Publications by authors named "Olivier Bouche"

192 Publications

Automatic Identification of Paraffin Pixels on FTIR Images Acquired on FFPE Human Samples.

Anal Chem 2021 Mar 16;93(8):3750-3761. Epub 2021 Feb 16.

BioSpecT EA 7506, Université de Reims Champagne Ardenne, 51 rue Cognacq-Jay, 51097 Reims, France.

The transfer of mid-infrared spectral histopathology to the clinic will be possible provided that its application in clinical practice is simple. Rapid analysis of formalin-fixed paraffin-embedded (FFPE) tissue section is thus a prerequisite. The chemical dewaxing of these samples before image acquisition used by the majority of studies is in contradiction with this principle. Fortunately, the in silico analysis of the images acquired on FFPE samples is possible using extended multiplicative signal correction (EMSC). However, the removal of pure paraffin pixels is essential to perform a relevant classification of tissue spectra. So far, this task was possible only if using manual and subjective histogram analysis. In this article, we thus propose a new automatic and multivariate methodology based on the analysis of optimized combinations of EMSC regression coefficients by validity indices and KMeans clustering to separate paraffin and tissue pixels. The validation of our method is performed using simulated infrared spectral images by measuring the Jaccard index between our partitions and the image model, with values always over 0.90 for diverse baseline complexity and signal-to-noise ratio. These encouraging results were also validated on real images by comparing our method with classical ones and by computing the Jaccard index between our partitions and the KMeans partitions obtained on the infrared image acquired on the same samples but after chemical dewaxing, with values always over 0.84.
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http://dx.doi.org/10.1021/acs.analchem.0c03910DOI Listing
March 2021

Avelumab versus standard second line treatment chemotherapy in metastatic colorectal cancer patients with microsatellite instability: The SAMCO-PRODIGE 54 randomised phase II trial.

Dig Liver Dis 2021 Mar 25;53(3):318-323. Epub 2020 Dec 25.

Gastroenterology Department and Medical Oncology Department, Poitiers University Hospital, Poitiers, France.

Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer (mCRC) patients except those with dMMR/MSI tumors. However, until very recently we had only non-comparative promising data in this population with anti-programmed cell death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies. This comparative phase II trial (NCT03186326), conducted in more than 100 centers in France, will include dMMR/MSI mCRC patients with progression after a first-line treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety of the anti-PDL1 Avelumab versus a standard second-line treatment. Main inclusion criteria were patients aged 18 to 75 years, ECOG performance status ≤2, dMMR/MSI mCRC and failure of a standard first-line regimen. Patient will be randomised to receive Avelumab 10 mg/kg versus standard second-line doublet chemotherapy plus a targeted agent according to tumor RAS status. Patients will be followed for 4 years. A gain of 5 months in median PFS is expected in favour of the Avelumab arm (12 vs 7 months; HR=0.58). Secondary endpoints include objective response rate, overall survival, quality of life and toxicity. In addition, circulating tumour DNA and microbiota will be explored to test their potential prognostic and predictive values. The study was opened in March 2018.
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http://dx.doi.org/10.1016/j.dld.2020.11.031DOI Listing
March 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

Pooled analysis of 115 patients from updated data of Epitopes-HPV01 and Epitopes-HPV02 studies in first-line advanced anal squamous cell carcinoma.

Ther Adv Med Oncol 2020 4;12:1758835920975356. Epub 2020 Dec 4.

Centre Hospitalier Universitaire de Besançon, Besançon, France.

Aims: The addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has shown promising efficacy in advanced squamous cell carcinoma of the anus (SCCA). Preliminary results of Epitopes-HPV01 study showed a high rate of long-lasting complete response to DCF. The prospective, multicenter, Epitopes-HPV02 trial then confirmed the high efficacy of the modified DCF (mDCF) regimen in terms of complete response rate and long-term survival in metastatic or non-resectable locally advanced recurrent SCCA. Here, we present updated results of the Epitopes-HPV01 and Epitopes-HPV02 studies.

Patients & Methods: Epitopes-HPV01 is a prospective study performed by the regional cancer network of Franche-Comté, France. Epitopes-HPV02 is a phase II study supported by two French collaborative oncological groups, performed in 25 centers. Both studies included patients with metastatic, or with unresectable local recurrent SCCA, treated with DCF regimen.

Results: In Epitopes-HPV01, 51 patients were enrolled between September 2012 and January 2019, and 49 patients were included for analysis; while 69 patients were included between September 2014 and December 2016 in Epitopes-HPV02, and 66 patients for analysis. Pooled analysis of 115 patients showed a median progression-free survival of 12.2 months [95% confidence interval (CI) 10.6-16.1] [11.0 months (9.3-16.0) in -HPV02, and 15.6 months (11.2-34.5) in -HPV01, ( = 0.06)]. The median overall survival was 39.2 months (26.0-109.1) [36.3 in -HPV02 (25.2-NR), and 61.1 months (21.4-120.0) in -HPV01 ( = 0.62)]. Objective response rate was 87.7% (90.9% in -HPV02 and 83.3% in -HPV01) with 40.3% of complete response (45.5% in -HPV02 and 33.3% in -HPV01). No differences were observed between standard DCF ( = 54) and mDCF ( = 58) in terms of OS ( = 0.57) and PFS ( = 0.99). 5-years PFS and OS rates were 24.5% and 44.4%, respectively, in the whole population. No treatment-related death was observed.

Conclusion: Updated results of Epitopes-HPV01 and 02 studies, as well as the pooled analysis, confirm mDCF as a standard treatment in patients with advanced SCCA.
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http://dx.doi.org/10.1177/1758835920975356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720302PMC
December 2020

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

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

Dramatic Changes in Oncology Care Pathways During the COVID-19 Pandemic: The French ONCOCARE-COV Study.

Oncologist 2021 02 11;26(2):e338-e341. Epub 2020 Nov 11.

Department of Ambulatory Oncology Care Unit, Reims, France.

The coronavirus disease 2019 (COVID-19) pandemic may have affected cancer management. We aimed to evaluate changes in every oncology care pathway essential step, from screening to treatment, during the pandemic. Monthly oncological activity differences between 2019 and 2020 (screening tests, histopathological analyzes, multidisciplinary tumor board meetings (MTBMs), diagnostic announcement procedures (DAPs), and treatments were calculated in two French areas experiencing different pandemic intensity (Reims and Colmar). COVID-19 has had a dramatic impact in terms of screening (-86% to -100%), diagnosis (-39%), and surgical treatment (-30%). This global decrease in all essential oncology care pathway steps contrasted with the relative stability of chemotherapy (-9%) and radiotherapy use (-16%). Outbreak occurred earlier and with more intensity in Colmar but had a comparable impact in both areas regarding MTMBs and DAPs. The current ONCOCARE-COV study is still in progress and with a longer follow-up to analyze postlockdown situation.
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http://dx.doi.org/10.1002/onco.13578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873337PMC
February 2021

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

Long-Term Prevalence of Sensory Chemotherapy-Induced Peripheral Neuropathy for 5 Years after Adjuvant FOLFOX Chemotherapy to Treat Colorectal Cancer: A Multicenter Cross-Sectional Study.

J Clin Med 2020 Jul 27;9(8). Epub 2020 Jul 27.

Université Clermont Auvergne, INSERM U1107 NEURO-DOL, CHU Clermont-Ferrand, F-63000 Clermont-Ferrand, France.

(1) Background: Oxaliplatin is among the most neurotoxic anticancer drugs. Little data are available on the long-term prevalence and consequences of chemotherapy-induced peripheral neuropathy (CIPN), even though the third largest population of cancer survivors is made up of survivors of colorectal cancer. (2) Methods: A multicenter, cross-sectional study was conducted in 16 French centers to assess the prevalence of CIPN, as well as its consequences (neuropathic pain, anxiety, depression, and quality of life) in cancer survivors during the 5 years after the end of adjuvant oxaliplatin chemotherapy. (3) Results: Out of 406 patients, the prevalence of CIPN was 31.3% (95% confidence interval: 26.8-36.0). Little improvement in CIPN was found over the 5 years, and 36.5% of patients with CIPN also had neuropathic pain. CIPN was associated with anxiety, depression, and deterioration of quality of life. None of the patients with CIPN were treated with duloxetine (recommendation from American Society of Clinical Oncology), and only 3.2%, 1.6%, and 1.6% were treated with pregabalin, gabapentin, and amitriptyline, respectively. (4) Conclusions: Five years after the end of chemotherapy, a quarter of patients suffered from CIPN. The present study showed marked psychological distress and uncovered a failure in management in these patients.
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http://dx.doi.org/10.3390/jcm9082400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465246PMC
July 2020

Expression of the Serrated Markers Annexin A10 or Gremlin1 in Colonic Adenocarcinomas: Morphology and Prognostic Values.

Pathol Oncol Res 2020 Oct 24;26(4):2509-2521. Epub 2020 Jun 24.

Department of Biopathology, Academic Hospital, rue du Général Koenig, 51100, Reims, France.

Describe clinical, histological and molecular charatcteristics and prognosis values of the serrated candidate markers AnnexinA10 and Gremlin1 in colon adenocarcinomas. Immunohistochemical expression of AnnexinA10 and Gremlin1 was evaluated on 346 colonic adenocarcinomas. Clinicopathological, molecular features and prognostic characteristics were then evaluated. A total of 40 colonic adenocarcinomas expressed AnnexinA10 (11.6%) and, 115 expressed Gremlin1 (40.4%). AnnexinA10 expression was significantly associated, on univariate analyses, with female gender (p = 0.03), right tumor location (p < 0.001), differentiation grade 3 (p < 0.001), serrated adenocarcinoma subtype (p < 0.001), serrated (p < 0.001), medullary (p = 0.005), and mucinous component (p = 0.004), cytoplasmic eosinophilia (p < 0.001), discernible nuclei (p = 0.001), preserved polarity (p < 0.001), lymphatic invasion (p = 0.01), BRAFV600E mutation (p < 0.001), MSI-H status (p < 0.001) and CIMP-H status (p = 0.019). Multivariate analyses revealed that mucinous component (p = 0.002), lymphatic invasion (p = 0.02) and BRAFV600E mutation (p < 0.001) were independently associated with AnnexinA10 expression. In addition, AnnexinA10 was an indicator of poorer overall survival (OS) in UICC stage IV adenocarcinomas (p = 0.01) only. Gremlin1 expression was neither associated with serrated adenocarcinoma subtype (p = 0.51) nor with AnnexinA10 expression (p = 0,31), but was significantly associated, in univariate analysis with male gender (p = 0.002), younger age (p = 0.002), left tumor location (p = 0.04), and MSS status (p = 0.03). Gremlin1 expression was associated with better OS only in UICC stage III colon adenocarcinomas (p = 0.006). Colon adenocarcinomas expressing AnnexinA10 have distinct clinico-pathological and molecular features. AnnexinA10 expression is an indicator of poorer OS in UICC stage IV patients. Gremlin1 expression is not associated with serrated adenocarcinomas subtype. Its expression was associated with better OS in UICC Stage III patients.
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http://dx.doi.org/10.1007/s12253-020-00857-5DOI Listing
October 2020

Sarcopenia: An important prognostic factor for males treated for a locally advanced esophageal carcinoma.

Dig Liver Dis 2020 09 31;52(9):1047-1052. Epub 2020 May 31.

Department of Oncology and Radiotherapy, Hopital Saint Louis, France. Electronic address:

Introduction: Sarcopenia is a prognostic factor of esophageal carcinoma (EC) before surgery, with less convincing data reported before chemoradiotherapy (CRT).

Material And Methods: All patients with a locally advanced EC who had been treated with upfront CRT, between 2010 and 2015, were included. The decision of surgery was made after CRT (40-50 Gy). Muscle mass was measured on a single third lumbar vertebra CT-scan slice. Sarcopenia was internationally defined as skeletal muscle index of ≤39cm2/m2 for women and ≤55cm2/m2 for men. Results were additionally analyzed according to clinical parameters, with a cut-off based on the mean skeletal muscle lumbar index (SMI) of the population studied.

Results: Overall, 104 patients were included (male: 69%). Mean SMI was 35cm2/m2 for women and 46cm2/m2 for men, with 81% of patients being sarcopenic (n = 84). The 3-year overall survival (OS) rate, of 34.6%, was not significantly associated with sarcopenia in the whole population. In men, there was, however, a highly significant correlation between SMI and OS (p = 0.003), which remained significant upon multivariate analysis (p = 0.02). When using the mean SMI as cut-off, sarcopenia was significantly associated with 3-year OS (43.3% vs. 26.2%, p = 0.02).

Conclusion: A high sarcopenia level appears negatively associated with OS in male EC patients treated with upfront CRT.
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http://dx.doi.org/10.1016/j.dld.2020.04.009DOI Listing
September 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

Atezolizumab plus modified docetaxel-cisplatin-5-fluorouracil (mDCF) regimen versus mDCF in patients with metastatic or unresectable locally advanced recurrent anal squamous cell carcinoma: a randomized, non-comparative phase II SCARCE GERCOR trial.

BMC Cancer 2020 Apr 25;20(1):352. Epub 2020 Apr 25.

Department of Oncology, University Hospital of Besançon, 3 Boulevard Alexander Flemingn, F-25030, Besançon, France.

Background: Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients.

Methods: Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy.

Discussion: Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA.

Trial Registration: NCT03519295.
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http://dx.doi.org/10.1186/s12885-020-06841-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183720PMC
April 2020

Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR).

Dig Liver Dis 2020 05 28;52(5):473-492. Epub 2020 Mar 28.

Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France. Electronic address:

Introduction: This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org).

Methods: All French medical societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019.

Results: The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET.

Conclusion: These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.
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http://dx.doi.org/10.1016/j.dld.2020.02.011DOI Listing
May 2020

Molecular description of ANGPT2 associated colorectal carcinoma.

Int J Cancer 2020 Oct 22;147(7):2007-2018. Epub 2020 May 22.

INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France.

Angiopoietin-2 (ANGPT2) is a prognostic factor in metastatic colorectal cancer (CRC). Nevertheless, it remains to be elucidated which molecular characteristics make up the ANGPT2-related poor-prognosis CRC subset. Public transcriptomic datasets were collected from Gene Expression Omnibus GEO and with the TCGAbiolinks R-package for the TCGA. After appropriate normalization, differential expression analysis was performed using Benjamini and Hochberg method for false discovery rate. Plasma from two prospective clinical trials were used to investigate the clinical impact of ANGPT2-related biomarkers. In the 935 samples included in four annotated platforms (GPL) and derived from localized CRC, ANGPT2 expression conferred a worst overall survival (HR = 1.20; p = 0.02). CRC stage, ANGPT2 expression but not Consortium Molecular Subtype (CMS) predict overall survival in multivariate analysis. ANGPT2 expression was not correlated with a specific CMS nor to RAS, RAF, MSI, p53, CIN, CIMP genomic alterations. Gene expression analysis revealed that ANGPT2 CRC subset is characterized by angiogenesis-related gene expression, presence of myeloid cells, stromal organization and resistance to chemotherapy. A prognostic model was proposed using seric levels of ANGPT2, STC1 and CD138 in 97 mCRC patients. Our results provide evidence that ANGPT2 is a prognostic factor in localized CRC and defined a specific CRC subset with potential clinical implementation.
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http://dx.doi.org/10.1002/ijc.32993DOI Listing
October 2020

Concurrent losses of skeletal muscle mass, adipose tissue and bone mineral density during bevacizumab / cytotoxic chemotherapy treatment for metastatic colorectal cancer.

Clin Nutr 2020 Nov 22;39(11):3319-3330. Epub 2020 Feb 22.

Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton, Canada. Electronic address:

Background: Changes in skeletal muscle mass (SMM), total adipose tissue mass (TAT) or bone mineral density (BMD) have been described in patients with cancer undergoing various treatments; simultaneous variations of all 3 tissues has not been reported.

Methods: Data were prospectively collected in a clinical study (NCT00489697) including patients with liver metastases of colorectal cancer who received 4 cycles of bevacizumab in combination with cytotoxic chemotherapy. Computerized tomography (CT) at baseline and after chemotherapy was used to quantify skeletal muscle and adipose tissue cross-sectional areas, and mean lumbar spine BMD using validated approaches.

Results: After exclusion of patients lacking adequate CT images or missing data, 72 subjects were included. Patients were 63% male, aged 63.2 ± 10.3 years, 100% had liver metastases and 54%, 24% and 22% respectively has 0, 1 and ≥2 extrahepatic metastases. 100% tolerated 4 cycles of treatment and none showed progressive disease at the end of treatment. The scan interval was 70 days (95% CI, 62.3 to 80.5). Thresholds for loss of tissue were defined as loss ≥ measurement error. 10% of patients showed no loss of any tissue and a further 43% lost one tissue (SMM, TAT or BMD); 47% of patients lost 2 tissues (16.5% lost SMM + TAT, 8% lost SMM + BMD, 10% lost TAT + BMD) or all 3 tissues (12.5%). Catabolic behavior (2 or 3 tissue loss vs 0 or 1 tissue loss) associated with disease burden, including unresectable primary tumor (p = 0.010), presence of extrahepatic (EH) metastases (p = 0.039) and number of EH metastases (p = 0.004). No association was found between the number of tissues lost and treatment response, which was uniformly high, or treatment toxicity, which was uniformly low.

Conclusion: Multiple tissues can be measured in routine CT images and these show considerable inter-individual variation. Substantial losses in some individuals appear to associate with disease burden.
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http://dx.doi.org/10.1016/j.clnu.2020.02.017DOI Listing
November 2020

Fully laparoscopic thermo-ablation of liver malignancies with or without liver resection: tumor location is an independent local recurrence risk factor.

Surg Endosc 2021 Feb 19;35(2):845-853. Epub 2020 Feb 19.

Department of HBP and Digestive Oncological Surgery, Robert Debré University- Hospital, Reims, France.

Background: The aim of this study was to analyze risk factors of local recurrence (LR) after exclusive laparoscopic thermo-ablation (TA) with or without associated liver resection.

Methods: Between 2012 and 2017, among 385 patients who underwent 820 TA in our department, 65 (17%) patients (HCC = 11, LM = 54) had exclusive laparoscopic TA representing 112 lesions (HCC = 17, LM = 95). TA was associated with other procedures in 57% of cases (liver resection 81%). All TA were done without liver clamping. Median tumor size was 1.8 cm [ranges from 0.3 to 4.5], 18% of the lesions were larger than 3 cm in size and 11% close to major liver vessels. Tumors locations were 77.5% in right liver, 36% in S7&S8, and 46% in S7&S8&S4a.

Results: Mortality was nil and morbidity rate 15.4% including Dindo-Clavien > II grade 3%. The median follow-up was 24 months [0.77-75]. Per lesion LR rate after TA was 18% (n = 19 patients) with a mean time of 7.6 months. Among patients with LR, 18 (95%) could have been re-treated successfully (new resection = 11, re-TA = 7). Multivariate analyses revealed that tumor location in S7 alone, S7&S8 and/or S7, S8, or S4a were independent risk factors of LR after TA.

Conclusions: Exclusive laparoscopic TA is a safe and an effective tool to treat liver malignancies with or without liver resection. Other than classical risk factors, tumor location in upper segments of the liver, are independent risk factors for LR.
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http://dx.doi.org/10.1007/s00464-020-07456-0DOI Listing
February 2021

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

Predictive factors for early progression during induction chemotherapy and chemotherapy-free interval: analysis from PRODIGE 9 trial.

Br J Cancer 2020 03 4;122(7):957-962. Epub 2020 Feb 4.

Oncology Department, Centre Georges-François Leclerc, Dijon, France.

Background: Identifying patients with metastatic colorectal cancer who will have an early disease progression during induction chemotherapy (IC) and identifying patients who may have a chemotherapy-free interval (CFI) after IC are two major challenges.

Methods: A logistic model was used to identify factors associated with early progression during IC and with short duration of the first CFI in 488 patients enrolled in the PRODIGE 9 trial. Independent factors were defined with a threshold 0.10.

Results: In multivariate analysis, baseline leukocytes >10 × 10/L (OR = 1.98 [1.02-3.8], p = 0.04), and stable or increasing CEA at 2 months (OR = 3.61 [1.68-7.75], p = 0.01) were independent factors associated with progression during IC. Male gender (OR = 1.725 [0.92-3.325], p = 0.09) and no tumour response at first evaluation (OR = 1.90 [0.96-3.76], p = 0.07) were significantly associated with a short CFI. The presence of BRAF V600E mutation was also associated with short CFI (OR = 4.59 [0.95; 22.3], p = 0.058).

Conclusion: High baseline leukocyte count and the lack of CEA decrease level at first evaluation were associated with early progression, and could be in favour of early chemotherapy intensification. Male gender, no tumour response at first evaluation and BRAF mutation are associated with a short CFI, and may be considered for maintenance chemotherapy after IC.

Clinical Trial Number: NCT00952029.
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http://dx.doi.org/10.1038/s41416-020-0735-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109054PMC
March 2020

Small bowel adenocarcinoma: Results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients.

Int J Cancer 2020 Aug 22;147(4):967-977. Epub 2020 Jan 22.

Department of Oncology, Saint Antoine Hospital, APHP, Paris, France.

Small bowel adenocarcinoma (SBA) is a rare tumour. We conducted a prospective cohort to describe the prevalence, survival and prognostic factors in unselected SBA patients. The study enrolled patients with all stages of newly diagnosed or recurrent SBA at 74 French centres between January 2009 and December 2012. In total, 347 patients were analysed; the median age was 63 years (range 23-90). The primary tumour was in the duodenum (60.6%), jejunum (20.7%) and ileum (18.7%). The prevalence of predisposing disease was 8.7%, 6.9%, 1.7%, 1.7% and 0.6% for Crohn disease, Lynch syndrome, familial adenomatous polyposis, celiac disease and Peutz-Jeghers syndrome, respectively. At diagnosis, 58.9%, 5.5% and 35.6% of patients had localised and resectable, locally advanced unresectable and metastatic disease, respectively. Crohn disease was significantly associated with younger age, poor differentiation and ileum location, whereas Lynch syndrome with younger age, poor differentiation, early stage and duodenum location. Adjuvant chemotherapy (oxaliplatin-based in 89.9%) was performed in 61.5% of patients with locally resected tumours. With a 54-months median follow-up, the 5-year overall survival (OS) was 87.9%, 78.2% and 55.5% in Stages I, II and III, respectively. The median OS of patients with Stage IV was 12.7 months. In patients with resected tumours, poor differentiation (p = 0.047) and T4 stage (p = 0.001) were associated with a higher risk of death. In conclusion, our study showed that the prognosis of advanced SBA remains poor. Tumour characteristics differed according to predisposing disease. In SBA-resected tumours, the prognostic factors for OS were grade and T stage.
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http://dx.doi.org/10.1002/ijc.32860DOI Listing
August 2020

Multicenter phase III randomized trial comparing laparoscopy and laparotomy for colon cancer surgery in patients older than 75 years: the CELL study, a Fédération de Recherche en Chirurgie (FRENCH) trial.

BMC Cancer 2019 Dec 4;19(1):1185. Epub 2019 Dec 4.

Department of Surgery, Paris-Sud University, Assistance Publique Hôpitaux de Paris, Bicetre Hospital, Le Kremlin-Bicetre, France.

Background: Several multicenter randomized controlled trials comparing laparoscopy and conventional open surgery for colon cancer have demonstrated that laparoscopic approach achieved the same oncological results while improving significantly early postoperative outcomes. These trials included few elderly patients, with a median age not exceeding 71 years. However, colon cancer is a disease of the elderly. More than 65% of patients operated on for colon cancer belong to this age group, and this proportion may become more pronounced in the coming years. In current practice, laparoscopy is underused in this population.

Methods: The CELL (Colectomy for cancer in the Elderly by Laparoscopy or Laparotomy) trial is a multicenter, open-label randomized, 2-arm phase III superiority trial. Patients aged 75 years or older with uncomplicated colonic adenocarcinoma or endoscopically unresectable colonic polyp will be randomized to either colectomy by laparoscopy or laparotomy. The primary endpoint of the study is overall postoperative morbidity, defined as any complication classification occurring up to 30 days after surgery. The secondary endpoints are: 30-day and 90-day postoperative mortality, 30-day readmission rate, quality of surgical resection, health-related quality of life and evolution of geriatric assessment. A 35 to 20% overall postoperative morbidity rate reduction is expected for patients operated on by laparoscopy compared with those who underwent surgery by laparotomy. With a two-sided α risk of 5% and a power of 80% (β = 0.20), 276 patients will be required in total.

Discussion: To date, no dedicated randomized controlled trial has been conducted to evaluate morbidity after colon cancer surgery by laparoscopy or laparotomy in the elderly and the benefits of laparoscopy is still debated in this context. Thus, a prospective multicenter randomized trial evaluating postoperative outcomes specifically in elderly patients operated on for colon cancer by laparoscopy or laparotomy with curative intent is warranted. If significant, such a study might change the current surgical practices and allow a significant improvement in the surgical management of this population, which will be the vast majority of patients treated for colon cancer in the coming years.

Trial Registration: ClinicalTrials.gov NCT03033719 (January 27, 2017).
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http://dx.doi.org/10.1186/s12885-019-6376-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894257PMC
December 2019

Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial.

Eur J Cancer 2020 01 21;124:91-101. Epub 2019 Nov 21.

ERYTECH, One Main Street, Suite 1150, Cambridge, MA 02142, USA.

Purpose: This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma.

Methods: Eligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population.

Results: 141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1-8.8) in the eryaspase arm versus 4.9 months (3.1-7.1) in the control arm (HR, 0.63; 95% CI, 0.39-1.01; P = 0.056) and 2.0 months (95% CI, 1.8-3.4) in the eryaspase arm versus 1.8 months (1.4-3.8) in the control arm (HR, 0.67; 95% CI, 0.40-1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37-0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]).

Conclusion: Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.
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http://dx.doi.org/10.1016/j.ejca.2019.10.020DOI Listing
January 2020

Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer.

World J Gastroenterol 2019 Aug;25(29):4007-4018

Oncology Department, Avicenne Hospital, Bobigny 93000, France.

Background: Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown.

Aim: To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management.

Methods: Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up.

Results: Overall, 229 patients (males, 57.6%; mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity; the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%; emollients, 75.5%; both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low.

Conclusion: The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient's quality of life appeared to be limited.
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http://dx.doi.org/10.3748/wjg.v25.i29.4007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689814PMC
August 2019

Gastrointestinal stromal tumours (GISTs): French Intergroup Clinical Practice Guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO).

Dig Liver Dis 2019 09 3;51(9):1223-1231. Epub 2019 Aug 3.

Departments of Hepatogastroenterology and Digestive Oncology, CHU Robert Debré Hospital, Reims, France.

Background: This document is a summary of the French Intergroup guidelines regarding the management of gastrointestinal stromal tumours (GISTs) updated in December 2018.

Design: This collaborative work summarizes clinical practice recommendations (guidelines) on the management of GISTs. It is based on recent literature review, ESMO recommendations and expert opinions.

Results: The diagnosis of GIST is based on histological examination and immunohistochemistry with markers KIT and DOG-1. Each case must be discussed within a multidisciplinary team. Complete surgical resection tumour, avoiding peroperative perforation, is the potentially curative treatment of localized GISTs. The estimation of the recurrence risk is essential, or adjuvant treatment,and follow-up adaptation. Genotyping (KIT and PDGFRA) of all but very low-risk GISTs is recommended. The nature of mutation has a prognostic value and predictive influence on drug efficacy. Imatinib, a tyrosine-kinase inhibitor, is the standard adjuvant treatment after R0 resection of a GIST with a high risk of recurrence, and the first line therapy for advanced GISTs. Suninitib and regorafenib are respectively the second- and third-line standard treatments for advanced GISTs.

Conclusion: Guidelines for management of GISTs are continuously evolving and need to be regularly updated. This constant progress is made possible through clinical and translational research.
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http://dx.doi.org/10.1016/j.dld.2019.07.006DOI Listing
September 2019

Metastatic colorectal cancer (mCRC): French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR).

Dig Liver Dis 2019 10 15;51(10):1357-1363. Epub 2019 Jul 15.

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

Introduction: This document is a summary of the French intergroup guidelines regarding the management of metastatic colorectal cancer (mCRC) published in January 2019, and available on the French Society of Gastroenterology website (SNFGE) (www.tncd.org).

Methods: This collaborative work was realized by all French medical and surgical societies involved in the management of mCRC. Recommendations are graded in three categories (A, B and C), according to the level of evidence found in the literature, up until December 2018.

Results: The management of metastatic colorectal cancer has become complex because of increasing available medical, radiological and surgical treatments alone or in combination. The therapeutic strategy should be defined before the first-line treatment, mostly depending on the presentation of the disease (resectability of the metastases, symptomatic and/or threatening disease), of the patient's condition (ECOG PS, comorbidities), and tumor biology (RAS, BRAF, MSI). The sequence of targeted therapies also seems to have an impact on the outcome (angiogenesis inhibition beyond progression). Surgical resection of metastases was the only curative intent treatment to date, joined recently by percutaneous tumor ablation tools (radiofrequency, microwave). Localized therapies such as hepatic intra-arterial infusion, radioembolization and hyperthermic intraperitoneal chemotherapy, also have seen their indications specified (liver-dominant disease and resectable peritoneal carcinomatosis). New treatments have been developed in heavily pretreated patients, increasing overall survival and preserving quality of life (regorafenib and trifluridine/tipiracil). Finally, immune checkpoint inhibitors have demonstrated high efficacy in MSI mCRC.

Conclusion: French guidelines for mCRC management are put together to help offer the best personalized therapeutic strategy in daily clinical practice, as the mCRC therapeutic landscape is complexifying. These recommendations are permanently being reviewed and updated. Each individual case must be discussed within a multidisciplinary team (MDT).
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http://dx.doi.org/10.1016/j.dld.2019.05.035DOI Listing
October 2019

Mutation Status in Circulating Tumor DNA from Patients with Metastatic Colorectal Cancer: Extended Mutation Analysis from the AGEO RASANC Study.

Cancers (Basel) 2019 Jul 17;11(7). Epub 2019 Jul 17.

Université Sorbonne Paris Cité, INSERM UMR-S1147 MEPPOT, CNRS SNC5014, Centre Universitaire des Saints-Pères, Equipe labellisée Ligue Nationale Contre le Cancer, 75006 Paris, France.

In patients with metastatic colorectal cancer (mCRC), and mutations are currently determined by tumor sample analysis. Here, we report mutation status analysis in paired tumor tissue and plasma samples of mCRC patients included in the AGEO RASANC prospective cohort study. Four hundred and twenty-five patients were enrolled. Plasma samples were analyzed by next-generation sequencing (NGS). When no mutation was identified, we used two methylated specific biomarkers (digital droplet PCR) to determine the presence or absence of circulating tumor DNA (ctDNA). Patients with conclusive ctDNA results were defined as those with at least one mutation or one methylated biomarker. The kappa coefficient and accuracy were 0.79 (95% CI: 0.67-0.91) and 97.3% (95% CI: 95.2-98.6%) between the status in plasma and tissue for patients with available paired samples ( = 405), and 0.89 (95% CI: 0.80-0.99) and 98.5% (95% CI: 96.4-99.5%) for those with conclusive ctDNA ( = 323). The absence of liver metastasis was the main factor associated to inconclusive ctDNA results. In patients with liver metastasis, the kappa coefficient was 0.91 (95% CI, 0.81-1.00) and accuracy was 98.6% (95% CI, 96.5-99.6%). We demonstrate satisfying concordance between tissue and plasma mutation detection, especially in patients with liver metastasis, arguing for plasma ctDNA testing for routine mutation analysis in these patients.
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http://dx.doi.org/10.3390/cancers11070998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679157PMC
July 2019

Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance.

Gastric Cancer 2020 01 2;23(1):73-81. Epub 2019 Jul 2.

Université de Paris, PARCC, INSERM, 75015, Paris, France.

Background: The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown.

Methods: Circulating natural killer (NK) cells, CD4 and CD8 T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56 cells (NK), CD8, and FoxP3 (Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples.

Results: Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (n = 27) than those with intestinal type (n = 40; median 6.3% vs 11.5%; p = 0.02 and median 3.3% vs 5.2%; p = 0.03, respectively). Proportions of circulating MDSC, CD4 and CD8 T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8 T cells, but not NK or FoxP3 cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field; p = 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with < 17% (HR 0.40; 95% CI [0.15-1.06]; p = 0.04). Patients with high CD8 TIL counts (> 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI [0.21-0.92]; p = 0.02). The prognostic value of CD8 TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI [0.18-0.96]; p = 0.039).

Conclusion: Diffuse/mixed-type AGC has lower rates of CD8 TILs and circulating NK cells and Tregs than the intestinal type. This "cold tumor" phenotype may be associated with a worse outcome.
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http://dx.doi.org/10.1007/s10120-019-00983-3DOI Listing
January 2020