Impact of high-risk features on disease-free survival (DFS) in patients (pts) with high-risk stage II colon cancer (CC) in ACHIEVE-2 trial as part of the IDEA collaboration.

4011 Background: The IDEA collaboration for high-risk stage 2 colorectal cancer patients (pts) demonstrated that for CAPOX, 3 months was non-inferior to 6 months treatment, while for FOLFOX, 6 months was superior to 3 months treatment. We investigated the impact of high risk features on disease-free survival (DFS). Methods: ACHIEVE-2, one of the 4 IDEA studies (SCOT, TOSCA, ACHIEVE-2, HORG), was an open-label, multicenter randomized trial for high-risk stage II colon cancer. High risk features are defined as one or more: T4, inadequate nodal harvest < 12, poorly differentiated, clinical sign of obstruction and perforation or vascular invasion. The association of high risk features with DFS were measured by Cox regression analyses. Results: Between 2014 and 2017, ACHIEVE-2 enrolled 525 pts, out of whom 514 pts were the modified ITT (mITT) population; 432 received CAPOX (84.0%) and 82 did mFOLFOX6 (16.0%). High-risk features included 35.8% of T4, 12.8% of inadequate nodal harvest, 11.5% of poorly differentiated, 19.3% of obstruction, 6.4% of perforation and 87.5% of vascular invasion; 47.3% had one features, 35.2% had two, 14.6% had three, and 2.9% had four or more. With a median follow-up of 36.1 months, 3-year DFS rates were 88% in both arms, with a hazard ratio (HR) of 1.12 (95% CI, 0.67-1.87, p=0.67). In multivariate analysis, T4 (HR 3.77 [2.18-6.53], p< 0.0001) and inadequate nodal harvest (HR 2.98 [1.59-5.59], p= 0.0006) remained independent significant negative prognostic factors. The 3-year DFS rates in T4 and Non-T4 diseases were 78% and 94% (p<0.0001), while 3-year DFS rate in pts with inadequate and adequate nodal harvest were 77% and 90% (p=0.0059). No interaction was observed between treatment duration and T4 or inadequate nodal harvest. Conclusions: Our findings indicated the relative impact of high risk features on DFS varies across factors; T4 and inadequate nodal harvest < 12 were more significant than the others. Our results must be interpreted within the combined analysis as well as within the reproducibility of results across the 4 trials. Clinical trial information: 000013036 .

Clinical utility of the systemic inflammatory response (SIR) in identifying high-risk stage II colon cancer.

220 Background: Surgery for TNM Stage II colon cancer is considered curative however approximately 20% of patients will have recurrence of their disease. A number of high risk pathological features guide the use of adjuvant chemotherapy. More recently the preoperative SIR has been consistently shown to have prognostic value but to date has not been utilised clinically as a high risk feature. The present study compared the influence of the SIR versus established high-risk clinical features on overall/cancer specific survival (OS/CSS). Methods: Patients in the West of Scotland undergoing curative resection for Stage II colon cancer from 2011-2015 were identified with survival updated until December 2018. Additional data was obtained from online records. Through uni/multivariate analysis (UVA/MVA) we compared the effect on survival of the SIR measured using the modified Glasgow Prognostic Score (mGPS), neutrophil-lymphocyte ratio (NLR) and lymphocyte-monocyte ratio (LMR) when entered individually into a multivariate model alongside established high-risk features. Results: 982 patients were identified having had a curative resection of Stage II colon cancer. Median follow up was 61 months and there were 307 deaths during follow up. For OS: emergency presentation, T stage, adjuvant chemotherapy, nodal harvest, margin involvement, mGPS, LMR, NLR (all p≤0.001) and EMVI (p < 0.05) were significant on UVA. On MVA: age (HR 1.51), T stage (HR 1.59), nodal harvest (HR 1.67), margin involvement (HR 1.94), adjuvant chemotherapy (HR 0.47), mGPS (HR 1.38), NLR (HR 1.35) and LMR (HR 1.50) remained significant (all p < 0.05). For CSS: age, emergency presentation, T stage, margin involvement, mGPS, NLR, LMR (all p < 0.001), nodal harvest and adjuvant chemotherapy (both p < 0.05) remained significant on UVA. On MVA emergency presentation (HR 1.88), T stage (HR 2.02), margin involvement (HR 2.98), adjuvant chemotherapy (HR 0.51) and mGPS (HR 1.34) remained significant (all p < 0.05). Conclusions: The present study suggests that the SIR is an independent predictor of worse OS/CSS in Stage II colon cancer and should be considered a high risk feature in future prospective studies.

Prospective pooled analysis of four randomized trials investigating duration of adjuvant (adj) oxaliplatin-based therapy (3 vs 6 months {m}) for patients (pts) with high-risk stage II colorectal cancer (CC).

3501 Background: 6m of oxaliplatin-based treatment is an option as adj chemotherapy for patients with high risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular/perineural invasion). The IDEA collaboration showed shorter treatment duration to be appropriate for most pts with stage III colon cancer. The results of the 4 IDEA studies with stage II pts are presented here. Methods: A prospective, pre-planned pooled analysis of high-risk stage II patients from 4 concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, HORG) was performed to evaluate non-inferiority (NI) of 3m compared with 6m (ref) of adj FOLFOX/CAPOX (regimen preselected, not randomized). The primary endpoint was disease-free survival (DFS), NI was to be declared if the 2-sided 80% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.2. 542 DFS events were required to provide 80% power to declare NI. NI was also examined within regimen, T4 (Yes v No) and inadequate nodal harvest (Yes v No) as pre-planned subgroups. Results: The primary analysis included 3273 randomised pts of which 1254 had FOLFOX and 2019 had CAPOX. There were 552 events and the median follow-up was 60.2 m. There was significantly less grade 3-5 toxicity with 3m treatment (p < .0001). The 5-year DFS rate was 80.7% and 84.0% for 3m and 6m treatment with an estimated DFS HR of 1.18 (80% CI:1.05-1.31, p for NI = 0.404). For CAPOX the estimated HR was 1.02 (80% CI: 0.88-1.17, p for NI = 0.087) and for FOLFOX the estimated HR was 1.42 (80% CI: 1.19-1.70, p for NI = 0.894). The test for interaction between duration and regimen was not statistically significant (p = .174 adjusted for multiple testing) but was stronger than that for the other subgroups examined. Conclusions: In the overall population non-inferiority for 3m adj treatment in pts with high-risk stage II CC was not shown. As with the stage III population the choice of adj regimen appears important (although this did not reach statistical significance) with a small difference in DFS between 3 and 6 m treatment if CAPOX is used. Clinical trial information: ISRCTN59757862.

Effect of lymphadenectomy on survival in patients with esophageal cancer.

65 Background: The number of resected lymph nodes is associated with overall and disease-free survival in some gastrointestinal malignancies. The impact of nodal harvest during esophagectomy remains to be determined. We examined the influence of lymphadenectomy on overall survival in patients with esophageal cancer. Methods: Utilizing a prospectively maintained comprehensive esophageal cancer database we identified patients who underwent esophagectomy with between 1994 and 2011. The association between disease free survival (DFS), overall survival (OS) and nodal harvest was evaluated using multivariable Cox regression models. The number of harvested nodes was examined as a categorical variable based on strata(S): 1) ≤8, 2) 9-12, 3) 13-20, and 4) >20. Results: We identified 635 patients, 541 males and 94 females with a median age of 65 years (28-86) and median follow-up of 22 months (0-168). Adenocarcinoma 559 (88 %) was the predominant histology where as squamous cell carcinoma represented 76 (12%) of the cases. The 5-year OS and DFS rate for S1-S4 was (43%, 42%, 55%, and 36%, p=0.1836) and (44%, 37%, 46%, and 36%, p=0.5166) respectively. There were 209 patients with metastatic disease in 1 or more lymph nodes. The 5-year OS and DFS for S1-S4 was (17%, 31%, 21%, and 27%, p=0.4372) and (17%, 23%, 16%, and 25%, p=0.2726). There were 418 node negative patients. The 5-year OS and DFS rates by S1-S4 was (54%, 51%, 79%, and 26%, p=0.0538) and (55%, 48%, 64%, and 27%, p=0.3703). Multivariate analysis revealed that patients within S3 exhibited a survival benefit adjusted odds ratio (AOR) 0.57 (CI 0.360-0.916, p=0.020). However patients within S1 were more likely to die, AOR 1.74 (CI 1.09-2.78, p=0.020). No survival benefit was demonstrated for patients within (S4) AOR 1.11 (CI 0.60-2.09, p=0.731). There were 171 (27.5%) recurrences with a median time to recurrence of 12.2 (1-101) months. There were no differences in recurrences between strata p=0.129. Conclusions: We demonstrated that patients with ≤8 lymph nodes resected were more likely to die of their disease compared to those with 13-20 nodes resected. Additionally, extended lymphadenectomy (>20 nodes) does not increase the likelihood of proper staging and does not improve patient outcome.

Prognostic significance of lymphadenectomy in patients with esophageal cancer receiving neoadjuvant chemoradiation.

87 Background: The optimal number of lymph nodes that should be harvested in esophageal cancer patients remains to be defined, particularly in patients that receive neoadjuvant therapies. We investigated the impact of nodal resection and survival in esophageal cancer patients treated with neoadjuvant chemoradiation (NT). Methods: Using our comprehensive esophageal cancer database we identified patients treated with NT followed by esophagectomy between 2000-2011. Clinical and pathologic data were compared using Fisher’s exact and chi-square while, Kaplan Meier estimates were used for survival analysis. Overall (OS) and disease-free survival (DFS) were compared with varying numbers of lymph nodes resected <10 and ≥10 (ST-1), <12 and ≥12 (ST-2), and <15 and ≥15 (ST-3). Multivariate analysis was analyzed by the Cox proportional hazard model. Results: We identified 358 patients treated with NT and esophagectomy with a median follow-up of 18.5 months (range, 0-116 months). There was no survival benefit demonstrated for patients with increased lymph nodes removed during their surgery (ST-1 OS p=0.400, DFS p=0.8727; ST-2 OS p=0.6833, DFS p=0.6092; ST-3 OS p=0.1798, DFS p=0.4028). Patients were further stratified by pathologic response to NT and nodal harvest. There were no differences in OS or DFS in patients with increased nodal harvest when analyzed by complete (pCR) (ST-1 OS p=0.7278, DFS p=0.3602; ST-2 OS p=0.6182, DFS p=0.3592; ST-3 OS p=0.4489, DFS p=0.6976), partial (pPR) (ST-1 OS p=0.3762, DFS p=0.5061; ST-2 OS p=0.8036, DFS p=0.6497; ST-3 OS p=0.0890, DFS p=0.3364), or non response (pNR) (ST-1 OS p=0.6825, DFS p=0.7161; ST-2 OS p=0.7084, DFS p=0.8351; ST-3 OS p=0.5002, DFS p=0.7314) to NT. Multivariate analysis demonstrated that age (p=0.028), t-stage (p=0.006), pPR (p=0.025), and pNR (p<0.0005) to NT were all independent predictors of mortality. Conclusions: In our experience, the number of lymph nodes resected was not predictive for overall or disease free survival in esophageal cancer patients treated with NT. In addition, extended lymph node resection did not improve survival for those with residual disease.