Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: A fédération nationale des centres de lutte contre le cancer (FNCLCC) french sarcoma group study (TAXOGEM study)
Floquet A.,Institute Bergonie |
Penel N.,Center Oscar Lambret |
Piperno-Neumann S.,University Pierre and Marie Curie |
Isambert N.,Center Georges Franois Leclerc |
And 7 more authors.
Oncologist | Year: 2012
Background. This study aimed to evaluate the efficacy and toxicity of single-agent gemcitabine versus gemcitabine plus docetaxel as second-line therapy in patients with uterine and nonuterine leiomyosarcoma (LMS). Patients and Methods. Patients had metastatic or unresectable LMS and had received one prior anthracyclinebasedregimen.Atotalof90patientsreceivedeithersingleagent gemcitabine (arm A; gemcitabine, 1,000 mg/m2i.v. for 100 minutes on days 1, 8, and 15 of a 28-day cycle) or a combination of gemcitabine and docetaxel (arm B; gemcitabine, 900 mg/m2i.v. for 90 minutes on days 1 and 8, plus docetaxel, 100 mg/m2i.v. for 1 hour on day 8 of a 21-day cycle with lenograstim). The primary endpoint was the objective response rate. Results.Theobjectiveresponserateswere19%and24% in arm A (gemcitabine) and arm B (gemcitabine plus docetaxel), respectively, for patients with uterine LMS. For patientswithnonuterineLMS,theobjectiveresponserates were14%and5%forarmsAandB,respectively.Themedianprogression-freesurvivaltimesforarmsAandBwere 5.5 months and 4.7 months, respectively, for patients with uterine LMS. For patients with nonuterine LMS, the median progression-free survival times were 6.3 months and 3.8monthsforarmsAandB,respectively.Onetoxicdeath occurred in arm B. Conclusions. Both single-agent gemcitabine and gemcitabine plus docetaxel were found to be effective second-line therapies for leiomyosarcomas, with a 3-month progression-freesurvivalrateof40%forLMSwithboth uterine and nonuterine sites of origin. Single-agent gemcitabine yielded results similar to those of gemcitabine plus docetaxel in this trial, but patients using single-agent gemcitabine experienced less toxicity. © AlphaMed Press.
Results of the GYNECO 02 study, an FNCLCC phase III trial comparing hysterectomy with No hysterectomy in patients with a (Clinical and Radiological) complete response after chemoradiation therapy for stage IB2 or II cervical cancer
Morice P.,Institute Gustave Roussy |
Morice P.,University Paris - Sud |
Morice P.,French Institute of Health and Medical Research |
Rouanet P.,Center Val dAurelle |
And 12 more authors.
Oncologist | Year: 2012
Background. Concomitant chemoradiation (CRT) (including brachytherapy) is considered the standard management for stage IB2 or II cervical cancer in many countries. Nevertheless, some of them discuss completion surgery (hysterectomy [HT]) after CRT. The aim of this study was to investigate the therapeutic impact of such surgery. Methods. A randomized trial was opened in France in 2003 to evaluate the interest in HT after CRT. Inclusion criteria were: (a) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging; (b) pelvic external radiation therapy (45 Gy with or without parametrial or nodal boost) with concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete clinical and radiological response 6 - 8 weeks after brachytherapy. Patients were randomized between HT (arm A) and no HT (arm B). Unfortunately this trial was closed because of poor accrual: 61 patients were enrolled (in 2003-2006) and are reported on here. Results. Thirty one and 30 patients were enrolled, respectively, in arm A and arm B. Twelve patients recurred (five of them died): respectively, eight and four in arm A and arm B. The 3-year event-free survival rates were 72% (standard error [SE], 9%) and 89% (SE, 6%) (not significant [NS]) in arm A and arm B, respectively. The 3-year overall survival rates were 86% (SE, 6%) and 97% (SE, 3%) (NS) in arm A and arm B, respectively. Conclusions. Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT (but this conclusion is limited by the lack of power). © AlphaMed Press.
Ladoire S.,Center Georges Francois Leclerc |
Ladoire S.,French Institute of Health and Medical Research |
Ladoire S.,University of Burgundy |
Dalban C.,Biostatistics and Epidemiological Unit |
And 11 more authors.
European Journal of Cancer | Year: 2014
Background 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 d'Action Concerté Sein-01 (PACS01) and PACS04 phase III randomised trials. Methods After a median follow-up of 5.9 years, 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 BMI ≥ 30 kg/m2. 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. Results 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. Conclusion 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. © 2013 Elsevier Ltd. All rights reserved.
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.
Guedj M.,Ligue Nationale Contre le Cancer |
Marisa L.,Ligue Nationale Contre le Cancer |
De Reynies A.,Ligue Nationale Contre le Cancer |
Orsetti B.,Institute Of Recherche En Cancerologie Of Montpellier |
And 30 more authors.
Oncogene | Year: 2012
The current histoclinical breast cancer classification is simple but imprecise. Several molecular classifications of breast cancers based on expression profiling have been proposed as alternatives. However, their reliability and clinical utility have been repeatedly questioned, notably because most of them were derived from relatively small initial patient populations. We analyzed the transcriptomes of 537 breast tumors using three unsupervised classification methods. A core subset of 355 tumors was assigned to six clusters by all three methods. These six subgroups overlapped with previously defined molecular classes of breast cancer, but also showed important differences, notably the absence of an ERBB2 subgroup and the division of the large luminal ER+ group into four subgroups, two of them being highly proliferative. Of the six subgroups, four were ER +PR +AR+, one was ER-/PR-/AR-and one was triple negative (AR-/ER-/PR-). ERBB2-amplified tumors were split between the ER-/PR-/AR+ subgroup and the highly proliferative ER+ LumC subgroup. Importantly, each of these six molecular subgroups showed specific copy-number alterations. Gene expression changes were correlated to specific signaling pathways. Each of these six subgroups showed very significant differences in tumor grade, metastatic sites, relapse-free survival or response to chemotherapy. All these findings were validated on large external datasets including more than 3000 tumors. Our data thus indicate that these six molecular subgroups represent well-defined clinico-biological entities of breast cancer. Their identification should facilitate the detection of novel prognostic factors or therapeutical targets in breast cancer. © 2012 Macmillan Publishers Limited All rights reserved.
Filleron T.,Institute Claudius Regaud |
Kramar A.,CRLC val dAurelle |
Kramar A.,Center Oscar Lambret |
Dalenc F.,Institute Claudius Regaud |
And 5 more authors.
Bulletin du Cancer | Year: 2012
Purpose. The role of post-therapeutic follow-up for breast cancer patients (pts) is open to debate. The aim of this study was to identify prognostic factors associated with the type of first event. Methods. Data of 2,820 pts included in three adjuvant trials for node-positive breast cancer were used. Competing risk methodology was used to identify prognostic factors associated with time to first failure according to type of event. Results. After a median follow-up of 53 months, 732 pts had disease-related events (114 locoregional, 58 contralateral, and 560 distant metastasis). The prognostic factors associated with high locoregional recurrence were young age, number of positive lymph nodes and grade III. In multivariate analysis, the type of first event influenced post-relapse survival. Nottingham Prognostic Index identified three groups of pts at different risk of relapse. Conclusion. Early relapse is rare in the first year after surgery and is associated with more aggressive disease. Using the Nottingham Prognostic Index, it is possible to identify pts at lower risks of relapse for whom it seems reasonable to limit the frequency of routine follow-up during the first years. For pts at higher risk of locoregional recurrence, regular follow-up should be maintained in order to detect potential curative events. ©John Libbey Eurotext.
Fourcade A.,Institute Gustave Roussy |
Blache J.-L.,Institute Paoli Calmettes |
Grenier C.,Federation Nationale des Centres de Lutte Contre le Cancer |
Bourgain J.-L.,Institute Gustave Roussy |
Minvielle E.,Institute Gustave Roussy
BMJ Quality and Safety | Year: 2012
Objective: Implementation of a surgical checklist depends on many organisational factors and on sociocultural patterns. The objective of this study was to identify barriers to effective implementation of a surgical checklist and to develop a best use strategy. Setting: 18 cancer centres in France. Design: The authors first assessed use compliance and completeness rates of the surgical checklist on a random sample of 80 surgical procedures performed under general or loco-regional anaesthesia in each of the 18 centres. They then developed a typology of the organisational and cultural barriers to effective checklist implementation and defined each barrier's contents using data from collective and semistructured individual interviews of key staff, the results of an email questionnaire sent to the 18 centres, and direct observations over 20 h in two centres. Results: The study consisted of 1440 surgical procedures, 1299 checklists, and 28 578 items. The mean compliance rate was 90.2% (0, 100). The mean completion rate was 61% (0, 84). 11 barriers to effective checklist implementation were identified. Their incidence varied widely across centres. The main barriers were duplication of items within existing checklists (16/18 centres), poor communication between surgeon and anaesthetist (10/18), time spent completing the checklist for no perceived benefit, and lack of understanding and timing of item checks (9/18), ambiguity (8/18), unaccounted risks (7/18) and a time-honoured hierarchy (6/18). Conclusions: Several of the barriers to the successful implementation of the surgical checklist depended on organisational and cultural factors within each centre. The authors propose a strategy for change for checklist design, use and assessment, which could be used to construct a feedback loop for local team organisation and national initiatives.
Jacquemier J.,French Institute of Health and Medical Research |
Boher J.-M.,French Institute of Health and Medical Research |
Roche H.,Institute Claudius Regaud |
Esterni B.,French Institute of Health and Medical Research |
And 14 more authors.
Breast Cancer Research | Year: 2011
Introduction: The PACS01 trial has demonstrated that a docetaxel addition to adjuvant anthracycline-based chemotherapy improves disease-free survival (DFS) and overall survival of node-positive early breast cancer (EBC). We searched for prognostic and predictive markers for docetaxel's benefit.Methods: Tumor samples from 1,099 recruited women were analyzed for the expression of 34 selected proteins using immunohistochemistry. The prognostic and predictive values of each marker and four molecular subtypes (luminal A, luminal B, HER2-overexpressing, and triple-negative) were tested.Results: Progesterone receptor-negativity (HR = 0.66; 95% CI 0.47 to 0.92, P = 0.013), and Ki67-positivity (HR = 1.53; 95% CI 1.12 to 2.08, P = 0.007) were independent adverse prognostic factors. Out of the 34 proteins, only Ki67-positivity was associated with DFS improvement with docetaxel addition (adjusted HR = 0.51, 95% CI 0.33 to 0.79 for Ki67-positive versus HR = 1.10, 95% CI 0.75 to 1.61 for Ki67-negative tumors, P for interaction = 0.012). Molecular subtyping predicted the docetaxel benefit, but without providing additional information to Ki67 status. The luminal A subtype did not benefit from docetaxel (HR = 1.16, 95% CI 0.73 to 1.84); the reduction in the relapse risk was 53% (HR = 0.47, 95% CI 0.22 to 1.01), 34% (HR = 0.66, 95% CI 0.37 to 1.19), and 12% (HR = 0.88, 95% CI 0.49 to 1.57) in the luminal B, HER2-overexpressing, and triple-negative subtypes, respectively.Conclusions: In patients with node-positive EBC receiving adjuvant anthracycline-based chemotherapy, the most powerful predictor of docetaxel benefit is Ki67-positivity. © 2011 Jacquemier et al.; licensee BioMed Central Ltd.
Brain E.,Institute Curie |
Isambert N.,Center Georges Francois Leclerc |
Isambert N.,French Institute of Health and Medical Research |
Dalenc F.,Institute Claudius Regaud |
And 11 more authors.
British Journal of Cancer | Year: 2012
BACKGROUND: To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab. METHODS: In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m -2) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated. RESULTS: Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3′ (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3-4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3-4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30-40% compared with DL1. CONCLUSION: The MTD LPT 1000 mg/VNR 22.5 mg m -2 (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance. © 2012 Cancer Research UK. All rights reserved.
Rezai K.,Institute Curie Hopital Rene Huguenin |
Urien S.,Institute Curie Hopital Rene Huguenin |
Urien S.,University of Paris Descartes |
Isambert N.,Center Georges Francois Leclerc |
And 7 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2011
Purpose: The objectives of this study were to investigate the pharmacokinetics of intra-venous vinorelbine combined with lapatinib as well as the effect of covariates in breast cancer patients. Methods: Women with HER2 + locally advanced or metastatic breast cancer progressing after ≤2 lines of trastuzumab-based treatment were treated with lapatinib per os starting 7 days (D) (D-7 to D0) before adding vinorelbine on a D1 & D8 every 3 weeks intravenous schedule. Lapatinib was given everyday. Dose levels [DL, lapatinib (mg)/vinorelbine (mg/m 2)] ranged from 750/20 to 1,250/25. A total of 29 patients, 37-76 years old, were treated with the combination of lapatinib + vinorelbine. For pharmacokinetic analysis, 7 time point samples were collected on D1 of cycle 1 for lapatinib and vinorelbine assays. For vinorelbine and lapatinib, respectively, whole blood and plasma concentrations were measured using ultra performance liquid chromatography with tandem mass spectrometry validated methods. Data analysis was performed using a non-linear mixed effect model program (Monolix version 3.1 s). Results: A three-compartment open model adequately described vinorelbine pharmacokinetics. Body weight (BW) and platelet count significantly influenced blood vinorelbine clearance (CL). BW significantly influenced volume (V) and CL terms. Platelet count influenced vinorelbine elimination CL. The final parameter estimates were as follows: CL = 24.9 L/h, V1 = 8.48 L, Q2 = 50.7 L/h, V2 = 1,320 L, Q3 = 66.1 L/h, and V3 = 62.4 L (Qi and Vi denote inter-compartmental clearance and peripheral volume of distribution, respectively), normalized for a 70-kg patient according to BW allometric scaling (CL is normalized for a 250,000 platelet count). A one-compartment model with linear elimination adequately fitted the lapatinib plasma concentration-time data. The population pharmacokinetic parameters were CL = 27.7 L/h, V = 357 L, and the absorption constant, ka = 0.44 h -1. The between-subject variabilities (BSV) could be well estimated for CL, V but not for ka. No covariate effect, including body surface area and vinorelbine dosage, could be identified for lapatinib. Conclusions: The pharmacokinetic modeling of vinorelbine and lapatinib was consistent with the results previously reported. BW and platelet count were confirmed as influencing blood CL of vinorelbine. A pharmacokinetic interaction occurred between vinorelbine and lapatinib probably due to lapatinib inhibition of CYP450-3A4. The combined lapatinib administration decreases statistically significant the vinorelbine CL. The maximal tolerated dose for the combination of lapatinib with vinorelbine on a q3w schedule is as follows: lapatinib 1,000 mg/day continuously and vinorelbine 22.5 mg/m 2 D1 & D8. © 2011 Springer-Verlag.