Adjuvant Chemotherapy For High-risk Stage Research Articles

Final analyses of the prospective controlled trial on the efficacy of uracil and tegafur/leucovorin as an adjuvant treatment for stage II colon cancer with risk factors for recurrence using propensity score-based methods (JFMC46-1201).

The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. Using propensity score matching, we previously reported that the 3-year disease-free survival (DFS) rate was significantly higher in patients treated with uracil and tegafur plus leucovorin (UFT/LV) against surgery alone. We report the final results, including updated 5-year overall survival (OS) rates and risk factor analysis outcomes. In total, 1902 high-risk stage II CC patients with T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and/or < 12 dissected lymph nodes were enrolled in this prospective, non-randomized controlled study based on their self-selected treatment. Oral UFT/LV therapy was administered for six months after surgery. Of the 1880 eligible patients, 402 in Group A (surgery alone) and 804 in Group B (UFT/LV) were propensity score-matched. The 5-year DFS rate was significantly higher in Group B than in Group A (P = 0.0008). The 5-year OS rates were not significantly different between groups. The inverse probability of treatment weighting revealed significantly higher 5-year DFS (P = 0.0006) and 5-year OS (P = 0.0122) rates in group B than in group A. Multivariate analyses revealed that male sex, age ≥ 70years, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for DFS and/or OS. The follow-up data from our prospective non-randomized controlled study revealed a considerable survival advantage in DFS offered by adjuvant chemotherapy with UFT/LV administered for six months over surgery alone in individuals with high-risk stage II CC. Japan Registry of Clinical Trials:jRCTs031180155(date of registration: 25/02/2019), UMIN Clinical Trials Registry:UMIN000007783 (date of registration: 18/04/2012).

The effects of oxaliplatin-based adjuvant chemotherapy in high-risk stage II colon cancer with mismatch repair-deficient: a retrospective study

BackgroundFor high-risk stageIImismatch repair deficient (dMMR) colon cancers, the benefit of adjuvant chemotherapy remains debatable. The principal aim of this study was to evaluate the prognostic value of high-risk factors and the effect of oxaliplatin-based adjuvant chemotherapy among dMMR stageIIcolon cancers.MethodsPatients with stage II dMMR colon cancers diagnosed between June 2011 and May 2018 were enrolled in the study. Clinicopathological characteristics, treatment, and follow-up data were retrospectively collected. The high-risk group was defined as having one of the following factors: pT4 disease, fewer than twelve lymph nodes harvested (< 12 LNs), poorly differentiated histology, perineural invasion (PNI), lymphatic vascular invasion (LVI), or elevated preoperative carcinoembryonic antigen (CEA). The low-risk group did not have any risk factors above. Factors associated with disease-free survival (DFS) were included in univariate and multivariate Cox analyses.ResultsWe collected a total of 262 consecutive patients with stage II dMMR colon cancer. 179 patients (68.3%) have at least one high-risk factor. With a median follow-up of 50.1 months, the low-risk group was associated with a tended to have a better 3-year DFS than the high-risk group (96.4% vs 89.4%; P = 0.056). Both elevated preoperative CEA (HR 2.93; 95% CI 1.26–6.82; P = 0.013) and pT4 disease (HR 2.58; 95% CI 1.06–6.25; P = 0.037) were independent risk factors of recurrence. Then, the 3-year DFS was 92.6% for the surgery alone group and 88.1% for the adjuvant chemotherapy group (HR 1.64; 95% CI 0.67–4.02; P = 0.280). Furthermore, no survival benefit from oxaliplatin-based adjuvant chemotherapy was observed in the high-risk group and in the subgroups with pT4 disease or < 12 LNs.ConclusionsThese data suggests that not all high-risk factors have a similar impact on stage II dMMR colon cancers. Elevated preoperative CEA and pT4 tumor stage are associated with increased recurrence risk. However, oxaliplatin-based adjuvant chemotherapy shows no survival benefits in stage II dMMR colon cancers, either with or without high-risk factors.

Interaction analysis of high-risk pathological features on adjuvant chemotherapy survival benefit in stage II colon cancer patients: a multi-center, retrospective study

BackgroundWe aimed to analyze the benefit of adjuvant chemotherapy in high-risk stage II colon cancer patients and the impact of high-risk factors on the prognostic effect of adjuvant chemotherapy.MethodsThis study is a multi-center, retrospective study, A total of 931 patients with stage II colon cancer who underwent curative surgery in 8 tertiary hospitals in China between 2016 and 2017 were enrolled in the study. Cox proportional hazard model was used to assess the risk factors of disease-free survival (DFS) and overall survival (OS) and to test the multiplicative interaction of pathological factors and adjuvant chemotherapy (ACT). The additive interaction was presented using the relative excess risk due to interaction (RERI). The Subpopulation Treatment Effect Pattern Plot (STEPP) was utilized to assess the interaction of continuous variables on the ACT effect.ResultsA total of 931 stage II colon cancer patients were enrolled in this study, the median age was 63 years old (interquartile range: 54–72 years) and 565 (60.7%) patients were male. Younger patients (median age, 58 years vs 65 years; P < 0.001) and patients with the following high-risk features, such as T4 tumors (30.8% vs 7.8%; P < 0.001), grade 3 lesions (36.0% vs 22.7%; P < 0.001), lymphovascular invasion (22.1% vs 6.8%; P < 0.001) and perineural invasion (19.4% vs 13.6%; P = 0.031) were more likely to receive ACT. Patients with perineural invasion showed a worse OS and marginally worse DFS (hazardous ratio [HR] 2.166, 95% confidence interval [CI] 1.282–3.660, P = 0.004; HR 1.583, 95% CI 0.985–2.545, P = 0.058, respectively). Computing the interaction on a multiplicative and additive scale revealed that there was a significant interaction between PNI and ACT in terms of DFS (HR for multiplicative interaction 0.196, p = 0.038; RERI, -1.996; 95%CI, -3.600 to -0.392) and OS (HR for multiplicative interaction 0.112, p = 0.042; RERI, -2.842; 95%CI, -4.959 to -0.725).ConclusionsPerineural invasion had prognostic value, and it could also influence the effect of ACT after curative surgery. However, other high-risk features showed no implication of efficacy for ACT in our study.Trial registrationThis study is registered on ClinicalTrials.gov, NCT03794193 (04/01/2019).

Cost-effectiveness of adjuvant chemotherapy for high-risk stage II and stage III colon cancer in South Africa.

Colon cancer incidence is rising in low- and middle-income countries (LMICs), where resource limitations and cost often dictate treatment decisions. In this study, we evaluate the cost-effectiveness of adjuvant chemotherapy for high-risk stage II and stage III colon cancer treatment in South Africa (ZA) and illustrate how such analyses can inform cancer treatment recommendations in a LMIC. We created a decision-analytic Markov model to compare lifetime costs and outcomes for patients with high-risk stage II and stage III colon cancer treated with three adjuvant chemotherapy regimens in a public hospital in ZA: capecitabine and oxaliplatin (CAPOX) for 3 and 6 months, and capecitabine for 6 months, compared to no adjuvant treatment. The primary outcome was the incremental cost-effectiveness ratio (ICER) in international dollars (I$) per disability-adjusted life-year (DALY) averted, at a willingness-to-pay (WTP) threshold equal to the 2021 ZA gross domestic product per capita (I$13,764/DALY averted). CAPOX for 3 months was cost-effective for both patients with high-risk stage II and patients with stage III colon cancer (ICER = I$250/DALY averted and I$1042/DALY averted, respectively), compared to no adjuvant chemotherapy. In subgroup analyses of patients by tumor stage and number of positive lymph nodes, for patients with high-risk stage II colon cancer and T4 tumors, and patients with stage III colon cancer with T4 or N2 disease. CAPOX for 6 months was cost-effective and the optimal strategy. The optimal strategy in other settings will vary by local WTP thresholds. Decision analytic tools can be used to identify cost-effective cancer treatment strategies in resource-constrained settings. Colon cancer incidence is increasing in low- and middle-income countries, including South Africa, where resource constraints can impact treatment decisions. This cost-effectiveness study evaluates three systemic adjuvant chemotherapy options, compared to surgery alone, for patients in South African public hospitals after surgical resection for high-risk stage II and stage III colon cancer. Doublet adjuvant chemotherapy (capecitabine and oxaliplatin) for 3 months is the cost-effective strategy and should be recommended in South Africa.

High Expression of CUL9 Is Prognostic and Predictive for Adjuvant Chemotherapy in High-Risk Stage II and Stage III Colon Cancer.

Simple SummaryThis retrospective study evaluated the clinical implications of CUL9 expression on the prognosis and the predictive value for postoperative adjuvant chemotherapy in consecutive patients with colon cancer. Among all 1078 patients, high expression of CUL9 was an independent prognostic factor on disease-free survival and overall survival. Prognostic biomarkers are keys to the risk stratification of patients and the decision to recommend adjuvant chemotherapy. Among 564 patients with high-risk stage II and stage III disease who were recommended to receive the standard 6 months of chemotherapy, those with high CUL9 expression from the full dose group had better disease-free survival than those from the reduced dose group. A test for the interaction between CUL9 expression and the treatment reached significance and was not confounded by T stage, N stage and histopathological grade. This indicated that CUL9 expression may further filter those patients to identify truly high-risk cases that benefit from the full dose of the standard 6 months of chemotherapy.We evaluated the clinical implications of CUL9 expression on the prognosis and the predictive value for adjuvant chemotherapy in colon cancer. A total of 1078 consecutive patients treated with radical resection from 2008 to 2012 were included. Formalin-fixed, paraffin-embedded specimens were used as immunohistochemistry (IHC) for CUL9. For all patients, high expression of CUL9 was identified as an independent prognostic factor for overall survival (HR = 1.613, 95% CI 1.305–1.993, p < 0.001) and disease-free survival (HR = 1.570, 95% CI 1.159–2.128, p = 0.004). The prognostic value of high CUL9 expression was confirmed in an independent validation cohort from the GEO database. The efficacy of adjuvant chemotherapy was analyzed among patients with high-risk stage II and stage III disease. Those with high CUL9 expression from the full dose group had better disease-free survival (HR = 0.477, 95% CI 0.276–0.825, p = 0.006) than those from the reduced dose group. The interaction test between CUL9 expression and the treatment reached significance and was not confounded by T stage, N stage and histopathological grade. In general, high expression of CUL9 was an independent prognostic factor in patients with colon cancer. In those with high-risk stage II and stage III disease, high expression of CUL9 was associated with the benefit from standard 6-months adjuvant chemotherapy regimens.

A national evaluation of the predictors of compliance and survival from adjuvant chemotherapy in high-risk stage II colon cancer: A National Cancer Database (NCDB) analysis

BackgroundGuidelines recommend adjuvant chemotherapy for stage II colon cancer with high-risk features, but there has been little study on compliance with guidelines. This work sought to evaluate compliance with adjuvant chemotherapy and factors associated with compliance in high-risk stage II colon cancer. This work’s hypothesis was that compliance with adjuvant chemotherapy recommendations is low, but improves overall survival when used. MethodsThe National Cancer Database was reviewed for stage II high-risk colon cancers that underwent curative resection from 2010 to 2017. The cases were stratified into adjuvant chemotherapy and no adjuvant chemotherapy cohorts. A multivariate logistic regression identified factors associated with adjuvant chemotherapy compliance. Propensity-score matching was performed to balance the cohorts and Kaplan-Meier analysis assessed overall survival. The main outcome measures were adjuvant chemotherapy compliance, factors associated with compliance, and overall survival in high-risk stage II colon cancer. ResultsA total of 52,609 patients were evaluated, and 23.2% received adjuvant chemotherapy. The factors associated with noncompliance included older age (odds ratio 0.919; 95% confidence interval 0.915–0.922; P < .001), Medicaid (odds ratio 0.720; 95% confidence interval 0.623–0.832; P < .001) payor, greater comorbidities (odds ratio 0.423; 95% confidence interval 0.334–0.530; P < .001), and residing in the Midwest (odds ratio 0.898; 95% confidence interval 0.812–0.994; P = .037). All of the known high-risk features were significantly independently associated with compliance. In a matched cohort, adjuvant chemotherapy significantly improved the 5-year overall survival (78.1% vs 66.6%; P < .001). ConclusionNationally, there is low compliance with adjuvant chemotherapy in high-risk stage II colon cancer. Despite the low compliance, adjuvant chemotherapy was associated with improved overall survival. Demographic variables were associated with poor compliance, whereas tumor factors were associated with increased compliance. These results highlighted the disparities in care and opportunities to improve outcomes in high-risk stage II colon cancer.

Prospective observational study of the efficacy of oral uracil and tegafur plus leucovorin for stage II colon cancer with risk factors for recurrence using propensity score matching (JFMC46-1201)

BackgroundThe efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors.MethodsWe enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm.ResultsOverall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%–83.4%]) than in NR-Group S (74.0% [69.3%–78.0%]) (hazard ratio, 0.64 [0.50–0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW.ConclusionsAdjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes.Trial registrationJapan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783, date of registration: 18/04/2012).

The impact of epidermal growth factor receptor mutation status on adjuvant chemotherapy for patients with high-risk stage I lung adenocarcinoma

ObjectiveThe aim of this study was to evaluate the role and effect of adjuvant chemotherapy based on epidermal growth factor receptor mutation status in patients with stage I lung adenocarcinoma. MethodsBetween 2010 and 2016, of 1901 patients with pathologic stage I (8th edition) non–small cell lung cancer, we identified 475 with high-risk (pT1c/T2a or positive for lymphovascular invasion) stage I lung adenocarcinoma who underwent lobectomy. We estimated propensity scores to adjust for confounding variables, including age, sex, Brinkman index, pulmonary functions, comorbidities, surgical approach, invasive component tumor size, visceral pleural, lymphatic, and vascular invasion, adenocarcinoma subtype, epidermal growth factor receptor mutation status, postoperative complications, and institution associated with the administration of adjuvant chemotherapy. The primary end point was recurrence-free survival. ResultsOf 292 patients without/unknown epidermal growth factor receptor mutation, 105 (36.0%) received adjuvant chemotherapy and 187 (64.0%) did not. In 69 pairs of patients who were propensity score matched, the 5-year recurrence-free survival was significantly better in those who underwent adjuvant chemotherapy (88.4%) than in those who did not (63.6%; P = .001). Of 183 patients with epidermal growth factor receptor mutation, 78 (42.6%) received adjuvant chemotherapy and 105 (57.4%) did not. In 49 pairs of propensity score–matched patients, there was no significant difference in the 5-year recurrence-free survival between those who underwent adjuvant chemotherapy (74.3%) and those who did not (80.5%; P = .573). ConclusionsThe effect of adjuvant chemotherapy for high-risk stage I lung adenocarcinoma varied by epidermal growth factor receptor mutation status. Epidermal growth factor receptor mutation status may help to identify patients with high-risk stage I lung adenocarcinoma who may benefit from adjuvant chemotherapy.

Effectiveness of oral fluoropyrimidine monotherapy as adjuvant chemotherapy for high-risk stage II colon cancer.

PurposeThe benefit of adjuvant chemotherapy for stage II colon cancer has not been clearly demonstrated even in cases with high-risk factors. This study aimed to compare the effectiveness of oral fluoropyrimidine monotherapy as adjuvant chemotherapy with that of intravenous fluoropyrimidine-based chemotherapy for high-risk stage II colon cancer.MethodsThis single-institution, retrospective study included patients who underwent curative resection for high-risk stage II colon cancer between 2003 and 2014. Patients were classified into 3 postoperative treatment groups: observation, oral fluoropyrimidine monotherapy group (OG), or intravenous fluoropyrimidine-based chemotherapy group (IVG).ResultsWe identified 356 patients, including 87 (24.4%) in the observation group, 172 (48.3%) in the OG, and 97 (27.2%) in the IVG. Patients in the OG were older (63.8 ± 10.7 vs. 56.5 ± 10.8, P < 0.001) and had a lower number of T4 lesions (12.8% vs. 35.1%, P < 0.001) than those in the IVG. Regarding survival outcomes, the 5-year overall and disease-free survival rates were not different between the OG and IVG (91.2% vs. 92.6% [P = 0.090] and 85.1% vs. 81.9% [P = 0.535], respectively). In multivariate analysis, age over 70 years and no adjuvant chemotherapy were associated with poor overall survival and disease-free survival. Fewer chemotherapy-related adverse events of grade ≥3 were observed in the OG than in the IVG (12.2% vs. 34.0%, P < 0.001).ConclusionIn high-risk stage II colon cancer, adjuvant oral fluoropyrimidine monotherapy can be an effective and convenient alternative to intravenous fluoropyrimidine-based chemotherapy as it has comparable oncological outcomes and reduced chemotherapy-related complications.

S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial

BackgroundThe ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy.Patients and methodsPatients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients’ data were updated in February 2020.ResultsA total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31).ConclusionOur final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups.

Final results of the ACTS-CC 02 trial: A randomized phase III trial of S-1/oxaliplatin (SOX) versus UFT/leucovorin as adjuvant chemotherapy for high-risk stage III colon cancer.

59 Background: As previously reported (Sunami E, et al. Clin Colorectal Cancer. 2020), the ACTS-CC 02 trial demonstrated that S-1 and oxaliplatin (SOX) was not superior to UFT/leucovorin (LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) after a median follow-up of more than 6 years. Methods: A total of 966 patients with high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300–600 mg/day of UFT according to body surface area [BSA] and 75 mg/day of LV on days 1-28, every 35 days, 5 courses) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80–120 mg/day of S-1 according to BSA on days 1-14, every 21 days, 8 courses). The primary endpoint was DFS. Patients’ data were updated in February 2020. Results: The subjects of this final efficacy analysis were 955 patients (478 in the UFT/LV group and 477 in the SOX group). Totally, Stage IIIA/IIIB/IIIC were 1.3%/50.2%/48.6% and T1/2/3/4 were 1.5%/4.0%/61.8%/32.7%. With median follow-up time of 74.3 months, the 5-year OS rate was 78.3% in the UFT/LV group and 79.1% in the SOX group (HR: 0.97; 95% CI: 0.76-1.24; p = 0.8175). The 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group (HR: 0.92; 95% CI: 0.76-1.11; p = 0.3973). In an exploratory analysis, the 5-year OS rate in patients with T4 disease was 65.2% and 70.8% in the UFT/LV group and SOX group, respectively (HR: 0.81; 95% CI: 0.56-1.17), and the 5-year DFS rate was 45.4% and 50.5% (HR: 0.87; 95% CI: 0.65-1.19), respectively. Notably, in patients with T4N2b disease, the 5-year OS rate was 51.0% and 64.1% in the UFT/LV group and SOX group, (HR: 0.72; 95% CI: 0.40-1.31) and the 5-year DFS rate was 31.1% and 37.2% (HR: 0.87; 95% CI: 0.50-1.31), respectively. Conclusions: In Japanese patients with high-risk stage III colon cancer, the 5-year OS rate was similar in the UFT/LV group and SOX group. However, the oxaliplatin-based regimen was suggested to be more effective for DFS and OS in patients with advanced disease, such as T4N2b. Clinical trial information: JapicCTI-101073.

ELF3 Overexpression as Prognostic Biomarker for Recurrence of Stage II Colorectal Cancer.

Adjuvant chemotherapy for high-risk Stage II colorectal cancer (CRC) is weakly recommended; however, no consensus exists on "high-risk" definition. Prognostic biomarker identification is important for selecting patients with poor prognosis who may benefit from adjuvant chemotherapy. Using Microarray data analyses, ELF3 was identified as a candidate gene highly expressed in Stage II CRC with distant recurrences. ELF3 mRNA expression in 168 Stage II CRC patients was subjected to quantitative RT-PCR analysis and ELF3 protein expression in 185 patients was quantified by immunohistochemical analysis. The relationship between mRNA and protein expression levels and patient characteristics were also investigated. The overall recurrence rate and relapse-free survival were significantly poorer in the ELF3 high-expression than the low-expression group at the mRNA and protein levels. High ELF3 mRNA and protein expression levels were independent poor prognostic factors. High ELF3 expression was associated with recurrence of Stage II.

Duration of FOLFOX Adjuvant Chemotherapy in High-Risk Stage II and Stage III Colon Cancer With Deficient Mismatch Repair.

BackgroundWe evaluated the impact of 3 months of mFOLFOX6 adjuvant chemotherapy or surgery alone in comparison with 6 months of mFOLFOX6 on disease-free survival (DFS) in deficient mismatch repair (dMMR) colon cancer (CC) patients.MethodsThis retrospective study identified a cohort of patients with high-risk stage II and III dMMR CC who underwent curative surgery between May 2011 and July 2019. DFS was compared using the Kaplan-Meier survival methods and Cox proportional hazards models. Propensity-score matching was performed to reduce imbalance in baseline characteristics.ResultsA total of 242 dMMR CC patients were identified; 66 patients received 6 months of mFOLFOX6, 87 patients received 3 months of mFOLFOX6, and 89 patients were treated with surgery alone. The 3-year DFS rate was 72.8% in 3-month therapy group and 86.1% in 6-month therapy group, with a hazard ratio (HR) of 2.78 (95CI%, 1.18 to 6.47; P= 0.019). The difference in DFS between surgery alone group and 6-month therapy group was also observed but was nonsignificant (HR= 2.30, 95%CI, 0.99 to 5.38; P=0.054). The benefit of 6-month therapy in DFS compared with 3-month therapy group was pronounced for patients with stage III (HR=2.81, 95%CI, 1.03 to 7.67; P=0.044) but not for high-risk stage II patients. Propensity score matched analysis confirmed a DFS benefit in the 6-month therapy group.ConclusionThis study suggested that a 6-month duration of mFOLFOX6 adjuvant chemotherapy in dMMR CC patients may be associated with improved DFS compared with 3-month therapy, particularly in patients with stage III. The observational nature of the study implies caution should be taken in the interpretation of these results.

National Evaluation of the Predictors of Compliance and Survival from Adjuvant Chemotherapy in High-Risk Stage II Colon Cancer: A National Cancer Database (NCDB) Analysis

National Evaluation of the Predictors of Compliance and Survival from Adjuvant Chemotherapy in High-Risk Stage II Colon Cancer: A National Cancer Database (NCDB) Analysis

407P Long-term effect of peripheral sensory neuropathy (PSN) of 3 or 6 months oxaliplatin-based adjuvant chemotherapy for high-risk stage II colon cancer: ACHIEVE-2 as part of the IDEA collaboration

The ACHIEVE-2 trial, a part of the IDEA collaboration, was a multicenter study randomizing patients with high-risk stage II resected colon cancer to either 3 or 6 months of mFOLFOX6/CAPOX. Previous our report in the ACHIEVE trial for stage III colon cancer patients (pts) showed that the incidence of long-lasting peripheral sensory neuropathy (PSN) was significantly lower for 3 months (3m) of therapy than for 6 months (6m) of therapy. More importantly, the incidence of long-lasting PSN was significantly lower for CAPOX than for FOLFOX. The present study aimed to evaluate the incidence of long-lasting PSN in the 3m arm as compared to the 6m arm in the ACHIEVE-2 trial. ACHIEVE-2 enrolled 514 patients. The incidence of PSN was evaluated every 3m up to three years. The grade of PSN was assessed using CTCAE ver 4.0. During the study treatment, PSN of grade 2/3 was observed more frequently in the 6m arm (36%/7%) than in the 3m arm (17%/1%). At two years from randomization, PSN of grade 1/2/3 lasted in 34%/2%/0% of pts in the 6m arm, whereas 20%/2%/0% of pts in the 3m arm. At three years, PSN of grade 1/2/3 lasted in 27%/2%/0% of pts in the 6m arm whereas 19%/1%/0% of patients in the 3m arm. Thus, PSN ≥ grade 1 was significantly less frequent in the 3m arm than in the 6m arm at two years (22% vs 36%, P=0.0049) and tended to be less frequent at three years (20% vs 29%, P=0.1630). Moreover, PSN ≥ grade 1 lasting for 3 years tended to be lower for CAPOX than for mFOLFOX6 in both the 3m (19% vs 25%, P=0.7375) and 6m arms (26% vs 47%, P=0.1252). The present study for high-risk stage II colon cancer showed that the incidence of long-lasting PSN was significantly lower for 3 months of therapy than for 6 months of therapy. Further, we confirmed a similar trend that the incidence was lower for CAPOX than for mFOLFOX6, although the result was not statistically significant due, possibly, to a lack of power. The role of regimen on long-lasting PSN is still a topic of ongoing debate and our result may warrant a further analysis using the whole data of the IDEA Collaboration.

Duration of FOLFOX adjuvant chemotherapy in high-risk stage II and stage III colon cancer with deficient DNA mismatch repair.

4075 Background: In the IDEA collaboration, noninferiority was not confirmed for 3 months versus 6 months of FOLFOX adjuvant chemotherapy among patients with high-risk stage II and stage III colon cancer (CC). Patients with deficient DNA mismatch repair (dMMR) have a good prognosis, but for whom, whether limiting the duration of adjuvant therapy will compromise oncologic outcomes remains undefined. We evaluated the impact of 3 months of FOLFOX adjuvant chemotherapy or surgery alone in comparison with 6 months of FOLFOX on disease-free survival (DFS) in dMMR CC patients. Methods: This retrospective study included all consecutive patients who underwent curative surgical resection for high-risk stage II or III dMMR CC between May, 2011 and July, 2019. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Results: A total of 242 dMMR CC patients were included (43.4% high-risk stage II, 56.6% stage III). The patients received 6 months of FOLFOX adjuvant chemotherapy (n = 66; median cycles [rang] = 12 [10-12]), 3 months of FOLFOX (n = 87; median cycles [rang] = 6 [4-8]), or surgery alone (n = 89). Three groups were generally well balanced, although more patients with stage III were in the 6-month therapy group (74.2%), compared with the 3-month therapy group (57.5%) and the surgery alone group (42.7%). As compared with 6 months of FOLFOX adjuvant chemotherapy in the overall population, 3 months therapy reduced DFS in multivariable analysis (HR, 2.78; 95CI, 1.18 to 6.47; P = 0.02), similar to surgery alone (HR, 2.30; 95CI, 0.99 to 5.38; P = 0.05). In the subgroup analysis, a therapy duration of 6 months was statistically superior to a duration of 3 months only in the patients with stage III, with a 3-year rate of DFS of 86.2% versus 70.8% (HR, 3.06; 95% CI, 1.14 to 8.19; P = 0.026). Conclusions: This study supports the 6-month duration of FOLFOX adjuvant chemotherapy in stage III dMMR CC.

Postoperative chemotherapy improves survival in patients with resected high-risk Stage II colorectal cancer: results of a systematic review and meta-analysis.

The aim was to assess the benefit of adjuvant chemotherapy in high-risk Stage II colorectal cancer. A systematic literature review and meta-analysis was performed comparing survival in patients with resected Stage II colorectal cancer and high-risk features having postoperative chemotherapy vs no chemotherapy. Of 1031 articles screened, 29 were included, reporting on 183749 participants. Adjuvant chemotherapy significantly improved overall survival [hazard ratio (HR)0.61, P<0.0001], disease-specific survival (HR =0.73, P=0.05) and disease-free survival (HR =0.59, P<0.0001) compared to no chemotherapy. Adjuvant chemotherapy significantly increased 5-year overall survival (OR=0.53, P=0.0008) and 5-year disease-free survival (OR= 0.50, P=0.001). Overall survival and disease-free survival remained significantly prolonged during subgroup analysis of studies published from 2015 onwards (HR =0.60, P<0.0001; HR =0.65, P=0.0001; respectively), in patients with two or more high-risk features (HR =0.59, P=0.0001; HR =0.70, P=0.03; respectively) and in colon cancer (HR =0.61, P<0.0001; HR =0.51, P=0.0001; respectively). Overall survival, disease-specific survival and disease-free survival during subgroup analysis of individual high-risk features were T4 tumour (HR =0.58, P<0.0001; HR = 0.50, P=0.003; HR = 0.75, P=0.05), <12 lymph nodes harvested (HR =0.67, P=0.0002; HR =0.80, P=0.17; HR =0.72, P=0.02), poor differentiation (HR =0.84, P=0.35; HR =0.85, P=0.23; HR =0.61, P=0.41), lymphovascular or perineural invasion (HR =0.55, P=0.05; HR =0.59, P=0.11; HR =0.76, P=0.05) and emergency surgery (HR =0.60, P=0.02; HR =0.68, P=0.19). Adjuvant chemotherapy in high-risk Stage II colorectal cancer results in a modest survival improvement and should be considered on an individual patient basis. Due to potential heterogeneity and selection bias of the included studies, and lack of separate rectal cancer data, further large randomized trials with predefined inclusion criteria and standardized chemotherapy regimens are required.

Patient Selection for Adjuvant Chemotherapy in High-Risk Stage II Colon Cancer: A Systematic Review and Meta-Analysis.

Patients with high-risk stage II colon cancer (CC) are recommended to undergo adjuvant chemotherapy (ACT). However, whether such patients can benefit from ACT remains unclear. This meta-analysis aimed to investigate the clinicopathologic parameters that are important for selecting patients for ACT in high-risk stage II CC. We systematically retrieved articles from PubMed, the Cochrane Library, and Embase that were published up to September 13, 2018. We analyzed overall survival (OS) and disease-free survival (DFS) based on hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 23 cohort studies and 1 randomized controlled trial were included in our study. Overall analyses showed that ACT improved OS (HR=0.64, 95% CI=0.51-0.80, P<0.001) and DFS (HR=0.46, 95% CI=0.28-0.76, P=0.002) in patients with high-risk stage II CC. Subgroup analyses showed that ACT improved OS in patients with localized intestinal perforation and obstruction and pT4 lesions and improved OS and DFS in patients with <12 sampled lymph nodes. However, ACT had no significant effect on OS in patients with lymphovascular invasion, perineural invasion, or poorly differentiated histology. Our study suggests that not all high-risk factors (lymphovascular invasion, perineural invasion, poorly differentiated histology) show a benefit from ACT. Randomized controlled trials selectively targeting high-risk patients will need to be conducted in the future.

Model-based evaluation of the cost effectiveness of 3versus6 months’ adjuvant chemotherapy in high-risk stage II colon cancer patients

Background:Our aim was to evaluate the cost effectiveness of 3 months’ adjuvant chemotherapy versus 6 months in high-risk (T4 stage + microsatellite stable) stage II colon cancer (CC) patients.Methods:Using the validated PATTERN Markov cohort model, which simulates the disease progression of stage II CC patients from diagnosis to death, we first evaluated a reference strategy in which high-risk patients were treated with chemotherapy for 6 months. In the second strategy, treatment duration was shortened to 3 months. Both strategies were evaluated for CAPOX (capecitabine plus oxaliplatin) and FOLFOX (fluorouracil, leucovorin and oxaliplatin). Based on trial data, we assumed that shortened treatment duration compared with a 6-month regimen was equally effective for CAPOX and less effective for FOLFOX. Adverse events were highest in the 6-month strategy. Analyses were conducted from a societal perspective using a lifelong time horizon. Outcomes were number of CC deaths per 1000 patients and total discounted costs and quality-adjusted life-years (QALYs) per patient (pp). Incremental net monetary benefit (iNMB) was calculated using a willingness-to-pay value of €50,000/QALY.Results:For CAPOX, the 6-month strategy resulted in 316 CC deaths per 1000 patients, 6.71 QALYs pp and total costs of €41,257 pp. The 3-month strategy resulted in an equal number of CC deaths, but higher QALYs (6.80 pp) and lower costs (€37,645 pp), leading to a iNMB of €8454 per person for 3 months versus 6 months. For FOLFOX, the 6-month strategy resulted in 316 CC deaths per 1000 patients, 6.71 QALYs pp and total costs of €47,135 pp. The 3-month strategy resulted in more CC deaths (393), lower QALYs (6.19 pp) and lower costs (€44,389 pp). An iNMB of −€23,189 was found for 3 months versus 6 months.Conclusion:Our findings indicate that 3 months’ adjuvant chemotherapy should be considered as standard of care in high-risk stage II CC patients for CAPOX, but not for FOLFOX.

560P - Real world data on adjuvant chemotherapy for high-risk stage II colorectal cancer: The role of tumour side

BackgroundAlthough controversial, available data suggest a possible benefit of adjuvant chemotherapy (CT) for high-risk stage II colorectal cancer (CRC). The impact of sidedness and adjuvant CT duration in this setting is uncertain. We aimed to evaluate the outcomes of high-risk stage II CRC patients (pts). MethodsWe performed a single-center retrospective analysis of pts with stage II CRC treated between Jan/2011 and Dec/2018. Study data were collected using REDCap®. We compared overall survival (OS) and recurrence-free survival (RFS) of high-risk pts who received or not adjuvant CT. High-risk was at least one of the following: T4 stage, < 12 lymph nodes resection, emergency presentation, lymphovascular invasion, perineural invasion or poor differentiation. CT consisted of fluoropyrimidine alone. Pts with known microsatellite instability were excluded. Survival analyses were estimated with the Kaplan-Meier method and compared by log-rank test. Prognostic factors, including tumor side and duration of CT, were evaluated with Cox regression. Results1047 pts with stage II CRC were evaluated, and 540 had high-risk criteria.157 (29%) pts had right tumor and 352 (65.2%) left. 335 (62%) received adjuvant CT. Duration of CT was 3 – 6 months for 305 (91%) pts. Pts who received adjuvant CT had superior RFS and OS in comparison with those who did not receive adjuvant CT (5-year RFS: 75.5% vs 65.6%, HR 0.58, 95% CI 0.41 – 0.82, P=0.002; 5-year OS: 87.7% vs 76.1%, HR 0.46, 95% CI 0.28 – 0.73, P=0.001). No difference in RFS and OS was observed according to tumor side (left vs right, HR 0.86, 95% CI 0.56 – 1.31, P=0.494). Prognostic factors in multivariable analysis were: T4 stage (HR 2.29, P=0.002), emergency presentation (HR 2.44, P=0.001), perineural invasion (HR 1.84, P=0.025), and adjuvant CT (HR 0.45, P=0.002). ConclusionsAdjuvant CT was associated with improved RFS and OS in patients with high-risk stage II CRC, with a total gain of 11.6% in 5-year OS. Tumor side did not influence the outcomes in this study. Legal entity responsible for the studyCamila Soares Araujo de Carvalho. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.