Institute Curie Rene Huguenin Hospital

Saint-Cloud, France

Institute Curie Rene Huguenin Hospital

Saint-Cloud, France

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Paoletti X.,French Institute of Health and Medical Research | Geoerger B.,University Paris - Sud | Doz F.,University Pierre and Marie Curie | Doz F.,University of Paris Descartes | And 4 more authors.
European Journal of Cancer | Year: 2013

Background: Dose-finding phase I trials in children are usually carried out once clinical data have already been accumulated in the adult population. The objectives, place and role of paediatric dose-finding trials are investigated in the era of molecularly targeted agents (MTAs). Methods: Phase I paediatric oncology trials of MTAs approved in adults before June 15th, 2012 were reviewed. The recommended phase II dose (RPIID) was compared to the body surface area (BSA)-adjusted approved dose in adults. Toxicity profile was compared to the findings from the corresponding adult phase I trials. Results: Fifteen MTAs out of a total of 25 MTAs approved in the adult population have been evaluated in 19 single-agent phase I paediatric trials. Trials included a median of 30 children with a median of four dose levels. The paediatric RPIID ranged between 90% and 130% of the BSA-adjusted approved dose in adults for 70% of the trials (75% of compounds). Overall, 63% of children did not receive an optimal dose. The most marked discrepancy involved sunitinib. Safety profiles described in phase I paediatric trials were usually similar to those reported in the adult population. Conclusions: These data suggest that dose-finding studies might not be necessary for all the MTAs in children. Except in the case of a narrow therapeutic index, early-phase trials validating pharmacokinetics, pharmacodynamic markers and efficacy findings from adults while controlling for toxicity appear to be a possible alternative to accelerate drug development in paediatric oncology. © 2013 Elsevier Ltd. All rights reserved.


Bernadou G.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Campone M.,French Institute of Health and Medical Research | Merlin J.-L.,University of Lorraine | Merlin J.-L.,Nancy Research Center for Automatic Control | And 12 more authors.
British Journal of Clinical Pharmacology | Year: 2016

Aims: Trastuzumab, an antibody binding to epidermal growth factor receptor-2 (HER2), has been approved to treat HER2-positive breast cancer in different settings. This study aimed at evaluating the influence of tumour size on trastuzumab pharmacokinetics (PK) in non-metastatic breast cancer patients treated with short term pre-operative trastuzumab. Methods: Trastuzumab PK data were obtained from a multicentre, randomized and comparative study. This antibody was administered pre-operatively to patients with localized HER2-positive breast cancer as a single 4 mg kg-1 loading dose followed by 5 weekly 2 mg kg-1 doses. Trastuzumab concentrations were measured repeatedly using an ELISA technique. Tumour size was evaluated at baseline using breast echography. Trastuzumab pharmacokinetics were studied using a population approach and a two compartment model. The influence of tumour burden on trastuzumab pharmacokinetics was quantified as a covariate. Results: A total of 784 trastuzumab concentrations were available from the 79 eligible patients. Estimated parameters (interindiviual standard deviation) were central volume of distribution =2.1 l (23%), peripheral volume of distribution =1.3 l (38%), intercompartment clearance =0.36 l day-1, with an elimination half-life of 11.8 days. Typical clearance was 0.22 l day-1 (19%) and its value was increased with tumour size. In patients with the highest tumour size, trastuzumab clearance was 50% [18%-92%] higher than in patients with the lowest tumour size. Conclusions: In non-metastatic breast cancer patients, trastuzumab clearance increases with tumour size. The elimination half-life of trastuzumab was shorter in the present population of patients than in metastatic breast cancer patients previously studied. © 2015 The British Pharmacological Society.


PubMed | Institute Curie Rene Huguenin Hospital, CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory, University of Lorraine, Gustave Roussy and 2 more.
Type: Clinical Trial, Phase II | Journal: British journal of clinical pharmacology | Year: 2016

Trastuzumab, an antibody binding to epidermal growth factor receptor-2 (HER2), has been approved to treat HER2-positive breast cancer in different settings. This study aimed at evaluating the influence of tumour size on trastuzumab pharmacokinetics (PK) in non-metastatic breast cancer patients treated with short term pre-operative trastuzumab.Trastuzumab PK data were obtained from a multicentre, randomized and comparative study. This antibody was administered pre-operatively to patients with localized HER2-positive breast cancer as a single 4mgkg(-1) loading dose followed by 5 weekly 2mgkg(-1) doses. Trastuzumab concentrations were measured repeatedly using an ELISA technique. Tumour size was evaluated at baseline using breast echography. Trastuzumab pharmacokinetics were studied using a population approach and a two compartment model. The influence of tumour burden on trastuzumab pharmacokinetics was quantified as a covariate.A total of 784 trastuzumab concentrations were available from the 79 eligible patients. Estimated parameters (interindiviual standard deviation) were central volume of distribution =2.1l (23%), peripheral volume of distribution =1.3l (38%), intercompartment clearance =0.36lday(-1) , with an elimination half-life of 11.8days. Typical clearance was 0.22lday(-1) (19%) and its value was increased with tumour size. In patients with the highest tumour size, trastuzumab clearance was 50% [18%-92%] higher than in patients with the lowest tumour size.In non-metastatic breast cancer patients, trastuzumab clearance increases with tumour size. The elimination half-life of trastuzumab was shorter in the present population of patients than in metastatic breast cancer patients previously studied.


Peres A.,Institute Curie Rene Huguenin Hospital | Peres A.,University Paris Diderot | Barranger E.,University Paris Diderot | Becette V.,Institute Curie Rene Huguenin Hospital | And 3 more authors.
Breast Cancer Research and Treatment | Year: 2012

Flat epithelial atypia (FEA) is a borderline lesion that might represent an early stage in the development of certain low-grade carcinomas in situ and invasive cancers. There are no guidelines on its management. Our objectives were to determine the upgrade to malignancy rate and identify a subpopulation of patients that might undergo just mammographic surveillance. We retrospectively reviewed the data for 271 FEA cases among 5,555 breast core biopsies obtained over a 7-year period (January 2003-2010). We collated clinical data (age, history of cancer, menopausal status), radiological data (lesion type, size, Bi-Rads category), technical data (number of biopsies, needle gauge, excision quality) and histological data and sought correlations between these factors and upgrade rate. The 271 FEA comprised 128 cases of pure FEA, 135 cases of FEA + atypical ductal hyperplasia, and 8 cases of FEA + atypical lobular hyperplasia. Overall, 184 patients underwent surgery and 46 mammographic surveillance. Surgery detected 34 cases of malignancy (23 CIS, 7 invasive cancers, and 4 mixed cases) giving a 15% upgrade rate. Quality of excision was the only factor associated with under-diagnosis. The presence of FEA at biopsy warrants surgery. © 2012 Springer Science+Business Media, LLC.


PubMed | Institute Curie Rene Huguenin Hospital
Type: Journal Article | Journal: Breast cancer research and treatment | Year: 2012

Flat epithelial atypia (FEA) is a borderline lesion that might represent an early stage in the development of certain low-grade carcinomas in situ and invasive cancers. There are no guidelines on its management. Our objectives were to determine the upgrade to malignancy rate and identify a subpopulation of patients that might undergo just mammographic surveillance. We retrospectively reviewed the data for 271 FEA cases among 5,555 breast core biopsies obtained over a 7-year period (January 2003-2010). We collated clinical data (age, history of cancer, menopausal status), radiological data (lesion type, size, Bi-Rads category), technical data (number of biopsies, needle gauge, excision quality) and histological data and sought correlations between these factors and upgrade rate. The 271 FEA comprised 128 cases of pure FEA, 135 cases of FEA + atypical ductal hyperplasia, and 8 cases of FEA + atypical lobular hyperplasia. Overall, 184 patients underwent surgery and 46 mammographic surveillance. Surgery detected 34 cases of malignancy (23 CIS, 7 invasive cancers, and 4 mixed cases) giving a 15% upgrade rate. Quality of excision was the only factor associated with under-diagnosis. The presence of FEA at biopsy warrants surgery.


PubMed | Institute Curie Rene Huguenin Hospital and University of Versailles
Type: | Journal: Gynecologic oncology | Year: 2017

To show laparoscopic surgery to treat vaginal shortening, with functional sequelae (sexual disorders), after radiotherapy and brachytherapy for vaginal carcinoma.Davydovs procedure was initially described to treat vaginal aplasia (Davydov & Zhvitiashvili, 1974). This surgery was then improved for the upper part of the vagina, performed by laparoscopy (Leblanc, 2010; Adamyan, 1995) [2-3]. We used surgical technique, based on Davydovs procedure, by laparoscopy, to cover the upper neovagina, with two large peritoneal flaps, one anterior with the pre-vesical peritoneum and a second one posterior with the peritoneum of Douglas pouch. This surgery can be performed with no use of intestinal gesture, skin grafting, flap or any foreign material. Leblanc et al. (2016) [4] reported promising results about eight patients with this technique.A 36-years old patient had been treated by chemotherapy, radiotherapy and brachytherapy for a vagina cancer with a para-rectal extension. After four years of remission, she was worried about an important vaginal atrophy related to a significant vaginal shortening (about 5cm), causing major dyspareunia. This situation had caused sexual disorders with a real impact on the quality of life. All non-invasive techniques (dilatators, lubricants) had led to failures. A colpoplasty by laparoscopic modified Davydovs procedure was performed. The post-operative follow-up was simple without complication. The vaginal mandrel was removed after 12days. The clinical examination after 4months demonstrates that size and elasticity of the neovaginal cavity was rewarding.This surgical technique requires training and experienced team, but seems to be promising way to restore a normal vaginal length.


PubMed | Institute Curie Rene Huguenin Hospital
Type: Case Reports | Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology | Year: 2010

Early assessment of radiotherapy (RT) quality in the ongoing EORTC trial comparing primary temozolomide versus RT in low-grade gliomas.RT plans provided for dummy cases were evaluated and compared against expert plans. We analysed: (1) tumour and organs-at-risk delineation, (2) geometric and dosimetric characteristics, (3) planning parameters, compliance with dose prescription and Dmax for OAR (4) indices: RTOG conformity index (CI), coverage factor (CF), tissue protection factor (PF); conformity number (CN = PF x CF); dose homogeneity in PTV (U).Forty-one RT plans were evaluated. Only two (5%) centres were requested to repeat CTV-PTV delineations. Three (7%) plans had a significant under-dosage and dose homogeneity in one deviated > 10%. Dose distribution was good with mean values of 1.5, 1, 0.68, and 0.68 (ideal values = 1) for CI, CF, PF, and CN, respectively. CI and CN strongly correlated with PF and they correlated with PTV. Planning with more beams seems to increase PTV(Dmin), improving CF. U correlated with PTV(Dmax).Preliminary results of the dummy run procedure indicate that most centres conformed to protocol requirements. To quantify plan quality we recommend systematic calculation of U and either CI or CN, both of which measure the amount of irradiated normal brain tissue.

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