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Background: To estimate net survival and cancer cure fraction (CF), i.e. the proportion of patients no longer at risk of dying from cancer progression/relapse, a clear distinction needs to be made between mortality from cancer and from other causes. Conventionally, CF is estimated assuming no excess mortality compared to the general population., Methods: A new modelling approach, that corrects for patients' extra risk of dying (RR) from causes other than the diagnosed cancer, was considered to estimate both indicators. We analysed EUROCARE-6 data on head and neck (H&N), colorectal, and breast cancer patients aged 40-79, diagnosed from 1998 to 2002 and followed-up to 31/12/2014, provided by 65 European cancer registries., Findings: Young male H&N cancer patients have 4 times the risk of dying from other causes than their peers, this risk decreases with age to 1.6. Similar results were observed for female. We observed an absolute increase in CF of 30 % using the new model instead of the conventional one. For colorectal cancer, CF with the new model increased by a maximum of 3 % for older patients and the RR ranged from 1 to 1.2 for both sexes. CF of female breast cancer ranged from 73 % to 79 % using the new cure model, with RR between 1.2 and 1.4., Interpretation: Not considering a RR> 1 leads to underestimate the proportion of patients not bound to die of their diagnosed cancer. Estimates of cancer mortality risk have an important impact on patients' quality of life., Competing Interests: Declaration of Competing Interest The sponsor have no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: This document is a summary of the French intergroup guidelines of the management of biliary tract cancers (BTC) (intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder carcinomas) published in September 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org)., Methods: This collaborative work was conducted under the auspices of French medical and surgical societies involved in the management of BTC. Recommendations were graded in three categories (A, B and C) according to the level of scientific evidence until August 2023., Results: BTC diagnosis and staging is mainly based on enhanced computed tomography, magnetic resonance imaging and (endoscopic) ultrasound-guided biopsy. Treatment strategy depends on BTC subtype and disease stage. Surgery followed by adjuvant capecitabine is recommended for localised disease. No neoadjuvant treatment is validated to date. Cisplatin-gemcitabine chemotherapy combined to the anti-PD-L1 inhibitor durvalumab is the first-line standard of care for advanced disease. Early systematic tumour molecular profiling is recommended to screen for actionable alterations (IDH1 mutations, FGFR2 rearrangements, HER2 amplification, BRAF V600E mutation, MSI/dMMR status, etc.) and guide subsequent lines of treatment. In the absence of actionable alterations, FOLFOX chemotherapy is the only second-line standard-of-care. No third-line chemotherapy standard is validated to date., Conclusion: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gael Roth declares consulting or advisory role or invitation as a speaker for Servier, AstraZeneca, Bristol-Myers Squibb, MSD, Amgen, Ipsen, Accord Healthcare, Pierre Fabre, Incyte, Netris Pharma and Alpha Tau, as well as travel accommodations, or expenses from Servier, AstraZeneca, Bristol Myers Squibb, MSD, Roche, Amgen, Viatris, Pierre Fabre and Ipsen. Research funding by Genoscience Pharma, Netris Pharma. Matthieu Sarabi declares consultancy/honoraria AstraZeneca, Servier, Roche and accommodations or expenses from Ipsen. Jean-Frédéric Blanc declares honoraria from incyte, servier, AZ, Roche, Tahio oncology, MSD. Anne-Laure Bretagne-Bignon declares consulting for Astra Zeneca, Servier, Ipsen and accommodations or congress registration support for Merck and Ipsen. Romain Coriat declares honoraria for lectures and Advisory board for: BAYER, Servier, Pierre Fabre, AAA, Merck, Amgen. Christelle de la Fouchardière declares holding an advisory role with Amgen, Bayer, BMS, Daichi-Sankyo, Eisai, Imescia, Incyte, Lilly, Merck, MSD, Pierre Fabre Oncologie, Roche, and Servier; receiving grants from Pierre Fabre and Servier outside of the submitted work; receiving fees from Ipsen, Eisai, Pierre Fabre, Servier, being an invited speaker outside of the submitted work. Julien Edeline declares consulting or advisory role for BTG, Bristol Myers Squibb, AstraZeneca, Bayer, Ipsen, AstraZeneca, MSD, Eisai, Boston Scientific, Roche, Basilea, Merck Serono, Servier; research Funding from Bristol Myers Squibb (Inst), BeiGene (Inst); travel, accommodations or expenses from Amgen, Bristol Myers Squibb, Roche. Astrid Lièvre declares honoraria for lectures from Amgen, Astellas, Astra-Zeneca, Bayer, BMS, Incyte, Ipsen, Leo-pharma, Mylan, Novartis, Pierre Fabre, Roche, Servier and Viatris; consulting/advisory relationship from AAA, Astellas, Bayer, BMS, Incyte, Pierre Fabre and Servier; travel, accommodations or congress registration support from Bayer, Boehringer, Ipsen, Mylan, MSD, Pierre Fabre, Roche and Servier; research funding from Bayer (Inst), Lilly (Inst). Sylvain Manfredi declares travel accommodation from MSD, AMGEN. Cindy Neuzillet declares Honoraria and consulting from Amgen, AstraZeneca, Baxter, Bristol-Myers Squibb, Fresenius Kabi, Incyte Biosciences, Merck, MSD, Mundipharma, Novartis, Nutricia, OSE Immunotherapeutics, Pierre Fabre, Roche, Sanofi, Servier, Viatris, as well as research funding AstraZeneca, Bristol-Myers Squibb, Fresenius Kabi, Nutricia, OSE Immunotherapeutics, Roche, Servier, Viatris. Valérie Paradis declares honoraria for lectures from Incyte. Anthony Turpin declares personal fees from Servier, Viatris, Incyte Bioscience, BMS, Merck and grants and personal fees from AstraZeneca and MSD. Olivier Bouché declares consulting or advisory role for Pierre Fabre, Amgen, Bayer, Servier, MSD, Deciphera, Apmonia Therapeutics and Merck outside the submitted work. David Malka declares honoraria for Roche, Amgen, Bayer, Merck Serono, Servier, Sanofi, Pierre Fabre, Viatris, Bristol Myers Squibb, MSD Oncology, LEO Pharma, Incyte, AstraZeneca; consulting or advisory role: Roche, Sanofi, Merck Serono, MSD, Servier, Bayer, Incyte, Amgen, Bristol Myers Squib, Taiho Oncology, AbbVie, AstraZeneca, Pierre Fabre; travel, accommodations or expenses from Roche, Bayer, Sanofi, Merck Serono, Amgen, Servier, Pierre Fabre, Bristol Myers Squibb/Pfizer, MSD, Viatris. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: It is intuitively thought that early relapse is associated with poor survival after recurrence (SAR) in resected colon cancer (CC) patients, but this has never been formally studied., Methods: We pooled data from stage III patients treated with oxaliplatin-based adjuvant therapy in two phase III trials, to analyse time to recurrence (TTR) and its relationship with SAR. TTR and SAR were also studied according to molecular status (mismatch repair (MMR), RAS, and BRAF V600E ). Early relapsing patients were defined as patients having a TTR event within 12 months after starting adjuvant chemotherapy., Results: 4548 stage III CC patients were included in the present analysis. Deficient MMR (dMMR) CC patients experienced fewer recurrences than proficient (p)MMR CC patients (18.8% versus 27.6%) but had a significantly shorter median TTR (mTTR; 0.74 versus 1.40 years, p < 0.0001). In pMMR patients, BRAF and RAS mutations were also associated with earlier mTTR as compared to double wild-type (WT) patients (0.99 versus 1.38 versus 1.54 years, respectively, p < 0.0001). Early recurrence occurred in 397 patients and was associated with a median SAR (2.2 versus 3.3 years, p = 0.0007). However, this association was mainly due to pMMR/RAS and BRAF V600E mutated tumours and was not confirmed in dMMR and pMMR/double WT subgroups., Conclusion: In resected stage III CC treated with standard oxaliplatin-based adjuvant therapy, TTR varies between dMMR, pMMR/RAS, or BRAF V600E mutated and pMMR/double WT tumours. In addition, early relapse is associated with poor survival, mainly due to patients resected for a pMMR/RAS or BRAF V600E mutated tumour., Competing Interests: Declaration of Competing Interest JT has received honoraria as a speaker or in an advisory role from Sanofi, Roche, Merck Serono, Amgen, Servier, Pierre Fabre, Lilly, AstraZeneca, and MSD. PLP has received honoraria as a speaker or in an advisory role from ESMO, Amgen, Servier, Pierre Fabre, Biocartis, and stocks from Methys DX. SL has received honoraria as an invited speaker from Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen, and has participated in an advisory board for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Servier, and Merck Sharp & Dohme. TA has attended advisory board meetings and received consulting fees from AstraZeneca, Astellas, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, GamaMabs Pharma SA, Gilead, GlaxoSmithKline, Merck & Co. Inc., Nordic Oncology, Pierre Fabre, Seagen, Servier and Transgene; has received honoraria from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Merck Serono, Pierre Fabre, Roche, Sanofi, Seagen and Servier; and has received support for meetings from Merck & Co. Inc., and Servier. CL was a consultant and had an advisory role for Novartis and AAA, and has received speaker honoraria from AMGEN, and Bayer. OB has received honoraria as a speaker and in an advisory role from Merck Serono, Amgen, Bayer, Servier, Pierre Fabre, Deciphera, Apmonia Therapeutics, and MSD. AL has received honoraria as a consultant and speaker from Advance Accelerator Applications, Amgen, Bayer, F. Hofmann-La Roche, Incyte Corporation, Ipsen Biopharmaceuticals Inc, Mylan Pharmaceuticals Inc, Novartis, Pierre Fabre Pharmaceuticals Inc, Sandoz, Sanofi Pasteur Inc and has received research grants from Bayer and Lilly Deutschland. CLO reports personal fees and non-financial support from Merck, Roche; personal fees from Servier; and personal fees from Amgen outside the submitted work. JBB has received personal fees from Amgen, Bayer, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Sanofi, Servier, and non-financial support from Amgen, Merck Serono, and Roche, outside the submitted work. JB is involved as an advisory board member for AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Ipsen, Servier, and Sanofi and has received honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Merck, MSD, Daiichi, Servier, Ipsen, Jansen, and Sanofi. CB has received honoraria as a consultant from Bayer, Molecular Partners, MSD, Pierre Fabre, and Servier, and has received research grants from Bayer, Roche, and Boehringer. All remaining authors have declared no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Following European guidelines, patients with aggressive metastatic or locally advanced, non-resectable, duodeno-pancreatic (DP) neuroendocrine tumours (NETs) should receive systemic combination chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases with or without significant hepatic invasion (&gt;30-50%), and/or bone metastases., Methods: This academic randomised, double-blind, placebo-controlled phase II study aims to evaluate lanreotide autogel 120 mg (LAN) as maintenance treatment after at least 2 months of first-line treatment (L1) in aggressive G1-G2 DP-NET. Patients were randomly assigned in a 1:1 ratio to receive LAN or placebo (PBO), every 28 days, until progression or toxicity. The primary end-point was progression-free survival (PFS) at 6 months., Results: Among the 118 planned patients, 53 were included. Of these, 81.1% had a G2 tumour, and 90.6% had metastatic disease. L1 therapy consisted of chemotherapy (96.8%). Median duration of L1 was 4.6 months (range: 2.0-7.7). At the time of randomisation, 81.1% of patients had stable disease. Median follow-up was 27.0 months (95% CI: 19.5; 31.2). PFS at 6 months was 73.1% (90% CI: 55.3; 86.6) in LAN versus 54.2% (90% CI: 35.8; 71.8) in PBO. Median PFS was 19.4 months (95% CI: 7.6; 32.6) and 7.6 months (95% CI: 3.0; 9.0), respectively. Median overall survival was 41.9 months in PBO and was not reached in LAN. The toxicity profile was mainly grade 1-2 expected toxicities., Conclusions: The encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed., Trial Registration: NCT02288377 (clinicaltrials.gov)., Competing Interests: Conflict of interest statement Côme Lepage worked as a member of the advisory board for Novartis, personal fees from Novartis, IPSEN, grants from Merck, IPSEN. Thomas Walter worked as a member of advisory boards for AAA, IPSEN, Keocyt and Novartis. Astrid Lièvre reports grants from Bayer Lilly, Merck and Novartis; personal fees from AAA, Amgen, Bayer, Bristol-Myers Squibb, Celgene, HalioDx, Incyte, Ipsen, Lilly, Merck, Novartis, Pierre Fabre, Roche, Sandoz, Sanofi and Servier; non-financial support from AAA, Amgen, Bayer, Incyte, Ipsen, Merck, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Servier and Integragen. David Tougeron reports grants from Bristol-Myers Squibb and Novartis; personal fees from Amgen, Bayer, Bristol-Myers SquibbIpsen, Novartis, Pierre Fabre, Roche, Sanofi and Servier. Catherine Lombard-Bohas worked as a member of advisory boards for AAA, IPSEN, Keocyt, Novartis. Jean-Louis Legoux worked as a member of an advisory board for Novartis, reports personal fees from Novartis, Pfizer (clinical research), Novartis, Keocyt, Servier (courses, training), Merck, Servier, Keocyt (invitations to national or international congresses). All remaining authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: Stratification of colon cancer (CC) of patients with stage II and III for risk of relapse is still needed especially to drive adjuvant therapy administration. Our study evaluates the prognostic performance of two known biomarkers, CDX2 and CD3, standalone or their combined information in stage II and III CC., Patients and Methods: CDX2 and CD3 expression was evaluated in Prodige-13 study gathering 443 stage II and 398 stage III primary CC on whole slide colectomy. We developed for this study an H-score to quantify CDX2 expression and used our artificial intelligence (AI)-guided tissue analysis ColoClass to detect CD3 in tumour core and invasive margin. Association between biomarkers and relapse-free survival was investigated., Results: Univariate analysis showed that the combined variable CD3-TC and CD3-IM was associated with prognosis in both stage II and stage III. CDX2, on the contrary, was associated with prognosis only in stage III. We subsequently associated CDX2 and combined immune parameters only in stage III. This multivariate analysis allowed us to distinguish a proportion of stage III CC harbouring a high CDX2 expression and a high immune infiltration with a particularly good prognosis compared to their counterpart., Conclusion: This study validated the prognostic role of CDX2 and CD3 evaluated with immunohistochemistry procedures in stage III but not in stage II. This association would be conceivable in a routine pathology laboratory and could help oncologist to consider chemotherapy de-escalation for a part of stage III patients., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Diabetes mellitus (DM) has been associated with increased colorectal cancer (CRC) risk and worse prognosis in metastatic CRC patients. In this large, pooled analysis of non-metastatic colon cancer (CC) patients, we investigated the impact of DM and metformin treatment on recurrence and survival., Patients and Methods: A patient-level pooled analysis from three randomised adjuvant trials was performed. All patients had resection with curative intent of stage II or III CC and were treated with standard adjuvant fluoropyrimidine and oxaliplatin (±cetuximab). We investigated the impact of DM and metformin treatment on time to recurrence (TTR) and overall survival (OS)., Results: Of 5922 CC patients who had a median follow-up of 6.8 years, 621 patients (10.5%) had DM at CC diagnosis. Of those with DM, 327 patients (52.7%) were defined as metformin users and 294 patients (47.3%) as non-metformin users. CC patients with DM had a significantly shorter TTR (adjHR: 1.21; 95% CI, 1.03-1.42; p = 0.017) and OS (adjHR: 1.29; 95% CI, 1.09-1.52; p = 0.003) compared to non-diabetic CC patients. Diabetic CC patients not receiving metformin had a significantly worse TTR (adjHR: 1.28; 95% CI, 1.02-1.60; p = 0.032) and OS (adjHR: 1.41; 95% CI, 1.13-1.77; p = 0.003) as compared to non-diabetic patients. These worse outcomes were not significant in metformin users (TTR: adjHR: 1.16; 95% CI, 0.94-1.43; p = 0.168; OS: adjHR: 1.19; 95% CI, 0.95-1.48, p = 0.127)., Conclusions: CC patients with DM had not only a significantly worse survival but also TTR. Furthermore, our data suggest that metformin may attenuate the detrimental effect of DM on CC patient outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Chemotherapy is effective in metastatic pancreatic adenocarcinoma (mPA), but new approaches are still needed to improve patients' survival and quality of life. We have previously published good efficacy and tolerability results on a sequential treatment strategy of gemcitabine followed by an intensified FOLFIRI (5FU+irinotecan) regimen. In the present study, we evaluated the same sequence but replaced gemcitabine by the new gemcitabine + nab-paclitaxel standard first-line combination., Patients and Methods: We randomised chemotherapy-naive patients with proven mPA, bilirubin levels ≤1.5 upper limit of normal values and performance status 0-2 to alternately receive gemcitabine + nab-paclitaxel for 2 months then FOLFIRI.3 for 2 months in arm A, or gemcitabine + nab-paclitaxel alone until progression in arm B. The primary objective was to increase the 6-month progression-free survival (PFS) rate from 40% (H 0 ) to 60% (H 1 ); using the binomial exact method, 124 patients were required. Analyses were carried out in preplanned modified intention-to-treat (mITT) and per-protocol (PP) populations., Results: Between November 2015 and November 2016, 127 patients were enrolled. Main grade III-IV toxicities (% in arm A/B) were: diarrhoea (12.5/1.7), neutropenia (46.9/31, including febrile neutropenia: 1.6/0), skin toxicity (6.3/13.8), and peripheral neuropathy (6.3/8.6). No toxic deaths occurred. The objective response rate was 40.3% (95% confidence interval [CI]: 28.1-53.6) in arm A and 26.7% (95% CI: 16.1-39.7) in arm B. The primary end-point (6-month PFS rate) was 45.2% [one-sided 95% CI: 34.3-56.4] in arm A and 23.3% in arm B [one-sided 95% CI: 14.3-32.3] in the mITT population. In the PP population, median PFS and OS were 7.6 months and 6 months and 14.5 months and 12.2 months in arm A and B, respectively., Conclusions: The FIRGEMAX strategy with gemcitabine + nab-paclitaxel alternating with FOLFIRI.3 every 2 months, appears feasible and effective, with manageable toxicities, in patients able to reach >2mo of treatment., Trial Registration Information: EudraCT: 2014-004449-28: NCT: 0282701., Competing Interests: Conflict of interest statement T.J. reported receiving honoraria from Merck, Roche, Amgen, Lilly, Sanofi, Samsung, MSD, Servier, Celgene, Pierre Fabre; has been a member of the consulting or advisory role for Roche, Merck KGaA, Amgen, Lilly, MSD, Servier, Pierre Fabre, Sanofi, Samsung; speakers' Bureau for Servier, Amgen, Roche, Sanofi, Merck, Lilly, Pierre Fabre. R.Y. reported receiving honoraria from Roche, Sanofi, Merck, Amgen, Bayer and Servier. B.J-.B reported receiving honoraria from Amgen, AstraZeneca, Bayer, Merck Serono, Pierre Fabre, Roche, Sanofi, Servier. All the remaining authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity., Methods: This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7-30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%., Results: Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5-43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14-23), 17 (13-22), and 51 (33-60) months. The most common grade III-IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%)., Conclusions: The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease., Trial Registration: NCT01678664 (clinicaltrials.gov)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim of the Study: The optimal therapeutic strategy in patients with rectal cancer and synchronous unresectable metastases remains unknown. We evaluated the efficacy of FOLFIRINOX induction therapy in this setting., Patients and Methods: Chemotherapy-naïve patients received at least 8 cycles of FOLFIRINOX. The primary end-point was the 4-month disease control (4 m DC) rate. Tumour responses were centrally reviewed and assessed by computed tomography scan for metastases (Response Evaluation Criteria in Solid Tumours criteria) and magnetic resonance imaging for rectal tumorus. With a Simon 2-stage design and a targeted (H1) 4 m DC > 75%, 65 patients were enrolled from July 2012 to February 2015: male, 78%; median age, 61 years; performance status, 0-1, 98%; liver metastases, 92%; ≥2 metastatic sites, 63%., Results: Fifty-six (85%) of the 65 patients received the 8 planned FOLFIRINOX cycles. The primary objective was achieved (4 m DC rate: 94%; 95% confidence interval [CI], 86.3-97.8). Primary tumour symptoms decreased from 72% at baseline to 10% at 4 months. Response rate was 86%, and a >70% primary tumour volume decrease was seen in 63% of patients. Forty-four patients (68%) had at least one grade 3 side-effect; no toxic deaths occurred. Median follow-up was 35.0 months (95% CI, 31.3-43.7). Median progression-free survival and overall survival were 10.9 m (95% CI, 8.8-12.9) and 33.4 m (95% CI, 22.6-38.2), respectively., Conclusion: Upfront FOLFIRINOX is feasible and allows good local and distant control. It therefore offers the opportunity to choose the best therapeutic strategy for each patient and to personalise treatment according to the local and distant efficacy results of this induction step., Trial Registration: Clinicaltrials.gov, NCT01674309., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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 <18.5). Interaction tests were performed between BMI effect and sex, age and the addition of antiangiogenics to chemotherapy., Results: The rate of BMI ≥25 patients was 41.5%, ranging from 37.6% (1991-1999 period) to 41.5% (2000-2006 period) and 44.8% (2007-2013 period). Comparison of overweight patients versus normal BMI range patients revealed a significant improvement of median overall survival (OS) (18.5 versus 16.3 months, HR = 0.88 [0.80-0.98] p = 0.02) and objective response rate (ORR) (42% versus 36% OR = 1.23 [1.01-1.50] p = 0.04) but a comparable median progression-free survival (PFS) (7.8 versus 7.2 months, HR = 0.96 [0.87-1.05] p = 0.35). Subgroup analyses revealed that overweight was significantly associated with better OS in men. OS and PFS were significantly shorter in thin patients., Conclusion: Overweight patients had a prolonged OS compared with normal weight patients with mCRC. The association of overweight with better OS was only observed in men. The pejorative prognosis of BMI <18.5 was confirmed., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use., Patients and Methods: According to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data., Results: Among the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients., Conclusion: Although this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Diagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC., Patients and Methods: All patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded., Results: 253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0-1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20-100). Median overall survival was 15.6 (13.6-17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE>2 upper limit of normal [ULN]; HR = 3.2), CgA>2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72)., Conclusions: We report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The EUROCARE study collects and analyses survival data from population-based cancer registries (CRs) in Europe in order to provide data on between-country differences in survival and time trends in survival., Methods: This study analyses data on liver cancer, gallbladder and extrahepatic biliary tract cancers ("biliary tract cancers"), and pancreatic cancer diagnosed in 2000-2007 from 88 CRs in 29 countries. Relative survival (RS) was estimated overall, by region, sex, age and period of diagnosis using the complete approach. Time trends in 5-year RS over 1999-2007 were also analysed using the period approach., Results: The prognosis of the studied cancers was poor. Age-standardised 5-year RS was 12% for liver cancer, 17% for biliary tract cancers and 7% for pancreatic cancer. There were some between-country differences in survival. In general, RS was low in Eastern Europe and high in Central and Southern Europe. For all sites, 5-year RS was similar in men and women and decreased with advancing age. No substantial changes in survival were reported for pancreatic cancer over the period 1999-2007. On average, there was a crude increase in 5-year RS of 3 percentage points between the periods 1999-2001 and 2005-2007 for liver cancer and biliary tract cancers., Conclusions: The major changes in imaging techniques over the study period for the diagnosis of the three studied cancers did not result in an improvement in the prognosis of these cancers. In the near future, new innovative treatments might be the best way to improve the prognosis in these cancers., (Copyright © 2015. Published by Elsevier Ltd.)

Background: Chemoradiotherapy (CHRT) is often advocated for locally-advanced biliary tract cancer (LABTC). However there was not comparative study with chemotherapy alone (CH)., Patients and Methods: Patients with hilar or extrahepatic non-metastatic, LABTC could be included in this phase II trial. The inclusion criteria required World Health Organisation (WHO) performance status ⩽ 2, bilirubinemia ⩽ 50 μM/L after biliary drainage if necessary, and possibility of external radiotherapy. Fluorouracil (5 FU) infusion and cisplatin, were given in association to radiotherapy (50 Gy) in the CHRT arm. Gemcitabine+oxaliplatin (GEMOX) was planned for 6 months in the CH arm. End-points were progression-free survival (PFS), overall survival (OS), toxicity and rate of biliary complications., Results: The trial was closed before completion due to slow recruitment. Eighteen and 16 patients were included in the CHRT and CH arms, respectively. Median follow up was 27.9 months (± 2.8). Grade III-IV toxicities were mostly haematological (23% and 25%), and gastrointestinal (11% and 6%), in the CHRT and CH arm, respectively. Biliary complications occurred in 28% of patients in the CHRT arm and 44% of patients in the CH arm (risk ratio (RR): 1.60 [0.65-3.92]). Median PFS was 5.8 months in the CHRT group and 11.0 months in the CH group (hazard ratio (HR): 0.65 [0.32-1.33]). Median OS was 13.5 months in the CHRT group and 19.9 months in the CH group (HR: 0.69 [0.31-1.55])., Conclusions: Combination of gemcitabine plus cisplatin seems to be at least as efficient as chemoradiotherapy (50 Gy plus 5 FU and cisplatin) in LABTC., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim of the Study: To describe trends in survival of non-resectable metastatic colorectal cancer (MCRC) over a 34-year period in a French population-based registry taking into account major advances in medical therapy., Patients and Methods: 3804 patients with non-resectable metastatic colorectal cancer diagnosed between 1976 and 2009 were included. Three periods (1976-96, 1997-2004 and 2005-09) were considered., Results: The proportion of patients receiving chemotherapy dramatically increased from 19% to 57% between the first two periods, then increased steadily thereafter reaching 59% during the last period (p<0.001). Median relative survival increased from 5.9 months during the 1976-96 period to 10.2 months during the 1997-2004 period but, despite the availability of targeted therapies, remained at 9.5 months during the 2005-09 period. During the last study period, less than 10% of elderly patients received targeted therapies compared to more than 40% for younger patients. Their median relative survival was 5.0 months compared to 15.6 months in younger patients., Conclusion: There was an improvement in survival in relation with the increased use of more effective medical treatment. However, at a population-based level, patients are not all treated equally and most of them, especially the elderly, do not benefit from the most up-to-date treatment options., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Quantitative immunochemical faecal occult blood tests have become the recommended tests for colorectal cancer screening. The aim of this study was to complete our knowledge on the performance of one of the quantitative immunochemical tests available, FOB-Gold, and to propose a possible strategy for an organised screening programme., Patients and Methods: Within the French organised screening programme, 23,231 average-risk individuals, aged 50-74 performed both a 3-day Hemoccult test and a 1-day FOB-Gold test. Performances of the immunochemical test were evaluated at different cut-off levels., Results: The positivity rate for the Hemoccult was 2.1% and for the FOB-Gold varied between 4.6% (cut-off value of 100 ng/mL, the lowest studied cut-off) and 2.1% (cut-off value of 352 ng/mL). The number of colonoscopies decreased with increasing cut-off values by 21.5% (150 ng/mL), 35.4% (200 ng/mL) and 53.3% (352 ng/mL). The corresponding miss rate for CRC was respectively 6.4%, 11.1% and 22.2%, and for advanced adenoma respectively 16.3%, 29.2% and 43.6%. Compared with the reference cut-off for the FOB-Gold (100 ng/mL) the miss rate for Hemoccult was 53% for CRC and 77% for advanced adenoma., Conclusion: The study suggests that in countries with colonoscopy facilities compatible with a screening test positivity rate of up to 5%, use of a 1-day test with a cut-off value between 100 and 150 ng/mL could be the recommended strategy. Further increasing the cut-off value up to the same positivity rate as Hemoccult could be used in areas with limited access to colonoscopy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background and Aims: Little is known about the epidemiology of rare epithelial digestive cancers. The aim of this study was to report on their incidence, prevalence and survival across Europe., Methods: The analysis was carried out on 50,646 cases diagnosed from 1995 to 2002 within a population of 162,000,000 in 21 European countries. Age-standardised incidence rates were computed using the European standard population. Prevalence rates, relative survival and period survival indicators for the years 2000-2002 were calculated. The expected number of new cases per year and of prevalent cases in Europe was estimated., Results: There were large variations in gallbladder epithelial cancer incidence rates: the incidence in Eastern Europe was 7 times higher than in the UK & Ireland. Differences between incidence rates were smaller for the other sites. The estimated number of new epithelial cancers arising in the EU each year was estimated to be 11,050 for extrahepatic bile duct cancer, 10,713 for gallbladder cancer, 5427 for anal cancer and 3595 for small intestine cancer. The corresponding estimated number of total prevalent cases was 18,483, 15,620, 40,589 and 13,276. There was also a large variation in the 5-year relative survival rate. For epithelial cancer of the anal canal, this varied between 66% (Central Europe) and 44% (Eastern Europe). The corresponding rates for small intestine cancers were 33% and 20%, for extrahepatic bile duct cancers, 17% and 12% and for gallbladder cancer 13% and 10%., Conclusion: There are large variations within Europe in the incidence and survival of rare digestive cancers according to geographic area., (Copyright © 2011. Published by Elsevier Ltd.)

Introduction: The objective of this study was to estimate prevalence of colorectal cancers requiring care or follow-up., Materials and Methods: Prevalence was observed in 2005 on the population-based digestive cancer registry of Burgundy (France). Total and 5-year partial prevalences were calculated. The prevalence of patients requiring follow-up was estimated using non-mixture cure models. The prevalence of patients with recurrence was estimated using annual recurrence rates., Results: Total prevalence was 262,244 cases in France. The mean variation in 5-year partial prevalence between successive 5-year periods was +8.0%. Time to cure was estimated to be 9.3 years, suggesting that follow-up is needed over a 10-year period, corresponding to 71.7% of prevalent cases. In 2005, 5.4% of prevalent cases had recurrent cancer requiring treatment., Conclusion: This study underlines the burden of colorectal cancer on the health system. Prevalence of patients requiring follow-up or treatment provides interesting information in addition to classic indicators.

The aim of this study was to compare the performance of a guaiac-based faecal occult blood test (G-FOBT) with that of an immunochemical faecal occult blood test (I-FOBT). A total of 17,215 average risk individuals aged 50 to 74 enrolled in a population-based organised screening programme and performed a 3-day G-FOBT and a 2-day I-FOBT simultaneously. Among participants, 3.1% were found positive for the G-FOBT and 6.9% for the I-FOBT (p<10(-4)). Among the 1205 participants who tested positive and underwent a colonoscopy, the number of detected cancers and advanced adenomas was respectively 2.6 times higher and 3.5 times higher with the I-FOBT than with the G-FOBT. The positive predictive value of I-FOBT was similar to that of the G-FOBT for cancers (5.9% versus 5.2%) and was higher for advanced adenomas (27.2% versus 17.5%). The I-FOBT was superior to the G-FOBT for the detection of both cancers and advanced adenomas. However, the screen positive rate that staff and financial resources can accommodate has yet to be determined.

Background: The aim of this study was to calculate the risk of metachronous colorectal cancers, to specify their characteristics and potential risk factors in a well-defined French population over a 27-year period., Patients and Methods: The 10,801 patients who had colorectal cancers totalled 61,879 person-years of follow-up. The actuarial method was used to obtain crude metachronous colorectal cancer rates. Standardised incidence ratios (SIRs) were calculated., Results: The cumulative rate of metachronous colorectal cancer was 1.8% at 5 years, 3.4% at 10 years and 7.2% at 20 years. The incidence of metachronous colorectal cancer following a first colorectal cancer was higher than expected (SIR: 1.5 [1.3-1.7] p<0.001). It remained greater throughout the study period, significantly only between the first and the fifth years following diagnosis (SIR: 1.9 [1.6-2.3] p<0.010). As compared to solitary cancers, metachronous cancers were diagnosed at earlier stages (23.5% versus 40.9% were stage I, p<0.001). None of the personal and tumour characteristics were predicting factors for the development of metachronous colorectal cancer., Conclusion: Patients with colorectal cancer are at greater risk of developing a metachronous colorectal cancer. Among them, no predicting factors for the development of metachronous tumours were found. Thus lifelong colonoscopic surveillance is needed.

The aim of this study was to investigate the effects of tumour and patient characteristics on trends in the survival of patients with cancer of the anus or rectum in England and Wales. A total of 132,542 adults (15-99 years) who were diagnosed during the 14 years 1986-1999 were followed up to 2001 through the National Health Service Central Register. Relative survival up to 5 years after diagnosis was estimated, using deprivation-specific life tables. Generalised linear models were used to estimate relative excess risks of death, adjusted for patient and tumour characteristics. The results showed that 5-year relative survival was higher in women, younger patients and more affluent patients, and higher for anal cancer than rectal cancer. Survival improved by more than 10% from the late 1980s (around 38%) to the late 1990s (49%). This trend was not explained by changes in the distribution of age, anatomical site, morphology or deprivation. The trend was more marked in younger and more affluent patients, and for adenocarcinoma and epidermoid carcinoma than for tumours with other morphology. The inequality in survival between affluent and deprived patients widened. It is concluded that improvements in survival may reflect improvements in disease stage, diagnostic technique or treatment. Which of these factors contribute to the widening socioeconomic inequalities in survival remains to be elucidated.