Recurrence-Free Survival in Patients With Surgically Resected Non-Small Cell Lung Cancer

BackgroundStandard treatment for early-stage or locoregionally advanced non-small cell lung cancer (NSCLC) includes surgical resection. Recurrence after surgery is commonly reported, but a summary estimate for postsurgical recurrence-free survival (RFS) in patients with NSCLC is lacking.Research QuestionWhat is the RFS after surgery in patients with stage I-III NSCLC at different time points, and what factors are associated with RFS?Study Design and MethodsA systematic search was performed in MEDLINE, EMBASE, and Cochrane databases between January 2011 and June 2021. The primary outcome was RFS at 1, 2, 3, and 5 years postresection. Single-arm, random-effects meta-analyses were done to calculate effect estimates and 95% CIs. Analyses were stratified by stage/substage as per the AJCC Cancer Staging Manual, and RFS was estimated (1) after pooling studies, using 7th or 8th edition staging criteria; and (2) among studies using only the 8th edition. Meta-regressions were performed to assess associations between RFS and patient demographic/clinical characteristics of interest.ResultsData from 471 studies comprising 1,060 surgical study arms were extracted. RFS estimates from 60,695 patients staged with the 7th or 8th edition were analyzed. RFS ranged from 96% at 1 year postresection to 82% at 5 years for stage I, and from 68% at 1 year to 34% at 5 years for stage III. Estimates for patients staged using only 8th edition criteria were slightly higher. Older age, higher percentage of male patients, advancing stage, larger tumor size, and geographical region (North America/Europe vs Asia) were significantly associated with worse RFS.InterpretationThis study presents a comprehensive assessment of reported RFS from published clinical literature, offering estimates at multiple postsurgical time points and by geographical region. Findings can inform treatment decisions, clinical trial design, and future research to improve outcomes among patients with NSCLC. Standard treatment for early-stage or locoregionally advanced non-small cell lung cancer (NSCLC) includes surgical resection. Recurrence after surgery is commonly reported, but a summary estimate for postsurgical recurrence-free survival (RFS) in patients with NSCLC is lacking. What is the RFS after surgery in patients with stage I-III NSCLC at different time points, and what factors are associated with RFS? A systematic search was performed in MEDLINE, EMBASE, and Cochrane databases between January 2011 and June 2021. The primary outcome was RFS at 1, 2, 3, and 5 years postresection. Single-arm, random-effects meta-analyses were done to calculate effect estimates and 95% CIs. Analyses were stratified by stage/substage as per the AJCC Cancer Staging Manual, and RFS was estimated (1) after pooling studies, using 7th or 8th edition staging criteria; and (2) among studies using only the 8th edition. Meta-regressions were performed to assess associations between RFS and patient demographic/clinical characteristics of interest. Data from 471 studies comprising 1,060 surgical study arms were extracted. RFS estimates from 60,695 patients staged with the 7th or 8th edition were analyzed. RFS ranged from 96% at 1 year postresection to 82% at 5 years for stage I, and from 68% at 1 year to 34% at 5 years for stage III. Estimates for patients staged using only 8th edition criteria were slightly higher. Older age, higher percentage of male patients, advancing stage, larger tumor size, and geographical region (North America/Europe vs Asia) were significantly associated with worse RFS. This study presents a comprehensive assessment of reported RFS from published clinical literature, offering estimates at multiple postsurgical time points and by geographical region. Findings can inform treatment decisions, clinical trial design, and future research to improve outcomes among patients with NSCLC. Take-home PointsStudy Questions: What are the RFS estimates after surgery in patients with clinical stage I-III NSCLC at various time points, and what factors are associated with RFS?Results: For patients staged with the AJCC 7th or 8th edition, RFS ranged from 95% at 1 year postresection to 81% at 5 years for stage I, and from 68% at 1 year to 34% at 5 years for stage III, with slightly higher estimates for patients staged using only the 8th edition criteria. Older age, higher percentage of male patients, advancing stage, larger tumor size, and geographical region (North America or Europe vs Asia) were significantly associated with worse RFS.Interpretation: This study presents a comprehensive assessment of reported RFS from published clinical literature that can inform treatment decisions, clinical trial design, and future research to improve outcomes among patients with NSCLC. Study Questions: What are the RFS estimates after surgery in patients with clinical stage I-III NSCLC at various time points, and what factors are associated with RFS? Results: For patients staged with the AJCC 7th or 8th edition, RFS ranged from 95% at 1 year postresection to 81% at 5 years for stage I, and from 68% at 1 year to 34% at 5 years for stage III, with slightly higher estimates for patients staged using only the 8th edition criteria. Older age, higher percentage of male patients, advancing stage, larger tumor size, and geographical region (North America or Europe vs Asia) were significantly associated with worse RFS. Interpretation: This study presents a comprehensive assessment of reported RFS from published clinical literature that can inform treatment decisions, clinical trial design, and future research to improve outcomes among patients with NSCLC. Lung cancer is the second most common cancer worldwide and the leading cause of cancer-related death.1Sung H. Ferlay J. Siegel R.L. et al.Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (45055) Google Scholar The two primary histologic subtypes are non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC).2Lemjabbar-Alaoui H. Hassan O.U. Yang Y.W. Buchanan P. Lung cancer: biology and treatment options.Biochim Biophys Acta. 2015; 1856: 189-210PubMed Google Scholar Surgical resection is part of the standard treatment for early-stage or locoregionally advanced NSCLC in patients fit enough to tolerate an operation; however, postoperative recurrence is common and ranges from 30% to 75%.3Uramoto H. Tanaka F. Recurrence after surgery in patients with NSCLC.Transl Lung Cancer Res. 2014; 3: 242-249PubMed Google Scholar,4Sasaki H. Suzuki A. Tatematsu T. et al.Prognosis of recurrent non-small cell lung cancer following complete resection.Oncol Lett. 2014; 7: 1300-1304Crossref PubMed Scopus (39) Google Scholar These estimates are derived from a few studies, most published more than 20 years ago. Two more systematic reviews included six studies5Stirling R.G. Chau C. Shareh A. Zalcberg J. Fischer B.M. Effect of follow-up surveillance after curative-intent treatment of NSCLC on detection of new and recurrent disease, retreatment, and survival: a systematic review and meta-analysis.J Thorac Oncol. 2021; 16: 784-797Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and 11 studies,6Hu J. Miao H. Li R. Wen Z. Surgery and subsequent risk of non-small cell lung cancer recurrence: a meta-analysis of observational studies.Transl Cancer Res. 2020; 9: 1960-1968Crossref PubMed Scopus (0) Google Scholar respectively, and neither published a summary estimate for recurrence-free survival (RFS). Compared with recurrence rates, RFS is reported at fixed time points, making it easier to meta-analyze than recurrence rates, which are often presented as the total number of events that occurred during study follow-up, with variable durations. RFS also captures deaths, which makes it a potential surrogate end point for overall survival (OS). With the implementation of the 8th edition of the American Joint Commission on Cancer (AJCC) TNM staging system as the standard classification for lung cancers in the United States in January 2018,7Detterbeck F.C. The eighth edition TNM stage classification for lung cancer: what does it mean on Main Street?.J Thorac Cardiovasc Surg. 2018; 155: 356-359Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar comparisons between studies may be impacted.8Lim W. Ridge C.A. Nicholson A.G. Mirsadraee S. The 8th lung cancer TNM classification and clinical staging system: review of the changes and clinical implications.Quant Imaging Med Surg. 2018; 8: 709-718Crossref PubMed Scopus (155) Google Scholar A contemporary and comprehensive review of recurrence outcomes in patients with surgically resected NSCLC is lacking. The aim of this systematic literature review (SLR) and meta-analysis was to summarize and analyze RFS and recurrence rates after surgery in patients with NSCLC over time by stage, incorporating different staging classifications (7th and 8th edition), and to examine factors associated with RFS. Institutional review board approval was not required for this work because no participants were recruited. An SLR protocol was not registered, but the review followed predefined screening and extraction criteria. This SLR and meta-analysis were conducted on the basis of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines.9Page M.J. McKenzie J.E. Bossuyt P.M. et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ. 2021; 372: n71Crossref PubMed Scopus (22975) Google Scholar A systematic search was conducted by an information specialist and peer-reviewed by a second information specialist, using PRESS (Peer Review of Electronic Search Strategies) guidelines.10McGowan J. Sampson M. Salzwedel D.M. Cogo E. Foerster V. Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement.J Clin Epidemiol. 2016; 75: 40-46Abstract Full Text Full Text PDF PubMed Google Scholar The detailed search strategy is presented in e-Tables 1 and 2. Example search terms used included key words and MeSH terms such as: “lung cancer,” “cancer recurrence,” “surgery,” and “survival analysis.” MEDLINE, EMBASE, and Cochrane databases were searched for English language studies conducted between January 2011 and June 2021, based on predefined PICOS (Population, Intervention, Comparator, Outcomes, and Study Design) criteria (e-Table 3). Studies enrolling adults with clinical stage I-III NSCLC who underwent lung surgery alone or in combination with other therapies (neoadjuvant or adjuvant) were eligible for inclusion. Resections of interest were wedge, segmentectomy, lobectomy, and pneumonectomy, with inclusion of all surgical approaches (video-assisted thoracoscopic surgery, robot-assisted thoracoscopic surgery, and thoracotomy). Eligible studies could be either single- or multiarm studies comparing distinct treatment methods. Studies that included a mix of surgery types were also included. Only studies including surgeries for primary lung cancer were included. Studies enrolling patients undergoing surgery for recurrent tumors or diagnostic purposes were excluded. Eligible studies must have reported one or more of the following recurrence outcomes: local, locoregional, regional, distant recurrence, local tumor recurrence, or RFS. Studies that reported disease-free survival (DFS) or progression-free survival (PFS) instead of RFS were also included, as these outcomes are often used interchangeably in practice. Included studies were single-arm, comparative observational studies, or randomized trials, whereas case reports, narrative reviews, and preclinical studies were excluded. Observational studies were included to capture all available evidence on surgery in patients with NSCLC. Studies focused on evaluating risk factors and predictors of recurrence outcomes were excluded. For a detailed list of inclusion and exclusion criteria, refer to e-Table 3. The search strategy was with screening of published reviews and meta-analysis for to included studies were to with a of at surgically patients, or at in the study included multiple surgery Studies with were with of was performed by two using the Scholar with by a were for and after which eligible studies were for that could be and fit the PICOS criteria were for Only studies reporting staging to the 7th or 8th AJCC TNM classification were included in the meta-analysis summary RFS RFS was estimated from of surgery to the of recurrence or from cause at 1, 2, 3, and 5 years to follow-up, or end of occurred Studies that or from RFS were not included in the to which can for survival of RFS is as an and instead in an RFS is which may cause in the estimated RFS using the because it the of a patient who is is of patients who F. E. of on the estimate of progression-free survival in clinical Clin Oncol. 2014; PubMed Scopus (39) Google in survival PubMed Scopus Google Scholar Studies in which the were risk were and included in the of key characteristics geographical number of male patients, follow-up tumor and outcome local progression-free survival and locoregional, and overall recurrence from studies was performed in Recurrence from or incidence were with to estimate outcome rates at time points of interest. were performed with the in random-effects meta-analyses were conducted by the of patients recurrence at time point by the 95% were Study in the meta-analyses was based on the because complete were not available for all Study arms were the of and studies could multiple arms with distinct resection from the meta-analyses are presented as by stage and time postresection. was with and in patient characteristics was by the of Meta-regressions were conducted to examine associations between RFS estimates and patient of male patients, and vs stage I, tumor study region and surgery pneumonectomy, and or surgical and of or for are reported as with 95% with 1 worse RFS and 1 RFS. were A summary of all by and time is presented as and assessment of included studies were conducted to of the (e-Table was also to 1 for a detailed of these The search of which were for Data from 471 studies 1,060 surgical study arms were Included studies were conducted in followed by America and Europe studies were and were conducted in than of study arms included between and The follow-up was to in of the study arms and not reported in RFS from these study arms were included in the meta-analyses and The mean was years all study were and study arms that used the 7th and 8th edition AJCC TNM The most reported stage was stage I, for of and of of the 7th and 8th edition study 8th edition study arms reported recurrence rates for clinical and Only staging was reported in of 7th edition and of 8th edition study which were not included in this staging information was reported in of 7th edition study arms and of 8th edition study RFS estimates from 60,695 patients study staged with AJCC 7th or 8th edition were with stage patients of the was included as an in of the study methods. for and RFS are in 2. RFS with advancing stage at the for stage I, for stage and for stage and time points for stage I, for stage and 34% for stage A was at and The RFS during follow-up was for stage at 1 year and at 5 whereas only 34% of stage patients were recurrence at 5 years in The meta-analyses of and were performed to for in patient RFS estimates at and for study arms were for stage patients and overall stage patients but higher for stage patients than were 7th and 8th edition 3). This was also at and Only six study arms reported RFS for clinical and the meta-analyses 1, e-Table RFS ranges for stage were than to stage and to the meta-analysis for stage the of the mean patient in stage study arms was with years in the stage study and years in the stage study by for and recurrence-free in a new RFS recurrence-free and overall recurrence ranges are in 2. Recurrence rates ranged but summary estimates were not because rates were reported by time distant recurrence is higher than recurrence, recurrence ranges be with because of of of Recurrence by Recurrence (7th (7th (7th (7th (7th in a new at 5 years was for study but all but two study arms not by stage, making estimates to meta-analyses of RFS by recurrence were not the worse of RFS were with age, tumor size, and study arms at The of RFS at 5 years from America/Europe were and and respectively, with were at follow-up, at which time an of male patients and more advanced stage and vs stage were associated with worse whereas the estimate for study arms than 1 but was not Study arms patients with approaches at follow-up were associated with RFS. stage was associated with worse of RFS at years and worse of RFS at 5 and tumor was associated with and worse of RFS at the time on advancing stage and tumor associated with worse RFS were at time points that RFS estimates all time points for stage and patients were higher in vs study arms vs and vs and for more Compared with the primary RFS point estimates in that included only study arms with no risk were slightly for stage at time point RFS point estimates from of studies using the for were to the primary for most and time points e-Table was in of stage and study and was a of between the and for most time points e-Table to the for on the and this is the SLR and meta-analysis RFS estimates after surgery in patients with NSCLC with early-stage or locoregionally advanced This comprehensive assessment of RFS included studies and recurrence from published clinical literature, of more than surgically patients with NSCLC. the RFS was for stage for stage 81% for stage I, for stage and 34% for stage a in RFS between stage and stage at all time points of interest. reviews have published summary estimates for the of postsurgical recurrence, but a summary estimate of RFS is lacking. and H. Tanaka F. Recurrence after surgery in patients with NSCLC.Transl Lung Cancer Res. 2014; 3: 242-249PubMed Google Scholar reported that 30% to of patients with NSCLC recurrence and of resection. and H. Suzuki A. Tatematsu T. et al.Prognosis of recurrent non-small cell lung cancer following complete resection.Oncol Lett. 2014; 7: 1300-1304Crossref PubMed Scopus (39) Google Scholar and and R.G. Chau C. Shareh A. Zalcberg J. Fischer B.M. Effect of follow-up surveillance after curative-intent treatment of NSCLC on detection of new and recurrent disease, retreatment, and survival: a systematic review and meta-analysis.J Thorac Oncol. 2021; 16: 784-797Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar presented recurrence ranges of 30% to and to The to on RFS in this study instead of overall recurrence was to a of published studies which is of interest to and and the assessment of RFS as a clinical trial end point in it may as a surrogate end point for and for the of Cancer and for Scholar recurrence is a outcome that does not and is by the risk the incidence of recurrence is reported in the NSCLC studies that recurrence the total number of during the follow-up Reporting in this makes comparisons between studies and of because of variable or follow-up durations. 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J. et al.The Lung Cancer Staging for of the TNM stage in the edition of the TNM for Lung Thorac Oncol. 2016; Full Text Full Text PDF PubMed Google Scholar that age, more advanced stage, and tumor were associated with worse RFS at all time points, with M. et cancer and after recurrence in a Cancer 2015; PubMed Google P. R. T. factors for local and distant recurrence after surgical treatment in patients with lung Lung 2016; Full Text Full Text PDF PubMed Google R. et to recurrence and survival of patients undergoing resection for lung cancer: an of a study Thorac Surg. 2016; Full Text Full Text PDF PubMed Scopus (0) Google M.J. et recurrence following lung resection for clinical stage non-small cell lung Full Text Full Text PDF PubMed Scopus (0) Google J. A. J. et and comparisons of outcomes of patients with clinical stage non-small cell lung cancer with resection or PubMed Scopus Google et risk factors for stage non-small cell lung 2015; PubMed Scopus (39) Google Scholar study arms patients with surgical approaches were associated with RFS at follow-up, the was not significantly different at other time point and must be with of the were from the literature, to 82% of included studies reported higher RFS estimates at all time points with studies in and in the For a trial enrolling patients with stage reported a of in H. M. M. et in lung cancer a 3, Full Text Full Text PDF PubMed Scopus Google Scholar a trial reported survival of and after and respectively, in more than patients with clinical stage in et or resection for stage lung J PubMed Scopus Google Scholar is with these studies and that higher RFS estimates all time points for stage patients in study RFS and outcomes in patients may be to the higher of who F. C. 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