Publications by authors named "Elsa Kalbacher"

29 Publications

  • Page 1 of 1

Renal dysfunction improves risk stratification and may call for a change in the management of intermediate- and high-risk acute pulmonary embolism: results from a multicenter cohort study with external validation.

Crit Care 2021 02 9;25(1):57. Epub 2021 Feb 9.

Department of Cardiology, University Hospital Jean Minjoz, 3 Boulevard Fleming, 25000, Besançon, France.

Background: Renal dysfunction influences outcomes after pulmonary embolism (PE). We aimed to determine the incremental value of adding renal dysfunction, defined by estimated glomerular filtration rate (eGFR), on top of the European Society of Cardiology (ESC) prognostic model, for the prediction of 30-day mortality in acute PE patients, which in turn could lead to the optimization of acute PE management.

Methods: We performed a multicenter, non-interventional retrospective post hoc analysis based on a prospectively collected cohort including consecutive confirmed acute PE stratified per ESC guidelines. We first identified which of three eGFR formulae most accurately predicted death. Changes in global model fit, discrimination, calibration and reclassification parameters were evaluated with the addition of eGFR to the prognostic model.

Results: Among 1943 patients (mean age 67.3 (17.1), 50.4% women), 107 (5.5%) had died at 30 days. The 4-variable Modification of Diet in Renal Disease (eGFR) formula predicted death most accurately. In total, 477 patients (24.5%) had eGFR < 60 ml/min. Observed mortality was higher for intermediate-low-risk and high-risk PE in patients with versus without renal dysfunction. The addition of eGFR information improved model fit, discriminatory capacity, and calibration of the ESC model. Reclassification parameters were significantly increased, yielding 18% reclassification of predicted mortality (p < 0.001). Predicted mortality reclassifications across risk categories were as follows: 63.1% from intermediate-low risk to eGFR-defined intermediate-high risk, 15.8% from intermediate-high risk to eGFR-defined intermediate-low risk, and 21.0% from intermediate-high risk to eGFR-defined high risk. External validation in a cohort of 14,234 eligible patients from the RIETE registry confirmed our findings with a significant improvement of Harrell's C index and reclassification parameters.

Conclusion: The addition of eGFR-derived renal dysfunction on top of the prognostic algorithm led to risk reclassification within the intermediate- and high-risk PE categories. The impact of risk stratification integrating renal dysfunction on therapeutic management for acute PE requires further studies.
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http://dx.doi.org/10.1186/s13054-021-03458-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874488PMC
February 2021

Early prescription of direct oral anticoagulant for the treatment of intermediate-high risk pulmonary embolism: a multi-center, observational cohort study.

Thromb Res 2020 12 8;196:476-482. Epub 2020 Oct 8.

Department of Cardiology, EA3920, University Hospital Besançon, Boulevard Fleming, 25030 Besançon, France.

Objectives: The safety and efficacy of direct oral anticoagulants (DOACs) in intermediate-high risk pulmonary embolism (PE) are unknown. The aims of the present study were to describe outcomes of patients receiving early apixaban or rivaroxaban prescription rather than the recommended delayed prescription strategy.

Methods: Retrospective post-hoc analysis based on prospectively collected data from a multicenter cohort including all consecutive PE patients stratified as intermediate-high risk. Group definitions were: early group with DOAC prescription <72 h after admission; delayed group with DOAC prescription between 72 h and discharge. The 30-day primary efficacy outcome was a clinical composite of all-cause death and hemodynamic decompensation. The 30-day primary safety outcome was major bleeding.

Results: Among 2411 patients admitted with PE, 302 were treated with a DOAC for an intermediate-high risk PE: 34.2% in the early group and 65.9% in the delayed group. The primary outcome occurred in 4.8% (including 1 death and 4 hemodynamic decompensations) in the early DOAC group and in 9.0% in the delayed DOAC group (OR, 0.44, 95% CI 0.15-1.30). The rate of major bleeding did not differ between groups (OR, 0.99; 95% CI 0.45-2.18). The length of stay was numerically shorter in the early group whereas the other outcomes did not differ significantly.

Conclusion: The rate of 30-day outcomes was low in patients receiving a DOAC earlier after admission. Patients in the early DOAC group had a numerically shorter length of stay, with similarly low rates of death and bleeding, and similar RV function recovery compared to the delayed strategy.
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http://dx.doi.org/10.1016/j.thromres.2020.10.003DOI Listing
December 2020

MILO/ENGOT-ov11: Binimetinib Versus Physician's Choice Chemotherapy in Recurrent or Persistent Low-Grade Serous Carcinomas of the Ovary, Fallopian Tube, or Primary Peritoneum.

J Clin Oncol 2020 11 21;38(32):3753-3762. Epub 2020 Aug 21.

Belgium and Luxemburg Gynaecological Oncology Group, University Hospitals Leuven, Leuven, Belgium.

Purpose: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC.

Methods: This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety.

Results: A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent.

Conclusion: Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and mutation might predict response to binimetinib.
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http://dx.doi.org/10.1200/JCO.20.01164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655017PMC
November 2020

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

Gynecol Oncol 2020 10 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

Clinical patterns and significance of non-compliance with guideline-recommended treatment of acute pulmonary embolism.

Arch Cardiovasc Dis 2020 Jan 2;113(1):31-39. Epub 2019 Nov 2.

Department of cardiology, EA3920, university hospital Besançon, boulevard Fleming, 25030 Besançon, France. Electronic address:

Background: Evidence-based clinical practice guidelines define initial management of acute pulmonary embolism (PE) according to risk stratification for early death.

Aims: The aims of the present study were to investigate patterns of non-compliance with guidelines for the acute PE treatment, and the associated risk of adverse events.

Methods: We performed an observational, multicentre, cohort study of acute PE. Inclusion criteria were all patients with pulmonary embolism admitted to the participating centres between January 2011 and April 2017. The measure of 100% compliance was used to allocate patients in the compliant or non-compliant groups. The primary outcome was all-cause death at 6 months. Secondary outcomes included recurrent venous thromboembolism and major bleeding.

Results: In total, 1285 patients were included. Treatment was not in compliance with the guidelines in 172 patients (13.4%). Four factors were identified to be related to non-compliance with the guidelines: shock or hypotension (relative risk [RR] 5.23, 95% confidence interval [CI] 2.64-10.30; P<0.001), renal insufficiency (RR 1.80, 95% CI 1.41-2.28; P<0.001), active cancer (RR 1.35, 95% CI 1.24-1.48; P<0.001) and right ventricular dysfunction at admission (RR 1.06, 95% CI 1.01-1.11; P=0.01). The primary endpoint of all-cause death at 6 months occurred in 62 of 172 patients (36.0%) in the non-compliant group and in 131 of 1113 patients (11.8%) in the compliant group (hazard ratio 2.02, 95% CI 1.45-2.81; P<0.001). The rates of recurrent venous thromboembolism (8.7% vs 1.1%; P<0.001) and major bleeding (13.4% vs 4.9%, P=0.04) from admission to 6-month follow-up were higher in the non-compliant group.

Conclusion: Non-compliance with guidelines was independently associated with worse outcomes, including death, recurrent venous thromboembolism and bleeding.
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http://dx.doi.org/10.1016/j.acvd.2019.09.009DOI Listing
January 2020

Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers.

Gynecol Oncol 2019 11 8;155(2):262-269. Epub 2019 Oct 8.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France; University Claude Bernard (UCBL Lyon1), Lyon, France.

Objective: To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice.

Methods: Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy.

Results: One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI) ≥ 12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI ≥ 12 months, CR and normalization of CA-125.

Conclusions: Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.
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http://dx.doi.org/10.1016/j.ygyno.2019.09.008DOI Listing
November 2019

Niraparib Maintenance Treatment Improves Time Without Symptoms or Toxicity (TWiST) Versus Routine Surveillance in Recurrent Ovarian Cancer: A TWiST Analysis of the ENGOT-OV16/NOVA Trial.

J Clin Oncol 2019 12 16;37(34):3183-3191. Epub 2019 Sep 16.

Nordic Society of Gynaecological Oncology and Copenhagen University Hospital, Copenhagen, Denmark.

Purpose: This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer.

Patients And Methods: Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline mutation-gmut and non-gmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post-random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs.

Results: In the gmut and non-gmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the gmut and non-gmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons.

Conclusion: Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.
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http://dx.doi.org/10.1200/JCO.19.00917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881097PMC
December 2019

[Relapse surveillance of patients with testicular germ cell tumor].

Bull Cancer 2019 Oct 5;106(10):903-914. Epub 2019 Sep 5.

CHU de Besançon, oncologie, 25030 Besançon cedex, France; Inserm, UMR1098, 25020 Besançon cedex, France; Université de Franche-Comté, UMR1098, SFR IBCT, 25020 Besançon, France.

Germ-cell tumors are the most common solid tumors in young men. The follow-up of these patients is very important in their management. In stage I testicular cancer, surveillance is the standard for low-risk disease. In addition to the early detection of relapse, follow-up should be directed towards prevention, detection and treatment of late toxicity, and secondary malignancies. Follow up consists in physical examination, laboratory analysis and radiological imaging. Recently, guidelines recommend risk-adapted surveillance strategy, with a reduction of CT scans numbers, due to the recognition of the risk of ionizing radiation exposure. However, efforts to maintain adequate compliance with follow up are required.
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http://dx.doi.org/10.1016/j.bulcan.2019.06.006DOI Listing
October 2019

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

[Sexual dysfunctions of patients treated with orchidectmoy, chemotherapy and retroperitoneal lymphadenectomy, need for systematic andrological care?]

Bull Cancer 2019 Oct 22;106(10):915-922. Epub 2019 May 22.

Centre hospitalier universitaire, Hôtel-Dieu, service d'urologie, 44000 Nantes, France.

Goal: Long-term evaluation of the incidence of sexual dysfunction from patients who were treated by orchidectomy, chemotherapy, and retroperitoneal lymphadenectomy for testicular cancer.

Methods: In 2018, patients who were treated in two academic hospitals by orchiectomy, chemotherapy, and retroperitoneal lymphadenectomy, and were in complete remission, were included. The patients included in this study filled the survey, which covered aspects of their sexuality (the Male Sexual Health Questionnaire) and answered additional questions, which evaluated psychological impact and modification of their sexuality since the management of their cancer.

Results: Twenty patients have been included, 70% of the patients treated for non-seminomatous germ cell tumor. Mean age was 36.4years±12.1 and the average duration of follow-up was 59months±34. Sexual dysfunction was found in 50% of the patients. Only 10% of the patients could preserve satisfying sexual activity during their treatment. Since the end of their treatment, 16%, 21% and 37% of patients respectively declared high libido loss, lower tumescent erections and persistence of anejaculation. In the end, nearly 70% of these patients wished a dedicated consultation with an urologist with subspecialty in andrology, in order to obtain further information during their care course.

Discussion: These patients have shown multicomponent sexual dysfunction. They could benefit from a new healthcare pathway implying early involvement of andrologist network.
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http://dx.doi.org/10.1016/j.bulcan.2019.03.020DOI Listing
October 2019

Prescription patterns of direct oral anticoagulants in pulmonary embolism: A prospective multicenter French registry.

Thromb Res 2019 02 8;174:27-33. Epub 2018 Dec 8.

Department of Cardiology, EA3920, University Hospital Besançon, Boulevard Fleming, 25030 Besançon, France. Electronic address:

Background: Data regarding the use of direct oral anticoagulants (DOACs) for the treatment of acute pulmonary embolism (PE) are sparse. We conducted a prospective multicentre registry study to describe patterns of DOAC prescription for the treatment of acute PE, and the associated risk of 6-month adverse events in daily practice.

Methods: We included all PE patients discharged since the availability of DOACs for the dedicated indication of acute PE treatment. Clinical data and 6-month outcomes, including death, recurrent venous thromboembolism (VTE), bleeding, and chronic thromboembolic pulmonary hypertension (CTEPH) were recorded prospectively. Temporal trends in DOAC prescription were tested.

Results: Between 09/2012 and 04/2017, 1082 patients were included: 60.6% (n = 656) were treated with DOACs and 39.4% (n = 426) with another anticoagulant. The prescription rate of DOACs increased sharply just after their release on the market to reach a plateau over time, between 56% and 72% of the total prescription per year in PE patients (p for trend = 0.33). Active malignancy and renal function impairment were factors independently associated with non-prescription of DOACs. Overall, prescription of DOACs was appropriate in 95.3% of patients. The rate of use of non-recommended DOAC doses was 4.2% (n = 28). The rate of death, recurrent VTE, bleeding and CTEPH were 2.4%, 1.2%, 7.2%, and 1.9%, respectively in the DOAC group.

Conclusion: The choice to prescribe DOACs or not is related to patient characteristics. The overall appropriateness of prescription is high, while the rate of adverse events observed in patients treated with DOAC is low in our registry.
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http://dx.doi.org/10.1016/j.thromres.2018.12.013DOI Listing
February 2019

Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study.

Lancet Oncol 2019 01 23;20(1):120-133. Epub 2018 Nov 23.

Medical Oncology Department, Centre Léon Bérard, Lyon, France.

Background: Regorafenib has proven activity in patients with pretreated gastrointestinal stromal tumours and colorectal and hepatocellular carcinoma. We designed REGOBONE to assess the efficacy and safety of regorafenib for patients with progressive metastatic osteosarcoma and other bone sarcomas. This trial comprised four parallel independent cohorts: osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. In this Article, we report the results of the osteosarcoma cohort.

Methods: In this non-comparative, double-blind, placebo-controlled, phase 2 trial, patients aged 10 years or older with histologically confirmed osteosarcoma whose disease had progressed after treatment with one to two previous lines of chemotherapy for metastatic disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive either oral regorafenib (160 mg/day, for 21 of 28 days) or matching placebo. Patients in both groups also received best supportive care. Randomisation was done using a web-based system and was stratified (permuted block) by age at inclusion (<18 vs ≥18 years old). Investigators and patients were masked to treatment allocation. Patients in the placebo group, after centrally confirmed progressive disease, could cross over to receive regorafenib. The primary endpoint was the proportion of patients without disease progression at 8 weeks. Analyses were done by modified intention to treat (ie, patients without any major entry criteria violation who initiated masked study drug treatment were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02389244, and the results presented here are the final analysis of the osteosarcoma cohort (others cohorts are ongoing).

Findings: Between Oct 10, 2014, and April 4, 2017, 43 adult patients were enrolled from 13 French comprehensive cancer centres. All patients received at least one dose of assigned treatment and were evaluable for safety; five patients were excluded for major protocol violations (two in the placebo group and three in the regorafenib group), leaving 38 patients who were evaluable for efficacy (12 in the placebo group and 26 in the regorafenib group). 17 of 26 patients (65%; one-sided 95% CI 47%) in the regorafenib group were non-progressive at 8 weeks compared with no patients in the placebo group. Ten patients in the placebo group crossed over to receive open-label regorafenib after centrally confirmed disease progression. 13 treatment-related serious adverse events occurred in seven (24%) of 29 patients in the regorafenib group versus none of 14 patients in the placebo group. The most common grade 3 or worse treatment-related adverse events during the double-blind period of treatment included hypertension (in seven [24%] of 29 patients in the regorafenib group vs none in the placebo group), hand-foot skin reaction (three [10%] vs none), fatigue (three [10%] vs one [3%]), hypophosphataemia (three [10%] vs none), and chest pain (three [10%] vs none). No treatment-related deaths occurred.

Interpretation: Regorafenib demonstrated clinically meaningful antitumour activity in adult patients with recurrent, progressive, metastatic osteosarcoma after failure of conventional chemotherapy, with a positive effect on delaying disease progression. Regorafenib should be further evaluated in the setting of advanced disease as well as potentially earlier in the disease course for patients at high risk of relapse. Regorafenib might have an important therapeutic role as an agent complementary to standard cytotoxic chemotherapy in the therapeutic armamentarium against osteosarcoma.

Funding: Bayer HealthCare.
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http://dx.doi.org/10.1016/S1470-2045(18)30742-3DOI Listing
January 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

Non-recommended dosing of direct oral anticoagulants in the treatment of acute pulmonary embolism is related to an increased rate of adverse events.

J Thromb Thrombolysis 2018 Oct;46(3):283-291

Department of Cardiology, EA3920, University Hospital Besançon, Boulevard Fleming, 25030, Besançon, France.

Dose adjustment of direct oral anticoagulants (DOACs) is not required in the setting of acute PE treatment according to the manufacturer's labelling, beyond the contraindication in severe renal insufficiency. We designed a prospective, multicenter cohort study to investigate the impact of prescription of non-recommended DOAC doses on 6-month adverse events. The primary endpoint was a composite of all-cause death, recurrent VTE, major bleeding, and chronic thromboembolic pulmonary hypertension (CTEPH). In total, among 656 patients discharged with DOACs between 09/2012 and 10/2016, 28 (4.3%) were not treated with a recommended DOAC dose. All the non-recommended DOAC dose prescriptions were under-dosed according to the drug labelling. After multivariate adjustment, age > 70 years, a history of coronary artery disease, creatinine clearance < 50 mL/min and concomitant aspirin therapy were independently associated with non-recommended DOAC dose prescription (C-statistic: 0.82; Hosmer Lemeshow test: 0.50). The primary composite endpoint occurred in 7/28 patients (25.0%) in the non-recommended dose group and in 38/628 patients (6.1%) in the recommended dose group, yielding a relative risk of 3.19 in the non-recommended dose group (95% CI 1.16-8.70; p < 0.001). The higher primary endpoint rate observed in the non-recommended dose group was driven by a significantly higher rate of major bleeding (7.1 vs. 1.4%; p = 0.008), with a non-significant trend toward a higher rate of death (7.1 vs. 2.2%; p = 0.23), recurrent VTE (3.6 vs. 1.4%; p = 0.31), and CTEPH (7.1 vs. 1.6%; p = 0.32). In conclusion, empiric dose reduction of DOACs was associated with 6-month adverse events in our real-life registry.
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http://dx.doi.org/10.1007/s11239-018-1690-6DOI Listing
October 2018

[Expectation about maintenance therapy among the GINECO French ovarian cancer cohort from the European NOGGO/ENGOT-ov22 Expression IV survey].

Bull Cancer 2018 May 12;105(5):465-474. Epub 2018 Mar 12.

Centre Francois-Baclesse, oncologie médicale, 3, avenue du Général-Harris, 14000 Caen, France. Electronic address:

Background: Expression IV survey evaluated the patients' expectations to a maintenance therapy.

Methods: From January 2015 to March 2016, 401 French patients, in first line or recurrent disease, answered a 24-items anonymous questionnaire. The results were specifically analyzed according to the demographic characteristics and treatment lines.

Results: Among the patients, 62% had already been informed about maintenance therapy. Thirty-seven percent of patients received a maintenance treatment: 111 patients during first line and 39 patients in relapse. Expectations of patients were: 1) the chance of cure (73%), 2) the tumor shrinkage (36%), 3) quality of life improvement (35%) and 4) tumor growth reduction (27%). Among the responders, 42% were willing to take the treatment for 6-24 months, 20% for 24-60 months and 38% until tumor progression. 64% of patients expected more than a 6 months progression-free survival. Patients older than 70 years were less informed than their younger counterparts (48% vs 66%) and had lesser hope for cure with maintenance treatment (60% vs 77%). Patients in relapse had more expectation than patients in remission (tumor shrinkage: 47% vs 22%, slowing of tumor growth: 37% vs 15%, improving the progression-free survival of more than 6 months: 71% vs 53%, respectively). Among patients, 48% in relapse consented to take a treatment until progression vs 24% of patients in remission.

Conclusion: This sub-analysis in French patients demonstrate a gap between the efficacy of maintenance therapy and the patients' expectations in ovarian cancer, particularly in relapsing disease justifying better information and explanations.
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http://dx.doi.org/10.1016/j.bulcan.2018.01.015DOI Listing
May 2018

[Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumors: Guidelines from the French national network dedicated to rare gynaecological cancer].

Bull Cancer 2018 Mar;105(3):299-314

Centre Léon-Bérard, 28, rue Laënnec, 69008 Lyon, France.

Introduction: Rare ovarian tumors include complex borderline ovarian tumors, sex-cord tumors, germ cell tumors, and rare epithelial tumors. Indications and modalities of fertility preservation, infertility management and 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 of experts in reproductive medicine and gynaecology have worked on guidelines about fertility preservation, contraception and menopause hormone therapy in women treated for ovarian rare tumors.

Methods: A panel of 39 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 selected, and concerned indications for fertility preservation, contraindications for ovarian stimulation (in the context of fertility preservation or for infertility management), contraceptive options (especially hormonal ones), and menopause hormone therapy for each tumor type. Overall, prudence has been recommended in the case of potentially hormone-sensitive tumors such as sex cord tumors, serous and endometrioid low-grade adenocarcinomas, as well as for high-risk serous borderline ovarian tumors.

Discussion: 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.bulcan.2017.10.032DOI Listing
March 2018

Cancer de l’ovaire : la rechute précoce.

Bull Cancer 2017 May;104 Suppl 1:S32-S38

Département de cancérologie gynécologique, centre Oscar-Lambret, Lille, France.

Ovarian Cancer: EARLY RELAPSE: Early relapse (primary or secondary) is defined by relapse of disease less than 6 months before the last infusion of chemotherapy (with a platinum compound). There is no carcinological surgical indication. Disease should be treated with a non-platinum single agent (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine or topotecan). Bevacizumab can be added if patients have not already received it (level of proof 1, grade A).
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http://dx.doi.org/10.1016/S0007-4551(17)30160-1DOI Listing
May 2017

Efficacy and safety of bevacizumab-containing neoadjuvant therapy followed by interval debulking surgery in advanced ovarian cancer: Results from the ANTHALYA trial.

Eur J Cancer 2017 01 1;70:133-142. Epub 2016 Dec 1.

Centre François Baclesse, Caen, France. Electronic address:

Aim: To investigate whether adding bevacizumab to neoadjuvant carboplatin-paclitaxel (CP) helps achieve optimal debulking, measured by complete resection rate (CRR) at interval debulking surgery (IDS), in patients with initially unresectable International Federation of Gynecology and Obstetrics stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma.

Methods: Multicentre, open-label, non-comparative phase II study. Ninety-five patients randomised (2:1) to receive four cycles of neoadjuvant CP ±3 concomitant cycles of bevacizumab 15 mg/kg (BCP) followed by IDS. Primary objective is to evaluate the CRR at IDS in the BCP group (reference CRR rate defined as 45% CRR). A stopping rule based on bevacizumab-related adverse events (AEs) of special interest was implemented.

Results: In the BCP group (N = 58), IDS was performed in 40 (69%) patients, of whom 85% had a complete resection. The CRR of this group was therefore 58.6% (34 patients), statistically over pre-defined 45%. The CRR in the CP group was 51.4%: 22 (60%) patients underwent IDS (85% had a complete resection). Grade ≥3 adverse events occurred in 62% of the BCP-treated patients and 63% of the CP-treated patients: mainly blood and lymphatic, gastrointestinal and vascular disorders, without more toxicity with BCP. Postoperative complications (mainly wound, infectious and gastrointestinal complications) occurred in 28% and 36% of the patients, respectively. The pre-specified safety stopping rule was not reached.

Conclusion: The primary objective was met as the CRR with BCP was significantly higher than the reference rate. Bevacizumab may be safely added to a preoperative program in patients deemed non-optimally resectable, whatever the final surgical decision. Bevacizumab's role in this setting should be further investigated.
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http://dx.doi.org/10.1016/j.ejca.2016.09.036DOI Listing
January 2017

Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors for Patients with Advanced Gastrointestinal Stromal Tumors.

Clin Drug Investig 2017 Jan;37(1):85-94

Department of Pharmacy, University Hospital, Boulevard Fleming, 25030, Besançon Cedex, France.

Introduction: The management of advanced gastrointestinal stromal tumors (GISTs) has been modified considerably by the availability of costly tyrosine kinase inhibitors (TKIs); however, the best therapeutic sequence in terms of cost and effectiveness remains unknown.

Objective: The aim of this study was to compare four potential strategies (reflecting the potential daily practice), each including imatinib 400 mg/day, as first-line treatment: S1 (imatinib/best supportive care [BSC]); S2 (imatinib/imatinib/BSC); S3 (imatinib/sunitinib/BSC); and S4 (imatinib/imatinib/sunitinib/BSC).

Methods: A Markov model was developed with a hypothetical cohort of patients and a lifetime horizon. Transition probabilities were estimated from the results of clinical trials. The analysis was performed from the French payer perspective, and only direct medical costs were included. Clinical and economic parameters were discounted, and the robustness of results was assessed.

Results: The least costly and effective strategy was S1, at a cost of €65,744 for 32.9 life months (reference). S3 was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of €48,277/life-year saved (LYS). S2 was dominated, and S4 yielded an ICER of €363,320/LYS compared with S3. Sensitivity analyses confirmed the robustness of these results; however, when taking into account a price reduction of 80 % for imatinib, S2 and S4 become the most cost-effective strategies.

Conclusion: Our approach is innovative to the extent that our analysis takes into account the sequential application of TKIs. The results suggest that the S1 strategy is the best cost-effective strategy, but a price reduction of imatinib impacts on the results. This approach must continue, including new drugs and their impact on the quality of life of patients with advanced GISTs.
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http://dx.doi.org/10.1007/s40261-016-0463-2DOI Listing
January 2017

Impact of Chemotherapy Beyond the Third Line in Patients With Recurrent Epithelial Ovarian Cancer.

Int J Gynecol Cancer 2016 Feb;26(2):261-7

*EA4267-UFR-33, School of Medecine and Pharmacy; †Medical Oncology Unit, J. Minjoz University Teaching Hospital; ‡INSERM U 645, EA-2284 IFR-133; and §Department of Surgery and ∥Pharmacy Department, J. Minjoz University Hospital, Besançon, France.

Objectives: The goal of this study was to determine the benefit in terms of time disease control (TDC) achieved by the succession of chemotherapy beyond the third line in patients treated for recurrent epithelial ovarian cancer. Secondary objectives were to identify patients who benefited from treatments beyond 3 lines and to estimate overall survival and disease-free progression lengths.

Materials And Methods: The cohort of 122 patients was identified from a pharmacy database of patients treated with chemotherapy between 1992 and 2010. The evaluation of benefit obtained by each line was based on TDC duration, defined as the interval between the beginning of the treatment and the date of progressive disease or death.

Results: Median TDC durations was 4.15 (0-54.7), 4 (0-21.7), 3.34 (0-29.6), 4.97 (0-29.2), and 3.13 months (0-15) for the fourth to eighth lines, respectively. Time to disease control was longer than 6 months in 34% to 40% of patients treated by lines 4 to 8. The most important factor influencing TDC length beyond the third line was the TDC duration observed in the 2 previous lines of therapy. Median overall survival after the third line was 15.3 months (95% confidence interval, 12-20 months). Factors associated with longer overall survival after 3 lines were performance status lower than 2 (P = 0.0058), no hepatic metastasis (P = 0.0098), no pulmonary metastasis (P = 0.0003), and platinum sensitivity (P = 0.04) CONCLUSIONS: These results may justify the administration of chemotherapy beyond the third line, in particular when the 2 previous lines are effective and resulted in disease control longer than 6 months.
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http://dx.doi.org/10.1097/IGC.0000000000000592DOI Listing
February 2016

Specific anticancer treatments in the last 3 months of life: a French experience.

Support Care Cancer 2013 Feb 27;21(2):405-12. Epub 2012 Jun 27.

Medical Oncology Unit, CHU of Tours, Bretonneau Hospital, 2 Boulevard Tonnellé, 37000, Tours, France.

Purpose: The treatment of patients with advanced cancer is becoming increasingly aggressive near the end of life, whereas poor literature is available. This study analyzes the management of patients with a solid cancer in their last 3 months of life in the Centre Hospitalier Universitaire de Besançon, France.

Methods: This retrospective study includes all adult patients with a solid tumor who died in medical oncology or radiotherapy unit in 2005, 2006, and 2007. Group A had received at least one specific anticancer treatment at the end of life, while group B did not.

Results: Of 167 included patients, 139 (83.2 %) received a specific treatment during the last 3 months of life. The reference unit was medical oncology for 76 % and radiotherapy for 24 % patients; overall survival was 18 and 9 months, and median age of metastatic evolution was 59 and 71 in group A and B, respectively. The number of previous lines of chemotherapy was on average 1.96 and 0.39, respectively. In a univariate analysis, differences appear for reference unit, age of death, and number of previous lines of chemotherapy, with a trend for chemosensitivity of the tumor in this small-sized study. No significant difference was found for sex, life-threatening metastases, or performance status.

Conclusion: These preliminary data suggest that when evaluating the utilization of care at the end of life, one needs to take into account factors such as the age of the patient and the chemosensitivity of the tumor.
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http://dx.doi.org/10.1007/s00520-012-1529-1DOI Listing
February 2013

[Immunotherapy: an emerging strategies against prostate castration resistant cancer].

Bull Cancer 2012 Jul;99 Suppl 1:S57-65

CHU Jean-Minjoz, oncologie médicale, boulevard Flemming, 25000 Besançon, France.

Castration resistant prostate cancer occurs when patients experience disease progression despite appropriate hormonal manipulations. In these patients, chemotherapy remains standard treatment. Preclinical and clinical data have demonstrated the potential utility of an immunotherapy-based approach for the treatment of prostate cancer (PC). The phase III trial (IMPACT) has recently reported an advantage for Sipuleucel-T over placebo, with an overall survival 4.1 months superior to placebo. Sipuleucel-T is also the first FDA-approved immunotherapy for prostate cancer. These promising results need to be confirmed with other large studies and within previous step of PC. Neoplasic cells can escape immune responses by multiple mechanisms. A better knowledge of these mechanisms is of major concern for the future development of new immunotherapies approach.
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http://dx.doi.org/10.1684/bdc.2012.1564DOI Listing
July 2012

Serum creatine kinase increase in patients treated with tyrosine kinase inhibitors for solid tumors.

Med Oncol 2012 Dec 24;29(4):3003-8. Epub 2012 Mar 24.

Medical Oncology Department, Centre Oscar Lambret, BP307, 59020, Lille, France.

Regarding the frequency of muscular complains with the use of tyrosine kinase inhibitors (TKIs), we hypothesize that creatine kinase (CK) elevation may be more frequent than usually reported. We conducted a prospective study on patients treated with TKIs for solid tumors, to assess the incidence of CK increase on treatment. Most of the patients (105/155) had a gastrointestinal stromal tumor. Treatments were carried out with the following drugs: imatinib (87 cases); sunitinib (21 cases); HER antagonists (14 cases), other TKIs (15 cases); and imatinib-based combinations (2 cases). Myalgias were found in 50/155 patients (32%). Fifty-four patients (35%; 95%CI, 27-42%) had elevated CK. According to NCI-CTC grading, there was 49/54 (31%) grade 1 and 5/54 (3%) grade 2 (2.5 to 5 times ULN). CK elevation was more frequent with imatinib than with other TKIs (39 cases, 45% vs. 14 cases, 21%, respectively; chi-squared test: P=0.003), and CK was more likely to be abnormal in patients treated with any TKI for more than 6 months. We found increased CK in about one-third of patients under TKIs for solid tumors, including 3% of patients with CK as high as 2.5-5 times ULN.
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http://dx.doi.org/10.1007/s12032-012-0204-1DOI Listing
December 2012

Efficacy of trabectedin in metastatic solitary fibrous tumor.

Rare Tumors 2011 Jul 18;3(3):e29. Epub 2011 Jul 18.

Department of Medical Oncology, Universitary Hospital Center J. Minjoz, Besançon, France;

Solitary fibrous tumor is a rare tumor type and has an unpredictable course. Local recurrence rate varies between 9 and 19%, and rate of metastatic involvement between 0 and 36 %. It is characterized by a typical architecture and immuno-histochemistry tests. The most important prognostic factor is the complete resection of primary tumor. Treatment of recurrences is not clearly established. If a solitary fibrous tumor is too advanced to allow surgical resection, radiotherapy and chemotherapy may be used. The most often used drugs are doxorubicine and\or ifosfamide. We report the case of man with metastatic solitary fibrous tumor treated with trabectedin, administered at a dose of 1.5 mg/m² every 3 weeks. After 3 cycles, metastases had significantly decreased. Recurrence of the disease was demonstrated 8 months after the start of trabectedin. This case shows that trabectedin is a possible treatment option.
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http://dx.doi.org/10.4081/rt.2011.e29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208416PMC
July 2011

Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas.

Cancer 2012 Jul 1;118(13):3330-6. Epub 2011 Nov 1.

Department of Medical Oncology, Institut Bergonié, Bordeaux, France.

Background: Data regarding the role of anthracyclines and taxanes as first-line treatments of metastatic angiosarcoma are limited.

Methods: Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed.

Results: Seventy-five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single-agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression-free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9-6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4-10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS.

Conclusions: First-line single-agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS.
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http://dx.doi.org/10.1002/cncr.26599DOI Listing
July 2012

[Follow-up in patients with early breast cancer].

Bull Cancer 2011 Oct;98(9):1091-106

CHU Jean-Minjoz, service d'oncologie médicale, boulevard Fleming, Besançon, France.

Breast cancer incidence remains the highest among gynaecologic neoplasms. Once they have achieved their treatments, patients should undergo careful follow-up. It aims at detecting early local recurrence or controlateral breast cancer. Based on large cohorts, clinical and radiological follow-up procedures come from guidelines realised by scientific organisations. We evaluated our regional practices in Franche-Comté and compared them to current guidelines. Patients with early breast cancer positive for hormonal receptors filled a questionnaire concerning their follow-up. It included patients treated from 1999 to 2005. When frequency of consultation is evaluated, only half of the patients undergo what is recommended. Whereas mammography and non-validated complementary exams are more regularly realised. Patients consulting more one practician have a better compliance. Our study underlines significant disparities among patients follow-up. Better interactions between physicians and a greater implication of patients in their follow-up would increase its quality.
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http://dx.doi.org/10.1684/bdc.2011.1431DOI Listing
October 2011

[KIT and KIT: from biology to clinical use].

Bull Cancer 2012 Feb;99(2):191-7

CHU Jean-Minjoz, 3, boulevard Fleming, 25030 Besançon Cedex, France.

Scientific knowledge on gastrointestinal stromal tumors (GIST) has highly progressed over the last 10 years. The molecular bases of oncogenic transformation, KIT activating mutations, were identified in 1998 by Hirota et al. The product of KIT proto-oncogene, KIT protein, is a transmembrane receptor with tyrosine kinase activity. Tyrosine kinase inhibitors targeting these mutated activated kinases, namely imatinib and more recently sunitinib, nilotinib, masitinib or sorafenib, have deeply modified GIST prognosis. Molecular biology in GIST is now becoming a routine tool for treatment selection. In patients with advanced GIST, imatinib should be given until progression, and then, other tyrosine kinase inhibitors targeting KIT should be used. In the adjuvant setting, the optimal duration of imatinib treatment remains unknown.
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http://dx.doi.org/10.1684/bdc.2011.1386DOI Listing
February 2012

Duration: escalation study of oral etoposide with carboplatin in patients with varied solid tumors.

Anticancer Drugs 2010 Nov;21(10):958-62

Medical Oncology Unit, CHU Minjoz cINSERM U645 Besancon, France.

Prolonged fractionated oral administration of etoposide may present a theoretical advantage over intravenous administration of the bolus. This phase I trial was carried out to determine the recommended duration of oral etoposide in combination with a fixed dose of carboplatin. Nineteen patients with varied solid tumors, who were not candidates for standard chemotherapy, were administered an escalating duration (6, 9 or 12 consecutive days) of oral etoposide (a 25 mg capsule three times daily) combined with carboplatin AUC5 administered on day 1, by a 30  min intravenous infusion, to define the maximum tolerated dose on the basis of the acute toxicities that were reported. Etoposide was started on day 2; the cycles repeated every 28 days until disease progression or toxicity. Pharmacokinetics was carried out during the two first cycles. The maximum tolerated dose was determined to be the 12-day treatment level, with two cases of grade 4 neutropenia, grade 3 anemia and thrombocytopenia. As no severe toxicity occurred with the 9-day treatment level and in an attempt to explore an optimal combination, a new 10-day treatment plan was studied in three patients. As one patient presented dose-limiting toxicity at that level, five additional patients were included to establish the recommended regimen. Nonhematological toxicities among all patients were moderate, consisting of grade 2 nausea and asthenia. No treatment-related death occurred. Objective responses were observed in four patients and stabilization in three patients. Pharmacokinetics highlighted no interaction between etoposide and carboplatin. Fractionated oral etoposide (3×25 mg/day) for 10 days in combination with carboplatin AUC 5 presents acceptable toxicity and efficacy. The main toxicity remains hematological.
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http://dx.doi.org/10.1097/CAD.0b013e32833fc0beDOI Listing
November 2010