Can neoadjuvant chemoradiotherapy be omitted in cT2N+ and cT3 mid-rectal cancer: Protocol for a prospective, observational, non-inferiority trial (CANO)

Can neoadjuvant chemoradiotherapy be omitted in cT2N+ and cT3 mid-rectal cancer: Protocol for a prospective, observational, non-inferiority trial (CANO) | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (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];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Can neoadjuvant chemoradiotherapy be omitted in cT2N+ and cT3 mid-rectal cancer: Protocol for a prospective, observational, non-inferiority trial (CANO) Feza Karakayali , View ORCID Profile Cigdem Arslan , Tayfun Bisgin , Ilknur Erenler Bayraktar , Onur Bayraktar , View ORCID Profile Aras Emre Canda doi: https://doi.org/10.1101/2025.03.14.25323938 Feza Karakayali 1 Department of Surgery, Faculty of Medicine, Baskent University , Istanbul, Türkiye Find this author on Google Scholar Find this author on PubMed Search for this author on this site Cigdem Arslan 2 Department of Surgery, Klinist Private Clinic , Istanbul, Türkiye Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Cigdem Arslan For correspondence: cigdemarslan{at}hotmail.it Tayfun Bisgin 3 Department of Surgery, Faculty of Medicine, Dokuz Eylul University , Izmir, Türkiye Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ilknur Erenler Bayraktar 4 Department of Surgery, Faculty of Medicine, Halic University , Istanbul, Türkiye Find this author on Google Scholar Find this author on PubMed Search for this author on this site Onur Bayraktar 4 Department of Surgery, Faculty of Medicine, Halic University , Istanbul, Türkiye Find this author on Google Scholar Find this author on PubMed Search for this author on this site Aras Emre Canda 5 Department of Surgery, Acibadem Kent Hospital , Izmir, Türkiye Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Aras Emre Canda Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Background Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer. However, nCRT is associated with significant morbidity, impacting patients’ quality of life. Recent advancements in MRI-based risk stratification have raised the possibility of omitting nCRT in selected patients without compromising oncologic outcomes. This study aims to evaluate whether upfront TME alone achieves non-inferior 3-year disease-free survival compared to the standard approach of nCRT followed by TME in patients with cT2N+ and cT3Nx mid-rectal cancer without mesorectal fascia involvement. Methods The CANO trial is a prospective, multicenter, observational non-inferiority study involving 1992 patients across Türkiye. Eligible patients will be classified into two groups: those undergoing direct TME and those receiving nCRT followed by TME. The primary endpoint is 3-year disease-free survival (DFS), with secondary outcomes including 5-year DFS, overall survival, local recurrence rates, and quality of life assessments using validated questionnaires. Data will be prospectively collected and monitored by the steering committee with predefined interim analyses. Discussion The CANO trial addresses the ongoing debate regarding selective omission of nCRT in low-risk mid-rectal cancer. By leveraging MRI-based risk stratification and a collaborative national network, the study aims to provide high-quality evidence supporting a more personalized treatment approach. The findings have the potential to reduce treatment-related morbidity without compromising oncologic safety, contributing to the refinement of current guidelines. Trial registration NCT06823297 [ ClinicalTrials.gov ] [registered before starting inclusion; Version 3, 03.02.2025]. Introduction Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) has been the standard treatment for locally advanced rectal cancer, significantly reducing local recurrence rates [ 1 – 4 ], particularly in cases with threatened mesorectal fascia (MRF) or a positive circumferential resection margin (CRM) [ 5 , 6 ]. However, despite its oncologic benefits, nCRT is associated with considerable morbidity, including bowel dysfunction, fecal incontinence, and sexual dysfunction, which can severely impact patients’ quality of life (QoL) [ 2 , 3 , 7 ]. Additionally, with advancements in rectal cancer surgery, the necessity of nCRT for all locally advanced rectal cancer cases has been increasingly debated. Several studies, including OCUM, MERCURY, and QuickSilver, have investigated more selective approaches to nCRT to minimize overtreatment while maintaining oncologic safety [ 8 – 10 ]. These studies have demonstrated that MRI-predicted negative CRM strongly indicates favorable oncologic outcomes, allowing for primary surgery without nCRT in appropriately selected patients. The OCUM trial, in particular, showed that patients with magnetic resonance imaging (MRI)-negative CRM undergoing upfront TME had an acceptably low local recurrence rate (<10%) at five years [ 8 ]. The MERCURY trial further validated MRI as a reliable tool for preoperative risk stratification, demonstrating a high accuracy in predicting negative CRM and a low risk of local recurrence in MRI-negative patients [ 9 ]. Despite these promising results, the optimal selection criteria for omitting nCRT remain a subject of ongoing research. Current European guidelines, including those from the European Society for Medical Oncology (ESMO), advocate a risk-adapted approach to nCRT. According to ESMO, patients with cT3a/b rectal tumors located above the levator muscles, without CRM involvement or extramural vascular invasion, are considered to have a low risk of local recurrence and may be candidates for upfront surgery without nCRT [ 11 ]. This contrasts with North American guidelines, which still recommend routine nCRT for stage II and III rectal cancers [ 12 ]. However, given that modern surgical techniques have significantly reduced the risk of CRM positivity and local recurrence, a more selective approach to nCRT may be warranted. This trial aims to investigate whether avoiding nCRT provides oncological outcomes equivalent to the standard approach in patients with locally advanced mid-rectal cancer who have a low risk of local recurrence. By leveraging MRI-based risk stratification and a real-world, multi-center cohort, this study seeks to refine patient selection criteria for nCRT and reduce unnecessary exposure to chemoradiotherapy in low-risk patients. Methods Study setting The CANO protocol has been designed by six principal investigators (steering committee) affiliated with five tertiary referral hospitals in Türkiye (Baskent University Hospital, Dokuz Eylul University Hospital, Halic University Memorial Sisli Hospital and Acibadem Kent Hospital) which are specialized in the treatment of colorectal. The study is coordinated by the study chair (FK) from Baskent University. The steering committee includes two members responsible for writing and updating the protocol (CA, TB), two members responsible for study secretariat and communication with participant centers (IEB, OB), and two members responsible for data storage, reliability, monitoring and safety (TB, AEC). All centers in Türkiye implementing a multidisciplinary approach to rectal cancer will be invited to participate in the study by Turkish Society of Colon and Rectal Surgery (TSCRS). The clinical administrative officer or department head of all centers will be reached by e-mail. The details of the protocol have been announced on the webpage prepared by the steering committee ( https://arastirma.tkrcd.org.tr/ ). Centers invited to participate in the study will be informed through this website and will also receive additional information via a webinar organized by TSCRS. In accordance with the guidelines of the Turkish Ministry of Health - Drug and Medical Devices Agency, centers that agree to participate in the study must submit a letter of support to TSCRS on behalf of the study chair (FK). This support letter must include the permission of the institutional data sharing; the signatures of the supervising researcher and clinical administrative officer/department head. Centers that submit their letters by the specified deadline (1 April 2025 anticipated) will be added to the study sites list as an update in the protocol on clinicaltrials.gov . Trial registration and ethical considerations The study protocol has been prepared in accordance with SPIRIT guidelines (S1) and approved by Baskent University Ethical Review Board on 08-01-2025 (Approval number: KA24/461) (S2-3). The trial protocol has been registered before starting inclusion ( NCT06823297 , ClinicalTrials.gov ). The study has not started patient recruitment yet and the anticipated recruitment date is 01.04.2025. The anticipated timeline is as follows: Primary recruitment completion: April, 2030, study completion: April, 2030. Given that patients undergoing TME will be included in this study, written informed consent will be obtained from all eligible patients prior to the surgery, in conjunction with the surgical consent. A distinct informed consent form for the study, prepared by the steering committee and approved by the ethics committee, exists separately from the institutional informed consent form (S4). The attending surgeon is responsible for providing the patient with comprehensive information regarding the study and securing this consent in written form. Another healthcare provider (nurse, resident, surgeon) will witness the consenting process. In this study, participant data and biological specimens are not being collected for ancillary studies. However, each institution participating in the study may include statements in their own surgical informed consent forms regarding the use of patient information and specimens in other studies. This responsibility lies with the respective institution and the surgeon. Funding The TSCRS is the sponsor of the study and covers all the expenses. Detailed information and contact is available on https://www.tkrcd.org.tr/en/ . The TSCRS is the official association of colorectal surgeons in Türkiye and operates as a non-profit organization. Funding covers the expenses related to secretarial services, website design, announcement of the protocol and data storage software. The funder plays no role in the design of the study, analysis, and interpretation of data and in writing the manuscript. However, all the investigators are members of society. TSCRS has also stated that it will cover any future expenses that may arise (S5). The authors do not have any financial relationship with the sponsor and receive any personal funding. The authors declare that they have no competing interests. The authors of this protocol and other researchers planned to be involved in the study in the future are members of TRCRS which is the official professional society of colorectal surgeons in Turkey and is a non-profit organization. Trial design The CANO trial is a prospective, non-randomized, observational, non-inferiority study. Patients undergoing TME will be included in the study, with a comparative analysis between those receiving neoadjuvant chemoradiotherapy and those who do not. The design precludes any possibility of cross-over between the groups. Main Question Does direct TME provide equivalent 3-year disease-free survival compared to TME following nCRT in mid-rectal cancer with cT2N+ and cT3Nx without MRF involvement? Eligibility criteria The study population consists of male and female patients aged 18 years and older who will undergo TME for histologically confirmed rectal cancer staged as locally advanced (cT2N0-T3N0-N+), without distant metastases or high-risk features such as MRF involvement or invasion of adjacent organs (cT4). Inclusion Criteria Pathologically confirmed rectal cancer Rectal cancer within 6-12 cm from anal verge confirmed by sigmoidoscopy or located between the anorectal junction and peritoneal reflection identified by MRI Clinically staged with pelvic MRI and thoracoabdominal computed tomography (CT) Local clinical stages cT2N+, cT3N0 and cT3N+ Patients without MRF involvement assessed by MRI (≤1 mm) Patients who underwent open, laparoscopic or robotic TME Exclusion Criteria cT4 tumors assessed by MRI Stage IV disease assessed by MRI and/or CT Emergency surgery Clinical obstruction Previous pelvic radiotherapy Patients treated without a multidisciplinary council decision Inflammatory bowel diseases (Crohn’s disease, Ulcerative colitis) Familial adenomatous polyposis (FAP), attenuated FAP, and other polyposis syndromes Hereditary non-polyposis colorectal cancer (Lynch syndrome) Synchronous colon tumors Patients undergoing surgeries other than TME (e.g. partial mesorectal excision, rectosigmoid resection, end colostomy) will not be included in the study. Following data entry, patients for whom pathology reports indicate that TME was not performed or who has missing data regarding inclusion criteria will be excluded from the study. Patients who are unable to complete neoadjuvant therapy for any reason (such as toxicity, non-compliance, or accessibility issues) will not be excluded from the study. These patients will be evaluated within the neoadjuvant therapy group. Accordingly, when analyzing this aspect, an intention-to-treat analysis will be conducted without cross-over. Interventions The standard of care for the treatment of locally advanced rectal cancer is TME. In patients with cT2N+, cT3N0, and cT3N+ mid-rectal tumors, the administration of nCRT, as well as the direct TME, are both considered guideline-concordant standard treatment approaches and are widely practiced [ 11 , 12 ]. In this study, data from patients undergoing TME as part of routine medical care will be collected prospectively. No additional interventions, treatments and follow-up protocols outside of standard care will be implemented. At the end of the study, patients will be categorized into two groups based on whether they received nCRT and the two groups will be compared in terms of primary and secondary endpoints. No treatment or monitoring protocols differing from routine practice will be proposed for patients or surgeons in the study. The natural prognosis of the treatment arms will be observed. All the patients undergoing TME described as a precise dissection of the rectum along with the surrounding mesorectal tissue and all pararectal lymph nodes are eligible for the study [ 13 ]. Direct TME Group Patients who undergo direct TME without neoadjuvant treatment. nCRT Group Patients who receive nCRT prior to TME. Neoadjuvan cRT treatments include all conventional chemoradiotherapy regimens or total neoadjuvant chemoradiotherapy regimens (standard short or long course radiation combined with any standard chemotherapy regimen) described in European and American guidelines [ 11 , 12 ]. The details of radiotherapy and chemotherapy treatments will be recorded, including dosage, frequency, duration, complications, completion status, and the waiting period between treatments. Routine follow-up information for all patients including morbidity, radiologic assessments, recurrence, mortality be recorded in the database for the first five years post-surgery. Outcomes Primary Outcome Measure year DFS: The proportion of patients who remain free of disease recurrence (local or distant) three years after surgical intervention. DFS will be assessed through clinical evaluations, imaging studies, and pathology reports at regular follow-up intervals. Secondary Outcome Measures 5-year DFS: The proportion of patients who remain free of disease recurrence (local or distant) five years after surgical intervention. 3- and 5-year Overall Survival: The proportion of patients alive at 3- and 5-years post-treatment, regardless of disease status. 3- and 5-year Local Recurrence Rate: The percentage of patients experiencing tumor recurrence at the primary site (anastomosis or pelvis) within 3 and 5 years. 1-, 3- and 5-year Colorectal Cancer Specific Quality of Life: Patient-reported outcomes assessed using the New Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire [ 14 ] 1-, 3- and 5-year Bowel Dysfunction Related Quality of Life: Patient-reported outcomes assessed using the low-anterior resection syndrome (LARS) score [ 15 ] Fig 1 represents the timeline of anticipated recruitment and outcome measures. Download figure Open in new tab Fig 1. The timeline showing patient recruitment and measurement timeframes for outcome measures. Sample size and recruitment The literature reports a mean 3-year disease-free survival rate of 85% for the sample to be included in the study [ 16 ]. For the non-inferiority analysis, the predetermined threshold value (Δ) is set at 5%, with α=0.05 (95% confidence interval) and β=0.2 (80% power), necessitating 905 patients in each group. Considering an anticipated exclusion of 10% of patients due to loss to follow-up, it is planned to include 996 patients in each group, resulting in a total of 1992 participants. According to data from the Turkish Ministry of Health, General Directorate of Public Health, a total of 24,312 patients were diagnosed with rectal cancer between 2020 and 2024, of whom 17,896 underwent surgery ( https://hsgm.saglik.gov.tr/tr/kanser.html ). Since this study will be conducted nationally under the sponsorship of the main society of Turkish colorectal surgeons TSCRS, we anticipate reaching the targeted patient number within five years from the start of the study. To achieve this goal, TSCRS will utilize various channels, including mailing, social media, and its website, to announce the study and inform surgeons about the protocol. Data collection and management Researchers will input patient data into the electronic database which is currently used in the TSCRS prospective registry (Redcap). This database includes all variables regarding demographic, clinical, surgical, oncologic and functional outcomes of the patients (S6). The patients’ baseline clinical tumor stages, clinical tumor stages before and after neoadjuvant treatments, type of surgery, early and late postoperative complications, postoperative pathological tumor stages, imaging results from the routine rectal cancer follow-up protocol, recurrence, and survival data will be prospectively entered into the database by the researchers. Patient reported outcomes will be collected by electronic surveys via TSCRS website. The Turkish versions of New Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire [ 14 ] and LARS score [ 15 ] have been validated before. Centers that submit support letters by the specified deadline will have a RedCap username and password created for each researcher in the TSCRS prospective database. Each center can participate in the study with a team consisting of one supervisor/faculty member/specialist doctor and a two-person data collection team (a physician, a medical specialty student, or a medical school student), making a total of three people. The team members are responsible for collecting the data, entering it into the database under the conditions set by the steering committee, and communicating with the research secretary when necessary. The supervisor of the team is responsible for the security and accuracy of the data. The entered data will be reviewed and approved by the controller researchers (TB, AEC) and the study secretary (employed by TSCRS) for reliability and errors. Access to data and confidentiality All protocols have been shared on open-access platforms including clinicaltrials.gov and the website of the trial ( https://arastirma.tkrcd.org.tr/ ). Access to the database containing patient information will be restricted to the steering committee only. The database may be shared with authorities upon request from ethical committees and health authorities. Upon request, de-identified patient information may be shared with third parties and external researchers. The data entered into the database by the investigators transferred to the SPSS worksheet by the study secretary and stored in a digital cloud system (Microsoft OneDrive) accessible only to steering committee and the study secretary. Consent forms will be delivered to the study secretary by the center supervisors and stored in the cloud by the study secretary. All physical and digital data collected during the study will be retained for 3 years after the completion of the study (a total of 8 years from the start of the study) and will then be permanently destroyed. Statistical methods During the study, missing data analyses and data quality assessments will be actively conducted, and steps to prevent data loss and enhance data quality will be planned in the most appropriate manner. Following the completion of the project, a final data quality assessment will be conducted to ensure the data is ready for analysis. Statistical analyses will be carried out by experts from the TSCRS Biostatistics and Bioinformatics Analysis Unit using SPSS (SPSS Inc, Chicago, IL) software packages. As the primary objective of the study, the effect of demographic and other pre-treatment clinical findings on 3-year disease-free survival will be investigated using multivariable regression models. As the secondary objective, the relationship between overall survival, local recurrence, perioperative complications, and post-treatment quality of life scores with the treatment methods used will also be analyzed using multivariable regression models. The interaction of these relationships with demographic and other clinical findings may also be included in the model. Patients lacking the main data specified in the inclusion and exclusion criteria, demographic data, and follow-up data related to the primary endpoint will be completely excluded from the study. Patients with missing data from other variables and secondary endpoints will only be excluded from those specific analyses. Secondary endpoints will be evaluated using data from patients with complete datasets. The data monitoring committee and interim analyses Two members of the steering committee (TB, AEC) are responsible for data monitoring. These investigators will coordinate with the data processing secretary employed by the sponsor (TSCRS) to check the reliability and completeness of the data on a weekly basis. They will present reports to the steering committee every month and to the participant investigators twice a year. They are responsible for interim analysis and adverse event monitoring every six months. The interim results of the study will be shared at national and international meetings and conferences as the primary and secondary endpoints are reached (in 1, 3 and 5 years after intervention). After completion of the study, the results will be prepared as a manuscript and published in a journal as well as clinicaltirals.gov. The data monitoring committee members are affiliated with the sponsor, TSCRS, which is a non-profit professional association, and all investigators who are going to be invited in this study are members of this association. An independent monitoring committee has not been established for the study. Adverse event reporting, safety and Criteria for discontinuing In this study, a non-standard treatment that is not currently implemented will not be evaluated. Consequently, side effects and adverse events will be documented as part of the routine monitoring process. However, the steering committee (TB, AEC) will assess interim analyses regarding any safety measures every six months. The study will be terminated if a new treatment relevant to patient groups in rectal cancer management is introduced during the study period and included in the guidelines, and/or there are unacceptable disease-free survival or local recurrence rates (a difference of more than 10%) in any treatment arm that could adversely affect the success of the project. To ensure the safe conduct of the project in the event of such risks, measures will be taken and monitored by the steering committee. The TSCRS will inform relevant parties and all members through e-mail, society website and social media accounts regarding important protocol amendments. The study will continue until the necessary number of patients is reached. The study will be terminated if a new treatment relevant to patient groups in rectal cancer management is introduced during the study period and included in the guidelines, and/or there are unacceptable disease-free survival or local recurrence rates (a difference of more than 10%) in any treatment arm. Discussion In line with current recommendations, some surgeons perform upfront TME for patients with T2-3 node-positive mid-rectal cancer in the absence of MRF involvement. However, in these cases, the common approach is to administer neoadjuvant chemoradiotherapy. This study seeks to evaluate whether upfront TME achieves non-inferior 3-year disease-free survival compared to the standard. Limitations The non-randomized, observational design introduces the potential for selection bias. Although intention-to-treat analysis will be conducted, residual confounding factors may still affect the comparability of the two treatment arms. Moreover, the trial’s reliance on MRI-based risk stratification, while evidence-based, may lead to variability in interpretations across different centers, particularly in the absence of centralized imaging review. The lack of blinding among investigators could also introduce information bias in the assessment of outcomes such as local recurrence and quality of life. Another limitation is the absence of central pathology review, which may impact the consistency of histopathological assessments. Additionally, the prolonged follow-up period of five years poses logistical challenges in maintaining patient retention and data completeness, despite the study’s comprehensive data management plan. Lastly, while the trial aims to address the overtreatment of low-risk rectal cancer, the ethical consideration of potentially omitting nCRT in patients who might benefit from it remains a critical issue. The steering committee’s predefined safety measures and monitoring are essential safeguards, but the non-inferiority design inherently carries the risk of accepting a small loss in efficacy for the sake of reducing treatment-related morbidity. Strengths The CANO trial presents several notable strengths that contribute to its potential impact on clinical practice and the broader colorectal cancer literature. First, the study’s prospective, multicenter design involving numerous institutions across Türkiye ensures a high level of external validity and generalizability. By enrolling a large cohort of 1992 patients, the trial will provide robust statistical power to detect non-inferiority between direct TME and nCRT followed by TME. Additionally, the study’s observational nature reflects real-world practice, which enhances the applicability of the findings to routine clinical settings. Another key strength is the rigorous inclusion and exclusion criteria based on MRI-based risk stratification, which aligns with contemporary guidelines advocating for personalized treatment strategies. The comprehensive data collection process, including both oncologic outcomes and patient-reported quality of life measures such as the LARS score and New Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire, allows for a holistic evaluation of treatment efficacy and its impact on patients’ well-being. The study’s voluntary, society-led approach fosters national collaboration among colorectal surgeons, potentially establishing a valuable model for future multicenter research initiatives in Türkiye. The transparent protocol submission and early feedback collection from the scientific community further strengthen the study’s methodological rigor. Conclusion The CANO trial has the potential to provide pivotal evidence on the selective use of neoadjuvant chemoradiotherapy in mid-rectal cancer. If successful, the results could guide a more personalized approach to rectal cancer treatment, minimizing overtreatment without compromising oncologic outcomes. The study’s findings will not only contribute to the literature but also serve as a model for future collaborative research efforts in Türkiye and beyond. Data Availability No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. NA Supporting information Acknowledgements None References 1. ↵ Peeters KC , Marijnen CA , Nagtegaal ID , Kranenbarg EK , Putter H , Wiggers T , et al. The TME trial after a median follow-up of 6 years: Increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma . Ann Surg . 2007 ; 246 ( 5 ): 693 – 701 . 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