Publications by authors named "Jean-Marc Phelip"

74 Publications

What is the Best Therapeutic Strategy for Metachronous Resectable Colorectal Liver Metastases After Adjuvant Oxaliplatin-Based Chemotherapy? A Multidisciplinary Inter-Group Survey.

World J Surg 2021 Mar 18;45(3):822-830. Epub 2020 Nov 18.

Department of Digestive Surgery and Surgical Oncology, Bicêtre Hospital, APHP, Le Kremlin Bicêtre, France.

Background: To report the current clinical practice of French physicians for metachronous resectable liver metastasis (LM) occurring after a FOLFOX adjuvant chemotherapy for primary cancer.

Methods: Twenty four clinical situations were proposed to a panel of experts via 4 learned societies. Clinical situations varied according time of recurrence (early between 6 and 12 month or > 12 month), extension of LM (limited ≤ 2 or extended > 2 lesions), presence of a neuropathy or not, and of a RAS or BRAF mutation.

Results: A total of 157 physicians participated in this study. A consensus was reached in 17 (71%) clinical situations. For an early limited recurrence, whatever presence of neuropathy, the preferred therapeutic approach (45%) was upfront surgery. For an early extended recurrence, whatever presence of neuropathy, there was a consensus (64%) for a preoperative chemotherapy by FOLFIRI + biologic agent. For a late recurrence without neuropathy, there was a consensus (50%) for a preoperative FOLFOX chemotherapy, whatever the extension of LM. For a late recurrence with neuropathy, upfront surgery was chosen (52%) for limited LM, and preoperative chemotherapy by FOLFIRI + biologic agent (73%) for extended LM. No response was influenced by the RAS mutation status. There was a strong consensus for intensified preoperative chemotherapy in all clinical situations for BRAF-mutated LM.

Conclusions: This national survey provides an overview of the practice patterns in the treatment of LM occurring after adjuvant FOLFOX for primary. It could be a basis to establish expert's recommendations for the clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00268-020-05837-zDOI Listing
March 2021

No Difference of Adalimumab Pharmacokinetics When Dosed at 40 mg Every Week or 80 mg Every Other Week in IBD Patients in Clinical Remission After Adalimumab Dose Intensification.

Dig Dis Sci 2020 Sep 16. Epub 2020 Sep 16.

Groupe Immunité des muqueuses et Agents Pathogènes (GIMAP), INSERM U1111- International center for research in infectiology (CIRI), Saint-Etienne, France.

Introduction: The pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other week (EOW) compared to weekly 40 mg has only been supported by modeling systems.

Aim Of The Study: To compare the trough levels of ADA (TLA) and the occurrence of anti-ADA antibodies (AAA) between these two treatment regimens.

Patients And Methods: This was a prospective study including all consecutive patients with inflammatory bowel disease (IBD) who had reached a longstanding and deep remission under treatment with ADA 40 mg once a week. In these patients, the ADA regimen was changed from 40 mg/week to 80 mg EOW. TLA and AAA levels using a drug-tolerant assay were monitored before and ten weeks after from the change in the ADA regimen and the results compared by a Wilcoxon paired test.

Results: Sixty-two patients (60% CD, mean age 35 years) were included. Before and ten weeks after the changes of ADA regimen, the median TLA were (6.9 µg/mL versus 7.0 µg/mL, respectively; P = 0.34) and the AAA levels (3.4 µg/ml-eq versus 3.0 µg/ml-eq, respectively; P = 0.25.) were quite similar. Likewise, quartiles of TLA (Kendall test r = 0.91; P < 0.001) and AAA (r = 0.78; P < 0.001) did not differ before and after ADA regimen. When stratifying all the patients into 4 groups based on drug/antibody levels (immunogenic, subtherapeutic, therapeutic, or supratherapeutic), no patient needed for returning to the previous weekly regimen. In terms of acceptability, more than 60% of patients preferred an injection EOW compared once a week.

Conclusions: In IBD patients who achieved a deep clinical remission under ADA 40 mg once a week, the pharmacokinetic of ADA was similar when ADA regimen was changed to 80 mg EOW. Given the patient's preference for the latter regimen, a modification of injection regimen should be systematically proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-020-06567-xDOI Listing
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2020.06.034DOI Listing
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bulcan.2020.04.017DOI Listing
September 2020

Safety, efficacy and patient-reported outcomes with trifluridine/tipiracil in pretreated metastatic colorectal cancer: results of the PRECONNECT study.

ESMO Open 2020 06;5(3):e000698

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Toscana, Italy.

Background: In RECOURSE (, trifluridine/tipiracil significantly improved overall survival and progression-free survival (PFS) versus placebo in patients with pretreated metastatic colorectal cancer (mCRC). PRECONNECT was designed to further characterise safety and clinical use of trifluridine/tipiracil.

Methods: In this ongoing, international, multicentre, open-label trial, patients with pretreated mCRC received oral trifluridine/tipiracil 35 mg/m twice daily on days 1-5 and 8-12 of each 28-day cycle. The primary endpoint was safety; secondary endpoints included PFS and quality of life (QoL).

Results: 793 patients (median age 62 years) from 13 countries received trifluridine/tipiracil for a median of 2.84 months (IQR 2.64). Adverse events (AEs) were experienced by 96.7%; the most common (≥20% of patients) were neutropaenia, asthenia/fatigue, nausea, anaemia and diarrhoea. Grade ≥3 AEs occurred in 73.9% of patients, with the most common being neutropaenia (39.1% of patients), anaemia (9.8%) and asthenia/fatigue (5.0%). Median PFS was 2.8 months (95% CI 2.7 to 2.9). Median time to Eastern Cooperative Oncology Group performance status deterioration (≥2) was 8.9 months (range 0.03-14.72). There was no clinically relevant change from baseline in QoL.

Conclusions: PRECONNECT showed consistent results with the previously demonstrated safety and efficacy profile of trifluridine/tipiracil, with no new safety concerns identified. QoL was maintained during treatment.

Trial Registration Number: NCT03306394.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2020-000698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264999PMC
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2019-0328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011620PMC
February 2020

Treatment guidelines of metastatic colorectal cancer in older patients from the French Society of Geriatric Oncology (SoFOG).

Dig Liver Dis 2020 05 3;52(5):493-505. Epub 2020 Feb 3.

Department of Geriatry, Georges Pompidou Hospital, APHP, University of Paris, Paris, France.

Background: Several guidelines dedicated to metastatic colorectal cancer (mCRC) are available. Since 2013 no recent guidelines are specifically dedicated to older patients and based on a systematic review.

Materials And Methods: A multidisciplinary Task Force with digestive oncologists, geriatricians and methodologists from the SoFOG was formed in 2016 to update recommendations on medical treatment of mCRC based on a systematic review of publications from 2000 to 2018. Search strategy has followed a standardized protocol from the formulation of clinical questions and definition of a search algorithm to the selection of complete articles for recommendations.

Results: The four selected key questions were: For which older patients with mCRC can we considered: (1) Any chemotherapy, (2) Mono or poly-chemotherapy, (3) Anti-angiogenic therapy, (4) Other targeted therapy. Main recommendations for older patients are: (1) Omission of chemotherapy should be discussed with a geriatrician for patients with severe comorbidities, advanced dementia, uncontrolled psychiatric disorder or severe loss of autonomy. (2) If tumor response is not the main aim, a mono-chemotherapy with 5-fluorouracil combined with bevacizumab is recommended as first-line. (3) For patients with symptoms related to metastases or with a planned metastasis ablation, a doublet chemotherapy combined with bevacizumab or anti-EGFR antibody in the context of a RAS wild type tumor is recommended as first-line. Preliminary data suggest that regorafenib may be used, in its registered indication, in patients under 80 with a performance status of 0 and no autonomy alterations and that trifluridine-tipiracil may be used with a tight supervising of hematological function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2019.12.145DOI Listing
May 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.
View Article and Find Full Text PDF

Download full-text PDF

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

Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial.

Gut 2020 07 24;69(7):1206-1212. Epub 2020 Jan 24.

Department of Immunology, CIC 1408, GIMAP, CHU Saint-Étienne, Saint-Etienne, Rhône-Alpes, France

Objectives: In patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period.

Design: Consecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn's disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable pharmacokinetics of the second anti-TNF were defined by the appearance of undetectable trough levels of anti-TNF with high antibodies (drug-sensitive assay) or by that of antibodies (drug-tolerant assay).

Results: Ninety patients (48 CDs) were included, and 45 of them received AZA after randomisation. The second anti-TNF was adalimumab or infliximab in 40 and 50 patients, respectively. Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy (p<0.001; median time of clinical failure since randomisation 18 vs >24 months). At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22 versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy. Only the use of combination therapy was associated with favourable outcomes after anti-TNF switch.

Conclusion: In case of immune-mediated LOR to a first anti-TNF, AZA should be associated with the second anti-TNF.

Trial Registration Number: 03580876.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2019-319758DOI Listing
July 2020

Folfirinox gemcitabine/nab-paclitaxel as first-line therapy in patients with metastatic pancreatic cancer: a comparative propensity score study.

Therap Adv Gastroenterol 2019 25;12:1756284819878660. Epub 2019 Sep 25.

Department of Gastroenterology and Gastro-intestinal Oncology, Hôpital Européen Georges-Pompidou, APHP, Paris Descartes University, Sorbonne Paris Cité, Paris, France.

Background: Folfirinox (FFX) and gemcitabine/nab-paclitaxel (GN) are both standard first-line treatments in patients with metastatic pancreatic cancer (mPC). However, data comparing these two chemotherapeutic regimens and their sequential use remain scarce.

Methods: Data from two independent cohorts enrolling patients treated with FFX ( = 107) or GN ( = 109) were retrospectively pooled. Primary endpoint was overall survival (OS). Progression-free survival (PFS) was the secondary endpoint. A propensity score based on age, gender, performance status (PS), and presence of liver metastases was used to make groups comparable.

Results: In the whole study population, OS was significantly higher in FFX (14 months; 95% CI: 10-21) than in GN groups (9 months; 95% CI: 8-12) before ( = 0.008) and after ( = 0.021) adjusting for age, number of metastatic sites, liver metastases, peritoneal carcinomatosis and CA19.9 level at baseline. PFS tends to be higher in FFX (6 months) than GN groups (5 months;  = 0.053). After matching ( = 49/group), patients were comparable for all baseline characteristics including PS. In the matched population, there was a trend toward greater OS in patients treated with FFX (HR = 0.67;  = 0.097). However, survival in each group was not solely a result of the first-line regimen. The proportion of patients who were fit for GN after FFX failure (FFX-GN sequence) was higher (46.9%) than the reverse sequence (20.4%;  = 0.01), which suggests a higher feasibility for the FFX-GN sequence. Corresponding median OS were 19 months 9.5 months, respectively ( = 0.094).

Conclusion: This study shows greater OS with FFX than with GN in patients with mPC. GN after FFX failure appears more feasible than the reverse sequence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1756284819878660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764033PMC
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).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2019.05.035DOI Listing
October 2019

Gastrointestinal anastomosis using a new lumen-apposing metal stent for biliary drainage is a good option in the palliative setting.

Endoscopy 2019 11 4;51(11):E335-E336. Epub 2019 Jun 4.

Department of Hepato-gastro-enterology, University Hospital of Saint-Etienne, Saint-Priest-en-Jarez, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0924-5380DOI Listing
November 2019

Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma.

J Hepatol 2019 09 22;71(3):516-522. Epub 2019 May 22.

Department of Hepato-Gastroenterology, University Hospital of Saint-Etienne - Hôpital Nord, Saint-Priest-en-Jarez, France.

Background & Aims: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). Combining sorafenib with another treatment, to improve overall survival (OS) within an acceptable safety profile, might be the next step forward in the management of patients with advanced HCC. We aimed to assess whether a combination of sorafenib and a statin improved survival in patients with HCC.

Methods: The objective of the PRODIGE-11 trial was to compare the respective clinical outcomes of the sorafenib-pravastatin combination (arm A) versus sorafenib alone (arm B) in patients with advanced HCC. Child-Pugh A patients with advanced HCC who were naive to systemic treatment (n = 323) were randomly assigned to sorafenib-pravastatin combination (n = 162) or sorafenib alone (n = 161). The primary endpoint was OS; secondary endpoints were progression-free survival, time to tumor progression, time to treatment failure, safety, and quality of life.

Results: After randomization, 312 patients received at least 1 dose of study treatment. After a median follow-up of 35 months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7 months vs. 10.5 months; hazard ratio = 1.00; p = 0.975); no difference was observed in secondary survival endpoints either. In the univariate analysis, the significant prognostic factors for OS were CLIP score, performance status, and quality of life scores. The multivariate analysis showed that the only prognostic factor for OS was the CLIP score. The main toxicity was diarrhea (which was severe in 11% of patients in arm A, and 8.9% in arm B), while severe nausea-vomiting was rare, and no toxicity-related deaths were reported.

Conclusion: Adding pravastatin to sorafenib did not improve survival in patients with advanced HCC.

Lay Summary: Sorafenib has proven efficacy for the treatment of patients with advanced hepatocellular carcinoma. However, overall survival remains poor in these patients, so we were interested to see if the addition of a statin, pravastatin, improved outcomes in patients with advanced HCC. This randomized-controlled trial demonstrated that the sorafenib-pravastatin combination did not improve overall survival in this study population compared to sorafenib alone. Clinical trial number: NCT01075555.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2019.04.021DOI Listing
September 2019

Early evaluation using a radiomic signature of unresectable hepatic metastases to predict outcome in patients with colorectal cancer treated with FOLFIRI and bevacizumab.

Gut 2020 03 17;69(3):531-539. Epub 2019 May 17.

Radiology, Hopital Maison Blanche, Reims, Champagne-Ardenne, France.

Purpose: The objective of this study was to build and validate a radiomic signature to predict early a poor outcome using baseline and 2-month evaluation CT and to compare it to the RECIST1·1 and morphological criteria defined by changes in homogeneity and borders.

Methods: This study is an ancillary study from the PRODIGE-9 multicentre prospective study for which 491 patients with metastatic colorectal cancer (mCRC) treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab had been analysed. In 230 patients, computed texture analysis was performed on the dominant liver lesion (DLL) at baseline and 2 months after chemotherapy. RECIST1·1 evaluation was performed at 6 months. A radiomic signature (Survival PrEdiction in patients treated by FOLFIRI and bevacizumab for mCRC using contrast-enhanced CT TextuRe Analysis (SPECTRA) Score) combining the significant predictive features was built using multivariable Cox analysis in 120 patients, then locked, and validated in 110 patients. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the logrank test. An external validation was performed in another cohort of 40 patients from the PRODIGE 20 Trial.

Results: In the training cohort, the significant predictive features for OS were: decrease in sum of the target liver lesions (STL), (adjusted hasard-ratio(aHR)=13·7, p=1·93×10), decrease in kurtosis (ssf=4) (aHR=1·08, p=0·001) and high baseline density of DLL, (aHR=0·98, p<0·001). Patients with a SPECTRA Score >0·02 had a lower OS in the training cohort (p<0·0001), in the validation cohort (p<0·0008) and in the external validation cohort (p=0·0027). SPECTRA Score at 2 months had the same prognostic value as RECIST at 6 months, while non-response according to RECIST1·1 at 2 months was not associated with a lower OS in the validation cohort (p=0·238). Morphological response was not associated with OS (p=0·41).

Conclusion: A radiomic signature (combining decrease in STL, density and computed texture analysis of the DLL) at baseline and 2-month CT was able to predict OS, and identify good responders better than RECIST1.1 criteria in patients with mCRC treated by FOLFIRI and bevacizumab as a first-line treatment. This tool should now be validated by further prospective studies.

Trial Registration: Clinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029.Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2018-316407DOI Listing
March 2020

Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial.

Lancet Gastroenterol Hepatol 2019 06 4;4(6):454-465. Epub 2019 Apr 4.

Onxeo, Paris, France.

Background: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed.

Methods: We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m doxorubicin-loaded nanoparticles (30 mg/m group), 20 mg/m doxorubicin-loaded nanoparticles (20 mg/m group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693.

Findings: Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m group; 130 to the 20 mg/m group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group.

Interpretation: Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed.

Funding: Onxeo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2468-1253(19)30040-8DOI Listing
June 2019

Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.

J Clin Oncol 2019 03 1;37(8):658-667. Epub 2019 Feb 1.

24 Centre Hospitalier Universitaire St Etienne, St Etienne, France.

Purpose: No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection.

Patients And Methods: We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m on day 1 and oxaliplatin 85 mg/m infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL.

Results: Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001).

Conclusion: There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.00050DOI Listing
March 2019

Modified FOLFIRINOX versus CisGem first-line chemotherapy for locally advanced non resectable or metastatic biliary tract cancer (AMEBICA)-PRODIGE 38: Study protocol for a randomized controlled multicenter phase II/III study.

Dig Liver Dis 2019 02 28;51(2):318-320. Epub 2018 Nov 28.

Hôpital privé Jean Mermoz, Lyon, France.

Introduction: Combination of cisplatine and Gemcitabine (CisGem) is the reference 1st line Chemotherapy in patients with advanced biliary cancer. FOLFIRINOX demonstrated an overall survival superiority when compared to gemcitabine in 1st line for patients with metastatic pancreatic adenocarcinoma. Because of similarities between pancreatic and biliary cancers, we proposed a randomized trial comparing mFOLFIRINOX and CisGEm.

Aim: PRODIGE38-AMEBICA is a phase II/III trial evaluating efficacy of modifed FOLFIRINOX (D1 bolus removed) or CisGEm on patients with locally advanced non resectable or metastatic biliary tract cancer.

Patients And Methods: Main inclusion criteria are histologically or cytologically proven biliary tract tumor (intra or extra hepatic or hilar or gallbladder carcinoma), measurable disease (metastases and/or primary tumor), Bilirubin <1,5 N and transaminases <5 N. The randomization (ratio 1:1) will be stratified on center, stage of the disease, tumor localization and previous adjuvant treatment. The Phase II trial has an objective of 73% patients alive and without progression at 6 months for Folfirinox (versus 59% for Gemcis). 128 additional patients should be added in the phase III trial with an objective of overall survival improvement of 4 months in favor of mFOLFIRINOX.

Conclusion: The study is opened in France (EudraCT no.: 2015-002282-35). All the patients (188) of the phase II part are currently randomized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2018.11.018DOI Listing
February 2019

First Characterization with Ultrasound Contrast Agent of a Fibrovascular Polyp Before Its Endoscopic Resection: A Case Report (with Videos).

Clin Endosc 2019 Mar 5;52(2):186-190. Epub 2018 Oct 5.

Department of Hepatogastroenterology, University Hospital of Saint-Etienne, Saint-Priest en Jarez, France.

We described for the first time the contrast enhancement of a giant fibrovascular esophageal polyp using ultrasound contrast agent, Sonovue® (Bracco, Milan, Italy) during echoendoscopy. Fine Doppler was unsuccessful in showing vascularization due to the mobile characteristic of the tumor. In contrast, via Sonovue® , tissue microcirculation was highlighted inside the entire head of the polyp, leading to better appreciate the risk of bleeding related to its resection. In a second part, we showed the feasibility of classic polypectomy for this giant polyp (5×5 cm) without complication and results of control endoscopy at 3 months. The present case is summarized in a video.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5946/ce.2018.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453852PMC
March 2019

Intensification of induction chemotherapy before consolidation chemoradiotherapy improves progression-free survival and time without treatment in patients with locally advanced pancreatic cancers.

Oncotarget 2018 Aug 10;9(62):31999-32009. Epub 2018 Aug 10.

Hepatogastroenterology Department, University Hospital of Saint-Etienne, Saint-Etienne, France.

Aims: To assess the interest of induction chemotherapy (ICT) intensification before chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer.

Methods: Charts of patients treated between February 2010 and November 2016 with consolidation capecitabin based-CRT were retrospectively reviewed in this bicentric study. Patients who underwent Gemcitabine as ICT (Group G) were compared to patients treated with intensive ICT (group I). Primary objectives were progression-free survival (PFS), defined as the time from the first day of ICT to progression or last follow-up, and Time without treatment (TWT), as the time from the last day of CRT to progression.

Results: Patients' characteristics were balanced between group I (Folforinox: = 24; GemOx: = 6) and group G ( = 16) including mean age (63.7 vs 68.1 years), and performance status (PS 0-1 :90% vs 93.7%). Median PFS (17.8 months vs 12 months; = 0.02) and TWT (7.4 months vs 2.5 months = 0.01) were statistically better in group I vs group G. These results remained statistically and clinically significant by comparing Folfirinox subgroup to Gemcitabine. A trend to a better median overall survival was observed in group I (20.4 months) vs group G (18.3 months; = 0.07). After adjusting for ICT duration, PS, and CA19.9 level, ICT intensification remains independently prognostic. Toxicity profile was in accordance with Literature.

Conclusion: This study shows ICT intensification before CRT is an interesting approach in patients with locally advanced pancreatic cancer. Further studies are needed to confirm these results, and to assess the specific role of CRT in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112837PMC
August 2018

Outcome and prognostic factors in 593 non-metastatic rectal cancer patients: a mono-institutional survey.

Sci Rep 2018 Jul 16;8(1):10708. Epub 2018 Jul 16.

Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, 108 bis, Avenue Albert Raimond, BP 60008, 42271, Saint-Priest en Jarez, France.

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

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-29040-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048026PMC
July 2018

Outcomes prediction in pre-operative radiotherapy locally advanced rectal cancer: leucocyte assessment as immune biomarker.

Oncotarget 2018 Apr 27;9(32):22368-22382. Epub 2018 Apr 27.

Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, Saint Priest en Jarez, France.

Objective: Leukocytes are hypothesized to reflect the inflammatory tumor microenvironment. We aimed to validate their prognostic significance in a large cohort of patients treated with pre-operative radiation for locally advanced rectal cancer (RC).

Results: From 2004 to 2015, 257 RC patients with available biological data underwent a pre-operative radiotherapy, with a median age of 66 years. The median rectal EQD2 was 49.2Gy. Most of patients experienced concurrent chemotherapy ( = 245, 95.4%), mainly with 5-FU (83.3%). Clear surgical margins (i.e. complete resection) were achieved in 234 patients (91.1%). A complete (Mandard TRG1: = 35, 13.6%) or almost complete pathological response (Mandard TRG2: = 56, 21.8%) were achieved in 91 patients (35.4%). With a median follow-up of 46.1 months, 8 patients (3.1%) experienced local relapse, 38 (14.8%) experienced metastases and 45 (17.5%) died. Elevated pre-radiation neutrophil to lymphocyte ratio (NLR > 2.8) was identified as an independent predictive factor of increased local relapse, of decreased progression-free survival and overall survival in multivariate analysis. Elevated NLR was marginally associated with incomplete pathological response in multivariate analysis, suggesting a possible value as a biomarker of radio-sensitivity.

Conclusions: Pre-radiation NLR is a simple and robust biomarker for risk stratification in locally advanced RC patients undergoing pre-operative radiotherapy, and might select the subpopulation eligible to treatment intensification or to neoadjuvant chemotherapy.

Material And Methods: Clinical records from consecutive patients treated in a single institution between 2004 and 2015 with curative-intent radiotherapy were retrospectively analyzed. Classical prognosis factors of RC and peripheral immune markers based on lymphocytes and neutrophil counts were studied.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976471PMC
April 2018

Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study.

Br J Cancer 2018 07 29;119(1):19-26. Epub 2018 May 29.

Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA, 02114, USA.

Background: Post-hoc analyses of AFP response and progression and their relationship with objective measures of response and survival were performed in patients from REACH.

Methods: Serum AFP was measured at baseline and every 3 cycles (2 weeks/cycle). Associations between AFP and radiographic progression and efficacy end points were analysed.

Results: Median percent AFP increase from baseline was smaller in the ramucirumab than in the placebo arm throughout treatment. Time to AFP progression (HR 0.621; P < 0.0001) and to radiographic progression (HR 0.613; P < 0.0001) favoured ramucirumab. Association between AFP and radiographic progression was shown at 6 (OR 6.44, 95% CI 4.03, 10.29; P < 0.0001) and 12 weeks (OR 2.28, 95% CI 1.47, 3.53; P = 0.0002). AFP response was higher with ramucirumab compared with placebo (P < 0.0001). More patients in the ramucirumab arm experienced tumour shrinkage and AFP response compared with placebo. Survival was longer in patients with AFP response (13.6 months) than in patients without (6.2 months), irrespective of treatment (HR 0.457, P < 0.0001).

Conclusions: Treatment with ramucirumab prolonged time to AFP progression, slowed AFP increase and was more likely to induce AFP response. Similar benefits in radiographic progression and response correlated with AFP changes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-018-0103-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035236PMC
July 2018

Overweight is associated to a better prognosis in metastatic colorectal cancer: A pooled analysis of FFCD trials.

Eur J Cancer 2018 07 26;98:1-9. Epub 2018 May 26.

Digestive Oncology Department, CHU La Timone, APHM, Aix-Marseille Univ, Marseille, France.

Background: Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.

Patients And Methods: A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI <18.5). Interaction tests were performed between BMI effect and sex, age and the addition of antiangiogenics to chemotherapy.

Results: The rate of BMI ≥25 patients was 41.5%, ranging from 37.6% (1991-1999 period) to 41.5% (2000-2006 period) and 44.8% (2007-2013 period). Comparison of overweight patients versus normal BMI range patients revealed a significant improvement of median overall survival (OS) (18.5 versus 16.3 months, HR = 0.88 [0.80-0.98] p = 0.02) and objective response rate (ORR) (42% versus 36% OR = 1.23 [1.01-1.50] p = 0.04) but a comparable median progression-free survival (PFS) (7.8 versus 7.2 months, HR = 0.96 [0.87-1.05] p = 0.35). Subgroup analyses revealed that overweight was significantly associated with better OS in men. OS and PFS were significantly shorter in thin patients.

Conclusion: Overweight patients had a prolonged OS compared with normal weight patients with mCRC. The association of overweight with better OS was only observed in men. The pejorative prognosis of BMI <18.5 was confirmed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2018.03.031DOI Listing
July 2018

Is the Pharmacokinetic Profile of a First Anti-TNF Predictive of the Clinical Outcome and Pharmacokinetics of a Second Anti-TNF?

Inflamm Bowel Dis 2018 08;24(9):2078-2085

Department of Gastroenterology, Hospices Civils de Lyon, University Claude Bernard Lyon and INSERM, Lyon, France.

Aim: The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of a second anti-TNF according to the pharmacokinetics of the first anti-TNF in patients with inflammatory bowel disease (IBD).

Methods: In patients in loss of response (LOR) to a first optimized anti-TNF and switched to a second anti-TNF, pharmacokinetics of anti-TNF were measured at the switch time, 30 weeks later, at the time of LOR, or at the end of the study (102 weeks).

Results: At the switch time, patients (n = 59) belonged to 4 groups according to the pharmacokinetics of the first anti-TNF: group 1 (n = 18), therapeutic trough levels; group 2 (n = 13) undetectable trough levels with antibodies against anti-TNF; group 3 (n = 13) without antibodies against anti-TNF; and group 4 (n = 15) subtherapeutic trough levels. After switching, the failure rates at week 30 and during the follow-up were as follows, respectively: in group 1 with therapeutic levels, 50% and 78%, despite therapeutic levels of the second anti-TNF in 83% of cases; in group 2 with undetectable levels and antibodies, 15% and 69% with undetectable levels of the second anti-TNF and antibodies in 85% of cases; in group 3 with undetectable levels without antibodies, 0% and 31% with therapeutic levels in 77% of cases; in group 4 with subtherapeutic levels, 13% and 33% with therapeutic levels in 73% of cases. Clinical remission rates were significantly lower (P ≤ 0.05) in groups 1 and 2 with therapeutic or undetectable levels with antibodies than in the 2 other groups.

Conclusion: In the case of LOR with therapeutic levels of the first anti-TNF or undetectable levels with antibodies, the switch to a second anti-TNF results in pharmacokinetic profile similar to the first one and again in LOR in most of the patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ibd/izy111DOI Listing
August 2018

Effect of Endocuff-assisted colonoscopy on adenoma detection rate: meta-analysis of randomized controlled trials.

Endoscopy 2018 09 26;50(9):846-860. Epub 2018 Apr 26.

Gastroenterology and Endoscopy Unit, Edouard Herriot Hospital, Lyon, France.

Background: Yield of Endocuff-assisted colonoscopy (EAC) compared with standard colonoscopy is conflicting in terms of adenoma detection rate (ADR). A meta-analysis of randomized controlled trials (RCTs) appears necessary.

Methods: PubMed and Google Scholar were searched in December 2017. Abstracts from Digestive Disease Week and United European Gastroenterology Week meetings were also searched to 2017. All RCTs comparing EAC with standard colonoscopy were included. Analysis was conducted by using the Mantel-Haenszel models. Heterogeneity was quantified using the test.

Results: Of the 265 articles reviewed, 12 RCTs were included, with a total of 8376 patients (EAC group 4225; standard colonoscopy group 4151). In the meta-analysis, ADR was significantly increased in the EAC group vs. the standard colonoscopy group (41.3 % vs. 34.2 %; risk ratio [RR] = 1.20, 95 % confidence interval [CI] 1.06 to 1.36;  = 0.003;  = 79 %), especially for operators with low-to-moderate ADRs (< 35 %): RR = 1.51, 95 %CI 1.35 to 1.69;  < 0.001;  = 43 %). In contrast, this benefit was not reached for operators with high ADRs (> 45 %): RR = 1.01, 95 %CI 0.93 to 1.09;  = 0.87;  = 0.0 %). The mean number of adenomas per patient tended to be higher with EAC (mean difference = 0.11 adenomas/patient, 95 %CI - 0.17 to 0.38). Similar results were shown for polyp detection rates (61.6 % vs. 51.4 %; RR = 1.20, 95 %CI 1.06 to 1.36;  = 0.004). Use of the Endocuff did not impact the cecal intubation rate (95.1 % vs. 95.7 %;  = 0.08), or the procedure time compared with standard colonoscopy. Adverse events related to Endocuff were rare and exclusively mild mucosal erosion (4.0 %; 95 %CI 2.0 % to 8.0 %).

Conclusion: With moderate-quality evidence, this study showed an improvement in ADR with EAC without major adverse events, especially for operators with low-to-moderate ADRs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0577-3500DOI Listing
September 2018

Bevacizumab Maintenance Versus No Maintenance During Chemotherapy-Free Intervals in Metastatic Colorectal Cancer: A Randomized Phase III Trial (PRODIGE 9).

J Clin Oncol 2018 03 18;36(7):674-681. Epub 2018 Jan 18.

Thomas Aparicio, Centre Hospitalier Universitaire (CHU) Saint Louis, Assistance Public Hôpitaux de Paris (APHP), and Université Paris 7, Sorbonne Paris Cité; Julien Taieb, Hôpital Européen Georges Pompidou, Paris; Francois Ghiringhelli, Centre Georges-François Leclerc; Karine Le Malicot, Fédération Francophone de Cancérologie Digestive; Come Lepage, CHU Le Bocage, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche (UMR) 1231, Dijon; Valérie Boige, Institut Gustave Roussy, Villejuif; Olivier Bouché, CHU Robert Debré, Reims; Jean-Marc Phelip, CHU Saint Etienne-Hôpital Nord, Saint Priest en Jarez; Eric François, Centre Antoine Lacassagne, Nice; Christian Borel, Paul Strauss Center, Strasbourg; Roger Faroux, Centre Hospitalier (CH) La Roche sur Yon, La Roche sur Yon; Laetitia Dahan, CHU La Timone, Aix-Marseille-University, Marseille; Stéphane Jacquot, Centre de Cancérologie du Grand Montpellier, Montpellier; Dominique Genet, Accompagnement de la Recherche Clinique Hospitalière (ARCH)/Polyclinique, Limoges; Faiza Khemissa, CH Saint Jean, Perpignan; Etienne Suc, Clinique Saint Jean du Languedoc, Toulouse; Françoise Desseigne, Centre Léon Bérard, Lyon; Patrick Texereau, CH Layne, Mont-De-Marsan; and Jaafar Bennouna, Institut de Cancérologie de l'Ouest, Saint Herblay, France.

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

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2017.75.2931DOI Listing
March 2018

Tolerance and outcomes of sorafenib in elderly patients treated for advanced hepatocellular carcinoma.

Dig Liver Dis 2017 Sep 23;49(9):1043-1049. Epub 2017 Jun 23.

Hepato-Gastroenterology Department, University Hospital of Saint-Etienne, Saint Priest en Jarez, France; University Jean Monnet, LINA EA 4624, France.

Introduction: Use of sorafenib remains debated in elderly patients treated for advanced hepatocellular carcinoma (HCC).

Methods: This was a bicentric retrospective study including all patients ≥75years and treated with sorafenib for advanced HCC between January 2010 and March 2014.

Results: Of the 51 patients included (median age: 78 years, range: 75-92; performance status (PS) 0-1: 98%; cirrhosis: 88.2%; Child-Pugh A: 95.6%) all experienced at least one adverse event (AE). About 2/3 of them (66.7%) had grade 3-4 toxicities, including fatigue (43.1%), hand foot skin syndrome (11.8%), anorexia (9.8%) or diarrhea (9.8%). After adjustment for arterial hypertension, heart failure, other(s) cardiovascular history(ies), and sorafenib dose at baseline, only patients ≥80 years were associated with severe AE (OR: 13.3; p=0.009). Discontinuation for toxicity was reported in 31 (60.8%) patients, mainly within the 3rd months, especially in those who had PS ≥1 at baseline (OR: 10.4; p=0.01), or other cardiovascular histories (OR: 30.9; p=0.016). In this setting, overall survival was significantly reduced (HR: 4.5; p<0.0001).

Conclusion: Tolerance of Sorafenib seems to be low in elderly, especially for patients aged ≥80 years or with PS ≥1. Starting with reduced dose of sorafenib does not seem to impact results. Some of these patients may truly benefit from the treatment in terms of survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2017.06.008DOI Listing
September 2017

Barrett's Oesophagus and Oesophageal Carcinogenesis Following Obesity Surgery: Helicobacter Pylori Must Be Eradicated?

Obes Surg 2017 09;27(9):2464-2465

Department of General Surgery, CHU Hospital, Jean Monnet University, Avenue Albert Raimond, 42270, Saint Etienne, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11695-017-2785-4DOI Listing
September 2017