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Factor influencing local regrowth after watch-and-wait for clinical complete response following chemoradiotherapy in rectal cancer: an individual participant data meta-analysis (InterCoRe consortium) 1 Sami A Chadi MD MSc 2,3 Lee Malcomson BSc 4 Joie Ensor PhD 4 Professor Richard D Riley PhD Buenos Aires 5 Carlos A Vaccaro MD PhD 5 Gustavo L Rossi MD Exeter, UK6 Ian R Daniels MD 6 Neil J Smart PhD 6 Melanie E Osborne MRCP FRCR Maastricht, NL7,8 Professor Geerard L Beets PhD 9 Monique Maas MD PhD NYU, US10 Danielle S Bitterman MD 11 Kevin Du MD PhD OnCoRe12 Simon Gollins DPhil 13 Professor Arthur Sun Myint FRCR 14 Fraser M Smith MD 15 Professor Mark P Saunders PhD 16 Nigel Scott MD 3 Professor Sarah T O’Dwyer MD Rio de Janeiro, Brazil17 Rodrigo Otavio de Castro Araujo MD 17 Marcus Valadao MD PhD 17 Alberto Lopes MD Taipei, Taiwan18 Cheng-Wen Hsiao MD?18 Chien-Liang Lai MD University of Pennsylvania, USA19 Radhika K Smith MD 19 Emily Carter Poulson MD Vejle, Denmark20,21 Ane Appelt PhD 20 Professor Anders Jakobsen DMSc 22 Professor Steven D Wexner MD PhD (Hon) 23 Professor Angelita Habr-Gama MD 24 Guilherme Sao Juli?o MD 23,24 Rodiguo Perez MD PhD 3,4 Professor Andrew G Renehan PhD Affiliations1 Division of Surgical Oncology and General Surgery, Princess Margaret Hospital and University Health Network, University of Toronto, Toronto, Ontario, Canada2 Manchester Cancer Research Centre and NIHR Manchester Biomdeical Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK 3 Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK4 Centre for Prognosis Research, Research Institute for Primary Care and Health Sciences, Keele University, Staffordshire, UK5 Servicio Cirugia General, Sector de Coloproctologia, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina6 Exeter Colorectal Unit, and Exeter Surgical Health Sciences Research Unit (HESRU), Royal Devon & Exeter NHS Foundation Trust, Exeter, Devon, UK 7 Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netheralnds 8 GROW, School of Oncology and Developmental Biology, University of Maastricht, The Netherlands9 Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands10 Harvard Radiation Oncology Program, Boston, MA, USA11 Department of Radiation Oncology, New York University Langone Medical Center, New York, NY, USA12 North Wales Cancer Treatment Centre, Rhyl, UK13 Clatterbridge Cancer Centre, Liverpool, UK14 Royal Liverpool Hospital NHS Foundation Trust, Liverpool, UK15 Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK 16 Royal Preston NHS Foundation Trust, Preston, UK17 Department of Abdominal and Pelvic Surgery, Instituto Nacional de C?ncer José Alencar Gomes da Silva - INCA, Rio de Janeiro, Brazil18 Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China19 Department of Surgery, Philadelphia VA Medical Center; Division of Colon and Rectal Surgery, Hospital of the University of Pennsylvania, Philadelphia, USA20 Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark21 Leeds Cancer Centre, St. James's University Hospital; and Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK22 Department of Colorectal Surgery?Cleveland Clinic Florida, Weston, Florida, USA.23 Instituto Angelita & Joaquim Gama, S?o Paulo, Brazil24 Ludwig Institute for Cancer Research, Molecular Biology and Genomics Lab, S?o Paulo Branch, BrazilRunning title: Rectal cancer watch and wait IPD meta-analysisKeywords: rectal cancer; clinical complete response; watch and wait; individual participant dataCorrespondence to:Professor Andrew G RenehanDivision of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health,University of Manchester, The Christie NHS Foundation Trust,Wilmslow RoadManchester, M20 4BX UKTel: +44 161 3060870E-mail: andrew.renehan@manchester.ac.ukAbstract: 393 words (max: 300); main text: 4758 words (max: 4000); x4 tables; x2 figures; 40 references (max: 40); supplemental material (19 pages); language: UK English.AbstractBackground: In patients with rectal cancer, ‘watch-and-wait’ (W&W) for clinical complete response (cCR) following neoadjuvant chemo-radiotherapy is a novel management strategy with potential to avoid major surgery. Study-level meta-analyses report wide variation in local regrowth rates. We performed an individual participant data (IPD) meta-analysis to evaluate factors influencing local regrowth occurrence as a potential explanation of this variation. Methods: We updated a recent systematic review search (MEDLINE and Embase, from 01 Jan 2016 to 05 May 2017; plus expert knowledge) to identify published studies in patients with rectal cancer reporting local regrowth following W&W for cCR following neoadjuvant chemo-radiotherapy. We restricted studies to those that defined cCR using criteria equivalent to S?o Paulo benchmarks, and requested IPD. We assessed study quality using an 11-item checklist. The primary outcome was 2-year local regrowth cumulative incidence estimated using a two-stage random-effects (RE) IPD meta-analysis. We evaluated the impact of clinical and treatment factors using Cox frailty models, expressed as hazard ratios (HRs). From these models, we derived percentage differences in mean theta as an approximation of the impact of measured covariates on between-centre heterogeneity.Results: We obtained IPD from 10 studies (11 datasets), totally 602 patients enrolled between 11 March 1990 and 13 February 2017, with a median follow-up of 37.6 (IQR: 25.0 – 58.7) months. Ten of the 11 studies were judged to be at low-risk of bias. There was wide between-centre variation in patient, tumour and treatment characteristics. The 2-year local regrowth cumulative incidence was 21.4% (RE 95% CIs: 15.3-27.6) with high levels of between-study heterogeneity (I2 = 61%). There was some evidence that increasing cT stage was associated with increased risk of local regrowth (RE HRper cT stage: 1.395, Ptrend = 0.048). In a sub-cohort of patients managed post-2008 (after which high-resolution MR pre-treatment staging became standard), 2-year local regrowth cumulative incidences were 19% (95% CIs: 13-28) for cT1/cT2, 31% (95% CIs: 26-37) for cT3, and 37% (95% CIs: 30-60) for cT4 (RE HRper cT stage: 1.482, Ptrend = 0.033). We estimated that measured factors contributed 4.8% to 45.3% to the explanation of observed between-centre heterogeneity. Interpretation: Among patients with rectal cancer and cCR managed by W&W, there was some evidence that increasing cT stage predicts for local regrowth. These data will inform clinician-patient decision-making in this setting. There is a research need to determine other predictors of a sustained clinical complete response. Funder: None.Registration: PROSPERO CRD42017070934Research in contextEvidence before this studyIn patients with rectal cancer who achieve a complete clinical response (cCR) after chemo-radiotherapy, the strategy of watch and wait (W&W) is new and offers an opportunity for patients to avoid major resection surgery. However, in the absence of randomised trials, this approach is not standard care. One recently published study-level meta-analysis of 23 studies (published and unpublished) including 871 patients, evaluated the outcome of patients managed by W&W and estimated a 2-year local regrowth rate of 15.7% but noted considerable between-study heterogeneity (I2 = 55.9%), with rates ranging from 3.3% to 33.3%. A second updated study-level meta-analysis of 17 published-only studies (692 patients) reported a 3-year cumulative risk of local regrowth of 21.6% (I2 = 66.5%). A register-based project, the International Watch and Wait Database (IWWD), reported on 880 patients with cCR managed by W&W, from 47 participating institutes (15 countries) and estimated a 2-year local regrowth cumulative incidence of 25.2%. Understanding factors that predict for local regrowth might explain the reported high levels of between-study heterogeneity. To-date, there is no large-scale study that has evaluated predictive factors for local regrowth because the study-level meta-analyses were unable to extract these data in an analysable form and there was considerable missingness in the IWWD registry-based report.Added value of this studyThis is the first reported individual participant data (IPD) meta-analysis in this field. By using the IPD methodology, there were two main advantages over study-level meta-analyses. First, we were able to test for predictive factors of local regrowth. And second, by incorporating Cox frailty models, we accounted for unmeasured factors at each study level. These factors might include centre-level protocols for staging, treatment, and follow-up. We obtained data from 10 studies (11 datasets) totally 602 patients, and with a median follow-up of 37.6 months, we estimated that the 2-year local regrowth cumulative incidence was 21.4%. There was some evidence that increasing cT stage was associated with increased risk of local regrowth, an association that remained after adjustments. We tested for other predictors including age, gender, cN stage, tumour distance to anal verge, serum CEA, radiotherapy dose, and time to W&W decision, and found no associations. Implications of all the available evidenceThe current literature notes wide variation in local regrowth rates after initial W&W and raised the concern that this strategy might not be generalisable to standard care. The present analysis exploited this heterogeneity of outcomes and demonstrated that the latter is partly explained by differences in study baseline characteristics. For the first time at-scale, the present analysis shows that increasing cT stage is associated with increased risk of subsequent local regrowth. In a sub-cohort of patients managed after 2008 (reflecting current standard practice using high-resolution MR pre-treatment staging), 2-year local regrowth cumulative incidences were 19% for cT1/T2, 31% for cT3, and 37% for cT4. These estimates will inform clinician-patient decision making and future trials in the field of organ-preservation in patients with rectal cancer.IntroductionSurgical resection is the mainstay of treatment for rectal cancer.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVubmVyPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

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ADDIN EN.CITE.DATA 1 In patients who receive pre-operative neoadjuvant chemo-radiotherapy, up to a quarter have complete tumour regression, recognisable as a clinical complete response (cCR).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5laGFuPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA 2 In these patients, ‘watch-and-wait’ (W&W) is a novel management strategy with potential to avoid major pelvic surgery. ADDIN EN.CITE <EndNote><Cite><Author>Breugom</Author><Year>2015</Year><RecNum>16</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">16</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Breugom, A. J.</author><author>van de Velde, C. J.</author></authors></contributors><auth-address>Leiden University Medical Centre, Department of Surgery, Leiden 2300 RC, Netherlands.&#xD;Leiden University Medical Centre, Department of Surgery, Leiden 2300 RC, Netherlands. Electronic address: C.J.H.van_de_Velde@lumc.nl.</auth-address><titles><title>Is it time for watchful waiting for rectal cancer?</title><secondary-title>Lancet Oncol</secondary-title><alt-title>The Lancet. Oncology</alt-title></titles><pages>875-6</pages><volume>16</volume><number>8</number><edition>2015/07/15</edition><dates><year>2015</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1474-5488 (Electronic)&#xD;1470-2045 (Linking)</isbn><accession-num>26156653</accession-num><urls></urls><electronic-resource-num>10.1016/s1470-2045(15)00015-7</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>3 This strategy originated from Habr-Gama and colleaguesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy

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ADDIN EN.CITE.DATA 9 A second updated study-level meta-analysis from Dattani et al. ADDIN EN.CITE <EndNote><Cite><Author>Dattani</Author><Year>2018</Year><RecNum>74</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>74</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">74</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dattani, M.</author><author>Heald, R. J.</author><author>Goussous, G.</author><author>Broadhurst, J.</author><author>Sao Juliao, G. P.</author><author>Habr-Gama, A.</author><author>Oliva Perez, R.</author><author>Moran, B. J.</author></authors></contributors><auth-address>Pelican Cancer Foundation, Basingstoke. Hampshire, UK.&#xD;University Hospitals Birmingham NHS Foundation Trust, UK.&#xD;Basingstoke and North Hampshire Hospital. Hampshire, UK.&#xD;Angelita &amp; Joaquim Gama Institute, Sao Paulo, SP, Brazil.</auth-address><titles><title>Oncological and Survival Outcomes in Watch and Wait Patients With a Clinical Complete Response After Neoadjuvant Chemoradiotherapy for Rectal Cancer: A Systematic Review and Pooled Analysis</title><secondary-title>Ann Surg</secondary-title><alt-title>Annals of surgery</alt-title></titles><periodical><full-title>Ann Surg</full-title><abbr-1>Annals of surgery</abbr-1></periodical><alt-periodical><full-title>Ann Surg</full-title><abbr-1>Annals of surgery</abbr-1></alt-periodical><edition>2018/05/11</edition><dates><year>2018</year><pub-dates><date>May 9</date></pub-dates></dates><isbn>1528-1140 (Electronic)&#xD;0003-4932 (Linking)</isbn><accession-num>29746338</accession-num><urls></urls><electronic-resource-num>10.1097/sla.0000000000002761</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>10 identified 17 published-only studies (692 patients) and estimated a 3-year cumulative risk of local regrowth of 21.6%, again with high levels of heterogeneity (I2 = 66.5%). Such between-study heterogeneity adds to concerns that W&W management, practiced as specialist centres, might not be generalisable to standard care. Alternatively, understanding factors that predict for local regrowth might explain the causes of between-study heterogeneity, ultimately better informing clinical pathways. Here, we perform and report an individual participant data (IPD) meta-analysis, obtaining IPD from 10 published studies (11 datasets) within the International Complete Response (InterCoRe) consortium. The central aim was to evaluate for factors influencing local regrowth. The InterCoRe project parallels the International Watch and Wait Database (IWWD),PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZhbGs8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

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ADDIN EN.CITE.DATA 9 and Dattani et al. ADDIN EN.CITE <EndNote><Cite><Author>Dattani</Author><Year>2018</Year><RecNum>74</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>74</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">74</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dattani, M.</author><author>Heald, R. J.</author><author>Goussous, G.</author><author>Broadhurst, J.</author><author>Sao Juliao, G. P.</author><author>Habr-Gama, A.</author><author>Oliva Perez, R.</author><author>Moran, B. J.</author></authors></contributors><auth-address>Pelican Cancer Foundation, Basingstoke. Hampshire, UK.&#xD;University Hospitals Birmingham NHS Foundation Trust, UK.&#xD;Basingstoke and North Hampshire Hospital. Hampshire, UK.&#xD;Angelita &amp; Joaquim Gama Institute, Sao Paulo, SP, Brazil.</auth-address><titles><title>Oncological and Survival Outcomes in Watch and Wait Patients With a Clinical Complete Response After Neoadjuvant Chemoradiotherapy for Rectal Cancer: A Systematic Review and Pooled Analysis</title><secondary-title>Ann Surg</secondary-title><alt-title>Annals of surgery</alt-title></titles><periodical><full-title>Ann Surg</full-title><abbr-1>Annals of surgery</abbr-1></periodical><alt-periodical><full-title>Ann Surg</full-title><abbr-1>Annals of surgery</abbr-1></alt-periodical><edition>2018/05/11</edition><dates><year>2018</year><pub-dates><date>May 9</date></pub-dates></dates><isbn>1528-1140 (Electronic)&#xD;0003-4932 (Linking)</isbn><accession-num>29746338</accession-num><urls></urls><electronic-resource-num>10.1097/sla.0000000000002761</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>10, and over the registry-based IWWD reported by van der Valk and colleagues.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZhbGs8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

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ADDIN EN.CITE.DATA 11 IPD afford the meta-analyst the opportunity to standardise inclusion criteria and analyses; obtain study results that had not been provided by the study publications; check modelling assumptions; ADDIN EN.CITE <EndNote><Cite><Author>Burke</Author><Year>2017</Year><RecNum>32</RecNum><DisplayText><style face="superscript">12</style></DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Burke, D. L.</author><author>Ensor, J.</author><author>Riley, R. D.</author></authors></contributors><auth-address>Research Institute for Primary Care and Health Sciences, Keele University, Staffordshire, U.K.</auth-address><titles><title>Meta-analysis using individual participant data: one-stage and two-stage approaches, and why they may differ</title><secondary-title>Stat Med</secondary-title><alt-title>Statistics in medicine</alt-title></titles><pages>855-875</pages><volume>36</volume><number>5</number><edition>2016/10/18</edition><dates><year>2017</year><pub-dates><date>Feb 28</date></pub-dates></dates><isbn>1097-0258 (Electronic)&#xD;0277-6715 (Linking)</isbn><accession-num>27747915</accession-num><urls></urls><custom2>PMC5297998</custom2><electronic-resource-num>10.1002/sim.7141</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>12 and importantly, for this study, model data as time-to-event cumulative incidence rather than crude rates. In the IPD meta-analysis framework, one models individual-level covariate-outcomes directly clustered within studies and minimises ecological bias compared with a meta-regression of aggregate data across studies. ADDIN EN.CITE <EndNote><Cite><Author>Riley</Author><Year>2010</Year><RecNum>51</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">51</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Riley, R. D.</author><author>Lambert, P. C.</author><author>Abo-Zaid, G.</author></authors></contributors><auth-address>Department of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham B15 2TT. r.d.riley@bham.ac.uk</auth-address><titles><title>Meta-analysis of individual participant data: rationale, conduct, and reporting</title><secondary-title>BMJ</secondary-title><alt-title>BMJ (Clinical research ed.)</alt-title></titles><pages>c221</pages><volume>340</volume><edition>2010/02/09</edition><keywords><keyword>Bias</keyword><keyword>Data Collection/ methods</keyword><keyword>Meta-Analysis as Topic</keyword><keyword>Review Literature as Topic</keyword><keyword>Risk Assessment</keyword></keywords><dates><year>2010</year><pub-dates><date>Feb 5</date></pub-dates></dates><isbn>1756-1833 (Electronic)&#xD;0959-535X (Linking)</isbn><accession-num>20139215</accession-num><urls></urls><electronic-resource-num>10.1136/bmj.c221</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>13 To-date, there is no large-scale study that has evaluated predictive factors for local regrowth because the study-level meta-analysesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYXR0YW5pPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48

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ADDIN EN.CITE.DATA 9, 10 were unable to extract these data in an analysable form and there was considerable missingness in the IWWD registry-based report.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZhbGs8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZhbGs8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

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ADDIN EN.CITE.DATA 11 Methods Reporting was in accordance with PRIMA-IPD recommendations,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV3YXJ0PC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA 14 and the protocol was registered with PROSPERO (CRD42017070934). Eligibility and study selectionThe PICO (Population; Intervention; Comparator; Outcome) was as follows. We sought to identify studies of patients with locally advanced rectal cancer where the intervention was W&W after cCR following neoadjuvant chemo-radiotherapy, as the predominant treatment modality within each reported study, and followed-up to local regrowth, as defined by the 2014 Champalimaud conference. ADDIN EN.CITE <EndNote><Cite><Author>Heald</Author><Year>2014</Year><RecNum>52</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>52</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">52</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heald, R. J.</author><author>Beets, G.</author><author>Carvalho, C.</author></authors></contributors><auth-address>Pelican Cancer Foundation, Basingstoke, UK.</auth-address><titles><title>Report from a consensus meeting: response to chemoradiotherapy in rectal cancer - predictor of cure and a crucial new choice for the patient: on behalf of the Champalimaud 2014 Faculty for &apos;Rectal cancer: when NOT to operate&apos;</title><secondary-title>Colorectal Dis</secondary-title><alt-title>Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland</alt-title></titles><pages>334-7</pages><volume>16</volume><number>5</number><edition>2014/04/15</edition><keywords><keyword>Chemoradiotherapy</keyword><keyword>Consensus Development Conferences as Topic</keyword><keyword>Humans</keyword><keyword>Rectal Neoplasms/surgery/ therapy</keyword><keyword>Treatment Outcome</keyword><keyword>Watchful Waiting</keyword></keywords><dates><year>2014</year><pub-dates><date>May</date></pub-dates></dates><isbn>1463-1318 (Electronic)&#xD;1462-8910 (Linking)</isbn><accession-num>24725662</accession-num><urls></urls><electronic-resource-num>10.1111/codi.12627</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>15 We anticipated that the majority of studies would be treatment single-arm series, and accordingly, did not seek a comparator. We used the systematic search published by Dossa and colleaguesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3NzYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 9 (as our PICO was equivalent) and updated using MEDLINE and Embase databases. From the main searches, we took a cut of identified studies from 01 Jan 2016 to 05 May 2017, and with studies identified through expert knowledge, added these to the studies identified by Dossa et al.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3NzYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 9 There was no language restriction. The search terms are detailed in webappendix p1.As the central theme was the evaluation of predictive factors, we sought to have a baseline ‘level playing field’ and only included studies where the definition of cCR was judged to have used criteria equivalent to those of the S?o Paulo benchmarks, described by Habr-Gama et al. in 2004PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ADDIN EN.CITE.DATA 16 – namely, absence of residual ulceration, stenosis, or mass within the rectum using clinical and endoscopic examination. As abstracts did not allow this assessment, we excluded a priori unpublished studies. While, the Habr-Gama ‘definition’ papersPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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Tm90ZT4A

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ADDIN EN.CITE.DATA 11 included proximal rectal tumours. Thus, we did not restrict by tumour distance from the anal verge. Data collection and harmonisation We approached chief investigators for identified studies and transferred fully anonymised data in encrypted files under centre-level governance arrangements. Data harmonisation is detailed in webappendix p2. To ensure homogeneity of patients entering into W&W management, from the received datasets, we excluded those who received short course radiotherapy as initial treatment; those treated by local excision or contact brachytherapy as part of the initial W&W management; and patients with distant metastases at baseline.Risk of bias assessment in individual studiesWe assessed study quality, modifying the Institute of Health Economics Quality Appraisal (IHEQA) Checklist for Case Series Studies. ADDIN EN.CITE <EndNote><Cite ExcludeYear="1"><Author>Moga</Author><RecNum>46</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>46</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">46</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Moga, C. </author><author>Guo, B. </author><author>Schopflocher, D. </author><author>Harstall, C. </author></authors></contributors><titles><title>Development of a quality appraisal tool for case series studies using a modified Delphi technique. Edmonton: Institute of Health Economics, 2012.</title></titles><dates></dates><urls></urls></record></Cite></EndNote>18 This checklist comprises 18 ‘yes/no’ items, with explanatory dictionaries. Only the first 11 items were relevant as subsequent items relate to reporting qualities, which did not apply to the IPD meta-analysis framework. Studies were considered to have a low-risk of bias if at least 80% of criteria were met, moderate-risk if 60% to 79% of criteria were met, and high-risk if less than 60% of criteria were met.Outcome measures The primary outcome was 2-year local regrowth cumulative incidence from date of W&W decision (we took this as equivalent to the date at which cCR was achieved). This allowed direct comparability with the aggregate-level meta-analysis from Dossa et al.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3NzYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 9 Secondary outcomes were: local regrowth cumulative incidence at 1-, 3-, 4- and 5-years; proportion of patients with local regrowth undergoing salvage surgery and proportion R0 (negative resection margin); 5-year overall survival (OS); 5-year non-regrowth disease-free survival (nrDFS), as detailed in our previous work;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5laGFuPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48

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ADDIN EN.CITE.DATA 2, 17 and 3-year distant metastasis rate, the latter three outcomes from date of first treatment. Post-protocol registration, we added 3-year post-salvage surgery survival, from date of salvage surgery.Statistical AnalysisWe used STATA version 14.0 (College Station, TX) in our analyses. For tables of study characteristics, we summarised proportions and medians (with inter-quartile ranges, IQRs) and compared with chi-squared and Kruskal- Wallis tests across studies.To derive summary estimates of local regrowth cumulative incidences, we took two approaches. In our main model, we used a two-stage IPD approach; first undertaking time-to-event analyses per dataset to determine 2-year local regrowth cumulative incidence with 95% confidence intervals (95% CIs) using 1 – Kaplan-Meier (KM) analyses, and then combined the outputs using a random-effects methods with the admetan command. We assessed between-study heterogeneity with the I2 statistic and assigned adjective low, moderate and high for values close to 25%, 50%, and 75%, respectively. ADDIN EN.CITE <EndNote><Cite><Author>Higgins</Author><Year>2002</Year><RecNum>66</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>66</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">66</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Higgins, J. P.</author><author>Thompson, S. G.</author></authors></contributors><auth-address>MRC Biostatistics Unit, Institute of Public Health, Robinson Way, Cambridge CB2 2SR, UK. julian.higgins@mrc-bsu.cam.ac.uk</auth-address><titles><title>Quantifying heterogeneity in a meta-analysis</title><secondary-title>Stat Med</secondary-title><alt-title>Statistics in medicine</alt-title></titles><pages>1539-58</pages><volume>21</volume><number>11</number><edition>2002/07/12</edition><keywords><keyword>Albumins/therapeutic use</keyword><keyword>Chemotherapy, Adjuvant/methods</keyword><keyword>Clinical Trials as Topic/ methods</keyword><keyword>Cognition Disorders/drug therapy</keyword><keyword>Cytidine Diphosphate Choline/therapeutic use</keyword><keyword>Fibrosis/therapy</keyword><keyword>Fracture Fixation/methods</keyword><keyword>Hip Fractures/surgery</keyword><keyword>Humans</keyword><keyword>Meta-Analysis as Topic</keyword><keyword>Resuscitation/methods</keyword><keyword>Sarcoma/drug therapy</keyword><keyword>Sclerotherapy</keyword><keyword>Statistics as Topic/ methods</keyword></keywords><dates><year>2002</year><pub-dates><date>Jun 15</date></pub-dates></dates><isbn>0277-6715 (Print)&#xD;0277-6715 (Linking)</isbn><accession-num>12111919</accession-num><urls></urls><electronic-resource-num>10.1002/sim.1186</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>19 We repeated this for 1-, 3-, 4- and 5-year local regrowth cumulative incidences. For yearly summary estimates, we additionally derived prediction intervals. Second, we pooled data from all datasets and reported 1- through 5-year local regrowth cumulative incidence as 1 – KM and 95% CIs, without accounting for within centre correlations. We denoted our main (preferred) analysis as ‘RE’ (random-effects); and our second analysis as ‘pooled’ analysis.We evaluated the impact of clinical and treatment covariates on local regrowth. Initially, we reported univariable pooled analysis, and compared as required using log-rank tests. For multivariable modelling, we used Cox frailty models, with results expressed as hazard ratios (HRs) and their 95% CIs. These models introduce a random-effects approach to account for associations and unobserved heterogeneity due to participation of different centres. ADDIN EN.CITE <EndNote><Cite><Author>Hougaard</Author><Year>1995</Year><RecNum>63</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>63</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">63</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hougaard, P.</author></authors></contributors><auth-address>Novo Nordisk, Bagsvaerd, Denmark.</auth-address><titles><title>Frailty models for survival data</title><secondary-title>Lifetime Data Anal</secondary-title><alt-title>Lifetime data analysis</alt-title></titles><pages>255-73</pages><volume>1</volume><number>3</number><edition>1995/01/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Child</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Models, Statistical</keyword><keyword>Mortality</keyword><keyword>Multivariate Analysis</keyword><keyword>Proportional Hazards Models</keyword><keyword>Survival Analysis</keyword><keyword>Twins</keyword></keywords><dates><year>1995</year></dates><isbn>1380-7870 (Print)&#xD;1380-7870 (Linking)</isbn><accession-num>9385105</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>20 In the context of the present study, this approach takes account of unmeasured factors, sometimes called ‘noise’, at each study level such as centre-level protocols for staging, treatment, and follow-up. Frailty models are increasingly reported in multi-centre trial analyses to account for centre-level variations in clinical practice outside the trial protocol.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsZS1Kb3JnZW5zZW48L0F1dGhvcj48WWVhcj4yMDE4

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ADDIN EN.CITE.DATA 22); and 7.6% for tumour distance to anal verge (AV), which formed the basis for multivariable model A (10 datasets). Time to decision for W&W was not calculable for the two S?o Paulo datasets – thus, model B was model A plus time to decision for W&W based on 8 datasets. Serum CEA values were missing in 45.3% - thus, model C was model A plus serum CEA. Radiotherapy dose was missing in only 6.5% - but was near totally coincident with centre status (the co-linearity problem mentioned above), this was reported only in univariable models. In multivariable models, the continuous variable, time to decision for W&W and serum CEA were modelling using fractional polynomials. ADDIN EN.CITE <EndNote><Cite><Author>Royston</Author><Year>2004</Year><RecNum>68</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>68</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">68</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Royston, P.</author><author>Sauerbrei, W.</author></authors></contributors><auth-address>MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK. patrick.royston@ctu.mrc.ac.uk</auth-address><titles><title>A new approach to modelling interactions between treatment and continuous covariates in clinical trials by using fractional polynomials</title><secondary-title>Stat Med</secondary-title><alt-title>Statistics in medicine</alt-title></titles><pages>2509-25</pages><volume>23</volume><number>16</number><edition>2004/08/03</edition><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Antineoplastic Agents, Hormonal/therapeutic use</keyword><keyword>Antineoplastic Agents, Phytogenic/therapeutic use</keyword><keyword>Breast Neoplasms/drug therapy</keyword><keyword>Diethylstilbestrol/therapeutic use</keyword><keyword>Disease-Free Survival</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Models, Statistical</keyword><keyword>Multivariate Analysis</keyword><keyword>Predictive Value of Tests</keyword><keyword>Prostatic Neoplasms/drug therapy</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Tamoxifen/therapeutic use</keyword></keywords><dates><year>2004</year><pub-dates><date>Aug 30</date></pub-dates></dates><isbn>0277-6715 (Print)&#xD;0277-6715 (Linking)</isbn><accession-num>15287081</accession-num><urls></urls><electronic-resource-num>10.1002/sim.1815</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>23For reporting proportions among patients undergoing salvage surgery, we used a two-stage IPD approach, first estimating proportions (using the metaprop command) with 95% CIs, and then combined using a random-effects methods. For the outcomes of OS, nrDFS and distant metastases, we used similar two-stage meta-analysis approaches as those for local-regrowth cumulative incidence.For interpretation of statistical significance, we used the language recommended by Pocock and Ware, ADDIN EN.CITE <EndNote><Cite><Author>Pocock</Author><Year>2009</Year><RecNum>64</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>64</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">64</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pocock, S. J.</author><author>Ware, J. H.</author></authors></contributors><auth-address>Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. stuart.pocock@lshtm.ac.uk</auth-address><titles><title>Translating statistical findings into plain English</title><secondary-title>Lancet</secondary-title><alt-title>Lancet </alt-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1></periodical><alt-periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1></alt-periodical><pages>1926-8</pages><volume>373</volume><number>9679</number><edition>2009/04/21</edition><keywords><keyword>Confidence Intervals</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Guidelines as Topic</keyword><keyword>Humans</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Research Design/standards</keyword><keyword>Treatment Outcome</keyword><keyword>Writing/standards</keyword></keywords><dates><year>2009</year><pub-dates><date>Jun 6</date></pub-dates></dates><isbn>1474-547X (Electronic)&#xD;0140-6736 (Linking)</isbn><accession-num>19375158</accession-num><urls></urls><electronic-resource-num>10.1016/s0140-6736(09)60499-2</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>24 namely: ‘weak evidence’ for 0.05 < p < 0.10; ‘some evidence’ for 0.01 < p < 0.05; and ‘strong evidence’ for p < 0.001.Post-protocol stratified analysisAfter full data collection, it became clear that enrolment dates ranged from 11 March 1990 to 13 February 2017; older than anticipated in the initial protocol. We posseted at there was risk of misclassification in pre-treatment staging across such a long period, and thus, we performed a post-protocol stratified analysis limited to patients enrolled into studies after 01 January 2008. We judged this to reflect contemporary clinical practice where pre-treatment staging is generally by high-resolution MR evaluation using the MERCURY study ADDIN EN.CITE <EndNote><Cite><Author>MERCURY_study_group</Author><Year>2006</Year><RecNum>65</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>65</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">65</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>MERCURY_study_group</author></authors></contributors><titles><title>Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study</title><secondary-title>BMJ</secondary-title><alt-title>BMJ (Clinical research ed.)</alt-title></titles><pages>779</pages><volume>333</volume><number>7572</number><edition>2006/09/21</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Feasibility Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/ standards</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neoplasm Staging/ methods/standards</keyword><keyword>Preoperative Care/methods/standards</keyword><keyword>Prospective Studies</keyword><keyword>Rectal Neoplasms/ pathology/surgery</keyword><keyword>Sensitivity and Specificity</keyword></keywords><dates><year>2006</year><pub-dates><date>Oct 14</date></pub-dates></dates><isbn>1756-1833 (Electronic)&#xD;0959-8138 (Linking)</isbn><accession-num>16984925</accession-num><urls></urls><custom2>PMC1602032</custom2><electronic-resource-num>10.1136/bmj.38937.646400.55</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>25 principles.Publication bias, data availability bias and reviewer selection biasWe assessed for publication bias using contour enhanced funnel plots and the asymmetry test in accordance with recommendations from Sterne et al. ADDIN EN.CITE <EndNote><Cite><Author>Sterne</Author><Year>2011</Year><RecNum>35</RecNum><DisplayText><style face="superscript">26</style></DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sterne, J. A.</author><author>Sutton, A. J.</author><author>Ioannidis, J. P.</author><author>Terrin, N.</author><author>Jones, D. R.</author><author>Lau, J.</author><author>Carpenter, J.</author><author>Rucker, G.</author><author>Harbord, R. M.</author><author>Schmid, C. H.</author><author>Tetzlaff, J.</author><author>Deeks, J. J.</author><author>Peters, J.</author><author>Macaskill, P.</author><author>Schwarzer, G.</author><author>Duval, S.</author><author>Altman, D. G.</author><author>Moher, D.</author><author>Higgins, J. P.</author></authors></contributors><auth-address>School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK. jonathan.sterne@bristol.ac.uk</auth-address><titles><title>Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials</title><secondary-title>BMJ</secondary-title><alt-title>BMJ (Clinical research ed.)</alt-title></titles><pages>d4002</pages><volume>343</volume><edition>2011/07/26</edition><keywords><keyword>Meta-Analysis as Topic</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Selection Bias</keyword><keyword>Statistics as Topic/ methods</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul 22</date></pub-dates></dates><isbn>1756-1833 (Electronic)&#xD;0959-535X (Linking)</isbn><accession-num>21784880</accession-num><urls></urls><electronic-resource-num>10.1136/bmj.d4002</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>26 As per principles set out by Ahmed et al., ADDIN EN.CITE <EndNote><Cite><Author>Ahmed</Author><Year>2012</Year><RecNum>33</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">33</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahmed, I.</author><author>Sutton, A. J.</author><author>Riley, R. D.</author></authors></contributors><auth-address>MRC Midlands Hub for Trials Methodology Research, School of Health and Population Sciences, University of Birmingham, Birmingham B15 2TT, UK.</auth-address><titles><title>Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: a database survey</title><secondary-title>BMJ</secondary-title><alt-title>BMJ (Clinical research ed.)</alt-title></titles><pages>d7762</pages><volume>344</volume><edition>2012/01/05</edition><keywords><keyword>Databases, Bibliographic</keyword><keyword>Meta-Analysis as Topic</keyword><keyword>Peer Review, Research</keyword><keyword>Publication Bias/ statistics &amp; numerical data</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Selection Bias</keyword></keywords><dates><year>2012</year><pub-dates><date>Jan 3</date></pub-dates></dates><isbn>1756-1833 (Electronic)&#xD;0959-535X (Linking)</isbn><accession-num>22214758</accession-num><urls></urls><electronic-resource-num>10.1136/bmj.d7762</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>27 we assessed for data availability bias (IPD not available - e.g. unpublished but available as summary estimates in abstract form) by adding summary estimates from abstracts (from the Dossa et al.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3NzYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 9 meta-analysis as 2-year local regrowth was also primary outcome) and comparing with our summary estimates for the IPD data. Role of the funding sourceThere was no funder of this study. Five members (SC, LM, JE, RR, AGR) of the writing sub-group had access to all the data. Senior members (SC, RR, GB, RP, AGR) of the writing sub-group shared the responsibility for the final decision to submit the report for publication.ResultsIncluded studiesThe flow diagram of the search, study identifications, and reasons for not including studies are detailed in webappendix p3-5. We initially received data from 11 studies, but excluded one study ADDIN EN.CITE <EndNote><Cite><Author>Smith</Author><Year>2016</Year><RecNum>23</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smith, F. M.</author><author>Al-Amin, A.</author><author>Wright, A.</author><author>Berry, J.</author><author>Nicoll, J. J.</author><author>Sun Myint, A.</author></authors></contributors><auth-address>Department of Surgery, North Cumbria University Hospitals NHS Trust, Carlisle, UK.&#xD;Department of Radiology, North Cumbria University Hospitals NHS Trust, Carlisle, UK.&#xD;Department of Clinical Oncology, North Cumbria University Hospitals NHS Trust, Carlisle, UK.&#xD;Papillon Suite, Clatterbridge Cancer Centre, Bebington, Wirral, Merseyside, UK.</auth-address><titles><title>Contact radiotherapy boost in association with &apos;watch and wait&apos; for rectal cancer: initial experience and outcomes from a shared programme between a district general hospital network and a regional oncology centre</title><secondary-title>Colorectal Dis</secondary-title><alt-title>Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland</alt-title></titles><pages>861-70</pages><volume>18</volume><number>9</number><edition>2016/02/16</edition><dates><year>2016</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1463-1318 (Electronic)&#xD;1462-8910 (Linking)</isbn><accession-num>26876570</accession-num><urls></urls><electronic-resource-num>10.1111/codi.13296</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>28 where all patients received contact Papillon brachytherapy. For the large S?o Paulo series, we judged that there were two distinct cohorts – patients in the early series (denoted as S?o Paulo I), which were referred from two centres (University of S?o Paulo; Angelita & Joaquim Gama Institute, AJGI) and received neoadjuvant chemo-radiotherapy as 50.4 Gy and 2 cycles of 5-fluorouracil;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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b3RlPn==

ADDIN EN.CITE.DATA 6 Our final analysis was from 10 studies (11 datasets).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcHBlbHQ8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 2, 4, 6, 8, 22, 29-34 We judged that the definitions for cCR, across all datasets were equivalent to S?o Paulo benchmarksPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ADDIN EN.CITE.DATA 5, 16 (evidenced in webappendix p6-7). The total number for analysis was 602 patients – 108 were not reported in previous publications. We noted two clinical indications among the studies: those termed standard practice neo-adjuvant chemoradiotherapy where cCR rates ranged from 12% to 49%, and two studies where there was an intentional enhanced cCR ranging from 68% ADDIN EN.CITE <EndNote><Cite><Author>Appelt</Author><Year>2015</Year><RecNum>20</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Appelt, A. L.</author><author>Ploen, J.</author><author>Harling, H.</author><author>Jensen, F. S.</author><author>Jensen, L. H.</author><author>Jorgensen, J. C.</author><author>Lindebjerg, J.</author><author>Rafaelsen, S. R.</author><author>Jakobsen, A.</author></authors></contributors><auth-address>Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark; Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: ane.lindegaard.appelt@rsyd.dk.&#xD;Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark.&#xD;Digestive Disease Center, Bispebjerg University Hospital, Copenhagen, Denmark.&#xD;Department of Surgery, Aalborg University Hospital, Aalborg, Denmark.</auth-address><titles><title>High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study</title><secondary-title>Lancet Oncol</secondary-title><alt-title>The Lancet. Oncology</alt-title></titles><pages>919-27</pages><volume>16</volume><number>8</number><edition>2015/07/15</edition><dates><year>2015</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1474-5488 (Electronic)&#xD;1470-2045 (Linking)</isbn><accession-num>26156652</accession-num><urls></urls><electronic-resource-num>10.1016/s1470-2045(15)00120-5</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>29 to 73%PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy

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ADDIN EN.CITE.DATA 4 (webappendix p8). Study characteristicsPatient, tumour and treatment characteristics, by dataset, are summarised in Table 1. There was wide variation in characteristics and pathways: for example, median ages ranged from 59 to 75 years (p = 0.0001); proportion of men ranged from 40% to 91% (p = 0.001)); median tumour distance to AV from 3 to 6 cm (p = 0.0001); proportion of combined cT3/ cT4 stage from 43% to 83% (p = 0.007); and proportion of cN+ stage from 13% to 76% (p < 0.0001); and median time to W&W from 6 to 17 weeks (p = 0.0001). There were differences in radiotherapy treatment protocols – for example, for larger series, the radiotherapy dose regimen was predominantly 45 Gy in OnCoRe;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5laGFuPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA 6 and exclusively 60 Gy in Vejle. ADDIN EN.CITE <EndNote><Cite><Author>Appelt</Author><Year>2015</Year><RecNum>20</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Appelt, A. L.</author><author>Ploen, J.</author><author>Harling, H.</author><author>Jensen, F. S.</author><author>Jensen, L. H.</author><author>Jorgensen, J. C.</author><author>Lindebjerg, J.</author><author>Rafaelsen, S. R.</author><author>Jakobsen, A.</author></authors></contributors><auth-address>Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark; Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: ane.lindegaard.appelt@rsyd.dk.&#xD;Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark.&#xD;Digestive Disease Center, Bispebjerg University Hospital, Copenhagen, Denmark.&#xD;Department of Surgery, Aalborg University Hospital, Aalborg, Denmark.</auth-address><titles><title>High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study</title><secondary-title>Lancet Oncol</secondary-title><alt-title>The Lancet. Oncology</alt-title></titles><pages>919-27</pages><volume>16</volume><number>8</number><edition>2015/07/15</edition><dates><year>2015</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1474-5488 (Electronic)&#xD;1470-2045 (Linking)</isbn><accession-num>26156652</accession-num><urls></urls><electronic-resource-num>10.1016/s1470-2045(15)00120-5</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>29 Concurrent chemotherapy (5-fluorouracil-based in 518 out of 570 or 91%) was used in all series, and was used at least 95% of patients in seven datasets.Assessment of Study Methodological QualityUsing the IHEQA Checklist, ADDIN EN.CITE <EndNote><Cite ExcludeYear="1"><Author>Moga</Author><RecNum>46</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>46</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">46</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Moga, C. </author><author>Guo, B. </author><author>Schopflocher, D. </author><author>Harstall, C. </author></authors></contributors><titles><title>Development of a quality appraisal tool for case series studies using a modified Delphi technique. Edmonton: Institute of Health Economics, 2012.</title></titles><dates></dates><urls></urls></record></Cite></EndNote>18 ten of the 11 studies were judged to be at low-risk; one studyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ0ZW5zPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA 8 was judged to be moderate-risk of bias (webappendix p9).Local regrowthOverall, median follow-up was 37.6 (IQR: 25.0 to 58.7) months, but between studies, median follow-up ranged from 12.4 to 60 months. There were 166 local re-growths (crude proportion: 27.6%). The summary 2-year local regrowth cumulative incidence was 21.4% (RE 95% CIs: 15.3-27.6). There was a were high level of between-study heterogeneity (I2 = 61%) (Figure 1). In the pooled analysis, the 1-, 2-, 3-, 4- and 5-year local regrowth rates were: 17.6% (95% CIs: 14.8-20.9), 24.7% (95% CIs: 21.4-28.5), 28.1% (95% CIs: 24.5-32.1), 31.1% (95% CIs: 27.2-35.5), and 31.6% (95% CIs: 27.6-36.0), respectively (Figure 2A). By contrast, for 2-stage random-effects meta-analysis, summary point estimates for years 1 to 5 were more conservative at 15.6% (95% CIs: 9.9-21.4), 21.4% (95% CIs: 15.3-27.6), 24.9% (95% CIs: 18.5-31.3), 27.3% (95% CIs: 19.8-34.8), and 28.0 (95% CIs: 20.3-35.8), but with wider 95% CIs (Figure 2B). Local regrowth occurred almost exclusively in the first three years (155 out of 166 or 93.4%). We assessed visually for proportionality of local regrowth curves with time across the 11 datasets, and found similar patterns in all datasets (webappendix p10).Cox frailty modelsWe tested for factors predicting local regrowth, initially for the total cohort, and then as a post-2008 sub-cohort analysis (Table 2). For the total cohort, there was some evidence that increasing cT stage was associated with increased risk of local regrowth. By univariable analysis, 2-year cumulative incidences were 18% (95% CIs: 13-25) for cT1/T2, 29% (95% CIs: 24-34) for cT3, and 31% (95% CIs: 17-52) for cT4. In the multivariable frailty model, including age, gender, CT stage, N stage and distance to AV (model A), the HR per cT stage increase was 1.395 (RE 95% CI: 1.002, 1.941, Ptrend = 0.048). There were no associations among other factors in model A (10 studies), model B (8 studies; incorporating time to W&W decision) or model C (8 studies; incorporating serum CEA). For the sub-cohort of patients managed after 2008, 2-year local regrowth cumulative incidence increased in a stepwise manner from 19% (95% CIs: 13-28) for cT1/cT2, 31% (95% CIs: 26-37) for cT3, to 37% (95% CIs: 30-60) for cT4. In model A, the HR was per cT stage increase was 1.496 (RE 95% CI: 1.032, 2.168, Ptrend = 0.033). We tested (likelihood ratio test) for = 0 and found statistical significance in all models, indicating that correlation within centres could not be ignored (Table 3). We compared theta values in each model (A to C) with and without added factors, and noted that the likelihood ratio test remained statistically significant and that the addition of the measured factors only modestly influenced theta. We estimated that this contribution ranged from 4.8% to 45.3%. Salvage surgeryOf the 166 patients with local regrowth, salvage surgery was performed in 137 (RE estimate: 89%, 95% CIs: 80-98), of which R0 status was achieved in 131 (RE: 98%, 95% CIs: 95-100) (Table 4). After histopathological examination, only four patients were pT4; the majority (59 patients) were pT3 (RE: 44%, 95% CIs: 30-58). Node positivity was noted in 18 resections (RE: 16%, 95% CIs: 5-27). The 137 patients with local regrowth undergoing salvage surgery were younger than the 29 patients treated by non-surgical strategies [median (IQR) age: 65.2 (57.4-71.2) versus 70.3 (60.9-76.0) years, p = 0.037). The commonest reason for no salvage surgery was synchronous distant metastases (12 patients) or unfit, mainly associated with older age (10 patients aged 75 years or older). The 3-year post-salvage survival rate was 80.1% (95% CIs: 70.3-87.0); the 3-year survival in patients not undergoing salvage surgery was 55.3% (95% CIs: 30.0-74.8) (webappendix p11). Accounting for age at local regrowth and between-centre variation, this was not statistical different (p = 0.153).Survival and distant metastases ratesThere were 68 deaths. The 5-year OS rate was 87.0 (RE 95% CIs: 81.5-92.4); and the 5-year nrDFS rate was 81.3% (RE 95% CIs: 74.9-87.6) (webappendix p12). Distant metastases were reported in 60 patients. The 3-year distant metastasis rate was 9.1% (RE 95% CIs: 8.7-9.5). The commonest sites of distant metastases were lung (31 of 60 patients) and liver (23 of 60 patients) (webappendix p13). Approximately half patients (31 of 60 patients) with distant metastases had local regrowth – these were identified synchronous with local regrowth in 12 patients; after local regrowth in 14 patients; and before local regrowth in only four. Publication, data availability and reviewer selection biasesWe visually inspected for asymmetry in the funnel plot for the 11 included datasets and found no evidence indicating publication bias (webappendix p14). For the primary outcome of 2-year local regrowth cumulative incidence, we found no evidence for data availability bias [RE: 21.4% (95% CIs: 15.1-27.7) versus 13.9% (95 CIs: 7.9-19.8), pinteraction = 0.111] (webappendix p15) and weak evidence for reviewer selection bias [RE: 21.4% (95% CIs: 15.1-27.7) versus 11.5% (95 CIs: 5.3-17.7), pinteraction = 0.089] (webappendix p16). DiscussionSummary of main findingsWe report five main findings. First, among studies of patients with rectal cancer and cCR managed by W&W, there was wide variation in baseline patient, tumour and treatment characteristics, but overall, the study quality was at low risk of bias. Second, the 2-year local regrowth cumulative incidence was approximately a fifth but there was wide variation across studies. Third, there was some evidence that increasing cT stage was associated with increased risk of local regrowth, particularly in sub-cohort of patients managed post-2008, but there was no clear signal of associations for other factors evaluated. Fourth, the observed between-study heterogeneity in local regrowth may partly be explained by study differences in measured factors, such as cT stage, but other unmeasured predictors might be relevant, and seeking these, should be a future research direction. Finally, we described several secondary outcomes, which will inform clinician-patient decision-making. 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ADDIN EN.CITE.DATA 9 performed a meta-analysis of 23 studies (published and unpublished) in 867 patients, and like our study, identified wide variation in baseline characteristics, but the authors were unable to directly test for differences. By contrast, our analysis directly reported these - for instance, median ages varied across the studies by as much as 16 years; and proportion of cT3/cT4 tumours varied from 43% ADDIN EN.CITE <EndNote><Cite><Author>Appelt</Author><Year>2015</Year><RecNum>20</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Appelt, A. L.</author><author>Ploen, J.</author><author>Harling, H.</author><author>Jensen, F. S.</author><author>Jensen, L. H.</author><author>Jorgensen, J. C.</author><author>Lindebjerg, J.</author><author>Rafaelsen, S. R.</author><author>Jakobsen, A.</author></authors></contributors><auth-address>Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark; Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: ane.lindegaard.appelt@rsyd.dk.&#xD;Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark.&#xD;Digestive Disease Center, Bispebjerg University Hospital, Copenhagen, Denmark.&#xD;Department of Surgery, Aalborg University Hospital, Aalborg, Denmark.</auth-address><titles><title>High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study</title><secondary-title>Lancet Oncol</secondary-title><alt-title>The Lancet. Oncology</alt-title></titles><pages>919-27</pages><volume>16</volume><number>8</number><edition>2015/07/15</edition><dates><year>2015</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1474-5488 (Electronic)&#xD;1470-2045 (Linking)</isbn><accession-num>26156652</accession-num><urls></urls><electronic-resource-num>10.1016/s1470-2045(15)00120-5</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>29 to 82%.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYWx0b248L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 9 but this difference was not statistically significant.Dattani et al. ADDIN EN.CITE <EndNote><Cite><Author>Dattani</Author><Year>2018</Year><RecNum>74</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>74</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">74</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dattani, M.</author><author>Heald, R. J.</author><author>Goussous, G.</author><author>Broadhurst, J.</author><author>Sao Juliao, G. P.</author><author>Habr-Gama, A.</author><author>Oliva Perez, R.</author><author>Moran, B. J.</author></authors></contributors><auth-address>Pelican Cancer Foundation, Basingstoke. Hampshire, UK.&#xD;University Hospitals Birmingham NHS Foundation Trust, UK.&#xD;Basingstoke and North Hampshire Hospital. Hampshire, UK.&#xD;Angelita &amp; Joaquim Gama Institute, Sao Paulo, SP, Brazil.</auth-address><titles><title>Oncological and Survival Outcomes in Watch and Wait Patients With a Clinical Complete Response After Neoadjuvant Chemoradiotherapy for Rectal Cancer: A Systematic Review and Pooled Analysis</title><secondary-title>Ann Surg</secondary-title><alt-title>Annals of surgery</alt-title></titles><periodical><full-title>Ann Surg</full-title><abbr-1>Annals of surgery</abbr-1></periodical><alt-periodical><full-title>Ann Surg</full-title><abbr-1>Annals of surgery</abbr-1></alt-periodical><edition>2018/05/11</edition><dates><year>2018</year><pub-dates><date>May 9</date></pub-dates></dates><isbn>1528-1140 (Electronic)&#xD;0003-4932 (Linking)</isbn><accession-num>29746338</accession-num><urls></urls><electronic-resource-num>10.1097/sla.0000000000002761</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>10 recently reported a study-level meta-analysis of 17 published-only studies in 692 patients. They reported a 3-year cumulative risk of local regrowth of 21.6%. This study did not have individual-level time to event data, but the investigators used a variety of methods to estimate numbers at risk at 3 years, thereby accounting for censoring. Thus, their estimate is broadly equivalent to our 2-year local regrowth cumulative incidence of 21.4%, The recent IWWD reportPEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZhbGs8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

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ADDIN EN.CITE.DATA 11 was a registry-based pooled analysis of 880 participants from 47 centres (15 countries). There were data from five centres (AJGI; OnCoRe; Maastricht; Hospital Italiano, Buenos Ares; Vejle) from our IPD meta-analysis that contributed 552 participants to IWWD. Not unexpectedly, there were similar estimates for several outcomes, but not all. For IWWDPEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZhbGs8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

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ADDIN EN.CITE.DATA 11 versus InterCoRe: 2-year local regrowth cumulative incidence was 25.2 (95% CIs: 22.2-28.5) versus 21.4% (RE 95% CIs: 15.3-27.6); 5-year OS was 84.7% (95% CIs: 80.9-87.7) versus 87.0% (RE 95% CIs: 81.5-92.4); and 3-year distant metastasis rate was 8.1% (95% CIs: 6.2-10.5) versus 9.1% (RE 95% CIs: 8.7-9.5). However, for patients with local regrowth, in the IWWD paper,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZhbGs8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

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ADDIN EN.CITE.DATA 11 against a background of missing data, the salvage surgery rate was estimated to be 69%; that for InterCoRe was 89% (RE 95% CIs: 80-98). R0 status was attained in 88% for IWWD; and almost all salvage operations in InterCoRe (98% RE 95% CIs: 95-100). We added the new finding that 3-year post-salvage OS was 80.1%. We additionally reported the new finding that 5-year nrDFS was 81.3% (RE 95% CIs: 74.9-87.6), previously arguing that this is an informative outcome of disease control. ADDIN EN.CITE <EndNote><Cite><Author>Renehan</Author><Year>2017</Year><RecNum>47</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Renehan, A. G.</author><author>Malcomson, L.</author><author>Emsley, R.</author></authors></contributors><auth-address>Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Electronic address: andrew.renehan@manchester.ac.uk.&#xD;Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.&#xD;Centre for Biostatistics, School of Health Sciences, University of Manchester, Manchester, UK.</auth-address><titles><title>Watch-and-wait approach for rectal cancer: concepts of a subject-specific method</title><secondary-title>Lancet Gastroenterol Hepatol</secondary-title><alt-title>The lancet. Gastroenterology &amp; hepatology</alt-title></titles><pages>627</pages><volume>2</volume><number>9</number><edition>2017/08/09</edition><dates><year>2017</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>2468-1253 (Electronic)</isbn><accession-num>28786383</accession-num><urls></urls><electronic-resource-num>10.1016/s2468-1253(17)30218-2</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>17 Although, there were individual-level data in IWWD,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZhbGs8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

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ADDIN EN.CITE.DATA 11 the data were pooled without taking account of between-study differences, and with high proportions of missing data for key confounder like cT stage (18%), the IWWD analysis was unable to evaluate for predictive factors of tumour local regrowth. From our analyses, we observed some evidence that increasing cT stage was associated with increased risk of local regrowth, and observation that had been noted at smaller scale from the S?o Paulo series.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

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ADDIN EN.CITE.DATA 36The systematic review of Kong et al. ADDIN EN.CITE <EndNote><Cite><Author>Kong</Author><Year>2017</Year><RecNum>56</RecNum><DisplayText><style face="superscript">35</style></DisplayText><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kong, J. C.</author><author>Guerra, G. R.</author><author>Warrier, S. K.</author><author>Ramsay, R. G.</author><author>Heriot, A. G.</author></authors></contributors><auth-address>1 Division of Cancer Surgery, University of Melbourne, Melbourne, Victoria, Australia 2 Differentiation and Transcription Laboratory, University of Melbourne, Melbourne, Victoria, Australia 3 Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.</auth-address><titles><title>Outcome and Salvage Surgery Following &quot;Watch and Wait&quot; for Rectal Cancer after Neoadjuvant Therapy: A Systematic Review</title><secondary-title>Dis Colon Rectum</secondary-title><alt-title>Diseases of the colon and rectum</alt-title></titles><pages>335-345</pages><volume>60</volume><number>3</number><edition>2017/02/09</edition><keywords><keyword>Combined Modality Therapy</keyword><keyword>Humans</keyword><keyword>Neoadjuvant Therapy</keyword><keyword>Neoplasm Recurrence, Local/etiology/mortality</keyword><keyword>Rectal Neoplasms/mortality/ therapy</keyword><keyword>Salvage Therapy</keyword><keyword>Survival Analysis</keyword><keyword>Watchful Waiting</keyword></keywords><dates><year>2017</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1530-0358 (Electronic)&#xD;0012-3706 (Linking)</isbn><accession-num>28177997</accession-num><urls></urls><electronic-resource-num>10.1097/dcr.0000000000000754</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>35 focused on the rate of salvage surgery among studies where patients were managed by W&W. They included nine studies (370 patients) of which 256 (69.2%) had sustained cCR. In their analysis, the salvage surgery rate was 83.8%; the equivalent rate in our analysis was 89% (RE 95% CIs: 80-98).Limitations and strengthsOur study has limitations. First, we did not collect data on surveillance protocols. The IWWD studyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFZhbGs8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

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ADDIN EN.CITE.DATA 11 reported wide variation in frequency and assessment tools, and in theory, this might contribute to the observed between-study heterogeneity in key outcomes. We broadly controlled for this using frailty models, which takes account of centre-level heterogeneity, such as follow-up protocols. Second, the IPD meta-analysis approach does not resolve that included studies might be susceptible to bias. We formally assessed for this and found the great majority of studies were low risk. Third, we only sought data from a subset of published studies. We assessed for reviewer selection bias and found only weak evidence. Fourth, we only approached investigators of published studies, and thus data availability bias might occur. Again, we assessed for this, and found no strong evidence. At first glance, a study weakness might be lack of a comparator group. There is debate what this comparator might be – from patients with rectal cancer undergoing resection surgery and found to have a pathological CR, to patients with a cCR and treated by surgery.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3NzYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3NzYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 9 We previously argued that choice of comparator group depends on the question.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5laGFuPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5laGFuPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA 9, 10 we assessed for predictors of local regrowth. To minimise the concern of baseline misclassification of cCR and facilitate interpretation of our predictions, we restricted studies to those that defined cCR using criteria equivalent to S?o Paulo benchmarks. Second, in common with IPD meta-analyses, in general, our platform allowed us to update and extend study-level information (for example, data on a sixth of participants were previously unreported); identify published studies which contained overlapping sets of participants; incorporated results from under-reported outcomes (for example, nrDFS ADDIN EN.CITE <EndNote><Cite><Author>Renehan</Author><Year>2017</Year><RecNum>47</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Renehan, A. G.</author><author>Malcomson, L.</author><author>Emsley, R.</author></authors></contributors><auth-address>Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Electronic address: andrew.renehan@manchester.ac.uk.&#xD;Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.&#xD;Centre for Biostatistics, School of Health Sciences, University of Manchester, Manchester, UK.</auth-address><titles><title>Watch-and-wait approach for rectal cancer: concepts of a subject-specific method</title><secondary-title>Lancet Gastroenterol Hepatol</secondary-title><alt-title>The lancet. Gastroenterology &amp; hepatology</alt-title></titles><pages>627</pages><volume>2</volume><number>9</number><edition>2017/08/09</edition><dates><year>2017</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>2468-1253 (Electronic)</isbn><accession-num>28786383</accession-num><urls></urls><electronic-resource-num>10.1016/s2468-1253(17)30218-2</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>17); verify results presented in the original study publications; standardised the strategy for statistical analysis; and assess model assumptions in each study. Specifically, we ran identical time-to-event analyses for each study, thus by-passing numbers at risk assumptions used in other meta-analyses. Third, we purposefully strengthened our analytical design seeking homogeneity of treatment – for example, some seriesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy

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ADDIN EN.CITE.DATA 38 Clinical implications The first clinical question is whether our findings have identified a patient sub-group unsuitable for W&W. The answer is no. For example, although in the post-2008 sub-analysis, cT4 tumours were associated with 2-year local regrowth cumulative incidence approximating 40%, there were still over half patients potentially benefiting from a sustained complete response. Going forward, there is a need to validate the associations between cT stage and local regrowth based on standardised MR-driven pre-treatment staging protocols.The second clinical question is whether there should be a stratified approach to follow-up? Conceivably, one might argue that cT3 and cT4 tumours are at high-risk of local regrowth, but given the high salvage rates and attained R0 rates, it is questionable whether high-intensity surveillance in this patient sub-group would materially influence long-term outcomes. Similarly, the rate of distant metastases in all these patients is low, arguing that more regular CT surveillance is unlikely to make a major clinical impact. Finally, what are the implications for future trials? There are now several ongoing and in-development trials where rectal organ preservation is the primary motivation. Our study included one such trial; ADDIN EN.CITE <EndNote><Cite><Author>Appelt</Author><Year>2015</Year><RecNum>20</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Appelt, A. L.</author><author>Ploen, J.</author><author>Harling, H.</author><author>Jensen, F. S.</author><author>Jensen, L. H.</author><author>Jorgensen, J. C.</author><author>Lindebjerg, J.</author><author>Rafaelsen, S. R.</author><author>Jakobsen, A.</author></authors></contributors><auth-address>Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark; Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: ane.lindegaard.appelt@rsyd.dk.&#xD;Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark.&#xD;Digestive Disease Center, Bispebjerg University Hospital, Copenhagen, Denmark.&#xD;Department of Surgery, Aalborg University Hospital, Aalborg, Denmark.</auth-address><titles><title>High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study</title><secondary-title>Lancet Oncol</secondary-title><alt-title>The Lancet. Oncology</alt-title></titles><pages>919-27</pages><volume>16</volume><number>8</number><edition>2015/07/15</edition><dates><year>2015</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1474-5488 (Electronic)&#xD;1470-2045 (Linking)</isbn><accession-num>26156652</accession-num><urls></urls><electronic-resource-num>10.1016/s1470-2045(15)00120-5</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>29 and the selection of patients in S?o Paulo II cohortPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJyLUdhbWE8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE.DATA 6 fulfil the same motivation. We showed that these sub-populations had similar local-regrowth rates as those achieving cCR through routine care.Unanswered questions and future researchThere are three key areas for research. First, there is a need to establish an internationally accepted definition of cCR, and in particular, establish the role of MR imaging in this definition. Second, there is a research need to determine other predictors of a sustained clinical complete response. There are several approaches including imaging, blood biomarkers, and tumour molecular phenotyping. Third, research is required to engage the options and preferences of patients. There is evidence that W&W is associated with substantially better quality of life and functional outcomes compared with the standard surgical resection.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdXBrZW5zPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48

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ADDIN EN.CITE.DATA 39 But, there is a major caveat that chemo-radiotherapy itself might be associated with long-term morbidity. In studies to-date, no study included MR-tailored approaches by surgery alone as a comparator. All three pathways (chemo-radiotherapy plus resection versus chemo-radiotherapy plus W&W versus tailored resection alone) need to be evaluated. Only then, can we truly appraise the role of W&W in the overall standard care management of locally advanced rectal cancer.Conflict of InterestAGR reports personal fees from Merck Serona, personal fees from Janssen-Cilag, grants and personal fees from Sanofi Pasteur MSD, outside the submitted work. MPS reports personal fees from Merck, personal fees from Amgen, personal fees from Servier, personal fees from Eisai, personal fees from Roche, outside the submitted work. ID reports personal fees and other from Medtronic UK, personal fees and other from Gore UK, personal fees and other from Bard, personal fees, non-financial support and other from Molyncke, outside the submitted work. NJS reports personal fees from Medtronic, personal fees from WL Gore, outside the submitted work. The remaining authors declare no conflicts.ContributionsSC performed literature searches, data extraction, and contributed to analyses, data interpretation and writing of the manuscript. SC, AGR, JE, RR, AH-G, SW contributed to the design of the study, data analysis and interpretation, and writing. LM assisted with the literature screening and data extraction and harmonisation. JE and RR contributed to statistical interpretation. SC, RP, AGR conceptualized the paper and contributed to all sections of the manuscript. All authors contributed to the final manuscript draft.AcknowledgementsThis research was supported by the NIHR Manchester Biomedical Research Centre. Table 1 Characteristics of 11 datasets of 602 patient with rectal cancer and cCR initially managed by watch and wait in the InterCoRe consortiumTotalsBuenos Aires, Arg ADDIN EN.CITE <EndNote><Cite><Author>Vaccaro</Author><Year>2016</Year><RecNum>22</RecNum><DisplayText><style face="superscript">34</style></DisplayText><record><rec-number>22</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">22</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vaccaro, C. A.</author><author>Yazyi, F. J.</author><author>Ojra Quintana, G.</author><author>Santino, J. P.</author><author>Sardi, M. E.</author><author>Beder, D.</author><author>Tognelli, J.</author><author>Bonadeo, F.</author><author>Lastiri, J. M.</author><author>Rossi, G. L.</author></authors></contributors><auth-address>Servicio Cirugia General, Sector de Coloproctologia, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. Electronic address: carlos.vaccaro@.ar.&#xD;Servicio Cirugia General, Sector de Coloproctologia, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.&#xD;Servicio Anatomia Patologica, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.&#xD;Servicio Oncologia Radiante, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.</auth-address><titles><title>Locally advanced rectal cancer: Preliminary results of rectal preservation after neoadjuvant chemoradiotherapy</title><secondary-title>Cir Esp</secondary-title><alt-title>Cirugia espanola</alt-title></titles><pages>274-9</pages><volume>94</volume><number>5</number><edition>2016/03/17</edition><dates><year>2016</year><pub-dates><date>May</date></pub-dates></dates><orig-pub>Cancer de recto localmente avanzado: resultados preliminares de la preservacion del recto despues de quimiorradioterapia neoadyuvante.</orig-pub><isbn>1578-147X (Electronic)&#xD;0009-739X (Linking)</isbn><accession-num>26980259</accession-num><urls></urls><electronic-resource-num>10.1016/j.ciresp.2015.12.007</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng&#xD;spa</language></record></Cite></EndNote>34Exeter, UKPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYWx0b248L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 8NYU, US ADDIN EN.CITE <EndNote><Cite><Author>Bitterman</Author><Year>2015</Year><RecNum>25</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>25</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">25</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bitterman, D. S.</author><author>Resende Salgado, L.</author><author>Moore, H. G.</author><author>Sanfilippo, N. J.</author><author>Gu, P.</author><author>Hatzaras, I.</author><author>Du, K. L.</author></authors></contributors><auth-address>Department of Radiation Oncology, New York University Langone Medical Center , New York, NY , USA.&#xD;Division of Colon and Rectal Surgery, New York University Langone Medical Center , New York, NY , USA.&#xD;Division of Hematology and Oncology, New York University Langone Medical Center , New York, NY , USA.&#xD;Division of Surgical Oncology, New York University Langone Medical Center , New York, NY , USA.</auth-address><titles><title>Predictors of Complete Response and Disease Recurrence Following Chemoradiation for Rectal Cancer</title><secondary-title>Front Oncol</secondary-title><alt-title>Frontiers in oncology</alt-title></titles><pages>286</pages><volume>5</volume><edition>2016/01/07</edition><dates><year>2015</year></dates><isbn>2234-943X (Linking)</isbn><accession-num>26734570</accession-num><urls></urls><custom2>PMC4686647</custom2><electronic-resource-num>10.3389/fonc.2015.00286</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>31OnCoRe, UKPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5laGFuPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA 22University Penn, US ADDIN EN.CITE <EndNote><Cite><Author>Smith</Author><Year>2015</Year><RecNum>26</RecNum><DisplayText><style face="superscript">40</style></DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smith, R. K.</author><author>Fry, R. D.</author><author>Mahmoud, N. N.</author><author>Paulson, E. C.</author></authors></contributors><auth-address>Department of General Surgery, Temple University Health System, 3401 Broad St., Philadelphia, PA, 19140, USA.</auth-address><titles><title>Surveillance after neoadjuvant therapy in advanced rectal cancer with complete clinical response can have comparable outcomes to total mesorectal excision</title><secondary-title>Int J Colorectal Dis</secondary-title><alt-title>International journal of colorectal disease</alt-title></titles><pages>769-74</pages><volume>30</volume><number>6</number><edition>2015/03/20</edition><keywords><keyword>Adenocarcinoma/surgery/ therapy</keyword><keyword>Chemoradiotherapy</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neoadjuvant Therapy</keyword><keyword>Neoplasm Metastasis</keyword><keyword>Neoplasm Recurrence, Local</keyword><keyword>Rectal Neoplasms/surgery/ therapy</keyword><keyword>Retrospective Studies</keyword><keyword>Survival Analysis</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1432-1262 (Electronic)&#xD;0179-1958 (Linking)</isbn><accession-num>25787162</accession-num><urls></urls><electronic-resource-num>10.1007/s00384-015-2165-2</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>40Vejle, DK ADDIN EN.CITE <EndNote><Cite><Author>Appelt</Author><Year>2015</Year><RecNum>20</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="axdvsdxf3pz0ste5e9f5twduxv0de9f0aaws">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Appelt, A. L.</author><author>Ploen, J.</author><author>Harling, H.</author><author>Jensen, F. S.</author><author>Jensen, L. H.</author><author>Jorgensen, J. C.</author><author>Lindebjerg, J.</author><author>Rafaelsen, S. R.</author><author>Jakobsen, A.</author></authors></contributors><auth-address>Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark; Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: ane.lindegaard.appelt@rsyd.dk.&#xD;Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark.&#xD;Digestive Disease Center, Bispebjerg University Hospital, Copenhagen, Denmark.&#xD;Department of Surgery, Aalborg University Hospital, Aalborg, Denmark.</auth-address><titles><title>High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study</title><secondary-title>Lancet Oncol</secondary-title><alt-title>The Lancet. Oncology</alt-title></titles><pages>919-27</pages><volume>16</volume><number>8</number><edition>2015/07/15</edition><dates><year>2015</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1474-5488 (Electronic)&#xD;1470-2045 (Linking)</isbn><accession-num>26156652</accession-num><urls></urls><electronic-resource-num>10.1016/s1470-2045(15)00120-5</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>29P valuesNumber of patients60223118481624213166181740Study period2005-142006-122005-142005-152005-172002-141990-20162001-162008-112001-142010-14Median age (range) years64(30-89)75 (31-89)64(47-81)63(33-84)63(52-82)67(41-88)64(43-81)62(30-86)59(31-82)64(35-86)63(43-81)68(46-86)0.0001*Men (%)401 (67)11 (48)10 (91)55 (66)6 (75)114 (70)17 (40)85 (65)42 (64)15 (83)14 (82)32 (80)0.001?Median time to W&W (range) weeks11(8-15)11 (8-16)12(11-16)12(8-20)8(6-19)11(10-14)17(10-26)Not availableNot available8(7-9)12(6-19)6(6-6)0.0001*≥ 2 ECOG performance status (%)Not availableNot availableNot available0 (0)9 (6)0 (0)Not availableNot availableNot availableNot availableNot availableMedian distance to AV (range) cm5 (4-7)5 (5-7)4 (3-6)5 (2-7)5 (2-9)5 (4-8)3 (2-5)5 (4-7)6 (5-7)6 (5-6)5 (2-6)6(5-6)0.0001*Median serum CEA (range) ng/ml2.5(1.5-3.8)2.9(1.5-7.1)Not available2.1(1.2-3.6)3.0(1.6-3.0)2.9(2.6-4.0)2.4(1.6-4.5)2.0(1.4-2.9)2.2(1.4-4.8)1.6(1.0-2.2)5.6(3.2-7.4)Not availableNot applicablecT stage cT1 & cT2 (%)163 (29)6 (30)2 (18)22 (26)2 (25)38 (23)8 (29)34 (28)25 (38)Not available3 (18)23 (58) cT3 & cT4 (%)393 (71)14 (70)9 (82)62 (74)6 (75)124 (77)20 (71)86 (72)41 (62)Not available14 (83)17 (43)0.007? Missing300000141101800cN stage cN0 (%)228 (50)9 (45)4 (36)20 (24)3 (38)51 (31)26 (87)89 (74)39 (59)13 (72)11 (65)23 (58) cN+(%)228 (50)11 (55)7 (64)64 (76)5 (63)111 (59)4 (13)31 (26)27 (41)5 (28)6 (35)17 (43)< 0.0001? Missing 3000012110000Radiotherapy dose regimens 45 cGy212 (38)531115352901410 50.4 cGy228 (41)181836637681080 54 cGy79 (14)000120764410 60 to 65 cGy44 (8)000010210040 Missing39070000250070Concurrent chemotherapy (%) 570 (95)23 (100)8 (73)84 (100)7 (88)143 (88)40 (95)126 (96)66 (100)18 (100)15 (88)40 (100)NAChemotherapy regimens 5FU/ LV66 (12)000000066000 Capecitabine250 (44)488251352110030 Infusional 5-FU202 (35)1900253811501850 Oxaliplatin9 (2) 00200000070 Tegafurur40 (7)000000000040 Others3 (<1)00003000000Adjuvant chemotherapy (%)51 (8)0035 (42)013 (8)1 (2)0002 (12)0NAMedian follow-up in months (IQR)37.6(25.0-58.7)36.2(36.2-36.2)60(38-81)38.4(24.7-57.6)12.4(10.4-52)36.9(22.8-53.1)50.4(32.7-63.8)49(18-86)41(25-58)33.7(25.4-52.6)60(35.4-91.8)35.5(25.6-42.2)Arg: Argentina. UK: United Kingdom. NL: the Netherlands. US: United States. NYU: New York University. Uni Penn: University of Pennsylvania. DK: Denmark. W&W: watch and wait. AV: Anal verge. CEA: carcinoembyronic antigen. 5-FU: 5-fluoruracil. 5-FU/ LV: Concomitant chemotherapy (5-FU - 450 mg/m2 and Leucovorin 50 mg fixed dose) delivered in a total of 6 cycles.NA: not applicable. IQR: inter-quartile range* Kruskal-Wallis test.? Chi-squared test.? Chi-squared test excluding missing data.Table 2 Factors predicting local regrowth in patients initially managed by W&W in the InterCoRe consortium, accounting for centre effect in frailty models for the total cohort and post-2008 sub-cohortTotal cohort (n: 602)Post-2008 sub-cohort (n: 459)IPD pooled analysisIPD frailty modelsIPD pooled analysisIPD frailty modelsUnivariableMultivariable*UnivariableMultivariable*No. of patients2-year local growth rate (95% CIs)Hazard ratio (95% CIs)Hazard ratio (95% CIs)No. of patients2-year local growth rate (95% CIs)Hazard ratio (95% CIs)Hazard ratio (95% CIs)All patients60225 (21-28)45927 (23-31)Age group Per 10 years 6021.007 (0.876, 1.157)0.952(0.820, 1.106)4590.924(0.786, 1.088)0.904(0.762, 1.072)Gender Women20123 (18-30)1.0001.00015522 (16-30)1.0001.000 Men40125 (21-30)1.165 (0.835, 1.627)1.193(0.932, 1.056)30429 (24-31)1.439(0.972, 2.132)1.534(1.023, 2.298)cT-stage cT1& cT2 16318 (13-25)1.0001.00012519 (13-28)1.0001.000 cT336729 (24-34)1.400(0.963, 2.029)1.428(0.954, 2.137)28231 (26-37)1.553(1.009, 2.392)1.657(1.065, 2.579) cT42631 (17-52)1.527(0.732, 3.185)1.864(0.840, 4.133)2237 (21-60)1.710(0.771, 3.794)1.904(0.849, 4.266)per cT stage increase1.348(0.997, 1.822)1.395(1.002, 1.941)1.454(1.039, 2.035)1.496(1.032, 2.168)cN-stage cN028825 (21-31)1.0001.00019228 (22-35)1.0001.000 cN+28824 (19-30)0.910(0.652, 1.270)0.869(0.607, 1.242)25626 (21-32)0.908(0.629, 1.309)0.751(0.512, 1.100)Distance to AV? < 6.0 cm31125 (20-30)1.0001.00026427 (22-33)1.0001.000 ≥ 6.0 cm24623 (18-29)0.937(0.666, 1.317)0.896(0.630, 1.273)16023 (17-31)0.810(0.549, 1.196)0.767(0.511, 1.153)Serum CEA categories? < 3.0 ng/ml21929 (23-35)1.000Not included?16432 (25-40)1.000Not included? 3.0 to 9.9 ng/ml8819 (12-29)0.704(0.422, 1.175)7120 (13-32)0.704(0.399, 1.243) ≥ 10 ng/ml2236 (20-55)1.544(0.790, 3.017)1839 (30-65)1.542(0.754, 3.155)Radiotherapy dose group 45 cGy21230 (24-37)1.000Not appropriate? 18733 (26-40)1.000Not appropriate? 50.4 cGy22819 (14-25)0.899(0.563, 1.437)16119 (13-26)0.568(0.328, 0.985) 54 cGy7930 (21-42)1.537(0.753, 3.140)3840 (26-60)1.492(0.740, 3.011) 60 to 65 cGy4426 (15-41)0.989(0.409, 2.394)4326 (15-42)0.812(0.3622, 1.821)Intention to enhance cCR rate Yes (2 centres)10626 (19-36)1.000Not appropriate?6728 (19-41)1.000Not appropriate? No (11 centres)49624 (21-29)1.126 (0.573, 2.213)39226 (22-31)1.105(0.531, 2.296)Time to W&W?? < 13 wks26423 (18-29)1.000Not included?23925 (20-33)1.000Not included? ≥ 13 wks14125 (19-34)1.211(0.805, 1.824)13427 (20-36)1.154(0.770, 1.730)CEA: carcinoembryonic antigen. AV: distance to anal verge. cT and cN staging according to AJCC 7th edition.Analyses in post-2008 sub-cohort limited to model of age, gender, cT-stage, cN stage and distance to AV (equivalent to model A in Table 3)* For full cohort, the complete case multivariable model was based on 514 patienst, equivalent to model A in Table 3. For post-2008 cohort, the complete case multivariable model was based on 393 patients.? Categorisation cut-off points for serum CEA and distance to AV were based on clinical reasons. Distance to AV of 6cm was taken as equivalent to that commonly used to define low-rectal cancers.? Not included in multivariable model due to substantial proportion of missingness.? Not appropriate due to coincidence of radiotherapy dose and study centre.?? Cut-off point of 13 weeks determined using spline approaches; equivalent to Model B in Table 3Table 3 Outputs from frailty models clustering for centres and assessing changes in between-study heterogeneity (theta) for local regrowth, with and without covariatesCovariates in modelNo. of datasetsNo. of patientsMean theta, (se)% difference in thetaLikelihood of theta = 0 AICTotal cohort Model ANo covariatesnone105140.1190 (0.0954)0.0021673.7With covariatesage, gender, cT stage, cN stage, distance to AV0.1248 (0.1013)4.8%0.0031680.2Model BNo covariatesnone83370.1812 (0.1481)0.001981.5With covariatesage, gender, cT stage, cN stage, distance to AV, time to W&W decision0.2633 (0.2134)45.3%0.001978.3Model CNo covariatesnone82780.2662 (0.2054)< 0.001872.2With covariatesage, gender, cT stage, cN stage, distance to AV, baseline serum CEA 0.2465 (0.1921)7.4%0.001870.9Post-2008 sub-cohortModel ANo covariatesnone103930.0964 (0.0776)0.0051234.4With covariatesage, gender, cT stage, cN stage, distance to AV0.1084 (0.0851)12.4%0.0031233.9W&W: watch and wait. Se: standard error. CEA: carcinoembyronic antigen. AV: anal verge. Distance to AV, time to W&W decision and serum CEA as continuous variables. Time to W&W decision as a spline pivoted as 13 weeks (determined from fractional polynomials)Table 4 Treatment of 166 patients with local regrowth initially managed by W&W in the InterCoRe consortiumPost-salvage surgery pathology findingsN (%)Positive CRMPositive DRMypT stage?T0/T1/T2/T3/T4/missingypN stage?N0/N+/ missingNo. of patients with local regrowth166Non-surgical treatments29* (17)Surgical treatments137 (83)Operation types Abdomino-perineal resection73 (52)401/7/22/35/2/656/9/8 Anterior resection29 (21)003/5/6/14/0/120/8/1 Hartmann’s procedure4 (3)010/0/0/3/0/12/1/1 Other radical operations6 (4)000/0/2/2/2/06/0/0 Transanal local excision or TEM25 (18)Not applicable10/5/13/5/0/0Not applicableTotals424/17/43/59/4/884/18/10Total colostomies80 (48)Values in parentheses are percentages and only cited if value greater than five. TEM: transrectal endoscopic micro-dissection. CRM: circumferential resection margin. DRM: distal resection margin.*Five patients had synchronous diagnoses of distant metastases.? The Taiwan study did not contribute to the pathological T and N staging.Figure legendsFigure 1 Forest plot of 11 datasets. Sorted by descending 2-year local regrowth cumulative incidences Summary estimate, 95% confidence intervals, and prediction intervals shown for random effects method, and restricted maximum likelihood estimators (reml).UK: United Kingdom. DK: Denmark. NYU NYC: New York University, New York City. Arg: Argentina. US: United States. NL: The Netherlands.Figure 2 A; pooled analysis with local regrowth cumulative incidence from 1 to 5 years, with 95% CIs. B; 2-stage random-effect meta-analysis with summary estimates for 1- through 5-years, with 95% CIs, and predictive intervals in green.References ADDIN EN.REFLIST 1.Brenner H, Kloor M, Pox CP. Colorectal cancer. 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