Kerr, Rachel

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.

PURPOSE The adjuvant treatment for stage III colon cancer (CC) is chemotherapy combining fluoropyrimidine (FP) and oxaliplatin (OX). FP regimen plus OX (FPOX) may benefit in high-risk stage II CC. We performed a pooled analysis of pivotal MOSAIC and C-07 studies evaluating FPOX for the treatment of high-risk stage II CC according to prognostic factors, number of high-risk factors, and current clinicopathologic risk classification on the basis of T stage, tumor perforation, and number of lymph nodes examined. PATIENTS AND METHODS One thousand five hundred and ninety-five patients with stage II CC receiving FP or FPOX were pooled. The overall survival (OS) benefit of OX was analyzed using Kaplan-Meier curves and unadjusted Cox models stratified by study. Three thousand and fifty-nine patients with stage III CC were used only for interaction tests between the allocated chemotherapy and stage. RESULTS In the pooled analysis of stage II patients, independent prognostic factors in multivariable analysis were sex, age, perforation/obstruction, and tumor sidedness. There was a significant interaction in OS between stage and allocated chemotherapy with hazard ratios (HRs) of 1.03 for stage II (95% CI, 0.82 to 1.29; P = .813) and 0.82 for stage III (95% CI, 0.73 to 0.92; P = .001; P int = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; P = .349). CONCLUSION No OS benefit of adjuvant OX was found in high-risk stage II CC, regardless of the definition used to characterize tumors as having a high risk for recurrence. Hence, our analysis suggests that OX should not be the standard of care for adjuvant chemotherapy for stage II CC, even in high-risk patients.

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.

PURPOSE Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. MATERIALS AND METHODS We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. RESULTS Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. CONCLUSION In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

3606 Background: Standard adjuvant CT for stage III CC are FOLFOX and CAPOX. Recently, IDEA study separated stage III patients (pts) into low risk (T1 to 3, N1) and high risk (T4 or N2). We recently confirmed benefit of OX in both risk groups. However, we observed a difference in the two high-risk subgroups, with benefit in N2 but not in T4 (Margalit O et al; Clin Colorectal Cancer 2021). This prompted us to compare outcomes (OS/TTR) between treatment with OX vs. without OX within sub-stage III CC groups defined by T and N. Methods: We pooled 4941 stage III CC pts from the three studies evaluating 6 months of CT with fluoropyrimidine (FP) ± OX: MOSAIC, C-07 and XELOXA. Baseline characteristics were compared using χ2 and t-test. OS was compared between OX and no OX in T and N subgroups. Kaplan-Meier analyses, adjusted and unadjusted Cox models stratified by study were used. Sub-groups classification was done according to OX benefit and verified by interaction test (Int) considered as significant with a P<0.1. We considered for recommendation of using OX-based adjuvant CT, 1) significant benefit in OS, 2) significant Int between substage and adjuvant therapy, and 3) the three individual trials showing similar results (benefit or non-benefit of OX). Results: In stage III population, T3 pts were 74.9%, T1-2 12.4%, T4 13.1%, while N stage was N1 64.7% and N2 35.3%. Population was well balanced according to treatment allocation in most subgroups. A significant benefit of OX was only observed in T3N1 and T3N2 (OS HR 0.76). Whatever N stage, there was no significant benefit of OX in the T1-2 and T4 subgroups. The effect of OX+FP vs FP alone in OS of the three studies differed between T3 and T1-2 subgroups (P = 0.047). Interaction was borderline between T3 and T4 subgroups (P = 0.10) but there was no interaction between T1-2 and T4 subgroups (P = 0.429). A benefit of OX in TTR remained in the T4 population. Discrepancy between advantage in time to relapse (TTR) and no advantage in OS was not explained by survival post relapse. Conclusions: Our analysis suggested that pts with T1-2N1-2 and T4N1-2 disease had no OS benefit of addition of OX to FP. The good survival achieved with FP alone in T1-2N1-2 pts (5-yr OS 89%) question the addition of OX. In the T4 population our results suggested that benefit of OX was limited and that further studies should assess this issue or at least stratify pts on T stage in the future adjuvant trials in CC. [Table: see text]

Abstract Background Disease-free survival (DFS) with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival (OS) with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence in patients who received adjuvant FOLFOX. Hence, reevaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed. Methods Individual patient data from 9 randomized studies conducted between 1998 and 2009 were included; 3 trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (RWLS2) and Copula bivariate (RCopula2) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation. Results Data from a total of 18 396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (T1-3 and N1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high or deficient mismatch repair tumors. Trial-level correlation between 3-year DFS and 5-year OS remained strong (RWLS2 = 0.82, 95% CI = 0.67 to 0.98; RCopula2 = 0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results. Conclusions Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

Abstract Background Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. Methods Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. Results Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P &lt; .001), disease-free survival (HR = 0.91, 95% CI = 0.84 to 0.98; P = .01), and survival after recurrence (HR = 0.88, 95% CI = 0.80 to 0.97; P = .008) in the analysis without molecular markers; however, age at onset of CC lost its prognostic value when outcome was adjusted for molecular markers. Conclusion Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.

3597 Background: Colon cancer (CC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years) is increasing. There are limited data suggesting that, as a group, patients with early onset CRC (eoCC) may have different phenotypic characteristics compared to those with late onset CRC (loCC, age ≥ 50 years). Methods: Individual patient data on 35,713 subjects with stage III CC from 25 randomized studies (recruiting between 1987 and 2009) in the ACCENT database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age group. Overall survival (OS), disease-free survival (DFS), recurrence free rate (RFR), and survival after recurrence (SAR) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for gender, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness and molecular markers. Results: Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III eoCC (n = 6246) had similar distributions according to gender, race, PS, risk group, tumor sidedness and T/N stage compared to those with loCC (n = 29467). Patients with eoCC were significantly less likely to be overweight (30.2% vs 36.2%) but more commonly had ≥ 12 lymph nodes resected (69.5% vs 58.7%). The eoCC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%), and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher frequency of Lynch syndrome in eoCC. In univariate analysis, patients with stage III eoCC had significantly better OS, DFS, and SAR; the difference between 3-year DFS and RFR strongly suggests the OS/DFS difference between these the eoCC and loCC may be due to increased competing risks and comorbidities in patients with loCC. In multivariate analysis, age at onset lost its prognostic value when outcome was adjusted for molecular markers. The clear relation between age of onset and KRAS/BRAF status was confirmed in the interaction analysis. Conclusions: Tumor biology was an important determinant of prognosis regardless of patient age. In multivariate analysis age of onset was not a statistically significant determinant of outcome.[Table: see text]

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.

PURPOSE: In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain. MATERIALS AND METHODS: Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors. RESULTS: MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses. CONCLUSION: Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.