Chemotherapy For High-risk Stage Research Articles

Optimal duration of oxaliplatin-based adjuvant chemotherapy in patients with different risk factors for stage II-III colon cancer: a meta-analysis.

The duration of oxaliplatin-based chemotherapy in high-risk stage II, low-risk stage III, and high-risk stage III colon cancer (CC) patients is controversial. To reduce the risk of adverse events (AEs) without compromising efficacy while improving chemotherapy compliance is crucial. The authors searched Cochrane, Embase, Pubmed, and Web of Science databases for articles from inception to August 8, 2023, the main outcomes were disease-free survival, overall survival, chemotherapy completion rates, and AE frequency. Six randomized controlled trials (RCTs) involving 10332 patients were included. Disease-free survival analysis revealed that only the high-risk stage III CC patients experienced better results with the 6-month FOLFOX regimen when compared with the 3-month regimen [Hazard ratio (HR): 1.32, 95% CI: 1.15-1.51, P <0.0001). Overall survival (OS) analysis revealed that extending the use of FOLFOX and CAPEOX regimens did not provide survival benefits for stage III CC patients (HR: 1.16, 95% CI: 0.9-1.49, and HR: 0.89, 95% CI: 0.67-1.18, P =0.40). The completion rate of the 3-month oxaliplatin-based adjuvant chemotherapy regimen was significantly higher than that of the 6-month regimen [Relative risk (RR): 1.16, 95% CI: 1.06-1.27, P =0.002]. Moreover, the 3-month regimen had significantly lower AE rates than the 6-month regimen (RR: 0.62, 95% CI: 0.57-0.68, P <0.00001), with differences mainly concentrated in grade 3/4 neutropenia (RR: 0.70, 95% CI: 0.59-0.85, P =0.0002), peripheral sensory neuropathy at ≥grade 2 (RR: 0.45, 95% CI: 0.38-0.53, P <0.00001), and hand-foot syndrome at ≥grade 2 (RR: 0.36, 95% CI: 0.17-0.77, P =0.009). The 6-month FOLFOX regimen should only be recommended for high-risk stage III CC, while the 3-month regimen can be recommended for other stages. A 3-month CAPEOX regimen can be recommended for stage II-III CC.

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).

A nomogram based on collagen signature for predicting the immunoscore in colorectal cancer.

The Immunoscore can categorize patients into high- and low-risk groups for prognostication in colorectal cancer (CRC). Collagen plays an important role in immunomodulatory functions in the tumor microenvironment (TME). However, the correlation between collagen and the Immunoscore in the TME is unclear. This study aimed to construct a collagen signature to illuminate the relationship between collagen structure and Immunoscore. A total of 327 consecutive patients with stage I-III stage CRC were included in a training cohort. The fully quantitative collagen features were extracted at the tumor center and invasive margin of the specimens using multiphoton imaging. LASSO regression was applied to construct the collagen signature. The association of the collagen signature with Immunoscore was assessed. A collagen nomogram was developed by incorporating the collagen signature and clinicopathological predictors after multivariable logistic regression. The performance of the collagen nomogram was evaluated via calibration, discrimination, and clinical usefulness and then tested in an independent validation cohort. The prognostic values of the collagen nomogram were assessed using Cox regression and the Kaplan-Meier method. The collagen signature was constructed based on 16 collagen features, which included 6 collagen features from the tumor center and 10 collagen features from the invasive margin. Patients with a high collagen signature were more likely to show a low Immunoscore (Lo IS) in both cohorts (P<0.001). A collagen nomogram integrating the collagen signature and clinicopathological predictors was developed. The collagen nomogram yielded satisfactory discrimination and calibration, with an AUC of 0.925 (95% CI: 0.895-0.956) in the training cohort and 0.911 (95% CI: 0.872-0.949) in the validation cohort. Decision curve analysis confirmed that the collagen nomogram was clinically useful. Furthermore, the collagen nomogram-predicted subgroup was significantly associated with prognosis. Moreover, patients with a low-probability Lo IS, rather than a high-probability Lo IS, could benefit from chemotherapy in high-risk stage II and stage III CRC patients. The collagen signature is significantly associated with the Immunoscore in the TME, and the collagen nomogram has the potential to individualize the prediction of the Immunoscore and identify CRC patients who could benefit from adjuvant chemotherapy.

Factors Associated with Receipt of Adjuvant Chemotherapy in Stage II Colon Cancer.

The benefits of chemotherapy in stage II colon cancer remain unclear, but it is recommended for high-risk stage II disease. Which patients receive chemotherapy and its impact on survival remains undetermined. The National Cancer Database was surveyed between 2004 and 2016 for stage II colon cancer patients. Patients were categorized as high- or average-risk as defined by the National Comprehensive Cancer Network. The demographic characteristics of high- and average-risk patients who did and did not receive chemotherapy were compared using univariate and multivariable analyses. The survival of high- and average-risk patients was compared based on receipt of chemotherapy with Cox hazard ratios and Kaplan-Meier curves. Overall, 84,424 patients met the inclusion criteria. A total of 34,868 patients were high-risk and 49,556 were average-risk. In high-risk patients, the risk factors for not receiving chemotherapy included increasing age, distance from the treatment facility, Charlson-Deyo score, and lack of insurance. In average-risk patients, factors associated with receipt of chemotherapy were decreasing age, distance from the treatment facility, Charlson-Deyo score, and non-academic association of the treatment facility. In both, chemotherapy was significantly associated with increased survival on the Kaplan-Meier curve. In the Cox hazard ratio, only high-risk patients benefited from chemotherapy (hazard ratio 1.183, confidence interval 1.116-1.254). Factors associated with not receiving chemotherapy in high-risk stage II colon cancers included increasing age, medical comorbidities, increasing distance from the treatment facility, and lack of insurance. Chemotherapy is associated with improved overall survival in high-risk patients.

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).

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.

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

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.

The influence of adjuvant chemotherapy dose intensity on overall survival in resected colon cancer: A multicenter retrospective analysis.

248 Background: Colorectal cancer remains the second leading cause of cancer death in developed countries. The benefit of using fluorouracil-based chemotherapy with oxaliplatin, such as FOLFOX (fluorouracil (5-FU), leucovorin, oxaliplatin) and CAPOX (capecitabine and oxaliplatin) is well established. The optimal dose intensity (DI) under which overall survival (OS) is inferior is not established. Methods: Patients (pts) treated with adjuvant chemotherapy between 2006 and 2011 for resected stage III colon cancer (CC) from four academic cancer centres in Canada were retrospectively analysed. Patients that received CAPOX and FOLFOX were examined for the relationship between DI and OS. Results: A total of 625 pts with resected high risk stage II or stage III CC that received adjuvant chemotherapy were analysed. The median age was 63. Pts with T4 and N2 disease comprised 35.4% and 29.9% of pts, respectively. Median follow-up was 3.2 years. There was available survival data for 319 pts. The median oxaliplatin DI was 70%. The frequency of pts reaching an oxaliplatin DI of &gt; 80% was 43%, while 76.6% of pts had a dose intensity of &gt; 80% for their FU component. An oxaliplatin DI of &gt; 80% was associated with a significant improvement in survival, HR = 0.42 (95%CI 0.21 – 0.81, p &lt; 0.01). Achieving a DI of &gt; 80% for capecitabine or 5-FU did not improve OS. Other factors associated with inferior OS included T4 (HR = 3.5, p = 0.03) and N2 (HR = 5.27, p = 0.0005) subgroups. The improvement in OS was not significant when restricting the analysis to pts with non-T4 and non-N2 disease (n = 144), HR = 0.16 (0.02 – 1.26; p = 0.08). Conclusions: Oxaliplatin DI of &gt; 80% is associated with improved OS in patients receiving chemotherapy for high risk stage II and stage III CC.

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.

Microsatellite Status Predicts Effectiveness of Adjuvant Chemotherapy in High-Risk Stage II Colon Cancer

Microsatellite Status Predicts Effectiveness of Adjuvant Chemotherapy in High-Risk Stage II Colon Cancer

1043P - Cancer-specific survival with or without adjuvant chemotherapy in high-risk stage I endometrial cancer

BackgroundControversies exist for utility of adjuvant chemotherapy (AC) in early stage high risk endometrial cancer (EC). Our study sought to evaluate overall, relapse-free and cancer-specific survivals (OS, RFS, CSS) in patients with high risk FIGO stage I EC. MethodsPer provincial guideline, high risk stage I EC eligible for AC was defined as 1) endometrioid histology, stage IB and grade 3 or 2) non-endometrioid histology with any myometrial invasion. We identified all consecutive patients with stage I EC from 6 cancer centres in British Columbia, Canada diagnosed between 2000 and 2010. CSS was defined as time between diagnosis and death due to endometrial cancer. Descriptive statistics were used to evaluate patient, disease and treatment characteristics; Cox proportional hazard regression was used to evaluate differences in OS, RFS and CSS. ResultsAmong stage I EC (n=1426), 24 with endometrioid histology and 214 with non-endometrioid histology with high risk characteristics were identified (n=238). Median age was 66 (range 33-91); stage IA=196, IB=50; grade 1=16, 2=20, 3=196; LVI+ 88. Among all high risk patients, OS (RR 0.37, 95% CI 0.20-0.71, p=0.002; median 6.3 vs 12.2 years) and RFS (RR 0.35, 95% CI 0.19-0.65, p=0.001; median 5.6 vs 12.2 years) were significantly better in patients who received AC, but CSS (RR 0.65, 95% CI 0.32-1.33, p=0.24; median not reached in both groups) was not statistically improved although numerically favoured AC. Similarly, among non-endometrioid histology, OS (RR 0.40, 95% CI 0.20-0.78, p=0.008; median 6.4 vs 12.2 years) and RFS (RR 0.38, 95% CI 0.20-0.72, p=0.03; median 5.9 vs 12.2 years) were significantly better in patients who received AC, but improvements in CSS with AC (RR 0.68, 95% CI 0.3-1.4, p=0.32; median not reached in both groups) were not statistically significant. ConclusionsDespite its use, there is insufficient evidence that AC reduces risk of death due to cancer in high risk stage I EC, although DSS is numerically improved in patients who received AC. Improvements in OS and RFS associated with chemotherapy may be largely attributed to other confounding factors. Future prospective studies are needed to clarify the role of contemporary AC in high risk stage I EC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

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

484 Background: The ACTS-CC 02 trial was designed to verify the superiority of postoperative adjuvant chemotherapy with S-1/oxaliplatin (SOX) over UFT/leucovorin (LV), one of the standard oral fluoropyrimidine regimens in Japan, in terms of disease-free survival (DFS) in patients (pts) with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). The results of the safety analysis have been reported previously (Clin Colorectal Cancer, 2018). We now present the 3-year DFS results as the primary endpoint. Methods: Pts who underwent curative resection for pathologically confirmed 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. Results: From April 2010 through October 2014, a total of 966 pts were enrolled at 260 institutions. The full analysis set, excluding pts who withdrew informed consent before protocol treatment, comprised 478 and 477 pts in the UFT/LV group and SOX group, respectively. The median age was 65.0 years. The ECOG PS was 0 in 94.0%, and the disease stage was IIIA/IIIB/IIIC in 1.3%/50.2%/48.6%. The 3-year DFS rate was 60.6% in the UFT/LV group and 62.7% in the SOX group (HR: 0.90; 95% CI: 0.74-1.09; p = 0.28); the superiority of SOX was not demonstrated. In stage IIIB, the 3-year DFS rate was 69.3% and 68.5% in the UFT/LV group and SOX group, respectively (HR: 1.01; 95% CI: 0.74-1.37; p = 0.95). In Stage IIIC, the 3-year DFS rate was 50.6% and 55.8% in the UFT/LV group and SOX group, respectively (HR: 0.82, 95% CI: 0.63-1.06; p = 0.12). Notably, in the N2b subgroup, the 3-year DFS rate was 46.0% and 54.7% in the UFT/LV group and SOX group, respectively (HR: 0.76, 95% CI: 0.55-1.05; p = 0.10). Conclusions: SOX was not shown to be superior to UFT/LV in pts with high-risk stage III colon cancer. However, the oxaliplatin-based regimen was suggested to be more effective in advanced disease, such as stage IIIC and N2b. Clinical trial information: JapicCTI-101073.

Evaluation of Guideline Adherence in Colorectal Cancer Treatment in The Netherlands: A Survey Among Medical Oncologists by the Dutch Colorectal Cancer Group

BackgroundClinical guidelines are generated to preserve high-quality evidence-based care. Data on the implementation of guidelines into clinical practice are scarce, despite that guideline adherence prevents over- and undertreatment and correlates with survival. Therefore, we investigated guideline adherence for the systemic treatment in high-risk stage II and stage III colon cancer and metastatic colorectal cancer. Patients and MethodsIn all Dutch hospitals (n = 88) 1 medical oncologist involved in colorectal cancer care was approached to participate. An online survey was conducted regarding the local standard of care for adjuvant chemotherapy in high-risk stage II and stage III colon cancer and first-line treatment regimens in metastatic colorectal cancer. Frequency tables were provided for categorical variables and compared for differences in guideline adherence according to hospital type (academic/teaching/regional). ResultsThe overall response rate was 70% (62 of 88). Reported guideline adherence was at least 60% of all presented settings. For high-risk stage II and stage III colon cancer, treatment strategies agreed with national guidelines in 66% and 84% of hospitals, and overtreatment patterns were identified in 28% and 13%, respectively. Targeted therapy was not routinely administered as first-line treatment in metastatic colorectal cancer (range from 63% to 71% in different settings). No differences in guideline adherence were observed among different hospital types. ConclusionGuideline adherence as reported by medical oncologists in The Netherlands is suboptimal. Possible explanations include unawareness or disagreement with the guidelines, or local financial restrictions. Our results recommend additional support of guideline implementation and monitoring in clinical practice, and investigating underlying causes in case of nonadherence.