. It is clear that there is a relationship between size, CTR, and histology, and it is probable that some patients in this study would have been better treated with lobectomy. The study analyzes outcomes by tumor location, but it would not have the power to inform the surgeon as to which locations would be best for segmentectomy versus lobectomy. Of note, the greatest number of segmentectomies were performed in the left upper lobe, and it is likely that S1-S3 and S4-S5 resections, technically straightforward, were significantly represented. Similarly, the prospect of an S6 resection is quite different than that of an S10 segmentectomy. How do we best select patients tomorrow? Patients with tumor diameter ≤2 cm and in outer third of lung should be strongly considered for segmentectomy. I think it is important to learn from the results related to the differential aggressiveness applied to patients with recurrence or new primary tumors, relating to whether segmentectomy or lobectomy had been performed. Similarly, we need to better understand how the outcomes related to respiratory and neurologic complications factor into decisions regarding operative approach. On one end of the spectrum are patients with small tumors, with low CTR, in the most-accessible segments. On the other are patients with larger, perhaps more central tumors and higher CTS requiring complex segmentectomy. Finally, it is not clear from either publication how thoracoscopic techniques were employed in JGOG0802, although it is reported than nearly 90% of resections were performed by video-assisted thoracoscopic surgery.1Saju 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,2Suzuki K. Saji H. Aokage K. Watanabe S.I. Okada M. Mizusawa J. et al.Comparison of pulmonary segmentectomy and lobectomy: safety results of a randomized trial.J Thorac Cardiovasc Surg. 2019; 158: 895-907Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar In addition to the large amount of data supporting minimally invasive approaches to early-stage lung cancer, the recently published randomized trial—Video-Assisted Thoracoscopic or Open Lobectomy (VIOLET)—again demonstrates the numerous advantages of thoracoscopic resection,4Lim 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 and the most important outcomes to compare in the future would be minimally invasive segmentectomy versus minimally invasive lobectomy. The results of the recently completed Cancer and Leukemia Group B 140503 trial will add to the great amount learned from JCOG0802. 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.