er-086526 and Sarcoma

Topics: Antineoplastic Combined Chemotherapy Protocols; Furans; Humans; Ketones; Liposarcoma; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome

Due to the rarity and heterogeneity of bone and soft-tissue sarcomas, investigation into molecular targets and new treatments has been particularly challenging. Although intensive chemotherapy and establishment of surgical procedures have improved the outcomes of patients with sarcoma, the curative rate of recurrent and metastatic sarcomas is still not satisfactory. Recent basic science research has revealed some of the mechanisms of progression and metastasis of malignancies including proliferation, apoptosis, angiogenesis, tumor microenvironment, migration, invasion, and regulation of antitumor immune systems. Based on these basic studies, new anticancer drugs, including pazopanib, trabectedin, eribulin, and immune checkpoint inhibitors have been developed and the efficacies and safety of the new drugs have been assessed by clinical trials. This review summarizes new molecular therapeutic targets and advances in the treatment for bone and soft tissue sarcomas.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone Neoplasms; Drug Therapy; Furans; Humans; Immunotherapy, Adoptive; Indazoles; Ipilimumab; Ketones; Nivolumab; Osteosarcoma; Progression-Free Survival; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sorafenib; Sulfonamides; Trabectedin

Topics: Adult; Anthracyclines; Antineoplastic Agents; Drug Discovery; Drugs, Investigational; Furans; Humans; Ketones; Liposarcoma; Sarcoma; Soft Tissue Neoplasms; Trabectedin

Eribulin is a structurally simplified, synthetic macrocyclic ketone analog of halichondrin B, which is a natural, polyether macrolide derived from marine sponges. Eribulin exerts its cytotoxicity by its unique microtubule dynamics inhibitory action. Eribulin was approved in 2010 by the US FDA as a third-line therapy for metastatic breast cancer patients previously treated with an anthracycline and a taxane. In 2016, it was approved for treatment of metastatic liposarcoma for patients who have progressed with anthracycline treatment. In this article, we review the pharmacokinetics, mechanism of action of eribulin with focus on preclinical and clinical data in sarcoma and also the role of miRNAs in soft tissue sarcomas.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Clinical Trials as Topic; Furans; Humans; Immunotherapy; Ketones; Sarcoma

Metastatic soft tissue sarcoma, a devastating disease, has a median overall survival of only 12-18 months. Treatment options remain scarce. However, eribulin mesylate, a first-in-class halichondrin B-based microtubule dynamics inhibitor, has recently been approved for the management of patients with advanced liposarcoma. Areas covered: Based on a review of the literature between 2005 and 2017, we present a summary of eribulin mesylate's mechanism of action and the studies showing its clinical efficacy in locally advanced or metastatic sarcomas. Expert commentary: Future development includes the definition of a biomarker signature related to patient outcome with eribulin. Further investigation via controlled clinical trials is needed to identify combination regimens that can optimize the efficacy of eribulin while providing an acceptable safety profile in sarcoma patients.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Disease-Free Survival; Epithelial-Mesenchymal Transition; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Neoplasm Metastasis; Sarcoma; Tubulin Modulators

Trabectedin and eribulin are two agents that have been recently approved for the treatment of specific soft tissue sarcoma subtypes. They have proved to be a much-needed line of additional treatment for patients with these rare tumors, but their activity remains admittedly modest in most cases. Further exploitation of these novel agents is likely to require a more granular understanding of the salient mechanisms of action. For example, if as some studies suggest, eribulin derives its benefit from restructuring of tumor vasculature to improve efficacy of subsequent lines of therapy, then patients may benefit from its use earlier in the treatment pathway. The sequencing of trabectedin with other agents is also worth examining. In a disease like myxoid liposarcoma, consideration should be given to using trabectedin before other salvage regimens like gemcitabine and docetaxel, given its tolerability and excellent efficacy against this sarcoma subtype. Also, to be further investigated is the use of trabectedin in sarcoma subtypes which were excluded from the phase III study, but in which activity has been documented in earlier trials and subsequent reports. Combinations of trabectedin with other agents, particularly doxorubicin, have been explored, but the data to date do not support the routine use of these regimens.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Dioxoles; Drug Evaluation, Preclinical; Furans; Humans; Ketones; Molecular Targeted Therapy; Sarcoma; Tetrahydroisoquinolines; Trabectedin; Treatment Outcome

Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Although treatment outcomes for patients with STS have improved greatly over the past few decades owing to the adoption of a multidisciplinary approach, patients with advanced disease have a poor prognosis. The development of anticancer drugs has been directed toward improving overall survival (OS). Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. However, there is no standard therapy for second-line and later treatment at present. Since 2012, three anticancer drugs-pazopanib, trabectedin, and eribulin-have been approved in Japan for the second-line or later treatment of patients with advanced STS of any histologic subtype. However, the chemosensitivity of STS to each of these drugs varies by histologic subtype and their safety profiles differ; thus, histologic subtype and patient characteristics must be considered when determining optimal treatment. In this article, we review data from clinical studies related to the efficacy of all three drugs, including their effect on OS, and propose optimal treatment strategies for advanced STS by histologic subtype. In addition, with regard to the safety profiles, we highlight the key issues to be considered when selecting patients for treatment with pazopanib, trabectedin, or eribulin and ensuring their appropriate use, based on our combined clinical experience as specialists in the treatment of patients with STS. The proposed treatment strategies as well as treatment precautions based on clinical experience would benefit patients by maximizing the therapeutic effects and enhancing the proper use of these drugs.. Eisai Co., Ltd.

Topics: Antineoplastic Agents, Alkylating; Dioxoles; Furans; Humans; Indazoles; Japan; Ketones; Pyrimidines; Sarcoma; Sulfonamides; Tetrahydroisoquinolines; Trabectedin

Immune checkpoint inhibitors have shown promising results in several cancers and are now put to the test in sarcomas. This brief summary presents data regarding the previously approved and newer agents for more common sarcomas and focuses on specific sarcoma histologic subtypes or novel approaches for which there is particular optimism. Approaches involving epigenetic agents, metabolic therapy, and modulators of the tumor microenvironment represent other ways the field of sarcoma medical oncology will progress in 2016 and beyond.. A recent series of successful randomized trials provides new systemic therapy options for patients with metastatic soft-tissue sarcomas in the United States, after a gap of more than 10 years in which no new drugs were approved. The agents with most recent approval include pazopanib, trabectedin, and eribulin. As a sign that progress is not linear, 2 cousins of ifosfamide failed to show benefit in phase 3 trials, despite prior positive results of randomized phase 2 trials.. The biological features of each sarcoma subtype are associated with specific sensitivity patterns to chemotherapy, and despite their rarity, future trials will need to emphasize specific histologic subtypes (many with well-defined genetic alterations) to best fit diagnosis to therapy.

Topics: Adult; Antineoplastic Agents; Dioxoles; Furans; Humans; Indazoles; Ketones; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sulfonamides; Tetrahydroisoquinolines; Trabectedin; Tumor Microenvironment

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Clinical Trials as Topic; Furans; Humans; Ketones; Sarcoma

Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination.. The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort.. Patients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose-escalation cohort (N = 10) and in the dose-expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment-related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose-limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m. Selinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients.. Effective therapies for advanced, triple-negative breast cancer and sarcoma represent an unmet need. Exportin 1 is associated with the transport of cancer-related proteins. Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin. In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple-negative breast cancer or sarcoma. The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support. The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple-negative breast cancer. This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple-negative breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Neutropenia; Prospective Studies; Sarcoma; Soft Tissue Neoplasms; Triple Negative Breast Neoplasms

Eribulin, a microtubule dynamics inhibitor, is approved for the treatment of patients with breast cancer and soft tissue sarcoma. We investigated the efficacy and safety of eribulin in Japanese patients with soft tissue sarcoma.. This open-label, multicenter, nonrandomized, Phase 2 study enrolled Japanese patients with measurable, advanced/metastatic soft tissue sarcoma of high/intermediate grade and ≥1 prior chemotherapy for advanced disease. Patients received eribulin mesilate 1.4 mg/m2 intravenously over 2–5 minutes on Days 1 and 8 of a 21-day cycle. The primary endpoint was progression-free rate at 12 weeks. Secondary endpoints included overall survival, progression-free survival and safety. Efficacy analyses were stratified by histology (liposarcoma or leiomyosarcoma, and other subtypes).. Overall, 52 patients were enrolled and 51 patients were treated. Patients with liposarcoma/leiomyosarcoma (n = 35) had similar characteristics to those with other subtypes (n = 16), except for a higher proportion of women (63% vs 38%, respectively) and patients with Eastern Cooperative Oncology Group performance status 0 (57% vs 44%). Progression-free rate at 12 weeks was 60% in liposarcoma/leiomyosarcoma patients, 31% in other subtypes and 51% overall. Median progression-free survival was 5.5 months in liposarcoma/leiomyosarcoma patients, 2.0 months in other subtypes and 4.1 months overall. Median overall survival was 17.0 months in liposarcoma/leiomyosarcoma patients, 7.6 months in other subtypes and 13.2 months overall. The most common Grade 3–4 adverse events were neutropenia (86%), leukopenia (75%), lymphopenia (33%), anemia (14%) and febrile neutropenia (8%).. Eribulin showed clinical activity with a manageable safety profile in previously treated Japanese patients with advanced/metastatic soft tissue sarcoma.

Topics: Adult; Aged; Disease-Free Survival; Female; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Sarcoma; Treatment Outcome

Recent phase II and III clinical trials demonstrated anti-tumour activity of eribulin, a tubulin-interacting cytotoxic agent, in patients with metastatic soft tissue sarcoma (STS). In this exploratory study, we aimed to identify putative microRNA biomarkers that associate with eribulin sensitivity or resistance in STS.. Archival tumour tissue from primary tumours or metastatic lesions was collected prior to eribulin treatment, from 65 consenting patients involved in the EORTC trial 62052. This phase II study (ClinicalTrials.gov identifier NCT00413192) included multiple subtypes of STS. Tissue was available from 21 leiomyosarcomas, 14 adipocytic sarcomas, 9 synovial sarcomas and 21 other sarcoma histotypes. Total RNA was isolated from formalin-fixed, paraffin-embedded tumour samples and analysed using Taqman. The expression of 26 individual microRNAs (p < 0.05) differed significantly between non-responders and responders. Additional microRNAs of potential relevance were identified when considering the different histological subgroups.. The expression level of particular microRNAs in STS tissue samples may predict response to eribulin. Further validation studies as well as a preclinical assessment of the underlying molecular mechanisms are required.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Disease-Free Survival; Female; Furans; Humans; Ketones; Leiomyosarcoma; Liposarcoma; Male; MicroRNAs; Middle Aged; Neoplasms, Connective and Soft Tissue; Sarcoma; Treatment Outcome; Young Adult

Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs, inducing cell-cycle arrest and tumour regression in preclinical models. We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma.. In this non-randomised multicentre phase 2 study, patients were included if they had progressive or high-grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease. They were stratified by the type of soft-tissue sarcoma they had. Eribulin was given intravenously at a concentration of 1·4 mg/m(2) over 2-5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks (RECIST 1.0), which we evaluated in all patients who started treatment. Safety analyses were done in all patients who started treatment. This trial is registered at ClinicalTrials.gov, number NCT00413192.. Of 128 patients included, 37 had adipocytic sarcoma, 40 had leiomyosarcoma, 19 had synovial sarcoma, and 32 had other sarcomas. 12 (31·6%) of 38 patients with leiomyosarcoma evaluable for the primary endpoint, 15 (46·9%) of 32 patients with adipocytic sarcoma, four (21·1%) of 19 with synovial sarcoma, and five (19·2%) of 26 in other sarcomas were progression-free at 12 weeks. The most common grade 3-4 adverse events were neutropenia (66 [52%] of 127 patients evaluable for safety), leucopenia (44 [35%]), anaemia (nine [7%]), fatigue (nine [7%]), febrile neutropenia (eight [6%]), abnormal alanine aminotransferase concentrations (six [5%]), mucositis (four [3%]), and sensory neuropathy (four [3%]).. Eribulin deserves further study in this setting, based on progression-free survival at 12 weeks in leiomyosarcoma and adipocytic sarcoma.. Eisai Limited, Hatfield, UK.

Topics: Adult; Aged; Antineoplastic Agents; Disease-Free Survival; Drug Administration Schedule; Europe; Female; Furans; Humans; Infusions, Intravenous; Ketones; Leiomyosarcoma; Male; Mesylates; Middle Aged; Sarcoma; Sarcoma, Synovial; Soft Tissue Neoplasms; Survival Rate; Time Factors; Treatment Outcome

eribulin, an anticancer agent that inhibits microtubule growth, along with trabectedin and pazopanib, has been approved for the treatment of advanced soft tissue sarcoma (STS). However, there has been no consensus on the optimal second-line therapy among these three agents following treatment failure with doxorubicin. Recently, the effects of eribulin on the tumor microenvironment and immunity have been reported in breast cancer, and peripheral blood immune markers have also been reported to be a predictor of eribulin efficacy, though this remains unverified in STS. We aimed to evaluate the predictive value of various peripheral blood immune markers in STS patients treated with eribulin.. we retrospectively reviewed the medical records of STS patients treated with eribulin and examined whether peripheral blood immune markers at different time points could be prognostic factors for STS patients treated with eribulin.. several peripheral blood immune markers were significantly associated with progression-free survival (PFS), specifically neutrophil-to-lymphocyte ratio (NLR) prestart (NLR before the initial administration of eribulin) (P = 0.019) and absolute lymphocyte count (ALC)8D (ALC on Day 8 of the first administration of eribulin) (P = 0.037). NLR prestart (P = 0.001) was significantly associated with overall survival. The combination of NLR prestart and ALC8D determined the PFS of STS patients treated with eribulin.. the combined indicator of low NLR prestart and high ALC8D predicted the survival of patients treated with eribulin as well as the histology of L-sarcoma. Though further validation was needed, this finding would provide valuable prognostic factor that help treatment decision in the absence of consensus on the optimal second-line therapy following doxorubicin treatment in STS patients.

Topics: Antineoplastic Agents; Doxorubicin; Humans; Prognosis; Retrospective Studies; Sarcoma; Tumor Microenvironment

Soft tissue sarcomas (STSs) are a heterogeneous group of cancers with over 100 described subtypes. While these cancers are infrequent, the prognosis is quite poor, particularly for those with stage IV metastatic disease. Patients for whom curative resection is difficult or those with recurrent metastatic disease are treated with chemotherapy, although the options are very limited. Eribulin is an approved treatment of all STS subtypes in Japan. Efficacy and safety data for the treatment of rare STS subtypes other than liposarcoma and leiomyosarcoma (L-type sarcomas) are limited. This nationwide, multicenter, prospective, post-marketing observational study was conducted to assess the real-world effectiveness and safety of eribulin in Japanese patients with STS.. Patients with all types of STS and who consented to eribulin treatment were eligible to participate. The observation period was 1 year, starting at treatment initiation, and clinical outcomes were followed up for 2 years after initiating treatment. The primary endpoint was overall survival (OS). Additional outcomes included time-to-treatment failure (TTF), objective response rate (ORR), disease control rate (DCR), and safety. ORR and DCR were evaluated using imaging findings. Effectiveness results were analyzed both for all patients and by STS subtype.. A total of 256 patients were enrolled; 252 and 254 were included in the effectiveness and safety analysis set, respectively. Most patients (83.1%) received an initial eribulin dose of 1.4 mg/m. Eribulin demonstrated effectiveness and a manageable safety profile for patients with STS, although the effectiveness of eribulin was not demonstrated for some non-L-type subtypes.. NCT03058406 ( ClinicalTrials.gov ).

Topics: Aged; Furans; Humans; Japan; Ketones; Marketing; Prospective Studies; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome

Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment.. Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated.. SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia.. Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

Topics: Aged; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Factor Analysis, Statistical; Female; Furans; Humans; Ketones; Neutropenia; Quality of Life; Retrospective Studies; Risk Factors; Sarcoma

Although the overall survival of advanced soft-tissue sarcoma (STS) patients has increased in recent years, the median progression-free survival is lower than 5 months, meaning that there is an unmet need in this population. Among second-line treatments for advanced STS, eribulin is an anti-microtubule agent that has been approved for liposarcoma. Here, we tested the combination of eribulin with gemcitabine in preclinical models of L-sarcoma. The effect in cell viability was measured by MTS and clonogenic assay. Cell cycle profiling was studied by flow cytometry, while apoptosis was measured by flow cytometry and Western blotting. The activity of eribulin plus gemcitabine was evaluated in in vivo patient-derived xenograft (PDX) models. In L-sarcoma cell lines, eribulin plus gemcitabine showed to be synergistic, increasing the number of hypodiploid events (increased subG1 population) and the accumulation of DNA damage. In in vivo PDX models of L-sarcomas, eribulin combined with gemcitabine was a viable scheme, delaying tumour growth after one cycle of treatment, being more effective in leiomyosarcoma. The combination of eribulin and gemcitabine was synergistic in L-sarcoma cultures and it showed to be active in in vivo studies. This combination deserves further exploration in the clinical context.

Topics: Furans; Gemcitabine; Humans; Ketones; Leiomyosarcoma; Sarcoma; Soft Tissue Neoplasms

Eribulin is a tubulin and microtubule-targeting drug that has clinical benefit in overall survival (OS) for patients with advanced soft tissue sarcoma. Eribulin's efficacy has been confirmed in several clinical trials, although no clinically useful biomarkers have been identified. We therefore sought to clarify the predictive factor of eribulin treatment, while focusing on systemic inflammation and immune response values.. This study included 33 advanced STS patients treated with eribulin between March 2016 and September 2019. We evaluated the associations of clinical factors influencing the efficacy of eribulin treatment and systemic inflammatory and immune response, including the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the lymphocyte-to-monocyte ratio (LMR), the systemic inflammation response index (SIRI), and the prognostic nutrition index (PNI), with progression-free survival (PFS) and OS using the Kaplan-Meier method and log-rank test.. NLR, LMR, PLR, SIRI, and PNI were unassociated with PFS. Compared with patients with SIRI <1.5, those with an SIRI ≥1.5 had a significantly shorter OS [median OS 15 months (95% confidence interval [CI] 8-not reached) vs. 7 months (95% CI 3-14), P = 0.04]. Moreover, the PFS tended to be shorter for patients with SIRI ≥1.5 who received chemotherapy after eribulin treatment than in those with SIRI >1.5 [median PFS 92.5 days (95% CI 27-204) vs. 133 days (95% CI 36-507), P = 0.08].. High SIRI values may predict poorer overall survival and the efficacy of subsequent drugs after eribulin treatment among patients with advanced soft tissue sarcoma.

Topics: Furans; Humans; Inflammation; Ketones; Sarcoma

Tumor lysis syndrome (TLS) is a complication of cancer treatment that requires urgent intervention. It is extremely rare in the treatment of soft tissue sarcoma (STS) of the limbs or trunk, and there are currently no reports of TLS occurrence from eribulin therapy. We report the case of a 78-year-old woman with an undiffer-entiated pleomorphic sarcoma on the right buttock. We initiated chemotherapy with intravenous eribulin mesylate. Deterioration of renal function, mild hyperkalemia, hyperuricemia, hypocalcemia, and hyperphos-phatemia were confirmed on examination, suggesting the presence of TLS. We present an extremely rare case of TLS from eribulin for STS.

Topics: Aged; Antineoplastic Agents; Buttocks; Fatal Outcome; Female; Furans; Humans; Ketones; Positron Emission Tomography Computed Tomography; Sarcoma; Soft Tissue Neoplasms; Tumor Lysis Syndrome

Eribulin is widely used for the treatment of breast cancer and soft-tissue sarcoma (STS). Previous studies identified the pre-treatment absolute lymphocyte count, baseline neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein concentration as potential prognostic markers in patients with breast cancer treated with eribulin. However, prognostic factors for eribulin treatment in patients with STS have not been identified.. This was a retrospective analysis of data collected prospectively from 53 patients who were treated with eribulin for recurrent or metastatic STS between March 2016 and August 2019. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit, progression-free survival, and overall survival.. L-Sarcoma histology [hazard ratio (HR)=28.20, 95% confidence intervaI (CI)=1.67-476.00; p=0.021] and pre-treatment NLR <3.0 (HR=9.96, 95% CI=1.28-77.7; p=0.028) were independent factors predictive of durable clinical benefit. In addition, pre-treatment NLR <3.0 (HR=0.34, 95% CI=0.16-0.74; p=0.0059) and male sex (HR=0.23, 95% CI=0.10-0.52; p<0.001) were independent factors predictive of better progression-free survival.. This retrospective study found that baseline NLR predicts the efficacy of eribulin for STS.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Female; Furans; Humans; Kaplan-Meier Estimate; Ketones; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neutrophils; Prognosis; Retreatment; Retrospective Studies; Sarcoma; Treatment Outcome

Eribulin is a novel microtubule inhibitor that, similar to other types of microtubule inhibitors, induces apoptosis by inhibiting the mitotic division of cells. Besides this direct effect on tumor cells, previous studies have shown that eribulin has the potential to induce tumor vascular remodeling in several different cancers; however, the mechanisms underlying this phenomenon remain unclear. In the present study, we aimed to elucidate whether eribulin is effective against synovial sarcoma, a relatively rare sarcoma that often affects adolescents and young adults, and to histologically investigate the microstructure of tumor vessels after the administration of eribulin. We found that eribulin exhibits potent antitumor activity against synovial sarcoma in a tumor xenograft model and that tumor vessels frequently have intervascular pillars, a hallmark of intussusceptive angiogenesis (IA), after the administration of eribulin. IA is a distinct form of angiogenesis that is involved in normal developmental processes as well as pathological conditions. Our data indicate that IA is potentially involved in eribulin-induced vascular remodeling and thereby suggest previously unacknowledged role of IA in regulating the tumor vasculature after eribulin administration.

Topics: Animals; Bevacizumab; Cell Line, Tumor; Cell Proliferation; Cell Shape; Endothelial Cells; Furans; Intussusception; Ketones; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Pericytes; Sarcoma; Tumor Hypoxia; Vascular Endothelial Growth Factor A; Vascular Remodeling; Xenograft Model Antitumor Assays

The median survival time of patients with advanced soft tissue sarcoma (STS) is typically <12 months. Since 2012, physicians were able to administer second- and/or third-line treatment easily in Japan, following the approval of new drugs, namely, pazopanib, eribulin, and trabectedin. We investigated the real-life experience of adults with advanced STS who received systemic therapy after the approval of the aforementioned new drugs.. We retrospectively evaluated 34 patients (median age: 66 years) with primary STS arising at the extremities/trunk or unresectable local and/or metastatic STS between 2012 and 2019. We evaluated the tumor response and patient survival after initial systemic treatment.. As first-line treatment, doxorubicin and ifosfamide and other drugs were administered to 7 and 27 patients, respectively. Of 31 patients with an evaluable tumor response, partial response was observed in 2 (6.5%) patients, and 16 (52%) patients showed stable disease at 8 weeks. The 1- and 2-year survival rates were 51.4% and 28.4%, respectively. The median overall survival (OS) time was 12.6 months. Tumor response to first-line therapy was related to patient prognosis.. New drugs may be beneficial for patients with advanced STS. When patients cannot receive anthracycline-based chemotherapy because of a high risk of side effects, we believe that the aforementioned drugs may be administered as the first-line treatment.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Female; Furans; Humans; Indazoles; Japan; Kaplan-Meier Estimate; Ketones; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Pyrimidines; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Survival Analysis; Trabectedin; Treatment Outcome

Doxorubicin is a first-line therapy for patients with unresectable advanced soft tissue sarcoma (STS). However, because of cardiotoxicities, it is not used for patients with cardiac problems. Eribulin has exhibited efficacy for advanced STS in second- or later-line treatments. In the present study, we retrospectively analyzed the efficacy and safety of first-line eribulin therapy for patients with advanced STS unable to receive doxorubicin. Six of 28 patients who received eribulin as any line treatment received eribulin as a first-line treatment. The reasons for avoiding doxorubicin were as follows: cardiac problems for four patients and advanced age for two. Median progression-free survival (PFS) of the patients who received eribulin as first-line and, second or later-line therapy were 9.7 months (95% CI: 1.0-not reached) and 3.9 months (95% CI: 2.7-5.9), which were not significantly different. The reasons for discontinuation of eribulin were disease progression and adverse events (2 fatigue and 1 neuropathy) for three patients each. No treatment-related cardiotoxicity was observed. The findings of this study indicated that eribulin exhibits meaningful efficacy for the patients with contraindications for doxorubicin as a first-line treatment without cardiac adverse events. However, appropriate safety management is necessary because older patients are typically among those intolerable of doxorubicin.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Combined Modality Therapy; Contraindications; Doxorubicin; Female; Furans; Humans; Ketones; Male; Middle Aged; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Survival Analysis

Despite the clinical benefits of eribulin on overall survival of advanced soft tissue sarcoma (STS) patients, treatment-related toxicity reduces their QOL. Body composition metrics (BCMs) are associated with poor outcome and drug toxicities in several cancers. This study investigated whether BCMs could predict drug toxicity occurrence in advanced STS patients treated with eribulin.. This study included 23 advanced STS patients treated with eribulin between March 2016 and April 2018. BCMs were evaluated using a CT scan obtained within 1 month before or after treatment initiation. The relationship of BCMs and other clinical factors was evaluated and CART analysis used to develop classification models for risk groups of drug toxicity.. Sixteen patients (69.6%) experienced any grade 3/4 toxicity. Eleven patients (47.8%) developed G4 hematologic toxicity, which was significantly higher in those with low skeletal muscle gauge (SMG) (P = 0.02) and low pretreatment neutrophil count (P = 0.0002). Six patients (26.1%) had grade 3/4 non-hematologic toxicity, and was higher in those with low SMG (P = 0.004), and low serum albumin level (P = 0.02). Five patients with high BMI (P = 0.03) experienced febrile neutropenia (FN) and low pretreatment neutrophil count (P = 0.02). CART analysis classified three risk groups, and area under the receiver operating characteristic curve (AUROCC) was 0.92, 0.88, 0.92 in G4 hematologic AE, G3/4 non-hematologic AE, FN, respectively.. SMG is a significant predictive factor of eribulin drug toxicity in advanced STS patients. Risk classification of drug toxicity through combining predictive factors, could improve the therapeutic strategy used in chemotherapy.

Topics: Adult; Aged; Antineoplastic Agents; Body Composition; Child; Female; Furans; Humans; Ketones; Male; Middle Aged; Quality of Life; Retrospective Studies; Risk Factors; Sarcoma; Soft Tissue Neoplasms; Tomography, X-Ray Computed; Treatment Outcome

An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth in vivo as well as in vitro. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line; Cell Line, Tumor; Cyclin-Dependent Kinases; Cyclins; Drug Synergism; Furans; Heterocyclic Compounds, 3-Ring; Humans; Ketones; Mice; Mice, Inbred BALB C; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Sarcoma; Soft Tissue Neoplasms

The efficacy and safety of eribulin in Japanese patients with advanced soft-tissue sarcomas (STS) have not been evaluated in a large-scale cohort study. Thus, we aimed to investigate the clinical outcome of 82 Japanese patients with STS receiving eribulin across multiple study centers retrospectively. Of 82 STS patients receiving eribulin treatment, 13 were treated for locally unresectable tumor, 46 for metastasis, and 23 for both. The primary endpoint of this study was to evaluate the efficacy of eribulin against STS. The median age was 60 years. Thirty-seven were diagnosed with L-sarcoma (leiomyosarcoma or liposarcoma) and 45 had non-L-sarcoma. The median progression-free survival (PFS) for all patients was 2.7 months, with 3.4 months in those with L-sarcoma and 2.2 months in those with non-L-sarcoma. Patients with L-sarcoma showed a better PFS than those with non-L-sarcoma. Overall, the median survival time was 11.1 months, and 12.3 months and 7.9 months in patients with L-sarcoma and non-L-sarcoma, respectively; however, there was no significant differences between the groups. The prognostic significance of PS = 0 and both existence of local and metastatic STS was evaluated by multivariate analysis. We also evaluated the overall survival (OS) in patients with undifferentiated pleomorphic sarcoma (UPS) and other non-L-sarcomas. Patients with UPS had better OS than those with the other non-L-sarcomas. In conclusion, there was a significant difference in PFS between patients with L-sarcoma and non-L-sarcoma following treatment with eribulin. The anti-tumor potential of eribulin was evident in patients with UPS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Furans; Humans; Ketones; Male; Middle Aged; Retrospective Studies; Sarcoma; Young Adult

Pneumothorax has been reported as a pazopanib-associated adverse event in patients with lung metastases of soft tissue sarcoma (STS). However, pneumothorax triggered by eribulin treatment has never been reported. We herein report two cases of spontaneous pneumothorax in patients with STS treated with eribulin. Both patients experienced pneumothorax accompanied by sudden dyspnea on day 9 or 10 of eribulin treatment. These two cases suggest that spontaneous pneumothorax may occur as an adverse event of eribulin treatment in such patients. We should therefore be alert for the potential development of pneumothorax during eribulin treatment of patients with STS and lung metastases.

Topics: Adult; Aged; Biopsy; Female; Furans; Humans; Ketones; Lung Neoplasms; Male; Neoplasm Metastasis; Pneumothorax; Sarcoma; Tomography, X-Ray Computed

Although eribulin is used to treat soft tissue sarcomas (STSs), treatment data for rare subtypes are limited. We conducted a post-marketing surveillance study to assess safety and efficacy of eribulin in STS patients stratified by subtype.. Japanese patients (n = 256) with advanced or metastatic STS receiving eribulin treatment were monitored for treatment status, adverse events, diagnostic imaging, and clinical outcomes at 3 months and 1 year. Interim analysis was performed. Patients will be monitored up to 2 years.. Interim analysis included 3-month (n = 255), imaging (n = 226), and 1-year (n = 105) data. STS subtype distribution was normal. Median number of eribulin cycles was 3.0 (range: 1-17 cycles). Among patients with imaging data, best overall tumor response (12 weeks) was partial response, 7.5% (n = 17); stable disease, 34.5% (n = 78); and stable disease ≥11 weeks, 10.2% (n = 23). Overall response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) for all patients were 7.5%, 42.0% and 17.7%, respectively. ORR, DCR, and CBR were 10.3%, 32.0% and 16.5%, respectively, for patients with STS subtypes other than liposarcoma and leiomyosarcoma and included responses from patients with rare STS subtypes. Adverse drug reactions (ADRs) occurred in 211 (82.7%) patients (42 [16.5%] patients had serious ADRs), and none led to death. ADRs leading to drug withdrawal and dose reduction occurred in 27 (10.6%) and 55 (21.6%) patients, respectively.. Eribulin was generally well tolerated and showed antitumor activity against STSs, including rare subtypes that currently have few treatment options.. NCT03058406 (ClinicalTrials.gov).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Furans; Humans; Ketones; Leiomyosarcoma; Liposarcoma; Male; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Young Adult

Epithelioid sarcoma (ES) is a rare and aggressive type of soft tissue sarcoma with resistance to systemic chemotherapy. Therefore, new treatment options are required for patients with advanced ES. Eribulin is a novel potential treatment option for patients with inoperative sarcoma. We herein report a case of a 27-year-old Japanese man with cystic lung metastases from an ES in the left forearm, resulting in long-term stable disease. A solid, metastatic sarcomatous nodule appeared in the right lung, as shown by computed tomography, within the first 2 months after surgery. After the lung metastasis was detected, he underwent a total of 37 cycles of chemotherapy in six regimens. However, multiple cystic lung metastases had progressed in segments S6 and S9/10; hence, eribulin treatment was initiated. After two courses of eribulin, the excess fluid density material in the cystic metastases was completely absorbed, and an additional four courses of treatment resulted in shrinkage of the cystic metastases. These effects lasted for 13 months without severe adverse effects. Cystic lung metastases are an extremely rare consequence of soft tissue sarcoma, and eribulin is one of the most promising options for the treatment of advanced ES.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arm; Chemotherapy, Adjuvant; Furans; Humans; Ketones; Lung Neoplasms; Male; Neoadjuvant Therapy; Sarcoma

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive mesenchymal neoplasm with no specific line of differentiation. Eribulin, a novel synthetic microtubule inhibitor, has shown anticancer activity in several tumors, including soft tissue sarcomas (STS). We investigated the molecular biology of UPS, and the mechanisms of action of this innovative microtubule-depolymerizing drug. A primary culture from a patient with UPS was established and characterized in terms of gene expression. The activity of eribulin was also compared with that of other drugs currently used for STS treatment, including trabectedin. Finally, Western blot analysis was performed to better elucidate the activity of eribulin. Our results showed an upregulation of epithelial mesenchymal transition-related genes, and a downregulation of epithelial markers. Furthermore, genes involved in chemoresistance were upregulated. Pharmacological analysis confirmed limited sensitivity to chemotherapy. Interestingly, eribulin exhibited a similar activity to that of standard treatments. Molecular analysis revealed the expression of cell cycle arrest-related and pro-apoptotic-related proteins. These findings are suggestive of aggressive behavior in UPS. Furthermore, the identification of chemoresistance-related genes could facilitate the development of innovative drugs to improve patient outcome. Overall, the results from the present study furnish a rationale for elucidating the role of eribulin for the treatment of UPS.

Topics: Aged; Antineoplastic Agents; Apoptosis Regulatory Proteins; Biomarkers, Tumor; Cell Cycle Checkpoints; Dioxoles; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Furans; Gene Expression Regulation, Neoplastic; Humans; Ketones; Male; Patients; Primary Cell Culture; Sarcoma; Tetrahydroisoquinolines; Trabectedin

Eribulin mesilate (eribulin), a first-in-class halichondrin B-based microtubule dynamics inhibitor, has been shown to promote vascular remodeling and reversal of epithelial-mesenchymal transition (EMT) apart from its antimitotic activity in breast cancer models.. Anti-proliferative activity of eribulin was examined in vitro and in vivo in several human soft tissue sarcoma (STS) cell lines. To assess tumor blood perfusion and phenotypic changes, eribulin was investigated in a leiomyosarcoma xenograft and in vitro in liposarcoma and leiomyosarcoma cell lines.. Eribulin showed anti-proliferative activity in vitro against all six cell lines investigated, with 50% inhibitory concentration values of around 1 nmol/l, as well as significant antitumor activity against four xenografts in vivo. In addition, eribulin significantly enhanced tumor blood perfusion in xenografts and induced morphological changes and up-regulation of differentiation marker genes.. In pre-clinical models, eribulin showed anti-proliferative activity against a variety of histopathological subtypes of STS. Eribulin might also cause tumor vasculature remodeling to enhance tumor blood perfusion and induce tumor cell differentiation.

Topics: Animals; Antimitotic Agents; Calcium-Binding Proteins; Calponins; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Furans; Gene Expression Regulation, Neoplastic; Humans; Ketones; Mice, Inbred BALB C; Microfilament Proteins; Sarcoma; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents, Alkylating; Dioxoles; Disease Progression; Furans; Humans; Ketones; Sarcoma; Soft Tissue Neoplasms; Tetrahydroisoquinolines; Time Factors; Trabectedin; Treatment Outcome; Tubulin Modulators

Topics: Antineoplastic Agents; Chromosomal Proteins, Non-Histone; Dioxoles; Disease-Free Survival; DNA-Binding Proteins; Furans; Humans; Indazoles; Ketones; Molecular Targeted Therapy; Mutation; Pyrimidines; Sarcoma; SMARCB1 Protein; Sulfonamides; Tetrahydroisoquinolines; Trabectedin; Transcription Factors

Uterine sarcomas are rare and comprise only 3% of all uterine cancers. Within the group of adult soft tissue sarcomas, they account for ∼7% of new cases. They consist of several distinct histological subtypes like leiomyosarcoma, endometrial stromal tumors, undifferentiated sarcomas, pure heterologous sarcomas, and mixed epithelial and mesenchymal tumors. Standard treatment in localized disease is abdominal hysterectomy. Bilateral salpingo-oophorectomy and lymphadenectomy have no proven value in leiomyosarcomas and high-grade undifferentiated sarcomas. However, in endometrial stromal tumors, given the hormonal reponsiveness of most tumors, salpingo-oophorectomy is generally recommended. Carcinosarcomas are treated according to current recommendations for epithelial uterine cancers. In leiomyosarcomas, postoperative radiation does not improve both relapse-free and overall survival. adjuvant chemotherapy seems to improve survival in the context of uncontrolled phase II trials. However, it is currently not considered standard of care in the absence of data from randomized trials. In contrast, adjuvant chemotherapy does improve overall survival in carcinosarcomas and is therefore considered standard of care. Systemic therapy for advanced uterine leiomyosarcomas, undifferentiated uterine sarcomas, and heterologous sarcomas is generally following the recommendations for adult soft tissue sarcomas. Endometrial stromal sarcomas are usually hormonal receptor positive, which allows endocrine therapy in most cases.

Topics: Chemotherapy, Adjuvant; Clinical Trials as Topic; Endometrial Stromal Tumors; Female; Furans; Humans; Ketones; Leiomyosarcoma; Neoplasm Staging; Sarcoma; Uterine Neoplasms

Topics: Antineoplastic Agents; Female; Furans; Humans; Ketones; Male; Mesylates; Sarcoma; Soft Tissue Neoplasms