Neoadjuvant Chemoradiotherapy Research Articles

Outcomes of neoadjvuant chemotherapy versus chemoradiation for esophageal adenocarcinoma: A National Cancer Database analysis.

416 Background: While neoadjuvant chemoradiation (NCRT) has been the acceptable standard of care for esophageal adenocarcinoma (EAC), there has been a paradigm shift from recent trials have shown that neoadjuvant chemotherapy (NAC) is either equivalent or superior to NCRT. We sought to examine the outcomes of NAC versus NCRT in esophageal cancer from the National Cancer Database (NCDB). Methods: Utilizing the NCDB, we identified esophagectomy patients with EAC who underwent multiagent NCT versus multiagent NCRT. Overall Survival (OS) was analyzed with the Kaplan-Meier method and multivariate analysis (MVA) was performed to identify predictors of OS. Propensity score matching (PSM) was used to correct for baseline differences between groups. Results: After PSM, we identified 1007 patients in each group. Groups were equally balanced in age, gender, T/N stage, grade, and facility volume. There was improved lymphadenectomy and higher use of adjuvant therapy in NCT patients. There were significant improvements in R0 resection and pathologic response associated with NCRT patients. There was a significant improvement in OS in NCT versus NCRT. The median and 5-year OS was 42.7 months and 42% in NCT patients versus 34.2 months and 35% in NCRT patients (p = 0.001). For pathologic complete responders, median and 5-year OS was 101 months and 64% in NCT patients versus 71.2 months and 53% in NCRT patients (p = 0.04). On MVA, improved mortality was associated with female gender, pathologic N0, >10 nodes removed, pathologic partial or complete response, R0, well/moderate grade, NCT, adjuvant chemotherapy, and higher facility volume. There was also no survival benefit to adjuvant chemoradiation. Conclusions: Despite higher R0 and pathologic response associated with NCRT, NCT was superior to NCRT for OS in EAC patients. NCRT needs to be re-examined in its role as a treatment recommendation for operable EAC patients. Multivariate analysis for overall survival. Variable HR 95% CI P value Age 1.01 1.00 – 1.02 0.004 SexMaleFemale Reference0.79 0.64 – 0.98 0.03 Charlson Deyo score01 Reference1.05 0.91 – 1.21 0.54 Pathologic N-stageN0N+ Reference1.82 1.58 – 2.10 <0.001 LN removed<10>10 Reference0.81 0.68 – 0.97 0.02 ResponseNonePartialComplete Reference0.810.61 0.69 – 0.940.50 – 0.75 0.008<0.001 Margin statusR0R1 Reference1.24 1.01 – 1.52 0.04 GradeWell/moderatePoor Reference1.35 1.18 – 1.54 <0.001 Preop radiationYesNo Reference0.77 0.67 – 0.88 <0.001 Adjuvant therapyNoneChemotherapyChemoradiation Reference0.770.83 0.65 – 0.920.64 – 1.08 0.0040.17 Facility volumeLow (≤10/year)Medium (11-19/year)High (≥20/year) Reference0.860.78 0.72 – 1.030.67 – 0.90 0.10<0.001

Comparison of long-term outcomes for neoadjuvant chemoradiation (NA-CRT) followed by surgery versus (V) definitive chemoradiation (D-CRT) in localized gastroesophageal cancer (GEC): A single-center analysis.

371 Background: The therapeutic approach in locally advanced GEC is evolving. NA-CRT followed by surgery has been recommended based on the CROSS trial. The SANO trial reports active surveillance may be an alternative in clinically complete response after D-CRT in both squamous cell carcinoma (SCC) and adenocarcinoma (AC). SCC and AC in GEC are different diseases with differences in tumor location, etiology, and biology. Despite the evolving landscape, there still may be a role for both CROSS and SANO approaches. In our large observational cohort study, we sought to compare the long-term outcomes in localized GEC across all histological subtypes treated with NA-CRT+Surgery V D-CR+Surveillance. Methods: A retrospective analysis comparing NA-CRT + surgery V D-CRT in localized GEC between 2007-2023 treated at the Princess Margaret Cancer Centre was completed. Baseline characteristics including age, gender, race, performance status and Charlson Comorbidity index (CCI) were reviewed. The primary and secondary endpoints were overall survival (OS) and disease-free survival (DFS), respectively and to compare these outcomes in both histologies. Cox proportional hazards analysis and Kaplan-Meier methods were employed. Outcomes were adjusted for baseline characteristics. Results: There were 529 patients (pts) included, 321 (61%) received NA-CRT+Surgery and 208 (39%) D-CR+Surveillance. Median age was 64yrs, 75% were male and 66% had N1+ disease. The proportion of pts with SCC treated with NA-CRT+Surgery and D-CR+Surveillance was 25% and 63%, respectively. There was a statistically significant difference in median OS and DFS between pts who received NA-CRT+surgery and D-CRT+surveillance (Table). Multivariate regression analysis shows a significant association between OS and age (adjusted HR 1.02, p=0.005), male sex (HR 1.55, p=0.003) but no significant association between OS and CCI (HR 1.1 p=0.36). In our subgroup analyses, there was no statistically significant difference in OS (p=0.33) and DFS (p=0.18) between SCC and AC. However, this was significant in D-CRT (OS p<0.0001, DFS p<0.001) favoring SCC. Conclusions: In contrast to the SANO trial, we found that NA-CRT+surgery was associated with a significantly better OS and DFS compared to D-CRT when subtypes were combined. However, in the D-CRT subgroup, SCC was associated with improved OS and DFS compared to AC. Thus, we continue to recommend current approaches in SCC. Awaited updates from SANO will inform whether active surveillance may also be appropriate in pts with AC subtype. Median (95% CI)NA-CRT Surgery Median (95% CI)D-CRT Log-rank test p-value OS (mo) 28.2 (15.1, 57.6) 15.6 (7.7, 33.7) P=<0.0001 DFS (mo) 17.9 (9.6, 40.8) 9.4 (5.0, 20.7) P=<0.0001 pathCR (%) 14 - R0 resection (%) 89 -

Evaluation of the impact of lymph node ratio on survival in patients with pancreatic cancer undergoing neoadjuvant therapy.

702 Background: Pancreatic cancer continues to have a dismal prognosis despite improvements in surgical care. Resection status and lymph node status continues to be key factors impacting prognosis. There remains significant debate on the utility of increasing nodal harvest in patients undergoing surgery, while others report an improvement in survival. We sought to evaluate the impact of lymph node positivity to lymph nodes resected in patients with pancreatic cancer undergoing resection. Methods: Utilizing the National Cancer Database, we identified patients diagnosed with pancreatic cancer who underwent neoadjuvant chemotherapy (NCT) or neoadjuvant chemoradiation (NCR) followed by resection. We then stratified by nodal status and calculated a LN+/LNR (lymph node resected) ratio. Pearson’s Chi-square test was used to compare categorical variables. Survival analysis was estimated by the Kaplan-Meier method and associated log-rank test. Propensity score matching (PSM) was completed for variables of age, sex, tumor size, LN removed, LN positive, pathogenic T- stage and N-stage, grade, 30- and 90-day mortality, R0 resection, facility volume, response, adjuvant therapy, and LNR. Significance was considered at p-value ≤0.05. Results: We identified 4117 patients with a median age of 65 (25-90). There were 2323 patients who underwent NCT and 1794 who underwent NCR. The median LN resected in the NCT was 18 vs 15 in the NCR, p<0.001. However, there were more LN+ in the NCT vs NCR, 2.1 vs 0.9, p<0.001. The R0 resection rates were lower in the NCT vs NCR 81% vs 86%, p<0.001. Additionally, complete response rates were higher amongst the NCR, 9.2% vs 4.7%, p<0.001. Lymph node ratios were consistently higher in the NCT cohorts among all ratio strata, p<0.001. Patients with pN+ disease had a median and 5-year survival of 26.4mo and 17% compared to their pN- counterparts at 38.8mo and 36%, p<0.001. Patients treated with NCT demonstrating a LNR of 0.01-0.1 had median and 5-year survival of 32.8 and 27%, LNR 0.11-0.4 (25.5mo and 12%), and LNR>0.4 (19.1mo and 10%), p<0.001. Patients treated with NCR demonstrating a LNR of 0.01-0.1 had median and 5-year survival of 29.1 and 21%, LNR 0.11-0.4 (25.8mo and 17%), and LNR>0.4 (21.3mo and 5%), p<0.001. PSM confirmed a higher LNR in the NCT cohort compared to NCR, p<0.001, however survival was also longer in these patients among the LNR 0.01-0.1, and 0.11-0.4, p<0.001. Conclusions: Lymph node status in patients with pancreatic cancer continues to be a significant prognostic indicator of survival. Moreover, lymph node ratio may be a more accurate predicter of survival in patients undergoing neoadjuvant chemotherapy and neoadjuvant chemoradiation.

Neoadjuvant SHR-1701 (a bifunctional anti-PD-L1/TGF-βRII agent) combined with chemoradiotherapy for resectable locally advanced esophageal squamous cell carcinoma (ESCC): A phase II trial.

410 Background: Neoadjuvant chemotherapy or chemoradiotherapy followed by surgery is the standard of care for resectable locally advanced ESCC. SHR-1701, a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II, may enhance antitumor activity in combination with neoadjuvant standard therapies in ESCC patients (pts). The aim of this phase II trial is to determine the safety and efficacy of neoadjuvant chemoradiotherapy plus SHR-1701 followed by esophagectomy in pts with locally advanced resectable ESCC. Methods: Pts with resectable thoracic ESCC, diagnosed as clinical stage of cT1b-cT2N+M0 or cT3-cT4aNxM0 per AJCC 8th were eligible. Preoperative therapy included SHR-1701 (30 mg/kg every 3 weeks for 2 cycles), albumin paclitaxel (50 mg/m 2 , once a week for 5 weeks), carboplatin (AUC=2, once a week for 5 weeks) and radiotherapy (41.4Gy in 23 fractions). Following esophagectomy, pts received SHR-1701 up to 1 year. The primary endpoint was pathological complete response (pCR) rate in the per-protocol population. Secondary endpoints included R0 resection rate, major pathological response (MPR) rate, disease free survival (DFS) and safety. Results: Between Dec. 2021 and Feb. 2023, 43 pts were screened and 41 met the inclusion criteria, among whom the clinical stage I, II, III, and IVa at baseline were 1 (2.4%), 8 (19.5%), 31 (75.6%), and 1 (2.4%), respectively. All 41 pts received neoadjuvant SHR-1701 combined with chemoradiotherapy. As of Mar. 2024, 30 pts underwent surgery, and all achieved R0 resection. There was no in-hospital and postoperative 30-day mortality. 9 (30.0%) pts achieved pCR in both primary tumor and lymph nodes (ypT0N0), and 12 (40.0%) pts had complete pathological response of the primary tumor with residual disease in lymph nodes alone (ypT0N+). Treatment-related adverse events (TRAEs) occurred in all pts, and most of TRAEs were grade 1-2. Notable toxicity included pneumonitis (31.7%) and anastomotic leak (12.2%). Conclusions: The addition of SHR-1701 to neoadjuvant chemoradiotherapy in ESCC demonstrated promising efficacy with acceptable toxicity, and might be a promising approach for neoadjuvant treatment. Clinical trial information: ChiCTR2000041562.

Survival analysis using neoadjuvant rectal score in patients with locally advanced rectal cancer who underwent surgery after neoadjuvant chemoradiotherapy: An ambispective study.

172 Background: Colorectal cancer, the third most common malignancy and a major cause of cancer deaths, is treated using a standard protocol of neoadjuvant chemoradiotherapy (NACTRT) or short-course radiotherapy (SCRT) followed by total mesorectal excision (TME) for locally advanced rectal cancers (LARC). Long-term follow-up is essential to determine study endpoints, necessitating surrogate markers for short-term outcomes. This study aims to stratify patients into risk groups based on their Neoadjuvant Rectal Cancer (NAR) score and evaluate its predictive value for oncological outcomes, including overall survival, disease-free survival (DFS), locoregional relapse-free interval (LRFI), and distant metastasis-free interval (DMFI), while also correlating clinicopathological characteristics with these outcomes. Methods: This ambispective observational study at the Regional Cancer Centre, Thiruvananthapuram, involved 459 patients with biopsy-proven, locally advanced rectal adenocarcinoma (T3/T4 and/or node positive) who underwent long-course neoadjuvant chemoradiotherapy (NACTRT) followed by curative surgery (Anterior Resection or Abdomino-Perineal Resection) between 2010 and 2015, with a minimum follow-up of three years. Exclusion criteria included previous malignancies, synchronous colorectal cancers, oligometastatic disease, and loss to follow-up. The study aimed to determine the predictive value of the Neoadjuvant Rectal Cancer (NAR) score for oncological outcomes. Clinicopathological details were collected from case records, imaging, and operative notes, and postoperative histopathological records were used to calculate the NAR score. Patients were categorized into three groups based on their NAR scores and followed prospectively for recurrence or death. Data were analyzed using frequency, percentages, mean, standard deviation, Chi-square test, Kaplan-Meier method, log-rank test, and Cox regression analysis, with a significance level set at p < 0.05. Results: 459 patients were included in the study, with 41.4% females, and 44% being less than 60 years. Most of the patients had lesion 5-10 cm from anal verge (46%). 77% of patients had T3 disease prior to the start of NATCTRT. 51.9% had underwent APR, and 80.4% had open surgery. 11.1% had PCR attained. 27% had disease recurrence of which most were distant metastasis. NAR was a significant predictor of overall survival, disease free survival, distant metastasis free interval and locoregional failure free interval. Other significant predictors of overall survival were pre-NACTRT T stage, pN stage, PLNR, CRM status and PCR, but only NAR was found to be significant on multivariate analysis. Conclusions: NAR score is a significant predictor of OS, DFS,LRFI and DMFI and can be used as a short term surrogate for survival data in anticipated trials.

Systematic literature review (SLR) of prognostic factors (PFs) in locally advanced rectal cancer (LARC) and mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer (RC).

303 Background: Innovative immunotherapies arebeing developed to improve clinical outcomes in patients (pts) withdMMR/MSI-H LARC who respond poorly to the current standard of care. A comprehensive overview of PFs in dMMR/MSI-H LARC may provide insight into the natural history of this disease to inform clinical study design and pt risk stratification. Methods: Systematic searches of bibliographic databases (EMBASE, MEDLINE, Cochrane; 2013–2023) and congress websites (2021–2023) were conducted to identify PFs for tumor response and survival outcomes in adult pts with LARC (SLR1) and dMMR/MSI-H RC (SLR2). Given the expected high volume of evidence, SLR1 was limited to large observational studies (≥1000 pts) and clinical trials (≥100 pts); SLR2 had no such limits. Results: 95 of 2307 publications met the inclusion criteria for SLR1. Of the PFs reported in ≥20 studies, older age, more lymph node involvement or fewer nodes assessed, higher T-stage or larger tumor size, higher histologic grade, and more comorbidities were most frequently significantly associated with poorer patient prognosis (Table). 3 of 289 publications met the inclusion criteria for SLR2. Neoadjuvant chemoradiation therapy (CRT) compared to chemotherapy (CT) was associated with statistically significant worse disease-free survival (DFS) and distant metastasis-free survival (DMFS), while T- or N-stage, age, and sex did not significantly impact these outcomes. Low vs middle tumor localization was also associated with worse DMFS. Stage III and IV disease were associated with worse RC-specific survival, while surgical procedure (segmental vs extended) showed no difference in overall survival (OS). The addition of neoadjuvant CRT or adjuvant CRT/CT to surgery alone had no impact on OS but was associated with worse DFS. Conclusions: Evidence regarding PFs in dMMR/MSI-H RC is scarce and may limit its interpretability, highlighting the need for further research that may be informed by the PFs identified from SLR1. The results from these SLRs may be helpful for optimizing patient management and treatment decision making, and to further contextualize RC clinical trials. PFs reported in ≥20 studies with ≥75% of studies reporting significant results in pts with LARC. PF Studies reporting PF (n) Studies reporting significant* impact of PF on prognosis (%) Poorer prognosis group Top 2 most frequently reported outcomes Age 59 81.4 Older OS, DFS Lymph node involvement/assessment 55 78.2 Yes or higher N stage OS, DFS T-stage or tumor size 53 79.2 Higher or larger OS, DFS Histologic grade 37 75.7 Higher OS, pathological complete response (pCR) Comorbidities 23 87.0 More OS, pCR *p-value <0.05 was considered significant as reported in the identified studies.

Severe Lymphopenia Predicts Poorer Survival in Patients With Rectal Cancer Undergoing Neoadjuvant Chemoradiation.

Chemoradiation-induced lymphopenia is common and associated with poorer survival in multiple solid malignancies. However, the association between chemoradiation-related lymphopenia and survival outcomes in rectal cancer is yet unclear. The objective of this study was to evaluate the prognostic impact of lymphopenia and its predictors in patients with rectal cancer undergoing neoadjuvant chemoradiation. The inclusion criteria for this single-institution retrospective study were as follows: (1) biopsy-proven diagnosis of rectal adenocarcinoma, (2) receipt of neoadjuvant chemoradiation followed by surgery, and (3) absolute lymphocyte count available prior to and within 12 weeks of chemoradiation. In general, chemoradiation consisted of 5-fluorouracil or capecitabine and radiotherapy with 50.4 Gy over 28 fractions. Lymphopenia was graded according to the Common Terminology Criteria for Adverse Events version 5.0. The primary variable of interest was absolute lymphocyte count nadir within 12 weeks of chemoradiation, dichotomized by <500/μL (grade 3 or worse lymphopenia). The primary endpoint was overall survival. Cox modeling and Kaplan-Meier methods were used to perform survival analyses. A total of 193 patients were identified with a median follow-up of 68 months. Overall clinical stage was 2 in 21% and 3 in 76%. Median baseline lymphocyte count for the entire cohort was 1700/μL. One hundred ten patients (57%) experienced chemoradiation-related severe lymphopenia. Pathologic complete response rate was 21%; 83% received adjuvant chemotherapy. Lower baseline lymphocyte count was significantly associated with increased risk for chemoradiation-related severe lymphopenia (odds ratio, 1.71). On multivariable Cox regression analysis, chemoradiation-related severe lymphopenia was significantly associated with worse disease-free survival (hazard ratio, 2.64) and overall survival (hazard ratio, 4.32). Five-year overall survival was 79% versus 92%, and 5-year disease-free survival was 70% versus 86% in the cohort that experienced versus did not experience severe lymphopenia, respectively. Chemoradiation-induced lymphopenia is common and a prognostic marker of poorer survival in rectal cancer. Closer observation in high-risk patients and treatment modifications may be potential approaches to mitigating treatment-related lymphopenia. Our findings also suggest an important role of the host immunity in rectal cancer outcomes and support future studies investigating ways to reduce treatment-induced lymphopenia.

Circulating tumour DNA in predicting and monitoring survival of patients with locally advanced rectal cancer undergoing multimodal treatment: long-term results from a prospective multicenter study.

Neoadjuvant chemoradiotherapy (nCRT) is the standard for locally advanced rectal cancer (LARC). However, distant metastasis remains the primary cause of treatment failure. Early identification of high-risk individuals for personalized treatment may offer a solution. Circulating tumour DNA (ctDNA) could assist in this process. From September 2017 to June 2019, the study prospectively recruited 113 patients with LARC (cT3-4N0M0 or cTanyN+M0) who underwent nCRT followed by radical surgery across 8 tertiary centers. ctDNA was analysed using large-panel targeted sequencing at baseline, during nCRT, pre-surgery, post-surgery, post-adjuvant chemotherapy (ACT), and during annual follow-ups for 3 years. We analysed 103 tissue and 669 plasma samples from 103 patients. With a median 53-month follow-up, significantly worse progression-free survival (PFS) and overall survival (OS) were observed if median variant allele frequency (mVAF) of baseline ctDNA per patient was ≥0.5% (PFS, HR 4.39, p<0.001; OS, HR 5.61, p=0.004) or ctDNA was still detectable two weeks into nCRT (PFS, HR 7.63, p<0.001; OS, HR 5.08, p<0.001). Furthermore, when compared to the low-risk (C1) group (characterized by "ctDNA undetected during nCRT with baseline mVAF <0.5%" or "ctDNA undetected during nCRT with TMB (tumour mutational burden)≥20/Mb"), the high-risk (C2) group (characterized by "ctDNA detected during nCRT" or "baseline mVAF ≥0.5% with TMB <20/Mb") showed significantly worse long-term outcomes (3y-PFS, 55.9% vs. 94.2%; 3y-OS, 79.4% vs. 100%). The ctDNA clearance during nCRT, baseline mVAF, and TMB may be effective prognostic indicators. Our findings reaffirm the clinical monitoring value of ctDNA and demonstrate the strong prognostic value of baseline ctDNA and its early clearance status in patients with LARC undergoing nCRT. This highlights the potential of dynamic ctDNA monitoring as actionable stratified indicators to guide personalized neoadjuvant treatment strategies. This work was supported by the Major Grants Program of Beijing Science and Technology Commission (No. D171100002617003) and the National High Level Hospital Clinical Research Funding (2022-PUMCH-C-005).

Total neoadjuvant therapy followed by total mesorectal excision and selective lateral lymph node dissection for locoregionally advanced low rectal cancer: A phase III randomized controlled trial (JCOG2207).

TPS312 Background: For locally advanced low rectal cancer (RC), total neoadjuvant therapy (TNT) followed by total mesorectal excision (TME) confers a survival advantage compared with neoadjuvant chemoradiotherapy (nCRT) in the West, even though the local control rate was similar between TNT and nCRT. The Japan Clinical Oncology Group (JCOG) Colorectal Cancer Study Group has been developing therapies for RC based on recurrence risk according to presence/absence of clinical lateral lymph node metastasis (cLLNM). Our previous study in Japan showed that the standard of care (SOC) for RC is TME with lateral lymph node dissection (LLND) plus adjuvant chemotherapy (CTx). However, the prognosis for cStage III low RC remains poor regardless of cLLNM status. Therefore, new treatment strategies are needed for this population. In cLLNM-positive cStage III low RC patients, previous research suggests that adding nCRT to LLND would reduce local recurrence and improve survival. TNT and LLND may further improve outcomes. In cLLNM-negative cStage III low RC, several reports have suggested that nCRT as an alternative addition to LLND has comparable efficacy in terms of local control. Thus, in these populations, if TNT can replace LLND, adverse events due to LLND can be avoided while improving prognosis. We hypothesize that TNT + TME + selective LLND would be the most promising strategy for cLLNM-positive and -negative cStage III low RC. Methods: Eligibility criteria include low rectal adenocarcinoma or adenosquamous carcinoma, cT2-cT4 tumor depth, clinically positive lymph node metastasis, no distant metastasis, no history of pelvic irradiation or rectal surgery, age 18-75 years, and sufficient organ function. Eligible patients are randomized (1:1) with adjustment factors of institution, sex, and cLLNM status. The experimental treatment arm receives TNT, short-course radiotherapy (25 Gy/5 fractions to whole pelvis), and consolidation chemotherapy consisting of 6 courses of CAPOX (oxaliplatin 130 mg/m2 on day 1 and capecitabine 2000 mg/m2/day on days 1-14). After completing TNT, TME + selective LLND are performed for cLLNM-positive cases or TME alone for cLLNM-negative cases. The SOC arm receives TME + LLND followed by adjuvant chemotherapy with 8 cycles of CAPOX (same as above). The primary endpoint is overall survival (OS) in the intention-to-treat population. To detect an increase in 5-year OS from 76% to 84%, corresponding to a target hazard ratio of 0.64, 408 patients (108 events) would achieve 75% power at a one-sided α of 0.05, an expected accrual period of 4 years, and a follow-up period of 5 years. The total sample size was set at 420 patients to account for patients lost to follow-up. Accrual in JCOG2207 began in October 2023. Clinical trial information: s031230415 .

Neoadjuvant chemoradiotherapy with ipilimumab and nivolumab in rectal cancer (CHINOREC): A prospective randomized, open-label, multicenter, phase II clinical trial.

139 Background: Immune checkpoint inhibitors (ICIs) seem only effective in a primed tumor immune microenvironment (TIME). Neoadjuvant radiotherapy (RT) has been shown to induce an immunogenic cell death (ICD) and thereby restores the susceptibility to ICI. This study evaluates the safety of neoadjuvant chemoradiotherapy (CRT) with concomitant ipilimumab (IPI) and nivolumab (NIVO) in curative rectal cancer (RC) patients. Methods: The CHINOREC study (ClinicalTrials.gov identifier NCT04124601) is a prospective, randomized (ratio 50:30), open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with RC received neoadjuvant CRT (50 Gy in 2 Gy fractions with concurrent capecitabine 1650 mg/m 2 /d) alone or in combination with IPI (1 mg/kg IV at day 7), following 3 cycles of NIVO (3 mg/kg IV Q2W, starting on day 14). Surgical resection was performed 10-12 weeks post CRT. The primary endpoint was surgical safety and feasibility (Clavien-Dindo Classification) of neoadjuvant CRT with sequential IPI and NIVO following surgical resection. Secondary outcome was complete response rate (clinical and pathological). Results: Between June 2020 and November 2023, 145 patients were screened and 80 randomly assigned to CRT (n=30) or CRT+IPI/NIVO (n=50). The primary endpoint (any surgical complication) did not differ between the 2 groups (78% vs. 77%). The reoperation rate (≥Grade IIIb) was comparable low in both groups (8% vs. 7%). No new safety signals were identified. The rate of major pathological response (MPR) and complete response (CR) was also comparable high in both arms (38% vs. 37% and 30% vs. 22%, respectively). Conclusions: Neoadjuvant IPI/NIVO can be safely applied concomitant with CRT in patients with RC, as it does not increase the rate of reoperation or surgical complications. The validity of the encouraging CR rate needs to be elucidated over time. Further translational analyses will elucidate mechanistic insight regarding improved fraction, dosing and timing of CRT and ICI. Clinical trial information: NCT04124601 .

Effects of the delay of surgery in localized rectal cancer.

63 Background: The treatment landscape for localized rectal cancer has evolved significantly in recent years, with long-course neoadjuvant chemoradiation (CRT) and total neoadjuvant therapy (TNT) emerging as the primary options. However, the optimal timing of surgery remains an important clinical question, particularly in resource-limited settings where surgical delays can occur. Data from previous studies have shown conflicting results. This retrospective study aimed to assess the impact of delaying surgery beyond the longer interval used in previous studies, focusing on its effects on Pathologic Complete Response (pCR), DFS, and OS. Methods: We conducted a retrospective cohort study using electronic medical records from three centers in Brazil between the years 2013-2024. The study included 236 patients with localized rectal cancer treated with neoadjuvant CRT and/or chemotherapy. Patients were divided into two pre-specified groups based on the interval between the end of neoadjuvant therapy and surgery: ≤11 weeks and &gt;11 weeks. The primary endpoint was DFS. Secondary endpoints were pCR rates, and OS. Descriptive statistics were used for population analysis, while the Kaplan-Meier method estimated DFS and OS, with comparisons made using the log-rank test. A Cox proportional-hazards model was used to estimate hazard ratios and 95% confidence intervals. Results: The median age of the study population was 62 years, with males comprising 56.4% of the sample. The majority of the sample consisted of stage III patients, making up 72.2%, followed by stage II patients at 25.8%, and stage I patients at 1.9%. Most patients (77.8%) had surgery more than 11 weeks after completing neoadjuvant therapy, with a median time to surgery of 16 weeks. The pCR rates did not significantly differ between the two groups (29% for ≤11 weeks vs. 21.5% for &gt;11 weeks; p = 0.271). After a median follow-up of 30 months, the median DFS was not reached, and there was no significant difference between the groups (HR: 0.86; 95% CI: 0.48-1.5; p = 0.63). Similarly, the median OS was not reached, and no difference was observed between the groups (HR: 0.85; 95% CI: 0.47-1.54; p = 0.88). Conclusions: Delaying surgery beyond 11 weeks did not result in greater tumor downstaging in patients with localized rectal cancer. Furthermore, DFS and OS were not significantly impacted by extended intervals between neoadjuvant therapy and surgery.

Surrogacy between pathological complete response and overall survival: An individual patient data analysis of eight RCTs on neoadjuvant treatment plus surgery for esophageal cancer.

498 Background: Overall survival (OS) is the gold standard endpoint of treatment efficacy but requires an extended follow-up period. This study aimed to determine the validity of pathological complete response (pCR) as a surrogate endpoint for OS. Methods: The individual-level surrogacy between categorical outcome and OS was assessed using Kendall correlation coefficient, τ. Because no method has been reported to estimate τ between categorical variables and OS, we proposed the new method using an inverse probability of censoring weighting (IPCW) estimator adjusted for tied data that occur when applied to categorical outcomes. To evaluate the validity of this new method, we conducted simulations to compare its estimation accuracy with existing methods. A systematic review for all phase III RCTs comparing therapies in perioperative settings for resectable advanced esophageal and gastroesophageal junction cancer was performed and individual patient data (IPD) were requested from all included trials. Finally, surrogacy between pCR and OS was assessed using our proposed method. Results: Across all scenarios with varying τ values, sample sizes, and censoring proportions, the proposed method showed the lowest bias compared to the existing statistical methods. In total, 23 eligible trials were identified and IPD were available from eight RCTs (JCOG1109, JCOG9907, JCOG9204, FFCD9901, FFCD9102, SAKK75/08, CROSS, and KOK), including 1688 patients who received neoadjuvant therapy. For trial-level analysis, pCR showed a strong correlation with a determination of correlation of 0.65 when limited to neoadjuvant chemotherapy (NAC) trials. For individual-level analysis, in patients who received NAC, the hazard ratio (HR) for OS of pCR was 0.25 (95% CI: 0.13 - 0.47), and τ between OS and pCR was 0.225. While in patients who received neoadjuvant chemoradiotherapy (NACRT), the HR was 0.54 (95% CI: 0.45 - 0.66), and τ was 0.189. Additionally, τ between OS and pathological grade (pGrade), OS and tumor regression grade (TRG) was 0.196 and 0.143, respectively. As a reference, hypothetical data showed that in order to achieve a τ of 0.8 between pCR and OS, it is necessary to be able to clearly identify the prognosis to the extent that an HR of 0.09 (95% CI: 0.08 - 0.11) can be obtained. Conclusions: While pCR is sensitive enough to stratify prognosis and exhibit strong trial-level surrogacy, no individual-level surrogacy was demonstrated, making them insufficient to replace OS. It should be noted that there are substantial differences in prognostic stratification and potential use of pCR as primary endpoints in clinical trials.

Clinical outcomes and molecular characteristics of patients with locoregional ampullary carcinoma.

732 Background: Ampullary carcinoma (AC) is a rare malignancy arising from the ampulla of Vater which has a more favorable prognosis compared to other pancreatic malignancies. Current guidelines favor surgical resection followed by adjuvant therapy for average risk patients (pts), however the type of regimen as well as other perioperative treatment modalities are still being explored. The objective of this retrospective study aims to provide insight into the management of locoregional disease. Methods: Pathology records from Mayo Clinic (AZ, FL, MN) denoting AC between 2010 to 2024 were searched using Mayo Data Explorer and selected for retrospective review. Pt demographics, treatment courses, and next generation sequencing (NGS) data were collected. Statistical analysis was conducted using SAS version 9.04. Results: A total of 137 pts (62% male, n = 85) were identified with median age 66 years old. Histologic subtypes were 54% pancreatobiliary (44/81), 40% intestinal (32/81), 6% mixed (5/81), with 56 pts unknown. Stages at diagnosis were 81% resectable (111/137), 11% locally advanced (15/137), and 8% metastatic (11/137). Nearly all (93%, n = 103/111) pts with localized disease had resection with a 97% R0 resection rate (100/103). Majority (68%, n = 75/111) of resectable pts had perioperative chemotherapy with 5-FU or gemcitabine-based regimens (24%, n = 18/75 neoadjuvant vs. 76%, n = 57/75 adjuvant). Perioperative chemoradiation was given in 17% (19/111) of pts. At median follow up of 30.5 months, recurrence rates were 40% (41/103), primarily to the liver (18/41). Median recurrence free survival (RFS) was 29.3 months (95% CI 24.7 – NE). Median overall survival (OS) has not been reached. The 5-year RFS and OS rates were 0.37 (95% CI 0.25 - 0.55) and 0.69 (95% CI 0.58 - 0.82), respectively. Univariate analysis showed no difference in OS with the addition of neoadjuvant or adjuvant chemotherapy or chemoradiation. Somatic NGS testing showed pathogenic mutations in 90% of pts (63/70): 57% KRAS (36/63; 44% G12D, 19% G12V, 8% G12C, 8% G12D, 19% others); 13% homologous recombination (HR) (8/63); 6% ERRB2 /Her2 amplification (4/63), and 5% mismatch repair (MMR) (3/63). Conclusions: AC has a favorable prognosis in resectable pts. However, high recurrence rates indicate the need for better systemic therapies and improved selection of pts who would benefit from these treatments. Future research should focus on refining perioperative strategies to enhance outcomes and reduce recurrence.

Phase II study of neoadjuvant FLOT and chemoradiation for trimodality therapy of esophageal/GEJ adenocarcinoma.

466 Background: Recent data support use of perioperative FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) chemotherapy over pre-operative chemoradiation (CRT) for patients with resectable esophageal/GEJ adenocarcinoma with limited studies evaluating combined FLOT/CRT. This prospective phase II study (NCT04028167) evaluated a neoadjuvant approach of FLOT followed by CRT for resectable esophageal/GEJ adenocarcinoma (EAC). Methods: Operable patients with cT1-2 N1-2 or cT3-4N any4 Nany non-metastatic EAC were eligible. Neoadjuvant treatment consisted of FLOT x 3 cycles followed by restaging PET and chemoradiation (41.4 Gy / 23 fractions to the primary site and regional lymphatics with weekly carboplatin/paclitaxel). Adjuvant nivolumab for non-pathologic complete response (pCR) was permitted. The primary endpoint was pCR rate among patients receiving the study regimen and undergoing resection, with secondary endpoints including disease free survival (DFS), overall survival (OS), toxicity, and correlative studies. DFS/OS was measured using the Kaplan Meier (KM) method. Interim results are presented after a planned safety analysis. Results: Since 4/2020, 23 patients with median age of 62 (range 40-73) have enrolled. cT3-4 and cN+ disease was present in 20/23 (87%) and 16/23 (70%) of patients, respectively. FLOT was completed by 21/23 patients (reasons for discontinuation included allergic reaction and G5 sepsis/endocarditis). All 21 patients initiating chemoradiation completed planned treatment and 17/21 underwent resection (2 refused surgery after achieving cCR, 1 died of cardiac arrest, 1 patient is awaiting surgery). A pCR was observed in 5/17 resected patients (29%), with pCR or near pCR observed in 9/17 (53%). The complete response rate (pCR + cCR for patients refusing surgery) was 7/19 (37%). Adjuvant nivolumab was administered in 9 patients. The median follow-up among all patients was 20 months with 2-year DFS and OS estimates of 61% and 73%. The regimen was tolerated with G3+ hematologic, G3+ gastrointestinal, and G3+ other toxicity observed in 39%, 13%, and 22% of patients, respectively. Conclusions: In a locoregionally advanced population, neoadjuvant sequential FLOT followed by CRT was well tolerated with encouraging DFS/OS and a high rate of complete response compared to prior studies. This hybrid platform may enhance both locoregional and distant control and is of interest for expanded evaluation. Clinical trial information: NCT04028167 .

Phase II study of neoadjuvant NALIRIFOX followed by chemoradiation with paclitaxel and carboplatin in locally advanced gastroesophageal cancer.

452 Background: We performed a single-arm phase II study of neoadjuvant NALIRIFOX and chemoradiation (CRT) with concurrent carboplatin/taxol (C/T) followed by surgery in patients with locally advanced gastroesophageal (GE) cancer. Methods: Patients were enrolled on an NCI sponsored, prospective, single arm study (NCT04656041). Key eligibility criteria included: histologically confirmed T3/4 or lymph node (LN) positive GE junction or esophageal cancer, ECOG PS ≤1, age 18+, and life expectancy &gt; 3 months. Exclusion criteria included: metastatic disease, prior chemotherapy or RT, or prior targeted therapy for diagnosis. Extensive LN disease beyond the surgical field (supraclavicular or para-aortic) was permitted if deemed feasible to be encompassed within a RT field. Laparoscopy was not required. Pts were treated with neoadjuvant NALIRIFOX x 4-8 cycles pending patient tolerance and physician discretion, restaging, CRT (50.4 Gy in 28 fractions) with concurrent C/T, restaging, followed by surgical resection. Dose reductions were at discretion of the treating physician. The primary study endpoint was the pathologic complete response rate following neoadjuvant treatment with NALIRIFOX and CRT with concurrent C/T. Major pathologic response (mPR) was defined as Tumor Regression Grade 0 and 1. Secondary endpoints included: 1) acute toxicity; 2) clinical response per RECIST criteria; 3) PFS and 4) OS. Results: From June 2021 to October 2023, 40 patients were enrolled. Median age was 64 (range: 47-82), and 31 patients were male (78%). All patients started NALIRIFOX, and the median number of NALIRIFOX received was 5 (range: 1-8). Reasons for discontinuation of NALIRIFOX were: physician discretion (n=29), subject withdrew from treatment (n=2), progressive disease (n=1), death (n=1). Rates of grade 3+ toxicity for overall, gastrointestinal, and hematologic attributed to NALIRIFOX were 55%, 35%, and 13% respectively. 35 patients started chemoRT (88%) and 33 patients completed chemoRT (83%). Rates of grade 3+ toxicity for overall, gastrointestinal, and hematologic attributed to chemoRT were 86%, 11%, and 9% respectively. Of 33 who completed chemoRT, two patients declined surgery (including 1 with clinical CR), and 31 (78%) patients went for surgical exploration. No patients were found with intraoperative metastases. Therefore, 31 (78%) patients underwent surgical resection. In total, 9 patients had pCR (29% in resected cohort, 23% in ITT cohort) and 15 had a major PR (48% in resected cohort, 38% in ITT cohort). In total, 10 (25% in ITT) patients had pCR or clinically CR at 1 year. Conclusions: Neoadjuvant NALIRIFOX followed by CRT is feasible with acceptable rates of treatment completion and grade 3+ toxicity. In our phase II trial, the rate of pCR is promising and further studies incorporating this regimen should be considered. Clinical trial information: NCT04656041 .

Preliminary results from the multicenter, randomized phase III trial (SCIENCE): Comparing chemotherapy plus sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant treatment in resectable locally advanced esophageal squamous cell carcinoma.

LBA329 Background: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (CRT) followed by surgery is the standard treatment for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC). Despite significant advancements in therapeutic strategies, the rate of recurrence remains high. Therefore, this multicenter, randomized, Phase III trial (SCIENCE) aims to evaluate and compare the efficacy of nCT and nCRT plus Sintilimab, and nCRT alone in patients with resectable LA-ESCC. Methods: Eligible patients with thoracic ESCC and had not received any prior treatment. Patients were clinically staged as locally advanced (cT1N2-3M0 or cT2-4aN0-3M0). Participants were randomized in a 1:1:1 ratio to one of three neoadjuvant treatment groups: Group A: Sintilimab combined with nCT (nab-paclitaxel plus carboplatin) for two cycles. Group B: Sintilimab combined with concurrent nCRT (nab-paclitaxel plus carboplatin chemotherapy and radiotherapy using IMRT/IGRT totaling 41.4 Gy). Group C: Concurrent nCRT alone. Surgical resection was planned 6-8 weeks after the completion of neoadjuvant therapy. The co-primary endpoints were pathological complete response (pCR) rate, and event-free survival (EFS), evaluated by investigators according to RECIST 1.1 criteria. Results: Between November 2022 and June 2024, 146 patients were enrolled and randomized into three groups: Group A (n = 46), Group B (n = 45), and Group C (n = 55). The majority of patients were male (89.7%; 131/146), with most clinical stage III disease (72.6%; 106/146) and tumors located in the middle thoracic esophagus (51.4%; 75/146). All patients completed the neoadjuvant treatment and underwent surgical resection and achieving a 100% R0 resection rate. The pCR rates differed significantly among the groups, with Group A achieving a pCR rate of 13%, Group B 60%, and Group C 47.3%. Both Group B and C demonstrated significantly higher pCR rates compared to Group A, with Group B versus Group A showing a difference of 47% (95% CI, 27.8–62.2; OR = 10; 95% CI, 3.7–30.8; P &lt; 0.0001) and Group C versus Group A showing a difference of 34.2% (95% CI, 16.4–49.1; OR = 6; 95% CI, 2.3–17.8; P = 0.0005). No perioperative deaths were reported. Treatment-emergent adverse events (TEAEs) of any grade were observed in 50% of patients in Group A, 86.7% in Group B, and 85.5% in Group C. Additionally, the incidence of Grade 3 or higher TEAEs during neoadjuvant treatment was 8.7% in Group A, 31.1% in Group B, and 36.4% in Group C. Conclusion: This Phase III trial demonstrates that nCRT, with or without Sintilimab, significantly enhances pCR rates compared to nCT with Sintilimab in LA-ESCC, without increasing surgical risks. Ongoing monitoring of EFS is necessary to validate these results. Clinical trial information: NCT05244798 .

Neoadjuvant cadonilimab plus anlotinib followed by surgery for locally advanced esophageal squamous cell carcinoma: A single arm, phase 2 trial.

TPS506 Background: Esophageal cancer (EC) is the seventh most common cancer in China, where most of patients have locally advanced esophageal squamous cell carcinoma (LA-ESCC) at the time of diagnosis. Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) followed by surgery is standard treatment strategy for LA-ESCC in China. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of ESCC. Programmed death 1 (PD-1) inhibitors are the most commonly used ICIs in treatment of ESCC. Lately, the phase 3 ESCORT-NEO/NCCES01 trial demonstrates that neoadjuvant PD-1 inhibitor plus chemotherapy obtains superior pCR rates compared to chemotherapy alone for LA-ESCC. Except for PD-1 inhibitors, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitor is another effective ICI for ESCC, especially combined with PD-1 inhibitor according to the CHECKMATE-648 study. Although neoadjuvant immunotherapy plus chemotherapy has brought earth-shaking changes to the treatment of LA-ESCC, the chemo-based treatment modality still results in a high incidence of adverse events, reduces the quality of life and compliance of patients. Cadonilimab is a dual immune antibody drug comprised of PD-1 antibody and CTLA-4 antibody. Anlotinib is an oral, small molecule anti-angiogenic targeted agent that has been approved for use in advanced or metastatic ESCC in China. Therefore, we launched this trial to assess the efficacy and safety of cadonilimab plus anlotinib, a novel "chemo-free" strategy, followed by surgery for LA-ESCC. Methods: Study design: This is a single-arm, phase 2 study (NCT06426797). The primary endpoint of this study is the pCR rate. The secondary endpoints include safety, major pathological response (MPR) rate, objective response rate (ORR), R0 resection rate, and event-free survival (EFS). Study procedures: Cadonilimab will be intravenously administered at day 1 with a dose of 10 mg/Kg every three weeks for three cycles. Anlotinib will be orally administered daily at day 1 to day 14 with a dose of 12mg every three weeks for three cycles. In the end, the subjects will receive subtotal esophagectomy 4 to 6 weeks later after the last dose of cadonilimab. Major inclusion criteria: 1. Age &gt; 18 years. 2. Histopathologically confirmed ESCC: c-stage II–IVA (8 th ed. AJCC). 3. Enough tissue for PD-L1 IHC test. 4. Eligible for anlotinib treatment. 5. ECOG performance status ≤ 2 points. Statistics: We hypothesized that the expected pCR rate would be 50%. 24 subjects are needed at an α-level of 0.05 (one-sided) and power of 80%. So, 25 subjects in total should be enrolled. The descriptive statistical method will be applied to the presentation of baseline characteristics, toxicities and measures of effectiveness. The Kaplan–Meier method will be used to calculate survival rates. Current enrollment: The study started on August 1 st , 2024, and 3 of planned 25 patients have been enrolled. Clinical trial information: NCT06426797 .

Predictive Value of Magnetic Resonance Complete Response After Neoadjuvant Therapy for Rectal Cancer.

Previous research has demonstrated that after neoadjuvant therapy for rectal cancer, the sensitivity of magnetic resonance complete response (mrCR) for detecting pathologic complete response (pCR) in the surgical specimen ranges from 74 to 94%. Patient and provider interest in nonoperative management of rectal cancer that responds favorably to neoadjuvant therapy has grown, necessitating stronger evidence for how well radiographic complete response truly predicts pCR. We sought to determine the current association between mrCR and pCR in locally advanced rectal cancer. We conducted a retrospective cohort study of patients with rectal adenocarcinoma who underwent neoadjuvant chemoradiation followed by index proctectomy at a single academic referral center from January 2012 to December 2021. Our primary outcomes were mrCR, defined as the absence of residual disease on restaging MRI, and pCR, defined as the absence of residual adenocarcinoma in surgical pathology specimens. Among 523 eligible patients, 157 met the inclusion criteria (38.9% females; 51.0% nonwhite; mean [SD] age, 58.6 [13.2] years). Overall, 8.9% of patients had mrCR and 7.0% had pCR. The sensitivity and positive predictive value of mrCR were 36.4% (95% CI: 10.9 to 69.2) and 28.6% (95% CI: 8.4 to 58.1). Our findings were qualitatively unchanged when only patients in the last 5 years of the study period were included. Study limitations include that neoadjuvant therapy regimens were not standardized and patients who were offered and elected to undergo nonoperative management were not included. The value of mrCR in predicting pathologic response following neoadjuvant therapy in locally advanced rectal cancer is low, and mrCR should be interpreted with caution when counseling patients about nonoperative management. Early, frequent surveillance is critical in patients who elect nonoperative management after mrCR.

OP-TNT: Phase II study of total neoadjuvant chemoradiotherapy followed by local resection for early distal rectal carcinoma.

177 Background: Surgery is standard of care for pMMR early distal rectal cancer (RC), which can be partially exempted by totally neoadjuvant chemoradiotherapy (TNT) followed by watch and wait. But long-term data showed that 1/3 patients had local growth( mostly in the rectal wall)in two years. This study investigates the efficacy and safety of TNT followed by local excision( LE) for early distal rectal carcinoma (cT1-3N0M0) in order to preserve organs. Methods: In this single-arm, phase 2 prospective trial, patients were eligible if they were aged 18 years or older, with a performance status of 0-1,newly diagnosed, biopsy proven pMMR/MSS RC which located ≤5cm from the anal verge and staged as cT1-3N0M0. Patients were assigned to receive TNT: 6 courses of CapOx(capecitabine 1000 g/m2 PO BID D1-14, oxaliplatin 130 mg/m2 IV QD D1,Q3W), combined with concurrent long-course radiotherapy (LCRT)(45 Gy/25 Fx to the pelvis with an SIB of 50 Gy/25 Fx to the tumor bed). Evaluation was performed 12 weeks after completion of LCRT. Patients who achieved a clinical complete response (cCR) or near clinical complete response (ncCR)were assigned to LE, whereas those with &gt;ypT1, positive margin, or neurovascular invasion after LE were recommended for total mesorectal excision (TME). The primary endpoint is the 3-year organ-preserving rate. Secondary endpoints include the pathological complete response (pCR)(encompassing response after LE and TME), adverse effects rate, 3y-disease-free survival (DFS)and 3y-overall survival (OS)rate. Results: From October 2022 to August 2024, 52 patients had completed therapy. Median age at evaluation and follow-up duration were 58.3 years and 11 months. Of the patients 78.8% (41/52) were defined as MRI stage T3, and 76.9%(40/52) located ≤3cm from the anal verge. Of 52 evaluable patients ,82.7% (43/52) achieved cCR/ncCR and had LE (6 via endoscopic resection and 37 through trans-anal minimally invasive surgery). Among these patients, 25.6% (11/43) were found to have residual tumors after LE, of which 6 were radical-operated while 5 refused this intervention. Nine patients who did not achieve cCR or ncCR received TME resection, and 6 of them were confirmed as pCR. The total pCR rate was 73.1% (38/52). Of all patients, 3 underwent abdominoperineal resection, and sphincter-preserving rate was 94.2%(49/52). No grade 3 or 4 adverse events were reported, and there were no treatment-related deaths. The main adverse event after local resection was the 1-3 months anterior resection syndrome. Conclusions: The results of interim analysis showed that tumor residue was found in patients with cCR/ncCR after TNT, similar to the regrowth rate previously reported. LE strategy may become prevention. Long-term outcomes are being followed up. Clinical trial information: NCT05563922 .

Salt-inducible kinase 2 confers radioresistance in colorectal cancer by facilitating homologous recombination repair.

Resistance to radiotherapy remains a critical barrier in treating colorectal cancer (CRC), particularly in cases of locally advanced rectal cancer (LARC). To identify key kinases involved in CRC radioresistance, we employed a kinase-targeted CRISPR-Cas9 library screen. This approach aimed to identify potential kinase inhibitors as radiosensitizers. Our screening identified salt-inducible kinase 2 (SIK2) as a critical factor in CRC radioresistance. Increased SIK2 expression correlated with reduced tumor regression and poorer outcomes in LARC patients undergoing neoadjuvant chemoradiotherapy. The depletion of SIK2 significantly enhanced radiation-induced apoptosis and tumor regression. Mechanistically, SIK2 interacts with valosin-containing protein (VCP), promoting its hyperphosphorylation. This modification improves VCP's capacity to extract K48-linked ubiquitin-conjugated proteins from chromatin, thus aiding the recruitment of RPA and RAD51 to DNA damage sites. This mechanism strengthens homologous recombination-mediated DNA repair, which contributes to radioresistance. Importantly, ARN-3236, a SIK2 inhibitor, markedly sensitized CRC cells to radiation both in vivo and in vitro, providing a potential strategy to overcome radioresistance. In summary, our findings reveal a novel mechanism by which SIK2 contributes to the radioresistance of CRC, proposing SIK2 as a potential therapeutic target with its inhibitor significantly enhancing CRC radiotherapy efficacy.