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This retrospective study was undertaken to provide more modern data of real-life management of non-metastatic rectal cancer, to compare therapeutic strategies, and to identify prognostic factors of overall survival (OS) in a large cohort of patients. Data on efficacy and on acute/late toxicity were retrospectively collected. Patients were diagnosed a non-metastatic rectal cancer between 2004 and 2015, and were treated at least with radiotherapy. OS was correlated with patient, tumor and treatment characteristics with univariate and multivariate analyses. Data of 593 consecutive non-metastatic rectal cancer patients were analyzed. Median follow-up was 41 months. Median OS was 9 years. Radiotherapy was delivered in pre-operative (n = 477, 80.5%), post-operative (n = 75, 12.6%) or exclusive (n = 41, 6.9%) setting. In the whole set of patients, age, nutritional condition, tumor stage, tumor differentiation, and surgery independently influenced OS. For patients experiencing surgery, OS was influenced by age, tumor differentiation and nodal status. Surgical resection is the cornerstone treatment for locally-advanced rectal cancer. Poor tumor differentiation and node involvement were identified as major predictive factor of poor OS. The research in treatment intensification and in identification of radioresistance biomarkers should therefore probably be focused on this particular subset of patients.

Background Post-hoc analyses of AFP response and progression and their relationship with objective measures of response and survival were performed in patients from REACH. Methods Serum AFP was measured at baseline and every 3 cycles (2 weeks/cycle). Associations between AFP and radiographic progression and efficacy end points were analysed. Results Median percent AFP increase from baseline was smaller in the ramucirumab than in the placebo arm throughout treatment. Time to AFP progression (HR 0.621; P P P P = 0.0002). AFP response was higher with ramucirumab compared with placebo (P P Conclusions Treatment with ramucirumab prolonged time to AFP progression, slowed AFP increase and was more likely to induce AFP response. Similar benefits in radiographic progression and response correlated with AFP changes.

// Alexis Vallard 1 , Max-Adrien Garcia 2 , Peng Diao 3 , Sophie Espenel 1 , Guy de Laroche 1 , Jean-Baptiste Guy 1 , Majed Ben Mrad 1 , Chloe Rancoule 1 , David Kaczmarek 4 , Thierry Muron 5 , Gregoire Pigne 1 , Jack Porcheron 6 , Michel Peoc'h 7 , Jean-Marc Phelip 8 , Julien Langrand-Escure 1 and Nicolas Magne 1 1 Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, Saint Priest en Jarez, France 2 Public Health Department, Hygee Institute, Saint Priest en Jarez, France 3 Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, Sichuan Province, China 4 Department of Thoracic and Digestive Surgery, Private Loire Hospital (HPL), Saint Etienne, France 5 Department of Medical Oncology, Lucien Neuwirth Cancer Institute, Saint Priest en Jarez, France 6 Department of Digestive and Oncologic Surgery, North University Hospital, Saint Priest en Jarez, France 7 Department of Pathology, North University Hospital, Saint Priest en Jarez, France 8 Department of Hepatology and Gastroenterology, North University Hospital, Saint Priest en Jarez, France Correspondence to: Nicolas Magne, email: nicolas.magne@icloire.fr Keywords: rectal cancer; chemoradiation; neutrophil; lymphocyte; ratio Received: September 01, 2017 Accepted: March 19, 2018 Published: April 27, 2018 ABSTRACT Objective: Leukocytes are hypothesized to reflect the inflammatory tumor microenvironment. We aimed to validate their prognostic significance in a large cohort of patients treated with pre-operative radiation for locally advanced rectal cancer (RC). Results: From 2004 to 2015, 257 RC patients with available biological data underwent a pre-operative radiotherapy, with a median age of 66 years. The median rectal EQD2 was 49.2Gy. Most of patients experienced concurrent chemotherapy ( n = 245, 95.4%), mainly with 5-FU (83.3%). Clear surgical margins (i.e. complete resection) were achieved in 234 patients (91.1%). A complete (Mandard TRG1: n = 35, 13.6%) or almost complete pathological response (Mandard TRG2: n = 56, 21.8%) were achieved in 91 patients (35.4%). With a median follow-up of 46.1 months, 8 patients (3.1%) experienced local relapse, 38 (14.8%) experienced metastases and 45 (17.5%) died. Elevated pre-radiation neutrophil to lymphocyte ratio (NLR > 2.8) was identified as an independent predictive factor of increased local relapse, of decreased progression-free survival and overall survival in multivariate analysis. Elevated NLR was marginally associated with incomplete pathological response in multivariate analysis, suggesting a possible value as a biomarker of radio-sensitivity. Conclusions: Pre-radiation NLR is a simple and robust biomarker for risk stratification in locally advanced RC patients undergoing pre-operative radiotherapy, and might select the subpopulation eligible to treatment intensification or to neoadjuvant chemotherapy. Material and Methods: Clinical records from consecutive patients treated in a single institution between 2004 and 2015 with curative-intent radiotherapy were retrospectively analyzed. Classical prognosis factors of RC and peripheral immune markers based on lymphocytes and neutrophil counts were studied.

Aim The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of a second anti-TNF according to the pharmacokinetics of the first anti-TNF in patients with inflammatory bowel disease (IBD). Methods In patients in loss of response (LOR) to a first optimized anti-TNF and switched to a second anti-TNF, pharmacokinetics of anti-TNF were measured at the switch time, 30 weeks later, at the time of LOR, or at the end of the study (102 weeks). Results At the switch time, patients (n = 59) belonged to 4 groups according to the pharmacokinetics of the first anti-TNF: group 1 (n = 18), therapeutic trough levels; group 2 (n = 13) undetectable trough levels with antibodies against anti-TNF; group 3 (n = 13) without antibodies against anti-TNF; and group 4 (n = 15) subtherapeutic trough levels. After switching, the failure rates at week 30 and during the follow-up were as follows, respectively: in group 1 with therapeutic levels, 50% and 78%, despite therapeutic levels of the second anti-TNF in 83% of cases; in group 2 with undetectable levels and antibodies, 15% and 69% with undetectable levels of the second anti-TNF and antibodies in 85% of cases; in group 3 with undetectable levels without antibodies, 0% and 31% with therapeutic levels in 77% of cases; in group 4 with subtherapeutic levels, 13% and 33% with therapeutic levels in 73% of cases. Clinical remission rates were significantly lower (P ≤ 0.05) in groups 1 and 2 with therapeutic or undetectable levels with antibodies than in the 2 other groups. Conclusion In the case of LOR with therapeutic levels of the first anti-TNF or undetectable levels with antibodies, the switch to a second anti-TNF results in pharmacokinetic profile similar to the first one and again in LOR in most of the patients.

Background Yield of Endocuff-assisted colonoscopy (EAC) compared with standard colonoscopy is conflicting in terms of adenoma detection rate (ADR). A meta-analysis of randomized controlled trials (RCTs) appears necessary. Methods PubMed and Google Scholar were searched in December 2017. Abstracts from Digestive Disease Week and United European Gastroenterology Week meetings were also searched to 2017. All RCTs comparing EAC with standard colonoscopy were included. Analysis was conducted by using the Mantel–Haenszel models. Heterogeneity was quantified using the I 2 test. Results Of the 265 articles reviewed, 12 RCTs were included, with a total of 8376 patients (EAC group 4225; standard colonoscopy group 4151). In the meta-analysis, ADR was significantly increased in the EAC group vs. the standard colonoscopy group (41.3 % vs. 34.2 %; risk ratio [RR] = 1.20, 95 % confidence interval [CI] 1.06 to 1.36; P = 0.003; I 2 = 79 %), especially for operators with low-to-moderate ADRs ( 45 %): RR = 1.01, 95 %CI 0.93 to 1.09; P = 0.87; I 2 = 0.0 %). The mean number of adenomas per patient tended to be higher with EAC (mean difference = 0.11 adenomas/patient, 95 %CI – 0.17 to 0.38). Similar results were shown for polyp detection rates (61.6 % vs. 51.4 %; RR = 1.20, 95 %CI 1.06 to 1.36; P = 0.004). Use of the Endocuff did not impact the cecal intubation rate (95.1 % vs. 95.7 %; P = 0.08), or the procedure time compared with standard colonoscopy. Adverse events related to Endocuff were rare and exclusively mild mucosal erosion (4.0 %; 95 %CI 2.0 % to 8.0 %). Conclusion With moderate-quality evidence, this study showed an improvement in ADR with EAC without major adverse events, especially for operators with low-to-moderate ADRs.

International audience; BACKGROUND: Infliximab (IFX) combined with azathioprine (AZA) is more effective than IFX monotherapy in inflammatory bowel disease (IBD). AIM: To identify the AZA optimal dose that is required for efficacy when receiving combination therapy. METHODS: Patients with IBD in durable remission on combination therapy were enrolled in a 1-year, open-label, prospective trial after randomisation into three groups: AZA steady (2-2.5~mg/kg/day, n=28) vs AZA down (dose was halved 1-1.25~mg/kg/day, n=27) vs AZA stopped (n=26). Primary endpoint was failure defined as occurrence of a clinical relapse and/or any change in IBD therapy. RESULTS: Eighty-one patients were included. Five (17.9%), 3 (11.1%), and 8 (30.8%) patients experienced failure at 1~year in groups AZA steady, AZA down and AZA stopped, respectively (P=.1 across the groups). The median trough levels of IFX at inclusion were close to those measured at the end of follow-up in group AZA steady (3.65 vs 3.45~μg/mL, P=.9) and in group AZA down (3.95 vs 3.60~μg/mL, P=.5), whereas these levels dropped from 4.25 to 2.15~μg/mL (P=.02) in group AZA stopped. Four (14.3%), four (14.8%) and 11 (42.3%) patients experienced an unfavourable evolution of IFX pharmacokinetics in groups AZA steady, AZA down and AZA stopped, respectively. A threshold of 6-TGN \textless105~pmoles/8.108 RBC was associated with an unfavourable evolution of IFX pharmacokinetics. CONCLUSIONS: Under combination therapy, AZA dose reduction, but not withdrawal, appears to be as effective as continuation of AZA at full dose.

A 71-year-old man, with history of plasmacytoma in relapse since one year, was hospitalized for a initial presentation of acute pancreatitis and hepatitis. Although there was a heterogeneous infiltration around the pancreas head, the diagnosis of an extramedullary localization of his plasmacytoma was not made until later. This delayed diagnosis was due to the lack of specific radiologic features and the lack of dilatation of biliary ducts at the admission. A diagnosis was made with a simple ultrasound guided paracentesis of the low abundance ascites after a transjugular hepatic biopsy, an endoscopic ultrasound-guided fine needle aspiration of the pancreatic mass, and a failed attempt of biliary drainage through endoscopic retrograde cholangiopancreatography. In order to document the difficulty of this diagnosis, characteristics of 63 patients suffering from this condition and diagnosis were identified and discussed through a systematic literature search.

Background: Folfirinox (FFX) and gemcitabine/nab-paclitaxel (GN) are both standard first-line treatments in patients with metastatic pancreatic cancer (mPC). However, data comparing these two chemotherapeutic regimens and their sequential use remain scarce. Methods: Data from two independent cohorts enrolling patients treated with FFX ( n = 107) or GN ( n = 109) were retrospectively pooled. Primary endpoint was overall survival (OS). Progression-free survival (PFS) was the secondary endpoint. A propensity score based on age, gender, performance status (PS), and presence of liver metastases was used to make groups comparable. Results: In the whole study population, OS was significantly higher in FFX (14 months; 95% CI: 10–21) than in GN groups (9 months; 95% CI: 8–12) before ( p = 0.008) and after ( p = 0.021) adjusting for age, number of metastatic sites, liver metastases, peritoneal carcinomatosis and CA19.9 level at baseline. PFS tends to be higher in FFX (6 months) than GN groups (5 months; p = 0.053). After matching ( n = 49/group), patients were comparable for all baseline characteristics including PS. In the matched population, there was a trend toward greater OS in patients treated with FFX (HR = 0.67; p = 0.097). However, survival in each group was not solely a result of the first-line regimen. The proportion of patients who were fit for GN after FFX failure (FFX–GN sequence) was higher (46.9%) than the reverse sequence (20.4%; p = 0.01), which suggests a higher feasibility for the FFX–GN sequence. Corresponding median OS were 19 months versus 9.5 months, respectively ( p = 0.094). Conclusion: This study shows greater OS with FFX than with GN in patients with mPC. GN after FFX failure appears more feasible than the reverse sequence.

ObjectivesIn patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period.DesignConsecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn’s disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable pharmacokinetics of the second anti-TNF were defined by the appearance of undetectable trough levels of anti-TNF with high antibodies (drug-sensitive assay) or by that of antibodies (drug-tolerant assay).ResultsNinety patients (48 CDs) were included, and 45 of them received AZA after randomisation. The second anti-TNF was adalimumab or infliximab in 40 and 50 patients, respectively. Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy (p24 months). At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22 versus 77% and 22% versus 78% (pConclusionIn case of immune-mediated LOR to a first anti-TNF, AZA should be associated with the second anti-TNF.Trial registration number03580876.

Summary Background Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed. Methods We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov , number NCT01655693 . Findings Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2–34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1–10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1–11·8) in the control group (HR 1·00 [95% CI 0·78–1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group. Interpretation Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed. Funding Onxeo.

4136 Background: Circulating tumor DNA has emerged as prognostic biomarker in oncology. Many different genes can be mutated within a tumor, complicating procedures, even with highly sensitive next-generation sequencing (NGS). DNA methylation in promotor of specific genes is an early key epigenetic change during oncogenesis. Specific methylated genes could be a potential relevant cancer biomarker that may substitute for NGS panels. The aim of this study was to assess the prognostic value of Met-DNA in mPAC. Methods: Prognostic value of Met-DNA was assessed in a prospective cohort (PLAPAN) of mPAC (training cohort), correlated with NGS, then in two prospective independent validation cohorts from two randomized phase II trials (PRODIGE 35 and 37). Plasma samples were collected before chemotherapy on EDTA-coated tubes. Met-DNA was quantified using two specific markers of pancreatic DNA methylation by digital droplet PCR and correlated with prospectively registered patient (pts) characteristics and oncologic outcomes (progression free survival (PFS) and overall survival (OS)). Results: 330 patients (pts) were enrolled. 60% (n = 58) of the 96 pts of the training cohort had at least one Met-DNA marker. The correlation with NGS assessment was R = 0.93 (Pearson; p < 0.001). 59.5% (n = 100/168) and 59% (n = 39/66) of pts had detectable Met-DNA in the 2 validation cohorts. In the training cohort, Met-DNA was correlated with poor OS (HR = 1.82; 95%CI 1.07-2.42; p = 0.026). In validation cohorts, Met-DNA was a prognostic factor of PFS (HR = 1.62; 95%CI 1.17-2.25, p = 004) and OS (HR = 1.79; 95%CI 1.28-2.49, p < 0.001) in PRODIGE 35, as in PRODIGE 37: PFS HR = 1.79 (95%CI 1.07-2.99; p = 0.026) and OS HR = 2.08 (95%CI [1.18-3.68], p = 0.01), respectively. In multivariate analysis adjusted on gender, age, CA19-9 > 40UI.mL, treatment arm, number of metastatic sites and stratified on center, Met-DNA was independently associated with poor OS in both trials: HR = 1.81 (95%CI 1.10-2.98; p = 0.02) and HR = 3.62 (95%CI: 1.32-9.93; p = 0.01). Conclusions: This study demonstrates that Met-DNA is a strong independent prognostic factor in mPAC. These results argue for patient’s stratification on ctDNA status for further randomized trials. Clinical trial information: NCT02827201 and NCT02352337.

Introduction This document is a summary of the French intergroup guidelines regarding the management of metastatic colorectal cancer (mCRC) published in January 2019, and available on the French Society of Gastroenterology website (SNFGE) ( www.tncd.org ). Methods This collaborative work was realized by all French medical and surgical societies involved in the management of mCRC. Recommendations are graded in three categories (A, B and C), according to the level of evidence found in the literature, up until December 2018. Results The management of metastatic colorectal cancer has become complex because of increasing available medical, radiological and surgical treatments alone or in combination. The therapeutic strategy should be defined before the first-line treatment, mostly depending on the presentation of the disease (resectability of the metastases, symptomatic and/or threatening disease), of the patient’s condition (ECOG PS, comorbidities), and tumor biology (RAS, BRAF, MSI). The sequence of targeted therapies also seems to have an impact on the outcome (angiogenesis inhibition beyond progression). Surgical resection of metastases was the only curative intent treatment to date, joined recently by percutaneous tumor ablation tools (radiofrequency, microwave). Localized therapies such as hepatic intra-arterial infusion, radioembolization and hyperthermic intraperitoneal chemotherapy, also have seen their indications specified (liver-dominant disease and resectable peritoneal carcinomatosis). New treatments have been developed in heavily pretreated patients, increasing overall survival and preserving quality of life (regorafenib and trifluridine/tipiracil). Finally, immune checkpoint inhibitors have demonstrated high efficacy in MSI mCRC. Conclusion French guidelines for mCRC management are put together to help offer the best personalized therapeutic strategy in daily clinical practice, as the mCRC therapeutic landscape is complexifying. These recommendations are permanently being reviewed and updated. Each individual case must be discussed within a multidisciplinary team (MDT).

PURPOSE No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection. PATIENTS AND METHODS We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL. RESULTS Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001). CONCLUSION There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.

IF 3.287 (2017); International audience; IntroductionCombination of cisplatine and Gemcitabine (CisGem) is the reference 1st line Chemotherapy in patients with advanced biliary cancer. FOLFIRINOX demonstrated an overall survival superiority when compared to gemcitabine in 1st line for patients with metastatic pancreatic adenocarcinoma. Because of similarities between pancreatic and biliary cancers, we proposed a randomized trial comparing mFOLFIRINOX and CisGEm.AimPRODIGE38-AMEBICA is a phase II/III trial evaluating efficacy of modifed FOLFIRINOX (D1 bolus removed) or CisGEm on patients with locally advanced non resectable or metastatic biliary tract cancer.Patients and methodsMain inclusion criteria are histologically or cytologically proven biliary tract tumor (intra or extra hepatic or hilar or gallbladder carcinoma), measurable disease (metastases and/or primary tumor), Bilirubin

Supplemental material, SupplTab1 for Folfirinox versus gemcitabine/nab-paclitaxel as first-line therapy in patients with metastatic pancreatic cancer: a comparative propensity score study by Nicolas Williet, Angélique Saint, Anne-Laure Pointet, David Tougeron, Simon Pernot, Astrid Pozet, Dominique Bechade, Isabelle Trouilloud, Nelson Lourenco, Vincent Hautefeuille, Christophe Locher, Jérome Desrame, Pascal Artru, Anne Thirot Bidault, Bertrand Le Roy, Denis Pezet, Jean-Marc Phelip and Julien Taieb in Therapeutic Advances in Gastroenterology

15 Background: Compared to observation, maintenance therapy with a fluoropyrimidine +/- bevacizumab showed significant improvement in progression-free survival (PFS) but not in overall survival (OS) in patients with unresectable metastatic colorectal cancer (mCRC) and disease control after first-line doublet chemotherapy (CT) +/- bevacizumab. Few studies are available on the role of maintenance therapy after induction anti-EGFR-based CT, and the benefit from anti-EGFR maintenance monotherapy during CT-free intervals (CFI) in patients with RAS wild-type (wt) mCRC. Methods: RAS wt unresectable mCRC patients with controlled disease after FOLFIRI + cetuximab (8 cycles) were randomized (1:1) to receive maintenance with bi-weekly cetuximab alone (arm A) or observation (arm B) until disease progression (PD)/unacceptable toxicity/death. Randomization was stratified according to tumor response, center, baseline Köhne Score, CEA and platelet count. In case of tumor progression during the CFI, FOLFIRI + cetuximab was to be reintroduced for 8 cycles, followed by a new CFI. Tumor response was assessed per RECIST1.1 every 8 weeks. The primary objective of this multicenter non-comparative randomized phase II trial was 6-month PFS rate after initiation of maintenance therapy. A total of 134 randomized and evaluable patients (67 per arm) were required (Fleming’s one-step design, one-sided α=5%, β=20%, H0: 40%; H1: 55%). Secondary endpoints were overall response rate (ORR), time to strategy failure, PFS, OS, safety, quality of life, circulating tumor cells and circulating tumor DNA detection and dynamic changes during treatment. Results: From January 2014 to April 2019, 214 patients were included and 139 randomized (67 arm A/72 arm B) in 35 centers. Baseline characteristics were: males, 67%/69%; median age, 64/68 years; ECOG PS 0, 54%/46%; previous adjuvant therapy, 25%/14%; single metastatic site, 58%/47%; right-sided primary, 24%/18%. The ORR in the overall and the randomized population was 55% and 72%, respectively. The median follow-up was 30 months. The 6-month PFS rate after initiation of maintenance therapy was 30% 95%CI[19; 42] in the maintenance arm, and 6% 95%CI[2;14] in the observation arm, with a median PFS of 5.3 95%CI[3.7;6.5] and 2.0 95%CI[1.8;2.8] months, respectively. Any grade treatment-related toxicity, including skin rash (40%/4%), diarrhea (33%/8%), and hypomagnesemia (46%/10%) was more frequent in arm A. Conclusions: Based on the study hypothesis, the cetuximab maintenance arm did not meet the primary objective. However, the clinically meaningful difference in PFS without any overlap in the confidence intervals between the two arms warrants further investigation. Clinical trial information: NCT02404935.

Objective. The aim of this study was to investigate the feasibility and future clinical applications of near-infrared (NIR) fluorescence imaging to guide liver resection surgery for metastatic cancer to improve resection margins. Summary Background Data. A subset of patients with metastatic hepatic tumors can be cured by surgery. The degree of long-term and disease-free survival is related to the quality of surgery, with the best resection defined as “R0” (complete removal of all tumor cells, as evidenced by microscopic examination of the margins). Although intraoperative ultrasonography can evaluate the surgical margins, surgeons need a new tool to perfect the surgical outcome. Methods. A preliminary study was performed on 3 patients. We used NIR imaging postoperatively “ex vivo” on the resected liver tissue. The liver tumors were preoperatively labelled by intravenously injecting the patient with indocyanine green (ICG), a NIR fluorescent agent (24 hours before surgery, 0.25 mg/kg). Fluorescent images were obtained using a miniaturized fluorescence imaging system (FluoStic, Fluoptics, Grenoble, France). Results. After liver resection, the surgical specimens from each patient were sliced into 10-mm sections in the operating room and analyzed with the FluoStic. All metastatic tumors presented rim-type fluorescence. Two specimens had incomplete rim fluorescence. The pathologist confirmed the presence of R1 margins (microscopic residual resection), even though the ultrasonographic analysis indicated that the result was R0. Conclusions. Surgical liver resection guided by NIR fluorescence can help detect potentially uncertain anatomical areas that may be missed by preoperative imaging and by ultrasonography during surgery. These preliminary results will need to be confirmed in a larger prospective patient series.

The purpose of this study was to assess the efficacy and tolerance of induction chemotherapy combining LV5FU2 with increased doses of irinotecan adapted to UGT1A1 genotyping and cetuximab in untreated potentially resectable liver metastases of colorectal cancer.Twenty-six patients, PS 0-1, with class II hepatic metastases received chemotherapy combining irinotecan 260 mg/m(2) on day 1 for UGT1A1 6/6 and 6/7 genotypes and 220 mg/m(2) for UGT1A1 7/7 genotypes, with leucovorin on day 1, 5FU 400 mg/m(2) bolus on day 1 and continuous 5FU infusion for 46 h, and cetuximab on day 1 (day 1 = day 14). Primary prevention with lenograstim (day 5-9) was given to UGT1A1 6/7 and 7/7 genotypes. The primary endpoint was the response rate (RECIST1.1), and the secondary endpoints were tolerance (NCI-CTC criteria) and R0 resection rate.The average number of cycles per patient was 6 (±1.9). The UGT1A1 genotype was 6/6 in 34.6 %, 6/7 in 53.9 %, and 7/7 in 11.5 % of patients. At 6 cycles, 18 patients (69.2 %) presented a partial response, 5 patients (19.2 %) had stable disease, 2 patients (7.7 %) died independently of chemotherapy, and 1 patient (3.9 %) refused the treatment after 3 cycles. Four patients received 2 more cycles and the cumulative response rate at 8 cycles was 76.9 % (20/26). There was no progression. Among assessable patients (n = 23), the overall response rate was 82.6 % and 21 patients (80.7 %) had a metastasis resection. The most frequent grade 3-4 toxicities were neutropenia (31 %), diarrhea (20.8 %), and anorexia (16.4 %). There were no deaths due to toxicity.High-dose FOLFIRI combined with cetuximab yielded high response rates and enabled complete resection of class II hepatic metastases in most patients. It seemed to be well-tolerated among healthy selected patients thanks to irinotecan dose adaptation according to UGT1A1 pharmacogenomics status. This intensified chemotherapy regimen needs to be confirmed in a randomized, phase III study.

Background & Aims Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). Combining sorafenib with another treatment, to improve overall survival (OS) within an acceptable safety profile, might be the next step forward in the management of patients with advanced HCC. We aimed to assess whether a combination of sorafenib and a statin improved survival in patients with HCC. Methods The objective of the PRODIGE-11 trial was to compare the respective clinical outcomes of the sorafenib-pravastatin combination (arm A) versus sorafenib alone (arm B) in patients with advanced HCC. Child-Pugh A patients with advanced HCC who were naive to systemic treatment (n = 323) were randomly assigned to sorafenib-pravastatin combination (n = 162) or sorafenib alone (n = 161). The primary endpoint was OS; secondary endpoints were progression-free survival, time to tumor progression, time to treatment failure, safety, and quality of life. Results After randomization, 312 patients received at least 1 dose of study treatment. After a median follow-up of 35 months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7 months vs. 10.5 months; hazard ratio = 1.00; p = 0.975); no difference was observed in secondary survival endpoints either. In the univariate analysis, the significant prognostic factors for OS were CLIP score, performance status, and quality of life scores. The multivariate analysis showed that the only prognostic factor for OS was the CLIP score. The main toxicity was diarrhea (which was severe in 11% of patients in arm A, and 8.9% in arm B), while severe nausea-vomiting was rare, and no toxicity-related deaths were reported. Conclusion Adding pravastatin to sorafenib did not improve survival in patients with advanced HCC. Lay summary Sorafenib has proven efficacy for the treatment of patients with advanced hepatocellular carcinoma. However, overall survival remains poor in these patients, so we were interested to see if the addition of a statin, pravastatin, improved outcomes in patients with advanced HCC. This randomized-controlled trial demonstrated that the sorafenib-pravastatin combination did not improve overall survival in this study population compared to sorafenib alone. Clinical trial number: NCT01075555.

IF 7.191 (2017); International audience; BACKGROUND:Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.PATIENTS AND METHODS:A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI

Purpose Conflicting results are reported for maintenance treatment with bevacizumab during chemotherapy-free intervals (CFI) in metastatic colorectal cancer after induction chemotherapy. Patients and Methods In this open-label, phase III, randomized controlled trial, we compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during CFI subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. After disease progression, the induction regimen was repeated for eight cycles, followed by a new CFI. Results From March 2010 to July 2013, 491 patients were randomly assigned. Disease progression or death occurred during induction chemotherapy in 85 patients (17%); 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups; the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses of the trial. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. In the per-protocol population, defined as patients with at least one reinduction after the first progression, the median duration of the first CFI was 4.3 months in both arms; the median TCD was 17.8 and 23.3 months ( P = .339), the median PFS was 9.9 and 9.5 months, and the median OS was 27.6 and 28.5 months in the maintenance and observation groups, respectively. Multivariable analysis revealed that female gender, WHO performance status ≥ 2, and unresected primary tumors were associated with a shorter TCD. Conclusion Bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.

Background: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma (HCC). We evaluated the intravenous perfusion of doxorubicin-loaded nanoparticles (DT) in HCC patients with prior failure of sorafenib therapy. Methods: We conducted a randomized, open label, 3 parallel groups, phase-3 trial at 70 sites in 11 countries. Patients with HCC with prior one or more systemic therapies including sorafenib were randomised 1:1:1 for DT-30 mg/m2 (DT-30), DT-20 mg/m2 (DT-20) or best standard of care (BSC); stratified by performance status, Child-Pugh score, DT dosage, macrovascular invasion, extrahepatic spread, alpha-fetoprotein level, number of prior systemic lines, reason of sorafenib discontinuation, and aetiology of HCC. The primary endpoint was overall survival. This trial is registered at ClinicalTrials.gov, number NCT01655693. Findings: Between June 2012 and January 2017, 541 patients were screened, 397 randomized (DT-30=133; DT-20=130; BSC=134; population for efficacy analysis), and 376 initiated treatments (DT-30=120; DT-20=122; BSC=134; population for safety analysis). After pooling the DT-30 and DT-20 arms in the analysis, pooled DT (pDT) did not improve overall survival with a hazard ratio of 1.00 (95% CI 0.78-1.28; p=0.99); median overall survival (95%CI) was 9.1 months (8.1-10.4) for pDT versus 9.0 months (7.1-11·8) for BSC. The hazard ratio for progression-free survival was 0.95 (95% CI 0.74-1.22; p=0.70) and for time to progression 0.96 (95%CI 0.74-1.23; p=0.74). Adverse events were reported in 94% (247/263) of pDT and 75% (100/134) of BSC. The most common grade 3 or 4 treatment-emergent adverse events included (pDT; BSC) neutropenia (8% [20/242]; 5% [6/134]), asthenia (3% [6/242]; 3% [4/134]), and thrombocytopenia (1% [3/242]; 7% [9/134]). Rates of drug-related death per investigators were 1% (3/242; pDT) and 1% (2/193; BSC). Interpretation: DT doesn't show benefit on survival in HCC patients with failure on prior sorafenib treatment, but it has a comforting safety profile. Trial Registration Number: ClinicalTrials.gov, number NCT01655693 Funding: ONXEO Conflict of Interest: PM has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, BMS, and MSD. JFB has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, and BMS. JPB has received consultancy and advisory fees from Onxeo, and Bayer. GP has received consultancy and advisory fees from Bayer, AbbVie, Novartis, and Gilead. AA has received consultancy and advisory fees from AbbVie, MSD, and Gilead. IW has received consultancy and advisory fees from Janssen, AbbVie, MSD, Marcyrl, Pharco, and Gilead. NY has received consultancy and advisory fees from Halozyme, Boston Biomedical Inc., Pharmacyclics, EMD Serono, Merck, Onxeo, Regeneron, and Momenta. Ethical Approval: The trial was approved by each centre’s ethics committee or institutional review board and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable local laws.

Background and aims Colonoscopy is currently the reference method to detect colorectal neoplasia, yet some adenomas remain undetected. The water infusion technique and dying with indigo carmine has shown interesting results for reducing this miss rate. The aim of this study was to compare the adenoma detection rate (adenoma and adenocarcinoma; ADR) and the mean number of adenomas per patient (MAP) for blue-water infusion colonoscopy (BWIC) versus standard colonoscopy. Methods We performed a multicenter, randomized controlled trial in eight units, including patients with a validated indication for colonoscopy (symptoms, familial or personal history, fecal occult blood test positive). Consenting patients were randomized 1:1 to BWIC or standard colonoscopy. All colonoscopies were performed by experienced colonoscopists. All colonoscopy quality indicators were prospectively recorded. Results Among the 1065 patients included, colonoscopies were performed completely for 983 patients (514 men; mean age 59.1). The ADR was not significantly different between the groups; 40.4 % in the BWIC group versus 37.5 % in the standard colonoscopy group (odds ratio [OR] 1.13; 95 % confidence interval [CI] 0.87 – 1.48; P = 0.35). MAP was significantly greater in the BWIC group (0.79) than in the standard colonoscopy group (0.64; P = 0.005). For advanced adenomas, the results were 50 (10.2 %) and 36 (7.3 %), respectively (P = 0.10). The cecal intubation rate was not different but the time to cecal intubation was significantly longer in BWIC group (9.9 versus 6.2 minutes; P Conclusion Despite the higher MAP with BWIC, the routine use of BWIC does not translate to a higher ADR. Whether increased detection ultimately results in a lower rate of interval carcinoma is not yet known.Clinical trials registration: EudraCT 2012-A00548 – 35; NCT01937429.

Introduction Use of sorafenib remains debated in elderly patients treated for advanced hepatocellular carcinoma (HCC). Methods This was a bicentric retrospective study including all patients ≥75 years and treated with sorafenib for advanced HCC between January 2010 and March 2014. Results Of the 51 patients included (median age: 78 years, range: 75–92; performance status (PS) 0–1: 98%; cirrhosis: 88.2%; Child–Pugh A: 95.6%) all experienced at least one adverse event (AE). About 2/3 of them (66.7%) had grade 3–4 toxicities, including fatigue (43.1%), hand foot skin syndrome (11.8%), anorexia (9.8%) or diarrhea (9.8%). After adjustment for arterial hypertension, heart failure, other(s) cardiovascular history(ies), and sorafenib dose at baseline, only patients ≥80 years were associated with severe AE (OR: 13.3; p = 0.009). Discontinuation for toxicity was reported in 31 (60.8%) patients, mainly within the 3rd months, especially in those who had PS ≥1 at baseline (OR: 10.4; p = 0.01), or other cardiovascular histories (OR: 30.9; p = 0.016). In this setting, overall survival was significantly reduced (HR: 4.5; p Conclusion Tolerance of Sorafenib seems to be low in elderly, especially for patients aged ≥80 years or with PS ≥1. Starting with reduced dose of sorafenib does not seem to impact results. Some of these patients may truly benefit from the treatment in terms of survival.

The efficacy and safety of treating elderly patients with colorectal cancer (CRC) is of concern. This study aimed to compare the short- and long-term outcomes of elective laparoscopic vs. open surgery to treat CRC in very elderly patients.All patients aged80 years and who had undergone a colectomy for CRC without metastasis between July 2005 and April 2012 were considered for inclusion. Demographic, clinical, operative, and postoperative data, plus overall and disease-free survival rates, were retrospectively collected and compared between two groups of patients that underwent an open procedure (OP group) or laparoscopy (LG).123 patients were enrolled (55 OPG, 68 LG). Median age was similar between the groups (84 vs. 83 years, respectively; NS). Duration of surgery was significantly lower in OPG (170 vs. 200min; p=0.030). Overall mortality at 3 months was 8.3%: it tended to be greater in the OPG (16.5% vs. 1.5%, NS). Morbidity was significantly greater in the OPG compared to the LG (52.7% vs. 27.5%; p=0.021), resulting in significantly longer hospital stay (12 vs. 8 days, respectively; p0.001). Pathological findings were similar between the two groups. Cumulative overall survival rates at 3 and 5 years were significantly greater after laparoscopy (85% and 72%) compared to open surgery (58.2% and 48%, respectively; p0.001).Our study suggests that laparoscopy is safe and could increase overall survival compared to open surgery in elderly patients suffering from CRC.This retrospective study compared the short- and longer-term outcomes of patients aged80 years and undergoing elective laparoscopic or open surgery for CRC between 2005 and 2012.

International audience; OBJECTIVES:Several decision algorithms based on the measurement of infliximab (IFX) trough levels and antibodies to IFX have been proposed. Whether such algorithms can be extrapolated to the pharmacokinetics of adalimumab (ADA) has yet to be determined.METHODS:A prospective study included all consecutive patients with inflammatory bowel disease (IBD) having a disease flare while being on ADA 40 mg every 2 weeks were included. All patients were primary responders to ADA therapy and were anti-tumor necrosis factor (TNF) naive. ADA trough levels and antibodies against ADA (AAA) were measured blinded to clinical data (Elisa LISA-Tracker, Theradiag). All patients were optimized with ADA 40 mg weekly. Four months later, in the absence of clinical remission (CR; Crohn's disease activity index 4.9 μg/ml; group B, ADA10 ng/ml.RESULTS:A total of 82 patients were included (55% CD; mean age=43 years, disease duration=7.4 years, duration of ADA therapy=17 months). After optimization of ADA treatment, 29.2% of patients achieved CR in group A (N=41), 67% in group B (N=24), and 12% in group C (N=17; P4.9 μg/ml are associated with failure of two anti-TNF agents (ADA and IFX) in 90% of cases, and switching to another drug class should be considered.

3575 Background: BRAF mutations are present in 5-15% of mCRC. V600E BRAF mutations account for ~80% of cases and are mostly found in right-sided tumors. Non-V600E BRAF mutations are rare (~2% of mCRC), mostly left-sided. Although BRAF V600E mutations are associated with a dismal prognosis, some studies suggest that non-V600E BRAF mutations may be associated with a favorable outcome. The chemosensitivity of non-V600E BRAF-mutated mCRC has never been studied. Methods: From 2017 to 2018, all consecutive patients (pts) with non-V600E BRAF-mutated mCRC (next generation sequencing) treated in the participating centers were included. Survival analyses were performed using Kaplan-Meier method and LogRank test. Results: A total of 108 pts in 34 centers in France were included between October 2017 and August 2018 (median age, 66 years [range, 58-77]; ECOG performance status 0-1, 86%). The primary was mostly left-sided (66%). Main metastatic sites were the liver (73%), lungs (33%), lymph nodes (39%) and peritoneum (26%). D594 (34%), G469 (15%), K601 (11%), N581 (7%) and L597 (7%) were the most frequent mutations. A concomitant RAS mutation was found in 22% of pts. Microsatellite instability (MSI) was found in 3/67 pts (4.5%). First-line chemotherapy (CTx) (n = 69) efficacy was (overall response rate/disease control rate) 49%/77% (anti-EGFR-containing CTx [n = 20], 75%/85%; antiangiogenic-containing CTx [n = 22], 55%/73%). Median overall survival (mOS) was 25.6 months (95% CI : 17.1-43.8) overall; it was 8.0 months with best supportive care alone (n = 10), 16.0 months with palliative CTx alone (n = 63), and attained 105.1 months with curative-intent management of metastases (n = 35). mOS did not differ according to sidedness (p = 0.22), type of mutation (p = 0.52), or its functional impact on BRAF (p = 0.19). Conclusions: Non-V600E BRAF-mutated mCRC retain sensitivity to CTx + biologics and harbor a good prognosis (especially when amenable to curative-intent surgery), regardless of the type of mutation and its impact on BRAF kinase function. Contrarily to BRAF V600E mutations, non-V600E mutations may occur along with RAS mutations, but uncommonly with MSI.

Colorectal cancer (CRC), the most common digestive cancer in rance, is a major public health problem. There are an estimated 0,000 new cases every year and 200,000 prevalent cases [1]. Its ncidence has increased by more than 50% over the past 20 years 24,000 new cases/year in 1980, 36,600 in 2000). On the other and, over the same period, the number of deaths has remained table (16,000 deaths in 2000), which reflects a major therapeutic rogress [2,3]. Around 75% of patients may benefit from surgical resection ith curative intent [4]. Among them, nearly 30% stage II and over 5% stage III patients present a loco-regional or distant recurrence r a metachronous cancer within 5 years of initial treatment [5]. his high risk of recurrence raises the question of postoperative onitoring in order to detect early recurrences and metachronous ancers at a curable stage. The annual incidence of adenomas is between 3 and 5%, and the umulative risk of metachronous cancer is 2% at 5 years and 7% t 20 years. Endoluminal recurrences and metachronous cancers re rare, therefore intensive endoscopic monitoring is not useful 5,6]. After resection of CRC, the French national thesaurus of good ractices in digestive cancer (TNCD) [7] recommends a colonoscopy ithin 6 months after surgery (if incomplete or of poor quality efore surgery), followed by another at 3 years and then every 5 ears in case of normal results. After excision of more than 3 adeomas or of one at-risk adenoma (size > 1 cm, villous contingent, igh grade dysplasia or in situ carcinoma), the first colonoscopy is erformed after 1 year.

Background Data on the value of therapeutic drug monitoring of infliximab (IFX) to predict mucosal healing (MH) in inflammatory bowel diseases (IBD) are scarce. Methods All consecutive patients with IBD receiving ongoing IFX (5 mg/kg) treatment and developing secondary failure to IFX were enrolled in a prospective study between June 2010 and May 2011. IFX trough levels, antibodies to IFX concentrations, C-reactive protein levels, and fecal calprotectin were measured before IFX optimization and at week 8. A proctosigmoidoscopy was performed on the day of first IFX optimization and at week 8 in all patients with ulcerative colitis (UC). MH was defined by fecal calprotectin 0.5 μg/mL was associated with MH (sensitivity [se], 0.88; specificity [sp], 0.77; P = 0.0001, area under the receiver operating characteristic curve, 0.89). On multivariate analysis, the only factor associated with MH after IFX optimization was a delta IFX >0.5 µg/mL (likelihood ratio = 2.02; 95% confidence interval, 1.01–4.08; P = 0.048) in patients with IBD. Conclusions Therapeutic drug monitoring of IFX strongly predicts the likelihood of achieving MH following IFX dose intensification in both CD and UC.

The best noninvasive method predicting clinical relapse remains undetermined in infliximab (IFX)-treated patients with Crohn's disease.All patients with CD on IFX maintenance treatment and in clinical remission for at least 16 weeks, between 2011 and 2014, were enrolled in a prospective single-center study. The Crohn's Disease Activity Index (CDAI), fecal calprotectin, C-reactive protein levels, antibodies (ATI), and trough level (TLI) of IFX were measured at every IFX infusion. The best thresholds of TLI (2 versus 3 μg/mL) and calprotectin (50 versus 250 μg/g stools) were identified across four logistic regression models.One hundred nineteen patients (mean age: 34 ± 12 yrs, mean disease duration: 7.8 yrs) were included. Mean follow-up was 20.4 months, and 17% of the patients were on IFX and azathioprine at inclusion. During follow-up, 37 patients (31.1%) relapsed, 78% within the first 6 months. The clinical characteristics of the relapsed and nonrelapsed patients were similar. After logistic regression, fecal calprotectin250 μg/g stools (OR: 4.09; 95% CI, 1.01-16.21; P = 0.049) and TLI2 μg/mL (OR: 14.85; 95% CI, 3.67-60; P0.0001) were associated with loss of response. A training cohort of 55 patients was isolated randomly to implement prediction rules for loss of response. The best predictive rules were the combination of a TLI2 μg/mL and a fecal calprotectin level250 μg/g stools (78.3%). These rules were validated on a test cohort of 64 patients with an accuracy of 87%, (sensitivity = 0.94, specificity = 0.84, positive predictive value = 0.73, and negative predictive value = 0.97).In IFX-treated patients with CD in clinical remission, a combination of TLI (2 μg/mL) and fecal calprotectin (250 μg/g of stools) is a good model for predicting loss of response. In contrast with previous data, low TLIs ranging from 2 to 3 μg/mL should neither systematically lead to the optimization of IFX use nor a switch in the treatment.

Randomized trials have shown a survival benefit for regorafenib over placebo in patients with metastatic colorectal cancer (mCRC) that progressed after standard therapies. We evaluated survival and safety outcomes in patients treated with regorafenib in a real-life setting.REBECCA is a cohort study nested within a compassionate use program designed to evaluate survival, safety, and potential prognostic factors for outcome associated with regorafenib in patients with mCRC refractory to standard therapies. Treatment effects according to various patient and tumour characteristics were evaluated using univariate and multivariate Cox proportional hazards regression models.Of 1178 patients in the compassionate use program, 654 were in the full analysis set. Median follow-up was 16.5 months. Median survival was 5.6 months. The 12-month survival rate was 22 %. Survival was independently and unfavourably affected by the following variables: poor performance status, short time from initial diagnosis of metastases to the start of regorafenib, low initial regorafenib dose,3 metastatic sites, presence of liver metastases, and KRAS mutations. We identified prognostic groups of patients with low, intermediate, and high risk of death, with a median survival of 9.2, 5.2, and 2.5 months, respectively. Five-hundred-twenty-four patients (80 %) experienced at least one regorafenib-related adverse event, most commonly, fatigue, hand-foot skin reaction, diarrhea, anorexia, arterial hypertension, and mucositis.The safety and efficacy profile of regorafenib in REBECCA are similar to those in randomized trials. Our prognostic model identified subgroups of mCRC patients who derived a minimal and maximum benefit from regorafenib.Clinicaltrials.gov NCT02310477 .

International audience; BACKGROUND & AIMS: We investigated whether serum trough levels of vedolizumab, a humanized monoclonal antibody against integrin α4β7, during the induction phase of treatment can determine whether patients will need additional doses (optimization of therapy) within the first 6 months. METHODS: We conducted an observational study of 47 consecutive patients with Crohn's disease (CD; n~= 31) or ulcerative colitis (UC; n~= 16) who had not responded to 2 previous treatment regimens with antagonists of tumor necrosis factor and were starting therapy with vedolizumab at 2 hospitals in France, from June 2014 through April 2016. All patients were given a 300-mg infusion of vedolizumab at the start of the study, Week 2, Week 6, and then every 8 weeks; patients were also given corticosteroids during the first 4-6 weeks. Patients not in remission at Week 6 were given additional doses of vedolizumab at Week 10 and then every 4 weeks (extended therapy or optimization). Remission at Week 6 of treatment was defined as CD activity score below 150 points for patients with CD and a partial Mayo Clinic score of \textless3 points, without concomitant corticosteroids, for patients with UC. Blood samples were collected each week and serum levels of vedolizumab and antibodies against vedolizumab were measured using an enzyme-linked immunosorbent assay. Median trough levels of vedolizumab and interquartile ranges were compared using the nonparametric Mann-Whitney test. The primary objective was to determine whether trough levels of vedolizumab measured during the first 6 weeks of induction therapy associated with the need for extended treatment within the first 6 months. RESULTS: Based on response to therapy at Week 6, extended treatment was required for 30 of the 47 patients (23 patients with CD and 7 patients with UC). At Week 2, trough levels of vedolizumab for patients selected for extended treatment were 23.0 μg/mL (interquartile range, 14.0-37.0 μg/mL), compared with 42.5 μg/mL in patients who did not receive extended treatment (interquartile range, 33.5-50.7; P~= .15). At Week 6, trough levels of vedolizumab \textless18.5 μg/mL were associated with need for extended therapy (100% positive predictive value, 46.2%; negative predictive value; area under the receiver operating characteristic curve, 0.72) within the first 6 months. Among patients who required extended treatment at Week 10, all of those with trough levels of vedolizumab \textless19.0 μg/mL at Week 6 had achieved clinical remission 4 weeks later (secondary responders). CONCLUSIONS: In a prospective study of patients with CD or UC receiving induction therapy with vedolizumab, low trough levels of vedolizumab at Week 6 (\textless19.0 μg/mL) are associated with need for additional doses (given at Week 10 and then every 4 weeks). All patients receiving these additional doses achieved a clinical response 4 weeks later.

Randomized trials have shown a survival benefit for regorafenib over placebo in patients with metastatic colorectal cancer (mCRC) that progressed after standard therapies. We evaluated survival and safety outcomes in patients treated with regorafenib in a real-life setting. REBECCA is a cohort study nested within a compassionate use program designed to evaluate survival, safety, and potential prognostic factors for outcome associated with regorafenib in patients with mCRC refractory to standard therapies. Treatment effects according to various patient and tumour characteristics were evaluated using univariate and multivariate Cox proportional hazards regression models. Of 1178 patients in the compassionate use program, 654 were in the full analysis set. Median follow-up was 16.5 months. Median survival was 5.6 months. The 12-month survival rate was 22 %. Survival was independently and unfavourably affected by the following variables: poor performance status, short time from initial diagnosis of metastases to the start of regorafenib, low initial regorafenib dose, >3 metastatic sites, presence of liver metastases, and KRAS mutations. We identified prognostic groups of patients with low, intermediate, and high risk of death, with a median survival of 9.2, 5.2, and 2.5 months, respectively. Five-hundred-twenty-four patients (80 %) experienced at least one regorafenib-related adverse event, most commonly, fatigue, hand-foot skin reaction, diarrhea, anorexia, arterial hypertension, and mucositis. The safety and efficacy profile of regorafenib in REBECCA are similar to those in randomized trials. Our prognostic model identified subgroups of mCRC patients who derived a minimal and maximum benefit from regorafenib. Clinicaltrials.gov NCT02310477 .

International audience; BACKGROUND:Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients.PATIENTS AND METHODS:Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2-irinotecan or simplified LV5FU2-irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2-irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR).RESULTS:From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2-irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75-92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66-1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67-1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75-1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55-0.92). More patients presented grade 3-4 toxicities in IRI (52.2% versus 76.3%).CONCLUSION:In this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2.CLINICALTRIALSGOV:NCT00303771.

Resume Introduction Le but de cette etude etait de determiner si l’existence d’un diabete avait une influence sur les manifestations cliniques et le pronostic du cancer du pancreas (CP). Patients et methodes Nous avons analyse retrospectivement les dossiers de 122 patients ayant un CP. Les patients ont ete repartis en deux groupes, ceux ayant un diabete (56 cas) et ceux n’ayant pas de diabete (66 cas). Les donnees demographiques, les manifestations cliniques du CP, les caracteristiques de la tumeur et le temps de survie ont ete compares entre les deux groupes de patients. Resultats L’âge moyen des patients, le pourcentage d’hommes, l’indice de masse corporelle au diagnostic, la prevalence de l’hypertension arterielle, de la dyslipidemie, la consommation du tabac, la prevalence de l’amaigrissement, des douleurs abdominales, des douleurs lombaires et des signes de dyspepsie etaient similaires dans les deux groupes, de meme que l’histologie et la taille de la tumeur. Le cancer etait situe dans la tete du pancreas chez 50 % des patients diabetiques contre 80 % chez les non-diabetiques ( p = 0,04). Le temps moyen de survie etait similaire. Conclusion Les manifestations cliniques, la taille de la tumeur et le pronostic du CP ne sont pas differents chez les patients diabetiques comparativement aux patients non diabetiques. La presence du diabete ne semble pas favoriser un diagnostic precoce du CP.

Purpose Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma. Although the 5-fluorouracil (5FU), folinic acid and cisplatin combination (LV5FU2-CDDP) is an option, the optimal order of the regimens must be determined. The first strategic phase III trial comparing LV5FU2-CDDP followed by gemcitabine versus gemcitabine followed by LV5FU2-CDDP was conducted. Methods Patients with metastatic pancreatic adenocarcinoma, performance status (PS) 0–2, without prior chemotherapy were randomly assigned (1:1) to receive either LV5FU2-CDDP followed by gemcitabine at disease progression or toxicity (Arm A), or the opposite sequence (Arm B). 202 patients had to be included and 170 deaths had to be observed to detect an expected improvement in median overall survival (OS) from 6.5 to 10 months in Arm A (two-sided α = 5% and β = 20%). Results 202 patients were included (Arm A, 102; Arm B, 100). Median age, male/female ratio, PS 0–1 and previous surgery were similar in the two arms. After a median follow-up of 44 months, median OS in Arm A was 6.6 months versus 8.0 months in Arm B (p = 0.85). Median progression-free survival was similar between Arms A and B. More grade 3/4 toxicities were observed when LV5FU2-CDDP was administered as a first-line treatment compared with gemcitabine: 79% versus 64% (p = 0.018). Conclusion This trial did not show any strategic advantage to using LV5FU2-CDDP as a first-line treatment and suggests that gemcitabine remains the standard first-line treatment. Sixty-one per cent of patients were able to receive a second line of chemotherapy.

e16221Background: Aim of our study was to assess the interest of induction chemotherapy (ICT) intensification before chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer Meth...

4000Background: Metastatic pancreatic cancer (mPC) still harbors a dismal prognosis (5-year overall survival [OS]

Background Adjuvant chemotherapy for stage II colon cancer is a controversial practice and is not recommended by the French Consensus Conference outside of therapeutic trial. Objective To assess, within a well-defined population, the influence of hospital characteristics in this practice. Patients and methods In the Rhone-Alpes region (10% of the French population), 534 patients presenting with colon cancer stage II were operated on in 81 hospitals in the year 2000. The influence of hospital characteristics on the use of adjuvant chemotherapy was assessed using a multivariate logistic regression. Results Overall, 19.5% of patients received adjuvant chemotherapy. Younger age, T4 tumour, hospital volume lower than 20 colon cancer surgeries [odds ratio (OR) 2.96; P