Clinicopathological Characteristics and Survival Outcomes in Young-Onset Rectal Cancer Treated with Total Neoadjuvant Therapy: Perspective from a Resource Limited Setting

Clinicopathological Characteristics and Survival Outcomes in Young-Onset Rectal Cancer Treated with Total Neoadjuvant Therapy: Perspective from a Resource Limited Setting | 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 Clinicopathological Characteristics and Survival Outcomes in Young-Onset Rectal Cancer Treated with Total Neoadjuvant Therapy: Perspective from a Resource Limited Setting Fajar Rafi Ranjha, Tabinda Sadaf, Asma Rashid, Aqueel Shahid, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7416785/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: The rising incidence of young-onset rectal cancer (YORC) is a significant concern, particularly in low- and middle-income countries like Pakistan. This study evaluates the clinical characteristics, treatment patterns, and outcomes of YORC patients treated at a specialized cancer center in Pakistan. Methods A retrospective review was conducted on patients under 50 years diagnosed with locally advanced rectal cancer between 2010 and 2020. Comprehensive staging, neoadjuvant chemotherapy, chemoradiation, surgical resection, and follow-up were analyzed. Key outcomes included progression-free survival (PFS), overall survival (OS), and recurrence patterns. Results Among 244 patients (median age 36 years), 67.2% were male. Most presented with advanced disease (89% stage III), with 79.5% having positive circumferential resection margins (CRM). Adenocarcinomas were predominant (75.0%), while mucinous/signet ring histology accounted for 25%. All received neoadjuvant therapy. Of the 175 patients who underwent surgery, 20.0% achieved a complete pathological response. At a median follow-up of four years, five-year OS and PFS were 70.7% and 56.1%, respectively for CRM positive and CRM negative patients. Recurrence occurred in 41.0% of cases, with distant metastases being more common than local relapse. Negative CRM status correlated with improved DFS. Conclusion Young rectal cancer patients in Pakistan often present with aggressive, advanced-stage disease. Despite intensive multimodal treatment, outcomes remain suboptimal, highlighting the need for earlier detection, improved access to care, and tailored treatment strategies. These findings underscore the importance of public awareness, screening programs, and further research into the biological distinctiveness of YORC in resource-limited settings. Rectal Cancer Young Patients Neoadjuvant Therapy Survival Outcomes Circumferential Resection Margin Disease-free Survival Figures Figure 1 Figure 2 Introduction Colorectal cancer (CRC) is increasingly recognized as a significant health concern worldwide with rectal cancer accounting for a considerable proportion of CRC cases. Historically associated with older populations, rectal cancer is now observed frequently in younger adults, especially in developing countries [ 1 ]. In Pakistan, young-onset rectal cancer (patients under 50 years of age) is a growing concern, with recent studies noting an increase in cases among individuals under 40 years of age [ 2 ]. This demographic shift has sparked interest in understanding the clinical outcomes and characteristics unique to young rectal cancer patients, as they often present with advanced stages and more aggressive tumor biology than older populations [ 3 ]. A recent study on colorectal cancer in Pakistan highlighted that patients under 40 years of age are more likely to present with poorly differentiated tumors, higher rates of lymph vascular invasion, and distant metastases than older patients [ 4 ]. Additionally, a systematic review of young-onset rectal cancer in South Asia indicated that diagnostic delays are common, attributed to low public awareness and limited screening efforts in this age group [ 5 ]. Such delays often result in more advanced disease at presentation, challenging the effectiveness of standard therapeutic options and affecting survival rates. The limited healthcare resources in Pakistan exacerbate these outcomes, with patients facing barriers such as access to diagnostic facilities, specialized care, and timely treatment. Studies have also indicated that socioeconomic factors play a substantial role, where younger patients from low-income or rural backgrounds experience delayed diagnoses and reduced access to optimal care, adversely affecting survival outcomes [ 6 ]. Total Neoadjuvant Therapy (TNT) - incorporating both neoadjuvant chemoradiation and systemic chemotherapy prior to surgical resection - has emerged as a promising treatment strategy in rectal cancer, offering improved compliance, pathological response, and potential organ preservation. However, data on its effectiveness and outcomes in young patients, particularly within resource-limited settings, remain scarce. This study aims to evaluate the clinicopathological characteristics, treatment response, and survival outcomes of young-onset rectal cancer patients treated with TNT in Pakistan. By examining real-world data from a resource-limited tertiary care center, this research seeks to contribute meaningful insights into the management challenges and prognostic implications in this unique and increasingly prevalent patient population. Methods A retrospective analysis was conducted on consecutive patients with histologically confirmed, locally advanced rectal cancer treated at our tertiary care institution between January 1, 2010, and December 31, 2020. The study protocol was approved by the Institutional Review Board and the hospital ethics committee. Informed consent was waived due to the retrospective nature of the study. Eligible patients were those younger than 50 years of age at presentation, with rectal tumors located within 15 cm of the anal verge. Patients were excluded if they had incomplete follow-up data, a prior history of colorectal cancer, or de novo metastatic disease at diagnosis. All included cases underwent centralized histopathological review and comprehensive staging workup, including colonoscopy, pelvic magnetic resonance imaging (MRI) for loco-regional staging, and contrast-enhanced computed tomography (CT) of the chest and abdomen to exclude distant metastases. Tumors were staged according to the American Joint Committee on Cancer (AJCC) staging classification. Each case was reviewed in a multidisciplinary tumor board to determine the optimal treatment plan. All patient were treated with total neoadjuvant therapy (TNT) approach. They were given four months of neoadjuvant chemotherapy with Capecitabine and Oxaliplatin, followed by long-course chemoradiotherapy (45-50.4 Gy in daily fractions) with concurrent Capecitabine or 5-Fluorouracil. Treatment response was assessed both clinically and radiologically using pelvic MRI and CT chest/abdomen approximately six weeks after completion of chemoradiotherapy. Surgical resection with total mesorectal excision (TME) was performed 10 to 14 weeks following chemoradiotherapy. A microscopically clear (R0) resection was defined as a tumor-free margin of ≥ 1 mm. Pathological complete response (pCR) was defined as the absence of viable tumor cells in the resected specimen. Postoperative adjuvant chemotherapy was administered based on final pathological staging and patient fitness. All patients were followed at three-month intervals with clinical evaluations, annual imaging with MRI and CT scans, and surveillance colonoscopy at years 1, 3, and 5, or earlier if clinically indicated. Data collected included demographic details, tumor grade, response to neoadjuvant treatment, type of surgical intervention, pathological staging (including resection margins and lymph node status), and patterns of failure (locoregional and distant). Progression-free survival (PFS) was defined as the interval from the date of diagnostic biopsy to the date of documented disease progression or relapse. Overall survival (OS) was calculated from the date of biopsy to the date of death from any cause. Survival curves were estimated using the Kaplan-Meier method. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY). Results A total of 244 consecutive patients with histologically confirmed rectal cancer, aged below 50 years, were included in this study. The median age at diagnosis was 36 years (range: 18–50). Clinic pathological characteristics are summarized in Table 1. The cohort comprised 164 males (67.2%) and 80 females (32.8%), with a male-to-female ratio of approximately 2:1. The most common presenting symptoms were altered bowel habits in 63 patients (26.0%) and rectal bleeding in 57 patients (23.0%), while 35 patients (14.0%) presented with symptoms of bowel obstruction. Adenocarcinoma was the predominant histological subtype, observed in 183 patients (75.0%). Mucinous and signet ring cell carcinoma subtypes were identified in 61 patients (25.0%). Tumor grading revealed 36 (14.8%) well-differentiated, 115 (47.1%) moderately differentiated, and 93 (37.7%) poorly differentiated tumors. Regarding tumor location, 140 patients (57.4%) had tumors located within 5 cm of the anal verge, while 104 (42.6%) had tumors situated more than 5 cm from the anal verge. Pre-treatment pelvic MRI revealed that 194 patients (79.5%) had positive circumferential resection margins (CRM), defined as direct involvement of or tumor within 1 mm of the mesorectal fascia. The remaining 50 patients (20.5%) had negative CRM. Most patients presented with locally advanced disease; 217 patients (89.0%) were classified as Dukes Stage III. Lymph node involvement was seen in 217 patients (89.0%), while 27 (11.0%) were node-negative on initial staging. All 244 patients received neoadjuvant chemotherapy comprising Capecitabine and Oxaliplatin, with a median of 4 cycles (range: 1–5). Additionally, 236 patients (96.7%) received long-course concurrent chemoradiotherapy (CRT) with Capecitabine or 5-Fluorouracil, at a median dose of 50.4 Gy (range: 45-50.4 Gy), and 8 patients (3.3%) received short-course radiotherapy (25 Gy in 5 fractions) (Table 2). Response assessment by pelvic MRI at 6–8 weeks post-CRT showed partial response in 150 patients (61.5%), stable disease in 58 (23.8%), near-complete response in 8 (3.3%), and progressive disease in 28 (11.5%). Surgical resection was performed in 175 patients (71.7%) following neoadjuvant therapy. 59 patients (24.2%) were deemed surgically unresectable due to persistent locally advanced or progressive disease, while 10 (4.1%) declined surgery, 89 patients (36.5%) had sphincter-sparing procedures and 86 ( 35.2%) had abdominoperineal resection. Pathological staging showed ypT0-2 disease in 93 patients (53.1%) and ypT3/4 in 82 patients (46.9%). Pathological node-negative status (ypN0) was achieved in 107 patients (61.1%), while 68 (38.9%) remained node-positive. A complete pathological response (pCR; ypT0N0) was achieved in 35 patients (20.0%). Among the 175 patients who underwent surgery, 68 patients (38.9%) with residual nodal disease received adjuvant chemotherapy. Of these, 54 (79.4%) received doublet therapy with Capecitabine and Oxaliplatin, while the remainder received single-agent Capecitabine or 5-Fluorouracil based on tolerance and performance status. At a median follow-up of 4 years, the 5-year overall survival (OS) was 70.7%, and the progression-free survival (PFS) was 56.1%. Recurrence was observed in 100 patients (41.0%), with 23 (9.4%) developing local or locoregional recurrence, and 77 (31.6%) developing distant metastases, subsequently treated with systemic chemotherapy. Survival analysis revealed significantly better disease-free survival in patients with negative CRM on pre-treatment MRI compared to those with positive CRM (Figs. 1 – 2 ), underscoring the prognostic impact of CRM involvement. Table No 1 Age Median(Range) 36(18–50) Male: Female 164:80 Pathology Adenocarcinoma 183(75.0%) Mucinous/Signet 61(25.0%) Grade Well Differentiated 36(14.8%) Moderately Differentiated 115(47.1%) Poorly Differentiated 93(37.7%) CRM a Positive 194(79.5%) Negative 50(20.5%) Distance from anal verge 5 cm 104(42.6%) Clinical Symptoms Altered bowel habits 63(26.0%) Bleeding PR 57(23.0%) Weight loss 45(18.0%) Abdominal pain 40(16.0%) Obstruction 35(14.0%) Family history of Colorectal cancer 35(14.0%) cT Staging T1-T2 4(1.6%) T3-T4 240(98.4%) cN Staging Positive 217(88.9%) Negative 27(11.1%) Dukes Staging Stage 1–2 27(11.0%) Stage 3 217(89.0%) a CRM = circumferential resection margin, PR = per rectal Table No 2 Neo Adjuvant Chemotherapy Yes 277(93%) No 17(7%) Median Number of Cycles 4(1–5) Radiation Long Course 236(96.7%) Short Course 8(3.3%) Response to Neoadjuvant Treatment Stable 58(23.8%) Partial 150(61.5%) Complete 8(3.3%) Progression 28(11.5%) Surgery Unresectable 59(24.2%) Surgery Denied 10(4.1%) Sphincter sparing surgery 89(36.5%) APR b 86(35.2%) Pathological staging (ypTypN) c ypT0N0 35(20%) ypT0-2 93(53.1%) ypT3-4 82(46.9%) ypN Positive 68(39%) ypN Negative 107(61.1%) Adjuvant chemotherapy Oxaliplatin doublet 54(79.4%) 5-Fu/Capcitabine 14(21%) Patterns of relapse Loco regional 23(23%) Distant 77(77%) a CAPOX = Capecitabine and Oxaliplatin, b APR = Abdominoperineal resection, cypT = Post-surgical T stage; ypN = Post-surgical N stage Discussion This study provides a comprehensive analysis of young-onset rectal cancer patients treated with total neoadjuvant therapy (TNT) over a decade in a resource-limited tertiary care setting. Our findings contribute valuable insight into the clinicopathological features, treatment response, and survival outcomes of this distinct and increasingly prevalent subgroup in low- and middle-income countries (LMICs). Colorectal cancer has a variable geographical distribution, with a vast contribution to cancer-related mortality and morbidity [ 7 , 8 ]. The incidence of young-onset rectal cancer has increased worldwide over the past two decades, with significantly worse survival as well [ 9 , 10 , 11 ]. Almost all the young patients with rectal cancer in our study experienced symptoms, and a sizable percentage of them had changed bowel habits and reported rectal bleeding as their primary clinical manifestation. This finding has also been corroborated by other research [ 12 , 13 ]. Similarities in presenting symptoms between older patients and adolescents and young adults (AYA) (with a cut-off age of 25 years) were also shown in another study by Kaplan et al. [ 14 ]. This demonstrates that young persons can develop colorectal cancer (CRC) without high-risk syndromes and can exhibit symptoms comparable to those of older patients [ 15 ]. In our study, 37% of the participants were found to have poorly differentiated carcinoma, while 25% exhibited mucinous and signet ring histology. The documented rate of poor differentiation in various studies ranges from 20–27% of patients, whereas the reported incidence of mucinous or signet ring cell differentiation varies from 10.2–18.1% and 7.6–11.5%, respectively [ 16 , 11 , 17 ]. In our study, the incidence of signet ring histology surpassed previous reports in the literature, indicating approximately 12.6% for the same age group and 10.8% among the elderly. In our study, a significant majority of the patients (88.9%) presented with advanced stage III disease characterized by loco-regional lymph node involvement, whereas 79.5% exhibited involvement of the mesorectal margins. These findings are comparable to those from Western populations. Colorectal cancer (CRC) diagnosed in younger individuals is more likely to be associated with regional lymph node involvement or metastasis to distant sites than in older patients. Specifically, 63% of patients with young-onset CRC are diagnosed with stage III or IV disease, compared to 49% of older patients with colon cancer. For rectal cancers, statistics show that 57% of young-onset patients present with advanced stages, whereas 46% of older patients do the same [ 18 , 19 ]. In terms of location, the most frequent tumor in our patients was low-lying rectal cancer involving the anal canal, with 57% of the tumors lying within 5 cm of the anal verge. These findings are consistent with those of a study by Patil et al. [ 20 ] from India, which showed that anorectal/rectal illness affected 54% of the patients, while a study by Laskar et al. [ 18 ] showed that low rectal tumors were more prevalent in patients in northeast India. All patients in our study received a TNT protocol consisting of neoadjuvant chemotherapy followed by long-course chemoradiotherapy. Despite this aggressive multimodal approach, only 20% achieved a complete pathological response (pCR), and over one-third remained node-positive after surgery. While TNT has shown promising results in improving pathological response and compliance, our findings suggest that its benefits may be limited by initial tumor burden and adverse biology in YORC, especially in LMICs where diagnostic delays are common. In our study, at a median follow-up of 4 years (range: 1–13), the five-year overall survival rate was 70.7%, while the disease-free survival was 56%, which is lower than that of patients with average-onset rectal cancer. In a meta-analysis published by Milena et al. for patients treated with neoadjuvant therapy, the five-year overall survival rate was reported to be 86% [ 14 ]. However, the impact of age on CRC prognosis remains controversial. A recent study by Foppa et al. reported similar findings, with early-onset patients having worse progression- or recurrence-free survival in their multivariate analysis [ 21 , 22 ]. These findings indicate that young patients with rectal cancer predominantly present with locally advanced disease, with a high proportion of patients having T3/T4 tumors and lymph node involvement at diagnosis. Despite the widespread use of neoadjuvant therapy, a significant number of patients have positive CRM on pre-treatment imaging. Although a substantial proportion of patients underwent surgery with clear margins, recurrence rates remained high, particularly with distant metastases. Survival outcomes suggest that CRM status strongly influences DFS, emphasizing the need for more effective treatment strategies to improve long-term outcomes in young rectal cancer patients. Some noteworthy strengths of our study include a large patient cohort, an extended follow-up period, and comprehensive information about treatment, health complications, and performance status. This study has certain limitations. Its retrospective design and single-center setting may limit the generalizability of the findings. The relatively small sample size and modest follow-up duration could affect the precision of survival estimates. The lack of molecular or genetic profiling and absence of long-term toxicity data restrict deeper insights into treatment personalization. Additionally, potential selection bias and incomplete data capture for some clinical variables may have influenced the results. Despite these limitations, the study offers valuable real-world insights into the treatment outcomes of young-onset rectal cancer in a resource-limited setting. Conclusion Our findings suggest that young-onset colorectal cancer may exhibit distinct clinical and tumor characteristics, pointing toward a potentially unique biological behavior in this patient population. This study provides insight into the clinic pathological features and treatment outcomes of young rectal cancer patients managed with total neoadjuvant therapy in a resource-constrained setting. A significant proportion of patients presented with locally advanced disease and positive circumferential resection margins. Total neoadjuvant therapy resulted in promising rates of tumor downstaging, sphincter preservation, and pathological complete response. Nonetheless, recurrence and distant metastases were frequent, highlighting the need for enhanced surveillance and more effective systemic treatment strategies. These results underscore the importance of early diagnosis, personalized risk stratification, and multidisciplinary care in improving outcomes. Further large-scale, multicenter studies with extended follow-up are needed to confirm these findings and guide future therapeutic strategies. Abbreviations CRC : colorectal cancer YORC : young onset colorectal cancet LMIC : low middle income country TNT : total neoadjuvant therapy TME: total mesorectal excision OS : overall survival DFS : disease free survival PFS : progression free survival Declarations Ethics approval and consent to participate This retrospective study was approved by the Institutional Review Board of Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan (IRB Reference No: EX-01-06-23-07). The requirement for individual informed consent was waived by the IRB due to the retrospective nature of the study. All methods were carried out in accordance with relevant guidelines and regulations (Declaration of Helsinki). Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding No specific funding was received for this study. Authors’ contributions Fajar Rafi Ranjha: Study conception, data collection, analysis, and manuscript drafting. Tabinda Sadaf and Asma Rashid: Study conception, design, supervision, and critical review. Aqueel Shahid: Data analysis, interpretation, and manuscript review. Muhammad Anas Tahseen Asar, Dr. Abdul Subhan Zahid, raheel mukhtar, Ahmad Rashid, and Haniya Rizwan: Data collection. All authors read and approved the final manuscript. Acknowledgements The authors would like to thank the Department of Clinical and Radiation Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, for their support. Authors’ information Dr. Fajar Rafi Ranjha is a Fellow in Clinical and Radiation Oncology at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. References Stoffel, E.M. and Murphy, C.C., 2020. Epidemiology and mechanisms of the increasing incidence of colon and rectal cancers in young adults. Gastroenterology, 158(2), pp.341-353. Bhurgri, A.A., 2022. Frequency of Rectal Cancer among Young and Older patients. Pakistan Journal of Medical & Health Sciences, 16(05), pp.28-28. Zaborowski, A.M., Murphy, B., Creavin, B., Rogers, A.C., Kennelly, R., Hanly, A., Martin, S.T., O'Connell, P.R., Sheahan, K. and Winter, D.C., 2020. Clinicopathological features and oncological outcomes of patients with young-onset rectal cancer. Journal of British Surgery, 107(5), pp.606-612. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7416785","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":521665899,"identity":"6e61637d-40b5-4f37-8c29-84f34e3d89b9","order_by":0,"name":"Fajar Rafi 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19:56:52","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":85488,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7416785/v1/47f9b809628d0950a5189ece.html"},{"id":92444896,"identity":"87949d79-b7dc-480e-aba6-9bdff2d7b1b0","added_by":"auto","created_at":"2025-09-29 19:56:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":328622,"visible":true,"origin":"","legend":"\u003cp\u003eshows comparison of Progression Free Survival between CRM negative and Positive Patients\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7416785/v1/d079d94922b68d77807f36ce.png"},{"id":92444897,"identity":"c720f460-bdf7-458d-bd30-ec2963e82dcf","added_by":"auto","created_at":"2025-09-29 19:56:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":316866,"visible":true,"origin":"","legend":"\u003cp\u003eshows comparison of Overall Survival between CRM negative and Positive Patients\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7416785/v1/9850ec90ae8240c37102e22b.png"},{"id":98624366,"identity":"b8ea4ac4-d9cd-4111-a5fa-7d4c1409fae9","added_by":"auto","created_at":"2025-12-19 17:08:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1633258,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7416785/v1/f2adaa69-80fc-4845-9629-b392e78f2f65.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinicopathological Characteristics and Survival Outcomes in Young-Onset Rectal Cancer Treated with Total Neoadjuvant Therapy: Perspective from a Resource Limited Setting","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is increasingly recognized as a significant health concern worldwide with rectal cancer accounting for a considerable proportion of CRC cases. Historically associated with older populations, rectal cancer is now observed frequently in younger adults, especially in developing countries [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In Pakistan, young-onset rectal cancer (patients under 50 years of age) is a growing concern, with recent studies noting an increase in cases among individuals under 40 years of age [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This demographic shift has sparked interest in understanding the clinical outcomes and characteristics unique to young rectal cancer patients, as they often present with advanced stages and more aggressive tumor biology than older populations [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA recent study on colorectal cancer in Pakistan highlighted that patients under 40 years of age are more likely to present with poorly differentiated tumors, higher rates of lymph vascular invasion, and distant metastases than older patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Additionally, a systematic review of young-onset rectal cancer in South Asia indicated that diagnostic delays are common, attributed to low public awareness and limited screening efforts in this age group [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Such delays often result in more advanced disease at presentation, challenging the effectiveness of standard therapeutic options and affecting survival rates.\u003c/p\u003e\u003cp\u003eThe limited healthcare resources in Pakistan exacerbate these outcomes, with patients facing barriers such as access to diagnostic facilities, specialized care, and timely treatment. Studies have also indicated that socioeconomic factors play a substantial role, where younger patients from low-income or rural backgrounds experience delayed diagnoses and reduced access to optimal care, adversely affecting survival outcomes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e Total Neoadjuvant Therapy (TNT) - incorporating both neoadjuvant chemoradiation and systemic chemotherapy prior to surgical resection - has emerged as a promising treatment strategy in rectal cancer, offering improved compliance, pathological response, and potential organ preservation. However, data on its effectiveness and outcomes in young patients, particularly within resource-limited settings, remain scarce.\u003c/p\u003e\u003cp\u003eThis study aims to evaluate the clinicopathological characteristics, treatment response, and survival outcomes of young-onset rectal cancer patients treated with TNT in Pakistan. By examining real-world data from a resource-limited tertiary care center, this research seeks to contribute meaningful insights into the management challenges and prognostic implications in this unique and increasingly prevalent patient population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA retrospective analysis was conducted on consecutive patients with histologically confirmed, locally advanced rectal cancer treated at our tertiary care institution between January 1, 2010, and December 31, 2020. The study protocol was approved by the Institutional Review Board and the hospital ethics committee. Informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e\u003cp\u003eEligible patients were those younger than 50 years of age at presentation, with rectal tumors located within 15 cm of the anal verge. Patients were excluded if they had incomplete follow-up data, a prior history of colorectal cancer, or de novo metastatic disease at diagnosis.\u003c/p\u003e\u003cp\u003eAll included cases underwent centralized histopathological review and comprehensive staging workup, including colonoscopy, pelvic magnetic resonance imaging (MRI) for loco-regional staging, and contrast-enhanced computed tomography (CT) of the chest and abdomen to exclude distant metastases. Tumors were staged according to the American Joint Committee on Cancer (AJCC) staging classification. Each case was reviewed in a multidisciplinary tumor board to determine the optimal treatment plan.\u003c/p\u003e\u003cp\u003eAll patient were treated with total neoadjuvant therapy (TNT) approach. They were given four months of neoadjuvant chemotherapy with Capecitabine and Oxaliplatin, followed by long-course chemoradiotherapy (45-50.4 Gy in daily fractions) with concurrent Capecitabine or 5-Fluorouracil. Treatment response was assessed both clinically and radiologically using pelvic MRI and CT chest/abdomen approximately six weeks after completion of chemoradiotherapy. Surgical resection with total mesorectal excision (TME) was performed 10 to 14 weeks following chemoradiotherapy.\u003c/p\u003e\u003cp\u003eA microscopically clear (R0) resection was defined as a tumor-free margin of \u0026ge;\u0026thinsp;1 mm. Pathological complete response (pCR) was defined as the absence of viable tumor cells in the resected specimen. Postoperative adjuvant chemotherapy was administered based on final pathological staging and patient fitness.\u003c/p\u003e\u003cp\u003eAll patients were followed at three-month intervals with clinical evaluations, annual imaging with MRI and CT scans, and surveillance colonoscopy at years 1, 3, and 5, or earlier if clinically indicated.\u003c/p\u003e\u003cp\u003eData collected included demographic details, tumor grade, response to neoadjuvant treatment, type of surgical intervention, pathological staging (including resection margins and lymph node status), and patterns of failure (locoregional and distant). Progression-free survival (PFS) was defined as the interval from the date of diagnostic biopsy to the date of documented disease progression or relapse. Overall survival (OS) was calculated from the date of biopsy to the date of death from any cause. Survival curves were estimated using the Kaplan-Meier method. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 244 consecutive patients with histologically confirmed rectal cancer, aged below 50 years, were included in this study. The median age at diagnosis was 36 years (range: 18\u0026ndash;50). Clinic pathological characteristics are summarized in Table\u0026nbsp;1. The cohort comprised 164 males (67.2%) and 80 females (32.8%), with a male-to-female ratio of approximately 2:1. The most common presenting symptoms were altered bowel habits in 63 patients (26.0%) and rectal bleeding in 57 patients (23.0%), while 35 patients (14.0%) presented with symptoms of bowel obstruction.\u003c/p\u003e\u003cp\u003eAdenocarcinoma was the predominant histological subtype, observed in 183 patients (75.0%). Mucinous and signet ring cell carcinoma subtypes were identified in 61 patients (25.0%). Tumor grading revealed 36 (14.8%) well-differentiated, 115 (47.1%) moderately differentiated, and 93 (37.7%) poorly differentiated tumors.\u003c/p\u003e\u003cp\u003eRegarding tumor location, 140 patients (57.4%) had tumors located within 5 cm of the anal verge, while 104 (42.6%) had tumors situated more than 5 cm from the anal verge. Pre-treatment pelvic MRI revealed that 194 patients (79.5%) had positive circumferential resection margins (CRM), defined as direct involvement of or tumor within 1 mm of the mesorectal fascia. The remaining 50 patients (20.5%) had negative CRM.\u003c/p\u003e\u003cp\u003eMost patients presented with locally advanced disease; 217 patients (89.0%) were classified as Dukes Stage III. Lymph node involvement was seen in 217 patients (89.0%), while 27 (11.0%) were node-negative on initial staging.\u003c/p\u003e\u003cp\u003eAll 244 patients received neoadjuvant chemotherapy comprising Capecitabine and Oxaliplatin, with a median of 4 cycles (range: 1\u0026ndash;5). Additionally, 236 patients (96.7%) received long-course concurrent chemoradiotherapy (CRT) with Capecitabine or 5-Fluorouracil, at a median dose of 50.4 Gy (range: 45-50.4 Gy), and 8 patients (3.3%) received short-course radiotherapy (25 Gy in 5 fractions) (Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eResponse assessment by pelvic MRI at 6\u0026ndash;8 weeks post-CRT showed partial response in 150 patients (61.5%), stable disease in 58 (23.8%), near-complete response in 8 (3.3%), and progressive disease in 28 (11.5%).\u003c/p\u003e\u003cp\u003eSurgical resection was performed in 175 patients (71.7%) following neoadjuvant therapy. 59 patients (24.2%) were deemed surgically unresectable due to persistent locally advanced or progressive disease, while 10 (4.1%) declined surgery, 89 patients (36.5%) had sphincter-sparing procedures and 86 ( 35.2%) had abdominoperineal resection.\u003c/p\u003e\u003cp\u003ePathological staging showed ypT0-2 disease in 93 patients (53.1%) and ypT3/4 in 82 patients (46.9%). Pathological node-negative status (ypN0) was achieved in 107 patients (61.1%), while 68 (38.9%) remained node-positive. A complete pathological response (pCR; ypT0N0) was achieved in 35 patients (20.0%).\u003c/p\u003e\u003cp\u003eAmong the 175 patients who underwent surgery, 68 patients (38.9%) with residual nodal disease received adjuvant chemotherapy. Of these, 54 (79.4%) received doublet therapy with Capecitabine and Oxaliplatin, while the remainder received single-agent Capecitabine or 5-Fluorouracil based on tolerance and performance status.\u003c/p\u003e\u003cp\u003eAt a median follow-up of 4 years, the 5-year overall survival (OS) was 70.7%, and the progression-free survival (PFS) was 56.1%. Recurrence was observed in 100 patients (41.0%), with 23 (9.4%) developing local or locoregional recurrence, and 77 (31.6%) developing distant metastases, subsequently treated with systemic chemotherapy.\u003c/p\u003e\u003cp\u003eSurvival analysis revealed significantly better disease-free survival in patients with negative CRM on pre-treatment MRI compared to those with positive CRM (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), underscoring the prognostic impact of CRM involvement.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTable No 1\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge Median(Range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36(18\u0026ndash;50)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale: Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e164:80\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ePathology\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdenocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e183(75.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMucinous/Signet\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61(25.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eGrade\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWell Differentiated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36(14.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModerately Differentiated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e115(47.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePoorly Differentiated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e93(37.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCRM\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e194(79.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50(20.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eDistance from anal verge\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5 cm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e140(57.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;5 cm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e104(42.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eClinical Symptoms\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAltered bowel habits\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e63(26.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBleeding PR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57(23.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeight loss\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45(18.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40(16.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eObstruction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35(14.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFamily history of Colorectal cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35(14.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ecT Staging\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT1-T2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(1.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT3-T4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e240(98.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ecN Staging\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e217(88.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27(11.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eDukes Staging\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage 1\u0026ndash;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27(11.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e217(89.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eCRM = circumferential resection margin, PR\u0026thinsp;=\u0026thinsp;per rectal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTable No 2\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eNeo Adjuvant Chemotherapy\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e277(93%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17(7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian Number of Cycles\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(1\u0026ndash;5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eRadiation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLong Course\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e236(96.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eShort Course\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8(3.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eResponse to Neoadjuvant Treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e58(23.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePartial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e150(61.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComplete\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8(3.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgression\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28(11.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eSurgery\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnresectable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59(24.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgery Denied\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10(4.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSphincter sparing surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e89(36.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPR\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e86(35.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ePathological staging (ypTypN)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eypT0N0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35(20%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eypT0-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e93(53.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eypT3-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e82(46.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eypN Positive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68(39%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eypN Negative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e107(61.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOxaliplatin\u0026nbsp; doublet\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e54(79.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5-Fu/Capcitabine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14(21%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ePatterns of relapse\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLoco regional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23(23%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDistant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77(77%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eCAPOX = Capecitabine and Oxaliplatin, \u003csup\u003eb\u003c/sup\u003eAPR = Abdominoperineal resection, cypT\u0026thinsp;=\u0026thinsp;Post-surgical T stage; ypN\u0026thinsp;=\u0026thinsp;Post-surgical N stage\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides a comprehensive analysis of young-onset rectal cancer patients treated with total neoadjuvant therapy (TNT) over a decade in a resource-limited tertiary care setting. Our findings contribute valuable insight into the clinicopathological features, treatment response, and survival outcomes of this distinct and increasingly prevalent subgroup in low- and middle-income countries (LMICs).\u003c/p\u003e\u003cp\u003eColorectal cancer has a variable geographical distribution, with a vast contribution to cancer-related mortality and morbidity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The incidence of young-onset rectal cancer has increased worldwide over the past two decades, with significantly worse survival as well [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Almost all the young patients with rectal cancer in our study experienced symptoms, and a sizable percentage of them had changed bowel habits and reported rectal bleeding as their primary clinical manifestation. This finding has also been corroborated by other research [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Similarities in presenting symptoms between older patients and adolescents and young adults (AYA) (with a cut-off age of 25 years) were also shown in another study by Kaplan et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This demonstrates that young persons can develop colorectal cancer (CRC) without high-risk syndromes and can exhibit symptoms comparable to those of older patients [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our study, 37% of the participants were found to have poorly differentiated carcinoma, while 25% exhibited mucinous and signet ring histology. The documented rate of poor differentiation in various studies ranges from 20\u0026ndash;27% of patients, whereas the reported incidence of mucinous or signet ring cell differentiation varies from 10.2\u0026ndash;18.1% and 7.6\u0026ndash;11.5%, respectively [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In our study, the incidence of signet ring histology surpassed previous reports in the literature, indicating approximately 12.6% for the same age group and 10.8% among the elderly.\u003c/p\u003e\u003cp\u003eIn our study, a significant majority of the patients (88.9%) presented with advanced stage III disease characterized by loco-regional lymph node involvement, whereas 79.5% exhibited involvement of the mesorectal margins. These findings are comparable to those from Western populations. Colorectal cancer (CRC) diagnosed in younger individuals is more likely to be associated with regional lymph node involvement or metastasis to distant sites than in older patients. Specifically, 63% of patients with young-onset CRC are diagnosed with stage III or IV disease, compared to 49% of older patients with colon cancer. For rectal cancers, statistics show that 57% of young-onset patients present with advanced stages, whereas 46% of older patients do the same [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn terms of location, the most frequent tumor in our patients was low-lying rectal cancer involving the anal canal, with 57% of the tumors lying within 5 cm of the anal verge. These findings are consistent with those of a study by Patil et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] from India, which showed that anorectal/rectal illness affected 54% of the patients, while a study by Laskar et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] showed that low rectal tumors were more prevalent in patients in northeast India.\u003c/p\u003e\u003cp\u003eAll patients in our study received a TNT protocol consisting of neoadjuvant chemotherapy followed by long-course chemoradiotherapy. Despite this aggressive multimodal approach, only 20% achieved a complete pathological response (pCR), and over one-third remained node-positive after surgery. While TNT has shown promising results in improving pathological response and compliance, our findings suggest that its benefits may be limited by initial tumor burden and adverse biology in YORC, especially in LMICs where diagnostic delays are common.\u003c/p\u003e\u003cp\u003eIn our study, at a median follow-up of 4 years (range: 1\u0026ndash;13), the five-year overall survival rate was 70.7%, while the disease-free survival was 56%, which is lower than that of patients with average-onset rectal cancer. In a meta-analysis published by Milena et al. for patients treated with neoadjuvant therapy, the five-year overall survival rate was reported to be 86% [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, the impact of age on CRC prognosis remains controversial. A recent study by Foppa et al. reported similar findings, with early-onset patients having worse progression- or recurrence-free survival in their multivariate analysis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThese findings indicate that young patients with rectal cancer predominantly present with locally advanced disease, with a high proportion of patients having T3/T4 tumors and lymph node involvement at diagnosis. Despite the widespread use of neoadjuvant therapy, a significant number of patients have positive CRM on pre-treatment imaging. Although a substantial proportion of patients underwent surgery with clear margins, recurrence rates remained high, particularly with distant metastases. Survival outcomes suggest that CRM status strongly influences DFS, emphasizing the need for more effective treatment strategies to improve long-term outcomes in young rectal cancer patients.\u003c/p\u003e\u003cp\u003eSome noteworthy strengths of our study include a large patient cohort, an extended follow-up period, and comprehensive information about treatment, health complications, and performance status.\u003c/p\u003e\u003cp\u003eThis study has certain limitations. Its retrospective design and single-center setting may limit the generalizability of the findings. The relatively small sample size and modest follow-up duration could affect the precision of survival estimates. The lack of molecular or genetic profiling and absence of long-term toxicity data restrict deeper insights into treatment personalization. Additionally, potential selection bias and incomplete data capture for some clinical variables may have influenced the results. Despite these limitations, the study offers valuable real-world insights into the treatment outcomes of young-onset rectal cancer in a resource-limited setting.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings suggest that young-onset colorectal cancer may exhibit distinct clinical and tumor characteristics, pointing toward a potentially unique biological behavior in this patient population. This study provides insight into the clinic pathological features and treatment outcomes of young rectal cancer patients managed with total neoadjuvant therapy in a resource-constrained setting. A significant proportion of patients presented with locally advanced disease and positive circumferential resection margins. Total neoadjuvant therapy resulted in promising rates of tumor downstaging, sphincter preservation, and pathological complete response. Nonetheless, recurrence and distant metastases were frequent, highlighting the need for enhanced surveillance and more effective systemic treatment strategies. These results underscore the importance of early diagnosis, personalized risk stratification, and multidisciplinary care in improving outcomes. Further large-scale, multicenter studies with extended follow-up are needed to confirm these findings and guide future therapeutic strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eCRC\u003c/strong\u003e : colorectal cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYORC\u003c/strong\u003e: young onset colorectal cancet\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLMIC\u003c/strong\u003e: low middle income country\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTNT\u003c/strong\u003e: total neoadjuvant therapy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTME:\u003c/strong\u003e total mesorectal excision\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e: overall survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDFS\u003c/strong\u003e: disease free survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePFS\u003c/strong\u003e: progression free survival\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThis retrospective study was approved by the Institutional Review Board of Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan \u003cstrong\u003e(IRB Reference No: EX-01-06-23-07).\u003c/strong\u003e The requirement for individual informed consent was waived by the IRB due to the retrospective nature of the study. All methods were carried out in accordance with relevant guidelines and regulations (Declaration of Helsinki).\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eNo specific funding was received for this study.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eFajar Rafi Ranjha: Study conception, data collection, analysis, and manuscript drafting.\u003cbr\u003e\u0026nbsp;Tabinda Sadaf and Asma Rashid: Study conception, design, supervision, and critical review.\u003cbr\u003e\u0026nbsp;Aqueel Shahid: Data analysis, interpretation, and manuscript review.\u003cbr\u003e\u0026nbsp;Muhammad Anas Tahseen Asar, Dr. Abdul Subhan Zahid, raheel mukhtar, Ahmad Rashid, and Haniya Rizwan: Data collection.\u003cbr\u003e\u0026nbsp;All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe authors would like to thank the Department of Clinical and Radiation Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, for their support.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAuthors\u0026rsquo; information\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eDr. Fajar Rafi Ranjha is a Fellow in Clinical and Radiation Oncology at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eStoffel, E.M. and Murphy, C.C., 2020. 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Clin Colorectal Cancer 16:293-299.e6, 2017\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Rectal Cancer, Young Patients, Neoadjuvant Therapy, Survival Outcomes, Circumferential Resection Margin, Disease-free Survival","lastPublishedDoi":"10.21203/rs.3.rs-7416785/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7416785/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e\u003cp\u003eThe rising incidence of young-onset rectal cancer (YORC) is a significant concern, particularly in low- and middle-income countries like Pakistan. This study evaluates the clinical characteristics, treatment patterns, and outcomes of YORC patients treated at a specialized cancer center in Pakistan.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA retrospective review was conducted on patients under 50 years diagnosed with locally advanced rectal cancer between 2010 and 2020. Comprehensive staging, neoadjuvant chemotherapy, chemoradiation, surgical resection, and follow-up were analyzed. Key outcomes included progression-free survival (PFS), overall survival (OS), and recurrence patterns.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong 244 patients (median age 36 years), 67.2% were male. Most presented with advanced disease (89% stage III), with 79.5% having positive circumferential resection margins (CRM). Adenocarcinomas were predominant (75.0%), while mucinous/signet ring histology accounted for 25%. All received neoadjuvant therapy. Of the 175 patients who underwent surgery, 20.0% achieved a complete pathological response. At a median follow-up of four years, five-year OS and PFS were 70.7% and 56.1%, respectively for CRM positive and CRM negative patients. Recurrence occurred in 41.0% of cases, with distant metastases being more common than local relapse. Negative CRM status correlated with improved DFS.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eYoung rectal cancer patients in Pakistan often present with aggressive, advanced-stage disease. Despite intensive multimodal treatment, outcomes remain suboptimal, highlighting the need for earlier detection, improved access to care, and tailored treatment strategies. These findings underscore the importance of public awareness, screening programs, and further research into the biological distinctiveness of YORC in resource-limited settings.\u003c/p\u003e","manuscriptTitle":"Clinicopathological Characteristics and Survival Outcomes in Young-Onset Rectal Cancer Treated with Total Neoadjuvant Therapy: Perspective from a Resource Limited Setting","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-29 19:56:47","doi":"10.21203/rs.3.rs-7416785/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"74018b3b-f65c-4721-adf4-903fc4f751b6","owner":[],"postedDate":"September 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-18T12:24:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-29 19:56:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7416785","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7416785","identity":"rs-7416785","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}