Olivier Dubreuil

VEGFA-VEGFR Pathway Blockade Inhibits Tumor-Induced Regulatory T-cell Proliferation in Colorectal Cancer

Multitarget antiangiogenic tyrosine kinase inhibitors (TKI) have been shown to reduce regulatory T cells (Treg) in tumor-bearing animals and patients with metastatic renal carcinomas. However, a direct role of the VEGF-A/VEGFR pathway inhibition in this phenomenon is a matter of debate and molecular mechanisms leading to Treg modulation in this setting have not been explored to date. Treg proportion, number, and proliferation were analyzed by flow cytometry in peripheral blood of patients with metastatic colorectal cancer (mCRC) treated with bevacizumab, a monoclonal antibody targeting specifically VEGF-A, and in colon cancer-bearing mice (CT26) treated with drugs targeting the VEGF/VEGFR axis. The direct impact of VEGF-A on Treg induction was assessed together with specific blockade of different isoforms of VEGFRs that may be involved. In CT26-bearing mice, anti-VEGF antibody and sunitinib treatments reduced Treg but masitinib, a TKI not targeting VEGFR, did not. Targeting VEGF-A/VEGFR axis seems sufficient to affect Treg percentages, without any changes in their function. Similarly, bevacizumab inhibited Treg accumulation in peripheral blood of patients with mCRCs. In vitro, Treg expressing VEGFR from tumor-bearing mice directly proliferated in response to VEGF-A. Anti-VEGF-A treatment decreased Treg proliferation in mice as well as in patients with mCRCs. VEGFR-2- but not VEGFR-1-specific blockade led to the same results. We identified a novel mechanism of tumor escape by which VEGF-A directly triggers Treg proliferation. This proliferation is inhibited by VEGF-A/VEGFR-2 blockade. Anti-VEGF-A therapies also have immunologic effects that may be used with a therapeutic goal in the future.

Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker

Purpose: Despite recent therapeutic advances, prognosis of patients with pancreatic adenocarcinoma remains poor. Analyses from tumor tissues present limitations; identification of informative marker from blood might be a promising alternative. The aim of this study was to assess the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma. Experimental Design: From 2011 to 2015, blood samples were prospectively collected from all consecutive patients with pancreatic adenocarcinoma treated in our center. Identification of ctDNA was done with next-generation sequencing targeted on referenced mutations in pancreatic adenocarcinoma and with picoliter droplet digital PCR. Results: A total of 135 patients with resectable (n = 31; 23%), locally advanced (n = 36; 27%), or metastatic (n = 68; 50%) pancreatic adenocarcinoma were included. In patients with advanced pancreatic adenocarcinoma (n = 104), 48% (n = 50) had ctDNA detectable with a median mutation allelic frequency (MAF) of 6.1%. The presence of ctDNA was strongly correlated with poor overall survival (OS; 6.5 vs. 19.0 months; P < 0.001) in univariate and multivariate analyses (HR = 1.96; P = 0.007). To evaluate the impact of ctDNA level, patients were grouped according to MAF tertiles: OS were 18.9, 7.8, and 4.9 months (P < 0.001). Among patients who had curative intent resection (n = 31), 6 had ctDNA detectable after surgery, with an MAF of 4.4%. The presence of ctDNA was associated with a shorter disease-free survival (4.6 vs.17.6 months; P = 0.03) and shorter OS (19.3 vs. 32.2 months; P = 0.027). Conclusions: ctDNA is an independent prognostic marker in advanced pancreatic adenocarcinoma. Furthermore, it arises as an indicator of shorter disease-free survival in resected patients when detected after surgery. Clin Cancer Res; 23(1); 116–23. ©2016 AACR.

Neoadjuvant sorafenib combined with gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma

This paper reports the first case of a patient with hepatocellular carcinoma with lymph node metastasis treated by sorafenib combined with gemcitabine plus oxaliplatin, with a partial response and normalization of α fetoprotein, which allowed curative surgery. The potential synergy between these three drugs needs to be confirmed, and is currently being investigated in a randomized phase II trial.

Double pancreatic and gastric adenocarcinomas: A rare association

Synchronous gastric and pancreatic cancers represent a very rare association. The role of tomodensitometry, endoscopic ultrasound and histology is primordial to differentiate between double tumors, local extension or metastasis. We report in our paper two cases of synchronous gastric and pancreatic cancers treated with Folforinox. Then, we discuss the risk factors, the diagnostic methods, the treatment modalities and the prognosis of these rare double cancers.

Patient-reported tolerance in treatments approved in neuroendocrine tumors: A national survey from the French Group of Endocrine Tumors

BACKGROUND Patients with advanced neuroendocrine tumors (NETs) benefit from an increasing number of treatments. The patients preference could help physicians to choose among these options. Our patient-reported survey aims to compare the perceived tolerance of NETs treatments. METHODS Patients treated by at least three different therapeutic options have evaluated their perceived tolerance from one (very good) to five (very poor) for each single treatment. Referent physician confirmed the type and ranking over time of each treatment. RESULTS Two hundred and fourty two treatments have been evaluated by 54 patients. Among patients and NETs characteristics, only a female gender was associated with poor perceived tolerance. Median perceived tolerance increased from 1 (somatostatin analogs, peptide receptor radionuclide therapy (PRRT)), 2 (surgery, radiofrequency ablation and oral chemotherapy), 3 (interferon and everolimus), to 4 (liver embolization, sunitinib and intravenous chemotherapy). In taking somatostatin analogs as reference, the odd ratios for poor perceived tolerance were 1.7 [0.6-5.1] for oral chemotherapy, 2.2 [0.9-5.3] for surgery of the primary tumor, 2.4 [0.6-9.5] for radiofrequency ablation, 2.8 [1.1-7.3] for surgery of metastasis, 3.4 [1.4-7.9] for everolimus, 3.7 [1.6-8.5] for liver embolization, 4.9 [2.2-10.7] for intravenous chemotherapy and 5.9 [2.6-13.1] for sunitinib. Only PRRT had negative odd ratio. CONCLUSION Our retrospective analysis suggests that perceived tolerance differ in between therapeutic options and may help physicians to sequence the therapeutic strategy.

Efficacy of a docetaxel-5FU-oxaliplatin regimen (TEFOX) in first-line treatment of advanced gastric signet ring cell carcinoma: an AGEO multicentre study

BackgroundTriplet chemotherapy, with docetaxel-5FU-oxaliplatin (TEFOX), has yielded promising results in patients with advanced and operable gastric adenocarcinoma. This may prove useful in treating signet ring cell carcinoma (SRCC), which is known to be chemoresistant and has a poor prognosis. We therefore evaluated TEFOX in patients with untreated advanced SRCC.MethodsPatients with metastatic or locally advanced non-resectable SRCC were treated with TEFOX. Chemotherapy was administered every 14 days, with combined docetaxel (50 mg/m2) and oxaliplatin (85 mg/m2) followed by 5FU (2400 mg/m2).ResultsAmong 65 patients enrolled, including 17 with linitis plastica, ORR and DCR were 66.1% and 87.6%, respectively. Median PFS and OS were 9.7 months (95% CI [6.9–11.4]) and 14.3 months (95% CI [11.6–21.6]) respectively. Twenty-six patients (40%) initially considered as unresectable had secondary resection (n = 24) or radiotherapy (n = 2) with curative intent, with median PFS and OS of 12.4 and 26.2 months, respectively.ConclusionsTEFOX appears to be effective as first-line treatment in advanced gastric SRCC and has an acceptable safety profile. It allowed a curative intent approach in 40% of patients. Considering the low chemosensitivity of SRCC reported with other chemotherapy regimens and pending for randomised studies, TEFOX might be an option in advanced gastric SRCC.

Evaluating bevacizumab in combination with FOLFIRI after the failure of platinum-etoposide regimen in patients with advanced poorly differentiated neuroendocrine carcinoma: The PRODIGE 41–BEVANEC randomized phase II study

INTRODUCTION Patients with gastroenteropancreatic (GEP), metastatic or locally advanced, non-resectable, grade 3 poorly-differentiated neuroendocrine carcinoma (NEC) are treated with cisplatin (or carboplatin)-etoposide in first-line palliative chemotherapy (CT1). However, nearly all patients will develop resistance and there is no standard second-line treatment. AIM PRODIGE 41-BEVANEC is an academic randomized, phase II study designed to evaluate the efficacy of bevacizumab in combination with FOLFIRI after failure of CT1 in unknown primary NEC and GEP-NEC. MATERIALS AND METHODS The main eligibility criteria are age ≥18 years, metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 3 GEP-NEC, and documented progressive disease during or after CT1 therapy. RESULTS A total of 124 patients will be randomly assigned (1:1) to receive either 5 mg/kg bevacizumab with FOLFIRI, or FOLFIRI alone, every 14 days until disease progression or unacceptable toxicity. The hypothesis is to demonstrate a 6-month overall survival for at least 50% of the patients in bevacizumab arm versus 35% in the control arm (FOLFIRI alone). Secondary endpoints are objective response, response duration, progression-free survival, toxicity, and biochemical response. CONCLUSION The study is currently opened in France (NCT02820857). The first patient was randomized on September 6, 2017.

Clinical outcome of portal vein thrombosis in patients with digestive cancers: A large AGEO multicenter study

INTRODUCTION Management of portal vein thrombosis (PVT) in cancer patients remains discussed. AIMS The objective of this multicenter retrospective study was to investigate the management and outcome of PVT in patients with digestive cancers other than hepatocellular carcinoma (HCC). METHOD Main inclusion criteria were trunk or branch PVT in patients with locally advanced or metastatic digestive cancers. Predictive factors of bleeding and overall survival (OS) were evaluated in univariate and multivariate analysis. RESULTS Between 2012 and 2016, 118 patients with PVT and digestive cancers were identified. The majority had a pancreatic cancer (50%). Sixty-six percent of patients had trunk PVT location. Endoscopic screening of portal hypertension was performed in only 7 patients (1%) and 5 had esophageal varices. Gastrointestinal bleeding occurred in 22 patients (19%) and 12 patient deaths (17%) were related to a gastrointestinal hemorrhage. Metastatic disease (HR=2.83 [95%CI 1.47-5.43], p<0.01) and gastrointestinal hemorrhage (HR=1.68 [95%CI 1.01-2.78], p=0.04) were associated with OS in multivariate analysis. Only trunk PVT location was significantly associated with gastrointestinal hemorrhage in multivariate analysis (HR=5.56 [95%CI 1.18-26.32], p=0.03). CONCLUSION A high rate of variceal bleeding leading to death was found in this cohort. Endoscopic screening and the efficacy of prophylactic treatment of variceal bleeding remain to be evaluated in a prospective study.

Impact of OPTIMOX-aflibercept as first-line therapy on time to health-related quality of life deterioration in patients with unresectable metastatic colorectal cancer: results of the GERCOR VELVET phase II single arm study.

e15009Background: Recent studies showed improvement of patients outcomes with addition of aflibercept to FOLFIRI as second-line therapy for metastatic colorectal cancer (mCRC). The addition of afli...

Sequential FOLFIRI.3 + Gemcitabine Improves Health-Related Quality of Life Deterioration-Free Survival of Patients with Metastatic Pancreatic Adenocarcinoma: A Randomized Phase II Trial

Background A randomized multicenter phase II trial was conducted to assess the sequential treatment strategy using FOLFIRI.3 and gemcitabine alternately (Arm 2) compared to gemcitabine alone (Arm 1) in patients with metastatic non pre-treated pancreatic adenocarcinoma. The primary endpoint was the progression-free survival (PFS) rate at 6 months. It concludes that the sequential treatment strategy appears to be feasible and effective with a PFS rate of 43.5% in Arm 2 at 6 months (26.1% in Arm 1). This paper reports the results of the longitudinal analysis of the health-related quality of life (HRQoL) as a secondary endpoint of this study. Methods HRQoL was evaluated using the EORTC QLQ-C30 at baseline and every two months until the end of the study or death. HRQoL deterioration-free survival (QFS) was defined as the time from randomization to a first significant deterioration as compared to the baseline score with no further significant improvement, or death. A propensity score was estimated comparing characteristics of partial and complete responders. Analyses were repeated with inverse probability weighting method using the propensity score. Multivariate Cox regression analyses were performed to identify independent factors influencing QFS. Results 98 patients were included between 2007 and 2011. Adjusting on the propensity score, patients of Arm 2 presented a longer QFS of Global Health Status (Hazard Ratio: 0.52 [0.31-0.85]), emotional functioning (0.35 [0.21–0.59]) and pain (0.50 [0.31 – 0.81]) than those of Arm 1. Conclusion Patients of Arm 2 presented a better HRQoL with a longer QFS than those of Arm 1. Moreover, the propensity score method allows to take into account the missing data depending on patients’ characteristics. Trial registration information Eudract N° 2006-005703-34. (Name of the Trial: FIRGEM).