A randomized phase II study of weekly nab-paclitaxel plus gemcitabine or simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic cancer: the AFUGEM GERCOR trial

International audienceBackground : Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC.Methods/design : AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m 2 ) plus sLV5FU2 (leucovorin 400 mg/m 2 followed by bolus 400 mg/m 2 5-fluorouracil and by 5-fluorouracil 2400 mg/m 2 as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed.Discussion : The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC

Long-Term Survival in Gastroesophageal Junction Adenocarcinoma: Ramucirumab

We report a case of long-term survival with complete response of liver metastases within RAINBOW, a randomized, controlled trial of ramucirumab 8 mg/kg intravenously (days 1, 15) versus placebo, both plus paclitaxel 80 mg/m2 intravenously (days 1, 8, 15), every 4 weeks in patients with previously treated advanced gastroesophageal junction adenocarcinoma. A 64-year-old man with gastroesophageal junction adenocarcinoma and liver metastases received first-line folinic acid, 5-fluorouracil plus oxaliplatin (FOLFOX) following jejunostomy. On liver progression, he enrolled in RAINBOW (April 2012), receiving ramucirumab. In November 2013, positron emission tomography scan was consistent with complete metabolic response, confirmed by a follow-up scan in March 2016

Rectal cancer with synchronous unresectable metastases: arguments for therapeutic choice

Environ 4 000 patients sont pris en charge chaque année en France pour un cancer du rectum avec des métastases synchrones jugées non résécables en réunion de concertation pluridisciplinaire (RCP). Il n’existe pas de consensus sur la stratégie thérapeutique à proposer et parmi les trois options possibles, les critères de choix restent relativement imprécis. – La chirurgie première est certes le meilleur traitement pour contrôler les symptômes rectaux mais elle n’a pas démontré qu’elle augmentait la survie et la résécabilité secondaire des métastases par rapport aux autres options et comporte un risque de résection incomplète, de complications pouvant retarder ou empêcher la chimiothérapie, de progression accélérée de la maladie métastatique et de mortalité comprise entre 1 et 5 %. – La radio-chimiothérapie première suivie d’une chirurgie permet le contrôle des symptômes rectaux mais retarde la chimiothérapie pour les métastases qui dominent le pronostic ; elle expose aux mêmes risques de complications que la chirurgie première. – La chimiothérapie première nous paraît intéressante en absence de complications locales sévères (occlusion, hémorragie) ; elle est potentiellement efficace sur les métastases à distance qui conditionnent le pronostic et sur la tumeur primitive qui répond souvent de manière similaire ; elle ne fige pas la stratégie et offre la possibilité de l’adapter à chaque évaluation selon la réponse, la tolérance et les possibilités de résection (tumeur primitive et métastases). Dans tous les cas, il est fondamental de discuter ces dossiers au cas par cas en RCP pour adapter la stratégie thérapeutique aux caractéristiques du patient, de la tumeur primitive et de l’extension métastatique, ainsi qu’à la réponse obtenue aux traitements proposés successivement.Rectal cancers with synchronous unresectable metastases are diagnosed in about 4 000 patients. There is yet no consensus on the therapeutic strategy for these cases which must be discussed during multidisciplinary meeting. Three options are available and arguments of choice remain relatively weak. – First-line resection of the primary rectal tumour is indeed the best treatment to control rectal symptoms but it does not seem to improve survival and secondary resectability of metastases when compared to other options; moreover incomplete resection or complications may delay chemotherapy, accelerate the metastastic process and mortality rate ranges from 1 to 5%. – First-line radio-chemotherapy followed by surgery allows for controlling rectal symptoms but delays chemotherapy for metastases dominating the prognosis; it exposes the patients to the same morbidity and mortality as first-line surgery. – First-line chemotherapy is the third valid option in the absence of major rectal symptoms (occlusion, haemorrhage); chemotherapy is potentially efficient on distant metastases bearing a high prognosis impact and on the primary rectal tumour, which often has a similar response. First-line chemotherapy allows for adapting the therapeutic strategy after each evaluation according to the tumour response, side effects and possibility of resection (primary rectal tumour and metastases). In all cases, medical records of such patients should be discussed during a multidisciplinary meeting to adapt the therapeutic strategy to the patient’s characteristics, primary rectal tumor, metastases staging and evolution

Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study

<p>Abstract</p> <p>Background</p> <p>The anti-VEGF antibody bevacizumab associated with an irinotecan or oxaliplatin-based chemotherapy was proved to be superior to the chemotherapy alone in first or second line treatment of metastatic colorectal cancer (mCRC). However, it was reported to have no efficacy in 3^rdor later-line, alone or with 5FU. The aim of this study was to evaluate the activity of bevacizumab combined with FOLFIRI or FOLFOX in mCRC who have failed prior chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin.</p> <p>Methods</p> <p>Thirty one consecutive patients treated between May 2005 and October 2006 were included in this retrospective study. All of them have progressed under a chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin and received bevacizumab (5 mg/kg) in combination with FOLFIRI or simplified FOLFOX4 every 14 days.</p> <p>Results</p> <p>Ten patients (32.2%) had an objective response (1 CR, 9 PR) and 12 (38.8%) were stabilized. The response and disease control rates were 45.4% and 100% when bevacizumab was administered in 2^ndor 3^rdline and 25% and 55% in 4^thor later line respectively (p = 0.024 and p = 0.008). Among the patients who had previously received the same chemotherapy than that associated with bevacizumab (n = 28) the overall response rate was 35.7% and 39.3% were stabilized. Median progression free survival (PFS) and overall survival (OS) were of 9.7 and 18.4 months respectively. Except a patient who presented a hypertension associated reversible posterior leukoencephalopathy syndrome, tolerance of bevacizumab was acceptable. A rectal bleeding occurred in one patient, an epistaxis in five. Grade 1/2 hypertension occurred in five patients.</p> <p>Conclusion</p> <p>This study suggests that bevacizumab combined with FOLFOX or FOLFIRI may have the possibility to be active in chemorefractory and selected mCRC patients who did not receive it previously.</p

Prediction of survival with second-line therapy in biliary tract cancer: Actualisation of the AGEO CT2BIL cohort and European multicentre validations

BACKGROUND: The benefit of second-line chemotherapy (L2) over standard first-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) chemotherapy in advanced biliary tract cancer (aBTC) is unclear. Our aim was to identify and validate prognostic factors for overall survival (OS) with L2 in aBTC to guide clinical decisions in this setting. METHODS: We performed a retrospective analysis of four prospective patient cohorts: a development cohort (28 French centres) and three validation cohorts from Italy, UK and France. All consecutive patients with aBTC receiving L2 after GEMCIS/GEMOX L1 between 2003 and 2016 were included. The association of clinicobiological data with OS was investigated in univariate and multivariate Cox analyses. A simple score was derived from the multivariate model. RESULTS: The development cohort included 405 patients treated with L1 GEMOX (91%) or GEMCIS. Of them, 55.3% were men, and median age was 64.8 years. Prior surgical resection was observed in 26.7%, and 94.8% had metastatic disease. Performance status (PS) was 0, 1 and 2 in 17.8%, 52.4% and 29.7%, respectively. Among 22 clinical parameters, eight were associated with OS in univariate analysis. In multivariate analysis, four were independent prognostic factors (p &lt; 0.05): PS, reason for L1 discontinuation, prior resection of primary tumour and peritoneal carcinomatosis. The model had the Harrell's concordance index of 0.655, a good calibration and was validated in the three external cohorts (N = 392). CONCLUSION: We validated previously reported predictive factors of OS with L2 and identified peritoneal carcinomatosis as a new pejorative factor in nearly 800 patients. Our model and score may be useful in daily practice and for future clinical trial design

Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer : An International Multicenter Cohort Study

Background. Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS.Methods. This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression.Results. The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS.Conclusions. This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.Peer reviewe

Diagnostic criteria, specific mutations, and genetic predisposition in gastrointestinal stromal tumors

Jean-Baptiste Bachet1,2, Jean-Fran&amp;ccedil;ois Emile1,31EA4340 &amp;ldquo;Epid&amp;eacute;miologie et oncog&amp;egrave;nes des tumeurs digestives&amp;rdquo;, Facult&amp;eacute; de m&amp;eacute;decine PIFO, UVSQ, Guyancourt, France; 2Service de Gastroent&amp;eacute;rologie et Oncologie Digestive, H&amp;ocirc;pital Ambroise Par&amp;eacute;, APHP, Boulogne, France; 3Service d&amp;rsquo;Anatomo-cyto-pathologie, H&amp;ocirc;pital Ambroise Par&amp;eacute;, APHP, Boulogne, FranceAbstract: In 1998, gastrointestinal stromal tumor (GIST) emerged as a distinct oncogenetic entity and subsequently became a paradigm of targeted therapies in solid tumors. Diagnosis of GIST relies on both histology and immunohistochemistry. Ninety-five percent of GISTs express either KIT or DOG-1. Approximately 80%&amp;ndash;90% of GISTs harbor gain-of-function mutations of either KIT or platelet-derived growth factor receptor alpha polypeptide (PDGFRA) receptor tyrosine kinase (RTK). More than 100 different mutations have been described, some of which are associated with specific clinical and/or histological characteristics. Detection of KIT or PDGFRA mutations is recommended in advanced GISTs because they are highly predictive of tumor response to RTK inhibitors, as well as in KIT-negative cases to confirm diagnosis. In most cases, GISTs are sporadic, but in rare cases, they are related with genetic predisposition, such as neurofibromatosis type 1, Carney triad, Carney&amp;ndash;Stratakis syndrome, and inherited KIT or PDGFRA germline mutations.Keywords: gastrointestinal stromal tumors, KIT, PDGFRA, genetic predispositions, imatini

Récepteurs tyrosine-kinase, voies de signalisation et tumeurs digestives

Les récepteurs tyrosine kinase (RTK) sont des pro-oncogènes impliqués dans la pathogénèse de nombreuses tumeurs digestives. Nous avons mené plusieurs travaux de recherche translationnelle et fondamentale sur le RTK KIT et les tumeurs stromales gastro-intestinales (GISTs). Les GISTs avec la delWK557-558 et celles avec une délétion emportant les deux résidus tyrosine de l'exon 11 de KIT semblaient avoir le même pronostique. Les GISTs homozygotes étaient par contre plus souvent malignes que les GISTs hétérozygotes. Les GISTs homozygotes seraient secondaires à une perte d heterozygotie sans perte de matériel génétique. A partir de lignées cellulaires, nous avons démontré que la biologie de KIT dans les cellules hétérozygotes était plus proche de celle des cellules hémizygotes KIT non muté que des hémizygotes KIT muté. Le statut hémizygote/hétérozygote d'une part et la perte ou non des résidus tyrosine de l'exon 11 de KIT d'autre part étaient associés à des profils d'expression d'ARNm et de miARN spécifiques. Enfin, nous avons pu décrire trois familles avec une mutation germinale de l'exon 13 de KIT et proposer des recommandations pour leur prise en charge.Receptor tyrosine kinases (RTKs) are pro-oncogenes involved in the pathogenesis of many gastrointestinal tumors. We conducted several studies of translational and basic research on the RTK KIT and the gastrointestinal stromal tumors (GISTs). GISTs with delWK557-558 and those with a deletion carrying the two tyrosine residues in KIT exon 11 had the same prognosis. Homozygous GISTs appear more often malignant than heterozygous GISTs. We then reported that homozygous GISTs may be secondary to loss of heterozygosity without loss of genetic material. From cell lines, we demonstrated that the biology of KIT in heterozygous cells was closer to that hemizygous unmutated KIT cells that hemizygous mutated KIT. The hemizygous/heterozygous status on the one hand and the loss or non-tyrosine residues of the KIT exon 11 on the other hand were associated with specific expression profiles of mRNA and miRNAs. Finally, we have described three families with a germline mutation in exon 13 of KIT, and we proposed recommendations for their management.VERSAILLES-BU Sciences et IUT (786462101) / SudocSudocFranceF

Dysfonction de l'anastomose porto-systémique en cas de syndrome de Budd-Chiari (retentissement sur la survie à long terme et facteurs prédictifs de sa survenue)

PARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Adjuvant chemotherapy in pancreatic cancer: state of the art and future perspectives

International audiencePurpose of review The modalities of management of resectable pancreatic ductal adenocarcinoma (PDAC) have evolved in recent years with new practice guidelines on adjuvant chemotherapy and results of randomized phase III trials. The aim of this review is to describe the state of the art in this setting and to highlight future possible perspectives.Recent findings Resectable PDAC is the tumor without vascular contact or a limited venous contact without vein irregularity. Several pathologic and biologic robust prognostic factors such as an R0 resection defined by a margin at least 1 mm have been validated. In phase III trials, the doublet gemcitabine-capecitabine provided a statistically significant, albeit modest overall survival benefit, but failed to show an improvement in relapse-free survival. Similarly, gemcitabine plus nab-paclitaxel did not increase disease-free survival. Modified FOLFIRINOX led to improved disease-free survival, overall survival, and metastasis-free survival, with acceptable toxicity. In the future, prognostic and/or predictive biomarkers could lead the optimization of therapeutic strategies and neoadjuvant treatment could become a standard of care in PDAC.Summary After curative intent resection, modified FOLFIRINOX is the standard of care in adjuvant in fit patients with PDAC. Others regimens (monotherapy or gemcitabine-based) are an option in unfit patients