Publications by authors named "Astrid Lievre"

94 Publications

Skeletal muscle loss during chemotherapy and its association with survival and systemic treatment toxicity in metastatic colorectal cancer: An AGEO prospective multicenter study.

Clin Res Hepatol Gastroenterol 2021 Mar 1;45(6):101603. Epub 2021 Mar 1.

Sorbonne Paris Cite, Paris Descartes University, Siric CARPEM, Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France. Electronic address:

Purpose: We showed in a previous study that the PG-SGA score is associated with survival and chemotherapy-related toxicities in metastatic colorectal cancer (mCRC) patients. The objective was to evaluate the association between pretherapeutic sarcopenia and variation in skeletal muscle index (SMI) during treatment with these outcomes in the same population.

Methods: This prospective, multicenter, observational study enrolled non-pretreated mCRC patients. SMI was measured on routine CT scan at day 0 (D0) and day 60 (D60). Nutritional factors were collected at D0. Progression-free survival (PFS) and overall survival (OS) were calculated from treatment start.

Results: 149 patients were included from 7/2013 to 11/2016. Pretherapeutic sarcopenia was not significantly associated with survival or chemotherapy-related toxicities. The decrease in SMI > 14% was significantly associated with shorter PFS (6 vs 9 mo; HR 1.8, 95% CI 1.1-3.1, p = 0.02) and OS (8.5 vs 26 mo; HR 2.6, 95% CI 1.4-4.8, p = 0.002), independently of hypoalbuminemia and malnutrition defined by PG-SGA. Patients with a SMI decrease > 14% had a higher rate of grade ≥ 2 clinical toxicities (40% vs 22%, OR 3.0, 95% CI 1.2-7.7, p = 0.02), but the difference was not statistically significant in multivariable analysis.

Conclusion: To our knowledge, this is the first study to assess prospectively the association of skeletal muscle loss with survival and treatment toxicities in non-pretreated patients with mCRC. Pretherapeutic sarcopenia was not associated with poor outcomes, but the loss of skeletal muscle mass within 60 days from treatment start was highly prognostic, independently of other prognostic and nutritional factors.
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http://dx.doi.org/10.1016/j.clinre.2020.101603DOI Listing
March 2021

Prognostic factors of Colorectal Cancer patients with Brain Metastases.

Radiother Oncol 2021 Feb 15. Epub 2021 Feb 15.

Poitiers University, Poitiers, France; Department of Gastroenterology, Poitiers University Hospital, Poitiers, France. Electronic address:

Introduction: Brain metastases (BMs) from colorectal cancer (CRC) are rare (≈2%) but are increasing with the improvement of CRC prognosis. The main objective of this study was to evaluate the prognostic factors of BM from CRC.

Materials And Methods: This multicenter retrospective study included all consecutive patients with BM from CRC diagnosed between 2000 and 2017. Theory/calculation Prognostic factors of OS were evaluated in univariate (log-rank test) and multivariate analyses (Cox regression model). These prognostic factors could help the management of patients with BM from CRC.

Results: A total of 358 patients were included with a median age of 65.5 years. Primary tumors were mostly located in the rectum (42.4%) or left colon (37.2%) and frequently KRAS-mutated (56.9%). The median time from metastatic CRC diagnosis to BM diagnosis was 18.5 ± 2.5 months. BMs were predominantly single (56.9%) and only supratentorial (54.4%). BM resection was performed in 33.0% of the cases and 73.2% of patients had brain radiotherapy alone or after surgery. Median OS was 5.1 ± 0.3 months. In multivariate analysis, age under 65 years, ECOG performance status 0-1, single BM and less than 3 chemotherapy lines before BM diagnosis were associated with better OS. Prognostic scores, i.e. recursive partitioning analysis (RPA), Graded Prognostic Assessment (GPA), Disease Specific-Graded Prognostic Assessment (DS-GPA), Gastro-Intestinal-Graded Prognostic Assessment (GI-GPA) and the nomogram were statistically significantly associated with OS but the most relevant prognosis criteria seemed the ECOG performance status 0-1.

Conclusions: ECOG performance status, number of BM and number of chemotherapy lines are the most relevant factors in the management of patients with BM from CRC.
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http://dx.doi.org/10.1016/j.radonc.2021.02.006DOI Listing
February 2021

MRI-Based Radiomics Input for Prediction of 2-Year Disease Recurrence in Anal Squamous Cell Carcinoma.

Cancers (Basel) 2021 Jan 7;13(2). Epub 2021 Jan 7.

Radiation Oncology Department, Hôpital Haut-Lévêque, CHU Bordeaux, 33600 Pessac, France.

Purpose: Chemo-radiotherapy (CRT) is the standard treatment for non-metastatic anal squamous cell carcinomas (ASCC). Despite excellent results for T1-2 stages, relapses still occur in around 35% of locally advanced tumors. Recent strategies focus on treatment intensification, but could benefit from a better patient selection. Our goal was to assess the prognostic value of pre-therapeutic MRI radiomics on 2-year disease control (DC).

Methods: We retrospectively selected patients with non-metastatic ASCC treated at the CHU Bordeaux and in the French FFCD0904 multicentric trial. Radiomic features were extracted from T2-weighted pre-therapeutic MRI delineated sequences. After random division between training and testing sets on a 2:1 ratio, univariate and multivariate analysis were performed on the training cohort to select optimal features. The correlation with 2-year DC was assessed using logistic regression models, with AUC and accuracy as performance gauges, and the prediction of disease-free survival using Cox regression and Kaplan-Meier analysis.

Results: A total of 82 patients were randomized in the training ( = 54) and testing sets ( = 28). At 2 years, 24 patients (29%) presented relapse. In the training set, two clinical (tumor size and CRT length) and two radiomic features (FirstOrder_Entropy and GLCM_JointEnergy) were associated with disease control in univariate analysis and included in the model. The clinical model was outperformed by the mixed (clinical and radiomic) model in both the training (AUC 0.758 versus 0.825, accuracy of 75.9% versus 87%) and testing (AUC 0.714 versus 0.898, accuracy of 78.6% versus 85.7%) sets, which led to distinctive high and low risk of disease relapse groups (HR 8.60, = 0.005).

Conclusion: A mixed model with two clinical and two radiomic features was predictive of 2-year disease control after CRT and could contribute to identify high risk patients amenable to treatment intensification with view of personalized medicine.
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http://dx.doi.org/10.3390/cancers13020193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827348PMC
January 2021

PRODIGE 59-DURIGAST trial: A randomised phase II study evaluating FOLFIRI + Durvalumab ± Tremelimumab in second-line of patients with advanced gastric cancer.

Dig Liver Dis 2020 Dec 21. Epub 2020 Dec 21.

Service d'Oncologie Médicale, CHU de Poitiers, Poitiers, France; Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, 2 rue de la Milétrie, Poitiers 86021, France. Electronic address:

Gastric or gastro-oesophageal junction (GEJ) adenocarcinomas present poor overall survival (OS). First-line chemotherapy regimen for patients with HER2-negative tumours is based on a doublet or triplet of fluoropyrimidine plus platinum salt ± taxane. Second-line chemotherapy (Docetaxel or Irinotecan) improves OS which nonetheless remains poor (around 5 months). The first results of immune checkpoint inhibitors (anti-PD-1) combined with chemotherapy in metastatic gastric and GEJ cancers were discordant in recent phase III trials. Data on dual-blockade (anti-PD-L1 or anti-PD-1 plus anti-CTLA-4) plus chemotherapy are lacking. DURIGAST is a randomised, multicenter, non-comparative, phase II study, evaluating safety and efficacy of FOLFIRI plus Durvalumab (anti-PD-L1) versus FOLFIRI plus Durvalumab and Tremelimumab (anti-CTLA-4) as second-line treatment of advanced gastric and GEJ adenocarcinoma. The primary objective is the rate of patients alive and without progression at 4 months. The main inclusion criteria are: patients with advanced gastric or GEJ adenocarcinoma, pre-treated with fluoropyrimidine + platinum salt ± taxane. Due to a lack of data on FOLFIRI, Durvalumab and Tremelimumab combination, a 2-step safety run-in phase has been performed before the randomised phase II. The safety run-in phase did not show any safety issue and the randomised phase II starts in September 2020.
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http://dx.doi.org/10.1016/j.dld.2020.11.036DOI Listing
December 2020

Management of digestive cancers during the COVID-19 second wave: A French intergroup point of view (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, SFR).

Dig Liver Dis 2021 03 17;53(3):306-308. Epub 2020 Dec 17.

Digestive Oncology Department, Reims University Hospital, Reims, France.

Introduction: The COVID-19 pandemic has major impact of healthcare systems, including cancer care pathways. The aim of this work is to discuss in a multidisciplinary approach the therapeutic and/or strategies adaptations for patients treated for a digestive cancer during the European second wave of COVID-19 pandemic.

Methods: A collaborative work was performed by several French societies to answer how to preserve digestive cancer care with no loss of chance during the second wave of COVID-19. In this context, all recommendations are graded as expert's agreement according to level evidence found in literature until October 2020 and the experience of the first wave of the COVID-19 pandemic.

Results: As far as possible, no therapeutic modification should be carried out. If necessary, therapeutic adjustments may be considered if they do not constitute a loss of chance for patients. Considering the level of evidence all therapeutic modifications need to be discussed in multidisciplinary tumor board meeting and with patient consent. By contrast to first wave cancer prevention, cancer screening, supportive care and clinical trials should be continued.

Conclusion: Recommendations proposed could limit cancer excess mortality due to the COVID-19 pandemic but should be adapted according to the situation in each hospital.
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http://dx.doi.org/10.1016/j.dld.2020.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836265PMC
March 2021

Panel gene profiling of small bowel adenocarcinoma: Results from the NADEGE prospective cohort.

Int J Cancer 2021 Apr 4;148(7):1731-1742. Epub 2021 Jan 4.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris, France.

Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. The NADEGE cohort has enrolled 347 patients with all stage SBA from 2009 to 2012. Next-generation sequencing investigates the presence of 740 hotspot somatic mutations in a panel of 46 genes involved in carcinogenesis. The mismatch repair (MMR) status was assessed by immunochemistry. We have collected 196 tumour samples and 125 had conclusive results for mutation analysis. The number of mutations was 0 in 9.6% of tumours, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. Overall, at least one genomic alteration was observed in 90.4% of tumour. The most frequent genomic alteration was in KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%) genes. KRAS mutations were more frequent in synchronous metastatic tumours than in localised tumours (72.7% vs 38.2%, P = .003). There was no significant difference in the mutation rates according to primary location for the most frequently altered gene. ATM, FGFR3 and FGFR1 gene alterations were associated with Lynch syndrome and IDH1 mutations with Crohn disease. dMMR tumours were associated with younger age, localised tumours, less KRAS but more SMARCB1 mutations. No genomic alteration was associated with overall survival. There is a trend for better survival in patient with dMMR tumours. In conclusion, there is a different genomic alteration profile in SBA according to predisposing diseases. No association between genomic alterations and prognoses was observed except for a trend of better prognoses associated with dMMR.
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http://dx.doi.org/10.1002/ijc.33392DOI Listing
April 2021

Nutrition and physical activity: French intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC, SFP-APA, SFNCM, AFSOS).

BMJ Support Palliat Care 2020 Nov 11. Epub 2020 Nov 11.

Department of Gastroenterology, IBD and Nutrition Support, CHU Beaujon, AP-HP, Paris 7 Diderot University, Clichy La Garenne, France.

This document is a summary of the French intergroup guidelines regarding the nutrition and physical activity (PA) management in digestive oncology. This collaborative work was produced under the auspices of all French medical and surgical societies involved in digestive oncology, nutrition and supportive care. It is based on published guidelines, recent literature review and expert opinions. Recommendations are graded according to the level of evidence. Malnutrition affects more than half of patients with digestive cancers and is often underdiagnosed. It has multiple negative consequences on survival, quality of life and risk of treatment complications. Consequently, in addition to anticancer treatments, supportive care including nutritional support and PA plays a central role in the management of digestive cancers. It is crucial to detect malnutrition (diagnostic criteria updated in 2019) early, to prevent it and to act against it at all stages of the cancer and at all times of the care pathway. In this context, we proposed recommendations for the evaluation and management in nutrition and PA in digestive oncology for each stage of the disease (perioperative setting, during radiation therapy, during systemic treatments, at the palliative phase, after cancer). Guidelines for nutrition and PA management aim at increasing awareness about malnutrition in oncology. They are continuously evolving and need to be regularly updated.
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http://dx.doi.org/10.1136/bmjspcare-2020-002751DOI Listing
November 2020

Non-Alcoholic Steatohepatitis as a Risk Factor for Intrahepatic Cholangiocarcinoma and Its Prognostic Role.

Cancers (Basel) 2020 Oct 29;12(11). Epub 2020 Oct 29.

Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40138 Bologna, Italy.

Non-alcoholic fatty liver disease (NAFLD) and its most aggressive form, non-alcoholic steatohepatitis (NASH), are causing a rise in the prevalence of hepatocellular carcinoma. Data about NAFLD/NASH and intrahepatic cholangiocarcinoma (iCCA) are few and contradictory, coming from population registries that do not correctly distinguish between NAFLD and NASH. We evaluated the prevalence of NAFLD and NASH in peritumoral tissue of resected iCCA ( = 180) and in needle biopsies of matched liver donors. Data of iCCA patients were subsequently analysed to compare NASH-related iCCA (Group A), iCCA arisen in a healthy liver (Group B) or in patients with classical iCCA risk factors (Group C). NASH was found in 22.5% of 129 iCCA patients without known risk factors and in 6.2% of matched controls (risk ratio 3.625, 95% confidence interval 1.723-7.626, < 0.001), while NAFLD was equally represented in both groups. The overall survival of NASH-related iCCA was inferior to that of patients with healthy liver (38.5 vs. 48.1 months, = 0.003) and similar to that of patients with known risk factors (31.9 months, = 0.948), regardless of liver fibrosis. The multivariable Cox regression confirmed NASH as a prognostic factor (hazard ratio 1.773, 95% confidence interval 1.156-2.718, = 0.009). We concluded that NASH (but not NAFLD) is a risk factor for iCCA and might affect its prognosis. Dissecting NASH from NAFLD by histology is necessary to correctly assess the actual role of these conditions. Prevention protocols for NASH patients should also consider the risk for iCCA and not only HCC. Mechanistic studies aimed to find a direct pathogenic link between NASH and iCCA could add further relevant information.
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http://dx.doi.org/10.3390/cancers12113182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692633PMC
October 2020

Risk factors for Coronavirus Disease 2019 (COVID-19) severity and mortality among solid cancer patients and impact of the disease on anticancer treatment: A French nationwide cohort study (GCO-002 CACOVID-19).

Eur J Cancer 2020 12 8;141:62-81. Epub 2020 Oct 8.

Department of Gastroenterology, Saint Louis Hospital, APHP, Université de Paris, Paris, FFCD, France.

Background: Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated.

Patients And Methods: In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and 11th June 2020. The primary end-point was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary end-points.

Results: From April 4 to 11th June 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), The Eastern Cooperative Oncology Group Performance Scale (ECOG PS) ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except for cytotoxic chemotherapy in the subgroup of patients with detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcriptase polymerase chain reaction (RT-PCR), which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment (such as chemotherapy, targeted or immune therapy) interrupted or stopped following diagnosis of COVID-19.

Conclusions: Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis.
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http://dx.doi.org/10.1016/j.ejca.2020.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543792PMC
December 2020

Immune scores in colorectal cancer: Where are we?

Eur J Cancer 2020 11 16;140:105-118. Epub 2020 Oct 16.

Department of Pathology, CHU de Caen, UNICAEN, Normandy Université, Caen, France.

There is growing evidence that the immune system may prevent the occurrence, growth and metastatic diffusion of colorectal cancer (CRC). The role played by the adaptive immune response at the tumour site is critical in the balance between tumour invasion and defence against cancer. Recent data have shown that the evaluation of this immune response may help to define the prognosis and possibly the treatment of localised CRC as well as metastatic CRC. Tumour infiltrates with T cells (CD3+), cytotoxic T cells (CD8+) and memory T cells (CD45RO+) are the immune parameters most consistently and strongly associated with good clinical outcome in CRC. Several scoring systems have been developed, including the Immunoscore®, based on the immunohistochemical determination with a digital image analysis system of the density of CD3+ and CD8+ lymphocytes in the centre and the invasive margin of the tumour. This review will focus on the different immunoscoring systems developed in CRC, their performance, their limitations and their potential for improving patients' care in the future.
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http://dx.doi.org/10.1016/j.ejca.2020.08.024DOI Listing
November 2020

Incidental anal fluorodeoxyglucose uptake: Should we further examine the patient?

World J Clin Cases 2020 Sep;8(17):3679-3690

Department of Gastroenterology, University Hospital of Rennes, Pontchaillou, Rennes 35000, France.

Background: There are no studies on incidental anal F-fluorodeoxyglucose (FDG) uptake.

Aim: To assess the rate and aetiologies of incidental anal FDG uptake and to evaluate the correlation between FDG positron-emission tomography/computed tomography (PET/CT) parameters and the diagnosis of an anorectal disease.

Methods: The data from patients with incidental anal FDG uptake were retrospectively analysed. Patients who underwent anorectal examinations were identified and compared to those who did not undergo examinations. Patients who were offered treatment were then identified and compared to those who did not receive treatment.

Results: Among the 43020 FDG PET/CT scans performed, 197 FDG PET/CT scans of 146 patients (0.45%) reported incidental anal uptake. Among the 134 patients included, 48 (35.8%) patients underwent anorectal examinations, and anorectal diseases were diagnosed in 33 (69.0%) of these patients and treated in 18/48 (37.5%) patients. Among the examined patients, those with a pathology requiring treatment had significantly smaller metabolic volumes (MV) 30 and MV41 values and higher maximal and mean standardized uptake value measurements than those who did not require treatment.

Conclusion: Incidental anal FDG uptake is rare, but a reliable anorectal diagnosis is commonly obtained when an anorectal examination is performed. The diagnosis of an anorectal disease induces treatment in more than one-third of the patients. These data should encourage practitioners to explore incidental anal FDG uptake systematically.
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http://dx.doi.org/10.12998/wjcc.v8.i17.3679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479548PMC
September 2020

Improving the screening of precancerous anal lesions in high-risk subjects with normal cytology: A longitudinal cohort study using simple tests.

Dig Liver Dis 2020 11 9;52(11):1359-1364. Epub 2020 Sep 9.

Department of Gastroenterology, University Hospital of Rennes, Pontchaillou, France; INSERM U1242, COSS (Chemistry Oncogenesis Stress Signaling), University of Rennes 1, Rennes, France.

For patients at high risk of anal cancer, annual screening strategies using invasive evaluation methods are stressful. According to a normal examination at baseline using simple and non invasive tests, the aim of the work was to quantify neoplastic events.

Patients And Method: Data from patients with a normal evaluation at the first visit were retrospectively extracted from a prospective database. The individual follow-up period was at least two years and three evaluations. Patients with abnormal cytology were assessed using high-resolution anoscopy and targeted biopsies.

Results: A total of 182 subjects (F/M: 10/90, aged 48.1(10.6) years, HIV: 81%) were followed for 41(11) months. Anal cytology remained normal in 94 patients (52%), but high-grade anal neoplasms occurred in 28 patients (15%). Patients with a negative HPV16 status at baseline had cumulative probabilities of high-grade AIN of 0.4%(0.1%-1.9%), 2.6%(1.2%-5.9%) and 7.5%(4.5%-12.2%) after 1 year, 2 years and 3 years of follow-up, respectively. These probabilities were lower than those of patients with a positive HPV16 at baseline and those with a previous history of AIN.

Conclusion: In patients with normal cytology and negative HPV16 at baseline, a three-year interval screening may be a less cumbersome alternative to traditional annual screening.
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http://dx.doi.org/10.1016/j.dld.2020.08.022DOI Listing
November 2020

FOLFIRINOX De-Escalation in Advanced Pancreatic Cancer: A Multicenter Real-Life Study.

Oncologist 2020 11 17;25(11):e1701-e1710. Epub 2020 Sep 17.

Oncology Multidisciplinary Research Group (GERCOR), Paris, France.

Background: Our study describes the feasibility and efficacy of a first-line FOLFIRINOX (5-fluorouracil [5FU], folinic acid, irinotecan, and oxaliplatin) induction chemotherapy (CT) followed by de-escalation as a maintenance strategy for advanced pancreatic cancer.

Materials And Methods: This multicenter retrospective study was conducted from January 2011 to December 2018. FOLFIRINOX de-escalation was defined as stopping oxaliplatin and/or irinotecan after at least four cycles of FOLFIRINOX, without evidence of disease progression. Maintenance schedules were fluoropyrimidine monotherapy (intravenous or oral [capecitabine]), FOLFOX (5FU, oxaliplatin), or FOLFIRI (5FU, irinotecan). Primary endpoint was overall survival (OS). Secondary endpoints were first progression-free survival (PFS1), second progression-free survival (PFS2), and toxicity.

Results: Among 321 patients treated with FOLFIRINOX, 147 (45.8%) were included. Median OS was 16.1 months (95% confidence interval [CI], 13.7-20.3) and median PFS1 was 9.4 months (95% CI, 8.5-10.4). The preferred maintenance regimen was FOLFIRI in 66 (45%) patients versus 5FU monotherapy in 52 (35%) and FOLFOX in 25 (17%) patients. Among 118 patients who received maintenance CT with FOLFIRI or 5FU, there was no difference in PFS1 (median, 9.0 vs. 10.1 months, respectively; p = .33) or OS (median, 16.6 vs. 18.7 months; p = .86) between the two maintenance regimens. Reintroduction of FOLFIRINOX was performed in 20.2% of patients, with a median PFS2 of 2.8 months (95% CI, 2.0-22.3). The rates of grade 3-4 toxicity were significantly higher with FOLFIRI maintenance CT than with 5FU (41% vs. 22%; p = .03), especially for neuropathy (73% vs. 9%).

Conclusion: 5FU monotherapy maintenance appeared to be as effective as FOLFIRI, in a FOLFIRINOX de-escalation strategy, which is largely used in France.

Implications For Practice: FOLFIRINOX de-escalation and maintenance is a feasible strategy in advanced pancreatic cancer that decreases chemotherapy toxicity to improve both survival and quality of life. Survivals in patients with maintenance therapy are clinically meaningful. Fluoropyrimidine monotherapy maintenance seems to be as efficient as FOLFIRI and should be a reference arm in future pancreatic cancer maintenance trials.
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http://dx.doi.org/10.1634/theoncologist.2020-0577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648331PMC
November 2020

Maintenance treatment with fluoropyrimidine plus bevacizumab versus fluoropyrimidine alone after induction chemotherapy for metastatic colorectal cancer: The BEVAMAINT - PRODIGE 71 - (FFCD 1710) phase III study.

Dig Liver Dis 2020 10 31;52(10):1143-1147. Epub 2020 Jul 31.

University hospital Saint Louis, APHP, Paris, France.

Background: Maintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens.

Methods: BEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) - but remains unresectable - after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.
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http://dx.doi.org/10.1016/j.dld.2020.06.034DOI Listing
October 2020

Sorafenib Plus Irinotecan Combination in Patients With RAS-mutated Metastatic Colorectal Cancer Refractory To Standard Combined Chemotherapies: A Multicenter, Randomized Phase 2 Trial (NEXIRI-2/PRODIGE 27).

Clin Colorectal Cancer 2020 Dec 15;19(4):301-310.e1. Epub 2020 May 15.

Medical Oncology Departement, Institut du Cancer de Montpellier (ICM), Univ. Montpellier, Montpellier, France; Institut régional du Cancer de Montpellier (IRCM), INSERM, Univ. Montpellier, ICM, Montpellier.

Background: No treatment option was available for patients with RAS-mutated (RASmt) metastatic colorectal cancer (mCRC) who progress after standard combined chemotherapies at the time of the study. After promising results in phase II, the aim of the present NEXIRI-2/PRODIGE 27 trial was to assess the 2-month non-progression rate for sorafenib (NEX) plus irinotecan (IRI), that is, NEXIRI, treatment.

Methods: Patients with RASmt mCRC after failure of oxaliplatin, IRI, fluoropyrimidines, and bevacizumab were randomized between NEXIRI (IRI 120-180 mg/m intravenous, D1 = D15 plus oral NEX 400 mg twice a day) versus IRI (180 mg/m) versus NEX. Primary endpoint was the 2-month non-progression rate. Secondary endpoints included progression-free and overall survival (PFS and OS), safety, and germline cyclin D1 (CCND1) rs9344 polymorphisms analyses.

Results: A total of 173 patients were included, 59 in NEXIRI, 57 in IRI, and 57 in NEX arms. The 2-month non-progression rate was 52.6% (95% confidence interval [CI]: 39%-66%), 21.4% (10%-33%), and 19.3% (9%-30%) for NEXIRI, IRI, and NEX. Median PFS was 3.6 (95% CI: 2-4.2), 1.7 (1.7-1.8), and 2 (1.8-2.3) months and the median OS was 7.2 (5.8-9.4), 6.3 (4.8-8), and 5.6 (3.9-7.7) months for NEXIRI, IRI, and NEX, respectively. For NEXIRI rs9344CCND1 A/A genotype patients, OS was 19.6 months (95% CI: 4.8-not reached). Main grade 3 toxicities included neutropenia, febrile neutropenia, diarrhea, hand-foot syndrome, and hypertension.

Conclusions: In patients with RASmt mCRC who progressed after standard combined chemotherapies, the results of 2-month non-progression rate and median PFS in the NEXIRI arm were in favor of an increase of the time before progression.
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http://dx.doi.org/10.1016/j.clcc.2020.04.008DOI Listing
December 2020

Coeliac-Like Disease Is a Rare Immune-Related Complication Induced by Nivolumab in NSCLC.

J Thorac Oncol 2020 08;15(8):e147-e148

CHU Rennes, Service de Pneumologie, CHU Rennes, Rennes, France; INSERM U1242, Chemestry Oncogenesis Stress and Signaling, CLCC Eugène Marquis, Rennes, France. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2019.12.119DOI Listing
August 2020

[BRAF V600E-mutant colorectal cancers: Where are we?]

Bull Cancer 2020 Sep 14;107(9):881-895. Epub 2020 Jul 14.

Centre hospitalier Lyon Sud, Lyon, France.

The BRAF mutation, observed in 8 % of colorectal cancers (CRC), introduces a particular phenotype and a poor prognosis at the localized or metastatic stage. BRAF mutant CRCs are more often localized in the right colon, poorly differentiated and mucinous. They affect an older population (more often female) and are associated with a more frequent metastatic lymph node and peritoneal evolution. The BRAF mutation is associated with a sporadic microsatellite instability (MSI) status in 20 to 40% of cases. In localized colon cancer, it does not imply any modification of the adjuvant treatment. In metastatic CRC, the first action must be the systematic search for an MSI phenotype, given its frequent association with the presence of a BRAF mutation, in order to propose immunotherapy that has been demonstrated to be very effective in MSI metastatic CRC. In non-MSI CRC, a first-line trichimiotherapy associated with bevacizumab is an option to be favored in patients in good general condition but the association with an anti-EGFR can be discussed, especially when the objective is tumor response. At the same time, surgical resection must be systematically discussed in the case of resectable hepatic metastases since the presence of a BRAF mutation is not a risk factor for recurrence and that prolonged survival may be observed after surgery. In the second or third line, the triplet encorafenib, binimetinib and cetuximab, as well as the doublet encorafenib and cetuximab are superior to the association of irinotecan plus cetuximab in terms of response and survival (phase III study BEACON) and represent a new therapeutic standard. Their use on the front line is under study.
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http://dx.doi.org/10.1016/j.bulcan.2020.04.017DOI Listing
September 2020

Reappraisal of the characteristics, management, and prognosis of intramucosal colorectal cancers and their comparison with T1 carcinomas.

Gastrointest Endosc 2021 Feb 24;93(2):477-485. Epub 2020 Jun 24.

Department of Gastroenterology, University Hospital, 35033 Rennes, France; Rennes 1 University, 35000 Rennes, France; ADECI 35 (Association pour le Dépistage des Cancers en Ille-et-Vilaine), 35040 Rennes, France; COSS (Chemistry Oncogenesis Stress Signaling), UMR_S 1242, Rennes, France.

Background And Aims: The recent description of "invasive" forms of intramucosal carcinoma (IMC) has rekindled interest in studying the characteristics, management, and prognosis of IMCs and comparing them with T1 colorectal cancers (CRCs).

Methods: This population-based study included 282 cases of IMC and 207 cases of T1 CRC diagnosed by colonoscopy after a positive fecal blood test through a screening program.

Results: IMC presented mainly in the form of pedunculated polyps (68.4%) located in the distal colon (69.9%) ≥20 mm in size (60.6%). IMCs were resected endoscopically in 227 (80.5%) patients and surgically resected in 55 (19.5%) patients. Surgical patients had more right-sided, more sessile, and larger lesions. There was no sign of lymphovascular invasion. Compared with T1 CRCs, IMCs demonstrated lower rates of sessile polyps (31.6% vs 49.8%, P < .0001), primary and ultimate surgical treatment (19.5% vs 39.1% and 19.9% vs 78.7%, P < .0001, respectively), lymph node metastasis in surgical patients (0% vs 9.5%, P = .041), cancer recurrence and cancer-related mortality (0% vs 5.6% and 0% vs 2.5%, respectively), and bleeding after endoscopic resection (1.8% vs 8.7%, P = .001). By multivariate analysis of the pooled cohort (IMC + T1 CRC, n = 489), the factors significantly associated with first-line surgery were shown to be polyp characteristics and the gastroenterologist who performed the colonoscopy.

Conclusions: IMCs account for a quarter of all screening-detected CRCs. They have an excellent prognosis regardless of whether endoscopic or surgical treatment is performed. IMCs differ significantly from T1 carcinomas in terms of management and prognosis.
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http://dx.doi.org/10.1016/j.gie.2020.06.052DOI Listing
February 2021

Fluropyrimidine single agent or doublet chemotherapy as second line treatment in advanced biliary tract cancer.

Int J Cancer 2020 Dec 7;147(11):3177-3188. Epub 2020 Jul 7.

Methodology and Quality of Life in Oncology Unit, Besançon University Hospital, Besançon, France.

Fluoropyrimidine (FP) plus platinum chemotherapy has been recently established as a second-line (L2) preferred option in advanced biliary tract cancer (aBTC) (ABC-06 phase III trial). However, the overall survival (OS) benefit was limited and comparison with FP monotherapy was not available. Our aim was to assess the OS of patients treated with a FP monotherapy compared to a doublet with irinotecan or platinum in L2. We performed a retrospective analysis of two large multicenter prospective cohorts: a French cohort (28 centers) and an Italian cohort (9 centers). All consecutive patients with aBTC receiving FP-based L2 after gemcitabine plus cisplatin/gemcitabine plus oxaliplatin L1 between 2003 and 2016 were included. A subgroup analysis according to performance status (PS) and an exploratory analysis according to platinum sensitivity in L1 were planned. In the French cohort (n = 351), no significant OS difference was observed between the FP monotherapy and doublet groups (median OS: 5.6 vs 6.8 months, P = .65). Stratification on Eastern Cooperative Oncology Group (ECOG) PS showed similar results in PS 0-1 and 2. Median OS was not different between FP monotherapy, platinum- and irinotecan-based doublets (5.6 vs 7.1 vs 6.7 months, P = .68). Similar findings were observed in the Italian cohort (n = 174) and in the sensitivity analysis in pooled cohorts (n = 525). No L2 regimen seemed superior over others in the platinum resistant/refractory or sensitive subgroups. Our results suggest that FP monotherapy is as active as FP doublets in aBTC in L2, regardless of the patient PS and country, and could be a therapeutic option in this setting.
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http://dx.doi.org/10.1002/ijc.33146DOI Listing
December 2020

Management of T1 colorectal cancers detected at screening colonoscopy: A study from the French national screening programme.

Dig Liver Dis 2020 08 3;52(8):909-917. Epub 2020 Jun 3.

Department of Gastroenterology, University Hospital, 35033, Rennes, France; Rennes 1 University, 35000, Rennes, France; ADECI 35 (Association pour le Dépistage des Cancers en Ille-et-Vilaine), 35040, Rennes, France; COSS (Chemistry Oncogenesis Stress Signaling), UMR_S 1242, Rennes, France.

Aim: The main aim of this study was to examine the management strategies that were used and to determine the outcomes (survival and recurrence rate) of screen-detected T1-CRC.

Methods: Medical records from 207 patients with T1-CRC diagnosed through the French national screening programme in one district from 2003 to 2015 were analysed. The 5-year overall, CRC-specific and CRC-free survival were calculated for the whole cohort and for the 3 groups treated by endoscopic resection (ER) alone, ER followed by subsequent surgery (ERSS), and primary surgery (PS).

Results: Of the 207 patients, 81 (39%) underwent PS, and 126 (61%) underwent primary ER, of whom 82 (64%) underwent subsequent surgery. The 5-year overall and cancer-specific survival rates were 95.5% (95% CI, 90.8; 97.9) and 98.8% (95% CI, 95.4; 99.7%), respectively. Long-term cancer-specific mortality and recurrence crude rates were 2.4% and 5.6%, respectively. The 5-year CRC-free survival rate was 96.1% (95% CI, 91.8; 98.1%) and did not differ amongst the 3 groups (ER alone, ERSS and PS).

Conclusion: This study demonstrates the good prognosis of screen-detected T1-CRC, regardless of the treatment strategy used. But, there is a room to improve the screening programme quality with regard to the management of screen-detected CRC.
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http://dx.doi.org/10.1016/j.dld.2020.04.022DOI Listing
August 2020

Downstaging with Radioembolization or Chemotherapy for Initially Unresectable Intrahepatic Cholangiocarcinoma.

Ann Surg Oncol 2020 Oct 29;27(10):3729-3737. Epub 2020 May 29.

Departement of Medical Oncology, Centre Eugène Marquis, Rennes, France.

Objective: The aim of this retrospective study was to compare the outcomes of patients resected for intrahepatic cholangiocarcinoma (ICC) with upfront surgery or after downstaging treatment.

Methods: All consecutive patients with ICC between January 1997 and November 2017 were included in a single-center database and retrospectively reviewed. Patients were divided into two groups: upfront resection or resection after downstaging using either chemotherapy alone or selective internal radiation therapy (SIRT) combined with chemotherapy. Survival rates of patients who underwent upfront surgery for ICC were compared with those of patients who underwent surgery after downstaging therapy.

Results: A total of 169 patients resected for ICC were included: 137 underwent upfront surgery and 32 received downstaging treatment because their tumor was initially unresectable (13 received chemotherapy, 19 received SIRT). Median OS was not different between the two groups: 32.3 months [95% confidence interval (CI) 23.9-40.7] with primary surgery versus 45.9 months (95% CI 32.3-59.4) with downstaging treatment (p = 0.54, log-rank test). In a multivariable Cox regression model, downstaging treatment was not associated with a better or worse prognosis; however, delivery of SIRT as a downstaging treatment was associated with a significant benefit in multivariable analysis (hazard ratio 0.34, 95% CI 0.14-0.84; p = 0.019).

Conclusions: Overall survival of patients resected after downstaging treatment was not different compared with the OS of patients resected upfront. Patients should therefore again be discussed with the surgeon following medical treatment. SIRT may be an efficient neoadjuvant therapy in patients with resectable ICC, in order to improve surgical results.
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http://dx.doi.org/10.1245/s10434-020-08486-7DOI Listing
October 2020

Place of anti-EGFR therapy in older patients with metastatic colorectal cancer in 2020.

J Geriatr Oncol 2020 11 23;11(8):1229-1236. Epub 2020 May 23.

Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France; Head of Geriatric Oncology, Paoli-Calmettes Institute, Marseille, France.

Almost half of the new cases of colorectal cancer concern patients aged ≥70 years. However, very few clinical trials have specifically included older patients. As a consequence, the treatment of these patients is controversial because the balance between clinical benefits and toxicities remains uncertain. In patients without comorbidities and with an ECOG performance score of 0-1, treatment indications are similar to those of younger patients. For frail patients, chemotherapy is possible, but a comprehensive geriatric assessment is recommended. Anti-EGFR (epidermal growth factor receptor) therapy is indicated either in combination with chemotherapy in the first-line or second-line setting or as monotherapy in the third-line setting (i.e., after failure of chemotherapy). For fit older patients, clinical trials that compared chemotherapy alone with doublet chemotherapy plus anti-EGFR in either first-line or second-line setting suggested that age is not an absolute contraindication for the use of this regimen. In frail patients, anti-EGFR monotherapy in the first-line, second-line or third-line setting has shown feasibility and antitumor activity and had mainly cutaneous toxicities that were easily managed. In any case, administration of treatment must be very cautious in older patients and the treatment dose needs to be adapted according to comorbidities.
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http://dx.doi.org/10.1016/j.jgo.2020.04.004DOI Listing
November 2020

COVID-19 epidemic: Proposed alternatives in the management of digestive cancers: A French intergroup clinical point of view (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR).

Dig Liver Dis 2020 06 14;52(6):597-603. Epub 2020 May 14.

Department of Hepatogastroenterology, Normandie Université, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, F 76000 Rouen, France. Electronic address:

Introduction: Patients treated for malignancy are considered at risk of severe COVID-19. This exceptional pandemic has affected countries on every level, particularly health systems which are experiencing saturation. Like many countries, France is currently greatly exposed, and a complete reorganization of hospitals is ongoing. We propose here adaptations of diagnostic procedures, therapies and care strategies for patients treated for digestive cancer during the COVID-19 epidemic.

Methods: French societies of gastroenterology and gastrointestinal (GI) oncology carried out this study to answer two main questions that have arisen (i) how can we limit high-risk situations for GI-cancer patients and (ii) how can we limit contact between patients and care centers to decrease patients' risk of contamination while continuing to treat their cancer. All recommendations are graded as experts' agreement according to the level of evidence found in the literature until March 2020.

Results: A proposal to adapt treatment strategies was made for the main GI oncology situations. Considering the level of evidence and the heterogeneous progression of the COVID-19 epidemic, all proposals need to be considered by a multidisciplinary team and implemented with patient consent.

Conclusion: COVID-19 epidemic may significantly affect patients treated for digestive malignancies. Healthcare teams need to consider adapting treatment sequences when feasible and according to the epidemic situation.
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http://dx.doi.org/10.1016/j.dld.2020.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255323PMC
June 2020

Withholding the Introduction of Anti-Epidermal Growth Factor Receptor: Impact on Outcomes in RAS Wild-Type Metastatic Colorectal Tumors: A Multicenter AGEO Study (the WAIT or ACT Study).

Oncologist 2020 02 2;25(2):e266-e275. Epub 2019 Oct 2.

Department of Gastroenterology, Cochin Hospital, Paris, France.

Background: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting.

Materials And Methods: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR).

Results: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007).

Conclusion: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF.

Implications For Practice: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.
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http://dx.doi.org/10.1634/theoncologist.2019-0328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011620PMC
February 2020

Nal-IRI/LV5-FU versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (OESIRI)-PRODIGE 62: A multicentre, randomised, non-comparative phase II study.

Dig Liver Dis 2020 03 30;52(3):347-350. Epub 2019 Dec 30.

Gastroenterology Department, Centre Hospitalo-Universitaire de Poitiers, University of Poitiers, Poitiers, France. Electronic address:

Half of patients newly diagnosed with esophageal squamous cell cancer (ESCC) have metastatic disease (mESCC) and therefore a poor prognosis. Furthermore, half of patients with initial loco-regional disease present disease recurrence after surgery and/or chemoradiation. In mESCC, the recommended first-line treatment combines 5-fluorouracil and cisplatin, although this has not been validated by a phase III trial. Patients with disease progression or recurrence after platinum-based chemotherapy and good performance status probably benefit from second-line chemotherapy. Several molecules have been evaluated in phase I/II trials or retrospective studies (docetaxel, paclitaxel and irinotecan) but no randomised studies are available. OESIRI is a multicentre, randomised, open-label phase II trial designed to evaluate efficacy and safety of liposomal irinotecan (nal-IRI) plus 5-FU versus paclitaxel as second-line therapy in patients with mESCC. The main inclusion criteria are histologically proven mESCC in progression after first-line platinum-based chemotherapy. Patients with initial resectable disease can be included if recurrence occurred within 6 months. The primary objective is to evaluate the percentage of patients alive 9 months after randomisation. Secondary endpoints are progression-free survival, overall survival, response rate, safety and quality of life. In addition, circulating tumour DNA will be monitored to assess its prognostic value.
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http://dx.doi.org/10.1016/j.dld.2019.11.014DOI Listing
March 2020

Radioembolization Plus Chemotherapy for First-line Treatment of Locally Advanced Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

JAMA Oncol 2019 Oct 31. Epub 2019 Oct 31.

Nuclear Medicine, Centre Eugène Marquis, Rennes, France.

Importance: Patients with unresectable intrahepatic cholangiocarcinoma (ICC) have a poor prognosis. Selective internal radiotherapy (SIRT) is a promising treatment option for hepatic tumors, but no prospective studies of combination SIRT with chemotherapy have been published to our knowledge.

Objective: To determine the response rate after SIRT combined with chemotherapy in patients with unresectable ICC.

Design, Setting, And Participants: This phase 2 clinical trial, the Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC) trial, included patients with unresectable ICC who have never received chemotherapy or intra-arterial therapy and were treated at 7 centers which had experience with SIRT between November 12, 2013, and June 21, 2016. Statistical analysis was performed from March 31, 2017, to June 17, 2019.

Interventions: Concomitant first-line chemotherapy with cisplatin, 25 mg/m2, and gemcitabine, 1000 mg/m2 (gemcitabine reduced to 300 mg/m2 for the cycles just before and after SIRT), on days 1 and 8 of a 21-day cycle for 8 cycles. Selective internal radiotherapy was administered during cycle 1 (1 hemiliver disease) or cycles 1 and 3 (disease involving both hemilivers) using glass Y90 microspheres.

Main Outcomes And Measures: Response rate at 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary end points were toxic effects, progression-free survival, overall survival, disease control rate, and response rate according to Choi criteria.

Results: Of 41 patients included in the study, 26 (63%) were male, with a mean (SD) age of 64.0 (10.7) years. Response rate according to RECIST was 39% (90% CI, 26%-53%) at 3 months according to local review and was confirmed at 41% as best response by central review; disease control rate was 98%. According to Choi criteria, the response rate was 93%. After a median follow-up of 36 months (95% CI, 26-52 months), median progression-free survival was 14 months (95% CI, 8-17 months), with progression-free survival rates of 55% at 12 months and 30% at 24 months. Median overall survival was 22 months (95% CI, 14-52 months), with overall survival rates of 75% at 12 months and 45% at 24 months. Of 41 patients, 29 (71%) had grades 3 to 4 toxic effects; 9 patients (22%) could be downstaged to surgical intervention, with 8 (20%) achieving R0 (microscopic-free margins) surgical resection. After a median of 46 months (95% CI, 31 months to not reached) after surgery, median relapse-free survival was not reached among patients who underwent resection.

Conclusions And Relevance: Combination chemotherapy and SIRT had antitumor activity as first-line treatment of unresectable ICC, and a significant proportion of patients were downstaged to surgical intervention. A phase 3 trial is ongoing.
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http://dx.doi.org/10.1001/jamaoncol.2019.3702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824230PMC
October 2019

Validated Nomogram Predicting 6-Month Survival in Pancreatic Cancer Patients Receiving First-Line 5-Fluorouracil, Oxaliplatin, and Irinotecan.

Clin Colorectal Cancer 2019 12 4;18(4):e394-e401. Epub 2019 Sep 4.

S.C. Oncologia, Department of Oncology, ASL BI, Biella, Italy.

Background: FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) is an option for fit patients with metastatic (MPC) and locally advanced unresectable (LAPC) pancreatic cancer. However, no criteria reliably identify patients with better outcomes.

Patients And Methods: We investigated putative prognostic factors among 137 MPC/LAPC patients treated with triplet chemotherapy. Association with 6-month survival status (primary endpoint) was assessed by multivariate logistic regression models. A nomogram predicting the risk of death at 6 months was built by assigning a numeric score to each identified variable, weighted on its level of association with survival. External validation was performed in an independent data set of 206 patients. The study was registered at ClinicalTrials.gov (NCT03590275).

Results: Four variables (performance status, liver metastases, baseline carbohydrate antigen 19-9 level, and neutrophil-to-lymphocyte ratio) were found to be associated with 6-month survival by multivariate analysis or had sufficient clinical plausibility to be included in the nomogram. Accuracy was confirmed in the validation cohort (C index = 0.762; 95% confidence interval, 0.713-0.825). After grouping all cases, 4 subsets with different outcomes were identified by 0, 1, 2, or > 2 poor prognostic features (P < .0001).

Conclusion: The nomogram we constructed accurately predicts the risk of death in the first 6 months after initiation of FOLFIRINOX in MPC/LAPC patients. This tool could be useful to guide communication about prognosis, and to inform the design and interpretation of clinical trials.
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http://dx.doi.org/10.1016/j.clcc.2019.08.004DOI Listing
December 2019

Chemotherapy in Resected Neuroendocrine Carcinomas of the Digestive Tract: A National Study from the French Group of Endocrine Tumours.

Neuroendocrinology 2020 21;110(5):404-412. Epub 2019 Aug 21.

Department of Medical Oncology, Saint-Antoine Hospital, Paris, France.

Background: Neuroendocrine carcinomas (NECs) of the digestive tract are rare and aggressive tumours. In localised disease the treatment is surgery. Based on expert consensus, international guidelines recommend the administration of adjuvant chemotherapy combining etoposide and platinum derivatives, justified by the high risk of metastatic relapse. However, no clinical study has proven the benefit of neoadjuvant or adjuvant chemotherapy.

Objectives: We aimed to evaluate the effect of neoadjuvant +/- adjuvant and adjuvant therapy in this indication.

Methods: We performed a retrospective observational French study to evaluate overall survival (OS) and disease-free survival (DFS), prognostic factors for survival, and chemotherapy toxicity.

Results: Seventy-three patients had surgical resection of a localised digestive NEC between January 1, 2000 and December 31, 2016. The majority of patients presented colorectal (35%) tumours and the median Ki-67 value was 70%. Forty-three patients received chemotherapy, either perioperative (neoadjuvant +/- adjuvant) or adjuvant. The median OS and DFS for the whole population was 24 and 9 months, respectively. The median OS and DFS for patients receiving chemotherapy was 62 and 13 months, respectively. Positive postoperative node status and Ki-67 ≥80% had a negative prognostic impact on OS and DFS. Administration of chemotherapy had a positive prognostic impact on OS and DFS. Sixteen grade 3/4 toxicities were reported without toxic death.

Conclusions: Our results suggest a positive effect on survival of chemotherapy in resected digestive NECs, but further studies are needed to confirm these results.
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http://dx.doi.org/10.1159/000502825DOI Listing
February 2021

Evaluation of two nutritional scores' association with systemic treatment toxicity and survival in metastatic colorectal cancer: an AGEO prospective multicentre study.

Eur J Cancer 2019 09 12;119:35-43. Epub 2019 Aug 12.

Sorbonne Paris Cite, Paris Descartes University, Siric CARPEM, Assistance Publique-Hôpitaux de Paris, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France. Electronic address:

Introduction: The Patient-Generated Subjective Global Assessment (PG-SGA) is currently the standard nutritional assessment tool for patients with cancer. In a retrospective assessment of a prospective cohort, we showed that the Nutritional Risk Index (NRI) seemed to be associated with treatment toxicity and survival in patients with metastatic colorectal cancer (mCRC).

Objective: The objective of this study was to compare these two nutritional tools (PG-SGA and NRI) on their correlation with chemotherapy-related toxicity and survival in non-pre-treated patients with mCRC.

Methods: This prospective multicentre observational study enrolled non-pre-treated patients with mCRC. PG-SGA and NRI were performed at the onset of first-line chemotherapy. Treatment-related toxicities were registered according to National Cancer Institute Common Toxicity Criteria Adverse Event version 4.0. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment.

Results: A total of 168 patients were included from eight French centres. Patients were considered malnourished in 41% of cases according to PG-SGA and 56% of cases according to the NRI. In multivariate analysis, malnutrition according to PG-SGA was significantly associated with chemotherapy-related grade ≥2 clinical toxicities (odds ratio: 3.7; 95% confidence interval [CI]: 1.7-8.4; p = 0.001) and OS (hazard ratio [HR]: 2.6; 95% CI: 1.3-5.3; p = 0.006), but not with PFS (HR: 1.5; 95% CI: 0.8-2.6; p = 0.2). Conversely, malnutrition according to the NRI was not significantly associated with these tolerance and efficacy parameters.

Conclusion: Although more complex to perform in daily oncology practice, the PG-SGA score appears to be the best nutritional assessment tool because of its strong association with clinically relevant oncological outcomes such as OS and treatment-related toxicities in patients with mCRC.
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http://dx.doi.org/10.1016/j.ejca.2019.07.011DOI Listing
September 2019

Inclusion of Older Patients with Cancer in Clinical Trials: The SAGE Prospective Multicenter Cohort Survey.

Oncologist 2019 12 19;24(12):e1351-e1359. Epub 2019 Jul 19.

Clinical Epidemiology and Ageing Unit, Institut Mondor de Recherche Biomédicale, Paris-Est University, Créteil, France.

Background: The primary objective was to evaluate the rates of older patients with colorectal cancer (CRC) who were eligible for a clinical trial, invited to participate, and, ultimately, included. The secondary objective was to assess the reasons for ineligibility, noninvitation, and noninclusion and factors associated.

Materials And Methods: The Sujets AGés dans les Essais Cliniques (SAGE; Older Subjects in Clinical Trials) multicenter prospective cohort was established in seven centers (10 departments of medical oncology, digestive oncology, and digestive surgery) between 2012 and 2016. All patients with CRC aged 65 or older were studied. The endpoints were clinical trial availability, patient's eligibility, invitation, and enrollment in a trial.

Results: We included 577 older patients (mean age ± SD: 75.6 ± 7 years; males: 56%; metastasis: 41%). Thirty-seven trials were ongoing (one trial for older patients). Of the 474 patients with at least one available trial for their cancer stage and site, 127 (27%) were eligible; 84 of these 127 (66%) were invited to participate, and 70 of these 84 (83%) were included. In a multivariate analysis, noninvitation was found to be associated with older age ( = .016): adjusted relative risk (95% confidence interval), 0.14 (0.02-0.60) for ≥80 vs. 65-69; 0.54 (0.18-1.04) for 75-79 vs. 65-69; 0.47 (0.17-0.93) for 70-74 vs. 65-69.

Conclusion: Three-quarters of older patients with CRC were ineligible for a clinical trial. One-third of the eligible patients were not invited to participate in a trial, and 17% of invited patients were not included. Few trials are reserved for older patients. Patients aged 80 or older were significantly less likely to be eligible for a trial and invited to participate. : NCT01754636.

Implications For Practice: The results of this study suggest that barriers to participation of older patients in clinical trials are particularly marked at age 80 years or older. Secondly, the results emphasize the need for trials for older patients. Thirdly, there is also a need for more pragmatic "real-world" trials, rather than solely randomized trials performed in idealized settings with strictly selected patients. Large prospective observational cohorts with a precise follow-up of toxicity, functional decline, and quality of life may constitute one way of generating more data on the risk-benefit ratio for cancer treatments in older patients.
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http://dx.doi.org/10.1634/theoncologist.2019-0166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975930PMC
December 2019