Adjuvant chemotherapy for colorectal cancer (CRC) with oxaliplatin and fluoropyrimidine was traditionally given for 6 months but is associated with cumulative peripheral neuropathy. The SCOT study (ISRCTN59757862) was an international, randomized, phase III, noninferiority trial investigating treatment reduction from 6 to 3 months. It originally reported noninferior disease-free survival with reduced toxicity and improved quality of life for 3 months of treatment in 6,088 patients. Here, we report overall survival (OS) with 38 months of additional follow-up. Patients with high-risk stage II and stage III CRC were assigned (1:1) to receive 3 or 6 months of either capecitabine and oxaliplatin (CAPOX) or infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX; bolus and infused fluorouracil with oxaliplatin) that were selected before random assignment. With a median of 113 months follow-up and 1,255 OS events, 5-year OS for 3 versus 6 months of treatment was 82.4% in both groups (hazard ratio, 0.96; 95% CI, 0.8 to 1.07), proving noninferiority of 3 months of treatment. Noninferiority of 3 months of treatment for OS was also shown in 1,087 patients with rectal cancer. The duration effect is regimen-dependent with noninferiority shown for CAPOX but not for FOLFOX. In summary, SCOT has shown noninferiority for OS with 3 months of adjuvant chemotherapy treatment, which should be recommended for most patients.

INTRODUCTION:We aimed to disentangle whether elevated body mass index (BMI) is directly associated with adverse survival in primary colorectal cancer (CRC), or indirectly through treatment-related mechanisms, e.g., dose-capping adjuvant chemotherapy (ACT) and toxicity, using individual participant data meta-analysis (IPD-MA) and causal inference approaches. METHODS:Using BMI from four CRC-ACT randomised trials [OCTOPUS], and two ACT adherence measures (average cumulative relative dose [ACRD]; average relative dose intensity [ARDI]), we performed two-stage random effects IPD-MA, assessing total (TE) and direct effects (DE) (excluding and including mediators, respectively) of pre-defined causal paths, with overall survival (OS) as primary outcome. FINDINGS:In 7264 patients, the TE of 5 kg/m2 BMI increments was a significant ACRD reduction (-1.15% [95% CI -1.92, -0.38]), and ACRD 5% increments were associated with improved OS (HR 0.94 [0.91, 0.96]), implying possible adverse indirect effects; though not large enough to induce an adverse TE of BMI on OS (HR 0.98 [0.90, 1.07]). BMI-ARDI relationships were similar (TE -1.08% [-1.44, -0.72]), but ARDI-OS relationships were inverted (HR 1.05 [1.01, 1.09]). BMI showed no association with grade 3+ toxicity (OR 1.01 (0.91, 1.14)). However, toxicity was associated with worse OS (TE HR 1.37 [1.17, 1.61]), which attenuated on adjusting for ACRD (DE HR 1.20 [1.02, 1.41]), suggesting partial mediation via a significant toxicity-ACRD relationship (-10.37% [-11.77, -8.97]). CONCLUSION:Our study establishes possible adverse indirect effects of obesity on CRC survival, through treatment-selection, supporting full BSA-based ACT dosing.

The definition of cure in stage II to III colon cancer (CC) remains unclear due to limitations in conventional end points, which include deaths and second primary tumors as events. These can complicate communication with patients regarding long-term outcomes. To distinguish relapses from competing health-related events to classify long-term outcomes years after surgery and explore when the incidence of true relapses of the initial CC approaches 0% to define cure in this disease. This pooled analysis of individual patient–level data from 15 phase 3 randomized clinical trials assessed time to CC-related relapse using Kaplan-Meier and Aalen-Johansen methods, with death and second primary tumors treated as competing risks. Cox regression models evaluated prognostic associations, stratified by sex, stage, and tumor. Patients with stage II to III CC who underwent adjuvant chemotherapy were included. All patients had undergone radical surgery for CC and received adjuvant chemotherapy with a median follow-up of at least 6 years. The Adjuvant Colon Cancer Endpoints (ACCENT) and the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) databases included adjuvant studies conducted between 1996 and 2015. Data were analyzed from February 2022 to June 2025. Adjuvant chemotherapy regimens varied across trials, including fluoropyrimidines alone or in combination with oxaliplatin or biologic agents. The primary outcome was time to CC-related recurrence. The predefined threshold for cure was a recurrence risk below 0.5%. Of 35 213 included patients, 19 346 (54.9%) were male, and the mean (SD) age was 60.2 (10.8) years. The incidence rate of recurrence peaked at 6.4% (1993 of 31 373) between month 6 and month 12 and decreased continuously until year 10 of follow-up never exceeding 0.5%. Recurrence rate appeared to increase again after year 10 and peaked at 2.0% during year 12.5 to year 13, a pattern observed exclusively in the MOSAIC trial. Competing-event analysis revealed that death and second primary tumors inflated the apparent recurrence rate, especially for older patients. The overall cumulative incidence of relapse with death as competing risk was lower among female patients (hazard ratio, 0.58; 95% CI, 0.45-0.76; P < .001). In this pooled analysis of phase 3 randomized clinical trials, a recurrence rate less than 0.5% occurred after 6 years from surgery, supporting a practical definition of cure. Recognizing this milestone may improve patient communication, guide follow-up duration, and reduce unnecessary long-term surveillance.

Importance:The definition of cure in stage II to III colon cancer (CC) remains unclear due to limitations in conventional end points, which include deaths and second primary tumors as events. These can complicate communication with patients regarding long-term outcomes. Objective:To distinguish relapses from competing health-related events to classify long-term outcomes years after surgery and explore when the incidence of true relapses of the initial CC approaches 0% to define cure in this disease. Design, Setting, and Participants:This pooled analysis of individual patient-level data from 15 phase 3 randomized clinical trials assessed time to CC-related relapse using Kaplan-Meier and Aalen-Johansen methods, with death and second primary tumors treated as competing risks. Cox regression models evaluated prognostic associations, stratified by sex, stage, and tumor. Patients with stage II to III CC who underwent adjuvant chemotherapy were included. All patients had undergone radical surgery for CC and received adjuvant chemotherapy with a median follow-up of at least 6 years. The Adjuvant Colon Cancer Endpoints (ACCENT) and the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) databases included adjuvant studies conducted between 1996 and 2015. Data were analyzed from February 2022 to June 2025. Exposures:Adjuvant chemotherapy regimens varied across trials, including fluoropyrimidines alone or in combination with oxaliplatin or biologic agents. Main Outcomes and Measures:The primary outcome was time to CC-related recurrence. The predefined threshold for cure was a recurrence risk below 0.5%. Results:Of 35 213 included patients, 19 346 (54.9%) were male, and the mean (SD) age was 60.2 (10.8) years. The incidence rate of recurrence peaked at 6.4% (1993 of 31 373) between month 6 and month 12 and decreased continuously until year 10 of follow-up never exceeding 0.5%. Recurrence rate appeared to increase again after year 10 and peaked at 2.0% during year 12.5 to year 13, a pattern observed exclusively in the MOSAIC trial. Competing-event analysis revealed that death and second primary tumors inflated the apparent recurrence rate, especially for older patients. The overall cumulative incidence of relapse with death as competing risk was lower among female patients (hazard ratio, 0.58; 95% CI, 0.45-0.76; P < .001). Conclusions and Relevance:In this pooled analysis of phase 3 randomized clinical trials, a recurrence rate less than 0.5% occurred after 6 years from surgery, supporting a practical definition of cure. Recognizing this milestone may improve patient communication, guide follow-up duration, and reduce unnecessary long-term surveillance.

Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (PInteraction = 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.

PURPOSE A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

BACKGROUND:Tumour-infiltrating CD8+ cytotoxic T cells confer favourable prognosis in colorectal cancer. The added prognostic value of other infiltrating immune cells is unclear and so we sought to investigate their prognostic value in two large clinical trial cohorts. METHODS:We used multiplex immunofluorescent staining of tissue microarrays to assess the densities of CD8+, CD20+, FoxP3+, and CD68+ cells in the intraepithelial and intrastromal compartments from tumour samples of patients with stage II-III colorectal cancer from the SCOT trial (ISRCTN59757862), which examined 3 months versus 6 months of adjuvant oxaliplatin-based chemotherapy, and from the QUASAR 2 trial (ISRCTN45133151), which compared adjuvant capecitabine with or without bevacizumab. Both trials included patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1. Immune marker predictors were analysed by multiple regression, and the prognostic and predictive values of markers for colorectal cancer recurrence-free interval by Cox regression were assessed using the SCOT cohort for discovery and QUASAR 2 cohort for validation. FINDINGS:After exclusion of cases without tissue microarrays and with technical failures, and following quality control, we included 2340 cases from the SCOT trial and 1069 from the QUASAR 2 trial in our analysis. Univariable analysis of associations with recurrence-free interval in cases from the SCOT trial showed a strong prognostic value of intraepithelial CD8 (CD8IE) as a continuous variable (hazard ratio [HR] for 75th vs 25th percentile [75vs25] 0·73 [95% CI 0·68-0·79], p=2·5 × 10-16), and of intrastromal FoxP3 (FoxP3IS; 0·71 [0·64-0·78], p=1·5 × 10-13) but not as strongly in the epithelium (FoxP3IE; 0·89 [0·84-0·96], p=1·5 × 10-4). Associations of other markers with recurrence-free interval were moderate. CD8IE and FoxP3IS retained independent prognostic value in bivariable and multivariable analysis, and, compared with either marker alone, a composite marker including both markers (CD8IE-FoxP3IS) was superior when assessed as a continuous variable (adjusted [a]HR75 vs 25 0·70 [95% CI 0·63-0·78], p=5·1 × 10-11) and when categorised into low, intermediate, and high density groups using previously published cutpoints (aHR for intermediate vs high 1·68 [95% CI 1·29-2·20], p=1·3 × 10-4; low vs high 2·58 [1·91-3·49], p=7·9 × 10-10), with performance similar to the gold-standard Immunoscore. The prognostic value of CD8IE-FoxP3IS was confirmed in cases from the QUASAR 2 trial, both as a continuous variable (aHR75 vs 25 0·84 [95% CI 0·73-0·96], p=0·012) and as a categorical variable for low versus high density (aHR 1·80 [95% CI 1·17-2·75], p=0·0071) but not for intermediate versus high (1·30 [0·89-1·88], p=0·17). INTERPRETATION:Combined evaluation of CD8IE and FoxP3IS could help to refine risk stratification in colorectal cancer. Investigation of FoxP3IS cells as an immunotherapy target in colorectal cancer might be merited. FUNDING:Medical Research Council, National Institute for Health Research, Cancer Research UK, Swedish Cancer Society, Roche, and Promedica Foundation.

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSP high ) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSP high group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

Importance:The timing of adjuvant chemotherapy after surgery for colorectal cancer and its association with long-term outcomes have been investigated in national cohort studies, with no consensus on the optimal time from surgery to adjuvant chemotherapy. Objective:To analyze the association between the timing of adjuvant chemotherapy after surgery for colorectal cancer and disease-free survival. Design, Setting, and Participants:This is a post hoc analysis of the phase 3 SCOT randomized clinical trial, from 244 centers in 6 countries, investigating the noninferiority of 3 vs 6 months of adjuvant chemotherapy. Patients with high-risk stage II or stage III nonmetastatic colorectal cancer who underwent curative-intended surgery were randomized to either 3 or 6 months of adjuvant chemotherapy consisting of fluoropyrimidine and oxaliplatin regimens. Those with complete information on the date of surgery, treatment type, and long-term follow-up were investigated for the primary and secondary end points. Data were analyzed from May 2022 to February 2024. Intervention:In the post hoc analysis, patients were grouped according to the start of adjuvant chemotherapy being less than 6 weeks vs greater than 6 weeks after surgery. Main Outcomes and Measures:The primary end point was disease-free survival. The secondary end points were adverse events in the total treatment period or the first cycle of adjuvant chemotherapy. Results:A total of 5719 patients (2251 [39.4%] female; mean [SD] age, 63.4 [9.3] years) were included in the primary analysis after data curation; among them, 914 were in the early-start group and 4805 were in the late-start group. Median (IQR) follow-up was 72.0 (47.3-88.1) months, with a median (IQR) of 56 (41-66) days from surgery to chemotherapy. Five-year disease-free survival was 78.0% (95% CI, 75.3%-80.8%) in the early-start group and 73.2% (95% CI, 72.0%-74.5%) in the late-start group. In an adjusted Cox regression analysis, the start of adjuvant chemotherapy greater than 6 weeks after surgery was associated with worse disease-free survival (hazard ratio, 1.24; 95% CI, 1.06-1.46; P = .01). In adjusted logistic regression models, there was no association with adverse events in the total treatment period (odds ratio, 0.82; 95% CI, 0.65-1.04; P = .09) or adverse events in the first cycle of treatment (odds ratio, 0.77; 95% CI, 0.56-1.09; P = .13). Conclusions and Relevance:In this international population of patients with high-risk stage II and stage III colorectal cancer, starting adjuvant chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival, with no difference in adverse events between the groups. Trial Registration:isrctn.org Identifier: ISRCTN59757862.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of oxaliplatin. CIPN can impair long-term quality of life and limit the dose of chemotherapy. We investigated the association of CIPN over time with age, sex, body mass index, baseline neuropathy, and chemotherapy regimen in people treated with adjuvant oxaliplatin-containing chemotherapy for colorectal cancer.Patients and methods: We carried out secondary analysis of data from the SCOT randomised controlled trial. SCOT compared 3 months to 6 months of oxaliplatin-containing adjuvant chemotherapy in 6088 people with colorectal cancer recruited between March 2008 and November 2013. Two different chemotherapy regimens were used: capecitabine with oxaliplatin (CAPOX) or fluorouracil with oxaliplatin (FOLFOX). CIPN was recorded with the Functional Assessment of Cancer Therapy/Gynaecologic Oncology Group-Neurotoxicity 4 tool in 2871 participants from baseline (randomisation) for up to 8 years. Longitudinal trends in CIPN [averages with 95% confidence intervals (CIs)] were plotted stratified by the investigated factors. Analysis of covariance (ANCOVA) was used to analyse the association of factors with CIPN adjusting for the SCOT randomisation arm and oxaliplatin dose. P < 0.01 was adopted as cut-off for statistical significance to account for multiple testing.Results: Patients receiving CAPOX had lower CIPN scores than those receiving FOLFOX. Chemotherapy regimen was associated with CIPN from 6 months (P < 0.001) to 2 years (P = 0.001). The adjusted ANCOVA coefficient for CAPOX at 6 months was -1.6 (95% CIs -2.2 to -0.9) and at 2 years it was -1.6 (95% CIs -2.5 to -0.7). People with baseline neuropathy scores >= 1 experienced higher CIPN than people with baseline neuropathy scores of 0 (P < 0.01 for all timepoints apart from 18 months). Age, sex, and body mass index did not link with CIPN.Conclusions: A neuropathy assessment before treatment with oxaliplatin can help identify people with an increased risk of CIPN. More research is needed to understand the CIPN-inducing effect of different chemotherapy regimens.

Tumour infiltrating CD8+ cytotoxic T cells confer favourable prognosis in colorectal cancer (CRC). The added prognostic value of other immune cells is unclear. We used multiparameter co-immunofluorescence to determine the density of CD8+, CD20+, FoxP3+ and CD68+ cells in the intraepithelial (IE) and intrastromal (IS) compartments in stage II/III CRCs from the SCOT and QUASAR2 trials. We determined marker prognostic and predictive value by Cox regression of SCOT cases, with validation in the QUASAR2 cohort. Our study included 2,340 SCOT and 1,069 QUASAR2 cases. Univariable analysis of recurrence-free interval (RFI) in SCOT revealed expected prognostic value of intraepithelial CD8 (CD8IE) (continuous variable: HR for cases at 75th vs 25th percentile (HR75vs25)= 0.73, 95% CI=0.68-0.79, P=2.5e-16) and, less expectedly FoxP3 within tumour stroma (FoxP3IS) (HR75vs25)= 0.71, 95% CI=0.64-0.78, P=1.5e-13), but not epithelium. CD8IE and FoxP3IS were independently prognostic in multivariable analysis, and a composite marker including both (CD8IE-Foxp3IS) was superior to either alone as a continuous variable (adjHR75vs25= 0.70; 95%CI=0.63–0.78; P=5.1e-11), and when categorised into three groups (Low/Int/High) using sample medians (Int vs High HR = 1.60, 95%CI=1.24–2.05, P=2.5e-04; Low vs High HR = 2.30, 95%CI=1.80–2.95; P=3.6e-11). These results were validated in the QUASAR2 trial. Pooled analysis of both studies revealed interactions between CD8IE-FoxP3IS and tumour sidedness (adjPINT=0.010), stromal proportion (adjPINT=0.018), and MMR status (adjPINT=0.079). CD8IE-FoxP3IS refined stage III risk groups, with clinical low risk (T1-3, N1), CD8IE-FoxP3IS low cases demonstrating similar 3-year recurrence-free probability to clinical high risk (T4 and/or N2), CD8IE-FoxP3IS high cases (79.2 vs 76.4%, adj log-rank P=0.16). Combined evaluation of CD8IE and FoxP3IS is superior to single markers and refines CRC risk stratification. FoxP3IS prognostic value is inconsistent with an immunosuppressive role; further investigation of these cells as an immunotherapy target is merited.

Abstract Multiplex immunofluorescence (mIF) imaging can provide comprehensive quantitative and spatial information for multiple immune markers for tumour immunoprofiling. However, application at scale to clinical trial samples sourced from multiple institutions is challenging due to pre‐analytical heterogeneity. This study reports an analytical approach to the largest multi‐parameter immunoprofiling study of clinical trial samples to date. We analysed 12,592 tissue microarray (TMA) spots from 3,545 colorectal cancers sourced from more than 240 institutions in two clinical trials (QUASAR 2 and SCOT) stained for CD4, CD8, CD20, CD68, FoxP3, pan‐cytokeratin, and DAPI by mIF. TMA slides were multi‐spectrally imaged and analysed by cell‐based and pixel‐based marker analysis. We developed an adaptive thresholding method to account for inter‐ and intra‐slide intensity variation in TMA analysis. Applying this method effectively ameliorated inter‐ and intra‐slide intensity variation improving the image analysis results compared with methods using a single global threshold. Correlation of CD8 data derived by our mIF analysis approach with single‐plex chromogenic immunohistochemistry CD8 data derived from subsequent sections indicates the validity of our method (Spearman's rank correlation coefficients ρ between 0.63 and 0.66, p ≪ 0.01) as compared with the current gold standard analysis approach. Evaluation of correlation between cell‐based and pixel‐based analysis results confirms equivalency (ρ > 0.8, p ≪ 0.01, except for CD20 in the epithelial region) of both analytical approaches. These data suggest that our adaptive thresholding approach can enable analysis of mIF‐stained clinical trial TMA datasets by digital pathology at scale for precision immunoprofiling.

SUMMARY Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRC). Automation of this would facilitate precision medicine, particularly if it provided information on likely aetiology. We developed AIMMer, an AI -based method for determination of MMR protein expression at single cell level in routine pathology samples. We applied it to over 2,000 colorectal cancers (CRC) from the SCOT clinical trial, which compared 3 vs 6 months of oxaliplatin-based adjuvant chemotherapy (FOLFOX or CAPOX). Benchmarking of AIMMeR against pathologist ground truth MMR calls revealed AUROC of 0.98, and positive predictive value (PPV) greater than 95% for the commonest pa[ern of somatic MMRd, and for retained MMR expression. Analysis of CRC recurrence confirmed the prognostic value of MMRd in oxaliplatin-treated patients. While MMRd did not predict differential benefit from chemotherapy duration, it correlated with difference in clinical outcome by chemotherapy regimen ( P Interaction =0.04). AIMMeR holds promise to reduce pathologist workflow and streamline clinical diagnostics in CRC.

AIM:Patients with loco-regional right-sided colorectal tumors have a worse overall survival (OS). Here we investigate the difference in disease free survival (DFS) between colorectal patients with right and left sided tumors in the SCOT study. METHODS:The SCOT study showed 3-months of oxaliplatin-containing adjuvant chemotherapy (OxFp) is non-inferior to 6-months for patients with stage III and high-risk stage II colorectal cancer. We divided the cohort into patients with left and right sided tumors, and evaluated the effect on DFS and the principle 3 versus 6-months analysis. RESULTS:6088 patients with Stage III/high risk Stage II colorectal cancers were randomized between 27th March 2008 and 29th November 2013 from 244 centers internationally. In February 2017 (3-years FU) information on sidedness was available for 3309 patients (1238 R-sided, 2071 L-sided). Patients with right-sided tumors had a significantly worse DFS (3-year DFS right: 73.3% (se = 1.3%), left: 80.2% (se = 0.9%) HR 1.423 (95% CI 1.237-1.637; P < .0001). Adjusting for T and N-stage reduced the HR to 1.230 (95% CI 1.066-1.420, P = .005). The data did not suggest that sidedness affected the impact of chemotherapy duration on 3-year DFS (R: HR 1.024 [0.831-1.261], L: HR 0.944 [0.783-1.139]). Test for heterogeneity, P = .571. Further sub-set analysis was limited due to cohort size. CONCLUSIONS:This is the first study to show that unselected patients with right-sided tumors had a worse DFS compared to left-sided tumors. Tumor sidedness did not impact upon the 3-months versus 6-months comparison in SCOT.

196 Background: The ESMO clinical practice guidelines recommend consideration of Immunoscore (IS) for risk assessment of early colon cancer patients. IS clinical performance was assessed in the SCOT and IDEA-HORG trials evaluating 3 vs. 6 months (3m vs. 6m) of mFOLFOX6 adjuvant chemotherapy in stage III colorectal cancer (CRC). Methods: 1,002 formalin-fixed paraffin-embedded (FFPE) tumor samples (762 from SCOT;240 from HORG) were collected, of which 851 were eligible for biomarker analysis. Eligible samples were classified into 2 groups using pre-defined cut-offs (IS-Low, IS- High) and the performance of IS to predict 3 year disease-free survival (3y-DFS) was evaluated. Results: IS was successfully assessed in 846 cases (99%). 615 (72.7%) samples were classified as IS-High (311 and 304 in 3m and 6m arm, respectively). No significant association between IS and patients’ gender, age, PS, BMI or primary tumour location was observed. However, a significant difference between IS-High (43.7%) and IS Low (57.1%) was observed in the proportion of high risk (T4 and/or N2) tumours (p=0.001). Patients with IS-High tumors had significantly longer 3y-DFS (79.4%, 95%CI: 75.9%-82.4%) compared to those with IS-Low tumors (65.0%, 95%CI: 58.3%-70.9%); adjusted hazard ratio (HR) 1.9 (95%CI: 1.46-2.46; p<0.0001). Similarly, IS-High was significantly correlated with longer 3y-DFS in both treatment arms: 78.5% (95% CI 73.4%-82.7%) for IS-High and 65.8% (95% CI 56.1%-73.9%) for IS-Low in 3m arm; 80.3% (95% CI 75.3%-84.5%) for IS-High and 64.4% (95% CI 54.8%-72.6%) for IS-Low in 6m arm. The estimated HRs according to treatment duration and IS classification were 1.80 (95% CI 1.25-2.60) in 3m arm, 2.00 (95% CI 1.38-2.92) in 6m arm and 1.89 (95% CI 1.46-2.47) in the total study population; interaction p = 0.687. Conclusions: The results of this study confirm the prognostic value of IS observed in the IDEA-France trial (Pagès F et al 2020). However, this analysis was not powered to determine the predictive value of IS for treatment duration. Similar analysis of patients treated with CAPOX is warranted.

Background: SCOT was an international, randomized phase 3 trial of 3 months vs 6 months of adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine in patients with colorectal cancer. We sought patients' preferences for 3 months vs 6 months of adjuvant chemotherapy in the SCOT trial. Methods: SCOT participants from Australia and New Zealand completed a validated questionnaire (at 3 and 18 months) to elicit the minimum survival benefits judged necessary to make an extra 3 months of adjuvant chemotherapy worthwhile, based on their experience. Standardized hypothetical scenarios used the following baseline survivals (with 3 months of chemotherapy): life expectancies (LE) of 5 years and 15 years and 5-year survival rates (5YS) of 65% and 85%. Results: Of the 160 participants, 82 were assigned 3 months adjuvant chemotherapy, and 78 were assigned 6 months. Adjuvant chemotherapy was FOLFOX in 121 (75.6%) and XELOX in 39 (24.4%). Preferences varied substantially and did not differ according to treatment group. The median survival benefits judged necessary to make the extra 3 months of chemotherapy worthwhile were an extra 3 years beyond a LE of 5 years; 3 years beyond a LE of 15 years; 15% beyond a 5YS of 65%; and 5% beyond a 5YS of 85%. Preferences were similar at 3 months and 18 months. Preferences were not predicted by participants' baseline characteristics. Conclusion: Preferences varied substantially, and the benefits many required to warrant an extra 3 months of adjuvant chemotherapy were larger than the benefits of an extra 3 months of chemotherapy calculated in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) meta-analysis.

PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.