TreatmENT of AnastomotiC LeakagE after colon cancer resection: the TENTACLE – Colon study

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Lemmens, Sander Ubels, Nynke G. Greijdanus, Kiedo Wienholts, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6220619/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 May, 2025 Read the published version in BMC Surgery → Version 1 posted 12 You are reading this latest preprint version Abstract Background Anastomotic leakage (AL) is a common and severe complication after colon cancer resection, but studies investigating various treatment strategies and factors influencing outcomes are scarce. Objectives (1) To identify predictive factors associated with 90-day mortality and 90-day Clavien-Dindo grade 4–5 complications amongst patients who developed AL following colon cancer resection with subsequent development and validation of prediction models, and (2) to explore and compare the effectiveness of various treatment strategies for AL following colon cancer resection, adjusting for type of index surgery, different leak entities and patient factors. Methods The TENTACLE – Colon is an international multicentre retrospective cohort study. Consecutive patients with AL after colon cancer resection operated between 1 January 2018 and 31 December 2022 from participating centres will be included. The planned sample size is 2000 patients. The primary outcome is 90-day mortality and the co-primary composite endpoint is Clavien-Dindo grade 4–5 complications. Secondary outcomes include: hospital and intensive care unit length of stay, number of radiological and surgical reinterventions within one year after resection, mortality (in-hospital, 30-day, and 1-year), the comprehensive complication index, and 1-year stoma-free survival. For objective 1, regression models will be used to identify predictors associated with 90-day mortality and grade 4–5 complications. For objective 2, comparative analyses of various treatment strategies will be performed for the specified outcomes, adjusting for patient, tumour, resection and leakage characteristics. Conclusion The TENTACLE – Colon study will be an important step towards evidence-based and personalized treatment of anastomotic leakage after colon cancer resection, potentially improving patient outcomes. treatment severity anastomotic leakage colon cancer resection Figures Figure 1 Introduction Anastomotic leakage (AL) is a common and severe complication after colon cancer resection. Recent studies report leak rates between 4.5% and 8.4%, despite ongoing improvements in perioperative care and surgical techniques. (1–6) AL is associated with re-intervention(s), prolonged hospital stay, a higher likelihood of permanent stomas, and mortality. (7–13) Numerous population-based studies have shown that postoperative mortality rates vary from 12–19% among colon cancer patients with AL. (1, 14, 15) Long-term consequences of AL include omission of adjuvant chemotherapy and a possible stage-dependent reduction in survival. (16, 17). Despite these alarming numbers, comparative studies evaluating different treatment strategies for AL are lacking. In current clinical practice, treatment decision-making is frequently based on the clinical presentation, resource availability, surgeon preference and experience, and leakage characteristics. Such leakage characteristics may include defect size and location, presence of ischemia, tension on the anastomosis, presence of a localized abscess, purulent peritonitis, faecal contamination, and sepsis. (18) However, little is known regarding these leakage characteristics, and to what extent these factors contribute to treatment decision-making and influence postoperative outcomes. Current treatment options for AL include conservative management with antibiotic regimens, surgical interventions (e.g. dismantling of the anastomosis), radiological drainage, endoscopic clipping, or a combination of these modalities. (19–22) Evidence regarding effectiveness of these treatment modalities remains scarce, and identifying the optimal treatment modality individualized for a specific patient with specific characteristics could improve patient outcomes. Therefore, this study has two main aims: (1) to identify predictive factors associated with 90-day mortality and 90-day Clavien-Dindo grade 4–5 complications amongst patients who developed AL following colon cancer resection and to develop and validate prediction models for these two main outcomes and (2) to explore and compare the effectiveness of various treatment strategies for AL following colon cancer resection, adjusting for type of index surgery, different leak entities and patient factors. Methods Study design The TENTACLE – Colon is an international multicentre retrospective cohort study in which all consecutive patients who developed AL after colon cancer resection operated between January 1st 2018 and December 31st 2022 will be included from each participating centre. Last date of follow-up of included patients will be registered. Data collection started in October 2024 and recruitment will continue until June 2025. See Fig. 1 for the timeline. The TENTACLE - Colon study is open for participation by all centres worldwide performing colon cancer resections. The TENTACLE - Colon study will be disseminated across multiple (inter)national surgical societies to increase the number of inclusions and optimize the probability of obtaining robust results. The current study is an investigator-initiated study without financial support. Study population Inclusion criteria are: (1) aged 18 years or older, (2) surgical resection for primary colon cancer (cT1-4b, N0-2, M0-1, colon cancer was defined as when the lower border of the colon cancer was above the level of the sigmoid take-off on imaging) with formation of a primary colonic anastomosis above the peritoneal reflection, with or without a diverting stoma, and (3) postoperative AL defined as: “any clinical, radiological or intraoperative sign(s) of disrupted integrity of the colonic anastomosis (i.e. ileo-colic, colo-colic or high colo-rectal anastomosis) and/or leakage from a blind loop of the colonic anastomosis. (23) This also includes suspected leaks with any degree of extraluminal air or fluid on computed tomography (CT) scan, perianastomotic abscess, purulent peritonitis without clear anastomotic defect, or any other suspicious condition in which there is no ultimate macroscopic proof of disrupted anastomosis.” Regarding the type of colon cancer resection, the following patients will also fulfil the inclusion criteria: patients who underwent cytoreductive surgery simultaneous with resection of the primary colon cancer with or without hyperthermic intraperitoneal chemotherapy, simultaneous ablations/resections of metastasis, multivisceral resection, emergency resection, patients diagnosed with perforated disease, peritumoural abscess and/or fistula, and acute obstructions. Exclusion criteria are (1) surgical resection for benign disease, (2) surgical resection for recurrent colon cancer, (3) diagnosis of any primary colon malignancy other than adenocarcinoma (e.g. neuroendocrine tumour, gastro-intestinal stromal tumour), and (3) any clinical condition that does not fulfil the broad definition of AL as used in this study (e.g. only free air on CT scan that is considered to be compatible with a certain postoperative day in the absence of any other clinical signs related to a potential anastomotic leakage). Study parameters Hospital characteristics Upon study entry, each participating centre will be required to complete a questionnaire to gather comprehensive information regarding institutional characteristics. This questionnaire covers the following subjects: hospital type, annual volume of colon cancer resections, estimated anastomotic leakage rate, number of hospital beds and availability of hospital resources, protocols, and diagnostic and treatment modalities. Patient and tumour characteristics The following patient characteristics will be collected: sex, age, height, weight, body mass index, Charlson Comorbidity Index, American Society of Anaesthesiologists classification, smoking status, baseline hemoglobin level and history of immunosuppressive medication. The following tumour characteristics will be collected: histology, location, pathological T-, N- and M-stage according to the Union for International Cancer Control classification, preoperative tumour-related complications, surgical interventions before index colon cancer resection, preoperative anaemia treatment, and neoadjuvant treatment. Surgical and intraoperative characteristics The following characteristics regarding preparation before colon cancer resection will be registered: setting of resection, preoperative antibiotic and mechanical bowel preparation use. The following surgical characteristics will be collected: date of resection, start and end time of resection, intention of resection, abdominal approach, conversion, type of resection, multivisceral resection, other simultaneous intervention applied, number and type(s) of anastomosis, configuration of colonic anastomosis, problems during anastomosis construction, stoma creation, indocyanine green assessment, intraoperative complications, blood loss during resection, and amount of blood transfusions. Diagnostic characteristics Collected diagnostic characteristics will be: date and time of diagnosis of AL, clinical setting at time of leak diagnosis, antibiotics and nasogastric tube use, modalities applied to assess anastomotic integrity, and clinical, biochemical and intensive care unit parameters. The following leakage characteristics at diagnosis will be collected: radiological characteristics, intraoperative characteristics, location and estimated circumference. Treatment of anastomotic leakage Details of all therapeutic modalities and strategies utilised will be collected, including primary, secondary, tertiary, and quarternary treatments: date and time of start treatment, need for re-admission, and (specification of) applied radiological, endoscopic, and surgical interventions. Follow-up of treatment The following characteristics will be collected to assess outcomes after leakage treatment: leak healing and modality that confirmed leak healing, date of initial hospital discharge, total length of intensive care unit stay, date of death (if applicable), recurrent colon cancer, stoma status, total number of radiological and surgical interventions within one year after colon cancer resection, adjuvant chemotherapy, and diagnosis of other complications with corresponding grading of severity. (24) Outcome measures The primary outcome is 90-day mortality, and the co-primary outcome is a composite endpoint of 90-day Clavien-Dindo grade 4–5 complications. (24) Secondary outcomes include: length of hospital stay, length of intensive care unit stay, number of radiological and surgical reinterventions within one year after resection, mortality (in-hospital, 30-day, and 1 year), comprehensive complications index, and 1-year stoma-free survival. (25) Sample size calculation This study is exploratory in nature, and its primary objective is to utilize a large detailed dataset to examine to what extent specific factors of AL are associated with the severity of the leakage and the impact of various treatment strategies on primary and secondary outcome parameters, with adjustment for relevant covariates. To establish a risk score comprising at least 12 candidate predictors, with a 10% incidence of 90-day mortality amongst AL patients following colon cancer resection and a root mean square percentage error of 5%, it is necessary to include 680 patients with AL. (26) However, to ensure robustness, to enable the development and validation of an evidence-based prediction model, and to create a solid foundation for future research related to AL, the aim is to include at least 2000 patients with AL following colon cancer resection. Pilot study After the study protocol and online case report file (CRF) were developed, the international steering committee consisting of 15 experts on AL after colon cancer resection working across 11 different countries participated in the pilot test (Table 1 ). During pilot testing, the experts were asked to include at least 5 patients into the online CRF and to provide feedback on the protocol and online CRF. The feedback was evaluated by the study group, and used to refine the protocol and CRF in order to meet international standards and clarity on definitions and the use of the online CRF. Table 1 International steering committee TENTACLE – Colon study. Member Hospital City Country 1. Hans de Wilt Radboudumc Nijmegen The Netherlands 2. Pieter Tanis ErasmusMC Rotterdam The Netherlands 3. Roel Hompes Amsterdamumc Amsterdam The Netherlands 4. Albert Wolthuis UZ Leuven Leuven Belgium 5. Kilian Brown Royal Prince Alfred Hospital Sydney Australia 6. Jérémie Lefevre Sorbonne Université, AP-HP, Hôpital Saint Antoine Paris France 7. Martin Rutegård Umeå University Umeå Sweden 8. Quentin Denost Clinique Tivoli Bordeaux France 9. Nicolas Rotholtz Hospital Alemán Buenos Aires Argentina 10. Thomas Pinkney University of Birmingham Birmingham United Kingdom 11. Rodrigo Perez Hospital Alemão Oswaldo Cruz São Paulo Brazil 12. Susan Gearhart Johns Hopkins Medicine Baltimore United States of America 13. Tsuyoshi Konishi The University of Texas MD Anderson Cancer Center Anderson United States of America 14. Matteo Frasson Valencia University Hospital La Fe Valencia Spain 15. Muhammed Elhadi Faculty of Medicine, University of Tripoli Tripoli Libya Data handling and regulatory considerations The Castor database system ( https://www.castoredc.com/ ) will be used to collect data through online CRFs. Castor is an officially certified online medical research database system that fully complies with all pertinent regulations (i.e. GDPR, HIPAA, ICH-GCP, ISO 27001, ISO 9001, FDA 21 CFR part 11) and strictly adheres to international security standards. The CRF contains information points, definitions, and guidelines to facilitate accurate scoring of the specified parameters. The data entered will exclusively be visible to collaborators from the designated hospital, and access to the complete study database will be limited to coordinating investigators and principal investigators. All pseudonymized patient data will be entered by or under supervision of the treating physician(s). Each patient will be coded with a unique patient number before being entered into the database. The physician will keep a password-protected file that can identify individual patients, which will be locked away in their practice. This file can be accessed by the local investigators if needed, for example in case a relevant new research question requires entry of additional data into the database. All (up to 4) collaborators from the participating centres will receive an invitation to the Castor database along with step-by-step manuals and an online training module to ensure homogeneity in the inclusion process and during data entry, and to ensure that all eligible patients with AL within 90 days after colon cancer resection will be screened. Data cleaning, verification and validation After a participating centre has finished data entry, the coordinating investigator will initiate data cleaning, verification and validation procedures to improve data completeness and to assess data quality and case ascertainment. Data cleaning will involve the use of algorithms to scrutinize the data for any missing values, data inconsistencies and typographical errors. All issues identified will be communicated to the respective local investigators enabling them to verify, adjust, or add the (missing) data. For data validation, data accuracy and case ascertainment will be assessed. Data accuracy will be assessed by cross-checking data recorded in Castor with medical records by a local independent validator. At random, 20% of the participating centres will be selected for data validation, wherein a subset of predefined key parameters of 10–20% of the inclusions of a centre will be validated. Case ascertainment will be assessed to identify a systematic difference in the selection of patients per centre, defined as the proportion of included cases compared to the total amount of eligible cases. To assess case ascertainment, collaborators will be asked whether they entered data of all consecutive patients with an AL within the study period, or whether a sample was included (and if so; for which period). Furthermore, participating centres will be asked about their annual number of colon cancer resections. The AL rate was conservatively estimated at 3% for all years within the study period. (27) If the number of included cases is lower than the estimated number of cases, the collaborators will be asked to substantiate this discrepancy. For all procedures, a step-by-step manual as well as additional support will be available. Data availability Data may be available upon reasonable request. Only collaborators with appropriate qualifications and pertinent research inquiries are eligible to request access to the data. The principal investigators of the TENTACLE – Colon study will assess the relevance and appropriateness of the request and their verdict is decisive. If data will be transferred, it will only be conducted under the appropriate ethical and data transfer agreements. Statistical analysis Statistical protocols have been drafted with an experienced biostatistician (M.v.G). These analytical strategies are in line with the previous TENTACLE – Esophagus and TENTACLE – Rectum projects. (18, 28–30) Main study objective 1 The goal of this study is to identify predictive factors associated with 90-day mortality and the co-primary composite endpoint Clavien Dindo grade 4–5 complications among patients who developed AL following colon cancer resection. Subsequently, a prediction model for these two endpoints will be developed with several clinically relevant patient, tumour, resection, diagnostic and leakage characteristics, and internally validated. The development and validation of the prediction models will be in agreement with the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis guidelines. (31) First, univariate analysis will be performed on parameters that are considered to be potentially relevant. These parameters will be entered into separate binary logistic regression models with 90-day mortality and Clavien Dindo grade 4–5 as outcome parameters in order to explore associations in the data. Second, relevant parameters that are also considered to be clinically relevant based on literature and/or expert opinion will be selected for multivariate analysis. Backwards stepwise selection will be used to exclude variables with P values > 0.05 from the model. Results will be presented as odds ratio with 95% confidence intervals (CI). A 2-tailed p < 0.05 will be considered statistically significant. Third, the multivariable models will be internally validated by bootstrapping, using 5000 bootstrap resamples. Finally, the models will be created based on the final bootstrapped multivariable regression analysis. The model will be incorporated in an online tool and will be made available at https://www.tentaclestudy.com/ . If the casemix is found to be strongly associated with outcome relative to the mortality score (to the extent that the mortality score is of limited value in the regression model), latent class analysis will be used. (32) The parameters used for the mortality score will be used to create casemix-corrected classes of AL severity. Sensitivity analysis will be performed in subgroups of patients undergoing various types of colectomies, and for different settings (e.g. elective, emergency) of colon cancer resection. These analyses will investigate whether the obtained model is useful for all types and settings of colon cancer resection. If substantial differences are observed between the initial and subgroup analyses, the possibility of composing different scoring systems will be considered. Main study objective 2 The second main objective is to explore and compare the effectiveness of various treatment strategies for AL following colon cancer resection, adjusting for patient, tumour, resection and leakage characteristics. Relevant treatment parameters identified in the first analysis will be considered independent variables in this analysis. The association between characteristics of colon cancer resection, AL, and outcome measures (e.g. 90-day mortality) will be evaluated for the exposures in regression analysis. Where appropriate, statistical adjustment using propensity score methods for patient, tumour, resection, and/or leakage characteristics, as well as timing, potential delay and clinical setting of AL diagnosis will be performed. Based on the results of this analysis, subgroups of patients will be created based on individual resection or leakage characteristics (or a combination of these). The efficacy of AL treatment strategies will be assessed in regression models for the different outcome parameters and adjusted for patient, tumour, resection and leakage characteristics, where appropriate. All analyses for objective 2 will be conducted using modified Poisson regression, with results expressed as risk ratios with corresponding 95% confidence intervals. Ethical considerations This study will be conducted in compliance with the principles of the declaration of Helsinki. The medical ethical committee of the Radboud university medical centre in Nijmegen, The Netherlands, has thoroughly reviewed all documents, including the study protocol and granted approval (file number: 2024–17491). The need for central informed consent was waived, but local ethical requirements may differ per geographical region, country, or hospital. The study protocol and relevant documents will be provided to all participating centres in case the centres need local ethical approval. The TENTACLE – Colon study is registered on Clinicaltrial.gov (NCT 06528054). The study protocol and the letter of ethical approval is also available on the website: https://www.tentaclestudy.com/ . Publications The TENTACLE study team aims to publish two main manuscripts covering the main objectives. These manuscripts will be submitted to peer-reviewed journals. All members of the international steering committee are fully involved in conducting this study and will be included as (co-)authors in the publications. All (up to) 4 collaborators and local independent validator (if applicable) will be granted (PubMed-citable) corporate authorship under the name ‘the TENTACLE – Colon Collaborative Group’ in all manuscripts using data of the TENTACLE – Colon study. The affiliation information of the collaborators will be the hospital whose patients were included. Discussion Anastomotic leakage (AL) remains a common and severe complication after colon cancer resection. Most research to date has focused on the prevention and prediction of AL, but large comparative studies evaluating various treatment modalities for AL are scarce. (33–35) As a result, the optimal treatment of AL after colon cancer resection and the subsequent important clinical outcomes remain largely unknown. There are several explanations for this knowledge gap. Treatment of AL is generally chosen on a case-by-case basis, depending on several patient and resection characteristics, and is influenced by the preferences and expertise of the treating surgeon. More specifically, AL is a heterogeneous and highly complex complication, which is likely to hamper the initiation of standardized institutional treatment protocols and the design of prospective studies. Furthermore, the diverse clinical presentation and wide variety of treatment approaches complicates the interpretation and generalizability of small underpowered studies. The TENTACLE – Colon study aims to address this knowledge gap and will therefore provide valuable insights into the severity and treatment of AL after colon cancer resection. This global effort, combined with detailed data collection, will facilitate robust (comparative) analyses and the results can provide a solid basis for evidence-based and personalized treatment decisions. The international success of the previous TENTACLE studies in esophageal and rectal cancer surgery underscores the relevance, feasibility and importance of the current study. (18, 28, 29, 36) The main strengths of the present study are the high level of detail of the data collected and the large number of planned patient inclusions. This large cohort is needed to perform regression analyses with various patient, tumour, resection and leakage characteristics to explore and identify distinct clinical presentations of colonic AL. For each clinical presentation, relevant subgroup analyses can be performed to compare relevant treatment strategies. The inclusion of a large cohort is feasible due to the international collaborative design of the current study, which increases the generalizability of findings across various populations. A pilot study was conducted among core collaborators from diverse continents to ensure that the online CRF includes parameters relevant to various geographical regions along with clear definitions. The main limitation is the retrospective design of the study. A prospective design was not considered feasible due to logistical reasons and the need to include a large cohort, while AL occurs in no more than 8.4% of patients. (1) However, the results of this study will be hypothesis generating, and this knowledge can be used to guide the design process of future prospective studies. Another limitation is the risk of confounding by indication, as patients receiving certain treatments may be inherently different from those receiving other treatments. In this study, regression analysis using sophisticated statistical techniques to account for confounding of detailed data within a large cohort should mitigate much of this expected confounding. However, residual confounding may occur if the regression analysis cannot adequately adjust for all confounding factors. Finally, given the international and collaborative nature of the study, there is a risk of selection bias as not all centres worldwide will be collaborating. This may bias the dataset towards patients from more scientifically invested centres, which may limit generalizability to some extent. For current clinical practice, the results of the TENTACLE – Colon study could have an impact on management of AL. The prediction model (i.e. the first main objective) will indicate the severity of AL in terms of mortality by considering patient, tumour, resection and leakage characteristics. Clinicians can use this model to distinguish patients at high risk of mortality from those at low risk. This is useful because the severity of AL is nowadays classified by how it is treated, but this classification can, by definition, not be used to prospectively guide clinical decision-making. (24) Furthermore, the evaluation of treatment strategies (i.e. the second main objective) for different subgroups of AL might indicate the best treatment strategy for each distinct clinical presentation. Currently, patients can be treated with a wide range of treatment modalities, mainly due to the lack of evidence to support a specific modality for a specific clinical presentation of AL. Therefore, clinicians can use the prediction model and insights from the treatment evaluations of different clinical presentations to faciliate evidence-based and personalized treatment decision-making when AL is diagnosed. In conclusion, the TENTACLE – Colon study is a large international multicentre collaborative study aiming to investigate which factors contribute to the severity of AL, and to evaluate treatment efficacy of different clinical presentations of AL. This study will be an important step towards evidence-based and personalized management of AL, which may improve patient outcomes. Abbreviations AL; anastomotic leakage. CT; computed tomography. CRF: case report file. Declarations Ethics : The study protocol and relevant documents have been approved by the medical ethical committee of the Radboud University Medical Center, Nijmegen, the Netherlands (file number: 2024-17491). The official (Dutch) name of this medical ethical committee is METC Oost-Nederland. The need for central informed consent was waived, but local ethical requirements may differ per geographical region, country or hospital. Consent for publication : All listed authors have approved this version of the manuscript. Data availability : Data may be available upon reasonable request. COI : The authors declare to have no conflicts of interest with regard to the present manuscript. Funding : The TENTACLE – Colon study is not funded. Acknowlegdements: none. Study registration: This study is registered at clinicaltrials.gov (NCT 06528054) since July 30 th , 2024. Author contributions: Jobbe M.G. Lemmens, Sander Ubels, Nynke G. Greijdanus, Kiedo Wienholts, Marleen M.H.J. van Gelder, Albert Wolthuis, Jérémie H. Lefevre, Kilian Brown, Matteo Frasson, Nicolas Rotholtz, Quentin Denost, Rodrigo O. Perez, Tsuyoshi Konishi, Martin Rutegård, Susan L. Gearhart, Thomas Pinkney, Muhammed Elhadi, and Roel Hompes: designing the study, writing manuscript, critically revising the manuscript, and final approval given. Pieter J. Tanis and Johannes H.W. de Wilt; designing the study, writing manuscript, critically revising the manuscript, supervising the study, and final approval given. References Arron MNN, Greijdanus NG, Ten Broek RPG, Dekker JWT, van Workum F, van Goor H, et al. Trends in risk factors of anastomotic leakage after colorectal cancer surgery (2011-2019): A Dutch population-based study. Colorectal Dis. 2021;23(12):3251-61. Hewett PJ, Allardyce RA, Bagshaw PF, Frampton CM, Frizelle FA, Rieger NA, et al. Short-term outcomes of the Australasian randomized clinical study comparing laparoscopic and conventional open surgical treatments for colon cancer: the ALCCaS trial. Ann Surg. 2008;248(5):728-38. Kehlet H, Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery. Ann Surg. 2008;248(2):189-98. Hohenberger W, Weber K, Matzel K, Papadopoulos T, Merkel S. Standardized surgery for colonic cancer: complete mesocolic excision and central ligation--technical notes and outcome. Colorectal Dis. 2009;11(4):354-64; discussion 64-5. Frasson M, Flor-Lorente B, Rodriguez JL, Granero-Castro P, Hervas D, Alvarez Rico MA, et al. Risk Factors for Anastomotic Leak After Colon Resection for Cancer: Multivariate Analysis and Nomogram From a Multicentric, Prospective, National Study With 3193 Patients. Ann Surg. 2015;262(2):321-30. Weber MC, Berlet M, Stoess C, Reischl S, Wilhelm D, Friess H, et al. A nationwide population-based study on the clinical and economic burden of anastomotic leakage in colorectal surgery. Langenbecks Arch Surg. 2023;408(1):55. Daams F, Luyer M, Lange JF. Colorectal anastomotic leakage: aspects of prevention, detection and treatment. World J Gastroenterol. 2013;19(15):2293-7. den Dulk M, Noter SL, Hendriks ER, Brouwers MA, van der Vlies CH, Oostenbroek RJ, et al. Improved diagnosis and treatment of anastomotic leakage after colorectal surgery. Eur J Surg Oncol. 2009;35(4):420-6. Collaborative EESA. ESCP Safe Anastomosis ProGramme in CoLorectal SurgEry (EAGLE): Study protocol for an international cluster randomised trial of a quality improvement intervention to reduce anastomotic leak following right colectomy. Colorectal Dis. 2021;23(10):2761-71. Buchs NC, Gervaz P, Secic M, Bucher P, Mugnier-Konrad B, Morel P. Incidence, consequences, and risk factors for anastomotic dehiscence after colorectal surgery: a prospective monocentric study. Int J Colorectal Dis. 2008;23(3):265-70. Krarup PM, Nordholm-Carstensen A, Jorgensen LN, Harling H. Anastomotic leak increases distant recurrence and long-term mortality after curative resection for colonic cancer: a nationwide cohort study. Ann Surg. 2014;259(5):930-8. Turrentine FE, Denlinger CE, Simpson VB, Garwood RA, Guerlain S, Agrawal A, et al. Morbidity, mortality, cost, and survival estimates of gastrointestinal anastomotic leaks. J Am Coll Surg. 2015;220(2):195-206. Brown SR, Mathew R, Keding A, Marshall HC, Brown JM, Jayne DG. The impact of postoperative complications on long-term quality of life after curative colorectal cancer surgery. Ann Surg. 2014;259(5):916-23. Kube R, Mroczkowski P, Granowski D, Benedix F, Sahm M, Schmidt U, et al. Anastomotic leakage after colon cancer surgery: a predictor of significant morbidity and hospital mortality, and diminished tumour-free survival. Eur J Surg Oncol. 2010;36(2):120-4. Alves A, Panis Y, Trancart D, Regimbeau JM, Pocard M, Valleur P. Factors associated with clinically significant anastomotic leakage after large bowel resection: multivariate analysis of 707 patients. World J Surg. 2002;26(4):499-502. Arron MNN, Greijdanus NG, Bastiaans S, Vissers PAJ, Verhoeven RHA, Ten Broek RPG, et al. Long-Term Oncological Outcomes After Colorectal Anastomotic Leakage: A Retrospective Dutch Population-based Study. Ann Surg. 2022;276(5):882-9. Gao P, Huang XZ, Song YX, Sun JX, Chen XW, Sun Y, et al. Impact of timing of adjuvant chemotherapy on survival in stage III colon cancer: a population-based study. BMC Cancer. 2018;18(1):234. Greijdanus NG, Wienholts K, Ubels S, Talboom K, Hannink G, Wolthuis A, et al. Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort. Ann Surg. 2023;278(5):772-80. Ozmen I, Grupa VEM, Bedrikovetski S, Dudi-Venkata NN, Huisman DE, Reudink M, et al. Risk Nomogram Does Not Predict Anastomotic Leakage After Colon Surgery Accurately: Results of the Multi-center LekCheck Study. Journal of Gastrointestinal Surgery. 2022;26(4):900-10. Hedrick TL, Kane W. Management of Acute Anastomotic Leaks. Clin Colon Rectal Surg. 2021;34(6):400-5. Phitayakorn R, Delaney CP, Reynolds HL, Champagne BJ, Heriot AG, Neary P, et al. Standardized algorithms for management of anastomotic leaks and related abdominal and pelvic abscesses after colorectal surgery. World J Surg. 2008;32(6):1147-56. Blumetti J, Chaudhry V, Cintron JR, Park JJ, Marecik S, Harrison JL, et al. Management of anastomotic leak: lessons learned from a large colon and rectal surgery training program. World J Surg. 2014;38(4):985-91. D'Souza N, Lord A, Shaw A, Patel A, Balyasnikova S, Tudyka V, et al. The sigmoid take-off: An anatomical imaging definition of the rectum validated on specimen analysis. Eur J Surg Oncol. 2020;46(9):1668-72. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205-13. Slankamenac K, Graf R, Barkun J, Puhan MA, Clavien PA. The comprehensive complication index: a novel continuous scale to measure surgical morbidity. Ann Surg. 2013;258(1):1-7. Riley RD, Ensor J, Snell KIE, Harrell FE, Jr., Martin GP, Reitsma JB, et al. Calculating the sample size required for developing a clinical prediction model. Bmj. 2020;368:m441. DCRA. Dutch ColoRectal Audit 2024 [Available from: https://dica.nl/registratie/darmkanker-dcra/. Ubels S, Verstegen M, Klarenbeek B, Bouwense S, van Berge Henegouwen M, Daams F, et al. Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score. Br J Surg. 2022;109(9):864-71. Ubels S, Verstegen MHP, Klarenbeek BR, Bouwense S, van Berge Henegouwen MI, Daams F, et al. Treatment of anastomotic leak after oesophagectomy for oesophageal cancer: large, collaborative, observational TENTACLE cohort study. Br J Surg. 2023;110(7):852-63. van Workum F, Talboom K, Hannink G, Wolthuis A, de Lacy BF, Lefevre JH, et al. Treatment of anastomotic leakage after rectal cancer resection: The TENTACLE-Rectum study. Colorectal Dis. 2021;23(4):982-8. Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. Bmj. 2015;350:g7594. Rabe-Hesketh S, Skrondal A. Classical latent variable models for medical research. Stat Methods Med Res. 2008;17(1):5-32. Castagneto-Gissey L, Russo MF, Casella-Mariolo J, Serao A, Marcellinaro R, D'Andrea V, et al. The Role of Antibiotic Prophylaxis in Anastomotic Leak Prevention during Elective Colorectal Surgery: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Antibiotics (Basel). 2023;12(2). Litchinko A, Buchs N, Balaphas A, Toso C, Liot E, Meurette G, et al. Score prediction of anastomotic leak in colorectal surgery: a systematic review. Surg Endosc. 2024;38(4):1723-30. Dias VE, Castro P, Padilha HT, Pillar LV, Godinho LBR, Tinoco ACA, et al. Preoperative risk factors associated with anastomotic leakage after colectomy for colorectal cancer: a systematic review and meta-analysis. Rev Col Bras Cir. 2022;49:e20223363. Greijdanus NG, Wienholts K, Ubels S, Talboom K, Hannink G, Wolthuis A, et al. Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients. Br J Surg. 2023;110(12):1863-76. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 15 May, 2025 Read the published version in BMC Surgery → Version 1 posted Editorial decision: Revision requested 04 Apr, 2025 Reviews received at journal 04 Apr, 2025 Reviews received at journal 27 Mar, 2025 Reviews received at journal 27 Mar, 2025 Reviewers agreed at journal 24 Mar, 2025 Reviewers agreed at journal 23 Mar, 2025 Reviewers agreed at journal 22 Mar, 2025 Reviewers agreed at journal 21 Mar, 2025 Reviewers invited by journal 21 Mar, 2025 Editor assigned by journal 20 Mar, 2025 Submission checks completed at journal 20 Mar, 2025 First submitted to journal 13 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6220619","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":434767146,"identity":"063cf6ce-9cf1-49cf-a606-337eaeeade80","order_by":0,"name":"Jobbe M.G. 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Lefevre","email":"","orcid":"","institution":"Sorbonne Université, AP- HP, Hôpital Saint Antoine","correspondingAuthor":false,"prefix":"","firstName":"Jérémie","middleName":"H.","lastName":"Lefevre","suffix":""},{"id":434767160,"identity":"4c9a9b26-0fd8-4b13-9256-06d82b7c2cb9","order_by":7,"name":"Kilian Brown","email":"","orcid":"","institution":"Royal Prince Alfred Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kilian","middleName":"","lastName":"Brown","suffix":""},{"id":434767163,"identity":"8d9f06e0-d998-4e02-9a22-9a61f40ee6a0","order_by":8,"name":"Matteo Frasson","email":"","orcid":"","institution":"Valencia University Hospital La Fe","correspondingAuthor":false,"prefix":"","firstName":"Matteo","middleName":"","lastName":"Frasson","suffix":""},{"id":434767164,"identity":"0ee7ba90-27c2-4f52-aa4e-d7f92a7b21b5","order_by":9,"name":"Nicolas Rotholtz","email":"","orcid":"","institution":"Hospital Alemán","correspondingAuthor":false,"prefix":"","firstName":"Nicolas","middleName":"","lastName":"Rotholtz","suffix":""},{"id":434767165,"identity":"20e8b897-c55f-40be-bd68-5901c6f8d382","order_by":10,"name":"Quentin Denost","email":"","orcid":"","institution":"Bordeaux Colorectal Institute","correspondingAuthor":false,"prefix":"","firstName":"Quentin","middleName":"","lastName":"Denost","suffix":""},{"id":434767166,"identity":"ee656d86-415c-4d7d-9d8d-88b48abbd188","order_by":11,"name":"Rodrigo O. 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Gearhart","email":"","orcid":"","institution":"Johns Hopkins University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Susan","middleName":"L.","lastName":"Gearhart","suffix":""},{"id":434767170,"identity":"a48377ae-c0d0-486b-b39a-05c3d78fef04","order_by":15,"name":"Thomas Pinkney","email":"","orcid":"","institution":"University of Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Pinkney","suffix":""},{"id":434767171,"identity":"1596111b-5d69-4078-9e73-a8a9a9f8965f","order_by":16,"name":"Muhammed Elhadi","email":"","orcid":"","institution":"University of Tripoli","correspondingAuthor":false,"prefix":"","firstName":"Muhammed","middleName":"","lastName":"Elhadi","suffix":""},{"id":434767172,"identity":"f637ce48-7586-444b-9d66-6b79af2dfddb","order_by":17,"name":"Roel Hompes","email":"","orcid":"","institution":"Amsterdam University Medical Centers, University of Amsterdam","correspondingAuthor":false,"prefix":"","firstName":"Roel","middleName":"","lastName":"Hompes","suffix":""},{"id":434767173,"identity":"48e0bd07-ad69-4f62-b62b-c54bed50a691","order_by":18,"name":"Pieter J. Tanis","email":"","orcid":"","institution":"Erasmus Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Pieter","middleName":"J.","lastName":"Tanis","suffix":""},{"id":434767174,"identity":"bc94a8ff-d6dd-4e55-a33b-8c28a831cb53","order_by":19,"name":"Johannes H.W. Wilt","email":"","orcid":"","institution":"Radboud University Medical Center, Radboud Institute for Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Johannes","middleName":"H.W.","lastName":"Wilt","suffix":""}],"badges":[],"createdAt":"2025-03-13 13:38:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6220619/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6220619/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12893-025-02954-1","type":"published","date":"2025-05-15T15:57:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79585866,"identity":"844afedb-ab85-4c51-975c-33eb512b0e7c","added_by":"auto","created_at":"2025-03-31 12:29:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":51532,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eTENTACLE – Colon study timeline\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6220619/v1/48a59ba789f5ced0feeb5035.png"},{"id":83067759,"identity":"b80c4b96-c77f-4d40-9f44-f45747c259fc","added_by":"auto","created_at":"2025-05-19 16:05:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":788450,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6220619/v1/4786ac70-cc03-42c8-92f8-08d2fd81c2da.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"TreatmENT of AnastomotiC LeakagE after colon cancer resection: the TENTACLE – Colon study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnastomotic leakage (AL) is a common and severe complication after colon cancer resection. Recent studies report leak rates between 4.5% and 8.4%, despite ongoing improvements in perioperative care and surgical techniques. (1\u0026ndash;6) AL is associated with re-intervention(s), prolonged hospital stay, a higher likelihood of permanent stomas, and mortality. (7\u0026ndash;13) Numerous population-based studies have shown that postoperative mortality rates vary from 12\u0026ndash;19% among colon cancer patients with AL. (1, 14, 15) Long-term consequences of AL include omission of adjuvant chemotherapy and a possible stage-dependent reduction in survival. (16, 17). Despite these alarming numbers, comparative studies evaluating different treatment strategies for AL are lacking.\u003c/p\u003e \u003cp\u003eIn current clinical practice, treatment decision-making is frequently based on the clinical presentation, resource availability, surgeon preference and experience, and leakage characteristics. Such leakage characteristics may include defect size and location, presence of ischemia, tension on the anastomosis, presence of a localized abscess, purulent peritonitis, faecal contamination, and sepsis. (18) However, little is known regarding these leakage characteristics, and to what extent these factors contribute to treatment decision-making and influence postoperative outcomes.\u003c/p\u003e \u003cp\u003eCurrent treatment options for AL include conservative management with antibiotic regimens, surgical interventions (e.g. dismantling of the anastomosis), radiological drainage, endoscopic clipping, or a combination of these modalities. (19\u0026ndash;22) Evidence regarding effectiveness of these treatment modalities remains scarce, and identifying the optimal treatment modality individualized for a specific patient with specific characteristics could improve patient outcomes.\u003c/p\u003e \u003cp\u003eTherefore, this study has two main aims: (1) to identify predictive factors associated with 90-day mortality and 90-day Clavien-Dindo grade 4\u0026ndash;5 complications amongst patients who developed AL following colon cancer resection and to develop and validate prediction models for these two main outcomes and (2) to explore and compare the effectiveness of various treatment strategies for AL following colon cancer resection, adjusting for type of index surgery, different leak entities and patient factors.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e The TENTACLE \u0026ndash; Colon is an international multicentre retrospective cohort study in which all consecutive patients who developed AL after colon cancer resection operated between January 1st 2018 and December 31st 2022 will be included from each participating centre. Last date of follow-up of included patients will be registered. Data collection started in October 2024 and recruitment will continue until June 2025. See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for the timeline.\u003c/p\u003e \u003cp\u003e The TENTACLE - Colon study is open for participation by all centres worldwide performing colon cancer resections. The TENTACLE - Colon study will be disseminated across multiple (inter)national surgical societies to increase the number of inclusions and optimize the probability of obtaining robust results. The current study is an investigator-initiated study without financial support.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003eInclusion criteria are: (1) aged 18 years or older, (2) surgical resection for primary colon cancer (cT1-4b, N0-2, M0-1, colon cancer was defined as when the lower border of the colon cancer was above the level of the sigmoid take-off on imaging) with formation of a primary colonic anastomosis above the peritoneal reflection, with or without a diverting stoma, and (3) postoperative AL defined as: \u0026ldquo;any clinical, radiological or intraoperative sign(s) of disrupted integrity of the colonic anastomosis (i.e. ileo-colic, colo-colic or high colo-rectal anastomosis) and/or leakage from a blind loop of the colonic anastomosis. (23) This also includes suspected leaks with any degree of extraluminal air or fluid on computed tomography (CT) scan, perianastomotic abscess, purulent peritonitis without clear anastomotic defect, or any other suspicious condition in which there is no ultimate macroscopic proof of disrupted anastomosis.\u0026rdquo;\u003c/p\u003e \u003cp\u003eRegarding the type of colon cancer resection, the following patients will also fulfil the inclusion criteria: patients who underwent cytoreductive surgery simultaneous with resection of the primary colon cancer with or without hyperthermic intraperitoneal chemotherapy, simultaneous ablations/resections of metastasis, multivisceral resection, emergency resection, patients diagnosed with perforated disease, peritumoural abscess and/or fistula, and acute obstructions.\u003c/p\u003e \u003cp\u003eExclusion criteria are (1) surgical resection for benign disease, (2) surgical resection for recurrent colon cancer, (3) diagnosis of any primary colon malignancy other than adenocarcinoma (e.g. neuroendocrine tumour, gastro-intestinal stromal tumour), and (3) any clinical condition that does not fulfil the broad definition of AL as used in this study (e.g. only free air on CT scan that is considered to be compatible with a certain postoperative day in the absence of any other clinical signs related to a potential anastomotic leakage).\u003c/p\u003e\n\u003ch3\u003eStudy parameters\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eHospital characteristics\u003c/h2\u003e \u003cp\u003eUpon study entry, each participating centre will be required to complete a questionnaire to gather comprehensive information regarding institutional characteristics. This questionnaire covers the following subjects: hospital type, annual volume of colon cancer resections, estimated anastomotic leakage rate, number of hospital beds and availability of hospital resources, protocols, and diagnostic and treatment modalities.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient and tumour characteristics\u003c/h3\u003e\n\u003cp\u003eThe following patient characteristics will be collected: sex, age, height, weight, body mass index, Charlson Comorbidity Index, American Society of Anaesthesiologists classification, smoking status, baseline hemoglobin level and history of immunosuppressive medication. The following tumour characteristics will be collected: histology, location, pathological T-, N- and M-stage according to the Union for International Cancer Control classification, preoperative tumour-related complications, surgical interventions before index colon cancer resection, preoperative anaemia treatment, and neoadjuvant treatment.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSurgical and intraoperative characteristics\u003c/h2\u003e \u003cp\u003eThe following characteristics regarding preparation before colon cancer resection will be registered: setting of resection, preoperative antibiotic and mechanical bowel preparation use. The following surgical characteristics will be collected: date of resection, start and end time of resection, intention of resection, abdominal approach, conversion, type of resection, multivisceral resection, other simultaneous intervention applied, number and type(s) of anastomosis, configuration of colonic anastomosis, problems during anastomosis construction, stoma creation, indocyanine green assessment, intraoperative complications, blood loss during resection, and amount of blood transfusions.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiagnostic characteristics\u003c/h3\u003e\n\u003cp\u003eCollected diagnostic characteristics will be: date and time of diagnosis of AL, clinical setting at time of leak diagnosis, antibiotics and nasogastric tube use, modalities applied to assess anastomotic integrity, and clinical, biochemical and intensive care unit parameters. The following leakage characteristics at diagnosis will be collected: radiological characteristics, intraoperative characteristics, location and estimated circumference.\u003c/p\u003e\n\u003ch3\u003eTreatment of anastomotic leakage\u003c/h3\u003e\n\u003cp\u003eDetails of all therapeutic modalities and strategies utilised will be collected, including primary, secondary, tertiary, and quarternary treatments: date and time of start treatment, need for re-admission, and (specification of) applied radiological, endoscopic, and surgical interventions.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up of treatment\u003c/h2\u003e \u003cp\u003eThe following characteristics will be collected to assess outcomes after leakage treatment: leak healing and modality that confirmed leak healing, date of initial hospital discharge, total length of intensive care unit stay, date of death (if applicable), recurrent colon cancer, stoma status, total number of radiological and surgical interventions within one year after colon cancer resection, adjuvant chemotherapy, and diagnosis of other complications with corresponding grading of severity. (24)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measures\u003c/h2\u003e \u003cp\u003eThe primary outcome is 90-day mortality, and the co-primary outcome is a composite endpoint of 90-day Clavien-Dindo grade 4\u0026ndash;5 complications. (24) Secondary outcomes include: length of hospital stay, length of intensive care unit stay, number of radiological and surgical reinterventions within one year after resection, mortality (in-hospital, 30-day, and 1 year), comprehensive complications index, and 1-year stoma-free survival. (25)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSample size calculation\u003c/h2\u003e \u003cp\u003eThis study is exploratory in nature, and its primary objective is to utilize a large detailed dataset to examine to what extent specific factors of AL are associated with the severity of the leakage and the impact of various treatment strategies on primary and secondary outcome parameters, with adjustment for relevant covariates.\u003c/p\u003e \u003cp\u003eTo establish a risk score comprising at least 12 candidate predictors, with a 10% incidence of 90-day mortality amongst AL patients following colon cancer resection and a root mean square percentage error of 5%, it is necessary to include 680 patients with AL. (26) However, to ensure robustness, to enable the development and validation of an evidence-based prediction model, and to create a solid foundation for future research related to AL, the aim is to include at least 2000 patients with AL following colon cancer resection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePilot study\u003c/h2\u003e \u003cp\u003eAfter the study protocol and online case report file (CRF) were developed, the international steering committee consisting of 15 experts on AL after colon cancer resection working across 11 different countries participated in the pilot test (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During pilot testing, the experts were asked to include at least 5 patients into the online CRF and to provide feedback on the protocol and online CRF. The feedback was evaluated by the study group, and used to refine the protocol and CRF in order to meet international standards and clarity on definitions and the use of the online CRF.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInternational steering committee TENTACLE \u0026ndash; Colon study.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMember\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHospital\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHans de Wilt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRadboudumc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNijmegen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThe Netherlands\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePieter Tanis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eErasmusMC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRotterdam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThe Netherlands\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRoel Hompes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAmsterdamumc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAmsterdam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThe Netherlands\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlbert Wolthuis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUZ Leuven\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLeuven\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBelgium\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKilian Brown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRoyal Prince Alfred Hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSydney\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAustralia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJ\u0026eacute;r\u0026eacute;mie Lefevre\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSorbonne Universit\u0026eacute;, AP-HP, H\u0026ocirc;pital Saint Antoine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eParis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMartin Ruteg\u0026aring;rd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUme\u0026aring; University\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUme\u0026aring;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSweden\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQuentin Denost\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinique Tivoli\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBordeaux\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNicolas Rotholtz\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHospital Alem\u0026aacute;n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBuenos Aires\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eArgentina\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThomas Pinkney\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUniversity of Birmingham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBirmingham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnited Kingdom\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRodrigo Perez\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHospital Alem\u0026atilde;o Oswaldo Cruz\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS\u0026atilde;o Paulo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSusan Gearhart\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJohns Hopkins Medicine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBaltimore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnited States of America\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTsuyoshi Konishi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe University of Texas MD Anderson Cancer Center\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAnderson\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnited States of America\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMatteo Frasson\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eValencia University Hospital La Fe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eValencia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSpain\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMuhammed Elhadi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFaculty of Medicine, University of Tripoli\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTripoli\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLibya\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eData handling and regulatory considerations\u003c/h2\u003e \u003cp\u003eThe Castor database system (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.castoredc.com/\u003c/span\u003e\u003cspan address=\"https://www.castoredc.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) will be used to collect data through online CRFs. Castor is an officially certified online medical research database system that fully complies with all pertinent regulations (i.e. GDPR, HIPAA, ICH-GCP, ISO 27001, ISO 9001, FDA 21 CFR part 11) and strictly adheres to international security standards. The CRF contains information points, definitions, and guidelines to facilitate accurate scoring of the specified parameters. The data entered will exclusively be visible to collaborators from the designated hospital, and access to the complete study database will be limited to coordinating investigators and principal investigators.\u003c/p\u003e \u003cp\u003eAll pseudonymized patient data will be entered by or under supervision of the treating physician(s). Each patient will be coded with a unique patient number before being entered into the database. The physician will keep a password-protected file that can identify individual patients, which will be locked away in their practice. This file can be accessed by the local investigators if needed, for example in case a relevant new research question requires entry of additional data into the database.\u003c/p\u003e \u003cp\u003eAll (up to 4) collaborators from the participating centres will receive an invitation to the Castor database along with step-by-step manuals and an online training module to ensure homogeneity in the inclusion process and during data entry, and to ensure that all eligible patients with AL within 90 days after colon cancer resection will be screened.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eData cleaning, verification and validation\u003c/h2\u003e \u003cp\u003eAfter a participating centre has finished data entry, the coordinating investigator will initiate data cleaning, verification and validation procedures to improve data completeness and to assess data quality and case ascertainment. Data cleaning will involve the use of algorithms to scrutinize the data for any missing values, data inconsistencies and typographical errors. All issues identified will be communicated to the respective local investigators enabling them to verify, adjust, or add the (missing) data. For data validation, data accuracy and case ascertainment will be assessed. Data accuracy will be assessed by cross-checking data recorded in Castor with medical records by a local independent validator. At random, 20% of the participating centres will be selected for data validation, wherein a subset of predefined key parameters of 10\u0026ndash;20% of the inclusions of a centre will be validated. Case ascertainment will be assessed to identify a systematic difference in the selection of patients per centre, defined as the proportion of included cases compared to the total amount of eligible cases. To assess case ascertainment, collaborators will be asked whether they entered data of all consecutive patients with an AL within the study period, or whether a sample was included (and if so; for which period). Furthermore, participating centres will be asked about their annual number of colon cancer resections. The AL rate was conservatively estimated at 3% for all years within the study period. (27) If the number of included cases is lower than the estimated number of cases, the collaborators will be asked to substantiate this discrepancy. For all procedures, a step-by-step manual as well as additional support will be available.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eData may be available upon reasonable request. Only collaborators with appropriate qualifications and pertinent research inquiries are eligible to request access to the data. The principal investigators of the TENTACLE \u0026ndash; Colon study will assess the relevance and appropriateness of the request and their verdict is decisive. If data will be transferred, it will only be conducted under the appropriate ethical and data transfer agreements.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical protocols have been drafted with an experienced biostatistician (M.v.G). These analytical strategies are in line with the previous TENTACLE \u0026ndash; Esophagus and TENTACLE \u0026ndash; Rectum projects. (18, 28\u0026ndash;30)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eMain study objective 1\u003c/h2\u003e \u003cp\u003eThe goal of this study is to identify predictive factors associated with 90-day mortality and the co-primary composite endpoint Clavien Dindo grade 4\u0026ndash;5 complications among patients who developed AL following colon cancer resection. Subsequently, a prediction model for these two endpoints will be developed with several clinically relevant patient, tumour, resection, diagnostic and leakage characteristics, and internally validated. The development and validation of the prediction models will be in agreement with the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis guidelines. (31) First, univariate analysis will be performed on parameters that are considered to be potentially relevant. These parameters will be entered into separate binary logistic regression models with 90-day mortality and Clavien Dindo grade 4\u0026ndash;5 as outcome parameters in order to explore associations in the data. Second, relevant parameters that are also considered to be clinically relevant based on literature and/or expert opinion will be selected for multivariate analysis. Backwards stepwise selection will be used to exclude variables with P values\u0026thinsp;\u0026gt;\u0026thinsp;0.05 from the model. Results will be presented as odds ratio with 95% confidence intervals (CI). A 2-tailed p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 will be considered statistically significant. Third, the multivariable models will be internally validated by bootstrapping, using 5000 bootstrap resamples. Finally, the models will be created based on the final bootstrapped multivariable regression analysis. The model will be incorporated in an online tool and will be made available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.tentaclestudy.com/\u003c/span\u003e\u003cspan address=\"https://www.tentaclestudy.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eIf the casemix is found to be strongly associated with outcome relative to the mortality score (to the extent that the mortality score is of limited value in the regression model), latent class analysis will be used. (32) The parameters used for the mortality score will be used to create casemix-corrected classes of AL severity.\u003c/p\u003e \u003cp\u003eSensitivity analysis will be performed in subgroups of patients undergoing various types of colectomies, and for different settings (e.g. elective, emergency) of colon cancer resection. These analyses will investigate whether the obtained model is useful for all types and settings of colon cancer resection. If substantial differences are observed between the initial and subgroup analyses, the possibility of composing different scoring systems will be considered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eMain study objective 2\u003c/h2\u003e \u003cp\u003eThe second main objective is to explore and compare the effectiveness of various treatment strategies for AL following colon cancer resection, adjusting for patient, tumour, resection and leakage characteristics.\u003c/p\u003e \u003cp\u003eRelevant treatment parameters identified in the first analysis will be considered independent variables in this analysis. The association between characteristics of colon cancer resection, AL, and outcome measures (e.g. 90-day mortality) will be evaluated for the exposures in regression analysis. Where appropriate, statistical adjustment using propensity score methods for patient, tumour, resection, and/or leakage characteristics, as well as timing, potential delay and clinical setting of AL diagnosis will be performed.\u003c/p\u003e \u003cp\u003eBased on the results of this analysis, subgroups of patients will be created based on individual resection or leakage characteristics (or a combination of these). The efficacy of AL treatment strategies will be assessed in regression models for the different outcome parameters and adjusted for patient, tumour, resection and leakage characteristics, where appropriate. All analyses for objective 2 will be conducted using modified Poisson regression, with results expressed as risk ratios with corresponding 95% confidence intervals.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eEthical considerations\u003c/h2\u003e \u003cp\u003e This study will be conducted in compliance with the principles of the declaration of Helsinki. The medical ethical committee of the Radboud university medical centre in Nijmegen, The Netherlands, has thoroughly reviewed all documents, including the study protocol and granted approval (file number: 2024\u0026ndash;17491). The need for central informed consent was waived, but local ethical requirements may differ per geographical region, country, or hospital. The study protocol and relevant documents will be provided to all participating centres in case the centres need local ethical approval. The TENTACLE \u0026ndash; Colon study is registered on Clinicaltrial.gov (NCT 06528054). The study protocol and the letter of ethical approval is also available on the website: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.tentaclestudy.com/\u003c/span\u003e\u003cspan address=\"https://www.tentaclestudy.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003ePublications\u003c/h2\u003e \u003cp\u003eThe TENTACLE study team aims to publish two main manuscripts covering the main objectives. These manuscripts will be submitted to peer-reviewed journals. All members of the international steering committee are fully involved in conducting this study and will be included as (co-)authors in the publications. All (up to) 4 collaborators and local independent validator (if applicable) will be granted (PubMed-citable) corporate authorship under the name \u0026lsquo;the TENTACLE \u0026ndash; Colon Collaborative Group\u0026rsquo; in all manuscripts using data of the TENTACLE \u0026ndash; Colon study. The affiliation information of the collaborators will be the hospital whose patients were included.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAnastomotic leakage (AL) remains a common and severe complication after colon cancer resection. Most research to date has focused on the prevention and prediction of AL, but large comparative studies evaluating various treatment modalities for AL are scarce. (33\u0026ndash;35) As a result, the optimal treatment of AL after colon cancer resection and the subsequent important clinical outcomes remain largely unknown. There are several explanations for this knowledge gap. Treatment of AL is generally chosen on a case-by-case basis, depending on several patient and resection characteristics, and is influenced by the preferences and expertise of the treating surgeon. More specifically, AL is a heterogeneous and highly complex complication, which is likely to hamper the initiation of standardized institutional treatment protocols and the design of prospective studies. Furthermore, the diverse clinical presentation and wide variety of treatment approaches complicates the interpretation and generalizability of small underpowered studies.\u003c/p\u003e \u003cp\u003eThe TENTACLE \u0026ndash; Colon study aims to address this knowledge gap and will therefore provide valuable insights into the severity and treatment of AL after colon cancer resection. This global effort, combined with detailed data collection, will facilitate robust (comparative) analyses and the results can provide a solid basis for evidence-based and personalized treatment decisions. The international success of the previous TENTACLE studies in esophageal and rectal cancer surgery underscores the relevance, feasibility and importance of the current study. (18, 28, 29, 36)\u003c/p\u003e \u003cp\u003eThe main strengths of the present study are the high level of detail of the data collected and the large number of planned patient inclusions. This large cohort is needed to perform regression analyses with various patient, tumour, resection and leakage characteristics to explore and identify distinct clinical presentations of colonic AL. For each clinical presentation, relevant subgroup analyses can be performed to compare relevant treatment strategies. The inclusion of a large cohort is feasible due to the international collaborative design of the current study, which increases the generalizability of findings across various populations. A pilot study was conducted among core collaborators from diverse continents to ensure that the online CRF includes parameters relevant to various geographical regions along with clear definitions.\u003c/p\u003e \u003cp\u003eThe main limitation is the retrospective design of the study. A prospective design was not considered feasible due to logistical reasons and the need to include a large cohort, while AL occurs in no more than 8.4% of patients. (1) However, the results of this study will be hypothesis generating, and this knowledge can be used to guide the design process of future prospective studies. Another limitation is the risk of confounding by indication, as patients receiving certain treatments may be inherently different from those receiving other treatments. In this study, regression analysis using sophisticated statistical techniques to account for confounding of detailed data within a large cohort should mitigate much of this expected confounding. However, residual confounding may occur if the regression analysis cannot adequately adjust for all confounding factors. Finally, given the international and collaborative nature of the study, there is a risk of selection bias as not all centres worldwide will be collaborating. This may bias the dataset towards patients from more scientifically invested centres, which may limit generalizability to some extent.\u003c/p\u003e \u003cp\u003eFor current clinical practice, the results of the TENTACLE \u0026ndash; Colon study could have an impact on management of AL. The prediction model (i.e. the first main objective) will indicate the severity of AL in terms of mortality by considering patient, tumour, resection and leakage characteristics. Clinicians can use this model to distinguish patients at high risk of mortality from those at low risk. This is useful because the severity of AL is nowadays classified by how it is treated, but this classification can, by definition, not be used to prospectively guide clinical decision-making. (24) Furthermore, the evaluation of treatment strategies (i.e. the second main objective) for different subgroups of AL might indicate the best treatment strategy for each distinct clinical presentation. Currently, patients can be treated with a wide range of treatment modalities, mainly due to the lack of evidence to support a specific modality for a specific clinical presentation of AL. Therefore, clinicians can use the prediction model and insights from the treatment evaluations of different clinical presentations to faciliate evidence-based and personalized treatment decision-making when AL is diagnosed.\u003c/p\u003e \u003cp\u003eIn conclusion, the TENTACLE \u0026ndash; Colon study is a large international multicentre collaborative study aiming to investigate which factors contribute to the severity of AL, and to evaluate treatment efficacy of different clinical presentations of AL. This study will be an important step towards evidence-based and personalized management of AL, which may improve patient outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAL; anastomotic leakage.\u003c/p\u003e\n\u003cp\u003eCT; computed tomography.\u003c/p\u003e\n\u003cp\u003eCRF: case report file.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eEthics\u003c/u\u003e\u003cstrong\u003e:\u003c/strong\u003e The study protocol and relevant documents have been approved by the medical ethical committee of the Radboud University Medical Center, Nijmegen, the Netherlands (file number: 2024-17491). The official (Dutch) name of this medical ethical committee is METC Oost-Nederland. The need for central informed consent was waived, but local ethical requirements may differ per geographical region, country or hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent for publication\u003c/u\u003e: All listed authors have approved this version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eData availability\u003c/u\u003e: Data may be available upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCOI\u003c/u\u003e\u003cstrong\u003e:\u003c/strong\u003e The authors declare to have no conflicts of interest with regard to the present manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding\u003c/u\u003e\u003cstrong\u003e:\u003c/strong\u003e The TENTACLE \u0026ndash; Colon study is not funded.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAcknowlegdements:\u003c/u\u003e none.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStudy registration:\u003c/u\u003e This study is registered at clinicaltrials.gov (NCT 06528054) since July 30\u003csup\u003eth\u003c/sup\u003e, 2024.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthor contributions:\u003c/u\u003e Jobbe M.G. Lemmens, Sander Ubels, Nynke G. Greijdanus, Kiedo Wienholts, Marleen M.H.J. van Gelder, Albert Wolthuis, J\u0026eacute;r\u0026eacute;mie H. Lefevre, Kilian Brown, Matteo Frasson, Nicolas Rotholtz, Quentin Denost, Rodrigo O. Perez, Tsuyoshi Konishi, Martin Ruteg\u0026aring;rd, Susan L. Gearhart, Thomas Pinkney, Muhammed Elhadi, and Roel Hompes: designing the study, writing manuscript, critically revising the manuscript, and final approval given. Pieter J. Tanis and Johannes H.W. de Wilt; designing the study, writing manuscript, critically revising the manuscript, supervising the study, and final approval given.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eArron MNN, Greijdanus NG, Ten Broek RPG, Dekker JWT, van Workum F, van Goor H, et al. Trends in risk factors of anastomotic leakage after colorectal cancer surgery (2011-2019): A Dutch population-based study. Colorectal Dis. 2021;23(12):3251-61.\u003c/li\u003e\n\u003cli\u003eHewett PJ, Allardyce RA, Bagshaw PF, Frampton CM, Frizelle FA, Rieger NA, et al. Short-term outcomes of the Australasian randomized clinical study comparing laparoscopic and conventional open surgical treatments for colon cancer: the ALCCaS trial. Ann Surg. 2008;248(5):728-38.\u003c/li\u003e\n\u003cli\u003eKehlet H, Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery. Ann Surg. 2008;248(2):189-98.\u003c/li\u003e\n\u003cli\u003eHohenberger W, Weber K, Matzel K, Papadopoulos T, Merkel S. Standardized surgery for colonic cancer: complete mesocolic excision and central ligation--technical notes and outcome. Colorectal Dis. 2009;11(4):354-64; discussion 64-5.\u003c/li\u003e\n\u003cli\u003eFrasson M, Flor-Lorente B, Rodriguez JL, Granero-Castro P, Hervas D, Alvarez Rico MA, et al. Risk Factors for Anastomotic Leak After Colon Resection for Cancer: Multivariate Analysis and Nomogram From a Multicentric, Prospective, National Study With 3193 Patients. Ann Surg. 2015;262(2):321-30.\u003c/li\u003e\n\u003cli\u003eWeber MC, Berlet M, Stoess C, Reischl S, Wilhelm D, Friess H, et al. A nationwide population-based study on the clinical and economic burden of anastomotic leakage in colorectal surgery. Langenbecks Arch Surg. 2023;408(1):55.\u003c/li\u003e\n\u003cli\u003eDaams F, Luyer M, Lange JF. Colorectal anastomotic leakage: aspects of prevention, detection and treatment. World J Gastroenterol. 2013;19(15):2293-7.\u003c/li\u003e\n\u003cli\u003eden Dulk M, Noter SL, Hendriks ER, Brouwers MA, van der Vlies CH, Oostenbroek RJ, et al. Improved diagnosis and treatment of anastomotic leakage after colorectal surgery. Eur J Surg Oncol. 2009;35(4):420-6.\u003c/li\u003e\n\u003cli\u003eCollaborative EESA. ESCP Safe Anastomosis ProGramme in CoLorectal SurgEry (EAGLE): Study protocol for an international cluster randomised trial of a quality improvement intervention to reduce anastomotic leak following right colectomy. Colorectal Dis. 2021;23(10):2761-71.\u003c/li\u003e\n\u003cli\u003eBuchs NC, Gervaz P, Secic M, Bucher P, Mugnier-Konrad B, Morel P. Incidence, consequences, and risk factors for anastomotic dehiscence after colorectal surgery: a prospective monocentric study. Int J Colorectal Dis. 2008;23(3):265-70.\u003c/li\u003e\n\u003cli\u003eKrarup PM, Nordholm-Carstensen A, Jorgensen LN, Harling H. Anastomotic leak increases distant recurrence and long-term mortality after curative resection for colonic cancer: a nationwide cohort study. Ann Surg. 2014;259(5):930-8.\u003c/li\u003e\n\u003cli\u003eTurrentine FE, Denlinger CE, Simpson VB, Garwood RA, Guerlain S, Agrawal A, et al. Morbidity, mortality, cost, and survival estimates of gastrointestinal anastomotic leaks. J Am Coll Surg. 2015;220(2):195-206.\u003c/li\u003e\n\u003cli\u003eBrown SR, Mathew R, Keding A, Marshall HC, Brown JM, Jayne DG. The impact of postoperative complications on long-term quality of life after curative colorectal cancer surgery. Ann Surg. 2014;259(5):916-23.\u003c/li\u003e\n\u003cli\u003eKube R, Mroczkowski P, Granowski D, Benedix F, Sahm M, Schmidt U, et al. Anastomotic leakage after colon cancer surgery: a predictor of significant morbidity and hospital mortality, and diminished tumour-free survival. Eur J Surg Oncol. 2010;36(2):120-4.\u003c/li\u003e\n\u003cli\u003eAlves A, Panis Y, Trancart D, Regimbeau JM, Pocard M, Valleur P. Factors associated with clinically significant anastomotic leakage after large bowel resection: multivariate analysis of 707 patients. World J Surg. 2002;26(4):499-502.\u003c/li\u003e\n\u003cli\u003eArron MNN, Greijdanus NG, Bastiaans S, Vissers PAJ, Verhoeven RHA, Ten Broek RPG, et al. Long-Term Oncological Outcomes After Colorectal Anastomotic Leakage: A Retrospective Dutch Population-based Study. Ann Surg. 2022;276(5):882-9.\u003c/li\u003e\n\u003cli\u003eGao P, Huang XZ, Song YX, Sun JX, Chen XW, Sun Y, et al. Impact of timing of adjuvant chemotherapy on survival in stage III colon cancer: a population-based study. BMC Cancer. 2018;18(1):234.\u003c/li\u003e\n\u003cli\u003eGreijdanus NG, Wienholts K, Ubels S, Talboom K, Hannink G, Wolthuis A, et al. Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort. Ann Surg. 2023;278(5):772-80.\u003c/li\u003e\n\u003cli\u003eOzmen I, Grupa VEM, Bedrikovetski S, Dudi-Venkata NN, Huisman DE, Reudink M, et al. Risk Nomogram Does Not Predict Anastomotic Leakage After Colon Surgery Accurately: Results of the Multi-center LekCheck Study. Journal of Gastrointestinal Surgery. 2022;26(4):900-10.\u003c/li\u003e\n\u003cli\u003eHedrick TL, Kane W. Management of Acute Anastomotic Leaks. Clin Colon Rectal Surg. 2021;34(6):400-5.\u003c/li\u003e\n\u003cli\u003ePhitayakorn R, Delaney CP, Reynolds HL, Champagne BJ, Heriot AG, Neary P, et al. Standardized algorithms for management of anastomotic leaks and related abdominal and pelvic abscesses after colorectal surgery. World J Surg. 2008;32(6):1147-56.\u003c/li\u003e\n\u003cli\u003eBlumetti J, Chaudhry V, Cintron JR, Park JJ, Marecik S, Harrison JL, et al. Management of anastomotic leak: lessons learned from a large colon and rectal surgery training program. World J Surg. 2014;38(4):985-91.\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Souza N, Lord A, Shaw A, Patel A, Balyasnikova S, Tudyka V, et al. The sigmoid take-off: An anatomical imaging definition of the rectum validated on specimen analysis. Eur J Surg Oncol. 2020;46(9):1668-72.\u003c/li\u003e\n\u003cli\u003eDindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205-13.\u003c/li\u003e\n\u003cli\u003eSlankamenac K, Graf R, Barkun J, Puhan MA, Clavien PA. The comprehensive complication index: a novel continuous scale to measure surgical morbidity. Ann Surg. 2013;258(1):1-7.\u003c/li\u003e\n\u003cli\u003eRiley RD, Ensor J, Snell KIE, Harrell FE, Jr., Martin GP, Reitsma JB, et al. Calculating the sample size required for developing a clinical prediction model. Bmj. 2020;368:m441.\u003c/li\u003e\n\u003cli\u003eDCRA. Dutch ColoRectal Audit 2024 [Available from: https://dica.nl/registratie/darmkanker-dcra/.\u003c/li\u003e\n\u003cli\u003eUbels S, Verstegen M, Klarenbeek B, Bouwense S, van Berge Henegouwen M, Daams F, et al. Severity of oEsophageal Anastomotic Leak in patients after oesophagectomy: the SEAL score. Br J Surg. 2022;109(9):864-71.\u003c/li\u003e\n\u003cli\u003eUbels S, Verstegen MHP, Klarenbeek BR, Bouwense S, van Berge Henegouwen MI, Daams F, et al. Treatment of anastomotic leak after oesophagectomy for oesophageal cancer: large, collaborative, observational TENTACLE cohort study. Br J Surg. 2023;110(7):852-63.\u003c/li\u003e\n\u003cli\u003evan Workum F, Talboom K, Hannink G, Wolthuis A, de Lacy BF, Lefevre JH, et al. Treatment of anastomotic leakage after rectal cancer resection: The TENTACLE-Rectum study. Colorectal Dis. 2021;23(4):982-8.\u003c/li\u003e\n\u003cli\u003eCollins GS, Reitsma JB, Altman DG, Moons KG. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. Bmj. 2015;350:g7594.\u003c/li\u003e\n\u003cli\u003eRabe-Hesketh S, Skrondal A. Classical latent variable models for medical research. Stat Methods Med Res. 2008;17(1):5-32.\u003c/li\u003e\n\u003cli\u003eCastagneto-Gissey L, Russo MF, Casella-Mariolo J, Serao A, Marcellinaro R, D\u0026apos;Andrea V, et al. The Role of Antibiotic Prophylaxis in Anastomotic Leak Prevention during Elective Colorectal Surgery: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Antibiotics (Basel). 2023;12(2).\u003c/li\u003e\n\u003cli\u003eLitchinko A, Buchs N, Balaphas A, Toso C, Liot E, Meurette G, et al. Score prediction of anastomotic leak in colorectal surgery: a systematic review. Surg Endosc. 2024;38(4):1723-30.\u003c/li\u003e\n\u003cli\u003eDias VE, Castro P, Padilha HT, Pillar LV, Godinho LBR, Tinoco ACA, et al. Preoperative risk factors associated with anastomotic leakage after colectomy for colorectal cancer: a systematic review and meta-analysis. Rev Col Bras Cir. 2022;49:e20223363.\u003c/li\u003e\n\u003cli\u003eGreijdanus NG, Wienholts K, Ubels S, Talboom K, Hannink G, Wolthuis A, et al. Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients. Br J Surg. 2023;110(12):1863-76.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bsur","sideBox":"Learn more about [BMC Surgery](http://bmcsurg.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bsur/default.aspx","title":"BMC Surgery","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"treatment, severity, anastomotic leakage, colon cancer resection","lastPublishedDoi":"10.21203/rs.3.rs-6220619/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6220619/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAnastomotic leakage (AL) is a common and severe complication after colon cancer resection, but studies investigating various treatment strategies and factors influencing outcomes are scarce.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003e(1) To identify predictive factors associated with 90-day mortality and 90-day Clavien-Dindo grade 4\u0026ndash;5 complications amongst patients who developed AL following colon cancer resection with subsequent development and validation of prediction models, and (2) to explore and compare the effectiveness of various treatment strategies for AL following colon cancer resection, adjusting for type of index surgery, different leak entities and patient factors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe TENTACLE \u0026ndash; Colon is an international multicentre retrospective cohort study. Consecutive patients with AL after colon cancer resection operated between 1 January 2018 and 31 December 2022 from participating centres will be included. The planned sample size is 2000 patients. The primary outcome is 90-day mortality and the co-primary composite endpoint is Clavien-Dindo grade 4\u0026ndash;5 complications. Secondary outcomes include: hospital and intensive care unit length of stay, number of radiological and surgical reinterventions within one year after resection, mortality (in-hospital, 30-day, and 1-year), the comprehensive complication index, and 1-year stoma-free survival. For objective 1, regression models will be used to identify predictors associated with 90-day mortality and grade 4\u0026ndash;5 complications. For objective 2, comparative analyses of various treatment strategies will be performed for the specified outcomes, adjusting for patient, tumour, resection and leakage characteristics.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe TENTACLE \u0026ndash; Colon study will be an important step towards evidence-based and personalized treatment of anastomotic leakage after colon cancer resection, potentially improving patient outcomes.\u003c/p\u003e","manuscriptTitle":"TreatmENT of AnastomotiC LeakagE after colon cancer resection: the TENTACLE – Colon study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-31 12:29:12","doi":"10.21203/rs.3.rs-6220619/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-04T18:09:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-04T16:45:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-27T07:59:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-27T05:06:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"258345505545230096787719396148732230525","date":"2025-03-24T14:53:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"184776989614601374581643974826991526864","date":"2025-03-23T15:31:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"161150316335967839783466987376134674069","date":"2025-03-22T15:51:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"70539732285447474438116890373775962249","date":"2025-03-22T00:52:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-21T14:54:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-21T03:52:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-21T03:50:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Surgery","date":"2025-03-13T13:30:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bsur","sideBox":"Learn more about [BMC Surgery](http://bmcsurg.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bsur/default.aspx","title":"BMC Surgery","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d5c8cb5a-fca1-4097-9c8a-68a4e5f2c5a3","owner":[],"postedDate":"March 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-19T15:59:27+00:00","versionOfRecord":{"articleIdentity":"rs-6220619","link":"https://doi.org/10.1186/s12893-025-02954-1","journal":{"identity":"bmc-surgery","isVorOnly":false,"title":"BMC Surgery"},"publishedOn":"2025-05-15 15:57:12","publishedOnDateReadable":"May 15th, 2025"},"versionCreatedAt":"2025-03-31 12:29:12","video":"","vorDoi":"10.1186/s12893-025-02954-1","vorDoiUrl":"https://doi.org/10.1186/s12893-025-02954-1","workflowStages":[]},"version":"v1","identity":"rs-6220619","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6220619","identity":"rs-6220619","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}