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Diabetes mellitus (DM) is a common comorbidity among cancer patients, but its impact on chemotherapy tolerance has not been widely studied. We aimed to compare the occurrence of severe grade 3/4 adverse events (G3/4 AEs) within 90 days of starting chemotherapy between patients with and without diabetes. We conducted a retrospective single-center study in Lille University Hospital Oncology Department, France. Patients who received the first cycle of chemotherapy for gastrointestinal, gynecological or cancer of unknown primary source between 1 May 2013 and 1 May 2016, were included. Overall, 609 patients were enrolled: 490 patients without diabetes (80.5%) and 119 patients with diabetes (19.5%). Within 90 days of starting chemotherapy, patients with diabetes had a significantly higher occurrence of AEs G3/4 compared to those with no diabetes (multivariate odds ratio [OR]: 1.57 [1.02-2.42], P = .04). More frequent G3/4 AEs in patients with diabetes were infection (26%), hematological disorders (13%), endocrine disorders (13%) and deterioration of the general condition (13%). In the year following the beginning of chemotherapy, patients with diabetes were twice as likely to be hospitalized as those without diabetes (univariate OR: 2.1 [1.40-3.15], P = .0003). After multivariate adjustment, diabetes was no longer significantly associated with the risk of hospitalization (P = .051). There were no differences between patients with and without diabetes regarding dose reduction and chemotherapy treatment delays (P = .61 and P = .30, respectively). Our study suggests the need for better consideration of DM in the personalized care plan to improve chemotherapy tolerance and quality of life of patients with DM.

BACKGROUND BRAF V600E-mutant colorectal cancers (CRCs) are associated with shorter survival than BRAF wild-type tumors. Therapeutic decision-making for colorectal liver metastases (CRLM) harboring this mutation remains difficult due to the scarce literature. Our aim was to study a large cohort of BRAF V600E-mutant CRLM patients in order to identify prognostic factors associated with overall survival. METHODS We retrospectively identified BRAF V600E-mutant CRCs diagnosed with liver-only metastases, resected or not, between April 2008 and December 2017, in 25 French centers. Clinical, molecular, pathological characteristics and treatment features were collected. Overall survival (OS) was defined as the time from CRLM diagnosis to death from any cause. Cox proportional hazard models were used for statistical analysis. RESULTSAmong the 105 patients included, 79 (75%) received chemotherapy, 18 (17%) underwent upfront CRLM surgery, and 8 (8%) received exclusive best supportive care. CRLM surgery was performed in 49 (46.7%) patients. CRLM were mainly synchronous (90%) with bilobar presentation (61%). The median OS was 34 months (range, 28.9–67.3 months) for resected patients and 10.6 (6.7–12.5) months for unresected patients (P P = 0.0064) and CRLM resection (HR = 0.169; 95% CI 0.082–0.348, P < 0.0001) were associated with significantly better OS. CONCLUSIONSIn the era of systemic cytotoxic chemotherapies, liver surgery seems to extend OS. Therefore, CRLM resectability should be assessed, regardless of mutational status.

Background Somatic mutations in the KRAS gene are the most common oncogenic mutations found in human cancers. However, no clinical features have been linked to KRAS mutations in colorectal cancer [CRC]. Purpose In this study, we attempted to identify the potential geographical population clusters of KRAS mutations in CRC patients in northern France. Patients and methods All patients with CRC who were identified to have KRAS mutations between 2008 and 2014 at the Regional Molecular Biology Platform at Lille University Hospital were included. 2,486 patients underwent a KRAS status available, with 40.9% of CRC with KRAS mutations in northern France. We retrospectively collected demographic and geographic data from these patients. The proportions of KRAS mutation were smoothed to take into account the variability related to low frequencies and spatial autocorrelation. Geographical clusters were searched using spatial scan statistical models. Results A mutation at KRAS codon 12 or 13 was found in 1,018 patients [40.9%]. We report 5 clusters of over-incidence but only one elongated cluster that was statistically significant [Cluster 1; proportion of KRAS mutation among CRC: 0.4570; RR=1.29; P=0.0314]. We made an ecological study which did not highlight a significant association between KRAS mutations and the distance to the Closest Waste Incineration Plant, and between KRAS mutations and The French Ecological Deprivation Index but few socio-economic and environmental data were available. Conclusion There was a spatial heterogeneity and a greater frequency of KRAS mutations in some areas close to major highways and big cities in northern France. These data demand deeper epidemiological investigations to identify environmental factors such as air pollution as key factors in the occurrence of KRAS mutations.

Background We studied the relationship between intermediate criteria and overall survival (OS) in metastatic colorectal cancer (mCRC) patients who received first-line chemotherapy with bevacizumab. Patients and Methods We assessed OS, progression-free survival (PFS), duration of disease control (DDC), the sum of the periods in which the disease did not progress, and the time to failure of strategy (TFS), which was defined as the entire period before the introduction of a second-line treatment. Linear correlation and regression models were used, and Prentice criteria were investigated. Results With a median follow-up of 57.6 months for 216 patients, the median OS was 24.5 months (95% confidence interval [CI], 21.3-29.7). The median PFS, DDC, and TFS were 8.9 (95% CI, 8.4-9.7), 11.0 (95% CI, 9.8-12.4), and 11.1 (95% CI, 10.0-13.0) months, respectively. The correlations between OS and DDC (Pearson coefficient, 0.79 [95% CI, 0.73-0.83], determination coefficient, 0.62) and OS and TFS (Pearson coefficient, 0.79 [95% CI, 0.73-0.84], determination coefficient, 0.63) were satisfactory. Linear regression analysis showed a significant association between OS and DDC, and between OS and TFS. Prentice criteria were verified for TFS as well as DDC. Conclusion DDC and TFS correlated with OS and are relevant as intermediate criteria in the setting of patients with mCRC treated with a first-line bevacizumab-based regimen.

Background: Prognosis of patients with locally advanced or metastatic pancreatic adenocarcinoma is poor. In this study, we assessed the predictive value of easily available baseline factors for prolonged survival. Patients and Methods: We conducted a retrospective study on patients who received gemcitabine between 1999 and 2010 for locally advanced or metastatic pancreatic adenocarcinoma. The primary end-point was the 12-month survival rate. Results: We included 195 patients. The median age was 62.9 years; the performance status was 0-1 in 80 and 2-3 in 92 patients. The median number of metastatic sites was one. A total of 73 patients (37.4%) were alive 12 months after beginning chemotherapy. In multivariate analysis, no liver metastasis, CA19-9 level

Background BRAF V600E-mutated colorectal liver metastases (CRLM) are associated with higher relapse rate and shorter survival time after resection as compared to BRAF wild-type CRLM. It remains unsure whether metastatic surgery has a benefit over chemotherapy alone in this setting. To address this question, we analyzed a large cohort of BRAF-mutated CRLM patients in order to evaluate the impact of liver surgery on overall survival (OS). Methods We retrospectively identified BRAF-mutated colorectal cancers diagnosed with liver-only metastases (n = 91) resected or not from October 1, 2003 to December 31,2017 in 24 French centers. The impact of CRLM resection on OS (primary endpoint) was analyzed by Kaplan-Meier method and Cox model. OS was defined from the time of CRLM diagnosis to death from any cause. Progression free survival (PFS) was defined from the time of first chemotherapy (even for resected patients) to first progression or death. Results Ninety-one patients were included: 43 (47%) with resected CRLM and 48 (53%) treated with chemotherapy only. Among resected CRLM, 34 (79%) received chemotherapy before surgery. BRAF V600E mutation was detected in 83 (91%) patients and non-V600E mutation in 8 (9%) patients. In comparison to resected CRLM, unresected CRLM were more often bilobar (76% versus 51%, p = 0.03) and greater than 5 (62% versus 34%, p = 0.02). There was no statistical difference in the other criteria especially in rates of synchronous metastases (94% versus 81%, p = 0.11). Median OS was 32.1 months for resected patients and 11.4 months for unresected patients (p Conclusions To our knowledge, this is the largest cohort of colorectal cancer with liver-only metastases harboring BRAF V600E mutation. Liver surgery extend significantly OS and therefore CRLM resectability should be assessed in BRAF-mutated colorectal cancer. Legal entity responsible for the study Ploquin, Anne. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

e15101 Background: Somatic mutations in the KRAS gene are present in about 40% of tumors from colorectal cancer (CRC) patients and are associated with a resistance to anti-EGFR therapies. However, no clinical features have been linked to KRAS mutations in CRC. In this study, we attempted to identify the potential geographical population clusters of KRAS mutations in CRC patients in northern France. Methods: All patients with CRC who were identified to have KRAS mutations performed by pyrosequencing between 2008 and 2014 at the Regional Molecular Biology Platform at Lille University Hospital were included. We retrospectively collected demographic and geographic data from these patients. The proportions of KRAS mutation were smoothed to take into account the variability related to low frequencies and spatial autocorrelation. Geographical clusters were searched using spatial scan statistical models. Then, we made an ecological study. Results: 2,486 patients underwent a KRAS status available. A mutation of KRAS codon 12 or 13 performed by pyrosequencing was found in 1,018 patients (40.9%). We report 5 clusters of over-incidence but only one elongated cluster that was statistically significant ranging from the city of Tourcoing to the city of Marquion (Cluster 1; smoothed proportion of KRAS mutation: 0.4570; RR = 1.29; p = 0.0314). The ecological study did not highlight a significant association between KRAS mutations and the distance to the Closest Waste Incineration Plant , and between KRAS mutations and The French Ecological Deprivation Index. There was a greater frequency of KRAS mutations in some areas close to major highways and big cities in northern France. Conclusions: There is a spatial heterogeneity of KRAS codon 12 or 13 mutations in CRC in northern France. These data demand deeper epidemiological investigations to identify environmental factors such as air pollution as key factors in the occurrence of KRAS mutations.

Background/aim Pancreatic adenocarcinoma (PA) is frequently associated with venous thromboembolic events (VTEs). Although the prognostic value of VTEs remains controversial, these events can darken the prognosis. In contrast, because they necessitate anticoagulant therapy, some authors found that VTEs improved the prognosis. Indeed, anticoagulants could have an anti-tumor action. Therefore, we evaluated the prognostic value of VTEs in patients with locally advanced or metastatic PA. Patients and methods This retrospective study included all patients followed in a medical oncology Department. The prognostic value of tumor parameters, initial patients' characteristics and VTEs were subjected to univariate and multivariate analyses. Results Based on 142 patients, analyses revealed independent pejorative prognostic value of: VTEs (hazard ratio (HR)=1.49 (95% confidence interval (CI)=1.03-2.15); p=0.03), interval between PA diagnosis and metastases occurrence (HR=0.97 (95% CI=0.94-0.99), p=0.02) and ≥1 metastatic sites (HR=1.82 (95% CI=1.076-3.087), p=0.02). Conclusion VTEs are an independent factor of poor prognosis in patients with advanced PA.

Background FOLFIRINOX is a polychemotherapy regimen currently used to treat inoperable pancreatic cancer in patients with a good performance status (PS). FOLFIRINOX lengthens overall survival time (OS), but no specific data are available in elderly patients. Methods All cases of inoperable pancreatic adenocarcinoma in patients over 70 years old treated with FOLFIRINOX were retrospectively reviewed between 2008 and 2015 in five institutions in France. The primary objective was to evaluate the safety and efficacy of FOLFIRINOX in the elderly. Results Forty-two patients with a median age of 73 years (range: 70–79) and a median PS of 1 (range: 0–2) were included. 88% of patients treated with FOLFIRINOX were enrolled between 2012 and 2015. 24 patients (57%) needed a primary dose reduction but this did not impact OS (median OS 11.7 months (6.9–16.4) compared to 16.6 months (0.37–32.8) without dose reduction, p = 0.69). Twelve patients (29%) experienced grade 3 toxicity. Sensory neuropathy occurred most often (56%). Primary prophylaxis with granulocyte colony stimulating factor (GCSF) was administered to 14 patients (33%). One treatment-related death occurred (septic shock), although this patient had not had primary prophylaxis with GCSF. Median follow-up was 86 months. Median OS was 11.6 months (95%CI: 8.9–14.3). Conclusion Median OS observed in the elderly was similar to OS previously reported in younger patients in the ACCORD 11 trial. FOLFIRINOX is effective in selected, fit elderly patients but with greater grade 3 neurotoxicity. Primary dose reduction and primary GCSF prophylaxis may control tolerance.

We previously identified three clinical predictive factors of efficacy of cetuximab-irinotecan. Here, we analyzed the clinical characteristics of patients with metastatic colorectal cancer (CRC) in order to detect potent correlations with KRAS mutations.We conducted a retrospective, multicenter study between 2008 and 2012. We included patients with metastatic colorectal adenocarcinomas, previously treated by irinotecan, and with an available KRAS mutation test.We included 299 patients. The median age was 60 years; the median number of metastatic sites was 2. One hundred and eight patients (36.1%) had a previous objective response to irinotecan. The median interval between diagnosis and irinotecan discontinuation was 1.94 years. A KRAS mutation was detected in 133 patients (44.5%). In univariate and multivariate analyses, none of the assessed factors was associated with the presence of a KRAS mutation.No easily clinically assessable parameter was significantly associated with KRAS mutations in patients with colorectal cancer.

International audience; Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) has emerged as an alternative for patients with bilobar colorectal liver metastasis deemed unresectable due to inadequate future remnant liver (FRL). Nevertheless, high morbidity and mortality rates have been reported. In this setting, including hepatobiliary scintigraphy in the clinical and surgical management of patients offered ALPPS has been advocated to both assess eligibility for ALPPS stagel and suitable time for ALPPS stage2. Recently, it was stated that partial ALPPS with a liver split restricted to 50% of the transection line (or up to the middle hepatic vein in case of right extended hepatectomy) and a shortened stagel allows improving the postoperative course without precluding the inter-stages FRL hypertrophy. We describe a case series of p-ALPPS with stagel performed laparoscopically, including sequential assessments of the FRL volumes and functions via pre-stagel and pre-stage2 computed tomography volumetry and HIDA SPECT-scintigraphy. In five patients, laparoscopic p-ALPPS was associated with rapid and significant gain of remnant functional volume - much better than previously observed for ALPPS - facilitating early stage2 without inflammatory adherences. In conclusion, laparoscopic p-ALPPS is feasible and seems less aggressive than the original ALPPS technique with total transection. It may be an interesting alternative to the classical portal vein embolization (PVE) and two-stage hepatectomy strategy.

BACKGROUND: Selecting patients with 'sufficient life expectancy' for Phase I oncology trials remains challenging. The Royal Marsden Hospital Score (RMS) previously identified high-risk patients as those with >= 2 of the following: albumin upper limit of normal; >2 metastatic sites. This study developed an alternative prognostic model, and compared its performance with that of the RMS. METHODS: The primary end point was the 90-day mortality rate. The new model was developed from the same database as RMS, but it used Chi-squared Automatic Interaction Detection (CHAID). The ROC characteristics of both methods were then validated in an independent database of 324 patients enrolled in European Organization on Research and Treatment of Cancer Phase I trials of cytotoxic agents between 2000 and 2009. RESULTS: The CHAID method identified high-risk patients as those with albumin = 33 gl(-1), but platelet counts >= 400.000mm(-3). In the validation data set, the rates of correctly classified patients were 0.79 vs 0.67 for the CHAID model and RMS, respectively. The negative predictive values (NPV) were similar for the CHAID model and RMS. CONCLUSION: The CHAID model and RMS provided a similarly high level of NPV, but the CHAID model gave a better accuracy in the validation set. Both CHAID model and RMS may improve the screening process in phase I trials. British Journal of Cancer (2012) 107, 1025-1030. doi:10.1038/bjc.2012.371 www.bjcancer.com Published online 21 August 2012 (c) 2012 Cancer Research UK

Life-expectancy superior to 3 months is a key-eligibility criterion for contemporary oncology phase 1 trials. Nevertheless, there is no reliable and consensual guidance for estimating this criterion. We have conducted a systematic review of published studies investigating the risk factor for 90-day mortality and the inherent generated scores. Nine studies have been published on this topic. Only two of these prognostic models have been validated on an independent dataset. Most of the models are based on a very subjective and investigator-dependent parameter: the performance status. The predictive performance of these prognostic models is poorly evaluated.

e15134 Background: Prognosis of pts with locally advanced or metastatic PA is poor, with median survival of 6-9 months. Yet, since the use of gemcitabine, some patients survive more than one year. Recently, FOLFIRINOX regimen yielded better results in selected patients, but with more toxicity. We assessed the value of baseline predictive factors of prolonged survival in non-selected pts treated with gemcitabine. Methods: We conducted a monocentric, retrospective study (1999 to 2010) on all pts treated for locally advanced or metastatic PA. Demographical, clinical, tumoral and biological variables were included into the analysis. The primary end-point was the 12 months survival. All parameters were assessed in univariate and multivariated analyses. We then built a prognostic scoring system integrating the independent prognostic factors. Results: The study was performed on 160 pts: median age 61.1 years, sex ratio (M/F) 93/67, ECOG 0-1/2-3: 60/98, jaundice 62 (38.8%), initially resectable : 36 (22.5%), intra-pancreatic primary location: head: 110 (68.8%), body: 19 (11.9%), tail: 27 (16.9%). The adenocarcinoma was histologically document in 124 cases (77.5%). The median number of metastasis sites was 1 (71.3% liver). The median Ca 19-9 concentration was 925 IU/ml. 155 pts (96.9%) received chemotherapy, of which 124 (80.0%) with gemcitabine in first line. Fifty-two patients (32.5%) were alive 12 months after diagnosis. In univariate analysis, male gender, PS, initial stage, differentiation, primary tumor location, Ca 19-9 were prognostic factors. In multivariate analysis, male gender, head or body locations and low Ca 19-9 concentration (< 111 IU/ml) were associated with a better prognosis. The score with a cut-off between 2 and 3 points was discriminant, with positive and negative predictive values of 64.7% IC-95% [59.2-70.2] and 75.3% IC-95% [74.4-76.2], respectively. The rate of correctly classified pts was 73.6% IC-95% [72.8-74.4]. Conclusions: Male gender, pancreatic head or body location, and Ca 19-9 < 111 are independent prognostic factors for prolonged survival. Further analyses are needed to determine more accurately pts suitable for gemcitabine or the more recently validated regimen FOLFIRINOX.