Biostatistics and Epidemiological Unit

Plombières-lès-Dijon, France

Biostatistics and Epidemiological Unit

Plombières-lès-Dijon, France

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Zaanan A.,University Paris - Sud | Costes L.,University Paris - Sud | Gauthier M.,Biostatistics and Epidemiological Unit | Malka D.,University Paris - Sud | And 11 more authors.
Annals of Oncology | Year: 2010

Background: Small-bowel adenocarcinoma (SBA) is a rare tumor of poor prognosis. Data on the efficacy of chemotherapy for advanced SBA are scarce. Patients and methods: All patients with advanced SBA who received frontline chemotherapy from 1996 to 2008 were eligible for this retrospective multicenter study. Results: Ninety-three consecutive patients were included. In the entire population, the median progression-free survival (PFS) and overall survival (OS) times were 6.6 and 15.1 months, respectively. Median PFS times among patients treated with LV5FU2 (n = 10), FOLFOX (n = 48), FOLFIRI (n = 19) and LV5FU2-cisplatin (n = 16) were 7.7, 6.9, 6.0 and 4.8 months, respectively, while median OS times were 13.5, 17.8, 10.6 and 9.3 months, respectively. In multivariate analysis, World Health Organization performance status (PS) (P < 0.0001) and elevated serum levels of carcinoembryonic antigen (CEA) (P = 0.02) and carbohydrate antigen 19-9 (CA 19-9) (P = 0.03) were the only variables significantly associated with poor OS. In the subgroup of patients treated with platinum-based chemotherapy, multivariate analysis showed that LV5FU2-cisplatin was associated with poorer PFS (P < 0.0001) and OS (P = 0.02) compared with FOLFOX. Conclusions: This is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Ladoire S.,Georges Francois Leclerc Center | Ladoire S.,University of Burgundy | Mignot G.,University of Burgundy | Dabakuyo S.,Biostatistics and Epidemiological Unit | And 12 more authors.
Journal of Pathology | Year: 2011

Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. However, the predictive value of tumour-infiltrating lymphocytes after neoadjuvant chemotherapy for breast cancer remains unknown. We hypothesized that the nature of the immune infiltrate following neoadjuvant chemotherapy would predict patient survival. In a series of 111 consecutive HER2- and a series of 51 non-HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy, we studied by immunohistochemistry tumour infiltration by FOXP3 and CD8 T lymphocytes before and after chemotherapy. Kaplan-Meier analysis and Cox modelling were used to assess relapse-free survival (RFS) and overall survival (OS). A predictive scoring system using American Joint Committee on Cancer (AJCC) pathological staging and immunological markers was created. Association of high CD8 and low FOXP3 cell infiltrates after chemotherapy was significantly associated with improved RFS (p = 0.02) and OS (p = 0.002), and outperformed classical predictive factors in multivariate analysis. A combined score associating CD8/FOXP3 ratio and pathological AJCC staging isolated a subgroup of patients with a long-term overall survival of 100%. Importantly, this score also identified patients with a favourable prognosis in an independent cohort of HER2-negative breast cancer patients. These results suggest that immunological CD8 and FOXP3 cell infiltrate after treatment is an independent predictive factor of survival in breast cancer patients treated with neoadjuvant chemotherapy and provides new insights into the role of the immune milieu and cancer. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Ladoire S.,Center Georges Francois Leclerc | Ladoire S.,University of Burgundy | Mignot G.,University of Burgundy | Dalban C.,Biostatistics and Epidemiological Unit | And 19 more authors.
Annals of Oncology | Year: 2012

Background: Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. Patients and methods: Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. Results: Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. Conclusion: FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Rambach L.,Center Georges Francois Leclerc | Bertaut A.,Biostatistics and Epidemiological Unit | Vincent J.,Center Georges Francois Leclerc | Vincent J.,French Institute of Health and Medical Research | And 8 more authors.
World Journal of Gastroenterology | Year: 2014

AIM: To establish whether chemotherapy-induced neutropenia is predictive of better outcome in patients with metastatic colorectal cancer (mCRC). METHODS: Survival and patient characteristics from consecutive mCRC patients treated in the Centre Georges Francois Leclerc, Dijon, France between January 2001 and December 2011 were analyzed. Patient and tumor characteristics, hematological toxicity (neutropenia, anemia, and thrombocytopenia), and type of chemotherapy received were recorded. RESULTS: We retrospectively analyzed data from 399 consecutive patients with mCRC who received at least one line of chemotherapy. Median follow up was 6.3 years. Eighty-eight percent of the patients received more than two lines of chemotherapy. By univariate analysis, whatever their grade, neutropenia and thrombocytopenia occurring during the first two lines of chemotherapy were significantly associated with better overall survival (HR = 0.55, 95%CI: 0.43-0.70, P < 0.0001 and HR = 0.70, 95%CI: 0.56-0.88, P = 0.025 respectively). In contrast, anemia during chemotherapy was significantly associated with poorer overall survival (HR = 1.9, 95%CI: 1.22-2.97, P = 0.005). Multivariate analysis revealed that both neutropenia and thrombocytopenia were significantly associated with better overall survival: HR = 0.43, 95%CI: 0.29-0.64, P < 0.0001 and HR = 0.69, 95%CI: 0.49-0.98, P = 0.036, respectively. CONCLUSION: These data suggest that occurrence of neutropenia or thrombocytopenia during firstor second-line chemotherapy for mCRC is associated with better survival. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.


Methy N.,University of Burgundy | Bedenne L.,University of Burgundy | Bonnetain F.,University of Burgundy | Bonnetain F.,Biostatistics and epidemiological unit
BMC Cancer | Year: 2010

Background: Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL).Methods: In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion.Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking.Results: Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS.DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations.Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed.Conclusion: The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient. © 2010 Methy et al; licensee BioMed Central Ltd.


PubMed | Center Francois Baclesse, University Hospital, Institute Gustave Roussy, Federation Nationale des Centres de Lutte Contre le Cancer and 4 more.
Type: Journal Article | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2014

To examine the association between baseline body mass index (BMI), and disease-free survival (DFS) and overall survival (OS) in a large French early-stage breast cancer population included in the UNICANCER Programme dAction Concert Sein-01 (PACS01) and PACS04 phase III randomised trials.After a median follow-up of 5.9years, this report analyses 4996 patients with node-positive breast cancer, and randomly assigned to adjuvant anthracycline-based chemotherapy combined or not with taxanes. Univariate analyses were used to study the effects of well known prognostic factors and BMI on DFS and OS. BMI was obtained at baseline, before chemotherapy initiation, and obesity was defined as a BMI30kg/m(2). Cox proportional hazards regression models were secondly used to assess the influence of BMI after adjusting for other factors. Exhaustive analysis of the dose intensity delivered was also studied for comparison between obese and non-obese patients.Obese patients initially present with more advanced disease at diagnosis compared to non-obese patients. By univariate analysis, obesity was moderately associated with poorer DFS (hazard ratio (HR)=1.18 [1.01-1.39] P=0.04), but mostly with poorer OS (HR=1.38 [1.13-1.69] P=0.002). Delivered dose intensity of anthracyclines and taxanes was not significantly different between obese and non-obese patients. After adjustment for disease characteristics, BMI had no influence either on DFS or OS.This report suggests that in a French population, obesity has no impact on breast cancer prognosis when modern adjuvant chemotherapy, at the appropriate dose intensity, is delivered.


Nouhaud E.,The Surgical Center | Crehange G.,The Surgical Center | Cueff A.,Biostatistics and Epidemiological Unit | Quivrin M.,The Surgical Center | And 5 more authors.
BMC Research Notes | Year: 2013

Abstract. Background: To evaluate the feasibility and efficacy of Stereotactic body radiation therapy (SBRT) for primary liver lesions and liver metastases treated with linear accelerators with or without rotational Intensity Modulated RadioTherapy (IMRT). Methods. Patients with either hepatocellular carcinoma, cholangiocarcinoma or metastatic liver lesions who had one to three lesions treated with SBRT in a single institution were retrospectively reviewed. Tumor response was evaluated according to EASL criteria 3 months after SBRT completion using MRI and/or abdominal CT scan. Responses were categorised as: Stable Disease (SD), Partial Response (PR), Complete Response (CR), Local Progression or Distant Progression in cases of new intra-hepatic lesions out-of-field or extra-hepatic metastases. Local Control (LC), Progression Free Survival (PFS), Overall Survival (OS) and treatment-related toxicities are reported. Results: Between 2007 and 2012, 20 patients with a total of 24 lesions were treated with SBRT. Fourteen patients presented hepatocellular carcinoma (HCC), the others had either metastatic lesions from colorectal cancer (CRC) or cholangiocarcinoma. The median diameter of the lesions was 23 mm (5-98).The dose per fraction ranged from 6 to 20 Gy with a median total dose of 60 Gy (range: 36-60 Gy). The dose was prescribed to the 80% isodose line covering the PTV.The median follow-up was 24 months (15.7-29.7).The actuarial LC rate was 78% for patients with HCC and 83% for those with adenocarcinoma and cholangiocarcinoma. Median OS was 37 months and OS rates were 83% at 12 and 24 months for HCC and 100% for adenocarcinoma. PFS was 54% for HCC and 50% for other types of tumors at 24 months.Acute grade 3-4 toxicities occurred in 2 patients; a small proportion of the other patients experienced grade 1 or 2 toxicities. Conclusions: SBRT provides excellent local control with minimal side effects in selected patients. © 2013 Nouhaud et al.; licensee BioMed Central Ltd.


Crehange G.,Anticancer Center Georges Francois Leclerc | Maingon P.,Anticancer Center Georges Francois Leclerc | Gauthier M.,Biostatistics and Epidemiological Unit | Parfait S.,CNRS Laboratory of Electronics Informatics and Images | And 8 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: To investigate the time course response of prostate metabolism to irradiation using magnetic resonance spectroscopy (MRS) at 3-month intervals and its impact on biochemical control. Methods and Materials: Between January 2008 and April 2010, 24 patients with localized prostate cancer were prospectively enrolled in the Evaluation of the Response to Irradiation with MR Spectroscopy (ERIS) trial. All the patients had been treated with intensity-modulated radiation therapy with or without long-term adjuvant hormonal therapy (LTHT) and underwent 3-T MRS and prostate-specific antigen (PSA) assays at baseline and every 3 months thereafter up to 12 months. Results: After radiation, the mean normalized citrate level (citrate/water) decreased significantly over time, both in the peripheral zone (PZ) (p = 0.0034) and in the entire prostate (p = 0.0008), whereas no significant change was observed in mean normalized choline levels (choline/water) in the PZ (p = 0.84) and in the entire prostate (p = 0.95). At 6 months after radiation, the mean choline level was significantly lower in the PZ for patients with a PSA value of ≤0.5 ng/mL at 12 months (4.9 ± 1.7 vs. 7.1 ± 1.5, p = 0.0378). Similar results were observed at 12 months in the PZ (6.2 ± 2.3 vs. 11.4 ± 4.1, p = 0.0117 for choline level and 3.4 ± 0.7 vs. 16.1 ± 6.1, p = 0.0054 for citrate level) and also in the entire prostate (6.2 ± 1.9 vs. 10.4 ± 3.2, p = 0.014 for choline level and 3.0 ± 0.8 vs. 13.3 ± 4.7, p = 0.0054 for citrate level). For patients receiving LTHT, there was no correlation between choline or citrate levels and PSA value, either at baseline or at follow-up. Conclusions: Low normalized choline in the PZ, 6 months after radiation, predicts which patients attained a PSA ≤0.5 ng/mL at 1 year. Further analyses with longer follow-up times are warranted to determine whether or not these new biomarkers can conclusively predict the early radiation response and the clinical outcome for patients with or without LTHT. © 2011 Elsevier Inc.


PubMed | Besancon University Hospital Center, Center Georges Francois Leclerc, Center Paul Strauss, hopital prive Drevon and 3 more.
Type: Journal Article | Journal: Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique | Year: 2016

To evaluate the maximum tolerated dose of simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) associated with temozolomide in patients with glioblastoma.Between November 2009 and January 2012, nine patients with malignant glioma were enrolled in this phase I clinical trial. Radiotherapy was delivered using fractions of 2.5Gy on the planning target volume b and of 1.9Gy on the planning target volume a. Volumes were defined as follow: gross tumour volume b: tumour taking up contrast on T1 weighted MRI images; clinical target volume b: gross tumour volume b+0.5cm (adapted to the anatomical structures) and lastly planning target volume b: clinical target volume b+0.5cm; gross tumour volume a: tumour (gross tumour volume b)+2cm and including oedema outlined on T2Flair MRI sequences; clinical target volume a gross tumour volume a+0.5cm (adapted to the anatomical structures); planning target volume a: clinical target volume a+0.5cm. Three patients were enrolled at each of the three levels of dose (70, 75 and 80Gy prescribed on the planning target volume b and 56, 60 and 60.8Gy on the planning target volume a). Radiotherapy was delivered with temozolomide according to the standard protocol. Dose-limiting toxicities were defined as any haematological toxicities at least grade 4 or as any radiotherapy-related non-haematological acute toxicities at least grade 3, according to the Common Terminology Criteria for Adverse Events, version 3.0.Until the last dose level of 80Gy, no patient showed dose-limiting toxicity.SIB-IMRT, at least until a dose of 80Gy in 32 daily fractions, associated with temozolomide is feasible and well tolerated.


Vegran F.,Center Georges Francois Leclerc | Boidot R.,Center Georges Francois Leclerc | Bonnetain F.,Biostatistics and Epidemiological Unit | Cadouot M.,Center Georges Francois Leclerc | And 2 more authors.
Endocrine-Related Cancer | Year: 2011

Survivin, an anti-apoptotic protein, was described as strongly expressed in human cancers including breast cancer. However, little is known about the association between Survivin variants (Survivin-2B, Survivin-ΔEx3, Survivin-3B, and Survivin-2α) and the other apoptotic-related genes. In this study, we analyzed the apoptosis gene signature of Survivin and its variant expression in breast cancer. Human Apoptosis Gene Arrays were used to screen genes that could be associated with Survivin variants. Expression of the five transcripts was measured by RT-PCR in 135 breast carcinomas and Cox survival analysis was analyzed according to the patient outcome. Significant associations between Survivin transcripts and apoptotic genes were found. Interestingly, Survivin-3B variant showed major inverse correlations with pro-apoptotic genes. In addition, in vitro results indicated that overexpression of Survivin-3B strongly inhibits 5-fluorouracil/epirubicin/cyclophosphamide-induced apoptosis in breast tumor cell lines. In breast carcinomas, uni- and multivariate analysis showed patients with high level of Survivin-3B expression had a shorter overall (P=0.030 and P=0.042 respectively), and disease-free (P=0.024 and P=0.009) survival. Our data suggest that Survivin-3B contributes to cell survival through the anti-apoptotic pathway and that its expression level could be an important factor in determining therapeutic strategies for breast carcinoma. © 2011 Society for Endocrinology.

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