Leon Berard Cancer Center

Sainte-Foy-lès-Lyon, France

Leon Berard Cancer Center

Sainte-Foy-lès-Lyon, France
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Gronchi A.,Italian National Cancer Institute | Bui B.N.,Institute Bergonie | Bonvalot S.,CNRS Gustave Roussy Institute | Pilotti S.,Italian National Cancer Institute | And 11 more authors.
Annals of Oncology | Year: 2012

Background: To evaluate neoadjuvant trabectedin (1.5 mg/m. 2 24-h i.v. infusion every 3 weeks; three to six cycles) in patients with locally advanced myoxid liposarcoma (ML) previously untreated with chemotherapy or radiation. Patients and methods: Primary efficacy end point was pathological complete response (pCR) or tumoral regression rate. Objective response according to RECIST (v.1.0) was a secondary end point. Results: Three of 23 assessable patients had pCR [13%; 95% confidence interval (CI), 3% to 34%]. Furthermore, very good and moderate histological responses were observed in another 2 and 10 patients, respectively. Histological decrement in the cellular and vascular tumor component and maturation of tumor cells to lipoblasts were observed in both myoxid and myoxid/round cell variants. Seven patients had partial response according to RECIST (objective response rate of 24%; 95% CI, 10% to 44%). No disease progression was reported. Neoadjuvant trabectedin was usually well tolerated, with a safety profile similar to that described in patients with soft tissue sarcoma or other tumor types. Conclusion: Trabectedin 1.5 mg/m. 2 given as a 24-h i.v. infusion every 3 weeks is a therapeutic option in the neoadjuvant setting of ML. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Dupuis J.,Henri Mondor University Hospital | Morschhauser F.,Claude Huriez University Hospital | Ghesquieres H.,Leon Berard Cancer Center | Tilly H.,Henri Becquerel Cancer Center | And 14 more authors.
The Lancet Haematology | Year: 2015

BACKGROUND: Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease. METHODS: We enrolled patients aged 18-80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1 and oral prednisone 40 mg/m2 on days 1-5) in association with varying doses of romidepsin. The starting dose was 10 mg/m2 intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526. FINDINGS: Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m2 had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m2 of romidepsin, an additional three at 10 mg/m2 (one dose-limiting toxicity), and six patients at 12 mg/m2 (three dose-limiting toxicities). We chose romidepsin 12 mg/m2 as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3-4 neutropenia, and 29 (78%) had grade 3-4 thrombocytopenia. INTERPRETATION: Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial. FUNDING: Celgene. © 2015 Elsevier Ltd. All rights reserved.

Garon E.B.,University of California at Los Angeles | Ciuleanu T.-E.,University of Medicine and Pharmacy, Cluj-Napoca | Arrieta O.,Instituto Nacional Of Cancerologia Incan | Prabhash K.,Tata Memorial Center | And 20 more authors.
The Lancet | Year: 2014

Background Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. Methods In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m 2 and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973. Findings Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. Interpretation Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. Funding Eli Lilly. © 2014 Elsevier Ltd.

Leyvraz S.,University of Lausanne | Piperno-Neumann S.,University Pierre and Marie Curie | Suciu S.,EORTC Headquarters | Baurain J.F.,Cliniques Universitaires Saint Luc | And 12 more authors.
Annals of Oncology | Year: 2014

Background: In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. Patients and methods: Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m2 on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. Results: Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. Conclusion: HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Garon E.B.,University of California at Los Angeles | Cao D.,Eli Lilly and Company | Alexandris E.,Imclone Systems | John W.J.,Eli Lilly and Company | And 2 more authors.
Clinical Lung Cancer | Year: 2012

This article describes the treatment rationale and study-related procedures for the A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV Non-Small-Cell Lung Cancer Following Disease Progression after One Prior Platinum-Based Therapy (REVEL) study (I4T-MC-JVBA; ClinicalTrials.gov NCT01168973). This international, randomized, placebo-controlled, double-blinded phase III trial examines the efficacy and safety of ramucirumab treatment administered in combination with docetaxel, as compared with docetaxel administered with placebo, in patients with stage IV non-small-cell lung cancer (NSCLC) whose disease progressed during or after first-line platinum-based chemotherapy with or without maintenance treatment. The primary end point is overall survival; secondary end points include progression-free survival, objective response rate, disease control rate, patient-reported outcomes, and assessment of safety and tolerability of ramucirumab. Eligible patients (enrollment N = 1242) are randomized at a 1:1 ratio to receive either docetaxel (75 mg/m2) plus ramucirumab (10 mg/kg) (Arm A) or docetaxel (75 mg/m2) plus placebo (Arm B). Both drugs are administered via intravenous infusion once every 3 weeks until evidence of disease progression, unacceptable toxicity, noncompliance, or patient's consent withdrawal. Efficacy and safety will be compared between the study arms and in patient subgroups including patients with nonsquamous versus squamous tumor histology and patients who received prior bevacizumab treatment. Multiple blood and tumor tissue biomarker samples are collected during the study. The goal of the REVEL study is to demonstrate that ramucirumab in combination with docetaxel improves overall survival of patients with NSCLC with progressive disease after first-line therapy, and to advance our knowledge of the role of angiogenesis blockade in patients with NSCLC by identifying patients who are likely to experience maximum benefit based on extensive clinical biomarker correlative analysis. © 2012 Elsevier Inc. All Rights Reserved.

Lynch R.,Barwon Health | Pitson G.,Barwon Health | Ball D.,University of Melbourne | Claude L.,Leon Berard Cancer Center | And 2 more authors.
Practical Radiation Oncology | Year: 2013

Purpose: To develop a reproducible definition for each mediastinal lymph node station based on the new TNM classification for lung cancer. Methods and Materials: This paper proposes an atlas using the new international lymph node map used in the seventh edition of the TNM classification for lung cancer. Four radiation oncologists and 1 diagnostic radiologist were involved in the project to put forward a reproducible radiologic description for the lung lymph node stations. Results: The International Association for the Study of Lung Cancer lymph node definitions for stations 1 to 11 have been described and illustrated on axial computed tomographic scan images using a certified radiotherapy planning system. Conclusions: This atlas will assist both diagnostic radiologists and radiation oncologists in accurately defining the lymph node stations on computed tomographic scan in patients diagnosed with lung cancer. © 2013 American Society for Radiation Oncology.

Dupre A.,Leon Berard Cancer Center | Lefranc A.,Leon Berard Cancer Center | Buc E.,Destaing University Hospital | Delpero J.R.,PaoliCalmettes Institute | And 4 more authors.
Annals of Surgery | Year: 2013

Objective: To assess by prospective randomized controlled trial the feasibility and efficacy of using a bioresorbable hyaluronic acid/carboxymethylcellulose membrane (HA membrane) to prevent abdominal and perihepatic adhesions in metastatic colorectal cancer patients requiring 2-stage hepatectomy. Background: Two-stage hepatectomy offers the possibility of long-term survival to selected patients whose liver metastases cannot be removed in a single procedure. However, the second operation is made more difficult by adhesions arising from the first. HA membrane reduces adhesions in gynecologic and abdominal surgery but this is the first trial in hepatectomy. Methods: Fifty-four candidates for 2-stage hepatectomy were randomized at the end of the first procedure to implantation of HA membrane (n = 41) or standard management (n = 13). Thirty patients from the membrane arm and 11 well-matched controls underwent the planned second hepatectomy. Results: Positioning of the HA membranes was feasible in all but one patient and did not increase complications associated with the first hepatectomy. At second hepatectomy, patients in the HA membrane arm required 33% less time than controls to achieve complete liver mobilization (median: 50 vs 75 minutes; primary endpoint). The risk of extensive adhesions was reduced in the HA membrane group (31% had grade 3-4 adhesions vs 55% in controls), as was adhesion severity (17% thick and hypervascular adhesions vs 46%). The proportion of patients with complications at second hepatectomy was higher in the control group (55% vs 23% in the HA membrane group, P = 0.07). Conclusion: Use of 4 HA membranes at the end of first hepatectomy reduced the extent and severity of adhesions and facilitated the second hepatectomy in patients with liver metastases who required a 2-stage hepatectomy. A larger study to confirm these findings is warranted. Copyright © 2013 by Lippincott Williams and Wilkins.

Cimarelli S.,Leon Berard Cancer Center | Montella A.,Biostatistics Unit | Bouteille C.,The Surgical Center | Mognetti T.,Leon Berard Cancer Center
International Journal of Clinical Oncology | Year: 2010

Background: The aim of the study was to analyze in breast tumors the correlation between [18F]fluorodeoxyglucose (FDG) uptake assessed by positron emission tomography (PET) and histopathological and immunohistochemical prognostic factors. Methods: FDG-PET combined with computed tomography (CT) was performed before surgery in 45 women with biopsy-proven primary breast cancer. The standardized uptake value (SUV) was compared with histopathological findings after surgery. Results: A positive relationship was found between SUV and histological grade (p < 0.0001), histological type (p = 0.001), tumor size (p < 0.0435), estrogen receptor status (p < 0.0005), and progesterone receptor status (p = 0.002). FDG-PET/CT revealed unknown distant metastatic lesions in 2 of 12 patients with triple-negative breast cancer. The sensitivity of FDG-PET/CT for detecting axillary lymph node metastases was, respectively, 21% and 100% for pN1 and pN2 cases, whereas specificity was 100% for pN0. Conclusion: SUV, a preoperative and noninvasive metabolic parameter, correlates with other known prognostic factors in breast cancer. This study provides valuable insight into the usefulness of FDG-PET/CT for preoperative staging of patients with triple-negative and poorly differentiated breast tumors but not for evaluating axillary lymph nodes and lobular carcinomas. © 2010 Japan Society of Clinical Oncology.

Bylicki O.,Louis Pradel Hospital | Rouviere D.,University Paul Sabatier | Cassier P.,Leon Berard Cancer Center | Chalabreysse L.,Hospices Civils de Lyon | And 6 more authors.
Journal of Thoracic Oncology | Year: 2015

BACKGROUND:: Solitary fibrous tumors of the pleura (SFTP) refer as to a heterogeneous group of mesenchymal malignancies with various anatomic and histology features. Upfront surgical resection is the standard approach, but recurrences may be aggressive and difficult to treat. The most widely accepted staging system has been proposed by De Perrot et al. Because SFTPs are rare, evidence to support a role for perioperative chemotherapy is scarce. Likewise, the predictive or prognostic relevance of the De Perrot system may be questioned. METHODS:: Multicenter retrospective study of patients with histologically proven SFTP with complete follow-up from surgical diagnostic to tumor recurrence and death. RESULTS:: Sixty-eight patients were included. Tumor stage was 0/I for 29 (43%) patients, II for 23 (34%) patients, III for seven (10%) patients, and IV for nine (13%) patients. Postoperative chemotherapy was given to seven patients, mostly with stage III/IV SFTP, mostly consisting of doxorubicin-based regimen. Recurrence rate and median relapse-free survival after surgery were 3%, 52%, 71%, and 80% (p < 0.001), and 107, 70, 29, 11 months (p < 0.001) for stage 0/I, II, III, and IV tumors, respectively. At time of tumor recurrence, 14 patients received exclusive chemotherapy. Highest disease control rates were observed with trabectedin, and gemcitabine-dacarbazine combination. CONCLUSION:: Our study confirms the prognostic value of the De Perrot staging system, as well as its possible predictive value for perioperative chemotherapy decision-making, whereas the efficacy of currently available regimens to significantly reduce the risk of tumor recurrence remains questionable. Trabectedin may be of interest for recurrent tumors. © 2014 by the International Association for the Study of Lung Cancer.

Levard A.,Leon Berard Cancer Center | Tassy L.,Leon Berard Cancer Center | Cassier P.A.,Leon Berard Cancer Center
Hematology/Oncology Clinics of North America | Year: 2013

Sarcomas are heterogeneous group of tumors that arise from tissues of mesenchymal origin. Current options for patients with advanced disease are limited, and only 2 drugs have been approved for these diseases over the last decade. Although several drugs are currently under development for soft-tissue sarcoma as a whole, improved understanding of sarcoma biology has led to the emergence of subtype-specific targeted therapy. This article reviews recent clinical data on emerging therapies for soft-tissue sarcoma. © 2013 Elsevier Inc.

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