Background: Locally advanced rectal cancer (LARC) treatment selection between neoadjuvant intensified chemotherapy (NIC) and standard chemoradiotherapy (CRT) lacks validated predictive biomarkers. Interleukin-1β (IL1B) polymorphisms modulate IL-1β expression and may influence treatment-specific outcomes through tumor microenvironment remodeling. Methods: In this prospective, single-center, randomized, open-label noninferiority trial (NCT05378919), 150 patients with stage II–III rectal cancer were randomized 1:1 to NIC (FOLFOX4, 8 cycles; n=68) or CRT (50 Gy/25 fractions with concurrent fluoropyrimidine; n=82). The primary endpoint was 5-year disease-free survival (DFS; noninferiority margin HR ≤1.29, NIC vs. CRT). IL1B rs1143634 and rs16944 were genotyped by TaqMan assay. Treatment–genotype interactions were assessed using Cox regression with multiplicative interaction terms. Results: Noninferiority was not demonstrated: 5-year DFS was 54.4% (NIC) versus 68.1% (CRT) in the ITT population (HR 1.52, 95% CI 0.90–2.56; p=0.114), with the upper CI bound exceeding the prespecified margin of 1.29. Per-protocol DFS was significantly inferior for NIC (62.5% vs. 82.1%; HR 2.27, 95% CI 1.06–4.76; p=0.029). Overall survival and cancer-specific survival (CSS) did not differ significantly between arms. A statistically significant treatment–genotype interaction was identified for rs1143634 in CSS (interaction p<0.001): T-allele carriage (CT+TT) was associated with inferior CSS exclusively in the NIC arm (HR 4.84, 95% CI 1.04–22.43; p=0.044), with no prognostic effect in the CRT arm (HR 0.69; p=0.494). A DFS interaction was also significant (p=0.047). rs16944 showed a borderline CSS interaction (p=0.082). Conclusions: NIC (FOLFOX4) did not achieve DFS noninferiority versus CRT in unselected LARC patients. IL1B rs1143634 demonstrates a treatment-arm-specific prognostic effect on cancer-specific survival, with a highly significant treatment–genotype interaction (p<0.001) identified within a prospective randomized design with prespecified translational hypotheses, satisfying the formal criterion for predictive biomarker classification. Prospective validation in an adequately powered, biomarker-stratified trial is warranted.

Background: Locally advanced rectal cancer (LARC) treatment selection between neoadjuvant intensified chemotherapy (NIC) and standard chemoradiotherapy (CRT) lacks validated predictive biomarkers. Interleukin-1β (IL1B) polymorphisms modulate IL-1β expression and may influence treatment-specific outcomes through tumor microenvironment remodeling. Methods: In this prospective, single-center, randomized, open-label noninferiority trial (NCT05378919), 150 patients with stage II–III rectal cancer were randomized 1:1 to NIC (FOLFOX4, 8 cycles; n = 68) or CRT (50 Gy/25 fractions with concurrent fluoropyrimidine; n = 82). The primary endpoint was 5-year disease-free survival (DFS; noninferiority margin HR ≤ 1.29, NIC vs. CRT). IL1B rs1143634 and rs16944 were genotyped by TaqMan assay. Treatment–genotype interactions were assessed using Cox regression with multiplicative interaction terms. Results: Noninferiority was not demonstrated: 5-year DFS was 49.3% (NIC) versus 64.1% (CRT) in the ITT population (HR 1.52, 95% CI 0.90–2.56; p = 0.111), with the upper CI bound exceeding the noninferiority margin of 1.29. Per-protocol DFS was significantly inferior for NIC (57.9% vs. 79.2%; HR 2.26, 95% CI 1.06–4.79; p = 0.029). Overall survival and cancer-specific survival (CSS) did not differ significantly between arms. A nominally significant treatment–genotype interaction was identified for rs1143634 in CSS (interaction p = 0.041 by Wald test; likelihood-ratio p = 0.028): T-allele carriage (CT + TT) was associated with inferior CSS exclusively in the NIC arm (HR 4.84, 95% CI 1.04–22.43; p = 0.044), with no prognostic effect in the CRT arm (HR 0.69; p = 0.494). No interaction was detected for DFS ( p = 0.294). rs16944 showed no interaction (CSS p = 0.214; DFS p = 0.851). The CSS interaction did not survive correction for multiple testing. Conclusions: NIC (FOLFOX4) did not achieve DFS noninferiority versus CRT in unselected LARC patients, although the trial was underpowered for this endpoint. IL1B rs1143634 demonstrates a treatment-arm-specific prognostic effect on cancer-specific survival, with a nominally significant treatment–genotype interaction ( p = 0.041) identified within a prospective randomized design; this exploratory finding does not survive correction for multiple testing, is based on a small number of cancer-specific events, and does not establish rs1143634 as a predictive biomarker. Prospective validation in an adequately powered, biomarker-stratified trial is warranted. Trial registration: ClinicalTrials.gov, NCT05378919, registered 18 May 2022 (retrospectively registered). Study start: September 2015.

Background and Objectives: Rectal cancer management has changed substantially over the past two decades. We evaluated 20-year trends in stage at diagnosis, treatment patterns, and survival at a Lithuanian tertiary referral centre. Materials and Methods: This retrospective cohort study included 839 patients who underwent resection for stage I–III rectal cancer between 2004 and 2023, divided into two periods: 2004–2013 (n = 426) and 2014–2023 (n = 413). Survival was analysed with Kaplan–Meier estimates and Cox proportional hazards regression, truncated at 60 months. Results: Patients in the later cohort were diagnosed at an earlier clinical stage (stage I: 12.6% vs. 2.4%) and more often received neoadjuvant or perioperative therapy (55.2% vs. 37.1%; p < 0.001). Among clinical stage III patients, receipt of neoadjuvant chemoradiotherapy or total neoadjuvant treatment rose from 15.9% to 70.9% (p < 0.001), while pathological complete response among treated patients remained stable (10.8% vs. 10.7%; p = 0.98). Five-year overall survival increased from 64.8% to 71.3% (HR 0.77; 95% CI 0.60–0.99; p = 0.039) and cancer-specific survival from 70.4% to 80.8% (HR 0.60; 95% CI 0.45–0.80; p = 0.0005). The cohort effect persisted after multivariable adjustment for CSS (HR 0.62; 95% CI 0.45–0.85; p = 0.003), with clinical stage explaining only ~13% of the crude effect; stage III sensitivity analysis confirmed the CSS gain (67.9% to 77.3%; p = 0.009). Conclusions: Cancer-specific survival improved substantially and independently of stage migration. The gain coincided with markedly wider and better-targeted delivery of effective neoadjuvant therapy rather than with improved per-patient tumour responsiveness. As an observational comparison of two historical cohorts, this study demonstrates association rather than causation; nonetheless, it provides real-world evidence consistent with the hypothesis that systematic implementation of evidence-based rectal cancer pathways translates into measurable survival benefit.