Publications by authors named "Magali Provansal"

26 Publications

  • Page 1 of 1

Effect of Weekly Paclitaxel With or Without Bevacizumab on Progression-Free Rate Among Patients With Relapsed Ovarian Sex Cord-Stromal Tumors: The ALIENOR/ENGOT-ov7 Randomized Clinical Trial.

JAMA Oncol 2020 Oct 8. Epub 2020 Oct 8.

GINECO and Centre Léon Bérard, Lyon, France.

Importance: To our knowledge, this is the first randomized trial in sex cord-stromal tumors, and it establishes weekly paclitaxel as standard-of-care therapy after platinum-based therapy in this setting.

Objective: To determine the efficacy of weekly paclitaxel with or without bevacizumab as treatment for relapsed sex cord-stromal tumors and evaluate whether the addition of bevacizumab to weekly paclitaxel improves 6-month progression-free rate.

Design, Setting, And Participants: This open-label, academic, international, randomized phase 2 trial (ALIENOR) was conducted at 28 referral centers in France, Germany, Italy, Japan, and Belgium in collaboration with the Rare Tumor committee of the Gynecologic Cancer InterGroup and used an adaptive bayesian design. It included 60 women with sex cord-stromal tumors that had relapsed after at least 1 platinum-based chemotherapy. Enrollment occurred from 2013 to 2016, and the final analysis database lock was on March 27, 2020 (median follow-up, 38.9 months).

Interventions: Participants were randomized to receive either paclitaxel (80 mg/m2, days 1, 8, and 15 every 4 weeks) alone or paclitaxel with bevacizumab (10 mg/kg, every 2 weeks) for 6 cycles followed by maintenance bevacizumab (15 mg/kg, every 3 weeks) for up to 1 year or until progression or unacceptable toxicity. Crossover to bevacizumab was permitted after progression during or following paclitaxel alone.

Main Outcomes And Measures: Six-month progression-free rate.

Results: Sixty patients (predominantly with granulosa cell tumors) were randomized, 32 to receive single-agent paclitaxel (median [interquartile range] age at inclusion, 60 [53-64] years) and 28 to receive paclitaxel-bevacizumab (median [interquartile range] age at inclusion, 55 [47-61] years; 1 did not receive treatment). The estimated 6-month progression-free rate was 71% (95% credible interval, 55%-84%) with paclitaxel alone and 72% (95% credible interval, 55%-87%) with paclitaxel-bevacizumab. The bayesian estimate for the probability that the 6-month progression-free rate distribution was higher with the combination than with paclitaxel alone was 57%, less than the predefined superiority threshold. The objective response rate increased from 25% (95% CI, 12%-43%) to 44% (95% CI, 26%-65%) with the addition of bevacizumab. One patient discontinued combination therapy within 6 months because of toxicity.

Conclusions And Relevance: Weekly paclitaxel is a new option for relapsed sex cord-stromal tumors. In this international randomized clinical trial of patients with relapsed sex cord-stromal tumors unsuitable for surgery, adding bevacizumab to weekly paclitaxel does not improve clinical benefit.

Trial Registration: ClinicalTrials.gov Identifier: NCT01770301.
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http://dx.doi.org/10.1001/jamaoncol.2020.4574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545353PMC
October 2020

Dose-intensive regimen treatment for small-cell carcinoma of the ovary of hypercalcemic type (SCCOHT).

Gynecol Oncol 2020 Oct 25;159(1):129-135. Epub 2020 Jul 25.

Gynecology Unit, Institut Gustave-Roussy, 114 rue Édouard-Vaillant, 94800 Villejuif, France. Electronic address:

Purpose: Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is a rare and rapidly lethal disease affecting young women. Cytoreductive surgery associated with chemotherapy followed by a high dose chemotherapy regimen (HDC) demonstrated improved outcomes in a unique prospective and several retrospective studies, and this report aimed to confirm these results in an independent and larger cohort.

Methods: Between 2006 and 2018, we conducted a multicentric prospective study on 44 women diagnosed with SCCOHT. Patients were treated homogeneously with optimal cytoreductive surgery and chemotherapy protocol for four to six cycles (PAVEP). In case of complete response, patients received HDC with stem-cell support, followed by pelvic radiotherapy. The primary endpoint was the event-free survival (EFS) in the per-protocol cohort. Secondary analysis explored the effect of HDC with outcomes.

Results: Mean age at diagnosis was 33 years old (range 13.8-75.8). 14 patients presented with stage FIGO I, 21 with stage III and 9 with stage IV. Median follow-up was 53.4 months. 38 patients underwent optimal surgery with up to 6 cycles of PAVEP. 30 received HDC, and 21 pelvic radiotherapy. 21 relapses were reported leading to death for 18 patients. Median EFS in the per-protocol cohort was 18.2 months, and 2-year EFS rate was 40%. HDC was significantly associated with better overall survival (p < .001). Grades 3/4 adverse events were frequent but, in most cases, manageable, although one grade-5 adverse-event occurred during HDC.

Conclusion: Intensive regimen containing multidrug chemotherapy, HDC and pelvic radiotherapy, for the management of SCCOHT, demonstrated encouraging survival and should be proposed for all patients. However, the significant toxicity cost associated is of concern and it should be restricted to expert centers.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.019DOI Listing
October 2020

GINECO Prospective Non-interventional PROSPECTYON Study: Trabectedin Plus Pegylated Liposomal Doxorubicin for Platinum-sensitive Recurrent Ovarian Cancer.

Anticancer Res 2020 Jul;40(7):3939-3945

ORACLE-Centre d'Oncologie de Gentilly, Nancy, France.

Background: Trabectedin and pegylated liposomal doxorubicin (PLD) is an effective combination therapy for platinum-sensitive recurrent ovarian cancer (ROC), particularly for disease relapsing within 6-12 months of platinum therapy. The non-interventional PROSPECTYON study evaluated trabectedin/PLD in French clinical practice.

Patients And Methods: Patients with ROC after at least one platinum-based regimen received 1.1 mg/m trabectedin plus 30 mg/m PLD every 3 weeks. Efficacy and safety were evaluated in subgroups according to platinum-free interval [6-12 versus ≥12 months (partially or fully platinum sensitive, respectively)].

Results: Recurrent disease was partially platinum-sensitive in 58 patients and fully sensitive in 33 patients treated between July 2014 and June 2016. Patients in both subgroups received a median of six cycles of trabectedin and PLD. The most common grade 3 or more toxicities were haematological. Median progression-free survival was 6 months for both subgroups.

Conclusion: Trabectedin/PLD is a valuable treatment option for partially or fully platinum-sensitive ROC.
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http://dx.doi.org/10.21873/anticanres.14385DOI Listing
July 2020

Fertility and prognosis of borderline ovarian tumor after conservative management: Results of the multicentric OPTIBOT study by the GINECO & TMRG group.

Gynecol Oncol 2020 04;157(1):29-35

Institut Curie, St Cloud, France; Inserm U900, Institut Curie, St Cloud, France. Electronic address:

Objectives: Description of fertility and prognosis of patients with borderline ovarian tumor (BOT) treated by fertility-sparing surgery through a longitudinal study from the French national cancer network.

Methods: All consecutive patients diagnosed with BOT from the French National Network dedicated to Ovarian Malignant Rare Tumors from 2010 and 2017 were selected. In 2018, an update was made by sending a questionnaire regarding recurrence and fertility to patients aged under 43 years at diagnosis and treated conservatively. We compared the characteristics of the patients with/without recurrence and with/without live birth.

Results: Fifty-two patients aged 18 to 42 years presented a desire of pregnancy. Thirty patients (58%) presented a FIGO IA tumor, and 20 patients were treated by bilateral cystectomies (38%). We observed at least one live birth for 33 patients (63%) and local recurrences in 20 patients (38%). Both recurrence and live birth in 17 patients (33%) were reported, with recurrence occurring before pregnancy, after a second fertility-sparing treatment, in half of the cases. No factors associated with recurrence or live birth in this study were identified. Moreover, in this population, both recurrence and live birth were independent of age, with a linear risk along time. Disease-free survival was worse for patients treated with bilateral cystectomy (n = 20, 38%), with no difference in terms of fertility.

Conclusion: Two third of the patients experienced life birth after conservation surgery. We did not highlight an age/time from surgery for which the risk of recurrence outweighs the chance of pregnancy and to radicalize surgery. Moreover, almost a quarter of the live birth occurred after recurrence, with no more further event to date in these patients. The results encourage to consider a second fertility-sparing surgery after local borderline recurrence in the case of pregnancy desire. All these decisions must be discussed in specialized multidisciplinary boards.
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http://dx.doi.org/10.1016/j.ygyno.2019.12.046DOI Listing
April 2020

Impact of time to radiation therapy in adjuvant settings in endometrial carcinoma: A multicentric retrospective study.

Eur J Obstet Gynecol Reprod Biol 2020 Apr 12;247:121-126. Epub 2020 Feb 12.

Department of Medical Oncology, Institut du Cancer de Montpellier, 34000 Montpellier, France.

Objective: Time to adjuvant treatment could have an impact on cancer prognosis. It is possible that robotic surgery lengthens the healing time of vaginal cuff after minimally invasive hysterectomy. The objective of this study was to state the impact of time to RT (TTR) on prognosis in endometrial carcinoma (EC) patients and to assess variables associated with TTR.

Study Design: We conducted a multicentric retrospective study in two cancer centers. We included EC patients, between January 1996 and January 2016. We searched variables associated with TTR and impact of TTR on end-points: local recurrence-free survival, metastatic-free survival, event-free survival and overall survival.

Results: 329 patients were included and 279 were analyzed for TTR impact. Robotic surgery was associated with shorter TTR (8 weeks, 8.9 w for laparotomy, 9.2 w for laparoscopy). Pelvic lymphadenectomy, para-aortic lymphadenectomy, discussion in multidisciplinary meeting and treatment center was independently associated with TTR. No impact of TTR was shown on metastatic-free survival, event-free survival and overall survival but there was a trend of a decreased local recurrence rate in case of prolonged TTR (HR = 1.08; CI95 %: 0.97-1.2).

Conclusion: Our study did not show any impact of treatment delay on survival end-points although prolonged TTR could moderate the benefit of radiotherapy on local control rate. Surgical route was not associated with TTR, particularly robot-associated laparoscopy did not lengthen treatment delay. TTR seems dependent of health-care organization and could represent a quality criterion of EC care for institutions.
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http://dx.doi.org/10.1016/j.ejogrb.2020.02.011DOI Listing
April 2020

Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumours: guidelines from the French national network dedicated to rare gynaecological cancers.

Eur J Cancer 2019 07 3;116:35-44. Epub 2019 Jun 3.

Leon Berard Cancer Center, 28 Rue Laënnec, 69008, Lyon, France; Université Claude Bernard Lyon 1, EA 7425 Hesper, Health Service and Performance Research, Domaine Rockefeller, 8 Avenue Rockefeller, 69373, Lyon Cedex 8, France; Groupe GINECO, France.

Introduction: Rare ovarian tumours include complex borderline ovarian tumours, sex-cord tumours, germ cell tumours and rare epithelial tumours. Indications and modalities of fertility preservation (FP), infertility management, contraindications for hormonal contraception or menopause hormone therapy are frequent issues in clinical practice. A panel of experts from the French national network dedicated to rare gynaecological cancers, and experts in reproductive medicine and gynaecology have built guidelines on FP, contraception and menopause hormone therapy in women treated for ovarian rare tumours.

Material And Methods: A panel of 35 experts from different specialties contributed to the preparation of the guidelines, following the DELPHI method (formal consensus method). Statements were drafted after a systematic literature review and then rated through two successive rounds.

Results: Thirty-five recommendations were identified, concerning indications for FP, contraindications for ovarian stimulation, contraceptive options and menopause hormone therapy for each tumour type.

Discussion: Overall, caution has been recommended in the case of potentially hormone-sensitive tumours such as sex-cord tumours, serous and endometrioid low-grade adenocarcinomas, as well as for high-risk serous borderline ovarian tumours.

Conclusion: In the context of a scarce literature, a formal consensus method allowed the elaboration of guidelines, which will help clinicians in the management of these patients.
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http://dx.doi.org/10.1016/j.ejca.2019.04.018DOI Listing
July 2019

Liquid Biopsies for Ovarian Carcinoma: How Blood Tests May Improve the Clinical Management of a Deadly Disease.

Cancers (Basel) 2019 Jun 4;11(6). Epub 2019 Jun 4.

CRCM-Predictive Oncology laboratory, Institut Paoli-Calmettes, Inserm, CNRS, Aix-Marseille Univ, 232 Boulevard Sainte Marguerite, 13009 Marseille, France.

Ovarian cancers (OvC) are frequent, with more than 22,000 new cases each year for 14,000 deaths in the United States. Except for patients with or mutations, diagnostic methods, prognostic tools, and therapeutic strategies have not much improved in the last two decades. High throughput tumor molecular analyses have identified important alterations involved in ovarian carcinoma growth and spreading. However, these data have not modified the clinical management of most of patients. Moreover, tumor sample collection requires invasive procedures not adapted to objectives, such as the screening, prediction, or assessment of treatment efficacy, monitoring of residual disease, and early diagnosis of relapse. In recent years, circulating tumor biomarkers (also known as "liquid biopsies") such as circulating tumor cells, circulating nucleotides (DNA or miRNA), or extracellular vesicles, have been massively explored through various indications, platforms, and goals, but their use has not yet been validated in routine practice. This review describes the methods of analysis and results related to liquid biopsies for ovarian epithelial cancer. The different settings that a patient can go through during her journey with OvC are explored: screening and early diagnosis, prognosis, prediction of response to systemic therapies for advanced stages, and monitoring of residual subclinical disease.
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http://dx.doi.org/10.3390/cancers11060774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627130PMC
June 2019

[Circulating tumor DNA assessment for gynaecological cancers management].

Bull Cancer 2019 Mar 11;106(3):237-252. Epub 2019 Feb 11.

Aix-Marseille university, CNRS U7258, Inserm U1068, institut Paoli-Calmettes, département d'oncologie médicale, CRCM, Marseille cedex 9, France; Aix-Marseille university, CNRS U7258, Inserm U1068, institut Paoli-Calmettes, CRCM, laboratoire d'oncologie prédictive, Marseille cedex 9, France. Electronic address:

Gynaecological cancers are frequent, with more than 16,000 cases per year in France for 6500 deaths. Few improvements in diagnostic methods, prognostic tools, and therapeutic strategies have occurred in the last two decades. Tumour genomic analyses from, at least in part, the Cancer Genome Atlas have identified some of the molecular alterations involved in gynaecological tumours growth and spreading. However, these data remain incomplete and have not led to dramatic changes in the clinical management of our patients. Moreover, they require invasive samples that are not suitable to objectives like screening/early diagnosis, assessment of treatment efficacy, monitoring of residual disease or early diagnosis of relapse. In the last years, the analysis of circulating tumour biomarkers (also called "liquid biopsies") based on tumour cells (circulating tumour cells) or tumour nucleotides (circulating DNA or RNA) has been massively explored through various indications, platforms, objectives; data related to circulating tumour DNA being the most important in terms of number of publications and interest for clinical practice. This review aims to describe the methods of analysis as well as the observations from the analysis of circulating tumour DNA in gynaecological tumours, from screening/early diagnosis to the adaptation of treatment for advanced stages, through choice of treatments and monitoring of subclinical disease.
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http://dx.doi.org/10.1016/j.bulcan.2018.11.018DOI Listing
March 2019

Non-pegylated liposomal doxorubicin (NPLD, Myocet®) + carboplatin in patients with platinum sensitive ovarian cancers: A ARCAGY-GINECO phase IB-II trial.

Gynecol Oncol 2019 01 14;152(1):68-75. Epub 2018 Nov 14.

CITOHL, Centre Hospitalier Lyon Sud, Institut de Cancérologie des Hospices Civils de Lyon (IDCRC-HCL), 69310 Pierre-Bénite, France; EMR UCBL/HCL 3738, Université Claude Bernard Lyon 1, Lyon, France. Electronic address:

Background: Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to 2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin.

Methods: MYCA was a multicenter 2-step phase Ib-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m during phase Ib step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months.

Results: From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3-39.7); the median PFS was 10.0 months (95% CI, 8.6-11.0). The median overall survival was 28.1 months (95% CI, 22.3-32.5); and the objective response rate was 58% (95% CI, 47-68). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia.

Conclusion: Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments.
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http://dx.doi.org/10.1016/j.ygyno.2018.10.043DOI Listing
January 2019

Safety Results and Analysis of Eribulin Efficacy according to Previous Microtubules-Inhibitors Sensitivity in the French Prospective Expanded Access Program for Heavily Pre-treated Metastatic Breast Cancer.

Cancer Res Treat 2018 Oct 28;50(4):1226-1237. Epub 2017 Dec 28.

Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.

Purpose: Eribulin is approved for advanced breast cancers refractory to anthracyclines and taxanes. Efficacy according to sensitivity to previous therapies has been poorly explored.

Materials And Methods: Safety data were collected prospectively and we retrospectively collected efficacy data from the five French centres that participated in the Eribulin E7389-G000-398 expanded access program. Our main objectiveswere exploration of safety and analysis of eribulin efficacy (progression-free survival [PFS] and overall survival [OS]) according to sensitivity to the last microtubule-inhibiting agent administered.

Results: Median eribulin treatment duration was 3.3 months for the 250 patients included in this prospective single-arm study. Two hundreds and thirty-nine patients (95.6%) experienced an adverse event (AE) related to treatment including 129 (51.6%) with grade ≥ 3 AEs. The most frequently observed toxicities were cytopenias (59.6% of included patients), gastrointestinal disorders (59.2%), and asthenia (56.4%). The most frequent grade 3-4 AE was neutropenia (37.2% with 4.8% febrile neutropenia). Median PFS and OS were 4.6 and 11.8 months, respectively. Patients classified as responders to the last microtubule-inhibiting therapy had a longer OS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.51 to 0.94; p=0.017), and tended to display a better PFS (HR, 0.78; 95% CI, 0.58 to 1.04; p=0.086). OS improvement was still significant in multivariate analysis (adjusted HR, 0.53; 95% CI, 0.35 to 0.79; p=0.002).

Conclusion: This work based on a prospective study suggests that identification of patients likely to be more sensitive to eribulin could be based on their previous response to microtubules inhibitors.
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http://dx.doi.org/10.4143/crt.2017.446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192912PMC
October 2018

PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer.

Eur J Cancer 2017 11 23;86:28-36. Epub 2017 Sep 23.

Aix-Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France. Electronic address:

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.

Patients And Methods: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.

Results: A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]).

Conclusion: Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.

Trial Registration Id: NCT01589861.
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http://dx.doi.org/10.1016/j.ejca.2017.08.025DOI Listing
November 2017

[Impact of Her2 and BRCA1/2 status in high-dose chemotherapy and autologous stem cells transplantation in the treatment of breast cancer: The Institut Paoli Calmettes' experience].

Bull Cancer 2017 Apr 16;104(4):332-343. Epub 2017 Feb 16.

Institut Paoli-Calmettes (IPC), département d'oncologie médicale, 232, boulevard de Sainte-Marguerite, 13009 Marseille cedex 9, France; Centre de recherches en cancérologie de Marseille (CRCM), UMR Inserm 1068/CNRS 7258/AMU 105/IPC, 232, boulevard de Sainte-Marguerite, 13009 Marseille, France; Aix-Marseille université, Jardin du Pharo, 58, boulevard Charles-Livon, 13284 Marseille, France. Electronic address:

Introduction: Studies evaluating chemotherapy high dose chemotherapy with autologous haematopoietic stem cell transplantation (HDC-ACSH) in the treatment of metastatic (MBC), locally advanced (LABC) and inflammatory (IBC) breast cancer have in common lack of biomarker information, in particular the HER2 status.

Patients And Methods: All consecutive female patients treated for breast cancer with HDC and AHSCT at Institut Paoli Calmettes between 2003 and 2012 were included. Patients were categorized in three subtypes based on hormonal receptor (HR) and HER2 status of the primary tumor: luminal, (HR+/HER2-), HER2 (HER2+, any HR) and triple negative (TN) (HER2- and HR-). The main objective was the analysis of overall survival (OS) according to the IHC subtypes.

Results: Three hundred and seventy-seven patients were included. For MBC, the TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95 % CI 11.76-44.4) compared to 44.64 months (95 % CI 40.32-67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (P<0.01). For IBC, HER2 subgroup appeared to have the best prognosis with a 5-year OS of 89 % (95 % CI 64-97) compared to 57 % (95 % CI 33-76) for the TN subgroup (HR 5.38, 95 % CI 1.14-25.44; P=0.034). For CSLA, luminal subgroup appeared to have the best prognosis with a 5-year OS of 92 % (95 % CI 71-98) against 75 % (95 % CI 46-90) for HER 2 subtype and 70 % (95 %CI 97-88) for TN subtype (P=0.301).

Conclusion: The HDC-ACSH does not change the prognosis value of IHC subtype in breast cancer patients.
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http://dx.doi.org/10.1016/j.bulcan.2016.12.007DOI Listing
April 2017

Prognostic impact of hormone receptor- and HER2-defined subtypes in inflammatory breast cancer treated with high-dose chemotherapy: a retrospective study.

J Cancer 2016 23;7(14):2077-2084. Epub 2016 Oct 23.

Aix-Marseille Université, Marseille, F-13284, France.; Centre de Thérapie Cellulaire, Département de Biologie du Cancer, Institut Paoli-Calmettes, Marseille, F-13273, France.; Centre d'Investigations Cliniques en Biothérapies, Inserm CBT-1409, Marseille, F-13009, France.

Studies examining high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDC-AHSCT) strategies in inflammatory breast cancer (IBC), showed encouraging results in terms of disease-free survival (DFS), and overall survival (OS). The lack of data regarding HER2 status in all of these studies prevented any prognostic analysis involving breast cancer subtypes. All consecutive female patients treated for IBC with HDC and AHSCT at Institut Paoli-Calmettes between 2003 and 2012 were included. Since 2005, trastuzumab was included in initial treatment. Patient, tumor and treatment characteristics were collected. Patients were categorized in three subtypes based on hormonal receptor (HR) and HER2 status of the primary tumor: Luminal, (HR+/HER2-), HER2 (HER2+, any HR), and triple negative (TN) (HER2- and HR-). The main objective was the analysis of OS according to the IHC subtypes. Sixty-seven patients were included. Eleven patients received trastuzumab. Median follow up was 80.04 months (95% CI 73.2-88.08). Five-year OS and DFS for the whole population patients were 74% (95% CI 61-83) and 65 % (95% CI 52-75), respectively. OS differed across subtypes (p=0.057) : HER2 subgroup appeared to have the best prognosis with a 5-year OS of 89% (95% CI 64-97) compared to 57% (95% CI 33-76) for the TN subgroup (HR 5.38, 95% CI 1.14-25.44; p=0.034). In IBC patients receiving HDC-AHSCT, OS favorably compares with data available in the literature on similar groups of patients. TN patients carried the least favourable OS and HER2 patients, half of them also receiving trastuzumab, had the best outcome. These findings provide additional information and options for patients with IBC and who could potentially benefit of HDC-AHSCT.
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http://dx.doi.org/10.7150/jca.15797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118671PMC
October 2016

Targeted NGS, array-CGH, and patient-derived tumor xenografts for precision medicine in advanced breast cancer: a single-center prospective study.

Oncotarget 2016 Nov;7(48):79428-79441

Aix Marseille Univ, CNRS U7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France.

Background: Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient-derived tumor xenografts (PDX) could be obtained in this population.

Results: Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%). A targeted therapy could be proposed to 22 patients (64%), either through a clinical trial (n=15) and/or using already registered drugs (n=21). Ten patients (29%) eventually received targeted treatment, 2 of them deriving clinical benefit. Of 22 patients subjected to mouse implantation, 10 had successful xenografting (45%), mostly in triple-negative aBC.

Methods: aBC patients accessible to tumor biopsy were prospectively enrolled at the Institut Paoli-Calmettes in the BC-BIO study (ClinicalTrials.gov, NCT01521676). Genomic profiling was established by whole-genome array comparative genomic hybridization (aCGH) and targeted next-generation sequencing (NGS) of 365 candidate cancer genes. For a subset of patients, a sample of fresh tumor was orthotopically implanted in humanized cleared fat pads of NSG mice for establishing PDX.

Conclusions: Precision medicine can be implemented in a single center in the context of clinical practice and may allow genomic-driven treatment in approximately 30% of aBC patients. PDX may be obtained in a significant fraction of cases.
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http://dx.doi.org/10.18632/oncotarget.12714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346725PMC
November 2016

Corrigendum to "Immunohistochemical subtypes predict survival in metastatic breast cancer receiving high-dose chemotherapy with autologous haematopoietic stem cell transplantation" [Eur J Cancer 57 (April 2016) 118-126].

Eur J Cancer 2016 11 24;67:223. Epub 2016 Sep 24.

Département d'Oncologie Médicale, Institut Paoli-Calmettes (IPC), Marseille, F-13273, France; Centre de Recherches en Cancérologie de Marseille (CRCM), UMR Inserm 1068/CNRS 7258/AMU 105/IPC, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2016.09.002DOI Listing
November 2016

Immunohistochemical subtypes predict survival in metastatic breast cancer receiving high-dose chemotherapy with autologous haematopoietic stem cell transplantation.

Eur J Cancer 2016 04 23;57:118-26. Epub 2016 Feb 23.

Département d'Oncologie Médicale, Institut Paoli-Calmettes (IPC), Marseille, F-13273, France; Centre de Recherches en Cancérologie de Marseille (CRCM), UMR Inserm 1068/CNRS 7258/AMU 105/IPC, Marseille, F-13009, France; Aix-Marseille Université, Marseille, F-13284, France. Electronic address:

Introduction: The objective of this study was to evaluate the outcome of patients affected with different subtypes of metastatic breast cancer (MBC) following treatment with high-dose chemotherapy (HDC) and autologous haematopoietic progenitor cell transplantation (AHSCT).

Methods: All consecutive female patients treated for MBC with HDC and AHSCT at the Institut Paoli-Calmettes between 2003 and 2012 were included. Patient, tumour and treatment characteristics were collected. Patients were categorised in three subtypes based on hormonal receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary tumour: luminal (L), (HR+/HER2-), HER2 (HER2+, any HR), and triple negative (TN) (HER2- and HR-). The main objective was the analysis of overall survival (OS) according to the immunohistochemical (IHC) subtypes.

Results: A total of 235 patients were included, median age was 46 (range 21-62). Median follow up was 53.28 months (95% confidence interval [CI] 45.12-57.6). The TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95% CI 11.76-44.4) compared to 44.64 months (95% CI 40.32-67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (p < 0.01). In the multivariate analysis, the TN subtype retained an independent poor prognosis value compared to the luminal subtype, with a hazard ratio of 2.03 (95% CI 1.26-3.29, p = 0.037).

Conclusion: HDC-AHSCT does not change the prognostic value of IHC subtypes in MBC patients. OS favourably compares with data available in the literature on similar groups of patients. These findings provide additional information and options for patients with MBC and who could potentially benefit of HDC-AHSCT.
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http://dx.doi.org/10.1016/j.ejca.2016.01.005DOI Listing
April 2016

Ovarian cancer patients at high risk of BRCA mutation: the constitutional genetic characterization does not change prognosis.

Fam Cancer 2016 10;15(4):497-506

Department of Medical Oncology, Institut Paoli-Calmettes, 232 Boulevard Sainte-Marguerite, 13273, Marseille Cedex 09, France.

Ovarian neoplasms secondary to germline BRCA mutations had been described to have a more favourable survival. There is only few data concerning the prognosis of non mutated patients presenting clinical features evocative of BRCA alterations. We retrospectively collected data from patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. Patients considered at high risk of BRCA mutation were tested for BRCA1/2 germline mutations. We described clinical, pathological and therapeutic features and compared prognosis of BRCA mutation carriers and non-mutated patients. Out of 617 ovarian cancer patients, we identified 104 patients who were considered at high risk of mutation. The 33 mutated patients were more likely to present a personal (33 vs. 10 %, p = 0.003) or a family (42 vs. 24 %, p = 0.06) history of breast/ovarian cancers. BRCA1/2 mutation carriers and wild type patients displayed similar prognosis: median progression-free survival (PFS) of 20.9 versus 37.7 months (p = 0.21); median overall survival (OS) of 151.2 versus 122.5 months (p = 0.52). Personal history of breast cancer increased both PFS [HR = 0.45 (95CI 0.25-0.81)] and OS [HR = 0.35 (95CI 0.16-0.75)]. In multivariate analysis, this parameter was an independent prognostic feature, whereas the identification of a BRCA1/2 mutation was not. In our cohort, all patients at high risk of BRCA mutation share a similar prognosis, whatever is their germline mutation status. Prognosis seems to be more influenced by clinical history than by germline mutations identification. If it is confirmed in larger and independent series, this result suggests that the hypothesis of other BRCA pathway alterations (BRCAness phenotype) deserves to be deeply explored.
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http://dx.doi.org/10.1007/s10689-016-9873-9DOI Listing
October 2016

METRO1: A Phase I Study of Metronomic Chemotherapy in Adults with Advanced Refractory Solid Tumors.

Anticancer Res 2016 Jan;36(1):293-9

Department of Oncology, Institut Paoli-Calmettes, Marseille, France Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS U7258, Marseille, France Aix-Marseille Université, Marseille, France.

Background: The present monocentric and prospective phase 1 study evaluated the safety of a metronomic chemotherapy in refractory tumors.

Patients And Methods: Patients with advanced solid cancer refractory to standard therapy received a combination of low-dose vinorelbine, cyclophosphamide and interferon-alpha. A dose escalation model with 3 levels was planned. The primary end-point was safety and tolerability, secondary end-points were treatment continuation rate at 4 months, progression-free survival (PFS), overall survival (OS), radiological assessment (MRI) of anti-angiogenic effect.

Results: Thirty patients were enrolled. No dose-limiting toxicity was observed. All but two adverse events were toxicities of grade 1-2. Treatment continuation rate at 4 months was 6.67% (2 out of 30 patients). Median PFS and OS were 1.6 and 6.1 months. Exploratory MRI analyses related to anti-angiogenic effect did not show any relevant modification.

Conclusion: This combination of metronomic chemotherapy is well-tolerated and deserves to be deeply explored in refractory solid tumors.
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January 2016

Satisfaction with fertility- and sexuality-related information in young women with breast cancer--ELIPPSE40 cohort.

BMC Cancer 2015 Aug 5;15:572. Epub 2015 Aug 5.

UMR912 "Economics and Social Sciences Applied to Health & Analysis of Medical Information" (SESSTIM), 13006,, Marseille, France.

Background: Young breast cancer survivors are often dissatisfied with the information provided on fertility and sexuality. Our aim was to discuss possible contributing factors and to propose strategies to increase patient satisfaction with such information.

Methods: Using the French National Health Insurance System database, we constituted the ELIPPSE40 regional cohort of 623 women, aged 18-40, diagnosed with breast cancer between 2005 and 2011. As of January 2014, 319 women had taken part in the 10-, 16-, 28 and 48-month telephone interviews. Satisfaction with the information provided about the potential impact of cancer and its treatment on fertility and sexuality was assessed at 48 months after diagnosis on 5-point Likert scales.

Results: Four years after diagnosis, only 53.0 and 42.6% of women were satisfied with fertility- and sexuality-related information, respectively, without any significant change over the 2009-2014 period (P = 0.585 and P = 0.676 respectively). The two issues were moderately correlated (ρ = 0.60; P <0.001). General satisfaction with medical follow-up was the only common correlate. Irrespective of sociodemographic and medical characteristics, satisfaction with fertility-related information was greater among women with a family history of breast/ovarian cancer who had the opportunity to ask questions at the time of cancer disclosure. Satisfaction with sexuality-related information increased with the spontaneous provision of information by physicians at cancer disclosure.

Conclusions: Promoting both patients' question asking behavior and more systematic information could improve communication between caregivers and young breast cancer survivors and address distinct unmet needs regarding fertility- and sexuality- related information.
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http://dx.doi.org/10.1186/s12885-015-1542-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523948PMC
August 2015

Prognostic factors for ovarian epithelial cancer in the elderly: a case-control study.

Int J Gynecol Cancer 2015 Jun;25(5):815-22

*Department of Medical Oncology, Institut Paoli-Calmettes; †Department of Molecular Oncology, INSERM U1068, CNRS U7258, Centre de Recherche en Cancérologie de Marseille; ‡Aix-Marseille University; and §Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France.

Objectives: Ovarian cancer is the leading cause of mortality by gynecologic cancers in Western countries. Many publications have suggested that age may be an independent prognostic factor in ovarian carcinoma. There are only few data concerning the impact of treatments and geriatric features within the elderly population.

Methods/materials: We collected data of older (≥ 70 years old) patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. First we described usual clinical and pathological features for these patients, as well as their outcome. We compared these parameters with that of young (<70 years old) patients treated during the same period. We then observed geriatric features in our set: Eastern Cooperative Oncology Group performance status, number of medications, Charlson index, body mass index, hemoglobin, and glomerular filtration rate. We finally looked for prognostic factors specific of the elderly population.

Results: One hundred nine elderly patients were identified and compared with 488 younger cases. There was no difference concerning clinicopathologic data. Surgery was more frequently complete in young women (58% vs 41.7%), and older patients received less chemotherapy courses and less taxanes (38.4% vs 67.1%). Young patients had a longer overall survival (median, 65.2 vs 26.2 months, P = 8.5E-10, log-rank test). Multivariate analyses confirmed that age was an independent prognostic factor and that within the elderly set the International Federation of Gynecology and Obstetrics stage, surgery results, number of chemotherapy cycles administered and performance status had a significant prognostic value. No clear correlation could be observed between geriatric characteristics and treatments administration.

Conclusions: Ovarian cancer prognosis is poorer for older women, but they are more frequently suboptimally treated. No correlation could be observed between geriatric factors and surgery or chemotherapy achievement. Treatment decision should be based on objective geriatric assessment in order to improve outcome in this population.
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http://dx.doi.org/10.1097/IGC.0000000000000418DOI Listing
June 2015

[Triple-negative breast cancer: histoclinical and molecular features, therapeutic management and perspectives].

Bull Cancer 2013 May;100(5):453-64

Institut Paoli-Calmettes, oncologie médicale, 232, boulevard Sainte-Marguerite, 13009 Marseille, France.

Triple-negative breast cancer (TNBC), as defined by the absence of estrogen and progesterone receptor expression, as well as the lack of HER2 overexpression/amplification, corresponds to 15% of breast cancer and represents an aggressive form of the disease. TNBC are frequently confounded with basal subtype in the molecular classification of breast cancer and also share some similarities with BRCA1-mutated tumors. Epidemiological and clinical characteristics are distinct from other subtypes, including a younger age at diagnosis, a higher risk of relapse in spite of increased chemosensitivity, and a higher incidence of lung and brain metastatic relapses. Conventional cytotoxics remain the mainstay of current systemic management but recent evaluation of more targeted therapeutics, including specific cytotoxics (such as the use of platinum salts), PARP and EGFR inhibition, and antiangiogenics have been performed, providing contrasted but rather disappointing results. Recent data indicate that TNBC represent a heterogeneous entity composed of multiple and distinct molecular subtypes, which should deserve specific targeted therapeutics.
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http://dx.doi.org/10.1684/bdc.2013.1740DOI Listing
May 2013

Fertility and pregnancy outcomes following conservative treatment for placenta accreta.

Hum Reprod 2010 Nov 10;25(11):2803-10. Epub 2010 Sep 10.

Department of Obstetrics and Gynecology, Angers University Hospital, Angers, France.

Background: The aim of this study was to estimate the fertility and pregnancy outcomes after successful conservative treatment for placenta accreta.

Methods: This retrospective national multicenter study included women with a history of conservative management for placenta accreta in French university hospitals from 1993 through 2007. Success of conservative treatment was defined by uterine preservation. Data were retrieved from medical files and telephone interviews.

Results: Follow-up data were available for 96 (73.3%) of the 131 women included in the study. There were eight women who had severe intrauterine synechiae and were amenorrheic. Of the 27 women who wanted more children, 3 women were attempting to become pregnant (mean duration: 11.7 months, range: 7-14 months), and 24 (88.9% [95% confidence interval (CI), 70.8-97.6%]) women had had 34 pregnancies (21 third-trimester deliveries, 1 ectopic pregnancy, 2 elective abortions and 10 miscarriages) with a mean time to conception of 17.3 months (range, 2-48 months). All 21 deliveries had resulted in healthy babies born after 34 weeks of gestation. Placenta accreta recurred in 6 of 21 cases [28.6% (95% CI, 11.3-52.2%)] and was associated with placenta previa in 4 cases. Post-partum hemorrhage occurred in four [19.0% (95% CI, 5.4-41.9%)] cases, related to placenta accreta in three and to uterine atony in one.

Conclusions: Successful conservative treatment for placenta accreta does not appear to compromise the patients' subsequent fertility or obstetrical outcome. Nevertheless, patients should be advised of the high risk that placenta accreta may recur during future pregnancies.
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http://dx.doi.org/10.1093/humrep/deq239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413618PMC
November 2010

Maternal outcome after conservative treatment of placenta accreta.

Obstet Gynecol 2010 Mar;115(3):526-534

From the Departments of Obstetrics and Gynecology, Angers University Hospital, Angers; Rouen University Hospital, Charles Nicolle, Rouen; Rennes University Hospital, Rennes; Maternité Port-Royal Hospital, Cochin APHP, University René Descartes, Paris; Centre Hospitalier Intercommunal de Créteil, University of Paris XII, Henri Mondor, Créteil; Conception Hospital, University of Mediterranee, Marseille; North Hospital, University of Mediterranee, Marseille; Antoine Béclère Hospital, University Paris Sud, Paris; Kremlin-Bicètre Hospital, University Paris Sud, Paris; Tours University Hospital, Tours; Nantes University Hospital, Nantes; CHU La Milétrie Hospital, University of Poitiers, Poitiers; Hôpital Necker-Enfants Malades, University René Descartes, Paris; Caen University Hospital, Caen; and Hôpital Bichat Claude-Bernard, APHP, University Paris-VII, Paris, France.

Objective: To estimate maternal outcome after conservative management of placenta accreta.

Methods: This retrospective multicenter study sought to include all women treated conservatively for placenta accreta in tertiary university hospital centers in France from 1993 to 2007. Conservative management was defined by the obstetrician's decision to leave the placenta in situ, partially or totally, with no attempt to remove it forcibly. The primary outcome was success of conservative treatment, defined by uterine preservation. The secondary outcome was a composite measure of severe maternal morbidity including sepsis, septic shock, peritonitis, uterine necrosis, fistula, injury to adjacent organs, acute pulmonary edema, acute renal failure, deep vein thrombophlebitis or pulmonary embolism, or death.

Results: Of the 40 university hospitals that agreed to participate in this study, 25 institutions had used conservative treatment at least once (range 1-46) and had treated a total of 167 women. Conservative treatment was successful for 131 of the women (78.4%, 95% confidence interval [CI] 71.4-84.4%); of the remaining 36 women, 18 had primary hysterectomy and 18 had delayed hysterectomy (10.8% each, 95% CI 6.5-16.5%). Severe maternal morbidity occurred in 10 cases (6.0%, 95% CI 2.9-10.7%). One woman died of myelosuppression and nephrotoxicity related to intraumbilical methotrexate administration. Spontaneous placental resorption occurred in 87 of 116 cases (75.0%, 95% CI 66.1-82.6%), with a median delay from delivery of 13.5 weeks (range 4-60 weeks).

Conclusion: Conservative treatment for placenta accreta can help women avoid hysterectomy and involves a low rate of severe maternal morbidity in centers with adequate equipment and resources.
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http://dx.doi.org/10.1097/AOG.0b013e3181d066d4DOI Listing
March 2010

Fertility and obstetric outcome after conservative management of placenta accreta.

Int J Gynaecol Obstet 2010 May 12;109(2):147-50. Epub 2010 Feb 12.

Department of Obstetrics and Gynecology, La Conception University Hospital, Marseille, France.

Objective: To determine the fertility and obstetric outcomes after conservative management of placenta accreta.

Methods: A retrospective observational cohort study of all identified cases of placenta accreta from 1993 to 2007 in 2 tertiary university hospitals in France. For patients treated conservatively, maternal and fetal morbidity, reproductive function, fertility, and subsequent pregnancies were recorded.

Results: During the study period, 46 patients were treated by conservative management; 6 patients underwent a secondary hysterectomy. Of the remaining 40 patients, 35 were followed up for a median of 65 months (range 18-156 months). Patients resumed their menstrual cycles after a median of 130 days (range 48-176 days). Menses were irregular in 11 patients (31%), but none had amenorrhea. Twelve of the 14 patients desiring another pregnancy achieved a total of 15 pregnancies; 2 patients had recurrent placenta accreta. Five spontaneous abortions and 1 termination of pregnancy occurred during the first trimester. The median term at delivery was 37 weeks (range, 35-40 weeks). Four patients delivered prematurely.

Conclusion: Conservative management of placenta accreta can preserve fertility, although the risk of recurrent placenta accreta appears to be high.
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http://dx.doi.org/10.1016/j.ijgo.2009.12.011DOI Listing
May 2010

Comparison of ropivacaine and lidocaine for paracervical block during surgical abortion.

Contraception 2008 May 21;77(5):382-5. Epub 2008 Mar 21.

Department of Obstetrics and Gynecology, La Conception University Hospital, 147 Boulevard Baille, Marseille Cedex 05, France.

Background: The study was conducted to compare the effectiveness of ropivacaine and lidocaine as paracervical analgesia for elective abortion by vacuum aspiration.

Study Design: This single-center double-blinded randomized study tested two different agents for paracervical analgesia in elective abortions: lidocaine (n=57) or ropivacaine (n=57). We assessed intra- and postoperative pain according to both a visual analogical scale rated from 0 to 10 and postoperative analgesic requirements.

Results: Mean intraoperative pain was significantly lower in the ropivacaine group (5.23+/-2.72 vs. 4.18+/-2.77, p=.048.). There was no significant difference in mean assessed pain at the end of the intervention or at 2 or 4 h afterward. The rate of subjects requiring additional postoperative analgesia did not differ significantly between the lidocaine and ropivacaine groups [8/59 (13.5%) vs. 6/59 (10.1%), p=.33].

Discussion: Intraoperative pain appears to be less with ropivacaine than with lidocaine. Nonetheless, the clinical difference was slight, as was therefore the benefit of using ropivacaine for paracervical block in elective abortions.
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http://dx.doi.org/10.1016/j.contraception.2008.01.009DOI Listing
May 2008