Publications by authors named "Cristian Villanueva"

31 Publications

Beneficial effects of melatonin on prostanoids pathways in pulmonary hypertensive neonates.

Vascul Pharmacol 2021 Mar 22:106853. Epub 2021 Mar 22.

Laboratory of Vascular Function & Reactivity, Pathophysiology Program, ICBM, Faculty of Medicine, Universidad de Chile, Chile; Pathophysiology Program, ICBM, Faculty of Medicine, Universidad de Chile, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Chile. Electronic address:

Pulmonary arterial hypertension of the newborn (PAHN) is a syndrome caused by chronic hypoxia, characterized by decreased vasodilator function, a marked vasoconstrictor activity, proliferation of smooth muscle cells (SMC) and thickening of the extracellular matrix in the pulmonary circulation, among other characteristics. Prostaglandins are derived from the arachidonic acid (AA) metabolism and are important regulators of pulmonary vascular tone. Since hypoxia induces oxidative stress and has been related to PAHN, a postnatal treatment with melatonin has been proposed due to its antioxidant properties. Here, we determined the effects of melatonin on pulmonary vascular homeostasis given by prostanoids. Ten PAHN newborn lambs were divided in two groups and treated either with vehicle or melatonin. After 1 week of treatment, we assessed pulmonary vascular prostanoids function and expression by wire myography, RT-PCR, Western Blot and immunohistochemistry. Melatonin improved in vivo and ex vivo pulmonary vasodilation. This was associated with an increased function and expression of vasodilator prostanoids at the expense of vasoconstrictor prostanoids. Our study demonstrates for the first time that melatonin may enhance the vasodilator prostanoid pathway in PAHN.
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http://dx.doi.org/10.1016/j.vph.2021.106853DOI Listing
March 2021

Feasibility of health-related quality of life (HRQoL) assessment for cancer patients using electronic patient-reported outcome (ePRO) in daily clinical practice.

Qual Life Res 2021 Jan 2. Epub 2021 Jan 2.

Methodological and Quality of Life Unit in Oncology, University Hospital of Besançon, 25000, Besançon, France.

Introduction: Routine Electronic Monitoring of Health-Related Quality of Life (HRQoL) (REMOQOL) in clinical care with real-time feedback to physicians could help to enhance patient-centered care. We evaluated the feasibility of REMOQOL in the French context in the QOLIBRY study. The primary objective was to assess the patients' compliance with REMOQOL.

Methods: The QOLIBRY study was a single-center, prospective study conducted in the University Hospital of Besançon (France). Eligible patients were those treated with systemic therapies for breast, lung or colorectal cancer at any stage. Patients were invited to complete the EORTC QLQ-C30 questionnaire and cancer-site-specific modules before each visit on tablets and/or computers in the hospital or at home. During the consultation, physicians had real-time access to visual summaries of HRQoL scores. Compliance was assessed as adequate if at least 66% of HRQoL assessments were completed during the 4 months of follow-up.

Results: Between March 2016 and October 2018, 177 patients were included in the QOLIBRY study. Median age was 64 years (IQR 54-71). The proportion of patients with an adequate compliance rate was 95.5% (n = 63) in the breast cancer cohort, 98.2% (n = 55) in the colorectal cancer cohort, and 90.9% (n = 50) in the lung cancer cohort. The physicians checked the HRQoL results in 73.1% of visits and prescribed supportive care and adapted patient management in 8.3% and 5.2% of visits, respectively.

Conclusion & Perspectives: The results of QOLIBRY study suggest that REMOQOL is feasible in the French context. However, information about HRQoL monitoring, training of the physicians in the use of the software, and recommendations for using HRQoL results to guide care are essential and must be improved.
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http://dx.doi.org/10.1007/s11136-020-02721-0DOI Listing
January 2021

Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial.

JAMA Oncol 2018 07;4(7):977-984

Breast Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal.

Importance: Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer.

Objective: To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer.

Design, Setting, And Participants: In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016).

Interventions: Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression.

Main Outcomes And Measures: The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment.

Results: A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer).

Conclusions And Relevance: The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.

Trial Registration: clinicaltrials.gov Identifier: NCT01698918.
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http://dx.doi.org/10.1001/jamaoncol.2018.0060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885212PMC
July 2018

Ribociclib plus letrozole versus letrozole alone in patients with de novo HR+, HER2- advanced breast cancer in the randomized MONALEESA-2 trial.

Breast Cancer Res Treat 2018 Feb 21;168(1):127-134. Epub 2017 Nov 21.

University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Purpose: Determine the efficacy and safety of first-line ribociclib plus letrozole in patients with de novo advanced breast cancer.

Methods: Postmenopausal women with HR+ , HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021). Patients were randomized to ribociclib (600 mg/day; 3 weeks-on/1 week-off) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was investigator-assessed progression-free survival; predefined subgroup analysis evaluated progression-free survival in patients with de novo advanced breast cancer. Secondary endpoints included safety and overall response rate.

Results: Six hundred and sixty-eight patients were enrolled, of whom 227 patients (34%; ribociclib plus letrozole vs placebo plus letrozole arm: n = 114 vs. n = 113) presented with de novo advanced breast cancer. Median progression-free survival was not reached in the ribociclib plus letrozole arm versus 16.4 months in the placebo plus letrozole arm in patients with de novo advanced breast cancer (hazard ratio 0.45, 95% confidence interval 0.27-0.75). The most common Grade 3/4 adverse events were neutropenia and leukopenia; incidence rates were similar to those observed in the full MONALEESA-2 population. Ribociclib dose interruptions and reductions in patients with de novo disease occurred at similar frequencies to the overall study population.

Conclusions: Ribociclib plus letrozole improved progression-free survival vs placebo plus letrozole and was well tolerated in postmenopausal women with HR+, HER2- de novo advanced breast cancer.
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http://dx.doi.org/10.1007/s10549-017-4518-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847028PMC
February 2018

Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial.

Breast Cancer Res Treat 2018 02 22;167(3):659-669. Epub 2017 Oct 22.

Sarah Cannon Research Institute, 250 25th Avenue North #100, Nashville, TN, 37203, USA.

Purpose: Determine the efficacy and safety of first-line ribociclib plus letrozole in elderly patients with HR+, HER2- advanced breast cancer.

Methods: 668 postmenopausal women with HR+, HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021); 295 patients were aged ≥ 65 years. Patients were randomized to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was PFS, which was evaluated in elderly (≥ 65 years) and younger (< 65 years) patients. Secondary endpoints included response rates and safety.

Results: Ribociclib plus letrozole significantly improved PFS vs placebo plus letrozole in elderly (hazard ratio: 0.608; 95% CI 0.394-0.937) and younger patients (hazard ratio: 0.523; 95% CI 0.378-0.723). Overall response rates were numerically higher in the ribociclib vs placebo arm, regardless of age. Ribociclib plus letrozole was well tolerated in elderly patients, with the safety profile similar to the overall study population. Nausea, vomiting, alopecia, and diarrhea were > 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm in both subgroups; most events were grade 1/2. In elderly patients, grade 1/2 anemia and fatigue were > 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm and discontinuation rates were similar in both arms.

Conclusions: Addition of ribociclib to letrozole is a valid therapeutic option for elderly patients with HR+, HER2- advanced breast cancer in the first-line setting.
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http://dx.doi.org/10.1007/s10549-017-4523-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807486PMC
February 2018

First description of a double heterozygosity for BRCA1 and BRCA2 pathogenic variants in a French metastatic breast cancer patient: A case report.

Oncol Rep 2017 Mar 3;37(3):1573-1578. Epub 2017 Feb 3.

Department of Medical Oncology, University Hospital, 25000 Besançon, France.

Hereditary breast and ovarian cancer syndrome is an autosomal dominant disease caused primarily by germline mutations in the BRCA1 or BRCA2 gene. Rare cases of double heterozygosity for BRCA1 and BRCA2 mutations have been reported quite exceptionally in non-Ashkenazi individuals. We describe the case of a woman who developed a bilateral breast cancer, discovered concomitantly, at 46 years old. Biopsies confirmed the presence of two breast cancers with distinct histology. BRCA analysis was tested due to a positive family history of breast cancer, and two pathogenic monoallelic mutations were detected, one in the BRCA1 gene and one in the BRCA2 gene. There is no known Ashkenazi Jewish ancestry. We report the first description of a never described double heterozygosity for BRCA1 and BRCA2 pathogenic variants in a French metastatic breast cancer patient, with two distinct histology, and two distinct mutations.
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http://dx.doi.org/10.3892/or.2017.5422DOI Listing
March 2017

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.

N Engl J Med 2016 11 7;375(18):1738-1748. Epub 2016 Oct 7.

From the University of Texas M.D. Anderson Cancer Center, Houston (G.N.H.), and Texas Oncology-Baylor Charles A. Sammons Cancer Center and the U.S. Oncology Network, Dallas (J.O.) - all in Texas; Davidoff Center, Rabin Medical Center, Tel Aviv University, Tel Aviv (S.M.S.), and Sheba Medical Center, Ramat Gan (S.P.-S.) - both in Israel; the Sarah Cannon Research Institute (H.A.B., D.Y.), Vanderbilt-Ingram Cancer Center (C.L.A.), and Tennessee Oncology (D.Y.) - all in Nashville; National Cancer Center Singapore, Singapore (Y.-S.Y.); Netherlands Cancer Institute and BOOG Study Center, Amsterdam (G.S.S.); Institut de Cancérologie de l'Ouest/René Gauducheau, Saint-Herblain (M.C.), Institut Gustave Roussy, Université Paris Sud, Villejuif (F.A.), University Hospital of Besançon, Besançon (C.V.), and Centre Léon Bérard, Lyon (T.B.) - all in France; Duke University Medical Center, Durham, NC (K.L.B.); Dana-Farber Cancer Institute, Boston (E.P.W.); University of Ulm, Ulm (W.J.), Onkologische Praxis, Velbert (A.N.), University of Tübingen, Tübingen (E.-M.G.), and Joint Practice for Interdisciplinary Oncology and Hematology, Freiburg (N.M.) - all in Germany; Tom Baker Cancer Centre, Calgary, AB, Canada (S.V.); University of Padua and Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy (P.C.); Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh (D.A.C.); Masaryk Memorial Cancer Institute, Brno, Czech Republic (K.P.); Florida Cancer Specialists-Sarah Cannon Research Institute, Fort Myers (L.L.H.); Breast Cancer Research Centre-Western Australia and Curtin University, Perth, Australia (A.C.); Department of Oncology, Vejle Hospital, Vejle, Denmark (E.J.); Arkhangelsk Clinical Oncology Dispensary, Arkhangelsk, Russia (O.B.); Hospital Universitario Virgen de la Victoria, Institute of Biomedical Research in Málaga, Málaga, Spain (E.A.); Oslo University Hospital, Oslo (E.W.); Virginia Cancer Specialists, Arlington (A.M.F.); Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan (L.-M.T.); Rainier Hematology-Oncology, Northwest Medical Specialties, Puyallup, WA (S.B.); Novartis Pharmaceuticals, East Hanover, NJ (F.X., M.M., C.G., S.H.); and Novartis Pharma, Basel, Switzerland (F.S.).

Background: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).

Methods: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10.

Results: The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively.

Conclusions: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).
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http://dx.doi.org/10.1056/NEJMoa1609709DOI Listing
November 2016

[Prevalence and management of pain in patients with metastatic cancer in Franche-Comté].

Bull Cancer 2016 Oct 29;103(10):849-860. Epub 2016 Sep 29.

CHRU de Besançon, pôle pharmacie, 3, boulevard Alexandre-Fleming, 25030 Besançon cedex, France; Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, interactions hôte-greffon-tumeur - ingénierie cellulaire et génique, Besançon, France. Electronic address:

Introduction: Pain management is a major public health problem, especially in oncology. In order to assess professional practice, the IRFC-FC conducted a survey amongst patients with metastatic osteophilic solid tumor in Franche-Comté. The aims were to assess the pain prevalence, and its characteristics, its management and its impact on patients' quality of life in patients in pain.

Methods: An observational, prospective and multicenter survey was conducted using a self-report questionnaire. Patients with metastatic breast or prostate cancer managed in 5 day-hospitals of the IRFC-FC over a period of three months were included.

Results: Two hundred thirty-three questionnaires were analyzed. Pain prevalence rate was 48.5%. Three quarters of patients in pain had chronic background pain, moderate to severe, with or without breakthrough pain. Considering their pain intensity and their analgesic therapy, 42.0% of patients seem to have an inadequate treatment. Eighty-five percent of treated patients reported to be compliant and felt that their pain was well managed despite a strong impact on their quality of life.

Conclusion: The setting of a specific clinical pathway is essential to secure the standardized, optimal and efficient management of patients in pain. The assessment of patient satisfaction and quality of life must be integrated in clinical practice to identify patients in pain for which the treatment is inappropriate.
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http://dx.doi.org/10.1016/j.bulcan.2016.08.007DOI Listing
October 2016

N-Acetylcysteine, a glutathione precursor, reverts vascular dysfunction and endothelial epigenetic programming in intrauterine growth restricted guinea pigs.

J Physiol 2017 02 4;595(4):1077-1092. Epub 2016 Dec 4.

Department of Neonatology, Division of Paediatrics, Faculty of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago 8330024, Santiago, Chile.

Key Points: Intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial epigenetic programming of the umbilical vessels. There is no evidence that this epigenetic programming is occurring on systemic fetal arteries. In IUGR guinea pigs we studied the functional and epigenetic programming of endothelial nitric oxide synthase (eNOS) (Nos3 gene) in umbilical and systemic fetal arteries, addressing the role of oxidative stress in this process by maternal treatment with N-acetylcysteine (NAC) during the second half of gestation. The present study suggests that IUGR endothelial cells have common molecular markers of programming in umbilical and systemic arteries. Notably, maternal treatment with NAC restores fetal growth by increasing placental efficiency and reverting the functional and epigenetic programming of eNOS in arterial endothelium in IUGR guinea pigs.

Abstract: In humans, intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial programming in umbilical vessels. We aimed to determine the effects of maternal antioxidant treatment with N-acetylcysteine (NAC) on fetal endothelial function and endothelial nitric oxide synthase (eNOS) programming in IUGR guinea pigs. IUGR was induced by implanting ameroid constrictors on uterine arteries of pregnant guinea pigs at mid gestation, half of the sows receiving NAC in the drinking water (from day 34 until term). Fetal biometry and placental vascular resistance were followed by ultrasound throughout gestation. At term, umbilical arteries and fetal aortae were isolated to assess endothelial function by wire-myography. Primary cultures of endothelial cells (ECs) from fetal aorta, femoral and umbilical arteries were used to determine eNOS mRNA levels by quantitative PCR and analyse DNA methylation in the Nos3 promoter by pyrosequencing. Doppler ultrasound measurements showed that NAC reduced placental vascular resistance in IUGR (P < 0.05) and recovered fetal weight (P < 0.05), increasing fetal-to-placental ratio at term (∼40%) (P < 0.001). In IUGR, NAC treatment restored eNOS-dependent relaxation in aorta and umbilical arteries (P < 0.05), normalizing eNOS mRNA levels in EC fetal and umbilical arteries (P < 0.05). IUGR-derived ECs had a decreased DNA methylation (∼30%) at CpG -170 (from the transcription start site) and this epigenetic signature was absent in NAC-treated fetuses (P < 0.001). These data show that IUGR-ECs have common molecular markers of eNOS programming in umbilical and systemic arteries and this effect is prevented by maternal treatment with antioxidants.
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http://dx.doi.org/10.1113/JP273396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309367PMC
February 2017

SOLTI NeoPARP: a phase II randomized study of two schedules of iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer.

Breast Cancer Res Treat 2015 Nov 4;154(2):351-7. Epub 2015 Nov 4.

SOLTI Breast Cancer Research Group, Barcelona, Spain.

Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II-IIIA TNBC were randomly assigned to receive PTX (80 mg/m(2), d1; n = 47) alone or in combination with iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of iniparib at these doses plus paclitaxel in early TNBC.
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http://dx.doi.org/10.1007/s10549-015-3616-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971774PMC
November 2015

[Efficacy, safety and cost of eribulin in patients with metastatic breast cancer].

Bull Cancer 2015 Sep 26;102(9):737-48. Epub 2015 May 26.

CHU de Besançon, hôpital Jean-Minjoz, pôle cancérologie-oncologie médicale, boulevard Fleming, 25000 Besançon cedex, France; Inserm U1098, 25000 Besançon, France; Université de Franche-Comté, SFR SMP, 25000 Besançon, France; EFS Bourgogne Franche-Comté, UMR1098, 25000 Besançon, France.

Eribulin gained its approval in March 2011 for the treatment of patients with locally advanced or metastatic breast cancer (MBC) whose disease has progressed despite anthracycline and taxane-containing regimens. This study retrospectively assessed the efficacy, safety and cost of this treatment for all patients with MBC treated by eribulin in Franche-Comté. Ninety-four patients received eribulin between July 2006 and October 2013. The median age was 62 years (35-83). Median overall survival was 10.3 months [95% CI: 7.6 to 17.9]. Median progression-free-survival was 3.8 months [95% CI: 2.9 to 5.0]. Clinical benefit was obtained in 55% evaluable patients [95% CI: 43.1 to 66.9] by RECIST criteria. Most common grade 3-4 adverse events (AEs) were neutropenia (38%), asthenia (10%) and peripheral neuropathy (7%). Median cost of the treatment was 9767 € per patient (6344-17,517). This analysis found similar results to the EMBRACE study despite less selected population. A medico-economic evaluation cost-utility type would assess the effectiveness of this strategy compared to standard treatments.
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http://dx.doi.org/10.1016/j.bulcan.2015.03.021DOI Listing
September 2015

Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial.

Lancet Oncol 2014 Oct 28;15(11):1269-78. Epub 2014 Sep 28.

Assistance-Publique Hôpitaux de Paris-Tenon, Institut Universitaire de Cancerologie Université Pierre et Marie Curie, Sorbonne Université, Paris, France.

Background: Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy.

Methods: In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379.

Findings: Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1-21·7) in the chemotherapy-alone group and 16·1 months (10·6-22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4-7·2] vs 4·2 months [3·9-4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61-0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone.

Interpretation: These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy.

Funding: F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(14)70439-5DOI Listing
October 2014

[Economic assessment of the routine use of Oncotype DX® assay for early breast cancer in Franche-Comte region].

Bull Cancer 2014 Jul-Aug;101(7-8):681-9

Inserm U645 EA-2284 IFR-133, Université de Franche-Comté, 25000 Besançon, France, CHU de Besançon, Oncologie médicale, Hôpital Jean Minjoz, boulevard Fleming 25030 Besançon cedex, France.

Oncotype DX® has been validated as quantifying the likelihood of distant recurrence at 10 years and overall chemotherapy benefit in patients with estrogen-receptor-positive and HER-2-negative early breast cancer. In 2012, this genomic signature was routinely available for patients in Franche-Comté, France. Patients eligible for Oncotype DX(®) testing had a ER-positive, HER-2-négative early breast cancer with a nodal involvement limited to 0 or 1 positive-node without extracapsular spread; an adjuvant chemotherapy was indicated based on usual prognostic factors. The aim was to assess the economic impact of Oncotype DX(®) testing in a French region. A cost-minimisation analysis from the French Public Healthcare System perspective was performed. The availability of Oncotype DX(®) in Franche-Comté, France, and its use in clinical routine allowed a decrease of 73 % of adjuvant chemotherapy without increase of the cost of the patients' management and with a potential reduction of the cost for the French Public Healthcare System. This strategy was successful and may allow the reimbursement of this test in France for patients with early breast cancer.
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http://dx.doi.org/10.1684/bdc.2014.1923DOI Listing
September 2014

Long-term follow-up of patients with metastatic breast cancer treated by trastuzumab: impact of institutions.

Breast 2014 Apr 22;23(2):165-9. Epub 2013 Dec 22.

Department of Medical Oncology, Besançon University Hospital, Besançon, France. Electronic address:

Purpose: Trastuzumab in Human Epidermal growth Receptor 2-positive (HER2+) metastatic breast cancer (MBC) was established as standard therapy since 2001. The objective of this study was to search for significant prognostic factors in patients with HER2+ MBC treated by trastuzumab taking into account the institution where the treatment was given.

Patients & Methods: All patients with HER2+ MBC treated by trastuzumab between 2001 and 2010 in the 8 hospitals of Franche Comte region were analysed. Univariate and multivariate analysis were conducted to search for factors related to overall survival (OS).

Results: Among 1234 patients with MBC treated by chemotherapy between 2001 and 2010, 217 patients received trastuzumab. In this subset, the median age was 60 years, 8% and 38% had brain and liver metastases at first occurrence of MBC, 36% of, tumours were hormonal receptors positive. Patients were treated in 48% and 52% of cases in specialized and in general hospitals, respectively. The median OS length was 45.2 months (IQR 23.2-89.3 months). In univariate analysis the following factors were significantly related to favourable OS: inclusion in clinical trials, treatment in a specialized hospital, positive hormonal receptors status, age <50. In multivariate analysis remained significant: treatment in specialized hospital (aHR 0.78; 95%CI 0.64-0.94; p = 0.03) and age <50 (aHR 0.76; 95%CI 0.59-0.95; p = 0.02).

Conclusion: Exposure to trastuzumab erases all established prognostic factors at the metastatic setting. The fact that patients treated in specialized hospitals presented a longer survival emphasizes the dramatic impact of this therapy and the relevance to optimize its use.
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http://dx.doi.org/10.1016/j.breast.2013.12.003DOI Listing
April 2014

First-line trastuzumab plus taxane-based chemotherapy for metastatic breast cancer: cost-minimization analysis.

J Oncol Pharm Pract 2014 Oct 24;20(5):362-8. Epub 2013 Oct 24.

Department of Pharmacy, University Teaching Hospital of Besançon, France INSERM U645 EA-2284 IFR-133, University of Franche-Comté, Besançon, France.

Aim: To carry out a cost-minimization analysis including a comparison of the costs arising from first-line treatment by trastuzumab plus docetaxel versus trastuzumab plus paclitaxel in patients with metastatic breast cancer.

Methods: All consecutive patients with human epidermal growth receptor 2-postive metastatic breast cancer who were treated at Besançon University Hospital and Saint Vincent private hospital between 2001 and 2010 by first-line therapy containing trastuzumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization, and healthcare travel.

Results: Progression-free survival difference between the two treatments was not significant (p = 0.65). First-line treatment by trastuzumab plus taxane was estimated at approximately €68,000 (p = 0.74). The drug costs represented around 70-75% of the total cost, mainly related to the use of trastuzumab.

Conclusion: Our economic analysis shows that although the costs of the two trastuzumab plus taxane regimens are similar, they may contribute to the on-going debate about the availability and use of innovative chemotherapy drugs, in particular in human epidermal growth factor receptor 2-positive metastatic breast cancer with new therapies such as trastuzumab-DM1 and pertuzumab.
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http://dx.doi.org/10.1177/1078155213508440DOI Listing
October 2014

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.

Lancet Oncol 2013 Jul 6;14(8):697-710. Epub 2013 Jun 6.

Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium.

Background: Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients.

Methods: This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m(2) on day 1 of each cycle) and fluorouracil (1000 mg/m(2) on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265.

Findings: Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8-12·2) in the panitumumab group and 9·0 months (8·1-11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729-1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6-6·6) in the panitumumab group and 4·6 months (4·1-5·4) in the control group (HR 0·780, 95% CI 0·659-0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7-13·7] vs 8·6 months [6·9-11·1]; HR 0·73 [95% CI 0·58-0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3-12·9] vs 12·6 months [7·7-17·4]; 1·00 [0·62-1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47-1·04]).

Interpretation: Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings.

Funding: Amgen Inc.
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http://dx.doi.org/10.1016/S1470-2045(13)70181-5DOI Listing
July 2013

Discordances in estrogen receptor status, progesterone receptor status, and HER2 status between primary breast cancer and metastasis.

Oncologist 2013 Jun 30;18(6):667-74. Epub 2013 May 30.

Department of Medical Oncology, University Hospital, Besançon, France.

Background: The primary aim of this retrospective study was to investigate intraindividual correlation of estrogen receptor (ER) status, progesterone receptor (PR) status, and HER2 status between primary breast cancer and metastatic breast cancer (mBC). Secondary aims included patients' characteristics, overall survival, feasibility of histopathological evaluation in the metastatic setting, and predictive factors associated with receptors status discordance.

Methods: Patients with either biopsy of metastatic relapse or surgery of metastasis were identified. Demographics, tumor characteristics, treatment characteristics, and ER, PR, and HER2 statuses were retrospectively obtained in patients' reports. Receptors statuses were assessed by immunohistochemistry with a positivity cutoff of more than 10% for ER and PR. HER2 was considered as positive if overexpression was scored at 3+ in immunohistochemistry or if amplification ratio was >2 in fluorescent in situ hybridization.

Results: From a cohort of 489 patients with mBC, 269 patients had histopathological samples of metastatic relapse. Histopathological analysis of the specimen confirmed the diagnosis of mBC in 235 patients. Discordance in one or more receptors between primary breast cancer and mBC was found in 99 patients (42%). A switch in receptor status was identified for ER in 17% of tumors (p = 4 × 10(-3)), PR in 29% of cancers (p < 4 × 10(-4)), and HER2 in 4% of lesions (p = .16). Exposure to chemotherapy and to anthracycline-based chemotherapy was statistically associated with switches in ER status. Seven (2%) second malignancies and three benign diseases (1%) were diagnosed.

Conclusions: This study confirms that discordance in ER and PR receptor expression between the primary breast tumor and the corresponding metastatic lesions is high, whereas HER2 status remains relatively constant. Chemotherapy, and specifically anthracycline-based chemotherapy, was associated with switch in ER status. These results were obtained in a selected population of patients; further studies are warranted to confirm these data and to determine the interest of systematic rebiopsy in the metastatic setting.
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http://dx.doi.org/10.1634/theoncologist.2012-0350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063392PMC
June 2013

A randomized, phase II, three-arm study of two schedules of ixabepilone or paclitaxel plus bevacizumab as first-line therapy for metastatic breast cancer.

Breast Cancer Res Treat 2013 Jun 7;139(2):411-9. Epub 2013 May 7.

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143-0875, USA.

The aim of this phase II trial was to estimate the objective response rate (ORR) of two different schedules of ixabepilone [weekly or every 3 weeks (Q3W)] combined with bevacizumab, relative to a reference arm of weekly paclitaxel and bevacizumab. Patients with human epidermal growth factor receptor 2-normal, chemotherapy-naïve metastatic breast cancer (MBC) were randomized 3:3:2 to ixabepilone 16 mg/m(2) weekly plus bevacizumab 10 mg/kg Q2W (Arm A: n = 46); ixabepilone 40 mg/m(2) Q3W (reduced to 32 mg/m(2) after four cycles of treatment) plus bevacizumab 15 mg/kg Q3W (Arm B: n = 45); or paclitaxel 90 mg/m(2) weekly plus bevacizumab 10 mg/kg intravenous infusion Q2W (Arm C: n = 32). Of 123 randomized patients, 122 were treated. All were followed for ≥19 months; 5 % of patients remained on study treatment at the time of this analysis. Grade 3 or 4 neutropenia was more common in Arm B (60 %) than Arms A (16 %) or C (22 %); other adverse events were similar. The investigator-assessed ORR was 48, 71, and 63 % for Arms A, B, and C, respectively. Median progression-free survival (randomized patients) was 9.6 months in Arm A, 11.9 months in Arm B, and 13.5 months in Arm C. In conclusion, ixabepilone Q3W plus bevacizumab has clinical activity as first-line therapy for MBC relative to paclitaxel plus bevacizumab, but with significantly greater risk of grade 3 or 4 neutropenia. In addition, these data suggest that weekly dosing of ixabepilone may be less active than Q3W dosing, but with less neutropenia.
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http://dx.doi.org/10.1007/s10549-013-2552-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669514PMC
June 2013

Safety and efficacy of cabazitaxel in the docetaxel-treated patients with hormone-refractory prostate cancer.

Clin Med Insights Oncol 2013 20;7:1-12. Epub 2012 Dec 20.

Centre Hospitalier Universitaire Besançon, Oncology, Besançon, France.

Prostate cancer (PC) is one of the most common cancers and is a leading cause of death. Its initial growth is dependent on androgens; most patients show an initial response to hormonal therapy but will experience disease progression when PC becomes resistant to castration. In 2004, two key randomized controlled trials demonstrated a benefit for docetaxel-based regimens in the treatment of men with castration-resistant prostate cancer (CRPC). Cabazitaxel (XRP6258, TXD258, and RPR116258A), a tubulin-binding taxane drug as potent as docetaxel in cell lines, was the first treatment able to prolong survival for metastatic CRPC in the post-docetaxel setting. This review describes pharmacologic parameters of this agent followed by a review of clinical trials involving cabazitaxel. Other available treatments and the place of cabazitaxel in metastatic CRPC setting are discussed.
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http://dx.doi.org/10.4137/CMO.S7256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547543PMC
January 2013

First-line bevacizumab plus taxane-based chemotherapy for metastatic breast cancer: cost-minimisation analysis.

Anticancer Res 2012 Aug;32(8):3547-52

Department of Pharmacy, University Hospital, 3 Boulevard Fleming, 25030 BESANCON Cedex, France.

Aim: To carry out a cost minimisation analysis including a comparison of the costs arising from first-line treatment by bevacizumab plus docetaxel (BD) versus bevacizumab plus paclitaxel (BP) of patients with metastatic breast cancer (mBC).

Patient And Methods: All consecutive patients with human epidermal growth receptor 2-negative mBC and treated at Besançon University hospital between 2006 and 2010 by a first-line therapy containing bevacizumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization and healthcare travel.

Results: Progression-free survival difference between the two treatments was insignificant (p-value=0.31). BP treatment was associated with a higher mean total cost than that of BD treatment, €53,093 ± 34,395 versus €60,196 ± 48,766, respectively.

Conclusion: Whereas bevacizumab is recommended for first-line treatment of mBC with paclitaxel-based chemotherapy, our study has shown that BD treatment is the most cost-efficient regimen. It could be an attractive option in France, with a potential cost saving of €24,000,000 per year.
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August 2012

Is extracapsular tumour spread a prognostic factor in patients with early breast cancer?

Int J Clin Oncol 2013 Aug 5;18(4):607-13. Epub 2012 Jul 5.

Department of Medical Oncology, University Hospital of Besancon, Besançon, France.

Background: This study searched for extra capsular tumour spread (ECS) as a prognostic factor for recurrence in terms of Disease Free Survival (DFS) and Overall Survival (OS).

Patients And Methods: For this study, from a retrospective database of the Doubs cancer registry, 823 eligible women with node positive breast cancer treated from February 1984 to November 2000 were identified. The following factors were evaluated: ECS, numbers of involved nodes, histological tumour grade, tumour size, status of estrogen and progesterone receptors, and age of patient. A Cox proportional hazards method was used to search for significant factors related to OS and DFS length.

Results: In the multivariate analysis, factors related to DFS length were found to be: tumour grade (aHR 0.76, 95 % CI 0.61-0.96, p = 0.02), ECS status (aHR 0.7, 95 % CI 0.49-0.96, p = 0.03), progesterone (PgR) status (aHR 0.63, 95 % CI 0.44-0.85 p = 0.008), number of nodes involved (aHR 0.75, 95 % CI 0.56-1, p = 0.05). The multivariate analysis for OS found as significant factors: tumour grade (aHR 0.76, 95 % CI 0.61-0.95; p = 0.02) and PgR status (aHR 0.8, 95 % CI 0.56-0.99, p = 0.02).

Conclusions: This study might suggest taking into account ECS status in the adjuvant decision-making process.
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http://dx.doi.org/10.1007/s10147-012-0439-zDOI Listing
August 2013

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

Extravasation of liposomal doxorubicin induces irritant reaction without vesicant injury.

Anticancer Res 2012 Apr;32(4):1481-3

University of Franche Comté, Besançon, France.

Anthracycline extravasation is an uncommon but very serious complication. Very few data are available in the literature concerning the consequences and the management of extravasation of liposomal doxorubicin. This report describes the cases of two patients with liposomal doxorubicin extravasation who developed irritant reaction without vesicant or necrotic lesions. It is concordant with other cases described in the literature and suggests that extravasation of liposomal doxorubicin can be relatively well tolerated. The process applied to extravasations of irritant and non-vesicant agents could be used to manage extravasations of liposomal doxorubicin.
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April 2012

Cabazitaxel: a novel microtubule inhibitor.

Drugs 2011 Jul;71(10):1251-8

Department of Medical Oncology, University Hospital, Besançon, France.

The development of drug resistance is a major obstacle to effective cancer therapy. Several agents are in clinical development with the goal of overcoming resistance. Among them is cabazitaxel, a semisynthetic taxoid that is able to overcome a common mechanism of resistance that limits the efficacy of other chemotherapeutic agents, including the older taxanes. The promise of cabazitaxel as a second-line chemotherapy option for advanced prostate cancer has been confirmed clinically in the phase III TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-Containing Regimen) trial. This trial showed that cabazitaxel is the first chemotherapeutic agent to demonstrate a survival benefit in metastatic castration-resistant prostate cancer (mCRPC) since the approval of docetaxel. On this basis, the US FDA and the European Medicines Agency approved cabazitaxel in June 2010 and January 2011, respectively, for the treatment of patients with mCRPC who have previously been treated with docetaxel. The most prevalent toxicity was neutropenia and the use of primary prophylaxis with granulocyte-colony stimulating factor is recommended in high risk patients. This article presents the preliminary antitumour activity, safety, tolerability and pharmacokinetic data of cabazitaxel, and an overview of the current status of clinical development.
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http://dx.doi.org/10.2165/11591390-000000000-00000DOI Listing
July 2011

Discordance in early breast cancer for tumour grade, estrogen receptor, progesteron receptors and human epidermal receptor-2 status between core needle biopsy and surgical excisional primary tumour.

Breast 2011 Jun 1;20(3):284-7. Epub 2011 Feb 1.

Department of Medical Oncology, University Hospital Jean Minjoz, 25030 Besançon Cedex, France.

The aim of the present study was to compare the tumour grade, Estrogen Receptor (ER), Progesteron Receptor (PgR) and Human Epidermal Receptor-2 (HER-2) status in the core needle biopsy (CNB) with those observed in the subsequent excisional primary tumour (EPT). All patients diagnosed with an early breast cancer in our University Hospital Center between January 1, 2005 and December 31, 2006 were included but exclusion criteria of patients with large tumour requiring neoadjuvant chemotherapy and cases with more than one tumour (multicentricity/multifocality tumours). Histological tumour grade assessed according to Nottingham Grading System (SBRm), ER, Pgr and HER-2 tumoural status were assessed twice in CNB and in EPT. A total of 175 patients were assessed. The concordance between CNB and EPT for Grade, ER, PgR and HER2 status were 75.4% (p > 0.00001), 84% (p > 0.00002), 78.3% (p = 0.002) and 98.3% (p = 0.486) respectively. In conclusion CNB can be used with confidence for HER2 determination. For grade, PgR and ER due to substantial discordance results from CNB should be used with caution.
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http://dx.doi.org/10.1016/j.breast.2010.12.007DOI Listing
June 2011

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

Safety profile of new anticancer drugs.

Expert Opin Drug Saf 2010 Mar;9(2):301-17

CHU Jean Minjoz, Medical Oncology Unit, Boulevard Flemming, 25 000 Besancon, France.

Importance Of The Field: The development of targeted anticancer therapies stems from advances in molecular biology. New agents range from antibodies that form complexes with antigens on the surface of the cancer cell to small molecules that have been engineered to block key enzymatic reactions. The interaction of the antibody or drug with its target inhibits key pathways involved in cell proliferation or metastasis, or activates pathways leading to cell death. Such pathways constitute ideal pharmacological targets. Clinical benefits from these novel therapeutic strategies are striking for patients with metastatic diseases.

Areas Covered: This review analyses the main toxicities among most common targeted therapies that have been approved by the FDA or European Medicines Agency for their clinical utilisation in solid tumours treatment.

What The Reader Will Gain: Here, the main toxicity and safety data among new anticancer targeted therapies are described. Data are organised through the pathways targeted by the drugs.

Take Home Message: The emergence of new targeted anticancer therapies promises more efficient and less toxic therapies. Generally, they are well tolerated, toxicities are commonly mild to moderate and can be handled rapidly. However, if most of these adverse events are manageable, life threatening and fatal complications can still occur.
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http://dx.doi.org/10.1517/14740330903530663DOI Listing
March 2010

Response rates: a valuable signal of promising activity?

Cancer J 2009 Sep-Oct;15(5):361-5

Department of Oncology, University Hospital J. Minjoz, Besancon, France.

A main criterion to identify activity in phase II studies is the response rates achieved in a well-defined subset of patients. The response could be defined as a measure of tumor shrinkage. For 30 years, metric methods have been used to assess this response. The World Health Organization was the first organization to propose a unified definition for response status. Over time, the latter evolved and 10 years ago an international consensus panel proposed the Response Evaluation Criteria in Solid Tumors criteria. Although these guidelines for response assessment have limitations and biases, they have nevertheless been proven useful and advantageous. This article reviews those criteria and describes their use.
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http://dx.doi.org/10.1097/PPO.0b013e3181bd045fDOI Listing
April 2010

Ixabepilone: a new active chemotherapy in the treatment of breast cancer.

Womens Health (Lond) 2009 Mar;5(2):115-21

University of Hospital Jean Minjoz, Department of Medical Oncology, Besançon, France.

Ixabepilone (BMS247550) is a semisynthetic derivative of the natural product that optimizes the properties observed with epothilone B. This compound has some similarities with taxanes in targeting and stabilizing microtubules, but it also has major differences. Interestingly, ixabepilone was evaluated in patients with well-characterized resistance to taxanes and was able to overcome the overexpression of multidrug resistance and was unaffected by mutations in the beta-tubulin genes. The interest in ixabepilone was clinically confirmed in Phase II and III clinical studies, which have demonstrated a strong activity in patients with metastatic breast cancer resistant to taxanes and in patients suffering from other types of chemoresistant tumors.
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http://dx.doi.org/10.2217/17455057.5.2.115DOI Listing
March 2009

Anticancer therapy in patients with porphyrias: evidence today.

Expert Opin Drug Saf 2008 Mar;7(2):159-65

Medical Oncology Unit, CHU Minjoz, Bvd Fleming, 25000 Besancon, France.

Background: Porphyrias are rare diseases, and for these patients every administration of drugs may induce an acute attack of porphyria. The list of safe compounds allowed in these patients is available for clinicians from specific websites cited in the text.

Objectives: However, data concerning anticancer therapy in patients with such diseases remain poor. Therefore any publications can help clinicians to deal with this very specific group of patients.

Methods: In our institution, three patients received docetaxel and hematologic growth factors (erythropoietin and GCSF) without unexpected toxicities. Aromatase inhibitors (anstrozole and letrozole) were also given in one patient without any related problem.

Conclusion: The present observation adds some useful data for the possible treatment of cancer in patients with porphyria.
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http://dx.doi.org/10.1517/14740338.7.2.159DOI Listing
March 2008