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Schmidt M, Hesse T, Hoffmann O, Heinrich BJ, Park-Simon TW, Grischke EM, Weide R, Müller Huesmann H, Lüdtke-Heckenkamp K, Fischer D, Zemlin C, Kögel M, Jia Y, Schmitz H, Engelbrecht C, Jackisch C. Eribulin-Induced Peripheral Neuropathy in Locally Advanced or Metastatic Breast Cancer: Final Analysis of the Prospective Cohort IRENE Study. Cancers (Basel) 2025; 17:457. [PMID: 39941823 PMCID: PMC11815746 DOI: 10.3390/cancers17030457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 02/16/2025] Open
Abstract
Eribulin is a preferred treatment for patients with advanced breast cancer (BC) following anthracyclines and taxanes. The final analysis of the IRENE study assessed the incidence and resolution of eribulin-induced peripheral neuropathy (EIPN), along with safety and quality of life (QoL), in patients with advanced/metastatic BC. IRENE was an observational, single-arm, prospective, multicenter cohort study. Patients aged ≥18 years with locally advanced/metastatic BC that progressed after 1-3 prior chemotherapeutic regimens received eribulin and were monitored for new-onset or worsening EIPN. Secondary endpoints included time to disease progression, safety, and health-related QoL. In total, 108 (32.2%) out of 335 patients experienced EIPN; 18 (5.4%) experienced grade ≥3 EIPN. Median time to EIPN resolution (EIPN ended or returned to baseline) was 78.7 weeks (95% CI 77.1-not estimable). Median time to disease progression was 4.5 months (95% CI 3.9-5.5). Treatment-emergent adverse events (TEAEs) occurred in 322 (96.1%) patients; serious TEAEs occurred in 185 (55.2%) patients. Incidence and resolution rates of EIPN were comparable with existing evidence from previous trials. TEAEs were consistent with the established eribulin safety profile, with no new safety signals. Eribulin treatment did not appear to affect QoL, as measured by EQ-5D-3L and EQ-VAS, or patient-reported neuropathy symptoms, as measured by the PNQ.
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Affiliation(s)
- Marcus Schmidt
- Department of Obstetrics and Gynecology, University Medical Center Mainz, 55131 Mainz, Germany
- Department of Obstetrics and Gynecology, Sana Klinikum Offenbach GmbH, 63069 Offenbach, Germany
| | - Tobias Hesse
- Department of Gynecology, Agaplesion Diakonieklinikum Rotenburg gGmbH, 27356 Rotenburg (Wuemme), Germany;
| | - Oliver Hoffmann
- Department of Gynecology and Obstetrics, Universitätsklinikum, 45147 Essen, Germany;
| | | | | | - Eva-Maria Grischke
- Department für Frauengesundheit, Universitäts-Frauenklinik Tübingen, 72076 Tübingen, Germany;
| | - Rudolf Weide
- Oncological Outpatient Department, Praxis für Hämatologie und Onkologie Koblenz, 56073 Koblenz, Germany;
| | - Harald Müller Huesmann
- Department of Hematology/Oncology, Brüderkrankenhaus St. Josef Paderborn, 33098 Paderborn, Germany;
| | - Kerstin Lüdtke-Heckenkamp
- Department of Hematology/Oncology, Niels Stensen Clinics, Franziskus Hospital, 49124 Georgsmarienhütte, Germany;
| | - Dorothea Fischer
- Department of Gynaecology and Obstetrics, Hospital Ernst von Bergmann, 14467 Potsdam, Germany;
| | - Cosima Zemlin
- Department for Gynecology, Obstetrics and Reproductive Medicine, Saarland University Medical Center, 66421 Homburg, Germany;
| | | | - Yan Jia
- Eisai Inc., Nutley, NJ 07110, USA;
| | - Helga Schmitz
- Medical Department, Eisai GmbH, 60549 Frankfurt, Germany;
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Erciyestepe M, Ekinci ÖB, Seçmeler Ş, Selvi O, Öztürk AE, Aydin O, Büyükkuşcu A, Atasever T, Çelik E, Ertürk K, Atci MM. Evaluation of ixabepilone efficacy and tolerability in metastatic breast cancer. Medicine (Baltimore) 2024; 103:e40649. [PMID: 39809199 PMCID: PMC11596583 DOI: 10.1097/md.0000000000040649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 11/05/2024] [Indexed: 01/16/2025] Open
Abstract
Although microtubule inhibitors are generally used in advanced stages, they provide the opportunity to prolong survival as an alternative when medical oncologists have difficulty finding options in their patients, who typically have a poor prognosis and most of whom are unresponsive to treatment. For this reason, we wanted to investigate the effect of ixabepilone treatment on survival in earlier metastatic lines. Our study also examined the frequency of side effects and survival differences in patients whose dose was reduced or whose treatment was discontinued. Our study includes patients diagnosed with metastatic breast cancer who received ixabepilone treatment between January 2011 and January 2021. Median overall survival (OS) in the group receiving ixabepilone on the 5th line and before was 22.0 months (95% CI: 21.0-22.9), in the group receiving ixabepilone after the 5th line was calculated as 10.0 months (95% CI: 8.9-11.0) (P < .001). Median OS (months) in the group receiving ixabepilone on the 4th line and before was 26.0 (95% CI: 23.6-28.3), in the group receiving ixabepilone after the 4th line was determined as 12.0 (95% CI: 10.5-13.4) (P < .001). Dose reduction or discontinuation of ixabepilone treatment in patients due to side effects did not affect OS and progression-free survival with ixabepilone statistically significantly. Ixabepilone treatment has side effects, similar to all other treatments used in metastatic breast cancer, however, these side effects are manageable. Additionally, since ixabepilone treatment is preferred in patients who have previously received many different chemotherapeutics and experienced cumulative toxicity, the side effects of ixabepilone may seem to be greater than they are. In our study, we showed that ixabepilone treatment has a statistically significant positive effect on survival if preferred in earlier metastatic lines. As similar studies increase in centers where ixabepilone treatment is generally given in advanced metastatic lines, treatment approaches may change in the coming years.
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Affiliation(s)
- Mert Erciyestepe
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Ömer Burak Ekinci
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Şaban Seçmeler
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Oğuzhan Selvi
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Ahmet Emin Öztürk
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Okan Aydin
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Asli Büyükkuşcu
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Tugay Atasever
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Emir Çelik
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Kayhan Ertürk
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
| | - Muhammed Mustafa Atci
- Department of Medical Oncology, Sağlik Bilimleri University, Prof. Dr. Cemil Taşcioğlu City Hospital, İstanbul, Turkey
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Oey O, Wijaya W, Redfern A. Eribulin in breast cancer: Current insights and therapeutic perspectives. World J Exp Med 2024; 14:92558. [PMID: 38948420 PMCID: PMC11212747 DOI: 10.5493/wjem.v14.i2.92558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/21/2024] [Accepted: 03/20/2024] [Indexed: 06/19/2024] Open
Abstract
Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition to its mitotic property, eribulin has non-mitotic properties including but not limited to, its ability to induce phenotypic reversal of epithelial to mesenchymal transition, vascular remodelling, reduction in immunosuppressive tumour microenvironment. Since approval, there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types, including hormone receptor positive, HER2 positive and triple negative breast cancer, many demonstrating promising activity. This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent, its toxicity profile, and potential future directions.
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Affiliation(s)
- Oliver Oey
- Faculty of Medicine, University of Western Australia, Nedlands 6009, Australia
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands 6009, WA, Australia
| | - Wynne Wijaya
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
- Department of Internal Medicine, Universitas Gadjah Mada, Sleman 55281, Indonesia
| | - Andrew Redfern
- Department of Medical Oncology, Fiona Stanley Hospital, Murdoch 6150, WA, Australia
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Lück HJ, Schmidt M, Hesse T, Hoffmann O, Heinrich BJ, Park-Simon TW, Grischke EM, Weide R, Müller-Huesmann H, Lüdtke-Heckenkamp K, Fischer D, Zemlin C, Kögel M, Wu J, Schmitz H, Engelbrecht C, Jackisch C. Incidence and Resolution of Eribulin-Induced Peripheral Neuropathy (IRENE) in Locally Advanced or Metastatic Breast Cancer: Prospective Cohort Study. Oncologist 2023; 28:e1152-e1159. [PMID: 37555463 PMCID: PMC10712709 DOI: 10.1093/oncolo/oyad191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 05/04/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Eribulin, a halichondrin-class microtubule dynamics inhibitor, is a preferred treatment option for patients with advanced breast cancer who have been pretreated with an anthracycline and a taxane. Peripheral neuropathy (PN) is a common side effect of chemotherapies for breast cancer and other tumors. The Incidence and Resolution of Eribulin-Induced Peripheral Neuropathy (IRENE) noninterventional postauthorization safety study assessed the incidence and severity of PN in patients with breast cancer treated with eribulin. PATIENTS AND METHODS IRENE is an ongoing observational, single-arm, prospective, multicenter, cohort study. Adult patients (≥18 years of age) with locally advanced or metastatic breast cancer and disease progression after 1-2 prior chemotherapeutic regimen(s) for advanced disease were treated with eribulin. Patients with eribulin-induced PN (new-onset PN or worsening of preexisting PN) were monitored until death or resolution of PN. Primary endpoints included the incidence, severity, and time to resolution of eribulin-induced PN. Secondary endpoints included time to disease progression and safety. RESULTS In this interim analysis (data cutoff date: July 1, 2019), 67 (32.4%) patients experienced any grade eribulin-induced PN, and 12 (5.8%) patients experienced grade ≥3 eribulin-induced PN. Median time to resolution of eribulin-induced PN was not reached. Median time to disease progression was 4.6 months (95% CI, 4.0-6.5). Treatment-emergent adverse events (TEAEs) occurred in 195 (93.8%) patients and serious TEAEs occurred in 107 (51.4%) patients. CONCLUSION The rates of any grade and grade ≥3 eribulin-induced PN observed in this real-world study were consistent with those observed in phase III randomized clinical trials. No new safety findings were observed.
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Affiliation(s)
- Hans-Joachim Lück
- Gynecologic Oncology, Gynäkologisch-Onkologische Praxis am Pelikanplatz, Hannover, Germany
| | - Marcus Schmidt
- Department of Obstetrics and Gynecology, University Medical Center Mainz, Mainz, Germany
| | - Tobias Hesse
- Department of Gynecology, Agaplesion Diakonieklinikum Rotenburg gGmbH, Rotenburg (Wuemme), Germany
| | - Oliver Hoffmann
- Department of Gynecology and Obstetrics, Universitätsklinikum Essen, Essen, Germany
| | | | | | | | - Rudolf Weide
- Oncological Outpatient Department, Praxis für Hämatologie und Onkologie Koblenz, Koblenz, Germany
| | - Harald Müller-Huesmann
- Department of Hematology/Oncology, Brüderkrankenhaus St. Josef Paderborn, Paderborn, Germany
| | - Kerstin Lüdtke-Heckenkamp
- Department of Hematology/Oncology, Niels Stensen Clinics, Franziskus Hospital, Georgsmarienhütte, Germany
| | - Dorothea Fischer
- Department of Gynaecology and Obstetrics, Hospital Ernst von Bergmann, Potsdam, Germany
| | - Cosima Zemlin
- Department for Gynecology, Obstetrics and Reproductive Medicine, Saarland University Medical Center, Homburg, Germany
| | | | - Jane Wu
- Biostatistics, Eisai Inc., Nutley, NJ, USA
| | | | | | - Christian Jackisch
- Department of Obstetrics and Gynecology, Sana Klinikum Offenbach GmbH, Offenbach, Germany
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Gu X, Zhu Q, Tian G, Song W, Wang T, Wang A, Chen X, Qin S. KIF11 manipulates SREBP2-dependent mevalonate cross talk to promote tumor progression in pancreatic ductal adenocarcinoma. Cancer Med 2022; 11:3282-3295. [PMID: 35619540 PMCID: PMC9468433 DOI: 10.1002/cam4.4683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 11/09/2022] Open
Abstract
Cholesterol metabolism is highly correlated with risks of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the underlying mechanisms of activation of cholesterol biogenesis remain inconclusive. KIF11 is a key component of the bipolar spindle and expresses highly in various malignancies. However, its functional role in PDAC tumorigenesis is still unclear. This study aims to elucidate the oncogenic functions of KIF11 in stimulating cholesterol metabolism, thereby driving PDAC progression. We utilized bioinformatics analysis to identify that KIF11 expressed highly in tumor samples versus paired normal tissues and high KIF11 correlated with high clinical stages of patients. Patients with high KIF11 had worse survival outcomes relative to those with low KIF11. Gene set enrichment analysis (GSEA) revealed that KIF11 correlated intensively with the mevalonate (MVA) metabolic pathway. Positive associations were observed between KIF11 and MVA-signature (HMGCR, FDFT1, SQLE, and MSMO1). KIF11 could elevate the free cholesterol content of PDAC cells and targeting MVA inhibited the in vitro growth of KIF11-overexpressing cells. Mechanistically, we found KIF11 could interact with SREBP2, the master regulator of MVA. High KIF11 could increase SREBP2 proteins, but not alter their mRNA levels. KIF11 could attenuate the ubiquitination-mediated degradation of SREBP2, thereby enhancing its stability and accumulation. Accordingly, KIF11 stimulated the expressions of MVA-signature and free cholesterol contents depending on SREBP2. In addition, KIF11 depended on SREBP2 to promote cell growth, migration, stemness, and colony formation abilities. The subcutaneous xenograft models indicated that targeting MVA biogenesis (atorvastatin) is effective to restrict the in vivo growth of KIF11high PDAC. Taken together, our study identified that KIF11 could activate the MVA cross talk to drive PDAC progression and inhibiting the KIF11/MVA axis provided a therapeutic vulnerability in the treatment of PDAC.
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Affiliation(s)
- Xiang Gu
- Department of RadiotherapyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Department of OncologyJiangdu People's Hospital Affiliated to Medical College of Yangzhou UniversityYangzhouChina
| | - Qunshan Zhu
- Department of General SurgeryJiangdu People's Hospital Affiliated to Medical College of Yangzhou UniversityYangzhouChina
| | - Guangyu Tian
- Department of OncologyJiangdu People's Hospital Affiliated to Medical College of Yangzhou UniversityYangzhouChina
| | - Wenbo Song
- Department of OncologyJiangdu People's Hospital Affiliated to Medical College of Yangzhou UniversityYangzhouChina
| | - Tao Wang
- Department of OncologyJiangdu People's Hospital Affiliated to Medical College of Yangzhou UniversityYangzhouChina
| | - Ali Wang
- Department of OncologyJiangdu People's Hospital Affiliated to Medical College of Yangzhou UniversityYangzhouChina
| | - Xiaojun Chen
- Department of OncologyJiangdu People's Hospital Affiliated to Medical College of Yangzhou UniversityYangzhouChina
| | - Songbing Qin
- Department of RadiotherapyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
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Singh R, Adhya P, Sharma SS. Redox-sensitive TRP channels: a promising pharmacological target in chemotherapy-induced peripheral neuropathy. Expert Opin Ther Targets 2021; 25:529-545. [PMID: 34289785 DOI: 10.1080/14728222.2021.1956464] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Chemotherapy-induced peripheral neuropathy (CIPN) and its related pain is a major side effect of certain chemotherapeutic agents used in cancer treatment. Available analgesics are mostly symptomatic, and on prolonged treatment, patients become refractive to them. Hence, the development of improved therapeutics that act on novel therapeutic targets is necessary. Potential targets include the redox-sensitive TRP channels [e.g. TRPA1, TRPC5, TRPC6, TRPM2, TRPM8, TRPV1, TRPV2, and TRPV4] which are activated under oxidative stress associated with CIPN. AREAS COVERED We have examined numerous neuropathy-inducing cancer chemotherapeutics and their pathophysiological mechanisms. Oxidative stress and its downstream targets, the redox-sensitive TRP channels, together with their potential pharmacological modulators, are discussed. Finally, we reflect upon the barriers to getting new therapeutic approaches into the clinic. The literature search was conducted in PubMed upto and including April 2021. EXPERT OPINION Redox-sensitive TRP channels are a promising target in CIPN. Pharmacological modulators of these channels have reduced pain in preclinical models and in clinical studies. Clinical scrutiny suggests that TRPA1, TRPM8, and TRPV1 are the most promising targets because of their pain-relieving potential. In addition to the analgesic effect, TRPV1 agonist-Capsaicin possesses a disease-modifying effect in CIPN through its restorative property in damaged sensory nerves.
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Affiliation(s)
- Ramandeep Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India
| | - Pratik Adhya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India
| | - Shyam Sunder Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India
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Ibrahim NK. Ixabepilone: Overview of Effectiveness, Safety, and Tolerability in Metastatic Breast Cancer. Front Oncol 2021; 11:617874. [PMID: 34295806 PMCID: PMC8290913 DOI: 10.3389/fonc.2021.617874] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 06/16/2021] [Indexed: 11/13/2022] Open
Abstract
Treatment algorithms for metastatic breast cancer describe sequential treatment with chemotherapy and, if appropriate, targeted therapy for as long as the patient receives benefit. The epothilone ixabepilone is a microtubule stabilizer approved as a monotherapy and in combination with capecitabine for the treatment of metastatic breast cancer in patients with demonstrated resistance to anthracyclines and taxanes. While chemotherapy and endocrine therapy form the backbone of treatment for metastatic breast cancer, the epothilone drug class has distinguished itself for efficacy and safety among patients with disease progression during treatment with chemotherapy. In phase III trials, ixabepilone has extended progression-free survival and increased overall response rates, with a manageable toxicity profile. Recent analyses of subpopulations within large pooled datasets have characterized the clinical benefit for progression-free survival and overall survival for ixabepilone in special populations, such as patients with triple-negative breast cancer or those who relapsed within 12 months of prior treatment. Additional investigation settings for ixabepilone therapy discussed here include adjuvant therapy, weekly dosing schedules, and ixabepilone in new combinations of treatment. As with other microtubule stabilizers, ixabepilone treatment can lead to peripheral neuropathy, but evidence-based management strategies may reverse these symptoms. Dose reductions did not appear to have an impact on the efficacy of ixabepilone plus capecitabine. Incorporation of ixabepilone into individualized treatment plans can extend progression-free survival in a patient population that continues to represent an unmet need.
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Affiliation(s)
- Nuhad K. Ibrahim
- Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Zhao Q, Hughes R, Neupane B, Mickle K, Su Y, Chabot I, Betts M, Kadambi A. Network meta-analysis of eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or metastatic breast cancer. BMC Cancer 2021; 21:758. [PMID: 34193107 PMCID: PMC8244131 DOI: 10.1186/s12885-021-08446-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 06/04/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Eribulin mesylate (ERI; Halaven®) is a microtubule inhibitor approved in the United States for metastatic breast cancer patients with at least two prior chemotherapy regimens for metastatic breast cancer, and in the European Union in locally advanced breast cancer or metastatic breast cancer patients who progressed after at least one chemotherapy for advanced disease. This network meta-analysis compared the efficacy and safety of ERI versus other chemotherapies in this setting. METHODS Systematic searches conducted in MEDLINE, Embase, and the Cochrane Central Register of Clinical Trials identified randomized controlled trials of locally advanced breast cancer/metastatic breast cancer chemotherapies in second- or later-line settings. Efficacy assessment included pre-specified subgroup analysis of breast cancer subtypes. Included studies were assessed for quality using the Centre for Reviews and Dissemination tool. Bayesian network meta-analysis estimated primary outcomes of overall survival and progression-free survival using fixed-effect models. Comparators included: capecitabine (CAP), gemcitabine (GEM), ixabepilone (IXA), utidelone (UTI), treatment by physician's choice (TPC), and vinorelbine (VIN). RESULTS The network meta-analysis included seven trials. Results showed that second- or later-line patients treated with ERI had statistically longer overall survival versus TPC (hazard ratio [HR]: 0.81; credible interval [CrI]: 0.66-0.99) or GEM+VIN (0.62; 0.42-0.90) and statistically longer progression-free survival versus TPC (0.76; 0.64-0.90), but statistically shorter progression-free survival versus CAP+IXA (1.40; 1.17-1.67) and CAP+UTI (1.61; 1.23-2.12). In triple negative breast cancer, ERI had statistically longer overall survival versus CAP (0.70; 0.54-0.90); no statistical differences in progression-free survival were observed in triple negative breast cancer. CONCLUSIONS This network meta-analysis suggests that ERI may provide an overall survival benefit in the overall locally advanced breast cancer/metastatic breast cancer populations and triple negative breast cancer subgroup compared to standard treatments. These findings support the use of ERI in second- or later-line treatment of patients with locally advanced breast cancer/metastatic breast cancer.
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Affiliation(s)
- Qi Zhao
- Global Value & Access, Eisai Inc, Woodcliff Lake, NJ, USA
| | - Rachel Hughes
- Evidence Synthesis, Modeling & Communication, Evidera, San Francisco, CA, USA
| | - Binod Neupane
- Evidence Synthesis, Modeling & Communication, Evidera, Montreal, QC, Canada
| | - Kristin Mickle
- Evidence Synthesis, Modeling & Communication, Evidera, Waltham, MA, USA
| | - Yun Su
- Global Value & Access, Eisai Inc., Woodcliff Lake, NJ, USA
| | - Isabelle Chabot
- Faculté de pharmacie, University of Montreal, Montreal, QC, Canada
| | - Marissa Betts
- Evidence Synthesis, Modeling & Communication, Evidera, Waltham, MA, USA
| | - Ananth Kadambi
- Evidence Synthesis, Modeling & Communication, Evidera, San Francisco, CA, USA.
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Tanni KA, Truong CB, Johnson BS, Qian J. Comparative effectiveness and safety of eribulin in advanced or metastatic breast cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol 2021; 163:103375. [PMID: 34087344 DOI: 10.1016/j.critrevonc.2021.103375] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/08/2021] [Accepted: 05/29/2021] [Indexed: 12/24/2022] Open
Abstract
Eribulin is one of the few recommended chemotherapies for locally advanced breast cancer (LABC) or metastatic breast cancer (MBC). We systematically searched MEDLINE Ovid, Cochrane Library, IPA, CINAHL, Web of Science and ProQuest Dissertations for studies evaluating eribulin versus non-eribulin regimens in LABC/MBC till January 15, 2021. Primary effectiveness and safety outcomes were overall survival (OS) and adverse events (AE), respectively. Hazard ratios (HR) and relative risks (RR) with 95 % confidence intervals (CIs) were calculated using fixed or random-effects meta-analyses. Of 1183 publications identified, 13 studies were included in this review. Eribulin based therapy showed significantly increased OS [HR (95 % CI) = 0.77 (0.67-0.88)] compared to non-eribulin in both main and sensitivity analyses, as well as subgroup analyses according to receptor expression and line of therapy. Incidence of all-grade neutropenia was the only significant AE in eribulin than non-eribulin groups. Eribulin has a manageable toxicity profile and provides significant survival benefit in LABC/MBC patients.
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Affiliation(s)
- Kaniz Afroz Tanni
- Department of Health Outcomes Research and Policy, Auburn University Harrison School of Pharmacy, Auburn, AL 36849, USA.
| | - Cong Bang Truong
- Department of Health Outcomes Research and Policy, Auburn University Harrison School of Pharmacy, Auburn, AL 36849, USA.
| | - Brandon S Johnson
- Spencer Cancer Center, East Alabama Medical Center, Opelika, AL 36801, USA.
| | - Jingjing Qian
- Department of Health Outcomes Research and Policy, Auburn University Harrison School of Pharmacy, Auburn, AL 36849, USA.
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Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial. Breast Cancer Res Treat 2021; 188:117-131. [PMID: 33763789 PMCID: PMC8233289 DOI: 10.1007/s10549-021-06184-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 03/05/2021] [Indexed: 12/16/2022]
Abstract
Purpose To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients. Methods Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety. Results The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%–81%) and 45% (27%–65%) in groups A1 and A2, respectively, and 19% (8%–35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively. Conclusions In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen. Trial registration:The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (http://www.umin.ac.jp/ctr/index-j.htm) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22. Supplementary Information The online version contains supplementary material available at 10.1007/s10549-021-06184-w.
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Yuan P, Xu B. Clinical Utility of Eribulin Mesylate in the Treatment of Breast Cancer: A Chinese Perspective. BREAST CANCER-TARGETS AND THERAPY 2021; 13:135-150. [PMID: 33658845 PMCID: PMC7917473 DOI: 10.2147/bctt.s231298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/12/2021] [Indexed: 12/23/2022]
Abstract
Eribulin mesylate, a synthetic derivative of the anti-mitotic agent halichondrin B, has a unique tubulin-based mechanism of action that is distinct from other anti-microtubule agents including taxanes and vinca alkaloids. Consistent with this unique activity, eribulin has shown clinical efficacy in patients with metastatic breast cancer (MBC) that progressed following prior taxane and anthracycline therapy. The evidence presented in this review indicates that eribulin represents a treatment option for patients with HER2-negative metastatic breast cancer. Improved survival outcomes and better tolerability compared with vinorelbine supported the first approval of eribulin in China in 2019; eribulin was approved for women with locally advanced/metastatic HER2-negative breast cancer after treatment failure with at least two chemotherapy regimens, including an anthracycline and a taxane. Eribulin has also shown promising efficacy in patients with HER2-positive advanced breast cancer when used in combination with trastuzumab or pertuzumab, and subgroup analyses from the Phase III clinical trials support the continued evaluation of eribulin in patients with triple-negative disease. The unique non-mitotic effects of eribulin, including vascular remodeling, coupled with its clinical efficacy and safety profile, may permit the broader use of this agent in patients with MBC.
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Affiliation(s)
- Peng Yuan
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Binghe Xu
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
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12
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Chemotherapy Options beyond the First Line in HER-Negative Metastatic Breast Cancer. JOURNAL OF ONCOLOGY 2020; 2020:9645294. [PMID: 33312203 PMCID: PMC7719522 DOI: 10.1155/2020/9645294] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 10/05/2020] [Accepted: 11/11/2020] [Indexed: 12/24/2022]
Abstract
Despite the recent advances in the biological understanding of breast cancer (BC), chemotherapy still represents a key component in the armamentarium for this disease. Different agents are available as mono-chemotherapy options in patients with locally advanced or metastatic BC (MBC) who progress after a first- and second-line treatment with anthracyclines and taxanes. However, no clear indication exists on what the best option is in some populations, such as heavily pretreated, elderly patients, triple-negative BC (TNBC), and those who do not respond to the first-line therapy. In this article, we summarize available literature evidence on different chemotherapy agents used beyond the first-line, in locally advanced or MBC patients, including rechallenge with anthracyclines and taxanes, antimetabolite and antimicrotubule agents, such as vinorelbine, capecitabine, eribulin, ixabepilone, and the newest developed agents, such as vinflunine, irinotecan, and etirinotecan.
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13
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Neurotoxicity of antineoplastic drugs: Mechanisms, susceptibility, and neuroprotective strategies. Adv Med Sci 2020; 65:265-285. [PMID: 32361484 DOI: 10.1016/j.advms.2020.04.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 12/22/2019] [Accepted: 04/13/2020] [Indexed: 02/06/2023]
Abstract
This review summarizes the adverse effects on the central and/or peripheral nervous systems that may occur in response to antineoplastic drugs. In particular, we describe the neurotoxic side effects of the most commonly used drugs, such as platinum compounds, doxorubicin, ifosfamide, 5-fluorouracil, vinca alkaloids, taxanes, methotrexate, bortezomib and thalidomide. Neurotoxicity may result from direct action of compounds on the nervous system or from metabolic alterations produced indirectly by these drugs, and either the central nervous system or the peripheral nervous system, or both, may be affected. The incidence and severity of neurotoxicity are principally related to the dose, to the duration of treatment, and to the dose intensity, though other factors, such as age, concurrent pathologies, and genetic predisposition may enhance the occurrence of side effects. To avoid or reduce the onset and severity of these neurotoxic effects, the use of neuroprotective compounds and/or strategies may be helpful, thereby enhancing the therapeutic effectiveness of antineoplastic drug.
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14
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Wu Y, Wang Q, Zhang J, Cao J, Wang B, Hu X. Incidence of peripheral neuropathy associated with eribulin mesylate versus vinorelbine in patients with metastatic breast cancer: sub-group analysis of a randomized phase III study. Support Care Cancer 2019; 28:3819-3829. [PMID: 31832821 DOI: 10.1007/s00520-019-05112-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 10/09/2019] [Indexed: 11/28/2022]
Abstract
BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most significant neurologic complications of chemotherapy, impacting patient's behavior and quality of life. CIPN is mostly sensory, with rare incidences of autonomic dysfunction and other neuropathy. METHODS We conducted a single-center sub-group analysis of patients with metastatic breast cancer enrolled in a phase III study (NCT02225470) set up to compare eribulin mesylate (1.4 mg/m2 on days 1 and 8 every 21 days) with vinorelbine (25 mg/m2 on days 1, 8, and 15 every 21 days). The analysis investigated incidence of peripheral neuropathy, time to onset of neuropathy, and safety. RESULTS Our analysis included 110 women with a mean age of 50.7 (SD = 10.9). The median accumulated dose of eribulin was 11.2 mg/m2 and 125.0 mg/m2 for vinorelbine. Among patients in the eribulin group, a performance status (ECOG PS) of 2 was correlated with peripheral sensory neuropathy (p = 0.015), and accumulated eribulin dose (≥ 10 mg/m2) was associated with all neuropathy and peripheral sensory neuropathy (p = 0.003 and p = 0.007, respectively). In the vinorelbine group, patient age (≥ 65 years) was positively associated with all neuropathy (p = 0.043). The time to onset of neuropathy appeared to be longer for eribulin versus vinorelbine (35.3 vs. 34.6 weeks; p = 0.046), with a significantly higher incidence of autonomic neuropathy at weeks 2 and 10 observed among patients receiving vinorelbine (p = 0.008 and p = 0.043, respectively). CONCLUSION Vinorelbine is associated with a higher incidence of autonomic neuropathy than eribulin in patients with metastatic breast cancer. Furthermore, the onset of neurotoxicity appears to occur earlier with vinorelbine than eribulin.
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Affiliation(s)
- Ying Wu
- Department of Medical Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Qin Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jian Zhang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jun Cao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Biyun Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xichun Hu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. .,Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Shanghai, 200032, China.
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15
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Islam B, Lustberg M, Staff NP, Kolb N, Alberti P, Argyriou AA. Vinca alkaloids, thalidomide and eribulin-induced peripheral neurotoxicity: From pathogenesis to treatment. J Peripher Nerv Syst 2019; 24 Suppl 2:S63-S73. [PMID: 31647152 DOI: 10.1111/jns.12334] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023]
Abstract
Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.
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Affiliation(s)
- Badrul Islam
- International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
| | - Maryam Lustberg
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer, Columbus, Ohio
| | - Nathan P Staff
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | - Noah Kolb
- Department of Neurological Sciences, University of Vermont, Burlington, Vermont
| | - Paola Alberti
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- NeuroMI (Milan Center for Neuroscience), Milan, Italy
| | - Andreas A Argyriou
- Department of Neurology, "Saint Andrew's" State General Hospital of Patras, Patras, Greece
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Perez-Garcia JM, Cortes J. The safety of eribulin for the treatment of metastatic breast cancer. Expert Opin Drug Saf 2019; 18:347-355. [PMID: 31107111 DOI: 10.1080/14740338.2019.1608946] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Introduction: Eribulin mesylate is a highly potent anticancer agent approved for use in pretreated metastatic breast cancer (MBC). Clinical trials of eribulin in MBC have demonstrated activity against this tumor type, and a phase 3 study in patients with MBC previously treated with an anthracycline and a taxane showed a significant increase in overall survival (OS) with eribulin versus control regimens. Areas covered: This review presents overviews of the development of eribulin, its pharmacology, and its efficacy in MBC. A detailed review of its safety profile is presented, and the safety of eribulin is compared with other agents commonly used to treat MBC. Expert opinion: As eribulin is the only drug shown to improve OS in patients with pretreated MBC, it is an important treatment option for many patients. Eribulin is currently considered a second-line (Europe) or third-line (United States) therapy, and studies have been examining use in the first-line setting. The use of eribulin in combination with other therapies is beginning to be explored because its manageable safety profile makes it an ideal combination-treatment partner. Emerging eribulin combination-treatment data suggest a manageable toxicity profile, and eribulin is set to be a key drug for the treatment of MBC in the future.
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Affiliation(s)
- Jose Manuel Perez-Garcia
- a Medica Scientia Innovation Research (MedSIR) , Barcelona , Spain.,b IOB Institute of Oncology, Quirónsalud Group , Madrid and Barcelona , Spain
| | - Javier Cortes
- a Medica Scientia Innovation Research (MedSIR) , Barcelona , Spain.,b IOB Institute of Oncology, Quirónsalud Group , Madrid and Barcelona , Spain.,c Vall d'Hebron Institute of Oncology , Barcelona , Spain
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17
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O'Shaughnessy J, Kaklamani V, Kalinsky K. Perspectives on the mechanism of action and clinical application of eribulin for metastatic breast cancer. Future Oncol 2019; 15:1641-1653. [DOI: 10.2217/fon-2018-0936] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Eribulin is a novel microtubule inhibitor with mitotic and nonmitotic mechanisms of action. Both pooled and subgroup analyses from large-scale Phase III clinical trials demonstrated that eribulin has substantial activity in patients with pretreated (anthracycline and a taxane) advanced or metastatic breast cancer. We review recent pharmacological and clinical findings pertaining to eribulin use in metastatic breast cancer – particularly highlighting eribulin in difficult-to-treat and aggressive disease, and safety data in specific patient populations. Additionally, recent advancements in our understanding of the mechanism of action of eribulin and potential future directions for its clinical development are discussed. Ongoing studies of eribulin in combination with immunotherapies and established cytotoxic agents may help shape the future landscape of breast cancer treatment.
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Affiliation(s)
- Joyce O'Shaughnessy
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX, USA
| | - Virginia Kaklamani
- Department of Medicine, Division of Hematology/Oncology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
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18
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Inoue K, Ninomiya J, Saito T, Okubo K, Nakakuma T, Yamada H, Kimizuka K, Higuchi T. Eribulin, trastuzumab, and pertuzumab as first-line therapy for patients with HER2-positive metastatic breast cancer: a phase II, multicenter, collaborative, open-label, single-arm clinical trial. Invest New Drugs 2019; 37:538-547. [PMID: 30848403 PMCID: PMC6538821 DOI: 10.1007/s10637-019-00755-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 03/01/2019] [Indexed: 01/04/2023]
Abstract
Purpose To examine the efficacy and safety of triple therapy with eribulin, trastuzumab, and pertuzumab in patients with HER2-positive metastatic breast cancer (MBC) who never received any prior therapy in the first-line metastatic/advanced setting. Methods Eribulin 1.4 mg/m2 (days 1 and 8), trastuzumab 8 mg/kg over 90 min and 6 mg/kg over 30 min, and pertuzumab 840 mg/body over 60 min and 420 mg/body over 30 min were administered intravenously in 21-day cycles. Results 25 women (median age, 57 years [range, 41–75 years]) received a median of 10 cycles (range, 0–34 cycles); 24 had performance status (PS) 0, 1 PS 1, 8 stage IV breast cancer, and 17 recurrence. Lung and liver metastases occurred in 9 and 9 patients, respectively. Median time to treatment failure with eribulin was 9.1 months (95% confidence interval [CI], 4.3–13.9 months), and median progression-free survival was 23.1 months (95% CI, 14.4–31.8 months). The overall response rate (complete response [CR] + partial response [PR]) was 80.0% (95% CI, 59.3–93.2%), and the clinical benefit rate (CR + PR + stable disease ≥24 weeks) was 84.0% (95% CI, 63.9–95.5%). The most common treatment-emergent adverse events (TEAEs) were alopecia (92.0%), fatigue (68.0%), and sensory peripheral neuropathy (60.0%). Grade 3/4 TEAEs occurred in 11 patients (44.0%). The only grade 4 TEAE was neutrophil count decreased (16.0%). Neither grade 4 peripheral neuropathy nor febrile neutropenia occurred. Conclusions ETP therapy showed acceptable efficacy and safety and is a potential first-line therapy for patients with HER2-positive MBC.
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Affiliation(s)
- Kenichi Inoue
- Division of Breast Oncology, Saitama Cancer Center, 780 Komuro, Ina-machi, Kita-adachi-gun, Saitama, 362-0806, Japan.
| | - Jun Ninomiya
- Department of Breast Surgery, Ninomiya Hospital, Soka, Japan
| | - Tsuyoshi Saito
- Department of Breast Surgery, Saitama Red Cross Hospital, Saitama, Japan
| | - Katsuhiko Okubo
- Department of Breast Unit, Toda Central General Hospital, Saitama, Japan
| | - Takashi Nakakuma
- Department of Breast Surgery, Ageo Central General Hospital, Ageo, Japan
| | | | - Kei Kimizuka
- Department of Breast Surgery, Kasukabe Medical Center, Kasukabe, Japan
| | - Tohru Higuchi
- Department of Breast Surgery, Saitama Red Cross Hospital, Saitama, Japan
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Cadoo KA, Kaufman PA, Seidman AD, Chang C, Xing D, Traina TA. Phase 2 Study of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Eribulin Mesylate With or Without Prophylactic Growth Factor for Adjuvant Treatment of Early-Stage Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer. Clin Breast Cancer 2018; 18:433-440.e1. [PMID: 29895438 PMCID: PMC6174098 DOI: 10.1016/j.clbc.2018.04.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 02/26/2018] [Accepted: 04/01/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND Eribulin has significantly improved overall survival for patients with metastatic breast cancer who received ≥ 2 prior chemotherapy regimens for advanced disease. This trial assessed eribulin as adjuvant therapy for patients with early-stage breast cancer. PATIENTS AND METHODS Patients with human epidermal growth factor receptor 2-negative, stage I to III breast cancer received doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 provided intravenously on day 1 of each 14-day cycle for 4 cycles, with pegfilgrastim on day 2, followed by 4 cycles of eribulin mesylate 1.4 mg/m2 provided intravenously on days 1 and 8 every 21 days. There were 2 cohorts, as follows: cohort 1: no prophylactic growth factor with eribulin (allowed at physician's discretion only); cohort 2: prophylactic filgrastim with eribulin. The primary end point was feasibility, defined as the percentage of patients who completed the eribulin portion of the regimen without a dose omission, delay, or reduction due to an eribulin-related adverse event. Relative dose intensity of eribulin and toxicities are summarized by cohort. Exploratory end points included 3-year disease-free survival and overall survival. RESULTS Eighty-one patients (cohort 1, n = 55; cohort 2, n = 26) entered the treatment phase; 88% completed treatment. Feasibility was 72.9 % (90% confidence interval, 60.4, 83.2) in cohort 1 and 60.0% (90% confidence interval, 41.7, 76.4) in cohort 2. The most frequent eribulin-related adverse events (all grades) were fatigue (75.9%), peripheral neuropathy (54.4%), nausea (39.2%), neutropenia (35.4% [31.5% of patients in cohort 1; 44.0% in cohort 2]), and arthralgia (26.6%). CONCLUSION The primary end point of > 80% feasibility was not met. No unexpected adverse events were observed, and 62% of patients received full dosing with no dose delay or reduction. Further investigation of this regimen with alternative dosing schedules or use of growth factors could be considered.
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Affiliation(s)
- Karen A Cadoo
- Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medicine, New York, NY.
| | - Peter A Kaufman
- Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Andrew D Seidman
- Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medicine, New York, NY
| | | | | | - Tiffany A Traina
- Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medicine, New York, NY
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20
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Cortes J, Schöffski P, Littlefield BA. Multiple modes of action of eribulin mesylate: Emerging data and clinical implications. Cancer Treat Rev 2018; 70:190-198. [DOI: 10.1016/j.ctrv.2018.08.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 08/14/2018] [Accepted: 08/17/2018] [Indexed: 02/07/2023]
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21
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Chemotherapy-induced peripheral neuropathy in breast cancer patients treated with eribulin: interim data from a post-marketing observational study. Breast Cancer 2018; 26:235-243. [PMID: 30324551 PMCID: PMC6394617 DOI: 10.1007/s12282-018-0919-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 10/03/2018] [Indexed: 02/06/2023]
Abstract
Background Few studies have examined chemotherapy-induced peripheral neuropathy (CIPN) following the administration of eribulin as first- or second-line therapy in patients with breast cancer. We therefore assessed CIPN incidence by severity and risk factors for CIPN in patients treated with eribulin for HER2-negative inoperable or recurrent breast cancer, regardless of line therapy status. Methods This multicenter, prospective, post-marketing observational study enrolled patients from September 2014 in Japan and followed them for 2 years. For this interim analysis, the data cut-off point was in November 2017. CIPN severity was assessed based on the Japanese version of the Common Terminology Criteria for Adverse Events, version 4.0. Results Among 634 patients included in the safety analysis, 374 patients did not have existing CIPN at baseline. CIPN was observed in 105 patients (28.1%), including 67 (17.9%), 34 (9.1%), and 4 (1.1%) patients with grade 1, 2, and 3 severity, respectively. Of the 105 patients, 85.7% patients continued, 7.6% reduced, interrupted or postponed, and 6.7% discontinued eribulin. The median time (min‒max) from baseline to CIPN onset was 60 (3‒337) days. Multivariate logistic regression identified a significant association between CIPN and hemoglobin level at baseline, starting dose of eribulin, and history of radiotherapy. Conclusions Our findings indicate that, with respect to CIPN, eribulin is well-tolerated, as approximately one-quarter of patients developed CIPN, most cases were grade 1 or 2, and the majority of patients continued eribulin after CIPN onset. Electronic supplementary material The online version of this article (10.1007/s12282-018-0919-8) contains supplementary material, which is available to authorized users.
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22
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Cook BM, Wozniak KM, Proctor DA, Bromberg RB, Wu Y, Slusher BS, Littlefield BA, Jordan MA, Wilson L, Feinstein SC. Differential Morphological and Biochemical Recovery from Chemotherapy-Induced Peripheral Neuropathy Following Paclitaxel, Ixabepilone, or Eribulin Treatment in Mouse Sciatic Nerves. Neurotox Res 2018; 34:677-692. [PMID: 30051419 DOI: 10.1007/s12640-018-9929-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 06/15/2018] [Accepted: 06/20/2018] [Indexed: 12/29/2022]
Abstract
The reversibility of chemotherapy-induced peripheral neuropathy (CIPN), a disabling and potentially permanent side effect of microtubule-targeting agents (MTAs), is becoming an increasingly important issue as treatment outcomes improve. The molecular mechanisms regulating the variability in time to onset, severity, and time to recovery from CIPN between the common MTAs paclitaxel and eribulin are unknown. Previously (Benbow et al. in Neurotox Res 29:299-313, 2016), we found that after 2 weeks of a maximum tolerated dose (MTD) in mice, paclitaxel treatment resulted in severe reductions in axon area density, higher frequency of myelin abnormalities, and increased numbers of Schwann cell nuclei in sciatic nerves. Biochemically, eribulin induced greater microtubule-stabilizing effects than paclitaxel. Here, we extended these comparative MTD studies to assess the recovery from these short-term effects of paclitaxel, eribulin, and a third MTA, ixabepilone, over the course of 6 months. Paclitaxel induced a persistent reduction in axon area density over the entire 6-month recovery period, unlike ixabepilone- or eribulin-treated animals. The abundance of myelin abnormalities rapidly declined after cessation of all drugs but recovered most slowly after paclitaxel treatment. Paclitaxel- and ixabepilone- but not eribulin-treated animals exhibited increased Schwann cell numbers during the recovery period. Tubulin composition and biochemistry rapidly returned from MTD-induced levels of α-tubulin, acetylated α-tubulin, and end-binding protein 1 to control levels following cessation of drug treatment. Taken together, sciatic nerve axons recovered more rapidly from morphological effects in eribulin- and ixabepilone-treated animals than in paclitaxel-treated animals and drug-induced increases in protein expression levels following paclitaxel and eribulin treatment were relatively transient.
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Affiliation(s)
- B M Cook
- Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, 93106, USA.,Department of Biomolecular Sciences and Engineering, University of California Santa Barbara, Santa Barbara, CA, 93016, USA
| | - K M Wozniak
- Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - D A Proctor
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, 93016, USA
| | - R B Bromberg
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, 93016, USA
| | - Y Wu
- Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - B S Slusher
- Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - B A Littlefield
- Scientific Administration, Eisai Research Institute, Andover, MA, 01810, USA
| | - M A Jordan
- Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, 93016, USA
| | - L Wilson
- Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, 93106, USA.,Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, 93016, USA
| | - Stuart C Feinstein
- Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, 93106, USA. .,Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, 93016, USA.
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Zhao B, Zhao H, Zhao J. Incidence and clinical parameters associated with eribulin mesylate-induced peripheral neuropathy. Crit Rev Oncol Hematol 2018; 128:110-117. [PMID: 29958626 DOI: 10.1016/j.critrevonc.2018.06.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/07/2018] [Accepted: 06/06/2018] [Indexed: 11/18/2022] Open
Abstract
Eribulin mesylate is a microtubule-targeting agent that has been approved for the treatment of breast cancer and liposarcoma. Due to its novel mechanism of action, eribulin therapy induces a distinct profile of adverse events, including peripheral neuropathy. However, the incidence and risk of eribulin-related neurotoxicities are unclear. Here, we conducted a systematic search of PubMed and Embase from their inception to October 2017. Eligible studies included trials in which eribulin was intravenously administered at a standard dose of 1.4 mg/m2 over 2-5 minutes on days 1 and 8 on a 21-day cycle. The events of all-grade and high-grade peripheral neuropathy were collected to calculate the overall incidence and relative risk (RR). A total of thirty-two studies containing 6129 subjects were included in this analysis. The incidences of all-grade and high-grade eribulin monotherapy-related peripheral neuropathy were 28% (95% confidence interval [CI], 24%-32%) and 4% (95% CI, 3%-5%), respectively. Subgroup analysis further revealed that a higher incidence of neurotoxicities was observed in patients with breast cancer and those with longer treatment duration. Moreover, eribulin-treated subjects had a significantly increased risk of all-grade (RR, 2.00; 95% CI, 1.70-2.35; p = 0.008) and high-grade (RR, 3.68; 95% CI, 2.30-5.89; p<0.001) neurotoxicities. Our results suggested that patients treated with eribulin had an increased risk of developing peripheral neuropathy.
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Affiliation(s)
- Bin Zhao
- The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
| | - Hong Zhao
- The Third Affiliated Hospital of Harbin Medical University, Harbin, 150081, China.
| | - Jiaxin Zhao
- The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
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24
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Wozniak KM, Vornov JJ, Wu Y, Liu Y, Carozzi VA, Rodriguez-Menendez V, Ballarini E, Alberti P, Pozzi E, Semperboni S, Cook BM, Littlefield BA, Nomoto K, Condon K, Eckley S, DesJardins C, Wilson L, Jordan MA, Feinstein SC, Cavaletti G, Polydefkis M, Slusher BS. Peripheral Neuropathy Induced by Microtubule-Targeted Chemotherapies: Insights into Acute Injury and Long-term Recovery. Cancer Res 2017; 78:817-829. [PMID: 29191802 DOI: 10.1158/0008-5472.can-17-1467] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 08/30/2017] [Accepted: 11/21/2017] [Indexed: 01/01/2023]
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3-6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. Cancer Res; 78(3); 817-29. ©2017 AACR.
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Affiliation(s)
- Krystyna M Wozniak
- Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | | | - Ying Wu
- Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Ying Liu
- Department of Neurology and the Cutaneous Nerve Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Valentina A Carozzi
- Experimental Neurology Unit and PhD program in Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Virginia Rodriguez-Menendez
- Experimental Neurology Unit and PhD program in Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Elisa Ballarini
- Experimental Neurology Unit and PhD program in Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Paola Alberti
- Experimental Neurology Unit and PhD program in Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Eleonora Pozzi
- Experimental Neurology Unit and PhD program in Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Sara Semperboni
- Experimental Neurology Unit and PhD program in Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Brett M Cook
- Neurosci Research Institute, University of California, Santa Barbara, California.,Biomolecular Science and Engineering Program, University of California, Santa Barbara, California
| | | | | | | | | | | | - Leslie Wilson
- Neurosci Research Institute, University of California, Santa Barbara, California.,Biomolecular Science and Engineering Program, University of California, Santa Barbara, California.,Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, California
| | - Mary A Jordan
- Neurosci Research Institute, University of California, Santa Barbara, California.,Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, California
| | - Stuart C Feinstein
- Neurosci Research Institute, University of California, Santa Barbara, California.,Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, California
| | - Guido Cavaletti
- Experimental Neurology Unit and PhD program in Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Michael Polydefkis
- Department of Neurology and the Cutaneous Nerve Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Barbara S Slusher
- Johns Hopkins Drug Discovery and Departments of Neurology, Psychiatry, Neuroscience, Medicine and Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.
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25
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Quaquarini E, Sottotetti F, D'Ambrosio D, Malovini A, Morganti S, Marinello A, Pavesi L, Frascaroli M. Eribulin across multiple lines of chemotherapy: a retrospective study on quality of life and efficacy in metastatic breast cancer patients. Future Oncol 2017; 13:11-23. [PMID: 28481185 DOI: 10.2217/fon-2016-0517] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
This study evaluates efficacy, tolerability and health-related quality of life of eribulin in patients with metastatic breast cancer. Predictive and/or prognostic factors of outcome were also analyzed. Among 44 women receiving eribulin mesylate, one patient had a complete response, 22.7% a partial response and 25% a stable disease. Median overall survival and median progression-free survival were 11.8 and 4.5 months, respectively. Treatment was well tolerated; the most frequent adverse events were neutropenia (52%), leukopenia (50%), fatigue (38%) and alopecia (40%). No significant reductions of health-related quality of life parameters were observed. Disease control during previous chemotherapy lines was related with better outcome with eribulin. In conclusion, eribulin treatment should be considered in a multiple chemotherapy lines strategy in metastatic breast cancer.
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Affiliation(s)
- Erica Quaquarini
- Operative Unit of Medical Oncology, Fondazione Maugeri-IRCCS, Via Maugeri 10, 27100 Pavia, Italy
| | - Federico Sottotetti
- Operative Unit of Medical Oncology, Fondazione Maugeri-IRCCS, Via Maugeri 10, 27100 Pavia, Italy
| | - Daniela D'Ambrosio
- Medical Physics Department, IRCCS Fondazione Maugeri, Via Salvatore Maugeri 4, 27100 Pavia, Italy
| | - Alberto Malovini
- Department of Computer Engineering & Systems Science, University of Pavia, Fondazione Maugeri-IRCCS, Via Maugeri 10, 27100 Pavia, Italy
| | - Stefania Morganti
- Operative Unit of Medical Oncology, Fondazione Maugeri-IRCCS, Via Maugeri 10, 27100 Pavia, Italy
| | - Arianna Marinello
- Operative Unit of Medical Oncology, Fondazione Maugeri-IRCCS, Via Maugeri 10, 27100 Pavia, Italy
| | - Lorenzo Pavesi
- Operative Unit of Medical Oncology, Fondazione Maugeri-IRCCS, Via Maugeri 10, 27100 Pavia, Italy
| | - Mara Frascaroli
- Operative Unit of Medical Oncology, Fondazione Maugeri-IRCCS, Via Maugeri 10, 27100 Pavia, Italy
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26
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Miglietta F, Dieci M, Griguolo G, Guarneri V, Conte P. Chemotherapy for advanced HER2-negative breast cancer: Can one algorithm fit all? Cancer Treat Rev 2017; 60:100-108. [DOI: 10.1016/j.ctrv.2017.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 09/04/2017] [Accepted: 09/06/2017] [Indexed: 12/28/2022]
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27
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Peng L, Hong Y, Ye X, Shi P, Zhang J, Wang Y, Zhao Q. Incidence and relative risk of peripheral neuropathy in cancer patients treated with eribulin: a meta-analysis. Oncotarget 2017; 8:112076-112084. [PMID: 29340112 PMCID: PMC5762380 DOI: 10.18632/oncotarget.21057] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 08/30/2017] [Indexed: 11/25/2022] Open
Abstract
Background Eribulin is a microtubule inhibitor, which is approved for the treatment of breast cancer. Peripheral neuropathy has been reported in the studies of eribulin, but the incidence and relative risk (RR) of eribulin-associated peripheral neuropathy varied greatly in cancer patients. The purpose of this meta-analysis was to determine the overall incidence and RR of eribulin-associated peripheral neuropathy in cancer patients. Materials and Methods Pubmed database and Embase and abstracts presented at the American Society of Clinical Oncology (ASCO) meetings were systematically reviewed for primary studies. Eligible studies included prospective clinical trials and expanded access programs of cancer patients treated with eribulin. Statistical analyses were performed to calculate the incidences, RRs, and 95% confidence intervals (CIs). Results Altogether, 4,849 patients from 19 clinical trials were selected for this meta-analysis. The incidences of all-grade and high-grade peripheral neuropathy were 27.5% (95% CI: 23.3-32.4%) and 4.7% (95% CI: 3.6-6.2%), respectively. The relative risks of peripheral neuropathy of eribulin compared to control were increased for all-grade (RR = 1.89, 95% CI: 1.10-3.25) but not statistically significant for high-grade (RR = 2.98, 95% CI: 0.71-12.42). Conclusions The use of eribulin is associated with an increased incidence of peripheral neuropathy. The RR is increased for all-grade peripheral neuropathy.
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Affiliation(s)
- Ling Peng
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yun Hong
- Department of Pharmacy, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Xianghua Ye
- Department of Radiotherapy, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Peng Shi
- Department of Medical Statistics, Children's Hospital of Fudan University, Shanghai, China.,Center for Evidence-Based Medicine, Fudan University, Shanghai, China
| | - Junyan Zhang
- Bothwin Clinical Study Consultant, Seattle, WA, USA
| | - Yina Wang
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Qiong Zhao
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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28
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Garrone O, Miraglio E, Vandone AM, Vanella P, Lingua D, Merlano MC. Eribulin in advanced breast cancer: safety, efficacy and new perspectives. Future Oncol 2017; 13:2759-2769. [PMID: 29219017 DOI: 10.2217/fon-2017-0283] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Eribulin is a synthetic analog of halichondrin B belonging to microtubule-targeted agents with a distinct mechanism of inhibition of microtubule dynamics. This molecule has multiple nonmitotic effects on tumor biology, exhibiting effects on epithelial-mesenchimal transition and tumor vasculature. We review here preclinical and clinical studies on eribulin. The mitotic and nonmitotic effects together with its favorable safety profile make eribulin a unique drug with high potential in the treatment of metastatic breast cancer. The new emphasis of eribulin mechanism of action on vascular remodeling, microenvironment modifications and reversal of epithelial-mesenchimal transition paves the way to rethinking the use of the drug in an immunological perspective.
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Affiliation(s)
- Ornella Garrone
- Medical Oncology A.O. S. Croce e Carle Ospedale di Insegnamento, Cuneo, Italy
| | - Emanuela Miraglio
- Medical Oncology A.O. S. Croce e Carle Ospedale di Insegnamento, Cuneo, Italy
| | - Anna Maria Vandone
- Medical Oncology A.O. S. Croce e Carle Ospedale di Insegnamento, Cuneo, Italy
| | - Paola Vanella
- Medical Oncology A.O. S. Croce e Carle Ospedale di Insegnamento, Cuneo, Italy
| | - Daniele Lingua
- Medical Oncology A.O. S. Croce e Carle Ospedale di Insegnamento, Cuneo, Italy
| | - Marco C Merlano
- Medical Oncology A.O. S. Croce e Carle Ospedale di Insegnamento, Cuneo, Italy
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29
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Lorusso V, Cinieri S, Latorre A, Porcu L, Del Mastro L, Puglisi F, Barni S. Efficacy and safety of eribulin in taxane-refractory patients in the ‘real world’. Future Oncol 2017; 13:971-978. [DOI: 10.2217/fon-2016-0530] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aim: Recent clinical, randomized and observational studies showed that eribulin, an analogous of Halichondrin B, was beneficial and well-tolerated in heavily pretreated metastatic breast cancer patients. Here, we aim to evaluate the effectiveness and safety of eribulin in taxane-refractory metastatic breast cancer patients. Patients & methods: In this subanalysis of the ESEMPIO study database, we selected 91 subjects with well-defined taxane refractoriness and complete data available. Results: 41 patients (45.2%) showed clinical benefit; one complete response (2.2%) and 16 partial responses (17.6%) were observed. Median progression-free survival and median overall survival were 3.1 and 11.6 months, respectively. The most experienced adverse event was asthenia/fatigue (58%), followed by neutropenia (30%). The treatment-related toxicity led to eribulin-dose reduction in 19 patients and suspension in nine. Conclusion: This study shows that eribulin is effective and well tolerated also in taxane-refractory patients in clinical practice.
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Affiliation(s)
- Vito Lorusso
- UOC Oncologia Medica, Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Saverio Cinieri
- Medical Oncology Division and Breast Unit, Ospedale A Perrino, Brindisi, Italy
| | - Agnese Latorre
- UOC Oncologia Medica, Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Luca Porcu
- Oncology Department, IRRCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Lucia Del Mastro
- Department of Medical Oncology, IRCCS AOU San Martino - IST, Genova, Italy
| | - Fabio Puglisi
- Oncology Department, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy
| | - Sandro Barni
- Oncology Unit, Oncology Department, ASST Bergamo Ovest Ospedale, Treviglio, Bergamo, Italy
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30
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Li J, Ren J, Sun W. Systematic review of ixabepilone for treating metastatic breast cancer. Breast Cancer 2016; 24:171-179. [PMID: 27491426 DOI: 10.1007/s12282-016-0717-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 07/27/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND Ixabepilone is now a Food and Drug Administration-approved therapeutic option for patients with metastatic breast cancer (MBC) whose disease has progressed despite prior anthracycline and taxane therapy. We conducted a systematic review and meta-analysis to systematically evaluate the efficacy and safety of ixabepilone for treating metastatic breast cancer. METHODS A systematic review and meta-analysis were conducted. Randomized controlled studies applying ixabepilone for treating MBC were included. The primary outcome was Overall Survival (OS). The authors of primary articles were contacted and methodological quality was evaluated. Subgroups were drawn based on intervention measures; heterogeneity and bias were discussed. RESULTS Eight studies with 5247 patients were included. Compared with a weekly schedule, a triweekly schedule of ixabepilone was better at improving overall response rate (ORR), while there were no differences in improving OS and progression-free survival (PFS). Ixabepilone plus capecitabine was superior to capecitabine monotherapy in improving OS, PFS and ORR. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. There was no difference in the improvement of ORR, clinical benefit rate (CBR) and disease control rate (DCR) between ixabepilone and eribulin. CONCLUSIONS Current evidence suggests that a triweekly schedule of ixabepilone is more effective than weekly dosing in improving ORR. Use of ixabepilone in combination with capecitabine possesses superior clinical efficacy to the use of capecitabine alone. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. The efficacy and safety between ixabepilone and eribulin were identical.
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Affiliation(s)
- Jing Li
- College of Pharmacy, Southwest University for Nationalities, Chengdu, Sichuan, People's Republic of China
| | - Jing Ren
- Sichuan Industrial Institute of Antibiotics of Chengdu University, No. 168 Huaguan Road, Longtan Industrial Park, Chengdu, 610041, Sichuan, People's Republic of China
| | - Wenxia Sun
- Sichuan Industrial Institute of Antibiotics of Chengdu University, No. 168 Huaguan Road, Longtan Industrial Park, Chengdu, 610041, Sichuan, People's Republic of China.
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31
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Park YH, Kim TY, Im YH, Lee KS, Park IH, Sohn J, Lee SH, Im SA, Kim JH, Kim SH, Lee SJ, Koh SJ, Lee KH, Choi YJ, Cho EK, Lee S, Kang SY, Seo JH, Kim SB, Jung KH. Feasibility and Efficacy of Eribulin Mesilate in Korean Patients with Metastatic Breast Cancer: Korean Multi-center Phase IV Clinical Study Results. Cancer Res Treat 2016; 49:423-429. [PMID: 27488876 PMCID: PMC5398406 DOI: 10.4143/crt.2016.191] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 07/13/2016] [Indexed: 01/26/2023] Open
Abstract
PURPOSE Eribulin mesilate was approved for the treatment of patients with locally advanced or metastatic breast cancer (MBC), who had received at least two chemotherapeutic regimens, including anthracycline and taxane. On the other hand, the efficacy and safety information of eribulin in Korean patients is limited by the lack of clinical trials. MATERIALS AND METHODS In this multicenter, open-label, single-arm, phase IV study, locally advanced or MBC patients were enrolled between June 2013 and April 2014 from 14 centers in Korea. One point four mg/m2 dose of eribulin was administered on days 1 and 8 of every 21 days. The primary endpoint was the frequency and intensity of the treatment emergent adverse event. The secondary endpoint was the disease control rate, which included the rate of complete responses, partial responses, and stable disease. RESULTS A total of 101 patients received at least one dose of eribulin and were included in the safety set. The patients received a total of 543 treatment cycles, with a median of three cycles (range, 1 to 31 cycles). The most common adverse event was neutropenia (91.1% of patients, 48.3% of cycles). The frequent non-hematological adverse events included alopecia, decrease in appetite, fatigue/asthenia, and myalgia/arthralgia. The peripheral neuropathy of any grade occurred in 27 patients (26.7%), including grade 3 in two patients. Disease control rate was 52.7% and 51.3% of patients in the full analysis set and per-protocol set, respectively. CONCLUSION This study demonstrated the feasible safety profile and activity of eribulin in Korean patients with MBC.
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Affiliation(s)
- Yeon Hee Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Yong Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Young-Hyuck Im
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keun-Seok Lee
- Division of Hematology and Medical Oncology, Department of Internal Medicine, National Cancer Center, Goyang, Korea
| | - In Hae Park
- Division of Hematology and Medical Oncology, Department of Internal Medicine, National Cancer Center, Goyang, Korea
| | - Joohyuk Sohn
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Soo-Hyeon Lee
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Seock-Ah Im
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jee Hyun Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Se Hyun Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Soo Jung Lee
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Korea
| | - Su-Jin Koh
- Division of Medical Oncology, Department of Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Ki Hyeong Lee
- Division of Hematology-Oncology, Department of Medicine, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Yoon Ji Choi
- Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Eun Kyung Cho
- Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Suee Lee
- Department of Internal Medicine, Dong-A University Medical Center, Busan, Korea
| | - Seok Yun Kang
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Ajou University School of Medicine, Suwon, Korea
| | - Jae Hong Seo
- Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Sung-Bae Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Hae Jung
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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32
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Smith JA, Slusher BS, Wozniak KM, Farah MH, Smiyun G, Wilson L, Feinstein S, Jordan MA. Structural Basis for Induction of Peripheral Neuropathy by Microtubule-Targeting Cancer Drugs. Cancer Res 2016; 76:5115-23. [DOI: 10.1158/0008-5472.can-15-3116] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 06/13/2016] [Indexed: 11/16/2022]
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33
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Aseyev O, Ribeiro JM, Cardoso F. Review on the clinical use of eribulin mesylate for the treatment of breast cancer. Expert Opin Pharmacother 2016; 17:589-600. [DOI: 10.1517/14656566.2016.1146683] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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34
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Benbow SJ, Cook BM, Reifert J, Wozniak KM, Slusher BS, Littlefield BA, Wilson L, Jordan MA, Feinstein SC. Effects of Paclitaxel and Eribulin in Mouse Sciatic Nerve: A Microtubule-Based Rationale for the Differential Induction of Chemotherapy-Induced Peripheral Neuropathy. Neurotox Res 2015; 29:299-313. [DOI: 10.1007/s12640-015-9580-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 11/18/2015] [Accepted: 11/19/2015] [Indexed: 12/15/2022]
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35
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Colley HE, Muthana M, Danson SJ, Jackson LV, Brett ML, Harrison J, Coole SF, Mason DP, Jennings LR, Wong M, Tulasi V, Norman D, Lockey PM, Williams L, Dossetter AG, Griffen EJ, Thompson MJ. An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer. J Med Chem 2015; 58:9309-33. [DOI: 10.1021/acs.jmedchem.5b01312] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Helen E. Colley
- School
of Clinical Dentistry, University of Sheffield, 19 Claremont Crescent, Sheffield S10 2TA, U.K
| | - Munitta Muthana
- Department
of Oncology, The University of Sheffield, Medical School, Beech
Hill Road, Sheffield S10
2RX, U.K
| | - Sarah J. Danson
- Academic
Unit of Clinical Oncology and Sheffield Experimental Medicine Centre, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, U.K
| | - Lucinda V. Jackson
- Department
of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K
| | - Matthew L. Brett
- Department
of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K
| | - Joanne Harrison
- Department
of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K
| | - Sean F. Coole
- Department
of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K
| | - Daniel P. Mason
- Department
of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K
| | - Luke R. Jennings
- School
of Clinical Dentistry, University of Sheffield, 19 Claremont Crescent, Sheffield S10 2TA, U.K
| | - Melanie Wong
- Charles River, 8−9 Spire
Green Centre, Harlow, Harlow, Essex CM19 5TR, U.K
| | - Vamshi Tulasi
- Charles River, 8−9 Spire
Green Centre, Harlow, Harlow, Essex CM19 5TR, U.K
| | - Dennis Norman
- Charles River, 8−9 Spire
Green Centre, Harlow, Harlow, Essex CM19 5TR, U.K
| | - Peter M. Lockey
- Charles River, 8−9 Spire
Green Centre, Harlow, Harlow, Essex CM19 5TR, U.K
| | - Lynne Williams
- Department
of Oncology, The University of Sheffield, Medical School, Beech
Hill Road, Sheffield S10
2RX, U.K
| | - Alexander G. Dossetter
- MedChemica Limited, Ebenezer House,
Ryecroft, Newcastle-Under-Lyme, Staffordshire ST5 2BE, U.K
| | - Edward J. Griffen
- MedChemica Limited, Ebenezer House,
Ryecroft, Newcastle-Under-Lyme, Staffordshire ST5 2BE, U.K
| | - Mark J. Thompson
- Department
of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K
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Swami U, Shah U, Goel S. Eribulin in Cancer Treatment. Mar Drugs 2015; 13:5016-58. [PMID: 26262627 PMCID: PMC4557013 DOI: 10.3390/md13085016] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 07/18/2015] [Accepted: 07/24/2015] [Indexed: 11/20/2022] Open
Abstract
Halichondrin B is a complex, natural, polyether macrolide derived from marine sponges. Eribulin is a structurally-simplified, synthetic, macrocyclic ketone analogue of Halichondrin B. Eribulin was approved by United States Food and Drug Administration in 2010 as a third-line therapy for metastatic breast cancer patients who have previously been treated with an anthracycline and a taxane. It has a unique microtubule dynamics inhibitory action. Phase III studies have either been completed or are currently ongoing in breast cancer, soft tissue sarcoma, and non-small cell lung cancer. Phase I and II studies in multiple cancers and various combinations are currently ongoing. This article reviews the available information on eribulin with respect to its clinical pharmacology, pharmacokinetics, pharmacodynamics, mechanism of action, metabolism, preclinical studies, and with special focus on clinical trials.
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Affiliation(s)
- Umang Swami
- University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242, USA.
| | - Umang Shah
- Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 1695 Eastchester Road, Bronx, NY 10461, USA.
| | - Sanjay Goel
- Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 1695 Eastchester Road, Bronx, NY 10461, USA.
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Iorfida M, Mazza M. Long-lasting control with eribulin in a taxane pretreated metastatic breast cancer patient. Future Oncol 2015; 11:23-6. [DOI: 10.2217/fon.15.149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Moreover, many chemotherapeutic agents need to be interrupted due to toxicity. Here we report an extremely long duration of chemotherapy with eribulin (11 courses) in a taxane-pretreated metastatic breast cancer patient. Therapy was well tolerated with no worsening of pre-existing neuropathy, achieving excellent outcomes and a good quality of life. This report adds to the pool of knowledge regarding the use of this important new metastatic breast cancer chemotherapeutic agent.
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Affiliation(s)
- Monica Iorfida
- Division of Medical Senology, European Institute of Oncology, Milan, Italy
| | - Manuelita Mazza
- Division of Medical Senology, European Institute of Oncology, Milan, Italy
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Staff NP, Windebank AJ. Peripheral neuropathy due to vitamin deficiency, toxins, and medications. Continuum (Minneap Minn) 2015; 20:1293-306. [PMID: 25299283 DOI: 10.1212/01.con.0000455880.06675.5a] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE OF REVIEW Peripheral neuropathies secondary to vitamin deficiencies, medications, or toxins are frequently considered but can be difficult to definitively diagnose. Accurate diagnosis is important since these conditions are often treatable and preventable. This article reviews the key features of different types of neuropathies caused by these etiologies and provides a comprehensive list of specific agents that must be kept in mind. RECENT FINDINGS While most agents that cause peripheral neuropathy have been known for years, newly developed medications that cause peripheral neuropathy are discussed. SUMMARY Peripheral nerves are susceptible to damage by a wide array of toxins, medications, and vitamin deficiencies. It is important to consider these etiologies when approaching patients with a variety of neuropathic presentations; additionally, etiologic clues may be provided by other systemic symptoms. While length-dependent sensorimotor axonal peripheral neuropathy is the most common presentation, several examples present in a subacute severe fashion, mimicking Guillain-Barré syndrome.
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Poupon L, Kerckhove N, Vein J, Lamoine S, Authier N, Busserolles J, Balayssac D. Minimizing chemotherapy-induced peripheral neuropathy: preclinical and clinical development of new perspectives. Expert Opin Drug Saf 2015; 14:1269-82. [DOI: 10.1517/14740338.2015.1056777] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Dybdal-Hargreaves NF, Risinger AL, Mooberry SL. Eribulin mesylate: mechanism of action of a unique microtubule-targeting agent. Clin Cancer Res 2015; 21:2445-52. [PMID: 25838395 DOI: 10.1158/1078-0432.ccr-14-3252] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 02/05/2015] [Indexed: 01/22/2023]
Abstract
Eribulin mesylate (eribulin), an analogue of the marine natural product halichondrin B, is a microtubule-depolymerizing drug that has utility in the treatment of patients with breast cancer. Clinical trial results have demonstrated that eribulin treatment provides a survival advantage to patients with metastatic or locally advanced breast cancer previously treated with an anthracycline and a taxane. Furthermore, a pooled analysis of two pivotal phase III trials has demonstrated that eribulin also improves overall survival in several patient subgroups, including in women with HER2-negative disease and triple-negative breast cancer. This review covers the preclinical research that led to the clinical testing and approval of eribulin, as well as subsequent research that was prompted by distinct and unexpected effects of eribulin in the clinic. Initial studies with halichondrin B demonstrated unique effects on tubulin binding that resulted in distinct microtubule-dependent events and antitumor actions. Consistent with the actions of the natural product, eribulin has potent microtubule-depolymerizing activities and properties that distinguish it from other microtubule-targeting agents. Here, we review new results that further differentiate the effects of eribulin from other agents on peripheral nerves, angiogenesis, vascular remodeling, and epithelial-to-mesenchymal transition. Together, these data highlight the distinct properties of eribulin and begin to delineate the mechanisms behind the increased survival benefit provided by eribulin for patients.
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Affiliation(s)
| | - April L Risinger
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas. Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Susan L Mooberry
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas. Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas
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Doherty MK, Morris PG. Eribulin for the treatment of metastatic breast cancer: an update on its safety and efficacy. Int J Womens Health 2015; 7:47-58. [PMID: 25610001 PMCID: PMC4294649 DOI: 10.2147/ijwh.s74462] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Breast cancer remains a leading cause of cancer-related death internationally. Treatment approaches for metastatic breast cancer have evolved in recent years; however chemotherapy remains a core component for the majority of patients. Agents such as anthracyclines and taxanes have been extensively studied and form standard treatment. Eribulin mesylate is a novel synthetic microtubule-directed chemotherapy, based on a naturally-occurring compound. Through phase I studies, eribulin was found to be tolerable and activity was seen in patients with metastatic breast cancer. Phase II studies in metastatic breast cancer further demonstrated its efficacy, with responses and survival which compare favorably with other studied chemotherapy agents. The phase III EMBRACE study showed superior survival for patients treated with eribulin compared with those who received a physician's choice control. This led to its approval for use in many countries in this setting. Its toxicity profile is well established and manageable for the most part, with the commonest reported toxicities being alopecia, fatigue, neutropenia and peripheral neuropathy. A second reported phase III study comparing eribulin to capecitabine failed to show an improvement in survival in pretreated patients. This article reviews the clinical pharmacology and mechanism of action of eribulin, and summarizes the results of the major preclinical and clinical studies of eribulin in metastatic breast cancer.
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Affiliation(s)
- Mark K Doherty
- Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland
| | - Patrick G Morris
- Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland
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Dasari B, Jimmidi R, Arya P. Selected hybrid natural products as tubulin modulators. Eur J Med Chem 2014; 94:497-508. [PMID: 25455639 DOI: 10.1016/j.ejmech.2014.10.062] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 10/10/2014] [Accepted: 10/20/2014] [Indexed: 01/09/2023]
Abstract
Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents. The present review article is focused on two such bioactive natural products, epothilone and halichondrin B, and covers some of the key papers published after 2005 that outline various synthetic approaches to obtain next generation structural analogs as well as the synthesis of hybrid compounds.
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Affiliation(s)
- Bhanudas Dasari
- Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, Telangana, India
| | - Ravikumar Jimmidi
- Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, Telangana, India
| | - Prabhat Arya
- Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, Telangana, India.
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Polastro L, Aftimos PG, Awada A. Eribulin Mesylate in the management of metastatic breast cancer and other solid cancers: a drug review. Expert Rev Anticancer Ther 2014; 14:649-65. [DOI: 10.1586/14737140.2014.920693] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Gamucci T, Michelotti A, Pizzuti L, Mentuccia L, Landucci E, Sperduti I, Di Lauro L, Fabi A, Tonini G, Sini V, Salesi N, Ferrarini I, Vaccaro A, Pavese I, Veltri E, Moscetti L, Marchetti P, Vici P. Eribulin mesylate in pretreated breast cancer patients: a multicenter retrospective observational study. J Cancer 2014; 5:320-7. [PMID: 24723974 PMCID: PMC3982178 DOI: 10.7150/jca.8748] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 02/26/2014] [Indexed: 02/05/2023] Open
Abstract
Background: Eribulin was recently approved in patients progressing after being treated with anthracyclines and taxanes and after two or more chemotherapy lines for advanced disease. Objectives: This multicenter observational retrospective study was performed in order to evaluate activity and tolerability of eribulin in real-world patient population. Methods: 133 advanced breast cancer patients pretreated with ≥ 2 chemotherapy lines for metastatic disease were retrospectively enrolled in the observational trial in 11 italian cancer centres. Results: A median of 5 cycles of eribulin (range, 1-15) were administered. Twenty-eight partial responses were observed, for an overall response rate of 21.1% (95%CI,14.1-28.0). A stable disease was recorded in 57 patients (42.8%), and a clinical benefit (response or stable disease lasting ≥ six months) was observed in 51 patients (38.3%, 95%CI, 30.1-46.6). The subgroup analysis showed that a significant improvement in term of partial response and clinical benefit was achieved when eribulin was administered in HER-2 negative tumors (p=0.01 and p=0.004, respectively) and when it is given as third-line (p=0.09 and p=0.02, respectively). Toxicity was manageable; fatigue is the most common side effect observed, usually of low-grade, and clearly cumulative-dose related. Conclusions: In this retrospective, observational analysis eribulin confirmed its efficacy and manageable tolerability even in real-world population and in heavily pretreated patients.
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Affiliation(s)
- Teresa Gamucci
- 1. Medical Oncology Unit ASL Frosinone, Frosinone, Italy
| | - Andrea Michelotti
- 2. Oncology Unit I, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Laura Pizzuti
- 3. Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, Italy
| | | | | | - Isabella Sperduti
- 4. Biostatistics Unit, Regina Elena National Cancer Institute, Rome, Italy
| | - Luigi Di Lauro
- 3. Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, Italy
| | - Alessandra Fabi
- 5. Division of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy
| | - Giuseppe Tonini
- 6. Department of Medical Oncology, University Campus Bio-Medico, Rome, Italy
| | - Valentina Sini
- 7. Oncology Unit, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Nello Salesi
- 8. Medical Oncology, S.M. Goretti Hospital, Latina, Italy
| | - Ilaria Ferrarini
- 2. Oncology Unit I, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Angela Vaccaro
- 1. Medical Oncology Unit ASL Frosinone, Frosinone, Italy
| | - Ida Pavese
- 9. Medical Oncology, San Pietro Hospital, Rome, Italy
| | - Enzo Veltri
- 8. Medical Oncology, S.M. Goretti Hospital, Latina, Italy
| | - Luca Moscetti
- 10. Division of Medical Oncology, Department of Oncology, Belcolle Hospital, ASL Viterbo, Viterbo, Italy
| | - Paolo Marchetti
- 7. Oncology Unit, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Patrizia Vici
- 3. Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, Italy
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