[Efficacy, safety and cost of eribulin in patients with metastatic breast cancer]. / Efficacité, tolérance et coût de l'éribuline chez des patientes présentant un cancer du sein métastatique.

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.

A framework to determine the effectiveness of dietary exposure mitigation to chemical contaminants.

In order to ensure the food safety, risk managers may implement measures to reduce human exposure to contaminants via food consumption. The evaluation of the effect of a measure is often an overlooked step in risk analysis process. The aim of this study was to develop a systematic approach for determining the effectiveness of mitigation measures to reduce dietary exposure to chemical contaminants. Based on expert opinion, a general framework for evaluation of the effectiveness of measures to reduce human exposure to food contaminants was developed. The general outline was refined by application to three different cases: 1) methyl mercury in fish and fish products, 2) deoxynivalenol in cereal grains, and 3) furan in heated products. It was found that many uncertainties and natural variations exist, which make it difficult to assess the impact of the mitigation measure. Whenever possible, quantitative methods should be used to describe the current variation and uncertainty. Additional data should be collected to cover natural variability and reduce uncertainty. For the time being, it is always better for the risk manager to have access to all available information, including an assessment of uncertainty; however, the proposed methodology provides a conceptual framework for addressing these systematically.

[Clinical efficacy and safety assessment of eribulin monotherapy in patients with metastatic breast cancer - a single- institute experience].

Eribulin mesylate, a novel microtubule inhibitor with a unique mechanism of action, was approved in Japan in April 2011 for the treatment of metastatic breast cancer patients who had been administered at least two prior chemotherapeutic agents. Here, we present a retrospective review of data from 27 patients who received eribulin monotherapy in our hospital. The overall response rate and clinical benefit rate were 25. 9% and 29. 6%, respectively, and the median progression-free survival was 9. 9 weeks(95% CI: 3. 5-16. 2 weeks). The toxicities of treatment were tolerable and manageable; responses were lower in patients who were triple negative subtype, and higher in patients who had responded to prior taxane treatment. The relative dose intensity of our data indicates that appropriate modification of dose and schedule may be an important part of eribulin monotherapy.

A phase I, open-label, single-arm study for QT assessment of eribulin mesylate in patients with advanced solid tumors.

BACKGROUND: Several cancer therapies can prolong cardiac repolarization. This study assessed the potential of eribulin to affect cardiac repolarization in patients with advanced solid tumors. METHODS: In this Phase I, open-label, single-arm study, patients received eribulin mesylate (1.4 mg/m(2); Days 1 and 8 of a 21-day cycle). The primary objective was to assess the effect of eribulin on the QTcF pre- and post-infusion; QTcF and QTcNi were compared for ability to remove heart-rate dependence of the QT interval. Relationship between concentration of eribulin and ΔQTc was explored using linear mixed-effects analysis. Secondary objectives explored pharmacokinetics, safety, and tolerability. RESULTS: Twenty-six patients were enrolled. QTcNi was more effective than QTcF in correcting for heart-rate dependency of the QT interval. On Day 1, mean ΔQTcNi were ~0 at all timepoints. An apparent time-dependent increase in ΔQTc was observed: on Day 8, changes from baseline were larger and more variable, without clear relation to plasma levels of eribulin. Day 8 predose ΔQTcNi was 5 ms, post-infusion mean values ranged from 2 to 9 ms (largest mean ΔQTcNi at 6 h). No new or unexpected toxicities were reported. CONCLUSION: Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients.

The European medicines agency review of eribulin for the treatment of patients with locally advanced or metastatic breast cancer: summary of the scientific assessment of the committee for medicinal products for human use.

The European Commission issued on March 17, 2011, a marketing authorization valid throughout the European Union (EU) for eribulin (Halaven; Eisai Limited). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a marketing authorization for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least 2 chemotherapeutic regimens for advanced disease. Eribulin mesylate is a structurally simplified synthetic analogue of halichondrin B, which is a natural product isolated from the marine sponge Halichondria okadai (ATC code L01XX41). Eribulin is a nontaxane, microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates leading to G(2)-M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. The recommended dose of eribulin is 1.23 mg/m(2) (equivalent to 1.4 mg/m(2) eribulin mesylate) to be administered intravenously over 2 to 5 min on days 1 and 8 of a 3-week cycle. In the pivotal trial, eribulin was associated with increased overall survival in patients with locally advanced or metastatic breast cancer who received at least 2 prior chemotherapy lines for advanced disease (median overall survival was 13.2 months in the eribulin arm vs. 10.6 months in the control arm; HR = 0.805; 95% confidence interval, 0.677-0.958; P = 0.014). The most common side effects are asthenia or fatigue and neutropenia. The objective of this article is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary report and product information, including product characteristics, are available on the European Medicines Agency website.

Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649.

Nonsteroidal anti-inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase-2 (COX-2)-dependent biosynthesis of prostacyclin (PGI(2)). CG100649 is a novel NSAID proposed to inhibit both COX-2 and carbonic anhydrase (CA)-I/-II. We compared its impact on prostanoid biosynthesis with that of celecoxib, an NSAID purposefully designed to selectively inhibit COX-2. In a controlled, double-blind randomized trial, single oral doses of 2 or 8 mg CG100649, 200 mg celecoxib, or placebo were well tolerated by healthy volunteers (n = 23). Both CG100649 and celecoxib had the effect of depressing urinary excretion of 2,3-dinor-6-keto-PGF(1α) (PGI-M); the effect of CG100649 was dose-dependent and more sustained (up to 240 h after the dose) than that of celecoxib. Neither CG100649 nor celecoxib significantly inhibited COX-1-dependent prostanoid formation. CA inhibition was not detected after administration of CG100649, despite its partitioning asymmetrically into erythrocytes. CG100649 and celecoxib are both relatively selective inhibitors of COX-2, but they differ in duration of action. Whether they have similar impact on cardiovascular events remains to be determined.

Eribulin mesylate (Halaven) for breast cancer.

Eribulin mesylate (Halaven-Eisai) has been approved by the FDA for treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapy regimens for metastatic cancer. Prior therapy should have included an anthracycline and a taxane in either an adjuvant or metastatic setting. Other drugs used to treat anthracycline- and taxane-refractory metastatic breast cancer include capecitabine (Xeloda), gemcitabine (Gemzar, and others) and vinorelbine (Navelbine, and others).

Eribulin mesylate: a promising new antineoplastic agent for locally advanced or metastatic breast cancer.

More than one million women worldwide are diagnosed with breast cancer every year. For those diagnosed with metastatic breast cancer, the 5-year survival rates are low as, ultimately, patients develop tumors that become refractory to treatment. In clinical trials, eribulin mesylate (E7389) - a novel nontaxane microtubule dynamics inhibitor - demonstrated efficacy in patients with various solid tumors, in particular, those with heavily pretreated metastatic breast cancer. The Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389 (EMBRACE) study observed a significant increase in overall survival with eribulin compared with treatment of physician's choice (median: 13.1 vs 10.6 months, respectively). Based on these results, eribulin recently received approval by the US FDA for the treatment of patients with metastatic breast cancer who have received at least two prior chemotherapeutic regimens including an anthracyline and a taxane. In addition, eribulin has a manageable tolerability profile, requires no premedication and has shorter infusion times than most other microtubule-targeted agents.

Assessment of inhalation exposures and potential health risks to the general population that resulted from the collapse of the World Trade Center towers.

In the days following the collapse of the World Trade Center (WTC) towers on September 11, 2001 (9/11), the U.S. Environmental Protection Agency (EPA) initiated numerous air monitoring activities to better understand the ongoing impact of emissions from that disaster. Using these data, EPA conducted an inhalation exposure and human health risk assessment to the general population. This assessment does not address exposures and potential impacts that could have occurred to rescue workers, firefighters, and other site workers, nor does it address exposures that could have occurred in the indoor environment. Contaminants evaluated include particulate matter (PM), metals, polychlorinated biphenyls, dioxins, asbestos, volatile organic compounds, particle-bound polycyclic aromatic hydrocarbons, silica, and synthetic vitreous fibers (SVFs). This evaluation yielded three principal findings. (1) Persons exposed to extremely high levels of ambient PM and its components, SVFs, and other contaminants during the collapse of the WTC towers, and for several hours afterward, were likely to be at risk for acute and potentially chronic respiratory effects. (2) Available data suggest that contaminant concentrations within and near ground zero (GZ) remained significantly elevated above background levels for a few days after 9/11. Because only limited data on these critical few days were available, exposures and potential health impacts could not be evaluated with certainty for this time period. (3) Except for inhalation exposures that may have occurred on 9/11 and a few days afterward, the ambient air concentration data suggest that persons in the general population were unlikely to suffer short-term or long-term adverse health effects caused by inhalation exposures. While this analysis by EPA evaluated the potential for health impacts based on measured air concentrations, epidemiological studies conducted by organizations other than EPA have attempted to identify actual impacts. Such studies have identified respiratory effects in worker and general populations, and developmental effects in newborns whose mothers were near GZ on 9/11 or shortly thereafter. While researchers are not able to identify specific times and even exactly which contaminants are the cause of these effects, they have nonetheless concluded that exposure to WTC contaminants (and/or maternal stress, in the case of developmental effects) resulted in these effects, and have identified the time period including 9/11 itself and the days and few weeks afterward as a period of most concern based on high concentrations of key pollutants in the air and dust.

Evaluation of the relative contribution of exposure routes in a health risk assessment of dioxin emissions from a municipal waste incinerator.

Polychlorinated dioxins (PCDDs) and furans (PCDFs) are perceived by the public as the most hazardous materials emitted from municipal waste incinerators. These compounds disperse in the atmosphere and deposit on environmental media, where they may bioconcentrate in the food chain, resulting in a number of potential sources for human exposure. We performed a cancer risk assessment of PCDD/PCDF emissions from a municipal waste incinerator to evaluate the relative contribution of various exposure routes. Three scenarios were examined, all of which predicted ingestion of fish to be a significant source of exposure. In the common case, representative of the general population consuming mainly foods from commercial sources, inhalation was predicted to be the source of greatest exposure, followed by ingestion of fish, beef, milk, vegetation, and soil. In addition to fish, milk and beef ingestion contributed significantly to total exposure under the highly-exposed and worst case scenarios. Life-time cancer risk from the emitted PCDD/PCDFs was assessed for each scenario and was estimated as 1.8 x 10(-7) (common case), 2.5 x 10(-6) (highly-exposed case), and 6.7 x 10(-6) (worst case). In view of the conservative assumptions used in the assessment, the relatively low magnitude of these risks suggests that the PCDD/PCDF emissions from this incinerator should not be considered a significant public health concern.