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Bosset J.-F.,Besancon University Hospital njoz | Calais G.,University of Tours | Maingon P.,Center Georges Francois Leclerc | Stojanovic-Rundic S.,Serbian Institute for Oncology and Radiology of Serbia | And 13 more authors.
The Lancet Oncology | Year: 2014

Background: EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy-irrespective of timing-significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. Methods: We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m2 per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m2 per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. Findings: 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8-13·1), 10-year overall survival was 49·4% (95% CI 44·6-54·1) for the preoperative radiotherapy group and 50·7% (45·9-55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83-1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0-56·4) for the adjuvant chemotherapy group and 48·4% (43·6-53·0) for the surveillance group (HR 0·91, 95% CI 0·77-1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5-48·8) for the preoperative radiotherapy group and 46·4% (41·7-50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79-1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2-51·6) for the adjuvant chemotherapy group and 43·7% (39·1-48·2) for the surveillance group (HR 0·91, 95% CI 0·77-1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1-27·6) with radiotherapy alone, 11·8% (7·8-15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1-18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7-15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). Interpretation: Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. Funding: EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs. © 2014 Elsevier Ltd.


Martin F.,French Institute of Health and Medical Research | Martin F.,University of Burgundy | Apetoh L.,French Institute of Health and Medical Research | Apetoh L.,University of Burgundy | And 4 more authors.
Trends in Molecular Medicine | Year: 2012

The immune system has important roles in limiting the spread of cancer and shaping the tumor microenvironment. Although the contributions of T helper 17 (Th17) cells (a subtype of CD4+ T lymphocytes) to autoimmunity and allergy response are well known, their roles in cancer remain ambiguous. Despite adoptive transfer studies indicating that mouse Th17 cells support anticancer immunity, the Th17 cells that naturally infiltrate experimental tumors appear to have a tumor-promoting effect. These contradictory properties can be related to the high degree of plasticity inherent in Th17 cells and their capacity to differentiate into tumoricidal Th1-like cells. Mouse Th17 cells induced by transforming growth factor-β (TGF-β) express CD39 and CD73 ectonucleotidases on their surfaces, which leads to adenosine release and suppression of T cell immunity. Here, we discuss how TGF-β acts as a molecular switch controlling the immunoregulatory properties of Th17 cells. © 2012 Elsevier Ltd.


Golden E.B.,New York University | Apetoh L.,French Institute of Health and Medical Research | Apetoh L.,University of Burgundy | Apetoh L.,Center Georges Francois Leclerc
Seminars in Radiation Oncology | Year: 2015

Advances in understanding the mechanisms that underlie the interplay between radiation-invoked immune responses and tumor regression are underway. Emerging applications of local radiotherapy as an immunologic adjuvant have provided radiation oncologists with a method for converting malignant cells into endogenous anticancer vaccines. The dispersion of radiotherapy-induced immune-stimulating tumor antigens released from dying tumor cells into the surrounding milieu (known as immunogenic cell death, Fig. 1), is one such exploitable process that contributes to the propagation of antitumor immunity. Downstream components of the immune system may suppress, promote, or ambiguously affect antitumoral responses. Additionally, host, tumor, and treatment-related characteristics govern the significance of these signals, thereby dictating therapeutic outcomes. Herein, we review the process of radiotherapy-induced immunogenic cell death and its role in generating an in situ vaccine to help refine radioimmunotherapy-based protocols. © 2015 The Authors.


Pot C.,University of Geneva | Apetoh L.,Center Georges Francois Leclerc | Apetoh L.,French Institute of Health and Medical Research | Apetoh L.,University of Burgundy | And 2 more authors.
Seminars in Immunology | Year: 2011

Accumulating evidence indicates that IL-27, a member of the IL-12 family of cytokines, alleviates the severity of autoimmune diseases in both mice and men. The IL-27-induced activation of signal transducer and activator of transcription (Stat)1 and Stat3 promotes the generation of IL-10- producing type 1 regulatory T (Tr1) cells that inhibit effector T cells. In addition, IL-27 also suppresses the development of pathogenic IL-17-producing CD4+ T cells (TH17) cells suggesting that pharmacological manipulations of IL-27 signaling pathway could be exploited therapeutically in regulating tissue inflammation. Here, we review how IL-27 controls inflammation through the regulation of Tr1 and TH17 responses. © 2011 Elsevier Ltd.


Coudert B.,Center Georges Francois Leclerc | Ciuleanu T.,Institute of Oncology Ion Chiricuta | Park K.,Sungkyunkwan University | Wu Y.-L.,Guangdong General Hospital | And 4 more authors.
Annals of Oncology | Year: 2012

Background: In the placebo-controlled phase III SATURN study, maintenance erlotinib after first-line chemotherapy demonstrated significantly prolonged progression-free survival (PFS) and overall survival (OS) in the overall study population of patients with advanced non-small-cell lung cancer (NSCLC). Methods: After four cycles of platinum-based doublet chemotherapy, patients without progressive disease (PD) were randomised to erlotinib (150 mg/day) or placebo until PD or unacceptable toxicity. In this pre-planned analysis, data are assessed according to response to first-line chemotherapy (complete/partial response [CR/PR] or stable disease [SD]). Results: Following first-line chemotherapy, 889 non-PD patients were included in the intention-to-treat population (55% SD; 44% CR/PR; <1% unknown response). Erlotinib maintenance therapy significantly prolonged PFS in both the SD (hazard ratio [HR] = 0.68; P < 0.0001) and CR/PR (HR = 0.74; P = 0.0059) groups, while OS was significantly prolonged in the SD group only (HR = 0.72; P = 0.0019). The erlotinib-related OS benefit in the SD group remained significant across subgroups, irrespective of tumour histology and/or EGFR mutation status. The incidence of adverse events was similar in the SD group and the overall population, and erlotinib treatment did not negatively impact quality of life. Conclusions: Patients with advanced NSCLC and SD following first-line platinum-based doublet chemotherapy derive a significant OS benefit from maintenance erlotinib therapy. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Fornier M.,Sloan Kettering Cancer Center | Fumoleau P.,Center Georges Francois Leclerc
Breast Journal | Year: 2012

Breast cancer that lacks expression of estrogen/progesterone receptors and overexpression of the human epidermal growth factor receptor2 (HER2), i.e. triple-negative breast cancer (TNBC), is not amenable to current targeted therapies and carries a poor prognosis. This review discusses the natural history of TNBC and published literature in the relevant treatment landscape, with a focus on newer therapies. Compared with other subtypes of breast cancer, TN tumors have higher response rates to neoadjuvant chemotherapy; however, this advantage is not clearly translated into the metastatic setting and has not improved these patients' overall survival. Numerous cytotoxic and targeted strategies have demonstrated efficacy or are under investigation. Strategies showing promise in this difficult-to-treat group of patients include cytotoxic therapy with platinum-containing agents, ixabepilone, and novel targeted approaches such as poly(ADP-ribose) polymerase inhibitors. © 2011 Wiley Periodicals, Inc.


Boidot R.,Center Georges Francois Leclerc | Vegran F.,Center Georges Francois Leclerc | Vegran F.,French Institute of Health and Medical Research | Lizard-Nacol S.,Center Georges Francois Leclerc
Molecular Biology Reports | Year: 2014

Survivin, a small member of the inhibitors of the apoptosis protein family, is highly deregulated in cancer. It is weakly expressed in normal tissues but very strongly expressed in malignant lesions. Survivin is involved in cell-cycle progression, especially in the G2/M transition, and has anti-apoptotic activity, which correlates with its strong expression in cases with a poor cancer treatment response and poor outcomes. Several therapies that target the survivin transcript or protein are currently being tested in clinical trials. However, focusing new therapies on the origins of survivin overexpression and targeting these upstream deregulations could be more effective. For this reason, it seems important to make an inventory of the transcriptional (de)regulation of survivin. This review will gather the important points concerning the regulation of survivin mRNA expression: structure of the survivin promoter, epigenetic modifications and genetic abnormalities, transcription factors, and signalling pathways that affect survivin mRNA expression. © 2013 Springer Science+Business Media Dordrecht.


Fumoleau P.,Center Georges Francois Leclerc | Guiu S.,Center Georges Francois Leclerc
Current Breast Cancer Reports | Year: 2013

The most successful tubulin-targeting agents in the treatment of breast cancer are the taxanes and the Vinca alkaloids. Vinorelbine, a vinca alkaloid derivative, has remarkable clinical activity in advanced breast cancer patients, and is currently used. Among the most critical limitations of Vinca alkaloids in metastatic breast cancer are their sensitivity to multidrug resistance pumps and the development of drug resistance. So, there is a need for new efficacious Vinca alkaloids agents that are associated with increased response and limited and manageable toxicity. Vinflunine is a novel microtubule inhibitor of the Vinca alkaloid class obtained by semi-synthesis using superacidic chemistry to selectively modify the catharantine moiety. In preclinical models, vinflunine is more active in vivo than the other Vinca alkaloids and resistance to vinflunine develops more slowly than that to vinorelbine. In addition, vinflunine in-vitro neurotoxicity is lower than that of vincristine and of vinorelbine. Encouraging phase II results and the favorable safety profile of vinflunine warrant further investigation of this novel agent in combination with other active agents in metastatic breast cancer. Comparative clinical trials have been initiated. © 2012 Springer Science+Business Media New York.


Vegran F.,INSER M U866 | Boidot R.,Center Georges Francois Leclerc
OncoImmunology | Year: 2013

Survivin-3B (S-3B), an alternative splice isoform of survivin, plays a key role in tumorigenesis. S-3B promotes the escape of malignant cells from immune recognition by blocking the cytotoxicity of natural killer (NK) cells. Such an effect reflects the ability of S-3B to interfere with the assembly of the so-called "death-inducing signaling complex" upon the interaction of FAS with its ligand (FAS L). S-3B also inhibits the activation of caspase-6, thus increasing the resistance of neoplastic cells to granzyme B and various chemotherapeutics. © 2013 Landes Bioscience.


Bruchard M.,French Institute of Health and Medical Research | Ghiringhelli F.,French Institute of Health and Medical Research | Ghiringhelli F.,Center Georges Francois Leclerc
Medecine/Sciences | Year: 2014

Immunosuppression is a mechanism developed by cancer cells to help them escape the immune system. Immunosuppression involves expansion of various cell types and production of a variety of cytokines. In this review, we explore the duality of three cancer induced cell populations, regulatory T lymphocytes, Th17 lymphocytes and MDSC, and also the pleiotropic effects of several cytokines induced during cancer development. © 2014 médecine/sciences-Inserm.

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