Methodology and Biostatistics Unit

Lille, France

Methodology and Biostatistics Unit

Lille, France
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Ray-Coquard I.,Center Leon Berard | Ray-Coquard I.,University of Lyon | Italiano A.,Institute Bergonie | Bompas E.,Center Rene Gauducheau | And 15 more authors.
Oncologist | Year: 2012

Background. Angiosarcomas account for <2% of all soft tissue sarcomas. This subtype is one of the most aggressive forms of soft tissue sarcoma. The prognosis for angiosarcoma patients in the advanced phase remains poor with current cytotoxic agents (progression-free survival [PFS] time of ~4 months and overall survival [OS] time of ~8 months). We investigated the antitumor activity of sorafenib in patients with metastatic or advanced angiosarcomas in a phase II trial. Methods. We conducted a stratified phase II trial. The primary endpoint was the progression-free rate (PFR) at 9 months according to the Response Evaluation Criteria in Solid Tumors.Atwo-stage design (optimal Simon design) was used. Patients received sorafenib (400 mg twice daily) for 9 months until unacceptable toxicity or tumor progression. Central pathological and radiological reviews were performed. Data on stratum A (superficial angiosarcoma) and stratum B (visceral angiosarcoma) are currently available. ©AlphaMed Press 1083- 7159/2012/$40.00/0.


Chevreau C.,Institute Claudius Regaud | Le Cesne A.,CNRS Gustave Roussy Institute | Ray-Coquard I.,Leon Berard Center | Italiano A.,Bergonie Institute | And 12 more authors.
Cancer | Year: 2013

BACKGROUND There is no standard treatment for progressive epithelioid hemangioendothelioma (EHE). To investigate the significant vascularization of EHE, the activity/toxicity of sorafenib in patients with progressive EHE was explored. METHODS In this multicenter, 1-stage, phase 2 trial of sorafenib (800 mg daily), the primary endpoint, which was chosen by default, was the 9-month progression-free rate. All patients had documented progressive disease at the time of study entry. RESULTS Fifteen patients were enrolled between June 2009 and February 2011. The median age was 57 years (range, 31-76 years), and the ratio of men to women was 9:6. The performance status was zero in 10 patients and 1 in 5 patients. Twelve patients had metastases, mainly in the lung (12 patients), liver (5 patients), and bone (3 patients). Five patients had received prior chemotherapy (doxorubicin in 5 patients and taxane in 3 patients). The median sorafenib treatment duration was 124 days (range, from 27 to >271 days). Seven patients required dose reductions or transient treatment discontinuation. The 9-month progression-free rate was 30.7% (4 of 13 patients). The 2-month, 4-month, and 6-month progression-free rate was 84.6% (11 of 13 patients), 46.4% (6 of 13 patients), and 38.4% (5 of 13 patients), respectively. Two partial responses were observed that lasted 2 months and 9 months. CONCLUSIONS Further clinical trials exploring sorafenib as treatment of progressive EHE are needed. © 2013 American Cancer Society.


Bompas E.,Center Rene Gauducheau | Le Cesne A.,Institute Gustave Roussy | Tresch-Bruneel E.,Methodology and Biostatistics Unit | Lebellec L.,Center Oscar Lambret | And 12 more authors.
Annals of Oncology | Year: 2015

Background: There is no consensual treatment of locally advanced or metastatic chordomas. Patients and methods: We conducted a multicenter, open-label, uncontrolled phase II trial of sorafenib (800 mg/day). The primary end point was the 9-month progression-free rate according to RECIST 1.1. All patients had documented progressive disease at the time of study entry. Results: Twenty-seven patients were enrolled between May 2011 and January 2014. The median age was 64 (range, 30-86) years. There were 17 men and 10 women. Twelve patients had been previously treated with chemotherapy and molecularly targeted agents. The maximum toxicity grade per patient was grade 3 in 21 cases (77.8%) and grade 4 in 4 cases (14.8%). Sorafenib provided an intent-to-treat best objective response of 1/27 [3.7%; 95% confidence interval (CI) 0.1% to 19.0%], a 9-month progression-free rate of 73.0% (95% CI 46.1-88.0) and a 12-month overall survival rate of 86.5% (95% CI 55.8-96.5). Survival curves were similar in pretreated and not pretreated patients. Discussion: Additional clinical trials further exploring sorafenib as a treatment of locally advanced or metastatic chordomas are warranted. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


PubMed | Institute Paoli Calmette, Methodology and Biostatistics Unit, Institute Bergonie, Institute Gustave Roussy and 9 more.
Type: Clinical Trial, Phase II | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2015

There is no consensual treatment of locally advanced or metastatic chordomas.We conducted a multicenter, open-label, uncontrolled phase II trial of sorafenib (800 mg/day). The primary end point was the 9-month progression-free rate according to RECIST 1.1. All patients had documented progressive disease at the time of study entry.Twenty-seven patients were enrolled between May 2011 and January 2014. The median age was 64 (range, 30-86) years. There were 17 men and 10 women. Twelve patients had been previously treated with chemotherapy and molecularly targeted agents. The maximum toxicity grade per patient was grade 3 in 21 cases (77.8%) and grade 4 in 4 cases (14.8%). Sorafenib provided an intent-to-treat best objective response of 1/27 [3.7%; 95% confidence interval (CI) 0.1% to 19.0%], a 9-month progression-free rate of 73.0% (95% CI 46.1-88.0) and a 12-month overall survival rate of 86.5% (95% CI 55.8-96.5). Survival curves were similar in pretreated and not pretreated patients.Additional clinical trials further exploring sorafenib as a treatment of locally advanced or metastatic chordomas are warranted.


PubMed | Methodology and Biostatistics Unit, Beaumont Hospital, Institute Of Cancerologie Of Louest, Clinical Research 18 Unit and 3 more.
Type: | Journal: BMC cancer | Year: 2016

Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial.PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio.This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors.NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).


Chibaudel B.,Institute Hospitalier Franco Britannique | Tournigand C.,Hopitaux de Paris | Bonnetain F.,Methodology and biostatistics Unit | Richa H.,Institute Hospitalier Franco Britannique | And 5 more authors.
Therapeutic Advances in Medical Oncology | Year: 2015

Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer (CRC), but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage. Several drugs and combinations are now available for use in treating patients with advanced CRC, but the optimal sequence of therapy remains unknown. Moreover, the administration of antitumor therapy can be modulated by periods of maintenance or treatment breaks rather than delivered as full therapy until disease progression or unacceptable toxicity, followed by reintroduction of prior full therapy when required, before switching to other drugs. Consequently, randomized strategy trials are needed to define the optimal treatment sequences. Molecular testing for Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) is mandatory but not sufficient to select appropriate patients for epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy. © The Author(s), 2015.


PubMed | SIRIC OncoLille, Center Francois Baclesse, Methodology and Biostatistics Unit, Institute Claudius Regaud and University of Nimes
Type: Review | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016

Time to progression (TTP) is often used as a primary end point in phase II clinical trials. Since the actual date of nadir and progression is never known, most calculated TTP are overestimated. This study evaluates the imprecision on the estimate of TTP under two hypothetical tumor kinetic settings and various assessment schedules.A two-component tumor growth model was used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression. Evolution of tumor burden (TB) was modelized according to two scenarios using either a cytotoxic or a cytostatic agent and several assessment schedules. TB, nadir, progression and TTP were simulated for each visit schedule.For cytotoxic agents, our model predicted response at 1.5 weeks, a TB at nadir of 40.2 mm (starting from 100 mm) occurring at 6.7 weeks and true progression at 11.2 weeks with a TB of 48.2 mm. For cytostatic agents, our model predicted no response, a TB at nadir of 77 mm occurring at 9.2 weeks and true progression at 19.4 weeks with a TB of 92 mm. Depending on the assessment schedule, estimated TTP was increased from 0.8 to 36.8 weeks and from 0.6 to 28.6 weeks when compared with the true TTP and varied from 5.2% to 298% and from 1.66 to 109.58% when compared with the true TB at progression for cytotoxic and cytostatic agents, respectively. Our model further shows that for cytotoxic agents, evaluation of TB every 6 weeks is optimal to capture the true nadir, the time to nadir, the true progression and the true TTP, whereas for cytostatic agents, this evaluation is optimal every 10 weeks.Our results emphasize the importance to estimate the effects of tested drugs on tumor shrinkage before design any phase II clinical trials to choose optimal TB evaluations timing.


Penel N.,Center Oscar Lambret | Penel N.,University of Lille Nord de France | Cousin S.,Center Oscar Lambret | Duhamel A.,University of Lille Nord de France | And 2 more authors.
Critical Reviews in Oncology/Hematology | Year: 2013

Background: Despite extensive research over the past 3 decades, few investigational drugs are considered as promising and these drugs failed to improve overall survival. Therefore we performed a systematic review of the literature to improve our understanding of the reasons that explain these failures. Methods: We reviewed 53 phase II trial reports that investigated new treatments in patients with advanced soft tissue sarcoma from 1999 to 2011. We critically reviewed the selected primary endpoint used in these trials. Results: Forty percent of trials were not interpretable because of major inherent methodological flaws. Only 3 primary endpoints were correlated with median overall survival (mOS): 3- and 6-month progression free rates and median progression-free survival. Nevertheless, the mOS was not significantly higher in the cases of active drugs. Discussion: We need to improve the definition of primary active endpoints and develop better designs for future trials. The current definition of promising drugs must be refined. © 2013 Elsevier Ireland Ltd.


Penel N.,Methodology and Biostatistics Unit | Penel N.,University of Lille Nord de France | Kramar A.,Methodology and Biostatistics Unit | Kramar A.,University of Lille Nord de France
BMC Medical Research Methodology | Year: 2012

Background: In most phase I oncology trials, it is often stated that the dose increments follow a "modified- Fibonacci sequence". This term, however, is vague. Methods: To better characterize this sequence, we reviewed 81 phase I trials based on this concept. Results: Out of 198 phase I oncology trials, 81 (41%) are based on modified-Fibonacci series. Actual incremental ratios varied in a large range from 0.80 to 2.08. The median of actual increments was about 2.00, 1.50, 1.33, 1.33, 1.33, 1.33, 1.30, 1.35. . .. The "modified Fibonacci-sequence" gathers heterogeneous variation of the genuine sequence, which does not tend to a constant number at higher dose-levels. Conclusion: This confusing term should be avoided. © 2012 Penel and Kramar; licensee BioMed Central Ltd.


Dewas S.,Charles de Gaulle University - Lille 3 | Bibault J.-E.,Charles de Gaulle University - Lille 3 | Mirabel X.,Charles de Gaulle University - Lille 3 | Fumagalli I.,Charles de Gaulle University - Lille 3 | And 5 more authors.
Radiation Oncology | Year: 2012

Purpose: Robotic Stereotactic Body Radiation Therapy with real-time tumor tracking has shown encouraging results for hepatic tumors with good efficacy and low toxicity. We studied the factors associated with local control of primary or secondary hepatic lesions post-SBRT.Methods and materials: Since 2007, 153 stereotactic liver treatments were administered to 120 patients using the CyberKnife® System. Ninety-nine liver metastases (72 patients), 48 hepatocellular carcinomas (42 patients), and six cholangiocarcinomas were treated. On average, three to four sessions were delivered over 12 days. Twenty-seven to 45 Gy was prescribed to the 80% isodose line. Margins consisted of 5 to 10 mm for clinical target volume (CTV) and 3 mm for planning target volume (PTV).Results: Median size was 33 mm (range, 5-112 mm). Median gross tumor volume (GTV) was 32.38 cm3 (range, 0.2-499.5 cm3). Median total dose was 45 Gy in three fractions. Median minimum dose was 27 Gy in three fractions. With a median follow-up of 15.0 months, local control rates at one and two years were 84% and 74.6%, respectively. The factors associated with better local control were lesion size < 50 mm (p = 0.019), GTV volume (p < 0.05), PTV volume (p < 0.01) and two treatment factors: a total dose of 45 Gy and a dose-per-fraction of 15 Gy (p = 0.019).Conclusions: Dose, tumor diameter and volume are prognostic factors for local control when a stereotactic radiation therapy for hepatic lesions is considered. These results should be considered in order to obtain a maximum therapeutic efficacy. © 2012 Dewas et al.; licensee BioMed Central Ltd.

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