Gustave Roussy Cancer Campus Grand Paris

Villejuif, France

Gustave Roussy Cancer Campus Grand Paris

Villejuif, France

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Duployez N.,Lille University Hospital Center | Duployez N.,French Institute of Health and Medical Research | Willekens C.,Gustave Roussy Cancer Campus Grand Paris | Marceau-Renaut A.,Lille University Hospital Center | And 5 more authors.
Expert Review of Hematology | Year: 2015

Core-binding factor acute myeloid leukemia (CBF-AML)-including AML with t(8;21) and AML with inv(16)-accounts for about 15% of adult AML and is associated with a relatively favorable prognosis. Nonetheless, relapse incidence may reach 40% in these patients. In this context, identification of prognostic markers is considered of great interest. Due to similarities between their molecular and prognostic features, t(8;21) and inv(16)-AML are usually grouped and reported together in clinical studies. However, considerable experimental evidences have highlighted that they represent two distinct entities and should be considered separately for further studies. This review summarizes recent laboratory and clinical findings in this particular subset of AML and how they could be used to improve management of patients in routine practice. © 2015 Informa UK, Ltd.


PubMed | Mount Vernon Hospital, University Utrecht, Gustave Roussy Cancer Campus Grand Paris, St Lukes Hospital and 4 more.
Type: Journal Article | Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology | Year: 2016

Image guided adaptive brachytherapy (IGABT) using intracavitary applicators (IC) has led to a significant improvement of local control in locally advanced cervical cancer (LACC). Further improvement has been obtained with combined intracavitary/interstitial (IC/IS) applicators. The aim of this analysis was to evaluate the impact on local control and late morbidity of application of combined IS/IC brachytherapy in a large multicentre population.610 patients with LACC from the retroEMBRACE study were included. Patients were divided into an IC group (N=310) and an IC/IS group (N=300). The IC/IS group was defined from the time point, when a centre performed IC/IS brachytherapy in more than 20% of cases.With systematic usage of IC/IS the D90 of CTVCombined IC/IS brachytherapy improves the therapeutic ratio in LACC by enabling a tumour specific dose escalation resulting in significantly higher local control in large tumours without adding treatment related late morbidity.


PubMed | University Hospital Gasthuisberg, University Utrecht, Gustave Roussy Cancer Campus Grand Paris, St Lukes Hospital and 8 more.
Type: Journal Article | Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology | Year: 2016

Image guided brachytherapy (IGBT) for locally advanced cervical cancer allows dose escalation to the high-risk clinical target volume (HRCTV) while sparing organs at risk (OAR). This is the first comprehensive report on clinical outcome in a large multi-institutional cohort.From twelve centres 731 patients, treated with definitive EBRTconcurrent chemotherapy followed by IGBT, were analysed. Kaplan-Meier estimates at 3/5years were calculated for local control (LC, primary endpoint), pelvic control (PC), overall survival (OS), cancer specific survival (CSS). In 610 patients, G3-4 late toxicity (CTCAEv3.0) was reported.Median follow up was 43months, percent of patients per FIGO stage IA/IB/IIA 22.8%, IIB 50.4%, IIIA-IVB 26.8%. 84.8% had squamous cell carcinomas; 40.5% lymph node involvement. Mean EBRT dose was 462.5Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 8715Gy (EQD2IGBT combined with radio-chemotherapy leads to excellent LC (91%), PC (87%), OS (74%), CSS (79%) with limited severe morbidity.


Eggermont A.M.M.,Gustave Roussy Cancer Campus Grand Paris | Chiarion-Sileni V.,Melanoma Oncology Unit | Grob J.-J.,Aix - Marseille University | Dummer R.,University of Zürich | And 18 more authors.
The Lancet Oncology | Year: 2015

Background: Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. Methods: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Findings: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. Interpretation: Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. Funding: Bristol-Myers Squibb. © 2015 Elsevier Ltd.


PubMed | Karolinska Institutet, University of Houston, University of Zürich, National Research Council Italy and 25 more.
Type: Journal Article | Journal: Journal of translational medicine | Year: 2016

The sixth Melanoma Bridge Meeting took place in Naples, Italy, December 1st-4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkins disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.); adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs), chimeric antigen receptors (CARs), and T cell receptor (TCR) modified T cells; (ii) tumor heterogeneity including changes in antigenic profiles over time and location in individual patient; and (iii) a variety of immune-suppressive mechanisms in the tumor microenvironment (TME) including T regulatory cells (Treg), myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines. In addition, complex interaction of tumor-immune system further increases the level of difficulties in the process of biomarkers development and their validation for clinical use. Recent clinical trial results have highlighted the potential for combination therapies that include immunomodulating agents such as anti-PD-1 and anti-CTLA-4. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors on T cells and other approaches such as adoptive cell transfer are tested for clinical efficacy in melanoma as well. These agents are also being tested in combination with targeted therapies to improve upon shorter-term responses thus far seen with targeted therapy. Various locoregional interventions that demonstrate promising results in treatment of advanced melanoma are also integrated with immunotherapy agents and the combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for melanoma patients population. This meetings specific focus was on advances in immunotherapy and combination therapy for melanoma. The importance of understanding of melanoma genomic background for development of novel therapies and biomarkers for clinical application to predict the treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into personalized-medicine approach for treatment of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. We also discussed the requirements for pre-analytical and analytical as well as clinical validation process as applied to biomarkers for cancer immunotherapy. The concept of the fit-for-purpose marker validation has been introduced to address the challenges and strategies for analytical and clinical validation design for specific assays.


PubMed | Gustave Roussy Cancer Campus Grand Paris, French Institute of Health and Medical Research and University Paris - Sud
Type: | Journal: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences | Year: 2016

A recent update of the hallmarks of cancer includes metabolism with deregulating cellular energetics. Activating mutations in isocitrate dehydrogenase (IDH) metabolic enzymes leading to the abnormal accumulation of 2-hydroxyglutaric acid (2-HGA) have been described in hematologic malignancies and solid tumours. The diagnostic value of 2-HGA levels in blood to identify IDH mutations and its prognostic significance have been reported. We developed a liquid chromatography tandem mass spectrometry method allowing a rapid, accurate and precise simultaneous quantification of both L and D enantiomers of 2-HGA in blood samples from acute myeloid leukaemia (AML) patients, suitable for clinical applications. The method was also develop for preclinical applications from cellular and tissues samples. Deuterated (R,S)-2-hydroxyglutaric acid, disodium salt was used as internal standard and added to samples before a solid phase extraction on Phenomenex STRATA-XL-A (200mg-3mL) 33m cartridges. A derivatization step with (+)- o,o-diacetyl-l-tartaric anhydride permitted to separate the two resulting diastereoisomers without chiral stationary phase, on a C18 column combined to a Xevo TQ-MS Waters mass spectrometer with an electrospray ionization (ESI) source. This method allows standard curves to be linear over the range 0.34-135.04M with r(2) values>0.999 and low matrix effects (<11.7%). This method, which was validated according to current EMA guidelines, is accurate between-run (<3.1%) and within-run (<7.9%) and precise between-run (<5.3CV%) and within-run (<6.2CV%), and is suitable for clinical and preclinical applications.


PubMed | University of Angers, Gustave Roussy Cancer Campus Grand Paris, Karolinska Institutet and European Organisation for Research and Treatment of Cancer Headquarters
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

Eighty percent of melanomas are diagnosed at a localised stage, when they are highly curable. Their survival rate induces long follow-up periods, transforming melanomainto a chronic disease and patients health-related quality of life (HRQoL). Understanding which patient characteristics are associated with poor HRQoL should allow a more personalised management of their HRQoL. Hence, we propose a systematic review for this purpose. Systematic literature searches were performed in three different electronic databases: PubMed, Web of Science and the Cochrane Library. Only studies published in English after 2005 until June 2016 and exploring HRQoL over a period of at least one year were considered. 10 articles were identified from seven different studies, representing a total of 4246 patients. All were observational: six were cross-sectional and only one was prospective. Several patient characteristics associated with HRQoL were identified. Women tend to have lower psychological HRQoL than men. Age was generally associated with variations in HRQoL levels, but there was no consistency across studies. Positive associations between marital status or social interactions and psychological subscales were highlighted by a few studies. Finally, the stage related severity of prognosis at initial diagnosis was systematically associated with worse HRQoL levels (either psychological, physical or global). Several patient characteristics could be identified in melanoma studies that were associated with HRQoL levels. However, these relations were not consistent across studies. Such findings highlight the current lack of empirical data available. Further evidence is needed on HRQoL factors in melanoma survivors.


PubMed | EORTC Headquarters, University of Amsterdam, Gustave Roussy Cancer Campus Grand Paris, Netherlands Cancer Institute and 5 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

We report on the long term outcome of the EORTC 18952 adjuvant interferon (IFN) trial in 1388 resected stage IIB/III melanoma patients and identify key predictive factors for outcome.We analysed outcome of the EORTC 18952 trial (4 weeks of IFN, 10 MU, 5 times/week for 4 weeks followed by 12 months IFN at 10 MU, 3 times/week versus followed by 24 months IFN at 5 MU 3 times/week versus observation) regarding relapse-free survival (RFS), distant metastasis-free interval/survival (DMFI/DMFS), and overall survival (OS), and analysed potential predictive factors of outcome.At a median follow-up of 11 years, the comparison of IFN 13 months versus IFN 25 months versus observation yielded estimated hazard ratios (HR) for RFS of 0.94 versus 0.84 (p = 0.06); for DMFI 0.95 versus 0.82 (p = 0.027); for DMFS 0.95 versus 0.84 (p = 0.07); and for OS 095 versus 0.84 (p = 0.08), respectively. The impact of treatment was greatest in the ulceration group, whereas in patients with non-ulcerated primaries the impact was null (HR 1.0). In patients with ulcerated melanoma the HR for IFN 13 months versus 25 months versus observation were for: RFS 0.82 (p = 0.16) versus 0.61 (p = 0.0008); DMFS 0.76 (p = 0.06) versus 0.57 (p = 0.0003); OS 0.80 (p = 0.13) versus 0.59 (p = 0.0007). In stage IIB/III-N1 (microscopic nodal involvement only) patients with ulcerated melanoma the HR estimates were for: RFS 0.85 versus 0.62; DMFS 0.80 versus 0.56; OS 0.77 versus 0.54.This long term report of the EORTC 18952 trial demonstrates the superiority of the 25-month IFN schedule and defines ulceration of the primary as the overriding predictive factor for IFN-sensitivity.


Rodon J.,Autonomous University of Barcelona | Soria J.C.,Gustave Roussy Cancer Campus Grand Paris | Berger R.,Oncology Institute | Batist G.,McGill University | And 11 more authors.
Annals of Oncology | Year: 2015

Advances in 'omics' technology and targeted therapeutic molecules are together driving the incorporation of molecularbased diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multinational trial (five countries, six sites) coordinated by the Worldwide Innovative Networking Consortium for personalized cancer therapy, we discovered key challenges in initiation and conduct of a prospective, omically driven study. To date, the time from study concept to activation has varied between 19 months at Gustave Roussy Cancer Campus in France to 30 months at the Segal Cancer Center, McGill University (Canada). It took 3+ years to be able to activate US sites due to national regulatory hurdles. Access to medications proposed by the molecular analysis remains a major challenge, since their availability through active clinical trials is highly variable over time within sites and across the network. Rules regarding the off-label use of drugs, or drugs not yet approved at all in some countries, pose a further challenge, and many biopharmaceutical companies lack a simple internal mechanism to supply the drugs even if they wish to do so. These various obstacles should be addressed to test and then implement precision medicine in cancer. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

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