Villejuif, France
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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, 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.

Poortmans P.M.,Radboud University Nijmegen | Poortmans P.M.,Institute Verbeeten | Collette S.,European Organization for Research and Treatment of Cancer EORTC | Kirkove C.,Catholic University of Louvain | And 23 more authors.
New England Journal of Medicine | Year: 2015

Background The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P = 0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P = 0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P = 0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P = 0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. © 2015 Massachusetts Medical Society.

Lavaud P.,Gustave Roussy Cancer Center | Andre F.,Gustave Roussy Cancer Center | Andre F.,University Paris - Sud
BMC Medicine | Year: 2014

Breast cancers over-express the human epidermal growth factor receptor 2 (HER2) in about 15% of patients. This transmembrane tyrosine kinase receptor activates downstream signaling pathways and leads to proliferation of cancer cells. Trastuzumab, an anti-HER2 monoclonal antibody, improves outcome in women with early and metastatic breast cancer. Resistance to trastuzumab involves the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, truncation of the Her2 receptor or lack of immune response. The last decade has seen major advances in strategies to overcome resistance to trastuzumab. This includes the development of antibody-drug conjugates, dual HER2 inhibition strategies, inhibition of PI3K/mTOR pathway and development of modulators of immune checkpoints. © 2014 Lavaud and Andre; licensee BioMed Central.

Honore C.,The Surgical Center | Amroun K.,The Surgical Center | Vilcot L.,Gustave Roussy Cancer Center | Mir O.,Gustave Roussy Cancer Center | And 5 more authors.
Annals of Surgical Oncology | Year: 2015

Background: With nearly 450 cases reported since 1991, desmoplastic small round cell tumor (DSRCT) is a rare abdominal tumor typically arising in adolescent and young adult white men. With no large series described, the best therapeutic strategy remains unclear. Methods: All consecutive patients treated in our tertiary care center between January 1991 and December 2013 for a DSRCT were retrospectively studied. Results: Thirty-eight patients with a median age of 27 years (range 13–57 years) were identified; 71 % were men. At the time of diagnosis, 47.4 % patients had extraperitoneal metastases (EPM): 78 % were located in the liver and 11 % were located in the lungs. Fourteen patients (37 %) were treated exclusively with systemic chemotherapy, with a median survival of 21.1 months. Twenty-three patients underwent surgery, 12 (52 %) experienced complete removal of all macroscopic disease, 5 (21.7 %) received additional intraperitoneal chemotherapy, and 7 (30 %) received postoperative whole abdominopelvic radiotherapy (WAP RT). With a median follow-up of 59.9 months, the median survival was 37.7 months, and the median disease-free survival was 15.5 months. The factors predictive of 3-year overall survival were the absence of EPM, complete surgical resection, postoperative WAP RT, and postoperative chemotherapy. The intraperitoneal chemotherapy had no impact on overall survival. Conclusions: DSRCT is a rare and aggressive disease. In patients without EPM, a multimodal treatment combining systemic chemotherapy, complete macroscopic resection, and postoperative WAP RT could enable prolonged survival. No benefit of surgery was demonstrated for patients with EPM. The value of associated hyperthermic intraperitoneal chemotherapy remains unproven. © 2014, Society of Surgical Oncology.

Nguyen T.V.F.,University of Franche Comte | Nguyen T.V.F.,Gustave Roussy Cancer Center | Anota A.,University of Franche Comte | Anota A.,Gustave Roussy Cancer Center | And 5 more authors.
BMC Cancer | Year: 2014

Background: In the oncology setting, there has been increasing interest in evaluating treatment outcomes in terms of quality of life and patient satisfaction. The aim of our study was to investigate the determinants of patient satisfaction, especially the relationship between quality of life and satisfaction with care and their changes over time, in curative treatment of cancer outpatients.Methods: Patients undergoing ambulatory chemotherapy or radiotherapy in two centers in France were invited to complete the OUT-PATSAT35, at the beginning of treatment, at the end of treatment, and three months after treatment. This questionnaire evaluates patients' perception of doctors and nurses, as well as other aspects of care organization and services. Additionally, for each patient, socio-demographic and clinical characteristics, and self-reported quality of life data (EORTC QLQ-C30) were collected.Results: Of the 691 patients initially included, 561 answered the assessment at all three time points. By cross-sectional analysis, at the end of the treatment, patients who experienced a deterioration of their global health reported less satisfaction on most scales (p ≤ 0.001). Three months after treatment, the same patients had lower satisfaction scores only in the evaluation of doctors (p ≤ 0.002). Furthermore, longitudinal analysis showed a significant relationship between a deterioration in global health and a decrease in satisfaction with their doctor and, conversely, between an improvement in global health and an increase in satisfaction on the overall satisfaction scale. Global health at baseline was largely and significantly associated with all satisfaction scores measured at the following assessment time points (p < 0.0001). Younger age (<55 years), radiotherapy (versus chemotherapy) and head and neck cancer (versus other localizations) were clinical factors significantly associated with less satisfaction on most scales evaluating doctors.Conclusions: Pre-treatment self-evaluated global health was found to be the major determinant of patient satisfaction with care. The subsequent deterioration of global health, during and after treatment, emphasized the decrease in satisfaction scores, mainly in the evaluation of doctors. Early initiatives aimed at improving the delivery of care in patients with poor health status should lead to improved perception of the quality of care received. © 2014 Nguyen et al.; licensee BioMed Central Ltd.

Honore C.,Gustave Roussy Cancer Center | Meeus P.,Center Leon Berard | Stoeckle E.,Institute Bergonie | Bonvalot S.,Institute Curie
Journal de Chirurgie Viscerale | Year: 2015

Four thousand new cases of soft tissue sarcomas are diagnosed each year in France, 23% of which are localized in the abdomen and pelvis; the treatment of non-metastatic tumor is based on wide surgical resection, the quality of which determines the long-term outcome. To ensure appropriate care, the European Society for Medical Oncology (ESMO) recommends that any patient with an unexplained soft tissue mass (of any size for deep lesions or of>5cm for superficial lesions) be referred to a specialized center with capacities for multidisciplinary team decision; appropriate imaging should be performed prior to treatment and a percutaneous image-guided needle biopsy should be routinely performed. In France, clinical and pathology networks (NetSarc and RRePS) currently offer patients a structured means to make a systematic diagnosis of soft tissue sarcoma and help to provide access to appropriate treatment in a specialized center. © 2015 Elsevier Masson SAS.

PubMed | Gustave Roussy cancer center
Type: Journal Article | Journal: Journal of visceral surgery | Year: 2016

Complete cytoreductive surgery (CCRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is the gold standard for curative treatment of peritoneal carcinomatosis (PC) arising from colorectal cancer, peritoneal mesothelioma and peritoneal pseudomyxoma peritonei (PMP). The results of HIPEC remain controversial in PC that originates from ovarian cancer, stomach cancer, neuroendocrine tumors, or sarcoma. HIPEC has also been used, although very rarely, for other malignant carcinomatoses. Its use has been exceptional due either to the rarity of the tumor or because such disease is usually widespread and rarely confined to the peritoneum. The aim of this study was to evaluate the results of CCRS plus HIPEC in patients with PC of unusual origin.We performed a retrospective analysis of all patients who underwent CCRS plus HIPEC for PC whose origin was neither gastric, ovarian or colorectal carcinoma, nor neuroendocrine tumor, mesothelioma, PMP or sarcoma.Between 1995 and 2013, 31 patients with 15 PC arising from unusual primary tumors underwent CCRS plus HIPEC. After a median follow-up of 90 months, 10 patients were alive and without recurrence. The overall survival rate at 5 years was 33% with a median survival of 37 months. In univariate analysis, factors of poor prognosis and predictors of recurrence were the performance of immediate postoperative intraperitoneal chemotherapy instead of HIPEC and a peritoneal index 12. No prognostic impact due to tumor origin could be demonstrated.The decision to perform CCRS plus HIPEC for PC arising from unusual cancer origins remains difficult. These patients should be prospectively entered into registries of rare tumors that involve the peritoneum in order to better define indications.

PubMed | Translational research and histocytopathology laboratory, French Institute of Health and Medical Research and Gustave Roussy Cancer Center
Type: | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016

Lymphocytic infiltration at diagnosis is prognostic in EOC, however the impact of NACT on tumour infiltrating lymphocytes (TILs) or PD-L1 expression remains poorly described.Patients with EOC and sequential samples (pre-NACT, post-NACT or relapse) were retrospectively identified. TILs were evaluated on whole sections; stromal TILs (sTILs) scored as percentage of stromal area with high sTILs defined as 50%; intra-epithelial TILs (ieTILs) scored semi-quantitatively (0-3) with high ieTILs 2. A smaller number were available for PD-L1 evaluation, cut-off for positivity was 5% staining.sTILs were detected in all tumours at diagnosis (range 2%-90%, median 20%), with 22% (25/113) showing high sTILs. Among evaluable paired pre/post-NACT samples (N=83), an overall increase in median sTILs from 20% to 30% was seen following NACT (P=0.0005); individually the impact of NACT varied with sTILs increasing in 51% (42/83), decreasing in 25%, and stable in 24%. Post-NACT sTILs were predictive of platinum-free interval (PFI), patients with PFI 6 months had significantly higher post-NACT sTILs (sTILs 28% vs 18% for PFI <6 months, P=0.026); pre-NACT sTILS were not predictive. At diagnosis, 23% showed high ieTILs, and following NACT 33% showed increasing ieTILs. Proportion of tumours with PD-L1-positive immune cells was 30% (15/50) pre-NACT and 53% (27/51) post-NACT (P=0.026). Among paired tumours, 63% of PD-L1-negative tumours became positive after NACT, furthermore cisplatin induced PD-L1 expression in PD-L1-negative EOC cell lines. On multivariate analysis, high sTILs both pre- and post-NACT were independent prognostic factors for progression-free survival (PFS) (HR 0.49, P=0.02 and HR 0.60, P=0.05, respectively). No prognostic impact of ieTILs or PD-L1 expression was detected.In EOC, sTILs levels are prognostic at diagnosis and remain prognostic after NACT. TILs and PD-L1 expression increase following NACT. Evaluation of immune parameters in the post-NACT tumour may help select patients for immunotherapy trials.

PubMed | Ghent University and Gustave Roussy Cancer Center
Type: | Journal: Head and neck pathology | Year: 2016

The assessment of tumor infiltrating lymphocytes (TILs) has recently emerged as a prognostic biomarker in several solid tumors. Quantification and subtyping of TILs reflects the immune response in the tumor microenvironment, contributing to either tumoral immune attack or escape and thereby affecting outcome. Despite the growing evidence of its value as prognosticator, TILs analysis has not yet found its way to daily clinical practice. The aim of this review is to evaluate whether the current knowledge on TILs in head and neck cancer justifies its clinical implementation. Therefore, we summarize the data on TILs in squamous cell cancer of the head and neck with focus on the most important subsets (T lymphocytes and more specifically CD8

News Article | December 8, 2016

The prize, donated by Frédérique Brupbacher in memory of her husband, Charles Rodolphe Brupbacher, will be awarded for the thirteenth time in February 2017. Endowed with prize money of CHF 100,000 for each award, the prize is considered one of the most prestigious research distinctions in the international cancer community. The prize goes to three outstanding researchers, this time for groundbreaking research on the impact of epigenetics, cell death, and gut microbiota on the progression of cancer. This research lays important groundwork for improving the understanding of cancer and for developing new, targeted therapies. Adrian Bird, recipient of the first prize, is Professor of Genetics at the Wellcome Trust Centre for Cell Biology of the University of Edinburgh. His work focuses on the interaction of genetics and epigenetics, an aspect of cancer development that has received little research attention to date. Methyl groups, which are added to the DNA, regulate the activity of numerous genes. The majority of the human genome carries such methyl groups. Within the genom there are also small regions, known as CpG islands, without such epigenetic marks. In tumor cells, CpG islands are often methylated, and these DNA methylation changes generally trigger an abnormal inactivation of the affected gene. Adrian Bird and his team investigated proteins that bind to CpG islands and influence DNA methylation and other epigenetic characteristics. These proteins, which control the interaction of genome and epigenome, are often deregulated in cancer and may thus play a significant role in oncogenesis. The second prize is being conferred jointly on physician Giudo Kroemer from the Centre de Recherche des Cordeliers of the Université Paris Descartes and immunologist Laurence Zitvogel from the Laboratory for Tumor Immunology and Immunotherapy of the Gustave Roussy Cancer Center. Their research focuses on how the immune system influences the development and treatment of cancer. The work of Guido Kroemer focuses on apoptosis - programmed cell death - the process by which cells self-eliminate when they become impaired. A further process, autophagy, plays a significant role in how cells survive the effects of toxic substances, such as during chemotherapy. Kroemer and his team were able to demonstrate that the death of cancer cells can stimulate the immune system, if autophagy has been activated in advance. This reactivates immunogenicity of the tumor cells, thus making them "visible" to defense cells and allowing them to be efficiently eliminated. The type of immune reaction triggered by dying cancer cells is thus decisive for the success of cancer treatment. In various papers, Laurence Zitvogel and her research team demonstrated that gut microbiota not only influences its immediate surroundings, but also affects the immune response to cancer cells in other regions of the body. They further proved that the bacteria strains Escherichia hirae and Barnesiella intestinihominis substantially improve the success of chemotherapy with cyclophosphamide in patients with lung and ovarian cancer. Bacteria from the Bacteroidales, Burkholderiales, and Bifidobacteriales groups also affect tumor micro-environment and enhance the effectiveness of antibody therapies for skin cancer. Until now, it was unknown - and unexpected - that gut microbiota can enhance the body's immune reaction to cancer cells outside of the gut.

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