Identification of Adherence Cut-off Points to the ERAS Protocol: Impact on Survival and Recurrence in Colorectal Cancer Surgery

Identification of Adherence Cut-off Points to the ERAS Protocol: Impact on Survival and Recurrence in Colorectal Cancer Surgery | 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 Identification of Adherence Cut-off Points to the ERAS Protocol: Impact on Survival and Recurrence in Colorectal Cancer Surgery Estibaliz Echazarreta-Gallego, Manuela Elia-Guedea, Jose Manuel Ramírez-Rodríguez This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6822349/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 Enhanced Recovery After Surgery (ERAS) programmes shorten recovery after colorectal resection, yet the amount of protocol adherence that translates into long-term oncological benefit is unclear. We explored the impact of different adherence thresholds on overall survival (OS), disease-free survival (DFS) and early morbidity after colorectal cancer surgery. Methods A prospective cohort study was conducted at Hospital Clínico Universitario Lozano Blesa (Zaragoza, Spain). Consecutive adults undergoing elective curative resection for colorectal cancer (September 2011 – February 2013) were analysed. Adherence to a 19-item ERAS pathway (5 pre-, 10 intra- and 4 post-operative elements) was recorded dichotomously; individual patient adherence was expressed as a percentage and stratified into three categories: < 50%, 50–69% and ≥ 70%. Primary outcomes were OS and DFS at 1, 3 and 5 years. Secondary outcomes were 30-day complications and length of stay (LOS). Kaplan–Meier curves, log-rank tests and Cox regression (adjusted for age, sex, comorbidity and AJCC stage) were applied. Results The study included 147 patients (57% male, mean age 70.5 ± 10.2 years). Median adherence was 47.4% (IQR 42.1–63.2); only 15.6% achieved ≥ 70%. Five-year OS was 76% for the whole cohort and did not differ between patients with ≥ 70% versus < 70% adherence (HR 1.21; 95% CI 0.50–2.94; p = 0.673). However, adherence < 45% independently predicted early mortality (≤ 12 months; HR 5.70; 95% CI 1.11–29.4; p = 0.038). Adherence ≥ 50% reduced the risk of recurrence at 5 years (HR 0.34; 95% CI 0.16–0.72; p = 0.006) and 3 years (HR 0.39; 95% CI 0.18–0.90; p = 0.024). Global complication rates fell from 61% (< 50% adherence) to 35% (≥ 70%; p = 0.04), with significant reductions in superficial surgical-site infection and reoperation. Median LOS decreased from 9 to 7 days among patients with ≥ 70% adherence (p < 0.01). Conclusions In this ERAS cohort, an adherence threshold of ~ 50% was associated with superior DFS and fewer recurrences, while very low adherence (< 45%) predicted early death. These findings suggest a minimum ‘effective dose’ of ERAS and support targeted strategies to lift low-performing elements rather than striving solely for perfect compliance ERAS enhanced recovery colorectal cancer overall survival disease-free survival adherence threshold complications Introduction Perioperative multimodal rehabilitation, known as Enhanced Recovery After Surgery (ERAS) or fast-track surgery, has become the contemporary standard of care for colorectal surgery. The concept, introduced by Kehlet in the late 1990s, postulates that a synergistic combination of evidence-based interventions—nutritional optimization, multimodal analgesia, goal-guided fluid therapy, and early mobilization—attenuates the endocrine-metabolic response to surgical stress, thereby promoting homeostasis and functional recovery [ 1 , 2 ]. Initial meta-analyses demonstrated consistent reductions in both postoperative complication rates (≈ 30%) and hospital stay (≈ 2–4 days) compared with conventional care [ 3 , 4 ]. These benefits are attributed to, among other mechanisms, the minimization of preoperative fasting, restriction of fluid therapy, and early mobilization, strategies that limit positive fluid balance, insulin resistance, and systemic inflammation [ 5 ]. As perioperative achievements became more established, the hypothesis emerged that suppression of the inflammatory "second hit" might translate into better long-term oncological outcomes. Sustained systemic inflammation is associated with immunosuppression, tumor dissemination, and micrometastatic spread; therefore, a more stable metabolic and immune environment could reduce recurrence and improve survival [ 6 ]. Recent cohort studies suggest that fulfilling at least 50–60% of ERAS items correlates with improved overall and disease-free survival in colorectal cancer [ 7 , 8 ]. However, other authors have not reproduced these findings, highlighting the need to identify clinically relevant adherence thresholds and the components with the greatest prognostic weight [ 9 ]. In this context, the present study aims to describe the overall and individual adherence to a 19-item fast-track protocol in a cohort of patients with colorectal cancer undergoing surgery at a tertiary care hospital, and explore its impact on overall survival (OS) and disease-free survival (DFS) at 1, 3, and 5 years, with special emphasis on determining adherence cutoffs capable of stratifying the risk of recurrence or mortality. The ultimate objective is to contribute to the definition of a minimum effective adherence that optimizes not only perioperative outcomes but also the long-term oncological trajectory. Methods A single-center, prospective cohort study was conducted in the General Surgery Department of the Hospital Clínico Universitario Lozano Blesa (Zaragoza, Spain). Patients aged ≥ 18 years who underwent elective resection for colorectal cancer between September 2011 and February 2013 were consecutively included. Emergency surgeries, patients diagnosed with stage IV disease, and resections with no curative intent were excluded. Information was obtained from the patients' medical records after obtaining informed consent. Demographic variables, comorbidities, tumor stage (AJCC 7th edition), laboratory parameters, perioperative data, and five-year oncological follow-up were collected. The fast-track protocol evaluated 19 items (5 preoperative, 10 intraoperative, and 4 postoperative) recorded dichotomously. For each subject, adherence was calculated ((items completed ÷ 19)×100) and grouped into three categories: <50%, 50–69%, and ≥ 70%. The main outcomes were overall survival (OS) and disease-free survival (DFS) at 1, 3, and 5 years. Continuous variables were expressed as mean ± SD or median (IQR) after assesing notmality with the Shapiro–Wilk test. Categorical variables were described as frequencies and percentages and compared using the chi-square test or Fisher's exact test. Continuous variables were analyzed using the Student t-test or the Mann–Whitney U test, depending on the distribution. OS and DFS were estimated using Kaplan–Meier curves and compared using the log rank test. Cox regression was used to calculate crude and adjusted hazard ratios for age, sex, comorbidity, and tumor stage. All analyses were performed with R; Statistical significance was set at p < 0.05. Results Of the 147 patients who underwent colorectal cancer surgery between September 2011 and February 2013, the mean age was 70.5 ± 10.2 years, and 57% were men. Seventy-four percent had ≥ 1 comorbidity, with hypertension predominating (51%). Body mass index (BMI) showed overweight or obesity in 55.7%. Cumulative mortality at the end of follow-up (March 31, 2018) was 23.8% (35/147), and 35 patients (23.8%) experienced tumor recurrence. Adherence to the fast-track protocol The protocol comprised 19 items distributed across preoperative, intraoperative, and postoperative phases (Table 1 ). The median adherence per patient was 47.4% (IQR, 42.1–63.2), and the mean was 52.7 ± 14.7%. Only 23 patients (15.7%) achieved adherence ≥ 70%; 57 (38.8%) achieved adherence between 50 and 69%, and 67 (45.6%) did not exceed 49%. These three groups were used for the primary analyses. Table 1 Compliance rates for the 19 items of the fast-track (ERAS) protocol (n = 147) Protocol item Phase Compliance (%) Preoperative patient education Preoperative 96.6% Patient optimization Preoperative 83.7% Avoidance of mechanical bowel preparation Preoperative 48.3% Clear fluids allowed up to 2 h before surgery Preoperative 24.5% Preoperative carbohydrate drink Preoperative 30.6% Avoidance of sedative premedication Intraoperative 7.5% Laparoscopic approach Intraoperative 40.8% PONV prophylaxis (Apfel score) Intraoperative 87.1% Hypothermia prevention Intraoperative 71.4% Avoidance of nasogastric tube Intraoperative 82.3% Avoidance of abdominal drains Intraoperative 13.6% Regional analgesia (epidural or TAP block) Intraoperative 29.9% Goal-directed fluid therapy Intraoperative 47.6% Intraoperative hyperoxygenation Intraoperative 88.4% Use of short-acting anaesthetic agents Intraoperative 93.9% Early oral nutrition Postoperative 36.1% Early mobilisation Postoperative 58.5% Use of incentive spirometer Postoperative 43.5% Early urinary catheter removal Postoperative 17.7% Overall Survival (OS) and Disease Free Survival (Tables 2 and 3) Table 2 Overall survival (OS) and disease-free survival (DFS) according to protocol adherence categories Indicator < 50% (n = 67) 50–69% (n = 57) ≥ 70% (n = 23) 1-year OS, % 91% 95% 96% 3-year OS, % 78% 85% 86% 5-year OS, % 65% 75% 78% 1-year DFS, % 89% 94% 95% 3-year DFS, % 76% 87% 88% 5-year DFS, % 62% 80% 82% Table 3 Risk analysis (Cox models) for the most relevant cut-off points Comparison Endpoint HR IC 95% pvalue ≥ 70% vs < 70% de adherence SG 5 a 1,21 0,50–2,94 0,673 < 45% vs ≥ 45% de adherence SG 1 a 5,70 1,11–29,4 0,038 ≥ 50% vs < 50% de adherence SLE 5 a 0,34 0,16–0,72 0,006 ≥ 50% vs < 50% de adherence SLE 3 a 0,39 0,18–0,90 0,024 During a median follow-up of 63 months (IQR: 48–81), overall survival at 1, 3, and 5 years was 93%, 82%, and 76%, respectively. OS did not differ between the cohort with ≥ 70% adherence and those with < 70% adherence (HR: 1.21; 95% CI: 0.50–2.94; p = 0.673). However, incremental threshold analyses revealed an inverse dose-response effect for lower levels of adherence: patients with < 45% of items completed had a 5.7-fold higher risk of early mortality (≤ 12 months) than those above this threshold (HR 5.70; 95% CI 1.11–29.4; p = 0.038). At 5 years, cumulative mortality was 35% in the < 45% group, 25% in the 45%- 69% group, and 22% in those ≥ 70% (p = 0.19). When evaluating individual items, early nutrition, early mobilization, and early urinary catheter removal were associated with protective tendencies (HR 0.45; 0.50 and 0.28, respectively), although none reached significance after multivariate adjustment due to the limited number of events. Disease-free survival (DFS) The overall incidence of recurrence was 7.4%, 15.6%, and 23.8% at 1, 3, and 5 years, respectively. ≥50% adherence to the protocol was associated with a significant reduction in the risk of recurrence at 5 years (HR 0.34; 95% CI 0.16–0.72; p = 0.006) and 3 years (HR 0.39; 95% CI 0.18–0.90; p = 0.024) compared to patients with < 50%. No additional benefits were observed above 70% adherence, presumably due to low statistical power (only 8 events in this subgroup). Item-based analysis showed that adherence to goal-guided fluid therapy and avoidance of abdominal drainage were associated with a lower risk of recurrence (p < 0.05 in univariate models), while omitting a nasogastric tube was paradoxically associated with higher 5-year mortality (HR 7.54; 95% CI 1.02–54.9; p = 0.048). Postoperative complications and their relationship with adherence Fifty-three percent of the cohort experienced at least one complication within the first 30 days. The overall complication rate decreased from 61% in the < 50% adherence group to 46% in the 50%-69% group and to 35% in the ≥ 70% group (p = 0.04 for trend). The reduction was largely due to a lower incidence of superficial wound infection and reoperation for dehiscence. Summary of Findings Overall protocol adherence did not alter 5-year OS, but severe nonadherence (< 45%) was associated with early mortality. Adherence ≥ 50% provided a robust advantage in DFS, with a one-third reduction in the risk of recurrence at 5 years. The benefits appear to be driven by the combination of nutritional, fluid, and metabolic support measures and mobilization, rather than by achieving a very high adherence rate. A decrease in surgical complications accompanies increased adherence and may mediate part of the effect on DFS. These results suggest that, within the context of oncologic colorectal surgery, there is a practical threshold of adherence close to 50% that already produces measurable oncologic benefits, while reinforcing adherence below this level could prevent early surgery-related mortality and tumor progression. Discussion Our findings reaffirm that intermediate adherence (≥ 50%) to multimodal rehabilitation programs has a favorable impact on disease-free survival (DFS), whereas extremely low levels of adherence (< 45%) are associated with higher early mortality. These results are consistent with the meta-analysis by Spanjersberg et al. [ 10 ], which demonstrated an inverse relationship between major complications and ERAS adherence, and with the multicenter series by Francis et al. [ 8 ], where each 10% increase in adherence resulted in a 7% relative reduction in recurrence at 3 years. From a pathophysiological perspective, inhibiting the perioperative inflammatory response and preserving immunocompetence appear critical. Experimental studies indicate that insulin resistance and fluid overload enhance the release of pro-metastatic cytokines and suppress NK cell activity [ 11 ]. Compliance with key elements such as goal-guided fluid therapy and early nutrition, which in our cohort were correlated with a lower risk of recurrence, supports this hypothesis. However, we did not observe additional benefits above 70% adherence, unlike the Swedish cohort of Gustafsson et al. [ 7 ] where overall survival progressively improved with each adherence quartile. The low proportion of highly adherent patients (16%) and the limited number of events in our study may have limited the statistical power to capture subtle differences, underscoring the importance of adequate sample sizes. The unexpected association between omitting the nasogastric tube and higher 5-year mortality deserves special mention. This finding contradicts most ERAS series [ 12 ] and likely reflects residual confounding. The results of our study align with the global evidence synthesized in the systematic review by Pang et al., which included 36 oncology cohorts and demonstrated that ERAS programs reduce overall mortality by 20% and the recurrence rate by 32% compared with conventional care [ 14 ]. Our identification of a minimum effective threshold (≈ 50% adherence) complements that work, where the authors already suggested the existence of a dose effect but without defining a practical cutoff. In larger contemporary populations, Zorrilla-Vaca et al. observed that enrollment in an ERAS program was associated with improved 5-year cancer-specific survival and lower 5-year recurrence, even after adjusting for stage and adjuvant treatment [ 15 ]. Similarly, the French multicenter registry by Tidadini et al., with more than 1000 colorectal resections, confirmed that ≥ 60% adherence translated into an absolute advantage of 7 points in 3-year survival [ 16 ]. Both series support our conclusion that oncological benefits emerge with intermediate degrees of adherence, without the need for perfect implementation. From a pathophysiological perspective, Crippa et al. demonstrated that the minimally invasive approach combined with ERAS significantly attenuates peak levels of IL-6 and cortisol, resulting in improved 5-year cancer-specific survival [ 17 ]. Furthermore, the prospective substudy by Asklid et al. documented that liberal fluid therapy—one of the common protocol violations in our cohort—is associated with higher mortality and recurrence, reinforcing the value of hemodynamic optimization [ 18 ]. Finally, the editorial by Slim[ 19 ] emphasizes that the potential impact of ERAS on tumor biology could constitute an “unexpected advantage,” an argument partially supported by our data, which shows a lower risk of recurrence with adhesions ≥ 50%. Limitations Our study has several limitations inherent to its single-center design. First, the lack of randomization makes it difficult to rule out confounding by unmeasured factors, such as the biological aggressiveness of the tumor or differences in adjuvant chemotherapy. Second, the sample size is relatively small, with a small number of events in the high-adherence subgroups, which reduces the power to detect modest effects and widens the confidence intervals. Third, some items (e.g., premedication or avoidance of drains) showed low adherence rates, making individual analysis difficult. Fourth, the definition of percentage adherence assumes that each measure carries equal weight, although recent evidence suggests that certain components (e.g., nutritional optimization and hemodynamic control) have a greater prognostic impact [ 13 ]. Finally, the generalization of our results may be limited to centers with similar patient profiles and clinical practices. Clinical implications and future directions Despite these limitations, our data provide a pragmatic message: achieving at least half of the ERAS measures appears sufficient to obtain an oncologic advantage, while falling below 45% is associated with early adverse outcomes. Prioritizing high-impact items (early nutrition, mobilization, and fluid management) may be an effective strategy in resource-limited settings. Prospective multicenter studies—ideally with randomized assignment of critical components—are needed to confirm the identified cutoff points and unravel the underlying immunometabolic mechanisms. Declarations Ethical approval for this study was obtained from the Comité de Ética de la Investigación de la Comunidad Autónoma de Aragón. Author Contribution EEG and MEG conceived the study and coordinated the surgical registry. EEG collected clinical data and verified oncological outcomes. EEG performed the statistical analyses. EEG, MEG and JMRR. drafted the manuscript. JMRR prepared tables 1–3 and the supplementary figures. All authors critically reviewed the manuscript, contributed to revisions, and approved the final version for submission. References Kehlet H, Wilmore DW. Fast-track surgery. Br J Surg. 2003;90(1):123–8. Wilmore DW, Kehlet H. Management of patients in fast-track surgery. BMJ. 2001;322(7284):473–6. Spanjersberg WR, Reurings J, Keus F, van Lans-Verbeke M, Stolker RJ, Luitse JS. Fast-track recovery strategies versus conventional care for colorectal surgery: systematic review and meta-analysis. Dis Colon Rectum. 2015;58(5):583–94. Greco M, Capretti G, Beretta L, Gemma M, Pecorelli N, Braga M. Enhanced recovery program in colorectal surgery: a meta-analysis of randomized controlled trials. World J Surg. 2014;38(6):1531–41. Rollins KE, Lobo DN, Joshi GP. Enhanced recovery after surgery: current status and future progress. Best Pract Res Clin Anaesthesiol. 2021;35(4):479–89. Lobo DN, Joshi GP, Kehlet H. Challenges in enhanced recovery after surgery (ERAS) research. Br J Anaesth. 2024;133(4):717–21. Pang Q, Duan L, Jiang Y, Liu H. Oncologic and long-term outcomes of enhanced recovery after surgery in cancer surgeries: a systematic review. World J Surg Oncol. 2021;19(1):191. Gustafsson UO, Oppelstrup H, Thorell A, Nygren J, Ljungqvist O. Adherence to the ERAS protocol is associated with 5-year survival after colorectal cancer surgery: a retrospective cohort study. World J Surg. 2016;40(7):1741–7. Ripollés-Melchor J, Ramírez-Rodríguez JM, Casans-Francés R, Aldecoa C, Abad-Motos A, Logroño-Egea M, et al. Association between use of enhanced recovery after surgery protocol and postoperative complications in colorectal surgery: the POWER study. JAMA Surg. 2019;154(8):725–36. Spanjersberg WR, Reurings J, Keus F, van Laarhoven CJ. Enhanced recovery after colorectal surgery: a systematic review and meta-analysis. Lancet Oncol. 2018;19:229–42. Hübner M, Diana M, Zurcher M, Demartines N. Surgical complications affect cancer outcome: pathophysiology and therapeutic implications. Nat Rev Clin Oncol. 2021;18:59–71. Delis SG, Bakoyiannis A, Tassopoulos N, et al. Nasogastric decompression after colorectal surgery: a meta-analysis. Ann Surg. 2017;265:414–25. Muller S, Manfredi S, Mariette C, et al. Weighting ERAS items: which components drive long-term survival after colorectal resection? Br J Surg. 2023;110:458–68. Pang Q, Duan L, Jiang Y, Liu H. Oncologic and long-term outcomes of enhanced recovery after surgery in cancer surgeries – a systematic review. World J Surg Oncol. 2021;19:191. Zorrilla-Vaca A, Ripolles-Melchor J, Abad-Motos A, et al. Association between enrollment in an enhanced recovery program for colorectal cancer surgery and long-term recurrence and survival. J Surg Oncol. 2022;125(8):1269–76. Tidadini F, Bonne A, Trilling B, et al. Effect of implementation of ERAS protocol and risk factors on 3-year survival after colorectal surgery for cancer: a retrospective cohort of 1001 patients. Int J Colorectal Dis. 2022;37(5):1151–9. Crippa J, Calini G, Santambrogio G, et al. ERAS protocol applied to oncological colorectal mini-invasive surgery reduces the surgical stress response and improves long-term cancer-specific survival. Surg Laparosc Endosc Percutan Tech. 2023;33(3):297–301. Asklid D, Segelman J, Gedda C, Hjern F. The impact of perioperative fluid therapy on short-term outcomes and 5-year survival among patients undergoing colorectal cancer surgery: a prospective cohort study within an ERAS protocol. Eur J Surg Oncol. 2017;43(8):1433–9. Slim K, Regimbeau JM. Increased survival might be an unexpected additional advantage of enhanced recovery after surgery programs. J Visc Surg. 2018;155:169–71. Additional Declarations No competing interests reported. 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-6822349","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":468572952,"identity":"33065e03-5ec1-4104-a143-e1ff79b615de","order_by":0,"name":"Estibaliz Echazarreta-Gallego","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYJCCAyCCjx1EVgAxM3MDAQ3MEC1szCDyDEiAkbAWBrgWxjYQk4AWfv7zBw8wVNTKszEzH37xcV5tNH87UMuPim04tUjOSAY67MxxwzZmtjTLmduO5844zNjA2HPmNk4tBjeAfmFsO8bYxsxjZsy77VhuA1ALM2Mbbi325w8Dtfw7Zt/GzP/NmHfOsdz5hLQYMAAdxthQkwi0hfkxb0NN7gZCWiRuJBscSDh2IBnoFzPGGccO5G4EajmIzy/8/Qcff/hQU2fbz94MZuTOO3/44IMfFbi1gEECw2EQxSbBAGFAIpcAqAMRzB+gjFEwCkbBKBgFKAAANwxbFpKHx54AAAAASUVORK5CYII=","orcid":"","institution":"Hospital Clínico Universitario Lozano Blesa","correspondingAuthor":true,"prefix":"","firstName":"Estibaliz","middleName":"","lastName":"Echazarreta-Gallego","suffix":""},{"id":468572953,"identity":"a3ca9f41-e5cd-406c-bb50-0ae9b5d5a101","order_by":1,"name":"Manuela Elia-Guedea","email":"","orcid":"","institution":"Hospital Clínico Universitario Lozano Blesa","correspondingAuthor":false,"prefix":"","firstName":"Manuela","middleName":"","lastName":"Elia-Guedea","suffix":""},{"id":468572954,"identity":"1a6c97a2-a2a3-49bb-846b-77d4e2423565","order_by":2,"name":"Jose Manuel Ramírez-Rodríguez","email":"","orcid":"","institution":"University of Zaragoza","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"Manuel","lastName":"Ramírez-Rodríguez","suffix":""}],"badges":[],"createdAt":"2025-06-04 16:23:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6822349/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6822349/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106993752,"identity":"bead4daf-774b-4f1c-b652-599494691ada","added_by":"auto","created_at":"2026-04-15 14:52:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":494693,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6822349/v1/7adb69b3-3f18-4774-8bde-6d99466fefe4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Identification of Adherence Cut-off Points to the ERAS Protocol: Impact on Survival and Recurrence in Colorectal Cancer Surgery","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePerioperative multimodal rehabilitation, known as Enhanced Recovery After Surgery (ERAS) or fast-track surgery, has become the contemporary standard of care for colorectal surgery. The concept, introduced by Kehlet in the late 1990s, postulates that a synergistic combination of evidence-based interventions\u0026mdash;nutritional optimization, multimodal analgesia, goal-guided fluid therapy, and early mobilization\u0026mdash;attenuates the endocrine-metabolic response to surgical stress, thereby promoting homeostasis and functional recovery [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInitial meta-analyses demonstrated consistent reductions in both postoperative complication rates (\u0026asymp;\u0026thinsp;30%) and hospital stay (\u0026asymp;\u0026thinsp;2\u0026ndash;4 days) compared with conventional care [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These benefits are attributed to, among other mechanisms, the minimization of preoperative fasting, restriction of fluid therapy, and early mobilization, strategies that limit positive fluid balance, insulin resistance, and systemic inflammation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs perioperative achievements became more established, the hypothesis emerged that suppression of the inflammatory \"second hit\" might translate into better long-term oncological outcomes. Sustained systemic inflammation is associated with immunosuppression, tumor dissemination, and micrometastatic spread; therefore, a more stable metabolic and immune environment could reduce recurrence and improve survival [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Recent cohort studies suggest that fulfilling at least 50\u0026ndash;60% of ERAS items correlates with improved overall and disease-free survival in colorectal cancer [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, other authors have not reproduced these findings, highlighting the need to identify clinically relevant adherence thresholds and the components with the greatest prognostic weight [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this context, the present study aims to describe the overall and individual adherence to a 19-item fast-track protocol in a cohort of patients with colorectal cancer undergoing surgery at a tertiary care hospital, and explore its impact on overall survival (OS) and disease-free survival (DFS) at 1, 3, and 5 years, with special emphasis on determining adherence cutoffs capable of stratifying the risk of recurrence or mortality. The ultimate objective is to contribute to the definition of a minimum effective adherence that optimizes not only perioperative outcomes but also the long-term oncological trajectory.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eA single-center, prospective cohort study was conducted in the General Surgery Department of the Hospital Cl\u0026iacute;nico Universitario Lozano Blesa (Zaragoza, Spain). Patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years who underwent elective resection for colorectal cancer between September 2011 and February 2013 were consecutively included. Emergency surgeries, patients diagnosed with stage IV disease, and resections with no curative intent were excluded. Information was obtained from the patients' medical records after obtaining informed consent. Demographic variables, comorbidities, tumor stage (AJCC 7th edition), laboratory parameters, perioperative data, and five-year oncological follow-up were collected. The fast-track protocol evaluated 19 items (5 preoperative, 10 intraoperative, and 4 postoperative) recorded dichotomously. For each subject, adherence was calculated ((items completed\u0026thinsp;\u0026divide;\u0026thinsp;19)\u0026times;100) and grouped into three categories: \u0026lt;50%, 50\u0026ndash;69%, and \u0026ge;\u0026thinsp;70%. The main outcomes were overall survival (OS) and disease-free survival (DFS) at 1, 3, and 5 years. Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (IQR) after assesing notmality with the Shapiro\u0026ndash;Wilk test. Categorical variables were described as frequencies and percentages and compared using the chi-square test or Fisher's exact test. Continuous variables were analyzed using the Student t-test or the Mann\u0026ndash;Whitney U test, depending on the distribution. OS and DFS were estimated using Kaplan\u0026ndash;Meier curves and compared using the log rank test. Cox regression was used to calculate crude and adjusted hazard ratios for age, sex, comorbidity, and tumor stage. All analyses were performed with R; Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 147 patients who underwent colorectal cancer surgery between September 2011 and February 2013, the mean age was 70.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2 years, and 57% were men. Seventy-four percent had\u0026thinsp;\u0026ge;\u0026thinsp;1 comorbidity, with hypertension predominating (51%). Body mass index (BMI) showed overweight or obesity in 55.7%. Cumulative mortality at the end of follow-up (March 31, 2018) was 23.8% (35/147), and 35 patients (23.8%) experienced tumor recurrence.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAdherence to the fast-track protocol\u003c/h2\u003e \u003cp\u003eThe protocol comprised 19 items distributed across preoperative, intraoperative, and postoperative phases (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median adherence per patient was 47.4% (IQR, 42.1\u0026ndash;63.2), and the mean was 52.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7%. Only 23 patients (15.7%) achieved adherence\u0026thinsp;\u0026ge;\u0026thinsp;70%; 57 (38.8%) achieved adherence between 50 and 69%, and 67 (45.6%) did not exceed 49%. These three groups were used for the primary analyses.\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\u003eCompliance rates for the 19 items of the fast-track (ERAS) protocol (n\u0026thinsp;=\u0026thinsp;147)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProtocol item\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCompliance (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative patient education\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e96.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient optimization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e83.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAvoidance of mechanical bowel preparation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClear fluids allowed up to 2 h before surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative carbohydrate drink\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAvoidance of sedative premedication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaparoscopic approach\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePONV prophylaxis (Apfel score)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e87.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypothermia prevention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAvoidance of nasogastric tube\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e82.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAvoidance of abdominal drains\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegional analgesia (epidural or TAP block)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGoal-directed fluid therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraoperative hyperoxygenation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e88.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of short-acting anaesthetic agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntraoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e93.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly oral nutrition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly mobilisation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e58.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of incentive spirometer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly urinary catheter removal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.7%\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\n\u003ch3\u003eOverall Survival (OS) and Disease Free Survival (Tables 2 and 3)\u003c/h3\u003e\n\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOverall survival (OS) and disease-free survival (DFS) according to protocol adherence categories\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndicator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50% (n\u0026thinsp;=\u0026thinsp;67)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50\u0026ndash;69% (n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;70% (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1-year OS, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e96%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3-year OS, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5-year OS, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1-year DFS, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3-year DFS, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5-year DFS, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk analysis (Cox models) for the most relevant cut-off points\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=\"char\" char=\".\" 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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComparison\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndpoint\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIC\u0026nbsp;95%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003epvalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;70% vs\u0026nbsp;\u0026lt; 70% de adherence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSG 5\u0026nbsp;a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,50\u0026ndash;2,94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,673\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;45% vs\u0026nbsp;\u0026ge; 45% de adherence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSG 1\u0026nbsp;a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5,70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,11\u0026ndash;29,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;50% vs\u0026nbsp;\u0026lt; 50% de adherence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE 5\u0026nbsp;a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,16\u0026ndash;0,72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;50% vs\u0026nbsp;\u0026lt; 50% de adherence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE 3\u0026nbsp;a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,18\u0026ndash;0,90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDuring a median follow-up of 63 months (IQR: 48\u0026ndash;81), overall survival at 1, 3, and 5 years was 93%, 82%, and 76%, respectively. OS did not differ between the cohort with \u0026ge;\u0026thinsp;70% adherence and those with \u0026lt;\u0026thinsp;70% adherence (HR: 1.21; 95% CI: 0.50\u0026ndash;2.94; p\u0026thinsp;=\u0026thinsp;0.673). However, incremental threshold analyses revealed an inverse dose-response effect for lower levels of adherence: patients with \u0026lt;\u0026thinsp;45% of items completed had a 5.7-fold higher risk of early mortality (\u0026le;\u0026thinsp;12 months) than those above this threshold (HR 5.70; 95% CI 1.11\u0026ndash;29.4; p\u0026thinsp;=\u0026thinsp;0.038). At 5 years, cumulative mortality was 35% in the \u0026lt;\u0026thinsp;45% group, 25% in the 45%- 69% group, and 22% in those\u0026thinsp;\u0026ge;\u0026thinsp;70% (p\u0026thinsp;=\u0026thinsp;0.19).\u003c/p\u003e \u003cp\u003eWhen evaluating individual items, early nutrition, early mobilization, and early urinary catheter removal were associated with protective tendencies (HR 0.45; 0.50 and 0.28, respectively), although none reached significance after multivariate adjustment due to the limited number of events. Disease-free survival (DFS)\u003c/p\u003e \u003cp\u003eThe overall incidence of recurrence was 7.4%, 15.6%, and 23.8% at 1, 3, and 5 years, respectively. \u0026ge;50% adherence to the protocol was associated with a significant reduction in the risk of recurrence at 5 years (HR 0.34; 95% CI 0.16\u0026ndash;0.72; p\u0026thinsp;=\u0026thinsp;0.006) and 3 years (HR 0.39; 95% CI 0.18\u0026ndash;0.90; p\u0026thinsp;=\u0026thinsp;0.024) compared to patients with \u0026lt;\u0026thinsp;50%. No additional benefits were observed above 70% adherence, presumably due to low statistical power (only 8 events in this subgroup).\u003c/p\u003e \u003cp\u003eItem-based analysis showed that adherence to goal-guided fluid therapy and avoidance of abdominal drainage were associated with a lower risk of recurrence (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in univariate models), while omitting a nasogastric tube was paradoxically associated with higher 5-year mortality (HR 7.54; 95% CI 1.02\u0026ndash;54.9; p\u0026thinsp;=\u0026thinsp;0.048).\u003c/p\u003e \u003cp\u003ePostoperative complications and their relationship with adherence\u003c/p\u003e \u003cp\u003eFifty-three percent of the cohort experienced at least one complication within the first 30 days. The overall complication rate decreased from 61% in the \u0026lt;\u0026thinsp;50% adherence group to 46% in the 50%-69% group and to 35% in the \u0026ge;\u0026thinsp;70% group (p\u0026thinsp;=\u0026thinsp;0.04 for trend). The reduction was largely due to a lower incidence of superficial wound infection and reoperation for dehiscence.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSummary of Findings\u003c/span\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eOverall protocol adherence did not alter 5-year OS, but severe nonadherence (\u0026lt;\u0026thinsp;45%) was associated with early mortality.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAdherence\u0026thinsp;\u0026ge;\u0026thinsp;50% provided a robust advantage in DFS, with a one-third reduction in the risk of recurrence at 5 years.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe benefits appear to be driven by the combination of nutritional, fluid, and metabolic support measures and mobilization, rather than by achieving a very high adherence rate.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eA decrease in surgical complications accompanies increased adherence and may mediate part of the effect on DFS.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThese results suggest that, within the context of oncologic colorectal surgery, there is a practical threshold of adherence close to 50% that already produces measurable oncologic benefits, while reinforcing adherence below this level could prevent early surgery-related mortality and tumor progression.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur findings reaffirm that intermediate adherence (\u0026ge;\u0026thinsp;50%) to multimodal rehabilitation programs has a favorable impact on disease-free survival (DFS), whereas extremely low levels of adherence (\u0026lt;\u0026thinsp;45%) are associated with higher early mortality. These results are consistent with the meta-analysis by Spanjersberg et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], which demonstrated an inverse relationship between major complications and ERAS adherence, and with the multicenter series by Francis et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], where each 10% increase in adherence resulted in a 7% relative reduction in recurrence at 3 years.\u003c/p\u003e \u003cp\u003eFrom a pathophysiological perspective, inhibiting the perioperative inflammatory response and preserving immunocompetence appear critical. Experimental studies indicate that insulin resistance and fluid overload enhance the release of pro-metastatic cytokines and suppress NK cell activity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Compliance with key elements such as goal-guided fluid therapy and early nutrition, which in our cohort were correlated with a lower risk of recurrence, supports this hypothesis.\u003c/p\u003e \u003cp\u003eHowever, we did not observe additional benefits above 70% adherence, unlike the Swedish cohort of Gustafsson et al. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] where overall survival progressively improved with each adherence quartile. The low proportion of highly adherent patients (16%) and the limited number of events in our study may have limited the statistical power to capture subtle differences, underscoring the importance of adequate sample sizes.\u003c/p\u003e \u003cp\u003eThe unexpected association between omitting the nasogastric tube and higher 5-year mortality deserves special mention. This finding contradicts most ERAS series [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and likely reflects residual confounding.\u003c/p\u003e \u003cp\u003eThe results of our study align with the global evidence synthesized in the systematic review by Pang et al., which included 36 oncology cohorts and demonstrated that ERAS programs reduce overall mortality by 20% and the recurrence rate by 32% compared with conventional care [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Our identification of a minimum effective threshold (\u0026asymp;\u0026thinsp;50% adherence) complements that work, where the authors already suggested the existence of a dose effect but without defining a practical cutoff.\u003c/p\u003e \u003cp\u003eIn larger contemporary populations, Zorrilla-Vaca et al. observed that enrollment in an ERAS program was associated with improved 5-year cancer-specific survival and lower 5-year recurrence, even after adjusting for stage and adjuvant treatment [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Similarly, the French multicenter registry by Tidadini et al., with more than 1000 colorectal resections, confirmed that \u0026ge;\u0026thinsp;60% adherence translated into an absolute advantage of 7 points in 3-year survival [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Both series support our conclusion that oncological benefits emerge with intermediate degrees of adherence, without the need for perfect implementation.\u003c/p\u003e \u003cp\u003eFrom a pathophysiological perspective, Crippa et al. demonstrated that the minimally invasive approach combined with ERAS significantly attenuates peak levels of IL-6 and cortisol, resulting in improved 5-year cancer-specific survival [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Furthermore, the prospective substudy by Asklid et al. documented that liberal fluid therapy\u0026mdash;one of the common protocol violations in our cohort\u0026mdash;is associated with higher mortality and recurrence, reinforcing the value of hemodynamic optimization [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Finally, the editorial by Slim[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] emphasizes that the potential impact of ERAS on tumor biology could constitute an \u0026ldquo;unexpected advantage,\u0026rdquo; an argument partially supported by our data, which shows a lower risk of recurrence with adhesions\u0026thinsp;\u0026ge;\u0026thinsp;50%.\u003c/p\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eOur study has several limitations inherent to its single-center design. First, the lack of randomization makes it difficult to rule out confounding by unmeasured factors, such as the biological aggressiveness of the tumor or differences in adjuvant chemotherapy. Second, the sample size is relatively small, with a small number of events in the high-adherence subgroups, which reduces the power to detect modest effects and widens the confidence intervals. Third, some items (e.g., premedication or avoidance of drains) showed low adherence rates, making individual analysis difficult. Fourth, the definition of percentage adherence assumes that each measure carries equal weight, although recent evidence suggests that certain components (e.g., nutritional optimization and hemodynamic control) have a greater prognostic impact [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Finally, the generalization of our results may be limited to centers with similar patient profiles and clinical practices.\u003c/p\u003e\n\u003ch3\u003eClinical implications and future directions\u003c/h3\u003e\n\u003cp\u003eDespite these limitations, our data provide a pragmatic message: achieving at least half of the ERAS measures appears sufficient to obtain an oncologic advantage, while falling below 45% is associated with early adverse outcomes. Prioritizing high-impact items (early nutrition, mobilization, and fluid management) may be an effective strategy in resource-limited settings. Prospective multicenter studies\u0026mdash;ideally with randomized assignment of critical components\u0026mdash;are needed to confirm the identified cutoff points and unravel the underlying immunometabolic mechanisms.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthical approval for this study was obtained from the Comit\u0026eacute; de \u0026Eacute;tica de la Investigaci\u0026oacute;n de la Comunidad Aut\u0026oacute;noma de Arag\u0026oacute;n.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eEEG and MEG conceived the study and coordinated the surgical registry. EEG collected clinical data and verified oncological outcomes. EEG performed the statistical analyses. EEG, MEG and JMRR. drafted the manuscript. JMRR prepared tables 1\u0026ndash;3 and the supplementary figures. All authors critically reviewed the manuscript, contributed to revisions, and approved the final version for submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKehlet H, Wilmore DW. Fast-track surgery. Br J Surg. 2003;90(1):123\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilmore DW, Kehlet H. Management of patients in fast-track surgery. BMJ. 2001;322(7284):473\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpanjersberg WR, Reurings J, Keus F, van Lans-Verbeke M, Stolker RJ, Luitse JS. Fast-track recovery strategies versus conventional care for colorectal surgery: systematic review and meta-analysis. Dis Colon Rectum. 2015;58(5):583\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreco M, Capretti G, Beretta L, Gemma M, Pecorelli N, Braga M. Enhanced recovery program in colorectal surgery: a meta-analysis of randomized controlled trials. World J Surg. 2014;38(6):1531\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRollins KE, Lobo DN, Joshi GP. Enhanced recovery after surgery: current status and future progress. Best Pract Res Clin Anaesthesiol. 2021;35(4):479\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLobo DN, Joshi GP, Kehlet H. Challenges in enhanced recovery after surgery (ERAS) research. Br J Anaesth. 2024;133(4):717\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePang Q, Duan L, Jiang Y, Liu H. Oncologic and long-term outcomes of enhanced recovery after surgery in cancer surgeries: a systematic review. World J Surg Oncol. 2021;19(1):191.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGustafsson UO, Oppelstrup H, Thorell A, Nygren J, Ljungqvist O. Adherence to the ERAS protocol is associated with 5-year survival after colorectal cancer surgery: a retrospective cohort study. World J Surg. 2016;40(7):1741\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRipoll\u0026eacute;s-Melchor J, Ram\u0026iacute;rez-Rodr\u0026iacute;guez JM, Casans-Franc\u0026eacute;s R, Aldecoa C, Abad-Motos A, Logro\u0026ntilde;o-Egea M, et al. Association between use of enhanced recovery after surgery protocol and postoperative complications in colorectal surgery: the POWER study. JAMA Surg. 2019;154(8):725\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpanjersberg WR, Reurings J, Keus F, van Laarhoven CJ. Enhanced recovery after colorectal surgery: a systematic review and meta-analysis. Lancet Oncol. 2018;19:229\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eH\u0026uuml;bner M, Diana M, Zurcher M, Demartines N. Surgical complications affect cancer outcome: pathophysiology and therapeutic implications. Nat Rev Clin Oncol. 2021;18:59\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelis SG, Bakoyiannis A, Tassopoulos N, et al. Nasogastric decompression after colorectal surgery: a meta-analysis. Ann Surg. 2017;265:414\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuller S, Manfredi S, Mariette C, et al. Weighting ERAS items: which components drive long-term survival after colorectal resection? Br J Surg. 2023;110:458\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePang Q, Duan L, Jiang Y, Liu H. Oncologic and long-term outcomes of enhanced recovery after surgery in cancer surgeries \u0026ndash; a systematic review. World J Surg Oncol. 2021;19:191.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZorrilla-Vaca A, Ripolles-Melchor J, Abad-Motos A, et al. Association between enrollment in an enhanced recovery program for colorectal cancer surgery and long-term recurrence and survival. J Surg Oncol. 2022;125(8):1269\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTidadini F, Bonne A, Trilling B, et al. Effect of implementation of ERAS protocol and risk factors on 3-year survival after colorectal surgery for cancer: a retrospective cohort of 1001 patients. Int J Colorectal Dis. 2022;37(5):1151\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrippa J, Calini G, Santambrogio G, et al. ERAS protocol applied to oncological colorectal mini-invasive surgery reduces the surgical stress response and improves long-term cancer-specific survival. Surg Laparosc Endosc Percutan Tech. 2023;33(3):297\u0026ndash;301.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsklid D, Segelman J, Gedda C, Hjern F. The impact of perioperative fluid therapy on short-term outcomes and 5-year survival among patients undergoing colorectal cancer surgery: a prospective cohort study within an ERAS protocol. Eur J Surg Oncol. 2017;43(8):1433\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlim K, Regimbeau JM. Increased survival might be an unexpected additional advantage of enhanced recovery after surgery programs. J Visc Surg. 2018;155:169\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","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":"ERAS, enhanced recovery, colorectal cancer, overall survival, disease-free survival, adherence threshold, complications","lastPublishedDoi":"10.21203/rs.3.rs-6822349/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6822349/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEnhanced Recovery After Surgery (ERAS) programmes shorten recovery after colorectal resection, yet the amount of protocol adherence that translates into long-term oncological benefit is unclear. We explored the impact of different adherence thresholds on overall survival (OS), disease-free survival (DFS) and early morbidity after colorectal cancer surgery.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA prospective cohort study was conducted at Hospital Cl\u0026iacute;nico Universitario Lozano Blesa (Zaragoza, Spain). Consecutive adults undergoing elective curative resection for colorectal cancer (September 2011 \u0026ndash; February 2013) were analysed. Adherence to a 19-item ERAS pathway (5 pre-, 10 intra- and 4 post-operative elements) was recorded dichotomously; individual patient adherence was expressed as a percentage and stratified into three categories: \u0026lt; 50%, 50\u0026ndash;69% and \u0026ge;\u0026thinsp;70%. Primary outcomes were OS and DFS at 1, 3 and 5 years. Secondary outcomes were 30-day complications and length of stay (LOS). Kaplan\u0026ndash;Meier curves, log-rank tests and Cox regression (adjusted for age, sex, comorbidity and AJCC stage) were applied.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe study included 147 patients (57% male, mean age 70.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2 years). Median adherence was 47.4% (IQR 42.1\u0026ndash;63.2); only 15.6% achieved\u0026thinsp;\u0026ge;\u0026thinsp;70%. Five-year OS was 76% for the whole cohort and did not differ between patients with \u0026ge;\u0026thinsp;70% versus \u0026lt;\u0026thinsp;70% adherence (HR 1.21; 95% CI 0.50\u0026ndash;2.94; p\u0026thinsp;=\u0026thinsp;0.673). However, adherence\u0026thinsp;\u0026lt;\u0026thinsp;45% independently predicted early mortality (\u0026le;\u0026thinsp;12 months; HR 5.70; 95% CI 1.11\u0026ndash;29.4; p\u0026thinsp;=\u0026thinsp;0.038). Adherence\u0026thinsp;\u0026ge;\u0026thinsp;50% reduced the risk of recurrence at 5 years (HR 0.34; 95% CI 0.16\u0026ndash;0.72; p\u0026thinsp;=\u0026thinsp;0.006) and 3 years (HR 0.39; 95% CI 0.18\u0026ndash;0.90; p\u0026thinsp;=\u0026thinsp;0.024). Global complication rates fell from 61% (\u0026lt;\u0026thinsp;50% adherence) to 35% (\u0026ge;\u0026thinsp;70%; p\u0026thinsp;=\u0026thinsp;0.04), with significant reductions in superficial surgical-site infection and reoperation. Median LOS decreased from 9 to 7 days among patients with \u0026ge;\u0026thinsp;70% adherence (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn this ERAS cohort, an adherence threshold of ~\u0026thinsp;50% was associated with superior DFS and fewer recurrences, while very low adherence (\u0026lt;\u0026thinsp;45%) predicted early death. These findings suggest a minimum \u0026lsquo;effective dose\u0026rsquo; of ERAS and support targeted strategies to lift low-performing elements rather than striving solely for perfect compliance\u003c/p\u003e","manuscriptTitle":"Identification of Adherence Cut-off Points to the ERAS Protocol: Impact on Survival and Recurrence in Colorectal Cancer Surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-03 06:39:17","doi":"10.21203/rs.3.rs-6822349/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","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":"a223051a-a1f7-4844-a391-4d7e20c26293","owner":[],"postedDate":"July 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-20T15:55:54+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-03 06:39:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6822349","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6822349","identity":"rs-6822349","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}