{"paper_id":"44f8aee5-324d-4cf9-951b-a0f2dab34a85","body_text":"Multimodal prehabilitation for colorectal cancer patients: study protocol of a nationwide multicentre study with uniform prehabilitation protocols | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Multimodal prehabilitation for colorectal cancer patients: study protocol of a nationwide multicentre study with uniform prehabilitation protocols C. R. Sabajo, J. P. Dieleman, J. W. Dekker, B. Heuvel, J. M. Klaase, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4000534/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The aim of prehabilitation is to optimize patient specific modifiable risk factors before major surgery, in order to enhance the individual resilience. In recent years, a considerable amount of research has been done on the effectiveness of prehabilitation. Due to the lack of universal guidelines, prehabilitation has been conducted in various ways, making it difficult to estimate its effect. In the Netherlands, proposed uniform prehabilitation protocols were developed. The aim of this study is to analyse clinical outcomes of prehabilitation when implemented as standard of care according to the proposed uniform protocols. Methods Uniform prehabilitation protocols were created based on the multimodal program of the PREHAB randomized controlled trial. All hospitals in the Netherlands that implemented prehabilitation according to the proposed protocols, for patients undergoing elective colorectal surgery, will be asked to participate. This study will recruit 535 patients who underwent prehabilitation and 535 one-to-one nearest neighbour propensity score matched patients who did not undergo prehabilitation (historical cohort). Clinical outcomes will be compared between the prehabilitation group and the historical cohort group using regression analyses. The primary outcome of interest is 90-day presence of postoperative complications. In addition, length of hospital stay and readmissions will be analysed. Discussion Prehabilitation has been proven to reduce the risk of complications and hospital length of stay. Prehabilitation has however been defined in various ways, since there is no standardized program. This multicentre cohort study will estimate the clinical effect of prehabilitation implemented as standard of care according to proposed uniform protocols. Furthermore, the presented protocols can be used by other hospitals to set up a prehabilitation program. colorectal cancer colorectal surgery prehabilitation uniform guidelines Background Prehabilitation is designed to enhance a patient's physical condition prior to a major surgery, resulting in faster recovery and fewer complications. The fitter the patient is before surgery, the greater the chance of a better outcome ( 1 , 2 ). The prehabilitation program is tailored to the individual and includes physical training, customized nutrition, mental support, comorbidities (e.g. diabetes) and anaemia optimization, and smoking and alcohol cessation. While it has been demonstrated that a patient's functional capacity can be improved through prehabilitation ( 3 , 4 ) it is not yet clear to what extent prehabilitation actually improves surgical outcomes. Due to the lack of uniform guidelines, the prehabilitation program has been implemented in different forms. In some studies, aerobic exercise in combination with resistance training was offered as prehabilitation ( 5 – 7 ) while in another study only yoga was offered ( 8 ). Several systematic reviews also found a lot of heterogeneity within prehabilitation studies ( 9 – 11 ). This heterogeneity makes it difficult to compare results between studies and depicts the need to develop uniform guidelines. With the international randomized controlled PREHAB study ( 12 ), the development of proposed uniform guidelines had begun. The protocol has for example been used as a blueprint for other studies. In the Netherlands, the Dutch Society of Surgery developed uniform prehabilitation protocols based on the international PREHAB RCT ( 12 ). These proposed uniform protocols were assessed and adjusted by relevant scientific associations of sport medicine, anaesthesiology, surgery, internal medicine, geriatrics, medical psychology, physical therapy and nutritionists. Furthermore, anaemia screening and management was added. The proposed protocols were created to ensure the quality of prehabilitation programs in the Netherlands, to eventually evaluate outcomes of prehabilitation in a bigger population, and to evaluate the feasibility of implementing such a program. The proposed uniform protocols describe the core points of the prehabilitation program for patients with colorectal cancer (CRC). They can be used by other hospitals, inside and outside the Netherlands, to set up prehabilitation. This paper describes the proposed uniform protocols created by the Dutch Society of Surgery and study protocol to evaluate its clinical effects. The study includes a nationwide multicentre study, which aims to evaluate clinical outcomes of prehabilitation when implemented as standard care, using the presented proposed uniform protocols. Also, length of stay and readmissions will be analysed. Methods This nationwide multicentre observational cohort study will be conducted in several hospitals in the Netherlands that implemented the proposed uniform protocols and followed prehabilitation training facilitated by Maxima Medical Centre (MMC) and the foundation Fit4Surgery. The Medical Ethics Committee of the Medical University of Groningen, issued the statement that this was not a WMO study under the reference number 2022/079. Study population Adult patients undergoing elective colorectal resection for cancer and participating in the prehabilitation program are eligible for inclusion into the intervention cohort. Patients from the same hospital but from 2 years before implementation of the proposed uniform protocols, will be eligible for inclusion into the reference cohort. The intervention and reference cohort will be matched one-to-one based on propensity scores. Informed consent and data All patients who underwent a prehabilitation program in one of the participating centres will be asked for informed consent. Based on local institutional review boards, patients will either be included upon providing written informed consent or upon applying the general opt-out procedure. From every participating hospital, a historical cohort will be included to match with the prehabilitation group. The reference cohort will comprise patients from 2 years before when prehabilitation was not yet implemented in the respective hospital. For both groups, data on patient characteristics, tumour and clinical outcome will be obtained from a nationwide quality registration database, the Dutch ColoRectal Audit (DCRA). The collected prehabilitation data will be combined with the DCRA data, based on date of birth, sex and operation date from the patient. The prehabilitation program The prehabilitation program as described by the proposed uniform protocols includes the following five modalities: Physical fitness Nutritional status Mental resilience Comorbidity, anaemia, and frailty Intoxications The prehabilitation program should last at least 3–4 weeks to see an effect from the program. A longer prehabilitation period does not seem to have a negative effect on oncological treatment ( 13 , 14 ). If a patient can undergo surgery before the prehabilitation program is completed, it is preferable to complete the prehabilitation program first. Also after the surgery a healthy lifestyle is encouraged. A visit to a physiotherapist postoperatively (> 6 weeks) is preferred, where physical fitness measurements are repeated. Ideally, prehabilitation should be linked to rehabilitation, and these should be well integrated. The flow chart in Appendix 1 shows the framework of screening, assessment, intervention, and re-assessment for each modality in the prehabilitation program. Shared decision-making is an integral part of all steps in the prehabilitation process. Interventions (according to the proposed uniform protocols) A more detailed overview of the interventions can be found in the appendices. 1. Physical fitness (Appendix 2) a. Endurance training: Three times a week supervised high-intensity interval training (HIIT) under the supervision of an (oncological) physiotherapist. Low-intensity training at home on the other days. The training program is individualized and is based on the initial physical fitness assessment. 2. Nutritional status (Appendix 3) a. Nutritional consultation with a dietitian: Aim for 1.2–1.5 grams of protein per kg of body weight per day and energy intake according to calculated energy needs. Protein supplementation or medical nutrition can be used to achieve recommendations. Supplementation of vitamins and minerals is recommended. 3. Mental resilience (Appendix 4) a. Providing information to the patient, taking into account the patient's health literacy, e.g. by a case manager. b. Psychological support: Consultation with case manager or specialized nurse. Referral to a medical psychologist in case of anxiety or depression. 4. Comorbidity, anaemia, and frailty (Appendix 5 and 6) a. Blood sugar level: Measure HbA1c. Refer patients without diabetes with a threshold value > 42 mmol/mol (6%) to GP/internist. Refer patients with non-insulin-dependent diabetes with a threshold value > 53 mmol/mol to GP/diabetes nurse. b. Anaemia: Optimize haemoglobin levels if the value is < 8.0 mmol/L in men and < 7.5 mmol/L in women. Optimize iron deficiency preferably with intravenous treatment (Appendix 6). c. Frailty: Referral to a geriatrician in case of frailty based on, for example, the Groningen Frailty Indicator, G8 questionnaire, 6CIT questionnaire, and/or MiniCog or if a delirium has occurred previously. 5. Intoxications (Appendix 7): Support for smoking cessation and cessation of other addictive substances. Study outcomes The primary outcome will be 90-day postoperative complications. This will be graded according to Dindo et al.( 15 ) and defined as presence or absence of any complication. Complications will also be scored with the Comprehensive Complication Index (CCI) ( 16 ). A CCI > 20 will be labelled as a severe complication. Secondary outcomes will be length of hospital stay and readmissions. Data on study outcomes is available in the DCRA database, which is a national mandatory audit. Prehabilitation data, for example start date of prehabilitation, number of training days, and outcomes of physical tests, will be collected separately and combined with the data from the DCRA. Statistical analysis A sample size calculation was made based on multiple logistic regression analysis for presence of post-operative complications within the 90 postoperative days. Age, ASA score, Charlson Comorbidity score, BMI and tumour location will be considered as potential confounders. For the sample size calculation the effect size was based on the PREHAB study ( 12 ), with a two-sided p-value for significance of 0.05 and a desired power of 80%. To show a reduction in overall complication rate from 42.2–31.7% (odds ratio (OR) = 0.62) and being able to adjust for the above confounding factors, 535 patients are needed in each group, resulting in a total required study population of 1070 patients. Propensity scores will be calculated using multiple logistic regression analysis including the aforementioned confounders as the independent variables and prehabilitation (yes/no) as the dependent variable. The resulting probabilities will be used to match each patient in the prehabilitation cohort with its nearest neighbour in the reference cohort. In case of multiple matches, a reference patient will be randomly selected. The effect of larger distances will be explored in sensitivity analyses. Baseline characteristics and clinical outcomes will be presented for the prehabilitation and reference cohort. Continuous variables will be presented as median with interquartile range (IQR) and will be tested using the Mann–Whitney U test. Categorical variables will be presented as number per category with percentages and will be analysed using the Chi-square or Fishers’ exact test as appropriate. To calculate ORs and regression coefficients with 95%-confidence intervals (95%CI), logistic and linear regression analyses will be used. Data will be analysed on an intention-to-treat basis. Per protocol analyses excluding patients who underwent insufficient prehabilitation will be done to explore the effect of prehabilitation compliance. The amount of missing data will be compared between the two study cohorts; baseline characteristics will be compared between patients with and without missing’s to explore the possibility and direction of bias through missing’s. Discussion This multicentre cohort study will include real-world data from hospitals in the Netherlands, where prehabilitation has been implemented according to the proposed uniform protocols for CRC patients and if hospitals followed the prehabilitation training provided by MMC and the foundation Fit4Surgery. Over the years, an increasing number of studies have been performed to evaluate the effect of prehabilitation. Several small trials showed less complications and/or reduced hospital length of stay due to prehabilitation ( 4 – 6 , 17 ). In addition, Barberan et al. ( 18 ) performed a RCT using a structured program, and showed that prehabilitation was a protective factor for postoperative complications in 76 CRC patients that underwent elective surgery. Klerk et al. ( 19 ) performed an RCT also with a standard program, in patients undergoing elective resection for CRC. They showed that prehabilitation significantly reduced overall postoperative medical complications, unplanned readmissions, and the median length of hospital stay. Berkel et al. ( 20 ) showed an almost 50% decrease in the incidence of postoperative complications due to prehabilitation for CRC patients in a selected group of patients with high risk of complications (anaerobic threshold < 11 ml/kg/min). Heil et al. also found in their emulated target trial a relevant reduction of complications and length of hospital stay in patients with a higher postoperative complication risk ( 21 ). The international PREHAB trial used an uniform multimodal program in both high risk and non-high risk patients and showed significantly lower severe complications, and medical complications in the prehabilitation group ( 12 ). In contrast to these previous studies, which performed prehabilitation in a study setting, outcomes of a prehabilitation program implemented as standard of care for CRC patients are still lacking. This study will therefore evaluate the outcomes of proposed uniform protocols for a multimodal prehabilitation program for CRC resections when implemented as standard of care throughout multiple hospitals in the Netherlands. Therefore, the provided uniform guidelines were created to enhance standardization and uniformity of the program. Prehabilitation is a multidisciplinary intervention, which can make it difficult to implement the program within a hospital. The proposed protocols might help hospitals to implement prehabilitation, since all involved interventions are described in detail. Hospitals in the Netherlands will receive training in how to implement prehabilitation with an optional additional training for physiotherapists. Hospitals can get reimbursement through the “Innovation Rule” initiated by the Dutch health Authorities (NZa) depending on the insurance company. In comparison to the protocol used in the PREHAB trial ( 12 ), optimization of anaemia has been added. The LekCheck study found that low preoperative haemoglobin was the most important factor involved in the development of an anastomotic leakage ( 22 ). Also, Berkel et al. found that a lower preoperative haemoglobin level was a risk for the development of complications ( 20 ). Furthermore, the FIT trial found that with the treatment of intravenous iron deficiency a significant improvement was seen in the preoperative haemoglobin level ( 23 ). Subsequently, the optimization of anaemia with intravenous iron was added to the proposed uniform protocols. Due to its nature, this study is a non-randomized, non-blinded study. However, since prehabilitation is, and will be, implemented as standard of care, data will be real-world data. Given the promising results of prehabilitation, a RCT is no longer suitable. It would not be ethical to withhold high-intensity training, mental support and nutritional, frailty and anaemia screening, assessment and interventions from patients. This paper presents the first standardized proposed uniform protocols for prehabilitation for CRC patients who will undergo elective surgery. The program consists of supervised high-intensity training, nutritional assessment with protein and vitamin supplements, mental health support, assessment of comorbidities and frailty, anaemia screening and optimization and cessation of smoking. Further, this paper presents the protocol of a nationwide multicentre study, which aims to evaluate clinical outcomes of prehabilitation when implemented as standard care, using the proposed uniform protocols. List of abbreviations 1RM One repetition maximum 6CIT Six-Item Cognitive Impairment test CCI Comprehensive Complication Index CGA Comprehensive geriatric assessment CPET Cardiopulmonary exercise testing CRC Colorectal Cancer DCRA Dutch ColoRectal Audit HADS Hospital Anxiety and Depression Scale HIIT High-intensity interval training HRmax Maximum heart rate iSWT Incremental shuttle walk test IQR Interquartile range MET Metabolic equivalents MMC Maxima Medical Centre NZa Dutch health Authorities PG-SGA Patient Generated Subjective Global Assessment RCT Randomised controlled trial SRT Steep Ramp Test VO2max Maximal oxygen consumption VSAQ Veterans-specific activity questionnaire Wpeak Peak power output Declarations Ethics approval The Medical Ethics Committee of the Medical University of Groningen approved this study. Availability of data and materials The data regarding clinical outcomes supporting the findings of this study are available on the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding None Authors' contributions CS conceptualised the study with input from GS and JK. CS wrote the first draft and JD, BH, GS and JM critically contributed to and refined this manuscript. All authors have read and approved the final manuscript. 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Levett D, Grimmett C. Psychological factors, prehabilitation and surgical outcomes: evidence and future directions. Anaesthesia 2019;74:36-42. Tsimopoulou I, Pasquali S, Howard R, Desai A, Gourevitch D, Tolosa I, et al. Psychological prehabilitation before cancer surgery: a systematic review. Annals of surgical oncology 2015;22:4117-4123. Thomas G, Tahir MR, Bongers BC, Kallen VL. A systematic review of randomised controlled trials. Eur J Anaesthesio 2019;36:933-945. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. The lancet 2013;381(9868):752-762. Cesari M, Marzetti E, Canevelli M, Guaraldi G. Geriatric syndromes: How to treat. Virulence 2017;8(5):577-585. Epstein AM, Hall JA, Besdine R, EDWARD Jr C, Feldstein M, McNEIL BJ, et al. The emergence of geriatric assessment units: the\" new technology of geriatrics\". Ann Intern Med 1987;106(2):299-303. Stuck AE, Siu AL, Wieland GD, Rubenstein LZ, Adams J. Comprehensive geriatric assessment: a meta-analysis of controlled trials. The Lancet 1993;342(8878):1032-1036. Feinstein AR. The pre-therapeutic classification of co-morbidity in chronic disease. J Chronic Dis 1970;23(7):455-468. Wilson MJ, Dekker JW, Bruns E, Borstlap W, Jeekel J, Zwaginga JJ, et al. Short‐term effect of preoperative intravenous iron therapy in colorectal cancer patients with anemia: results of a cohort study. Transfusion 2018;58(3):795-803. Busti F, Marchi G, Ugolini S, Castagna A, Girelli D. Anemia and iron deficiency in cancer patients: role of iron replacement therapy. Pharmaceuticals 2018;11(4):94. Dekker E, Tanis PJ, Vleugels JL, Kasi PM, Wallace M. Pure-AMC. Lancet 2019;394:1467-1480. Acheson AG, Brookes MJ, Spahn DR. Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a systematic review and meta-analysis. Ann Surg 2012;256(2):235-244. Musallam KM, Tamim HM, Richards T, Spahn DR, Rosendaal FR, Habbal A, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. The Lancet 2011;378(9800):1396-1407. Fowler AJ, Ahmad T, Phull MK, Allard S, Gillies MA, Pearse RM. Meta-analysis of the association between preoperative anaemia and mortality after surgery. Journal of British Surgery 2015;102(11):1314-1324. Wilson MJ, Van Haaren M, Harlaar JJ, Park HC, Bonjer HJ, Jeekel J, et al. Long-term prognostic value of preoperative anemia in patients with colorectal cancer: a systematic review and meta-analysis. Surg Oncol 2017;26(1):96-104. Bruns ER, Borstlap WA, van Duijvendijk P, van der Zaag-Loonen HJ, Buskens CJ, van Munster BC, et al. The association of preoperative anemia and the postoperative course and oncological outcome in patients undergoing rectal cancer surgery: A multicenter snapshot study. Diseases of the Colon & Rectum 2019;62(7):823-831. Muñoz M, Acheson AG, Auerbach M, Besser M, Habler O, Kehlet H, et al. International consensus statement on the peri‐operative management of anaemia and iron deficiency. Anaesthesia 2017;72(2):233-247. World Health Organization. WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. a. 2011; Available at: http://www.who.int/vmnis/indicators/haemoglobin. Munting KE, Klein AA. Optimisation of pre‐operative anaemia in patients before elective major surgery–why, who, when and how? Anaesthesia 2019;74:49-57. Grønkjær M, Eliasen M, Skov-Ettrup LS, Tolstrup JS, Christiansen AH, Mikkelsen SS, et al. Preoperative smoking status and postoperative complications: a systematic review and meta-analysis. Ann Surg 2014;259(1):52-71. Gajdos C, Hawn MT, Campagna EJ, Henderson WG, Singh JA, Houston T. Adverse effects of smoking on postoperative outcomes in cancer patients. Annals of surgical oncology 2012;19:1430-1438. Steiner LA. Postoperative delirium. Part 1: pathophysiology and risk factors. European Journal of Anaesthesiology| EJA 2011;28(9):628-636. Additional Declarations No competing interests reported. Supplementary Files Appendices.docx Cite Share Download PDF Status: Posted Version 1 posted 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-4000534\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":275765531,\"identity\":\"03fdca35-c94e-4b2a-af55-7ddd8d180a26\",\"order_by\":0,\"name\":\"C. R. Sabajo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University Medical Center Groningen\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"C.\",\"middleName\":\"R.\",\"lastName\":\"Sabajo\",\"suffix\":\"\"},{\"id\":275765532,\"identity\":\"3f2a1f3d-ccff-449f-b8a7-9ab1cce1ecc8\",\"order_by\":1,\"name\":\"J. P. Dieleman\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Máxima Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"J.\",\"middleName\":\"P.\",\"lastName\":\"Dieleman\",\"suffix\":\"\"},{\"id\":275765533,\"identity\":\"62054ab7-c8f8-41e4-8901-9a96c67f6e1c\",\"order_by\":2,\"name\":\"J. W. Dekker\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Reinier De Graaf Gasthuis\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"J.\",\"middleName\":\"W.\",\"lastName\":\"Dekker\",\"suffix\":\"\"},{\"id\":275765534,\"identity\":\"ab9600d0-7426-472a-906a-3495304247c8\",\"order_by\":3,\"name\":\"B. Heuvel\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Radboud University Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"B.\",\"middleName\":\"\",\"lastName\":\"Heuvel\",\"suffix\":\"\"},{\"id\":275765535,\"identity\":\"a3a93b65-d110-4218-a26b-4618be66ad13\",\"order_by\":4,\"name\":\"J. M. 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Slooter\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsklEQVRIiWNgGAWjYHACxgNgir0BTMkQpQeoxYCBgQeik4cELRIJRGqRd2B/cOBDxR8585mvUzf8YLhDWIvhAR6DgzPOGBjL3M7ddrOH4RkRWhp4GA7zthkkzpDO3XabgeEwMVrYH4C01M+QPEukFnmg10FaEiQkeInUYsAM9oux4QwekF8MiLGlvf3hgw8VcvIS7Ge33fhRcViOsC2HUbkENQBtaSBC0SgYBaNgFIxwAADUTDqzp0GTkQAAAABJRU5ErkJggg==\",\"orcid\":\"\",\"institution\":\"Máxima Medical Center\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"G.\",\"middleName\":\"D.\",\"lastName\":\"Slooter\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-02-29 16:31:18\",\"currentVersionCode\":1,\"declarations\":{\"humanSubjects\":false,\"vertebrateSubjects\":false,\"conflictsOfInterestStatement\":false,\"humanSubjectEthicalGuidelines\":false,\"humanSubjectConsent\":false,\"humanSubjectClinicalTrial\":false,\"humanSubjectCaseReport\":false,\"vertebrateSubjectEthicalGuidelines\":false},\"doi\":\"10.21203/rs.3.rs-4000534/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-4000534/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":52177715,\"identity\":\"43779b58-0148-497b-8644-ff0839680604\",\"added_by\":\"auto\",\"created_at\":\"2024-03-07 17:14:42\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":273644,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4000534/v1/4e9c9403-6326-4623-af0c-ec5e195c39d7.pdf\"},{\"id\":52037408,\"identity\":\"d177fa03-6c9c-4f11-8f43-9c85e896a3a1\",\"added_by\":\"auto\",\"created_at\":\"2024-03-05 17:21:42\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":739152,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Appendices.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4000534/v1/c3b295a16d8cbd5708c2f1e0.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Multimodal prehabilitation for colorectal cancer patients: study protocol of a nationwide multicentre study with uniform prehabilitation protocols\",\"fulltext\":[{\"header\":\"Background\",\"content\":\"\\u003cp\\u003ePrehabilitation is designed to enhance a patient's physical condition prior to a major surgery, resulting in faster recovery and fewer complications. The fitter the patient is before surgery, the greater the chance of a better outcome (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e). The prehabilitation program is tailored to the individual and includes physical training, customized nutrition, mental support, comorbidities (e.g. diabetes) and anaemia optimization, and smoking and alcohol cessation.\\u003c/p\\u003e \\u003cp\\u003eWhile it has been demonstrated that a patient's functional capacity can be improved through prehabilitation (\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e) it is not yet clear to what extent prehabilitation actually improves surgical outcomes. Due to the lack of uniform guidelines, the prehabilitation program has been implemented in different forms. In some studies, aerobic exercise in combination with resistance training was offered as prehabilitation (\\u003cspan additionalcitationids=\\\"CR6\\\" citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e) while in another study only yoga was offered (\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e). Several systematic reviews also found a lot of heterogeneity within prehabilitation studies (\\u003cspan additionalcitationids=\\\"CR10\\\" citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e). This heterogeneity makes it difficult to compare results between studies and depicts the need to develop uniform guidelines.\\u003c/p\\u003e \\u003cp\\u003eWith the international randomized controlled PREHAB study (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e), the development of proposed uniform guidelines had begun. The protocol has for example been used as a blueprint for other studies. In the Netherlands, the Dutch Society of Surgery developed uniform prehabilitation protocols based on the international PREHAB RCT (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e). These proposed uniform protocols were assessed and adjusted by relevant scientific associations of sport medicine, anaesthesiology, surgery, internal medicine, geriatrics, medical psychology, physical therapy and nutritionists. Furthermore, anaemia screening and management was added. The proposed protocols were created to ensure the quality of prehabilitation programs in the Netherlands, to eventually evaluate outcomes of prehabilitation in a bigger population, and to evaluate the feasibility of implementing such a program. The proposed uniform protocols describe the core points of the prehabilitation program for patients with colorectal cancer (CRC). They can be used by other hospitals, inside and outside the Netherlands, to set up prehabilitation.\\u003c/p\\u003e \\u003cp\\u003eThis paper describes the proposed uniform protocols created by the Dutch Society of Surgery and study protocol to evaluate its clinical effects. The study includes a nationwide multicentre study, which aims to evaluate clinical outcomes of prehabilitation when implemented as standard care, using the presented proposed uniform protocols. Also, length of stay and readmissions will be analysed.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003eThis nationwide multicentre observational cohort study will be conducted in several hospitals in the Netherlands that implemented the proposed uniform protocols and followed prehabilitation training facilitated by Maxima Medical Centre (MMC) and the foundation Fit4Surgery. The Medical Ethics Committee of the Medical University of Groningen, issued the statement that this was not a WMO study under the reference number 2022/079.\\u003c/p\\u003e\\n\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eStudy population\\u003c/h2\\u003e\\n\\u003cp\\u003eAdult patients undergoing elective colorectal resection for cancer and participating in the prehabilitation program are eligible for inclusion into the intervention cohort. Patients from the same hospital but from 2 years before implementation of the proposed uniform protocols, will be eligible for inclusion into the reference cohort. The intervention and reference cohort will be matched one-to-one based on propensity scores.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eInformed consent\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003eand data\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll patients who underwent a prehabilitation program in one of the participating centres will be asked for informed consent. Based on local institutional review boards, patients will either be included upon providing written informed consent or upon applying the general opt-out procedure. From every participating hospital, a historical cohort will be included to match with the prehabilitation group. The reference cohort will comprise patients from 2 years before when prehabilitation was not yet implemented in the respective hospital.\\u003c/p\\u003e\\n\\u003cp\\u003eFor both groups, data on patient characteristics, tumour and clinical outcome will be obtained from a nationwide quality registration database, the Dutch ColoRectal Audit (DCRA). The collected prehabilitation data will be combined with the DCRA data, based on date of birth, sex and operation date from the patient.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eThe prehabilitation program\\u003c/h2\\u003e\\n\\u003cp\\u003eThe prehabilitation program as described by the proposed uniform protocols includes the following five modalities:\\u003c/p\\u003e\\n\\u003cul\\u003e\\n\\u003cli\\u003e\\n\\u003cp\\u003ePhysical fitness\\u003c/p\\u003e\\n\\u003c/li\\u003e\\n\\u003cli\\u003e\\n\\u003cp\\u003eNutritional status\\u003c/p\\u003e\\n\\u003c/li\\u003e\\n\\u003cli\\u003e\\n\\u003cp\\u003eMental resilience\\u003c/p\\u003e\\n\\u003c/li\\u003e\\n\\u003cli\\u003e\\n\\u003cp\\u003eComorbidity, anaemia, and frailty\\u003c/p\\u003e\\n\\u003c/li\\u003e\\n\\u003cli\\u003e\\n\\u003cp\\u003eIntoxications\\u003c/p\\u003e\\n\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003eThe prehabilitation program should last at least 3\\u0026ndash;4 weeks to see an effect from the program. A longer prehabilitation period does not seem to have a negative effect on oncological treatment (\\u003cspan class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e). If a patient can undergo surgery before the prehabilitation program is completed, it is preferable to complete the prehabilitation program first. Also after the surgery a healthy lifestyle is encouraged. A visit to a physiotherapist postoperatively (\\u0026gt;\\u0026thinsp;6 weeks) is preferred, where physical fitness measurements are repeated. Ideally, prehabilitation should be linked to rehabilitation, and these should be well integrated.\\u003c/p\\u003e\\n\\u003cp\\u003eThe flow chart in Appendix 1 shows the framework of screening, assessment, intervention, and re-assessment for each modality in the prehabilitation program. Shared decision-making is an integral part of all steps in the prehabilitation process.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eInterventions (according to the proposed uniform protocols)\\u003c/h2\\u003e\\n\\u003cp\\u003eA more detailed overview of the interventions can be found in the appendices.\\u003c/p\\u003e\\n\\u003cp\\u003e1. Physical fitness (Appendix 2)\\u003c/p\\u003e\\n\\u003cp\\u003ea. Endurance training: Three times a week supervised high-intensity interval training (HIIT) under the supervision of an (oncological) physiotherapist. Low-intensity training at home on the other days. The training program is individualized and is based on the initial physical fitness assessment.\\u003c/p\\u003e\\n\\u003cp\\u003e2. Nutritional status (Appendix 3)\\u003c/p\\u003e\\n\\u003cp\\u003ea. Nutritional consultation with a dietitian: Aim for 1.2\\u0026ndash;1.5 grams of protein per kg of body weight per day and energy intake according to calculated energy needs. Protein supplementation or medical nutrition can be used to achieve recommendations. Supplementation of vitamins and minerals is recommended.\\u003c/p\\u003e\\n\\u003cp\\u003e3. Mental resilience (Appendix 4)\\u003c/p\\u003e\\n\\u003cp\\u003ea. Providing information to the patient, taking into account the patient's health literacy, e.g. by a case manager.\\u003c/p\\u003e\\n\\u003cp\\u003eb. Psychological support: Consultation with case manager or specialized nurse. Referral to a medical psychologist in case of anxiety or depression.\\u003c/p\\u003e\\n\\u003cp\\u003e4. Comorbidity, anaemia, and frailty (Appendix 5 and 6)\\u003c/p\\u003e\\n\\u003cp\\u003ea. Blood sugar level: Measure HbA1c. Refer patients without diabetes with a threshold value\\u0026thinsp;\\u0026gt;\\u0026thinsp;42 mmol/mol (6%) to GP/internist. Refer patients with non-insulin-dependent diabetes with a threshold value\\u0026thinsp;\\u0026gt;\\u0026thinsp;53 mmol/mol to GP/diabetes nurse.\\u003c/p\\u003e\\n\\u003cp\\u003eb. Anaemia: Optimize haemoglobin levels if the value is \\u0026lt;\\u0026thinsp;8.0 mmol/L in men and \\u0026lt;\\u0026thinsp;7.5 mmol/L in women. Optimize iron deficiency preferably with intravenous treatment (Appendix 6).\\u003c/p\\u003e\\n\\u003cp\\u003ec. Frailty: Referral to a geriatrician in case of frailty based on, for example, the Groningen Frailty Indicator, G8 questionnaire, 6CIT questionnaire, and/or MiniCog or if a delirium has occurred previously.\\u003c/p\\u003e\\n\\u003cp\\u003e5. Intoxications (Appendix 7): Support for smoking cessation and cessation of other addictive substances.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eStudy outcomes\\u003c/h2\\u003e\\n\\u003cp\\u003eThe primary outcome will be 90-day postoperative complications. This will be graded according to Dindo et al.(\\u003cspan class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e) and defined as presence or absence of any complication. Complications will also be scored with the Comprehensive Complication Index (CCI) (\\u003cspan class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e). A CCI\\u0026thinsp;\\u0026gt;\\u0026thinsp;20 will be labelled as a severe complication. Secondary outcomes will be length of hospital stay and readmissions.\\u003c/p\\u003e\\n\\u003cp\\u003eData on study outcomes is available in the DCRA database, which is a national mandatory audit. Prehabilitation data, for example start date of prehabilitation, number of training days, and outcomes of physical tests, will be collected separately and combined with the data from the DCRA.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e\\n\\u003cp\\u003eA sample size calculation was made based on multiple logistic regression analysis for presence of post-operative complications within the 90 postoperative days. Age, ASA score, Charlson Comorbidity score, BMI and tumour location will be considered as potential confounders. For the sample size calculation the effect size was based on the PREHAB study (\\u003cspan class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e), with a two-sided p-value for significance of 0.05 and a desired power of 80%. To show a reduction in overall complication rate from 42.2\\u0026ndash;31.7% (odds ratio (OR)\\u0026thinsp;=\\u0026thinsp;0.62) and being able to adjust for the above confounding factors, 535 patients are needed in each group, resulting in a total required study population of 1070 patients.\\u003c/p\\u003e\\n\\u003cp\\u003ePropensity scores will be calculated using multiple logistic regression analysis including the aforementioned confounders as the independent variables and prehabilitation (yes/no) as the dependent variable. The resulting probabilities will be used to match each patient in the prehabilitation cohort with its nearest neighbour in the reference cohort. In case of multiple matches, a reference patient will be randomly selected. The effect of larger distances will be explored in sensitivity analyses.\\u003c/p\\u003e\\n\\u003cp\\u003eBaseline characteristics and clinical outcomes will be presented for the prehabilitation and reference cohort. Continuous variables will be presented as median with interquartile range (IQR) and will be tested using the Mann\\u0026ndash;Whitney U test. Categorical variables will be presented as number per category with percentages and will be analysed using the Chi-square or Fishers\\u0026rsquo; exact test as appropriate. To calculate ORs and regression coefficients with 95%-confidence intervals (95%CI), logistic and linear regression analyses will be used. Data will be analysed on an intention-to-treat basis. Per protocol analyses excluding patients who underwent insufficient prehabilitation will be done to explore the effect of prehabilitation compliance. The amount of missing data will be compared between the two study cohorts; baseline characteristics will be compared between patients with and without missing\\u0026rsquo;s to explore the possibility and direction of bias through missing\\u0026rsquo;s.\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003e This multicentre cohort study will include real-world data from hospitals in the Netherlands, where prehabilitation has been implemented according to the proposed uniform protocols for CRC patients and if hospitals followed the prehabilitation training provided by MMC and the foundation Fit4Surgery.\\u003c/p\\u003e \\u003cp\\u003eOver the years, an increasing number of studies have been performed to evaluate the effect of prehabilitation. Several small trials showed less complications and/or reduced hospital length of stay due to prehabilitation (\\u003cspan additionalcitationids=\\\"CR5\\\" citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e). In addition, Barberan et al. (\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e) performed a RCT using a structured program, and showed that prehabilitation was a protective factor for postoperative complications in 76 CRC patients that underwent elective surgery. Klerk et al. (\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e) performed an RCT also with a standard program, in patients undergoing elective resection for CRC. They showed that prehabilitation significantly reduced overall postoperative medical complications, unplanned readmissions, and the median length of hospital stay. Berkel et al. (\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e) showed an almost 50% decrease in the incidence of postoperative complications due to prehabilitation for CRC patients in a selected group of patients with high risk of complications (anaerobic threshold\\u0026thinsp;\\u0026lt;\\u0026thinsp;11 ml/kg/min). Heil et al. also found in their emulated target trial a relevant reduction of complications and length of hospital stay in patients with a higher postoperative complication risk (\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e). The international PREHAB trial used an uniform multimodal program in both high risk and non-high risk patients and showed significantly lower severe complications, and medical complications in the prehabilitation group (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn contrast to these previous studies, which performed prehabilitation in a study setting, outcomes of a prehabilitation program implemented as standard of care for CRC patients are still lacking. This study will therefore evaluate the outcomes of proposed uniform protocols for a multimodal prehabilitation program for CRC resections when implemented as standard of care throughout multiple hospitals in the Netherlands. Therefore, the provided uniform guidelines were created to enhance standardization and uniformity of the program. Prehabilitation is a multidisciplinary intervention, which can make it difficult to implement the program within a hospital. The proposed protocols might help hospitals to implement prehabilitation, since all involved interventions are described in detail. Hospitals in the Netherlands will receive training in how to implement prehabilitation with an optional additional training for physiotherapists. Hospitals can get reimbursement through the \\u0026ldquo;Innovation Rule\\u0026rdquo; initiated by the Dutch health Authorities (NZa) depending on the insurance company.\\u003c/p\\u003e \\u003cp\\u003eIn comparison to the protocol used in the PREHAB trial (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e), optimization of anaemia has been added. The LekCheck study found that low preoperative haemoglobin was the most important factor involved in the development of an anastomotic leakage (\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e). Also, Berkel et al. found that a lower preoperative haemoglobin level was a risk for the development of complications (\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e). Furthermore, the FIT trial found that with the treatment of intravenous iron deficiency a significant improvement was seen in the preoperative haemoglobin level (\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e). Subsequently, the optimization of anaemia with intravenous iron was added to the proposed uniform protocols.\\u003c/p\\u003e \\u003cp\\u003eDue to its nature, this study is a non-randomized, non-blinded study. However, since prehabilitation is, and will be, implemented as standard of care, data will be real-world data. Given the promising results of prehabilitation, a RCT is no longer suitable. It would not be ethical to withhold high-intensity training, mental support and nutritional, frailty and anaemia screening, assessment and interventions from patients.\\u003c/p\\u003e \\u003cp\\u003eThis paper presents the first standardized proposed uniform protocols for prehabilitation for CRC patients who will undergo elective surgery. The program consists of supervised high-intensity training, nutritional assessment with protein and vitamin supplements, mental health support, assessment of comorbidities and frailty, anaemia screening and optimization and cessation of smoking. Further, this paper presents the protocol of a nationwide multicentre study, which aims to evaluate clinical outcomes of prehabilitation when implemented as standard care, using the proposed uniform protocols.\\u003c/p\\u003e\"},{\"header\":\"List of abbreviations \",\"content\":\"\\u003cp\\u003e1RM One repetition maximum\\u003c/p\\u003e\\n\\u003cp\\u003e6CIT Six-Item Cognitive Impairment test\\u003c/p\\u003e\\n\\u003cp\\u003eCCI Comprehensive Complication Index\\u003c/p\\u003e\\n\\u003cp\\u003eCGA Comprehensive geriatric assessment\\u003c/p\\u003e\\n\\u003cp\\u003eCPET Cardiopulmonary exercise testing\\u003c/p\\u003e\\n\\u003cp\\u003eCRC Colorectal Cancer\\u003c/p\\u003e\\n\\u003cp\\u003eDCRA Dutch ColoRectal Audit\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eHADS Hospital Anxiety and Depression Scale\\u003c/p\\u003e\\n\\u003cp\\u003eHIIT High-intensity interval training\\u003c/p\\u003e\\n\\u003cp\\u003eHRmax Maximum heart rate\\u003c/p\\u003e\\n\\u003cp\\u003eiSWT Incremental shuttle walk test\\u003c/p\\u003e\\n\\u003cp\\u003eIQR Interquartile range\\u003c/p\\u003e\\n\\u003cp\\u003eMET Metabolic equivalents\\u003c/p\\u003e\\n\\u003cp\\u003eMMC Maxima Medical Centre\\u003c/p\\u003e\\n\\u003cp\\u003eNZa Dutch health Authorities\\u003c/p\\u003e\\n\\u003cp\\u003ePG-SGA Patient Generated Subjective Global Assessment\\u003c/p\\u003e\\n\\u003cp\\u003eRCT Randomised controlled trial\\u003c/p\\u003e\\n\\u003cp\\u003eSRT Steep Ramp Test\\u003c/p\\u003e\\n\\u003cp\\u003eVO2max Maximal oxygen consumption\\u003c/p\\u003e\\n\\u003cp\\u003eVSAQ Veterans-specific activity questionnaire\\u003c/p\\u003e\\n\\u003cp\\u003eWpeak Peak power output\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe Medical Ethics Committee of the Medical University of Groningen approved this study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data regarding clinical outcomes supporting the findings of this study are available on the corresponding author on reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare that they have no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNone\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors' contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eCS conceptualised the study with input from GS and JK. CS wrote the first draft and JD, BH, GS and JM critically contributed to and refined this manuscript. All authors have read and approved the final manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eKnowledge Institute of the Federation of Medical Specialists\\u003c/p\\u003e\\n\\u003cp\\u003eDutch Surgical Society (NVVH)\\u003c/p\\u003e\\n\\u003cp\\u003eDutch Association for Anesthesiology (NVA)\\u003c/p\\u003e\\n\\u003cp\\u003eDutch Association of Internists (NIV)\\u003c/p\\u003e\\n\\u003cp\\u003eDutch Association for Clinical Geriatrics (NVKG)\\u003c/p\\u003e\\n\\u003cp\\u003eAssociation for Sports Medicine (VSG)\\u003c/p\\u003e\\n\\u003cp\\u003eRoyal Dutch Society for Physical Therapy (KNGF)\\u003c/p\\u003e\\n\\u003cp\\u003eDutch Association of Dietitians (NVD)\\u003c/p\\u003e\\n\\u003cp\\u003eNational Association of Medical Psychology (LVMP)\\u003c/p\\u003e\\n\\u003cp\\u003eDutch College of General Practitioners (NHG)\\u003c/p\\u003e\\n\\u003cp\\u003eDutch Federation of Cancer Patient Organizations (NFK)\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eVan Beijsterveld CA, Bongers BC, Den Dulk M, Van Kuijk SMJ, Dejong KCH, Van Meeteren NLU. 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A systematic review of randomised controlled trials. Eur J Anaesthesio 2019;36:933-945.\\u003c/li\\u003e\\n\\u003cli\\u003eClegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. The lancet 2013;381(9868):752-762.\\u003c/li\\u003e\\n\\u003cli\\u003eCesari M, Marzetti E, Canevelli M, Guaraldi G. Geriatric syndromes: How to treat. Virulence 2017;8(5):577-585.\\u003c/li\\u003e\\n\\u003cli\\u003eEpstein AM, Hall JA, Besdine R, EDWARD Jr C, Feldstein M, McNEIL BJ, et al. The emergence of geriatric assessment units: the\\u0026quot; new technology of geriatrics\\u0026quot;. Ann Intern Med 1987;106(2):299-303.\\u003c/li\\u003e\\n\\u003cli\\u003eStuck AE, Siu AL, Wieland GD, Rubenstein LZ, Adams J. Comprehensive geriatric assessment: a meta-analysis of controlled trials. The Lancet 1993;342(8878):1032-1036.\\u003c/li\\u003e\\n\\u003cli\\u003eFeinstein AR. The pre-therapeutic classification of co-morbidity in chronic disease. 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Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. The Lancet 2011;378(9800):1396-1407.\\u003c/li\\u003e\\n\\u003cli\\u003eFowler AJ, Ahmad T, Phull MK, Allard S, Gillies MA, Pearse RM. Meta-analysis of the association between preoperative anaemia and mortality after surgery. Journal of British Surgery 2015;102(11):1314-1324.\\u003c/li\\u003e\\n\\u003cli\\u003eWilson MJ, Van Haaren M, Harlaar JJ, Park HC, Bonjer HJ, Jeekel J, et al. Long-term prognostic value of preoperative anemia in patients with colorectal cancer: a systematic review and meta-analysis. Surg Oncol 2017;26(1):96-104.\\u003c/li\\u003e\\n\\u003cli\\u003eBruns ER, Borstlap WA, van Duijvendijk P, van der Zaag-Loonen HJ, Buskens CJ, van Munster BC, et al. The association of preoperative anemia and the postoperative course and oncological outcome in patients undergoing rectal cancer surgery: A multicenter snapshot study. Diseases of the Colon \\u0026amp; Rectum 2019;62(7):823-831.\\u003c/li\\u003e\\n\\u003cli\\u003eMu\\u0026ntilde;oz M, Acheson AG, Auerbach M, Besser M, Habler O, Kehlet H, et al. International consensus statement on the peri‐operative management of anaemia and iron deficiency. Anaesthesia 2017;72(2):233-247.\\u003c/li\\u003e\\n\\u003cli\\u003eWorld Health Organization. WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. a. 2011; Available at: http://www.who.int/vmnis/indicators/haemoglobin.\\u003c/li\\u003e\\n\\u003cli\\u003eMunting KE, Klein AA. Optimisation of pre‐operative anaemia in patients before elective major surgery\\u0026ndash;why, who, when and how? Anaesthesia 2019;74:49-57.\\u003c/li\\u003e\\n\\u003cli\\u003eGr\\u0026oslash;nkj\\u0026aelig;r M, Eliasen M, Skov-Ettrup LS, Tolstrup JS, Christiansen AH, Mikkelsen SS, et al. Preoperative smoking status and postoperative complications: a systematic review and meta-analysis. Ann Surg 2014;259(1):52-71.\\u003c/li\\u003e\\n\\u003cli\\u003eGajdos C, Hawn MT, Campagna EJ, Henderson WG, Singh JA, Houston T. Adverse effects of smoking on postoperative outcomes in cancer patients. Annals of surgical oncology 2012;19:1430-1438.\\u003c/li\\u003e\\n\\u003cli\\u003eSteiner LA. Postoperative delirium. Part 1: pathophysiology and risk factors. European Journal of Anaesthesiology| EJA 2011;28(9):628-636.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":true,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"colorectal cancer, colorectal surgery, prehabilitation, uniform guidelines\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4000534/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4000534/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eThe aim of prehabilitation is to optimize patient specific modifiable risk factors before major surgery, in order to enhance the individual resilience. In recent years, a considerable amount of research has been done on the effectiveness of prehabilitation. Due to the lack of universal guidelines, prehabilitation has been conducted in various ways, making it difficult to estimate its effect. In the Netherlands, proposed uniform prehabilitation protocols were developed. The aim of this study is to analyse clinical outcomes of prehabilitation when implemented as standard of care according to the proposed uniform protocols.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eUniform prehabilitation protocols were created based on the multimodal program of the PREHAB randomized controlled trial. All hospitals in the Netherlands that implemented prehabilitation according to the proposed protocols, for patients undergoing elective colorectal surgery, will be asked to participate. This study will recruit 535 patients who underwent prehabilitation and 535 one-to-one nearest neighbour propensity score matched patients who did not undergo prehabilitation (historical cohort). Clinical outcomes will be compared between the prehabilitation group and the historical cohort group using regression analyses. The primary outcome of interest is 90-day presence of postoperative complications. In addition, length of hospital stay and readmissions will be analysed.\\u003c/p\\u003e\\u003ch2\\u003eDiscussion\\u003c/h2\\u003e \\u003cp\\u003ePrehabilitation has been proven to reduce the risk of complications and hospital length of stay. Prehabilitation has however been defined in various ways, since there is no standardized program. This multicentre cohort study will estimate the clinical effect of prehabilitation implemented as standard of care according to proposed uniform protocols. Furthermore, the presented protocols can be used by other hospitals to set up a prehabilitation program.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Multimodal prehabilitation for colorectal cancer patients: study protocol of a nationwide multicentre study with uniform prehabilitation protocols\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-03-05 17:21:37\",\"doi\":\"10.21203/rs.3.rs-4000534/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"c94f3717-f4c1-4aa8-9ea6-8d525eaecc10\",\"owner\":[],\"postedDate\":\"March 5th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-03-07T17:13:47+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2024-03-05 17:21:37\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4000534\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4000534\",\"identity\":\"rs-4000534\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}