Background:Despite decreasing colon cancer (CC) incidence worldwide, an inverse trend is being registered since the late 1990s in people <50 years old, possibly due to an increasing exposure to lifestyle-related risk factors/exposome. Early-onset CC (EOCC) typically manifests in more advanced stages and may harbor a distinct genetic profile. However, its prognosis remains controversial, and disease stratification through gene expression-based subtyping could potentially provide insight. Materials and methods:We collected data from stage III CC patients enrolled in PETACC-8 and IDEA-France and we analyzed them according to a cut-off of 50 years of age, defining EOCC and late-onset CC (LOCC). Molecular analyses were carried out to evaluate mismatch repair deficiency (dMMR) and extended genetic profile. RNA-sequencing analyses were carried out to determine consensus molecular subtypes (CMS). Results:A total of 2607 LOCC and 366 EOCC were included. When compared to LOCC, EOCC were in better general conditions and presented more advanced-stage diseases. EOCC were more often dMMR, CMS1, RAS wild-type, and mutated for PTEN, CTNNB1, ERBB2, and DDR2. Relapse-free survival (RFS) was similar in the two age groups (3-year rate 74% versus 76%), but differences were observed according to CMS. In CMS1, a better RFS was observed in mismatch repair-proficient (pMMR) EOCC versus LOCC (3-year rate 82% versus 63%, P = 0.041), while this was not observed in dMMR CMS1. Conclusions:In conclusion, EOCCs are diagnosed in more advanced stages, are more often dMMR, harbor a specific genetic profile, and have similar RFS when compared to LOCC, even if the age effect on RFS appeared to vary among CMS groups.

Nearly half of patients (pts) with CRC are over 70 years old in clinical practice. STRATEGIC-1 compared FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab (Arm A) to OPTIMOX-bevacizumab followed by FOLFIRI-bevacizumab and EGFR monoclonal antibody +/- irinotecan (Arm B) in pts with previously untreated RAS/BRAF wild-type unresectable mCRC. To elucidate the impact of age on treatment efficacy, we evaluated duration of disease control (DDC) and overall survival (OS). A subgroup analysis of pts ≥70 years old was preplaned. Pts were divided into two age groups, <70 and ≥70 years, at the time of diagnosis. DDC and OS were expressed by the Kaplan-Meier method and compared by log-rank testing and Cox regression. In the general population (N=263), 187 pts (71%) and 76 pts (29%) were <70 and ≥70 years old, respectively. In Arm A (N=131) and in Arm B (N=132), 35 pts (27%) and 41 pts (31%) were ≥70 years old, respectively. Subgroup analysis showed that age had similar prognostic value in terms of DDC (22.0 months in younger vs 25.3 months in elderly [HR=0.91, 0.66-1.25; P=0.553]) and OS (36.5 months vs 34.9 months [HR=1.08, 0.78-1.48; P=0.648], respectively). Although OS was significantly improved in Arm A (HR=1.45, 1.02-2.08; P=0.039) in <70 pts, median OS was better in Arm B in ≥70 pts (42.1 vs 33.7 months; but statistically non-significant [P=0.161]). The effect of age on the treatment efficacy is shown in Table.Table: 390PPts <70 yearsPts ≥70 yearsArm AArm BHR (95%CI)PArm AArm BHR (95%CI)PNo.96913541DDC, median (months)22.820.91.05 (0.75-1.48)0.76422.528.90.83 (0.48-1.42)0.483OS, median (months)42.631.71.45 (1.02-2.08)0.03933.742.10.90 (0.53-1.53)0.161 Open table in a new tab These results confirm the polychemotherapy regimens efficiency associated to targeted therapies despite of the age, but elderly were underrepresented in trial compared to real life. The best choice of first-line chemotherapy in older pts remains unclear. The COLAGE GERCOR study, assessing the quality of life in elderly treated by FOLFOX-bevacizumab vs the standard first-line treatment (capecitabine-bevacizumab), and further studies are needed to better target elderly with mCRC.

Aims To evaluate the clinical outcomes of patients affected by bile duct cancers (BDC) involving the liver hilum treated with EUS-guided hepaticogastrostomy (EUS-HGS).

Colon adenocarcinoma occurs mainly in older patients (pts). Oxaliplatin based adjuvant chemotherapy has demonstrated an improvement on disease-free survival (DFS) after a stage III colon cancer resection in young pts. Nevertheless, the benefit of adjuvant chemotherapy is matter of debate in old pts.

Histological growth characteristics at the invasive front may reflect tumor aggressiveness. Specifically, tumor budding (TB), defined as single cancer cells or cluster comprising less than five cells and representing the dynamic process of epithelial-mesenchymal transition, is listed among prognostic markers in colon cancer (CC). However, its use for a better disease stratification needs to be further explored. Its prognostic role was thus evaluated in a phase III trial investigating 3 vs 6 months of oxaliplatin-based adjuvant treatment in stage III CC patients.

Neuroendocrine Carcinomas (NECs) are a distinct family of poorly differentiated morphology, sharing molecular, clinical and outcome characteristics. No standard-of-care exists after the failure of first-line platinum-based chemotherapy (CT) regimens. Nivo±ipi has been reported to provide survival benefit versus standard CT in metastatic solid cancers. GCO-001 NIPINEC is a multicenter, non-comparative, randomized (1:1) phase 2 trial with a two-step design (early stopping for futility after 50% of accrual). Main inclusion criteria were histologically proven NEC (large- and small-cell for gastroenteropancreatic (GEP) NECs, and large-cell for lung NECs), in 2nd or 3rd line refractory to platinum-based CT, and PS 0-2. Patients received nivo 3 mg/kg q2w ± ipi 1 mg/kg q6w, for 2 years or until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) at 8 weeks assessed by investigators (power of 90%, alpha risk at 5% two-sided). Other endpoints included progression-free survival (PFS), overall survival (OS) and safety. NCT number: NCT03591731. From Dec 2018 to Mar 2021, 185 patients (93 GEP and 92 lung) were enrolled in 50 centers. Median age was 64.4 years (range 26.4–87.1), 71% males, 70% smokers, 91% with ECOG PS 0 or 1, 24% with asymptomatic brain metastases. 170 (92%) patients were evaluable for the primary endpoint. ORR at 8 weeks was 7.2% (95%CI [2.7-15.1]) with nivo and 14.9% (95%CI [8.2-24.2]) with nivo+ipi. Median PFS was 1.8 months (95%CI [1.7-2.0]) with nivo and 1.9 months (95%CI [1.6-2.1]) with nivo+ipi. Median OS was 7.2 months (95%CI [3.7-14.1]) with nivo and 5.8 months (95%CI [3.3-7.6]) with nivo+ipi. 3 patients (3.5%) and 7 patients (8.9%) experienced treatment discontinuation because of toxicity with nivo and nivo+ipi respectively. 2 treatment-related deaths were observed with nivo (meningoencephalitis and pneumonitis). Most frequent grade ≥ 3 AEs were asthenia (7.3%), anaemia (6.3%) and alkaline phosphatase increased (5.8%). Nivo+Ipi only reached the primary endpoint in 2nd/3rd line NECs pts with acceptable toxicity.

Combination chemotherapy (CT) with cisplatin and gemcitabine (CISGEM) is the first-line standard of care for patients with advanced biliary tract cancers (BTC). FOLFIRINOX demonstrated an overall survival (OS) improvement in metastatic pancreatic adenocarcinoma compared to gemcitabine monotherapy. We aimed to compare FOLFIRINOX to CISGEM in advanced BTC. This open-label, randomized phase II-III study was carried out in 43 French centers. Patients with locally advanced (unresectable) or metastatic BTC, ECOG PS 0-1, were randomly assigned (1:1 ratio) to receive either modified FOLFIRINOX (mFOLFIRINOX, without 5FU bolus at day 1) or CISGEM for 6 months. The primary endpoint in phase II was the progression-free survival rate at 6 months (PFS6) according to RECIST v1.1. 94 patients per arm were needed to test the H1 hypothesis that PFS6 was ≥ 60% (one-sided alpha=5%, power=85%, 73% is expected). 190 patients were randomized (mFOLFIRINOX, 94; CISGEM, 96). Among them, 185 were evaluable (modified intention to treat population, mITT) for the primary endpoint (n=92 and 93, respectively). After a median follow-up of 21 months, the primary endpoint was not reached in the mFOLFIRINOX arm, with a PFS6 of 44.6% [90%CI: 35.7-53.7]. Median PFS (mITT) was 6.2 months [95%CI: 5.5-7.8] in the mFOLFIRINOX arm versus 7.4 months [95%CI: 5.6-8.7] in the CISGEM arm. Median OS was 11.7 months [95%CI: 9.5-14.2] versus 14.3 months [95%CI: 11.3-16.5] respectively. The disease control rates were 66.2% and 69.9% respectively (mainly stable disease). Rates of grade 3-4 adverse events were similar in the mFOLFIRINOX (72.8%) and CISGEM (72.0%) arms, mainly digestive (28.3% vs. 12.9%) and hematologic (32.6% vs. 57.0%). First-line chemotherapy with mFOLFIRINOX did not meet the primary endpoint. CISGEM remains the first-line standard of care for advanced BTC.

Background Half of patients newly diagnosed with esophagus squamous cell cancer (ESCC) has a metastatic ESCC (mESCC) and half of patients with initial loco-regional disease presents disease recurrence after surgery and/or chemoradiation. Although not validated by a phase III trial, first-line palliative chemotherapy combines fluoropyrimidine with platinum salt. Patients with disease progression after platinum-based chemotherapy and good performance status may benefit from a second-line chemotherapy. Based on phase I/II trials or retrospective studies, the most commonly used regimens in second-line setting of mESCC are paclitaxel monotherapy or irinotecan monotherapy or combined with 5FU (FOLFIRI). Up to now, there is no randomized trial available. Trial design OESIRI is a multicenter, open-label, randomized phase II trial designed to evaluate efficacy and safety of nanoliposomal irinotecan (NalIRI) plus 5FU versus paclitaxel as second-line therapy in mESCC. Main inclusion criteria are histologically proven mESCC after failure of first-line platinum-based chemotherapy and WHO performance status ≤ 2. Patients initially treated by surgery and chemotherapy or definitive chemoradiation are eligible if relapse occurred less than 6 months after the end of the treatment. In the experimental arm, patients will receive, every 14 days, intravenous (IV) infusion of NalIRI (80 mg/m2) followed by 5FU (2400 mg/m2 over 46 h). In the control arm, patients will receive at days 1, 8 and 14 of a 28 days-cycle, an IV infusion of paclitaxel (80 mg/m2). The primary objective is to evaluate the percentage of patients alive 9 months after randomisation. The clinical hypotheses are to extent the 9-months survival rate from 40% to 60%. With a one-sided type one error α of 5%, a power of 85%, a 5% rate of patients lost to follow-up, 53 patients per arm (n = 106) will be randomized. Secondary endpoints are progression-free survival, overall survival, response rate, safety and quality of life. Circulating tumor DNA will be monitored to assess its predictive value of response to treatment. Inclusions started in January 2019 and theoretical end of recruitment is January 2022. Legal entity responsible for the study Federation Francaise de Cancerologie Digestive. Funding Servier. Disclosure All authors have declared no conflicts of interest.

Background ctDNA has been recently suggested as a major prognostic factor in resected stage II and III colon cancer patients (pts)1,2. Its predictive value for adjuvant treatment intensity or duration is currently unknown. We have analyzed here ctDNA from pts enrolled in the IDEA-FRANCE trial3, its prognostic value and its predictive value for treatment duration (3 or 6 months). Methods ctDNA was tested by using the detection of 2 methylated markers (WIF1 and NPY) by digital droplet PCR accordingly to a method developed and validated for colorectal cancer 4-6. Comparisons for pts and tumour characteristics and DFS will be done between the ctDNA tested pts and the full study population and between ctDNA positive and negative pts. DFS has been analyzed in the 6 and 3M treatment arms according to ctDNA results. Subgroup analyses for high- and low-risk pts were pre-planned. Results Of the 1345/2010 pts that consented to the IDEA translational research program, with available blood sample for ctDNA testing, 805 have been sampled before chemotherapy start and fully analyzed. More PS 0 (77% vs 71%) and more T4 and/or N2 (28% vs 23%) were observed in the 805 pts studied here than in the 1205 pts left. 696 pts were found ctDNA- and 109 ctDNA + (13.5%). ctDNA+ pts were more often T4, poorly differentiated and with tumour perforation. 2-year DFS was 64% vs 82% in ctDNA+ and – pts, respectively (HR :1.75 (95%CI 1.25-2.45) p = 0.001). In multivariate analysis including Age, Gender, MSI, perforation, T stage, N stage and treatment arm, ctDNA was confirmed as an independent prognostic marker (adj.HR: 1.85 (95%CI 1.31 to 2.61) p Conclusions In this first ctDNA assessment on a large series coming from a phase III clinical trial we found 13.5% of pts with ctDNA post-surgery. ctDNA was confirmed as an independent prognostic marker. In this series, 6 months of treatment seems better in both ctDNA+ and- pts. [1]Tie J, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer.Sci Transl Med. 2016 Jul 6;8(346):346ra92. [2]Scholer LV, et al. Clinical Implications of Monitoring Circulating Tumor DNA in Patients with Colorectal Cancer. Clin Cancer Res. 2017 Sep 15;23(18):5437-5445. [3] Andre T, et al.Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, phase III Trial.J Clin Oncol. 2018 May 20;36(15):1469-1477. [4] Garrigou S, et al. A Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer Biomarker. Clin Chem. 2016;62:1129-1139. [5] Garlan F, et al. Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study). Clin Cancer Res.2017;23:5416-5425. [6] Bachet JB, et al. RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study. Ann Oncol. 2018May 1;29(5):1211-1219. Clinical trial identification NCT00958737. Legal entity responsible for the study Gercor-Prodige. Funding Clinical trial: INCa, GERCOR; Translational project: ARC (Association de Recherche contre le Cancer, Paris, France). Disclosure J. Taieb: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: pierre fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi. D. Vernerey: Honoraria (self), Advisory / Consultancy: HalioDX; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Janssen. J. Bennouna: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background: FOLFIRI (5FU/leucovorin/irinotecan) + aflibercept significantly improves median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients (pts) with previously treated metastatic colorectal cancer (mCRC). The aim of this study was to investigate efficacy and tolerability of adding aflibercept to FOLFIRI in the first line setting. Methods: Pts with untreated documented mCRC received aflibercept plus FOLFIRI every 14 days until progression or unacceptable toxicity in an open, phase II single arm, multicenter trial. The primary endpoint was the 6-months PFS rate. Secondary endpoints were overall PFS, OS and tolerability. A two- steps Simon design was used with H0: 55% and H1= 75%, respectively (one-sided α = 5%, 1-β=90%). Data were analyzed in intention to treat population. The study was stopped at the first stage. Results: 41 patients were included and 40 analyzed (1 consent withdrawal) in 9 French centers between 10/2014 and 02/2017. Median age was 65 y (46-81), 42% were men, 53% had two or more metastatic sites. Eighteen patients (54.5%, IC [38.940; 69.509]) were alive and non-progressive at 6 months. Treatment with FOLFIRI plus aflibercept was therefore considered ineffective, inclusions were stopped. Median follow-up was 20.5 months (95% CI (15,11 ; 27,86)). ORR was 54% and disease control rate was 80%. Median duration of treatment was 5.2 months, median PFS and OS were 8,3 and 21.9 months respectively. Grade 3-4 adverse events were mainly gastrointestinal (18 pts, 45% : mucositis (15%), diarrhea (12,5%), abdominal pain (10%)) and vascular (13 pts, 32,5% : hypertension (17,5%) and venous thromboembolism (15%)). Severe hematological toxicities occurred in 7,5% of pts. 87.5% of patients had at least one dose modification during treatment. 37 pts received a second line therapy. Conclusions: First line FOLFIRI+ aflibercept for mCRC pts is feasible but with significant toxicities leading to dose reduction in the majority of patients. Median PFS and OS were close to those reported with classical doublet and targeted agents in this setting. Clinical trial identification: EudraCT: 2013-004081-33. Legal entity responsible for the study: Fédération Francophone de Cancérologie Digestive. Funding: Sanofi. Disclosure: S. Pernot: Honoraria: Amgen, Sanofi; Travel, accomodations, expenses: Amgen, Merck, Servier, Bayer T. Aparicio: Conference: Pfizer, Roche, Sanofi, Léo Pharma, Amgen, BMS, Servier, Shire, Ipsen; Board: Pierre Fabre Ipsen, HalioDX, BMS; Travels: Ipsen, Novartis, Roche, Hospira; Research: Novartis. L. Dahan: Honoraria: Sanofi, Amgen. T. Lecomte: Consultant, expert: Sanofi; Courses, trainings: Lilly, Merck, Amgen; Invitations to national or international congresses: Amgen C. Lepage: Clinical research: Ipsen, Novartis Oncology; Courses: Advanced Accelerator Applications; Invitations to national or international congresses: Amgen, Ipsen, Novartis Oncology, Bayer. J. Taieb: Consultancy: Roche, Merck KGaA, Amgen, Celgene, Lilly, Baxalta, Servier, Sirtex Medical; Speaker's bureau: Servier, Amgen, Baxalta, Roche/Genentech, Sanofi, Merck, Lilly. All other authors have declared no conflicts of interest.

Introduction: New chemotherapy regimens and targeted therapies have improved the prognosis of metastatic colorectal cancer (mCRC). Pathologic response of CRC liver metastases (mets.) after pre-operative treatment is now recognized as a prognostic factor. We report herein the first description of histologic response of resected CRC liver mets. treated in second line (2nd) with chemotherapy (FOLFIRI: folinic acid/5-fluorouracil/irinotecan) and a new anti-angiogenic therapeutic compound, (ziv-)aflibercept, in the phase IIIb AFEQT (NCT01670721).Methods: Patients (pts) characteristics were: 5 male, 4 female, mean age 64, median age 63, 4 with unique, 5 with multiple (2 to 6) liver mets. Pathologic response from 23 resected liver mets. was assessed according to the Blazer classification: complete response, major response (<50% residual tumor cells), minor response (>50% residual tumor cells TC). Features of regression included fibrosis, acellular mucin pools and infarct-like necrosis (ILN). For multiple liver mets., the mean of the percentages of residual tumor cells and regression features in the different mets. were used to define the pathologic response.Results: All pts. presented features of regression. 5 pts had a minor response (residual tumor: 55 to 77%), 3 pts. had a major response (residual tumor: 4 to 31%) and one a complete response. Infarct-like necrosis, a recently identified regression feature in liver mets. after anti-angiogenic treatment, was observed in 6 of 9 pts and notably in the complete responder pt.Conclusion: This study highlights for the first time the impact of preoperative chemotherapy regimen and new targeted anti-angiogenic treatment (ziv-) aflibercept, on the pathologic response of CRC liver mets. Major and complete responses can be obtained in the setting of a 2nd line. Prospective studies are warranted to confirm these promising first data and their clinical impact. Introduction: New chemotherapy regimens and targeted therapies have improved the prognosis of metastatic colorectal cancer (mCRC). Pathologic response of CRC liver metastases (mets.) after pre-operative treatment is now recognized as a prognostic factor. We report herein the first description of histologic response of resected CRC liver mets. treated in second line (2nd) with chemotherapy (FOLFIRI: folinic acid/5-fluorouracil/irinotecan) and a new anti-angiogenic therapeutic compound, (ziv-)aflibercept, in the phase IIIb AFEQT (NCT01670721). Methods: Patients (pts) characteristics were: 5 male, 4 female, mean age 64, median age 63, 4 with unique, 5 with multiple (2 to 6) liver mets. Pathologic response from 23 resected liver mets. was assessed according to the Blazer classification: complete response, major response (<50% residual tumor cells), minor response (>50% residual tumor cells TC). Features of regression included fibrosis, acellular mucin pools and infarct-like necrosis (ILN). For multiple liver mets., the mean of the percentages of residual tumor cells and regression features in the different mets. were used to define the pathologic response. Results: All pts. presented features of regression. 5 pts had a minor response (residual tumor: 55 to 77%), 3 pts. had a major response (residual tumor: 4 to 31%) and one a complete response. Infarct-like necrosis, a recently identified regression feature in liver mets. after anti-angiogenic treatment, was observed in 6 of 9 pts and notably in the complete responder pt. Conclusion: This study highlights for the first time the impact of preoperative chemotherapy regimen and new targeted anti-angiogenic treatment (ziv-) aflibercept, on the pathologic response of CRC liver mets. Major and complete responses can be obtained in the setting of a 2nd line. Prospective studies are warranted to confirm these promising first data and their clinical impact.