Functional Outcomes in Rectal Cancer Patients Treated with Immunotherapy and Neoadjuvant Therapy: A Retrospective Analysis

Functional Outcomes in Rectal Cancer Patients Treated with Immunotherapy and Neoadjuvant Therapy: A Retrospective Analysis | 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 Functional Outcomes in Rectal Cancer Patients Treated with Immunotherapy and Neoadjuvant Therapy: A Retrospective Analysis Xu Li, Gan Mao, Yisong Gao, Tianyu Song, Zilong Wu, Chong Li, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6283768/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jun, 2025 Read the published version in Langenbeck's Archives of Surgery → Version 1 posted 9 You are reading this latest preprint version Abstract Objective This study aims to evaluate bowel and urogenital function in patients with locally advanced low rectal cancer treated with immunotherapy combined with neoadjuvant therapy followed by surgery, compared to surgery alone. Methods We conducted a retrospective analysis of 162 patients with locally advanced low rectal cancer treated at Union Hospital, affiliated with Tongji Medical College, Huazhong University of Science and Technology, from May 2021 to May 2024. Seventy-three patients underwent short-course radiotherapy combined with chemotherapy and immunotherapy followed by surgery (SCRT-CIT group), while 89 patients received surgery alone (non-SCRT-CIT group). Standardized questionnaires assessed bowel and urogenital function. Logistic regression analysis was used to identify independent predictors of functional outcomes. Results The incidence of major low anterior resection syndrome (LARS) was significantly higher in the SCRT-CIT group (59.0%) compared to the non-SCRT-CIT group (9.2%). Multivariate analysis identified SCRT-CIT as an independent risk factor for bowel dysfunction (odds ratio [OR] = 16.31, 95% confidence interval [CI] 6.69–39.77, P < 0.001). SCRT-CIT was also associated with an increased risk of erectile dysfunction in men (OR = 5.49, 95% CI 1.92–15.70, P = 0.001) and reduced sexual duration (P = 0.003). In women, SCRT-CIT correlated with a higher prevalence of dyspareunia (P = 0.004) and reduced sexual satisfaction (P = 0.003). Conclusion SCRT-CIT combined with surgery is associated with a significantly higher risk of bowel dysfunction, male erectile dysfunction, reduced sexual duration, and female sexual impairments, including dyspareunia and diminished sexual satisfaction. These findings underscore the importance of comprehensive functional assessments and individualized management for patients undergoing SCRT-CIT for locally advanced low rectal cancer. Rectal cancer Immunotherapy Locally advanced rectal cancer Functional outcome Figures Figure 1 Introduction Colorectal cancer accounts for 9.6% of all malignant tumors globally, ranking third in incidence, and 9.3% of cancer-related deaths, ranking second. China has a particularly high incidence of colorectal cancer[1]. Neoadjuvant therapy combined with surgery is a critical approach in the treatment of rectal cancer, enabling complete tumor resection along with surrounding tissues. While this approach is applicable to tumors in various anatomical locations, it often leads to significant postoperative complications, including bowel and urogenital dysfunction, which can adversely impact patients’ quality of life[2、3、4]. In recent years, there has been increasing attention on postoperative functional outcomes[5]. However, rectal cancer surgery is frequently associated with severe side effects, particularly impairments in bowel and urogenital function. Bowel dysfunction, in particular, is the most common postoperative complication[6]. The Low Anterior Resection Syndrome (LARS) score is a well-established tool for assessing bowel function comprehensively[7]. This study utilizes validated questionnaires—including the LARS, International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5), and Female Sexual Function Index (FSFI)—to evaluate postoperative functional outcomes. Urinary dysfunction is often attributed to intraoperative damage to nerve fibers, though the effect of neoadjuvant therapy on urinary function remains inconsistently reported in the literature[8、9]. As a novel preoperative treatment strategy for patients with locally advanced rectal cancer, short-course radiotherapy combined with immunotherapy (SCRT-CIT) has demonstrated significantly higher pathological complete response (pCR) rates compared to traditional neoadjuvant therapies[10]. This retrospective study aims to analyze the bowel and urogenital functional outcomes in patients with locally advanced low rectal cancer (≤ 6 cm) who underwent SCRT-CIT followed by surgery at our hospital over the past three years. A secondary objective is to identify potential risk factors associated with bowel incontinence and urogenital dysfunction. Methods Study Participants The study collected cases of locally advanced low rectal cancer from the gastrointestinal surgery departments of Union Hospital, affiliated with Tongji Medical College, Huazhong University of Science and Technology, from May 2021 to May 2024. Inclusion criteria required patients to: (i) Patients aged 18–75 years. (ii) Postoperative pathological diagnosis of adenocarcinoma. (iii) Tumor located ≤ 6 cm from the anal verge. (iv) Clinical staging of cT3-4Nx or cTxN+. (v) Elective surgical treatment. (vi) Patients who received either surgery alone or SCRT-CIT followed by surgery. Exclusion criteria included: (i) Emergency surgery. (ii) Incomplete clinical or pathological data. Eligible patients were contacted by telephone to obtain informed consent and were subsequently invited to complete validated questionnaires assessing bowel function and urogenital function. The study was conducted in accordance with the ethical guidelines established by the Institutional Ethics Committee of the Medical College, and approval for the retrospective analysis was obtained from the committee. Responses were collected and analyzed statistically. The tumor’s distance from the anal verge was determined using pelvic MRI in combination with digital rectal examination. Pelvic MRI was also utilized to assess the clinical staging of rectal cancer[11、12]. All personally identifiable information has been de-identified to ensure participant confidentiality and compliance with ethical research standards. Treatments Methods Patients in the SCRT-CIT group underwent neoadjuvant therapy comprising short-course radiotherapy (a total of 25 Gy in 5 days), followed by two cycles of camrelizumab (200 mg/m² via intravenous infusion on Day 1 of a 3-week cycle) combined with CAPOX (oxaliplatin 130 mg/m² on Day 1 and capecitabine 1000 mg/m² twice daily from Day 1 to Day 14 of a 3-week cycle). Radical surgery was performed within 10 weeks after the completion of therapy, following the principles of total mesorectal excision (TME) to ensure optimal oncological and functional outcomes. Radical surgical resection was performed on patients in the non-SCRT-CIT group directly. Standard rectal cancer surgery was performed and the decision to perform sphincter-preserving surgery was based on the distance of the tumor’s lower margin from the anal verge, intraoperative conditions, patient preferences, and the technical expertise of surgeon. Data Collection and Measurement The Low Anterior Resection Syndrome (LARS) score was employed to assess bowel dysfunction[13]. This questionnaire tool evaluates five symptoms: incontinence of flatus, incontinence of liquid stool, stool frequency, clustering of bowel movements, and urgency. Scores range from 0 to 42, classifying patients into no LARS (0–20), minor LARS ( 21 – 29 ), or major LARS (30–42). The Chinese version of the LARS score has been shown to have robust psychometric properties and is suitable for clinical and research use in Chinese populations[13]. The International Prostate Symptom Score (IPSS) was used to evaluate urinary function. This tool assesses seven domains, including incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia. Scores range from 0 to 35 and are categorized into mild (0–7), moderate ( 8 – 19 ), and severe (20–35) urinary symptoms[14]. For univariate and multivariate analyses, patients scoring 8 or higher (indicating severe or moderate urinary dysfunction) were classified as having urinary dysfunction. The International Index of Erectile Function-5 (IIEF-5) was used to evaluate erectile dysfunction in male patients. The five questions are scored on a 5-point scale, with lower scores indicating more severe dysfunction. Classifications include severe ED (0–7), moderate ED ( 8 – 11 ), mild ED ( 12 – 21 ), and no dysfunction ( 22 – 25 )[15]. For univariate and multivariate analyses, male patients scoring 11 or fewer points (indicating severe or moderate erectile dysfunction) were classified as having sexual dysfunction. The sexual pleasure and dyspareunia domains of the Selected domains of the Female Sexual Function Index (FSFI) were used to evaluate the sexual function of female patients. Sexual pleasure was categorized as unchanged, reduced, or absent, while dyspareunia was classified as present or absent. Statistical Analysis Clinical variables such as age, sex, tumor height, SCRT-CIT therapy, and sphincter-preserving surgery were analyzed to identify predictors of bowel and urogenital function outcomes. Statistical analyses were conducted using R software (version 4.3.2). Measurement data following a normal distribution are expressed as the mean ± standard deviation (mean ± SD), and intergroup comparisons were performed using the t-test. While categorical variables were presented as frequencies and percentages. The Pearson's chi-square test or Fisher’s exact test was used for group comparisons and univariate and multivariate logistic regression analyses were applied to identify factors independently associated with functional outcomes. Age, BMI and tumor height were classified based on the mean of the raw data, as the mean represents the central tendency of the data. A p-value < 0.05 was considered statistically significant. Results A total of 298 patients meeting the inclusion criteria were initially identified, among whom 30 patients were excluded due to death, 83 could not be contacted, and 23 declined to participate. Data from 162 patients comprising 118 males and 44 female patients were ultimately collected and analyzed. The participation data are summarized in Fig. 1, and the patients’ characteristics are outlined in Table 1. Bowel Dysfunction The LARS questionnaire was completed by 126 patients. The results of questionnaires found that 42 patients suffered from major LARS, 29 minor LARS and 55 no LARS. Univariate analysis revealed that bowel dysfunction was significantly associated with SCRT-CIT treatment (p < 0.001) and tumor distance from the anal verge (p = 0.006) (Table 2). No significant differences were observed in terms of sex, age, tumor stage, BMI, or hypertension. Multivariate analysis demonstrated that SCRT-CIT treatment [odds ratio (OR) = 16.31; 95% confidence interval (CI), 6.69–39.77; p < 0.01] was an independent risk factor for bowel dysfunction. However, tumor height [OR = 0.53; 95% CI, 0.25–1.15; p = 0.109] was not independently associated with bowel dysfunction (Table 3 ). Urinary Dysfunction The IPSS questionnaire was completed by 126 patients, revealing that only one patient, who had undergone SCRT-CIT treatment, experienced severe urinary dysfunction. Additionally, 28 patients had moderate dysfunction, and 97 patients had mild dysfunction. For analytical purposes, moderate and severe dysfunction were combined into one group, as both have a greater impact on quality of life compared to mild dysfunction. In the univariate and multivariate analyses, no other variables were found to be associated with urinary dysfunction. Specifically, sex, age, tumor stage, BMI, hypertension, tumor height, and SCRT-CIT treatment did not significantly affect urinary function (p > 0.05) (Table 2). Male Sexual Function Among 118 male patients, 83 completed the IIEF-5 questionnaire and provided data on changes in sexual duration, after excluding those who reported no sexual activity before surgery or declined to discuss sexual function. In the SCRT-CIT group (n = 41), 13 patients had severe erectile dysfunction (ED), 9 had moderate ED, 19 had mild ED, and no patients had normal erectile function. In the surgery alone group (n = 42), 5 patients had severe ED, 3 had moderate ED, 28 had mild ED, and 6 maintained normal erectile function. The difference in erectile function between the two groups was statistically significant ( p = 0.002). Furthermore, 23 patients in the SCRT-CIT group reported significantly shortened sexual duration, compared to only 6 patients in the surgery-only group ( p < 0.001). For statistical analysis, moderate and severe ED were combined into a single group due to their greater impact on quality of life. Univariate analysis indicated that ED was significantly associated with SCRT-CIT treatment ( p = 0.002) (Table 2). No significant associations were found with sex, age, tumor stage, BMI, or hypertension. Multivariate analysis confirmed that SCRT-CIT treatment [OR = 5.49; 95% CI, 1.92–15.70; p = 0.001] was an independent risk factor for ED (Table 3 ). Female Sexual Function Of the 44 female patients, 31 patients provided valid responses after excluding those without preoperative sexual activity or those unwilling to discuss sexual function. The result indicated that 2 patients experienced complete loss of sexual pleasure, when compared with the preoperative status. A slight decline was experienced by 7 patients. And 22 described no modification of sexual pleasure compared with preoperative status. Additionally, 12 patients experienced dyspareunia. Patients with decline or absent sexual pleasure were combined into one group for analysis, and comparisons were made with patients reporting no change in sexual pleasure. Both univariate and multivariate analyses revealed that reduced sexual pleasure and dyspareunia were significantly associated with SCRT-CIT treatment ( p < 0.05) (Table 4 , Table 5 ) Discussion Immunotherapy has emerged as the first-line treatment for patients with microsatellite instability-high (MSI-H) rectal cancer, offering superior efficacy and a lower risk of side effects[16]. A meta-analysis of 10 studies demonstrated that immunotherapy significantly improves the pathological complete response (pCR) rate and major pathological response (MPR) rate in non-metastatic rectal cancer[17]. This novel approach not only reduces the risk of local recurrence but also emphasizes the importance of improving patients’ quality of life and long-term prognosis. Based on these findings, the present study aims to collect functional data from patients who underwent rectal cancer surgery with or without short-course radiotherapy combined with sequential chemotherapy and immunotherapy. The primary focus was on bowel and urogenital functions. The Chinese version of the LARS questionnaire, known for its high sensitivity and specificity, was used to evaluate bowel dysfunction in patients with low rectal cancer[18]. Univariate analysis showed significant differences in bowel function associated with treatment modality and tumor height in patients with low rectal cancer. However, multivariate analysis indicated that tumor height was not an independent factor influencing bowel function. This finding could be attributed to the fact that SCRT-CIT improves sphincter preservation rates in low rectal cancer, while patients undergoing direct surgery often had lower preservation rates. Consequently, patients with tumors ≤ 4.3 cm from the anal verge were more likely to receive SCRT-CIT, potentially introducing variability in outcomes[19]. However, Battersby et al[20] and Qin Q et al[23] found that low-lying rectal cancer is associated with impaired rectum-related quality of life based on LARS score, compared with mid and high rectal cancers. SCRT-CIT is an emerging treatment strategy that has demonstrated remarkable success in rectal cancer therapy. Most existing studies focus on the impact of neoadjuvant therapy on bowel function[21、22、23、24]. Our study specifically examined the effects of SCRT-CIT on bowel function, and multivariate regression analysis revealed a statistically significant difference between the SCRT-CIT and surgery alone groups, with SCRT-CIT having a negative impact on postoperative bowel function. While sphincter-preserving surgery is generally preferred over stoma formation for rectal cancer, a systematic review concluded that this approach does not necessarily resolve all functional issues, as LARS remains a significant postoperative concern[25、26]. The high incidence of bowel dysfunction and the expectation of favorable tumor prognosis also pose significant challenges to the combination of SCRT-CIT with radical rectal cancer surgery. Urinary dysfunction is another common complication. Numerous studies have reported that urinary dysfunction is primarily caused by pelvic autonomic nerve damage during surgery[27、28]. In this study, the International Prostate Symptom Score (IPSS), a globally recognized tool, was used to assess lower urinary tract symptoms in both male and female patients[14]. No statistically significant differences in urinary dysfunction rates were observed between the two groups. Although radiotherapy is considered a risk factor for urogenital complications, it typically causes temporary urinary dysfunction due to fibrosis of the bladder and urethral sphincter, along with vascular damage, which usually resolves within three months post-surgery[29]. Several randomized controlled trials have also reported minimal impact of radiotherapy on postoperative urinary function, which aligns with our findings[30]. With changes in lifestyle and diet, the age of onset for rectal cancer has been gradually decreasing. In recent years, the diagnosis rate of rectal cancer in patients under 50 has significantly increased[31]. Younger patients often face unique challenges, such as the ability to maintain employment, care for families, and sustain a normal sexual relationship with their partners[32]. These factors impact the patient's quality of life while also highlighting the need to address their mental health, as they may contribute to an increased risk of anxiety and depression, ultimately affecting their overall prognosis. In this study, erectile dysfunction was found to be significantly different between the two groups of male patients. Additionally, sexual duration was notably shorter postoperatively in the SCRT-CIT group compared to pre-surgery, and multivariate logistic analysis confirmed that this difference was statistically significant (p = 0.003). This finding indicates that the treatment regimen has a significant impact on the recovery of postoperative sexual function and quality of life in male patients, and should be given due attention in clinical practice. Due to the difficulty in obtaining comprehensive data from female patients, this study evaluated only two aspects of sexual function—dyspareunia and the loss of sexual pleasure—using specific items from the FSFI questionnaire. Data were collected from 31 female patients, and significant differences between the two groups were identified. Nevertheless, because of the limited sample size, this result may be subject to some degree of bias. Therefore, future studies should aim to increase the sample size to further validate these findings and comprehensively assess the quality and recovery of postoperative sexual life in female patients. Several limitations of this study should be taken into account when interpreting the findings. First, the small sample size, particularly for female patients, limits the statistical power and generalizability of the results. Second, as a retrospective study, preoperative functional outcome data were unavailable, preventing direct comparisons between preoperative and postoperative functional outcomes. Additionally, the retrospective design does not allow for repeated assessments over a defined postoperative timeline, thereby limiting the ability to evaluate changes in functional outcomes over time. Despite these constraints, our findings identify SCRT-CIT as an independent risk factor for LARS and sexual dysfunction, underscoring its impact on postoperative quality of life. Conclusion Immunotherapy combined with neoadjuvant therapy for low rectal cancer may increases the incidence of LARS and sexual dysfunction, while its impact on urinary function shows no statistically significant difference. When treating individual rectal cancer patients, the benefits of immunotherapy combined with neoadjuvant therapy should be carefully weighed against the risk of increased functional impairments. Declarations Acknowledgements Acknowledge anyone who contributed towards the article who does not meet the criteria for authorship including anyone who provided professional writing services or materials. Funding This study was supported by the National Nature Science Foundation of China (No.81902703, 82072736, 82273319, 82322052) Ethical approval statement The requirement for informed consent was waived by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. The study was conducted in accordance with the ethical guidelines established by the Institutional Ethics Committee of the Medical College, and approval for the retrospective analysis was obtained from the committee. Ethics approval number: [2025] Ethics Review No. (0190-01). Written informed consent was obtained from all patients. Consent for publication This study received consent for publication from all the participants. Competing interests The authors declare no competing interests. Data availability No datasets were generated or analysed during the current study. Authors and Affiliations Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China Chong Li, Gan Mao, Yisong Gao, Tianyu Song, Suao Liu，Zilong Wu, Ruizhi Zhang, Kaixiong Tao, Wei Li Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China Wenxiang Nie Correspondence: Wei Li, [email protected] ; Kaixiong Tao, [email protected] Contributions Xu Li and Gan Mao were responsible for writing and editing manuscript; Xu Li, Gan Mao, Yisong Gao, Chong Li, Tianyu Song, Wenxiang Nie, Suao Liu, Zilong Wu, Zhenyu Lin and Tao Zhang were responsible for collecting data; Xu Li, Yisong Gao, Tianyu Song and Ruizhi Zhang were responsible for analysising data; Kaixiong Tao and Wei Li were responsible for developing project and editing manuscript, they are the co-corresponding authors. Ethics declarations The requirement for informed consent was waived by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. The study was conducted in accordance with the ethical guidelines established by the Institutional Ethics Committee of the Medical College, and approval for the retrospective analysis was obtained from the committee. [2025] Ethics Review No. (0190-01). Written informed consent was obtained from all patients. References Bray F, Laversanne M, Sung H, et al. (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74(3):229-263. Li X, Li X, Fu R, et al. (2022) Efficacy of Neoadjuvant Therapy in Improving Long-Term Survival of Patients with Resectable Rectal Cancer: A Meta-Analysis. Anticancer Agents Med Chem 22(6):1068-1079. Kwaan MR, Fan Y, Jarosek S, et al. 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Supplementary Files Tables.docx Cite Share Download PDF Status: Published Journal Publication published 03 Jun, 2025 Read the published version in Langenbeck's Archives of Surgery → Version 1 posted Editorial decision: Revision requested 27 Apr, 2025 Reviews received at journal 24 Apr, 2025 Reviews received at journal 24 Apr, 2025 Reviewers agreed at journal 01 Apr, 2025 Reviewers agreed at journal 01 Apr, 2025 Reviewers invited by journal 31 Mar, 2025 Editor assigned by journal 26 Mar, 2025 Submission checks completed at journal 25 Mar, 2025 First submitted to journal 22 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Technology","correspondingAuthor":false,"prefix":"","firstName":"Suao","middleName":"","lastName":"Liu","suffix":""},{"id":436834815,"identity":"2414bad6-6588-48af-8e7d-dc240bc36f68","order_by":8,"name":"Ruizhi Zhang","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Ruizhi","middleName":"","lastName":"Zhang","suffix":""},{"id":436834817,"identity":"bb4228eb-d096-4694-b652-da229fb6f900","order_by":9,"name":"Zhenyu Lin","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Zhenyu","middleName":"","lastName":"Lin","suffix":""},{"id":436834820,"identity":"7bad6a55-9f12-487c-a2a1-f3260838a3cc","order_by":10,"name":"Tao Zhang","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Zhang","suffix":""},{"id":436834821,"identity":"d4de578e-6579-4641-9f8c-006e0907c33c","order_by":11,"name":"Wei Li","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Li","suffix":""},{"id":436834823,"identity":"b723ca26-83c8-4f73-a1ce-57ab5551b12b","order_by":12,"name":"Kaixiong Tao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYBACCQbGBoYECJvxMVTQgDgtPAwMzMZgAcJaoACohU2aKC2S7YfbJB5U3LHbz374WHVhW10dA3vzNgmGmjs4tUjzJDYbJJx5ltzDk5Z2e2bbYQkGnmNlEgzHnuHUIseQ2Pggse1wMg9Djtlt3rYDEgwSOWYSjA2HcWvhf9hwAKyF/41ZMW9bnQSD/Bv8WqQlILbY8QANZ+ZtYwbawoNfi+SMhyC/HE7gufEsWZrn3GHJNp60YouEY7i1SJxPfyb5o+KwPXt/8sHPPGV1/Pzshzfe+FCDWwsMJDbAWGwgIoGgBgYGeyLUjIJRMApGwUgFAM7lT3VWBl+9AAAAAElFTkSuQmCC","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Kaixiong","middleName":"","lastName":"Tao","suffix":""}],"badges":[],"createdAt":"2025-03-22 13:08:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6283768/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6283768/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00423-025-03746-0","type":"published","date":"2025-06-03T15:57:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81698775,"identity":"0dd85b1e-8389-4d93-982d-1ee94d2dc3fc","added_by":"auto","created_at":"2025-04-30 12:54:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":12433,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chat\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6283768/v1/d61119a208f9390e9d7eba1e.png"},{"id":84242363,"identity":"eb405293-282c-4f8a-bcaf-e95f985aed75","added_by":"auto","created_at":"2025-06-09 16:06:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":844103,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6283768/v1/d7bb55ee-d929-4b86-bb1b-90a230d6827a.pdf"},{"id":81698781,"identity":"6abb682b-5581-427d-bcd2-6b32936aebbd","added_by":"auto","created_at":"2025-04-30 12:54:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":81641,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6283768/v1/cfe4d203ed96e0878a2a1ede.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Functional Outcomes in Rectal Cancer Patients Treated with Immunotherapy and Neoadjuvant Therapy: A Retrospective Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer accounts for 9.6% of all malignant tumors globally, ranking third in incidence, and 9.3% of cancer-related deaths, ranking second. China has a particularly high incidence of colorectal cancer[1]. Neoadjuvant therapy combined with surgery is a critical approach in the treatment of rectal cancer, enabling complete tumor resection along with surrounding tissues. While this approach is applicable to tumors in various anatomical locations, it often leads to significant postoperative complications, including bowel and urogenital dysfunction, which can adversely impact patients\u0026rsquo; quality of life[2、3、4].\u003c/p\u003e \u003cp\u003eIn recent years, there has been increasing attention on postoperative functional outcomes[5]. However, rectal cancer surgery is frequently associated with severe side effects, particularly impairments in bowel and urogenital function. Bowel dysfunction, in particular, is the most common postoperative complication[6]. The Low Anterior Resection Syndrome (LARS) score is a well-established tool for assessing bowel function comprehensively[7]. This study utilizes validated questionnaires\u0026mdash;including the LARS, International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5), and Female Sexual Function Index (FSFI)\u0026mdash;to evaluate postoperative functional outcomes.\u003c/p\u003e \u003cp\u003eUrinary dysfunction is often attributed to intraoperative damage to nerve fibers, though the effect of neoadjuvant therapy on urinary function remains inconsistently reported in the literature[8、9]. As a novel preoperative treatment strategy for patients with locally advanced rectal cancer, short-course radiotherapy combined with immunotherapy (SCRT-CIT) has demonstrated significantly higher pathological complete response (pCR) rates compared to traditional neoadjuvant therapies[10].\u003c/p\u003e \u003cp\u003eThis retrospective study aims to analyze the bowel and urogenital functional outcomes in patients with locally advanced low rectal cancer (\u0026le;\u0026thinsp;6 cm) who underwent SCRT-CIT followed by surgery at our hospital over the past three years. A secondary objective is to identify potential risk factors associated with bowel incontinence and urogenital dysfunction.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy Participants\u003c/p\u003e \u003cp\u003e The study collected cases of locally advanced low rectal cancer from the gastrointestinal surgery departments of Union Hospital, affiliated with Tongji Medical College, Huazhong University of Science and Technology, from May 2021 to May 2024. Inclusion criteria required patients to: (i) Patients aged 18\u0026ndash;75 years. (ii) Postoperative pathological diagnosis of adenocarcinoma. (iii) Tumor located\u0026thinsp;\u0026le;\u0026thinsp;6 cm from the anal verge. (iv) Clinical staging of cT3-4Nx or cTxN+. (v) Elective surgical treatment. (vi) Patients who received either surgery alone or SCRT-CIT followed by surgery. Exclusion criteria included: (i) Emergency surgery. (ii) Incomplete clinical or pathological data. Eligible patients were contacted by telephone to obtain informed consent and were subsequently invited to complete validated questionnaires assessing bowel function and urogenital function. The study was conducted in accordance with the ethical guidelines established by the Institutional Ethics Committee of the Medical College, and approval for the retrospective analysis was obtained from the committee. Responses were collected and analyzed statistically. The tumor\u0026rsquo;s distance from the anal verge was determined using pelvic MRI in combination with digital rectal examination. Pelvic MRI was also utilized to assess the clinical staging of rectal cancer[11、12].\u003c/p\u003e \u003cp\u003eAll personally identifiable information has been de-identified to ensure participant confidentiality and compliance with ethical research standards.\u003c/p\u003e \u003cp\u003eTreatments Methods\u003c/p\u003e \u003cp\u003ePatients in the SCRT-CIT group underwent neoadjuvant therapy comprising short-course radiotherapy (a total of 25 Gy in 5 days), followed by two cycles of camrelizumab (200 mg/m\u0026sup2; via intravenous infusion on Day 1 of a 3-week cycle) combined with CAPOX (oxaliplatin 130 mg/m\u0026sup2; on Day 1 and capecitabine 1000 mg/m\u0026sup2; twice daily from Day 1 to Day 14 of a 3-week cycle). Radical surgery was performed within 10 weeks after the completion of therapy, following the principles of total mesorectal excision (TME) to ensure optimal oncological and functional outcomes.\u003c/p\u003e \u003cp\u003eRadical surgical resection was performed on patients in the non-SCRT-CIT group directly. Standard rectal cancer surgery was performed and the decision to perform sphincter-preserving surgery was based on the distance of the tumor\u0026rsquo;s lower margin from the anal verge, intraoperative conditions, patient preferences, and the technical expertise of surgeon.\u003c/p\u003e \u003cp\u003eData Collection and Measurement\u003c/p\u003e \u003cp\u003eThe Low Anterior Resection Syndrome (LARS) score was employed to assess bowel dysfunction[13]. This questionnaire tool evaluates five symptoms: incontinence of flatus, incontinence of liquid stool, stool frequency, clustering of bowel movements, and urgency. Scores range from 0 to 42, classifying patients into no LARS (0\u0026ndash;20), minor LARS (\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), or major LARS (30\u0026ndash;42). The Chinese version of the LARS score has been shown to have robust psychometric properties and is suitable for clinical and research use in Chinese populations[13].\u003c/p\u003e \u003cp\u003eThe International Prostate Symptom Score (IPSS) was used to evaluate urinary function. This tool assesses seven domains, including incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia. Scores range from 0 to 35 and are categorized into mild (0\u0026ndash;7), moderate (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), and severe (20\u0026ndash;35) urinary symptoms[14]. For univariate and multivariate analyses, patients scoring 8 or higher (indicating severe or moderate urinary dysfunction) were classified as having urinary dysfunction.\u003c/p\u003e \u003cp\u003eThe International Index of Erectile Function-5 (IIEF-5) was used to evaluate erectile dysfunction in male patients. The five questions are scored on a 5-point scale, with lower scores indicating more severe dysfunction. Classifications include severe ED (0\u0026ndash;7), moderate ED (\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), mild ED (\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), and no dysfunction (\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)[15]. For univariate and multivariate analyses, male patients scoring 11 or fewer points (indicating severe or moderate erectile dysfunction) were classified as having sexual dysfunction.\u003c/p\u003e \u003cp\u003eThe sexual pleasure and dyspareunia domains of the Selected domains of the Female Sexual Function Index (FSFI) were used to evaluate the sexual function of female patients. Sexual pleasure was categorized as unchanged, reduced, or absent, while dyspareunia was classified as present or absent.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eClinical variables such as age, sex, tumor height, SCRT-CIT therapy, and sphincter-preserving surgery were analyzed to identify predictors of bowel and urogenital function outcomes. Statistical analyses were conducted using R software (version 4.3.2). Measurement data following a normal distribution are expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD), and intergroup comparisons were performed using the t-test. While categorical variables were presented as frequencies and percentages. The Pearson's chi-square test or Fisher\u0026rsquo;s exact test was used for group comparisons and univariate and multivariate logistic regression analyses were applied to identify factors independently associated with functional outcomes. Age, BMI and tumor height were classified based on the mean of the raw data, as the mean represents the central tendency of the data. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 298 patients meeting the inclusion criteria were initially identified, among whom 30 patients were excluded due to death, 83 could not be contacted, and 23 declined to participate. Data from 162 patients comprising 118 males and 44 female patients were ultimately collected and analyzed. The participation data are summarized in Fig.\u0026nbsp;1, and the patients\u0026rsquo; characteristics are outlined in Table\u0026nbsp;1.\u003c/p\u003e\n\u003cp\u003eBowel Dysfunction\u003c/p\u003e\n\u003cp\u003eThe LARS questionnaire was completed by 126 patients. The results of questionnaires found that 42 patients suffered from major LARS, 29 minor LARS and 55 no LARS. Univariate analysis revealed that bowel dysfunction was significantly associated with SCRT-CIT treatment (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and tumor distance from the anal verge (p\u0026thinsp;=\u0026thinsp;0.006) (Table 2). No significant differences were observed in terms of sex, age, tumor stage, BMI, or hypertension. Multivariate analysis demonstrated that SCRT-CIT treatment [odds ratio (OR)\u0026thinsp;=\u0026thinsp;16.31; 95% confidence interval (CI), 6.69\u0026ndash;39.77; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01] was an independent risk factor for bowel dysfunction. However, tumor height [OR\u0026thinsp;=\u0026thinsp;0.53; 95% CI, 0.25\u0026ndash;1.15; p\u0026thinsp;=\u0026thinsp;0.109] was not independently associated with bowel dysfunction (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eUrinary Dysfunction\u003c/p\u003e\n\u003cp\u003eThe IPSS questionnaire was completed by 126 patients, revealing that only one patient, who had undergone SCRT-CIT treatment, experienced severe urinary dysfunction. Additionally, 28 patients had moderate dysfunction, and 97 patients had mild dysfunction. For analytical purposes, moderate and severe dysfunction were combined into one group, as both have a greater impact on quality of life compared to mild dysfunction. In the univariate and multivariate analyses, no other variables were found to be associated with urinary dysfunction. Specifically, sex, age, tumor stage, BMI, hypertension, tumor height, and SCRT-CIT treatment did not significantly affect urinary function (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eMale Sexual Function\u003c/p\u003e\n\u003cp\u003eAmong 118 male patients, 83 completed the IIEF-5 questionnaire and provided data on changes in sexual duration, after excluding those who reported no sexual activity before surgery or declined to discuss sexual function. In the SCRT-CIT group (n\u0026thinsp;=\u0026thinsp;41), 13 patients had severe erectile dysfunction (ED), 9 had moderate ED, 19 had mild ED, and no patients had normal erectile function. In the surgery alone group (n\u0026thinsp;=\u0026thinsp;42), 5 patients had severe ED, 3 had moderate ED, 28 had mild ED, and 6 maintained normal erectile function. The difference in erectile function between the two groups was statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). Furthermore, 23 patients in the SCRT-CIT group reported significantly shortened sexual duration, compared to only 6 patients in the surgery-only group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). For statistical analysis, moderate and severe ED were combined into a single group due to their greater impact on quality of life. Univariate analysis indicated that ED was significantly associated with SCRT-CIT treatment (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) (Table 2). No significant associations were found with sex, age, tumor stage, BMI, or hypertension. Multivariate analysis confirmed that SCRT-CIT treatment [OR\u0026thinsp;=\u0026thinsp;5.49; 95% CI, 1.92\u0026ndash;15.70; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001] was an independent risk factor for ED (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eFemale Sexual Function\u003c/p\u003e\n\u003cp\u003eOf the 44 female patients, 31 patients provided valid responses after excluding those without preoperative sexual activity or those unwilling to discuss sexual function. The result indicated that 2 patients experienced complete loss of sexual pleasure, when compared with the preoperative status. A slight decline was experienced by 7 patients. And 22 described no modification of sexual pleasure compared with preoperative status. Additionally, 12 patients experienced dyspareunia. Patients with decline or absent sexual pleasure were combined into one group for analysis, and comparisons were made with patients reporting no change in sexual pleasure. Both univariate and multivariate analyses revealed that reduced sexual pleasure and dyspareunia were significantly associated with SCRT-CIT treatment ( \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n"},{"header":"Discussion","content":"\u003cp\u003eImmunotherapy has emerged as the first-line treatment for patients with microsatellite instability-high (MSI-H) rectal cancer, offering superior efficacy and a lower risk of side effects[16]. A meta-analysis of 10 studies demonstrated that immunotherapy significantly improves the pathological complete response (pCR) rate and major pathological response (MPR) rate in non-metastatic rectal cancer[17]. This novel approach not only reduces the risk of local recurrence but also emphasizes the importance of improving patients\u0026rsquo; quality of life and long-term prognosis. Based on these findings, the present study aims to collect functional data from patients who underwent rectal cancer surgery with or without short-course radiotherapy combined with sequential chemotherapy and immunotherapy. The primary focus was on bowel and urogenital functions.\u003c/p\u003e \u003cp\u003eThe Chinese version of the LARS questionnaire, known for its high sensitivity and specificity, was used to evaluate bowel dysfunction in patients with low rectal cancer[18]. Univariate analysis showed significant differences in bowel function associated with treatment modality and tumor height in patients with low rectal cancer. However, multivariate analysis indicated that tumor height was not an independent factor influencing bowel function. This finding could be attributed to the fact that SCRT-CIT improves sphincter preservation rates in low rectal cancer, while patients undergoing direct surgery often had lower preservation rates. Consequently, patients with tumors\u0026thinsp;\u0026le;\u0026thinsp;4.3 cm from the anal verge were more likely to receive SCRT-CIT, potentially introducing variability in outcomes[19]. However, Battersby et al[20] and Qin Q et al[23] found that low-lying rectal cancer is associated with impaired rectum-related quality of life based on LARS score, compared with mid and high rectal cancers. SCRT-CIT is an emerging treatment strategy that has demonstrated remarkable success in rectal cancer therapy. Most existing studies focus on the impact of neoadjuvant therapy on bowel function[21、22、23、24]. Our study specifically examined the effects of SCRT-CIT on bowel function, and multivariate regression analysis revealed a statistically significant difference between the SCRT-CIT and surgery alone groups, with SCRT-CIT having a negative impact on postoperative bowel function. While sphincter-preserving surgery is generally preferred over stoma formation for rectal cancer, a systematic review concluded that this approach does not necessarily resolve all functional issues, as LARS remains a significant postoperative concern[25、26]. The high incidence of bowel dysfunction and the expectation of favorable tumor prognosis also pose significant challenges to the combination of SCRT-CIT with radical rectal cancer surgery.\u003c/p\u003e \u003cp\u003eUrinary dysfunction is another common complication. Numerous studies have reported that urinary dysfunction is primarily caused by pelvic autonomic nerve damage during surgery[27、28]. In this study, the International Prostate Symptom Score (IPSS), a globally recognized tool, was used to assess lower urinary tract symptoms in both male and female patients[14]. No statistically significant differences in urinary dysfunction rates were observed between the two groups. Although radiotherapy is considered a risk factor for urogenital complications, it typically causes temporary urinary dysfunction due to fibrosis of the bladder and urethral sphincter, along with vascular damage, which usually resolves within three months post-surgery[29]. Several randomized controlled trials have also reported minimal impact of radiotherapy on postoperative urinary function, which aligns with our findings[30].\u003c/p\u003e \u003cp\u003eWith changes in lifestyle and diet, the age of onset for rectal cancer has been gradually decreasing. In recent years, the diagnosis rate of rectal cancer in patients under 50 has significantly increased[31]. Younger patients often face unique challenges, such as the ability to maintain employment, care for families, and sustain a normal sexual relationship with their partners[32]. These factors impact the patient's quality of life while also highlighting the need to address their mental health, as they may contribute to an increased risk of anxiety and depression, ultimately affecting their overall prognosis. In this study, erectile dysfunction was found to be significantly different between the two groups of male patients. Additionally, sexual duration was notably shorter postoperatively in the SCRT-CIT group compared to pre-surgery, and multivariate logistic analysis confirmed that this difference was statistically significant (p\u0026thinsp;=\u0026thinsp;0.003). This finding indicates that the treatment regimen has a significant impact on the recovery of postoperative sexual function and quality of life in male patients, and should be given due attention in clinical practice.\u003c/p\u003e \u003cp\u003eDue to the difficulty in obtaining comprehensive data from female patients, this study evaluated only two aspects of sexual function\u0026mdash;dyspareunia and the loss of sexual pleasure\u0026mdash;using specific items from the FSFI questionnaire. Data were collected from 31 female patients, and significant differences between the two groups were identified. Nevertheless, because of the limited sample size, this result may be subject to some degree of bias. Therefore, future studies should aim to increase the sample size to further validate these findings and comprehensively assess the quality and recovery of postoperative sexual life in female patients.\u003c/p\u003e \u003cp\u003eSeveral limitations of this study should be taken into account when interpreting the findings. First, the small sample size, particularly for female patients, limits the statistical power and generalizability of the results. Second, as a retrospective study, preoperative functional outcome data were unavailable, preventing direct comparisons between preoperative and postoperative functional outcomes. Additionally, the retrospective design does not allow for repeated assessments over a defined postoperative timeline, thereby limiting the ability to evaluate changes in functional outcomes over time. Despite these constraints, our findings identify SCRT-CIT as an independent risk factor for LARS and sexual dysfunction, underscoring its impact on postoperative quality of life.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eImmunotherapy combined with neoadjuvant therapy for low rectal cancer may increases the incidence of LARS and sexual dysfunction, while its impact on urinary function shows no statistically significant difference. When treating individual rectal cancer patients, the benefits of immunotherapy combined with neoadjuvant therapy should be carefully weighed against the risk of increased functional impairments.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledge anyone who contributed towards the article who does not meet the criteria for authorship including anyone who provided professional writing services or materials.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThis study was supported by the National Nature Science Foundation of China (No.81902703, 82072736, 82273319, 82322052)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe requirement for informed consent was waived by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. The study was conducted in accordance with the ethical guidelines established by the Institutional Ethics Committee of the Medical College, and approval for the retrospective analysis was obtained from the committee. Ethics approval number: [2025] Ethics Review No. (0190-01). Written informed consent was obtained from all patients.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThis study received consent for publication from all the participants.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe authors declare no competing interests.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNo datasets were generated or analysed during the current study.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China\u003c/p\u003e\n\u003cp\u003eChong Li, Gan Mao, Yisong Gao, Tianyu Song, Suao Liu，Zilong Wu, Ruizhi Zhang, Kaixiong Tao, Wei Li\u003c/p\u003e\n\u003cp\u003eDepartment of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China\u003c/p\u003e\n\u003cp\u003eWenxiang Nie\u003c/p\u003e\n\u003cp\u003eCorrespondence: Wei Li, [email protected]; Kaixiong Tao, [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXu Li and Gan Mao were responsible for writing and editing manuscript; Xu Li, Gan Mao, Yisong Gao, Chong Li, Tianyu Song, Wenxiang Nie, Suao Liu, Zilong Wu, Zhenyu Lin and Tao Zhang were responsible for collecting data; Xu Li, Yisong Gao, Tianyu Song and Ruizhi Zhang were responsible for analysising data; Kaixiong Tao and Wei Li were responsible for developing project and editing manuscript, they are the co-corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe requirement for informed consent was waived by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. The study was conducted in accordance with the ethical guidelines established by the Institutional Ethics Committee of the Medical College, and approval for the retrospective analysis was obtained from the committee. [2025] Ethics Review No. (0190-01). Written informed consent was obtained from all patients.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, et al. (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74(3):229-263.\u003c/li\u003e\n\u003cli\u003eLi X, Li X, Fu R, et al. (2022) Efficacy of Neoadjuvant Therapy in Improving Long-Term Survival of Patients with Resectable Rectal Cancer: A Meta-Analysis. Anticancer Agents Med Chem 22(6):1068-1079.\u003c/li\u003e\n\u003cli\u003eKwaan MR, Fan Y, Jarosek S, et al. (2017) Long-term risk of urinary adverse events in curatively treated patients with rectal cancer: a population-based analysis. Dis Colon Rectum 60:682-690. \u003c/li\u003e\n\u003cli\u003eKauff DW, Lang H, Kneist W. (2017) Risk factor analysis for newlydeveloped urogenital dysfunction after total mesorectal excision and impact of pelvic intraoperative neuromonitoring-aprospective 2-year follow-up study. J Gastrointest Surg 21:1038-1047. \u003c/li\u003e\n\u003cli\u003eHovdenak I, Thaysen HV, Bernstein IT, et al. (2024) Quality of life and symptom burden after rectal cancer surgery: a randomised controlled trial comparing patient-led versus standard follow-up. J Cancer Surviv 18(5):1709-1722. \u003c/li\u003e\n\u003cli\u003eLoos M, Quentmeier P, Schuster T, et al. (2013) Effect of preoperative radio(chemo) therapy on long-term functional outcome in rectal cancer patients: a systematic review and meta-analysis. Ann Surg Oncol 20:1816-28.\u003c/li\u003e\n\u003cli\u003eBang GA, Moto GRB, Ngoumfe JCC,et al. (2024) Bowel function after anterior rectal resection for cancer: short and long-term prospective evaluation with low anterior rectal syndrome (LARS) score in a cohort of Cameroonian patients. The Pan African medical journal 47: 171. \u003c/li\u003e\n\u003cli\u003eKarlsson L, Bock D, Asplund D, et al. (2020) Urinary dysfunction in patients with rectal cancer: a prospective cohort study. Colorectal Dis 22(1):18-28.\u003c/li\u003e\n\u003cli\u003ePrabhudesai AG, Cornes P, Glees JP, et al. (2005) Long-term morbidity following short-course, preoperative radiotherapy and total mesorectal excision for rectal cancer. Surgeon 3:347\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eLin ZY, Zhang P, Chi P, et al. (2024) Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial. Ann Oncol 35(10):882-891. \u003c/li\u003e\n\u003cli\u003eBeets-Tan RGH, Lambregts DMJ, Maas M, et al. (2018) Magnetic resonance imaging for clinical management of rectal cancer: Updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol 28(4):1465-1475.\u003c/li\u003e\n\u003cli\u003eRouleau Fournier F, Motamedi MAK, Brown CJ,et al. (2022) Oncologic Outcomes Associated With MRI-detected Extramural Venous Invasion (mrEMVI) in Rectal Cancer: A Systematic Review and Meta-analysis. Ann Surg 275(2):303-314. \u003c/li\u003e\n\u003cli\u003eHou XT, Pang D, Lu Q, et al. (2015) Validation of the Chinese version of the low anterior resection syndrome score for measuring bowel dysfunction after sphincter-preserving surgery among rectal cancer patients. Eur J Oncol Nurs 19:495\u0026ndash;501.\u003c/li\u003e\n\u003cli\u003eUrological Sciences Research Foundation. International Prostate Symptom Score (IPSS). https://www.usrf.org/questionnaires/AUA_SymptomScore.html (accessed 1 December 2020)\u003c/li\u003e\n\u003cli\u003eRosen RC , Riley A, Wagner G, et al. (1997) The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction 49(6):822-30.\u003c/li\u003e\n\u003cli\u003eAndr\u0026eacute; T, Shiu KK, Kim TW, et al. (2020) Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med 383(23):2207-2218. \u003c/li\u003e\n\u003cli\u003eZhou L, Yang XQ, Zhao GY, et al. (2023) Meta-analysis of neoadjuvant immunotherapy for non-metastatic colorectal cancer. Front Immunol 14:1044353.\u003c/li\u003e\n\u003cli\u003eHou XT, Pang D, Lu Q, et al. (2015) Validation of the Chinese version of the low anterior resection syndrome score for measuring bowel dysfunction after sphincter-preserving surgery among rectal cancer patients. Eur J Oncol Nurs 19(5):495-501.\u003c/li\u003e\n\u003cli\u003eZhou L, Yu G, Shen Y, et al. (2022) The clinical efficacy and safety of neoadjuvant chemoradiation therapy with immunotherapy for the organ preservation of ultra low rectal cancer: A single arm and open label exploratory study. Chicago: ASCO; Available at: https://meetings.asco.org/abstracts-presentations/208587.\u003c/li\u003e\n\u003cli\u003eBattersby NJ, Juul T, Christensen P, et al. (2016) United Kingdom Low Anterior Resection Syndrome Study Group. Predicting the Risk of Bowel-Related Quality-of-Life Impairment After Restorative Resection for Rectal Cancer: A Multicenter Cross-Sectional Study. Dis Colon Rectum 59(4):270-80.\u003c/li\u003e\n\u003cli\u003eContin P, Kulu Y, Bruckner T, et al. (2014) Comparative analysis of late functional outcome following preoperative radiation therapy or chemoradiotherapy and surgery or surgery alone in rectal cancer. Int J Colorectal Dis 29(2):165-75.\u003c/li\u003e\n\u003cli\u003eCroese AD, Zubair ON, Lonie J, et al. (2018) Prevalence of low anterior resection syndrome at a regional Australian centre. ANZ J Surg 88(12):E813-E817.\u003c/li\u003e\n\u003cli\u003eQin Q, Huang B, Cao W, et al. (2017) Bowel Dysfunction After Low Anterior Resection With Neoadjuvant Chemoradiotherapy or Chemotherapy Alone for Rectal Cancer: A Cross-Sectional Study from China. Dis Colon Rectum 60(7):697-705.\u003c/li\u003e\n\u003cli\u003eWang Y, Shen L, Wan J, et al. (2022) Neoadjuvant chemoradiotherapy combined with immunotherapy for locally advanced rectal cancer: A new era for anal preservation. Front Immunol 13:1067036. \u003c/li\u003e\n\u003cli\u003ePachler J, Wille-J\u0026oslash;rgensen P. (2005) Quality of life after rectal resection for cancer, with or without permanent colostomy. Cochrane Database Syst Rev (2):CD004323.\u003c/li\u003e\n\u003cli\u003eBossema ER, Seunti\u0026euml;ns MW, Marijnen CA, et al. The relation between illness cognitions and quality of life in people with and without a stoma following rectal cancer treatment. Psychooncology. 2011 Apr;20(4):428-34.\u003c/li\u003e\n\u003cli\u003eTorrijo I, Balciscueta Z, Tabet J, et al. (2021) Prospective study of urinary function and analysis of risk factors after rectal cancer surgery. Tech Coloproctol 25(6):727-737.\u003c/li\u003e\n\u003cli\u003eAdam JP, Denost Q, Capdepont M, et al. (2016) Prospective and Longitudinal Study of Urogenital Dysfunction After Proctectomy for Rectal Cancer. Dis Colon Rectum 59(9):822-30.\u003c/li\u003e\n\u003cli\u003eDulskas A, Miliauskas P, Tikuisis R, et al. (2016) The functional results of radical rectal cancer surgery: review of the literature. Acta Chir Belg 116(1):1-10. \u003c/li\u003e\n\u003cli\u003eHuang M, Lin J, Yu X, et al. (2016) Erectile and urinary function in men with rectal cancer treated by neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy alone: a randomized trial report. Int J Colorectal Dis 31(7):1349-57. \u003c/li\u003e\n\u003cli\u003eSiegel RL, Fedewa SA, Anderson WF, et al. (2017) Colorectal Cancer Incidence Patterns in the United States, 1974-2013. J Natl Cancer Inst 109(8):djw322.\u003c/li\u003e\n\u003cli\u003eWarner EL, Kent EE, Trevino KM, et al. (2016) Social well-being among adolescents and young adults with cancer: A systematic review. Cancer 122(7):1029-37.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"langenbecks-archives-of-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"laos","sideBox":"Learn more about [Langenbeck's Archives of Surgery](http://link.springer.com/journal/423)","snPcode":"423","submissionUrl":"https://submission.nature.com/new-submission/423/3","title":"Langenbeck's Archives of Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Rectal cancer, Immunotherapy, Locally advanced rectal cancer, Functional outcome","lastPublishedDoi":"10.21203/rs.3.rs-6283768/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6283768/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aims to evaluate bowel and urogenital function in patients with locally advanced low rectal cancer treated with immunotherapy combined with neoadjuvant therapy followed by surgery, compared to surgery alone.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e We conducted a retrospective analysis of 162 patients with locally advanced low rectal cancer treated at Union Hospital, affiliated with Tongji Medical College, Huazhong University of Science and Technology, from May 2021 to May 2024. Seventy-three patients underwent short-course radiotherapy combined with chemotherapy and immunotherapy followed by surgery (SCRT-CIT group), while 89 patients received surgery alone (non-SCRT-CIT group). Standardized questionnaires assessed bowel and urogenital function. Logistic regression analysis was used to identify independent predictors of functional outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe incidence of major low anterior resection syndrome (LARS) was significantly higher in the SCRT-CIT group (59.0%) compared to the non-SCRT-CIT group (9.2%). Multivariate analysis identified SCRT-CIT as an independent risk factor for bowel dysfunction (odds ratio [OR]\u0026thinsp;=\u0026thinsp;16.31, 95% confidence interval [CI] 6.69\u0026ndash;39.77, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). SCRT-CIT was also associated with an increased risk of erectile dysfunction in men (OR\u0026thinsp;=\u0026thinsp;5.49, 95% CI 1.92\u0026ndash;15.70, P\u0026thinsp;=\u0026thinsp;0.001) and reduced sexual duration (P\u0026thinsp;=\u0026thinsp;0.003). In women, SCRT-CIT correlated with a higher prevalence of dyspareunia (P\u0026thinsp;=\u0026thinsp;0.004) and reduced sexual satisfaction (P\u0026thinsp;=\u0026thinsp;0.003).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSCRT-CIT combined with surgery is associated with a significantly higher risk of bowel dysfunction, male erectile dysfunction, reduced sexual duration, and female sexual impairments, including dyspareunia and diminished sexual satisfaction. These findings underscore the importance of comprehensive functional assessments and individualized management for patients undergoing SCRT-CIT for locally advanced low rectal cancer.\u003c/p\u003e","manuscriptTitle":"Functional Outcomes in Rectal Cancer Patients Treated with Immunotherapy and Neoadjuvant Therapy: A Retrospective Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-30 12:00:08","doi":"10.21203/rs.3.rs-6283768/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-27T08:45:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-24T15:16:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-24T08:33:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"42825911249695877749877832389872250144","date":"2025-04-01T10:51:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"55154471561077252753467549803279643262","date":"2025-04-01T07:24:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-31T18:15:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-26T12:02:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-25T23:10:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Langenbeck's Archives of Surgery","date":"2025-03-22T12:57:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"langenbecks-archives-of-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"laos","sideBox":"Learn more about [Langenbeck's Archives of Surgery](http://link.springer.com/journal/423)","snPcode":"423","submissionUrl":"https://submission.nature.com/new-submission/423/3","title":"Langenbeck's Archives of Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"18c78bd0-46b6-4b2d-91d4-9ad7468e8ccf","owner":[],"postedDate":"April 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-09T15:58:51+00:00","versionOfRecord":{"articleIdentity":"rs-6283768","link":"https://doi.org/10.1007/s00423-025-03746-0","journal":{"identity":"langenbecks-archives-of-surgery","isVorOnly":false,"title":"Langenbeck's Archives of Surgery"},"publishedOn":"2025-06-03 15:57:00","publishedOnDateReadable":"June 3rd, 2025"},"versionCreatedAt":"2025-04-30 12:00:08","video":"","vorDoi":"10.1007/s00423-025-03746-0","vorDoiUrl":"https://doi.org/10.1007/s00423-025-03746-0","workflowStages":[]},"version":"v1","identity":"rs-6283768","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6283768","identity":"rs-6283768","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}