|Year : 2016 | Volume
| Issue : 3 | Page : 460-463
Eribulin in heavily pretreated metastatic breast cancer: A tertiary care center experience from India
J Bajpai, A Ramaswamy, S Gupta, J Ghosh, S Gulia
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||24-Feb-2017|
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Heavily pretreated metastatic breast cancer (MBC) remains a major therapeutic challenge with limited treatment options this. Eribulin, an anti-microtubule agent, has been recently approved for this indication. There are sparse data from the Asian region for eribulin and merits exploration. MATERIALS AND METHODS: This was a single institution retrospective analysis of MBC patients treated with eribulin from 2013 to 2014. These patients had received at least 2 lines of prior therapy for metastatic disease. Patients received standard doses of eribulin and were monitored for toxicity and responses. RESULTS: Eighteen patients were included in this analysis. They had received a median of 6 lines of therapy previously (including adjuvant treatment) and had significant visceral involvement (median 3 organs). A median of 4 cycles of eribulin was delivered. There were no complete responses; partial responses were seen in 33% (6/18), stable disease status in 28% (5/18) patients, and progressive disease on eribulin in 39% (7/18) patients. The median progression-free survival was 15 weeks (3.5 months), and median overall survival was 27 weeks (6.2 months). Significant Grade 3/4 toxicities seen included peripheral neuropathy in 28% (5/18) and neutropenia in 28% (5/18) of patients while dose reductions were required in 22% (4/18) of patients. CONCLUSION: Eribulin offers a viable, well-tolerated regimen that provides meaningful clinical benefit in Indian patients with MBC.
Keywords: Eribulin, metastatic breast cancer, response, toxicity
|How to cite this article:|
Bajpai J, Ramaswamy A, Gupta S, Ghosh J, Gulia S. Eribulin in heavily pretreated metastatic breast cancer: A tertiary care center experience from India. Indian J Cancer 2016;53:460-3
|How to cite this URL:|
Bajpai J, Ramaswamy A, Gupta S, Ghosh J, Gulia S. Eribulin in heavily pretreated metastatic breast cancer: A tertiary care center experience from India. Indian J Cancer [serial online] 2016 [cited 2017 Jul 22];53:460-3. Available from: http://www.indianjcancer.com/text.asp?2016/53/3/460/200653
| » Introduction|| |
Metastatic breast cancer (MBC) patients constitute an important component of the spectrum of breast cancer patients, with a 5 years median overall survival (OS) rate between 20% and 30%. Approximately 5% of patients present with upfront metastasis and a further 30% of early, breast cancer patients develop metastases at a later date. Although it is not curable, meaningful improvements in survival can be achieved with use of systemic therapies. Heavily pretreated MBC is rather more difficult to treat with only a handful of chemotherapeutics available for this population. A reduced bone marrow reserve in such patients and residual, cumulative toxicity, for example, peripheral neuropathy, makes selection of an appropriate regimen a difficult decision.,
While the gold standard for evaluating the efficacy of any treatment is OS, it is a difficult to achieve endpoint in the metastatic setting and hence, progression-free survival (PFS) is gaining acceptance as an appropriate endpoint by many investigators, but not all.
Traditional chemotherapeutic agents, such as gemcitabine,, liposomal doxorubicin,, vinorelbine, and platinum  (especially in the TNBC subgroup), have been used in the metastatic setting, with response rates between 10% and 35%. However, the drugs that have generated active and ongoing interest are capecitabine,,, ixabepilone,, nab-paclitaxel, and now, eribulin.
Eribulin (eribulin mesylate; Halaven) is a synthetic analog of halichondrin B, a natural compound isolated from the Japanese marine sponge, Halichondria okadai. It acts by inhibiting the microtubule growth phase without affecting the shortening phase, thereby causing tubulin sequestration into nonproductive aggregates., It has shown OS benefit in MBC compared with treatment of the physician's choice (13.2 months vs. 10.5 months, respectively; hazard ratio 0:81; P = 0.014) in the Phase III EMBRACE study  and was found equivalent to capecitabine in the 301 study. Eribulin has been approved for use in MBC patients who have progressed on at least 2 lines of therapy. However, the experience from the developing world in real life situations is sparse. Hence, we aimed at evaluating patterns of use, outcomes, and toxicity of eribulin in the Indian context. To the best of our knowledge, this is one of the earliest data sets from India regarding this drug.
| » Materials and Methods|| |
The study was a retrospective single institution analysis, with a cohort comprising of MBC patients, all previously treated with at least 2 lines of chemotherapy (necessarily including anthracyclines and taxanes, even if received in the adjuvant setting). Patients treated with eribulin and having received at least 2 doses of eribulin as per the standard schedule of 1.4 mg/m 2 over 2–5 min intravenous on days 1 and 8, on a 3 weekly schedule, were included in the study. Eribulin was continued until disease progression, intolerance to therapy, or patient refusal. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4, was used for measuring toxicity while treatment efficacy was evaluated radiologically or by clinical evaluation.
A retrospective review of clinical evaluation and treatment records for all the patients was carried out and stored on an anonymous database for analysis.
Response rates including complete response, partial response (PR), and stable disease (SD) were calculated. The associations and prognostic factors evaluated were number of metastatic organs involved (n ≤ 2 vs. n > 2), number of prior therapies (n ≤ 5 vs. n ≥ 6), endocrine receptor (ER) status, Her2 status, and PFS on therapy before eribulin. These factors were analyzed by the Chi-square test or Fisher exact test, as required. PFS and OS were calculated by the Kaplan–Meier product-limit method. PFS was calculated from date of first dose of eribulin to date of first documented progression, loss to follow-up or death. OS was defined as the time from the first dose of eribulin to death from any cause or last date of documented follow-up.
| » Results|| |
From November 2013 to November 2014, 18 patients with metastatic, pretreated breast cancer treated in our institution were found assessable. Main patient and tumor characteristics are reported in [Table 1].
The median age was 44.5 years (31–63), median European Cooperative Oncology Group performance status 1, ER-positive 50%, (9/18), Her2 amplified 17% (3/18), and triple negative subtype in 33% (6/18). 56% (10/18) of patients had more than 2 sites of disease, with the most common sites of disease being bone 50% (9/18), liver 50% (9/18), and nodal sites 50% (9/18). Visceral lung lesions 33% (6/18), pleural effusion 28% (5/18), and 1 patient with brain metastases were the other common sites of disease. The median number of eribulin cycles received in these patients was 4 (range: 1–6).
All 18 patients were evaluable for response [Table 2] and survival analysis. While complete responses were not seen, PR were seen in 33% (6/18) and SD in 28% (5/18) of patients, resulting in a clinical benefit in 61% (11/18) patients. There were no statistically significant differences in response between the various subgroups, based on receptor subtype.
Evaluation of survival data revealed a median PFS of 15 weeks (3.5 months) [Figure 1]. There were no significant differences across different subgroups we had compared as prognostic factors. Median OS was 27 weeks (6.2 months) [Figure 2]. Across subgroups examined, there was no significant difference in OS, with all groups experiencing similar outcomes.
On analysis of toxicity [Table 3], eribulin appeared to be well tolerated. While considering hematological toxicity, Grade 3/4 neutropenia was seen in 28% (5/18) patients with one patient having febrile neutropenia, necessitating hospital admission, and intravenous antibiotics. The other toxicities could be managed on outpatient basis. Grade 3/4 anemia was seen in 11% (2/18), but no Grade 3/4 thrombocytopenia occurred.
Besides hematological toxicity, Grade 3 peripheral neuropathy (PN) was seen in 28% (5/18) patients. PN was cumulative-dose related, usually appearing after the 2nd or 3rd cycle. All 5 patients with Grade 3 PN had partial resolution of symptoms on dose reduction (25%). Grade 3 transaminitis was seen in 5.5% (1/18) of patients – this resolved prior to the beginning of next cycle and did not necessitate dose reduction. Grade 1/2 fatigue was seen in 22% (4/18) of patients, with no Grade 3/4 fatigue seen. 22% (4/18) of our patients required dose reduction by 25% – doses were maintained at reduced levels and were not increased back to full doses in all patients. Patients with Grade 3/4 neutropenia were given secondary granulocyte-colony stimulating factor (G-CSF) prophylaxis during further cycles of eribulin if not on primary G-CSF prophylaxis.
| » Discussion|| |
The goals of treatment in MBC continue to remain symptomatic palliation and disease control, with quality of life issues being of paramount importance as disease is incurable. However, as of date, there is growing evidence that up to 40% of patients may benefit for up to 6 months on the 3rd line or further lines of therapy.
Despite the multiple options available, there is no consensus as to which drug is to be preferred in pretreated MBC.,, There is extensive literature on capecitabine use as third line therapy after taxanes and anthracyclines – a recent pooled analysis of data from trials where capecitabine was used as the second line or beyond showed response rate of 19%, PFS of 3.7 months, and OS of 13 months. Ixabepilone, an anti-tubulin drug, is a first agent in its class and has shown response rates of 11.5% as monotherapy  and up to 43% in combination with capecitabine. Nab-paclitaxel is the other agent which has shown good response rates (33–48%) with an acceptable toxicity profile: However, none of them could show an OS benefit in MBC.,,,
In this context, the EMBRACE trial  as well as the subsequent trial comparing capecitabine versus eribulin (study 301) throws some light on potential preferences. The EMBRACE trial is the only trial to date which has shown that monotherapy, eribulin, prolongs OS in pretreated MBC. Eribulin showed RR of 12%, clinical benefit rate (CBR) of 23%, PFS 3.6 months, and OS of 13.1 months. Study 301, the second pivotal study with regard to eribulin, showed that while eribulin offered no OS (15.9 vs. 14.5 months) or PFS benefit (4.1 vs. 4.2 months) when compared to capecitabine, it was equally well tolerated with comparable outcomes. RR of 11% and CBR of 26.2% were seen in study 301, which was similar to the EMBRACE study. Another retrospective observational multicenter study from Italy, consisting 133 patients, showed slightly higher RR of 23.1% and CBR of 38.3%, lending credence to the use of eribulin in heavily pretreated patients. A Phase 2 study from Japan, by Aogi et al., showed response rates, CBR, PFS, and OS of 21.3%, 27.5%, 3.9 months, and 11.1 months, respectively, mirroring the EMBRACE data.
Our patient population involved 18, relatively young (median age 44.5) heavily pretreated (an average of 6 lines of prior therapy) MBCs, who had progressed rapidly on prior therapy (72% within 3 months). Within the constraints of such a small cohort, we have some encouraging data regarding eribulin. We observed response rates of 33%, clinical benefit in 61%, PFS of 15 weeks (3.5 months), and OS of 27 (6.2 months) weeks. While PFS is comparable to western data, the OS in our analysis was lower than other studies evaluating eribulin.,,, A possible reason for this is the heavily pretreated nature and resistant biology of disease in our patients. In the EMBRACE trial, the median number of prior therapies was 4 lines and in study 301, it was 2 while it is 6 in this study. With such small numbers, as expected, there were no major differences in responses and survival across various subgroups with eribulin.
Toxicity and tolerance are a major concern in this group of patients. As seen in EMBRACE and study 301, eribulin was well tolerated. While there were many Grade 1/2 toxicities in EMBRACE (majorly fatigue, neuropathy, and neutropenia), the major Grade 3/4 side effects were neutropenia (45%), leukopenia (14%), and PN (8%). The incidence of serious adverse effects in patients receiving eribulin was 5%. Study 301 showed a similar side effect profile with no major differences.
A major focus of our analysis was evaluation of toxicity. Eribulin was well tolerated in our patients, with only 1 patient having Grade IV toxicity – Grade IV neutropenia with neutropenic fever. The incidence of Grade 3/4 neutropenia was 28% in this study, which is less than that seen in published data. A potential reason for this is our use of G-CSF as primary or secondary prophylaxis, in anticipation of potential toxicity in the presence of compromised bone marrow reserve of the heavily pretreated patients. We commonly use 3 doses of G-CSF after D8 dose of eribulin. Grade 3/4 PN was seen in 39% of our patients, which is more than seen with the EMBRACE and study 301 studies. Reasons could be higher incidence of diabetes (diagnosed as well as masked), B12 and B6 deficiency, and poor nutritional status of these patients. About 22% (4/18) of our patients required dose reduction – 3 due to Grade III PN and 1 due to Grade IV neutropenia. Fatigue has been reported as a major side effect, up to 70% in the retrospective Italian study  – our analysis showed a 22% incidence of fatigue (only Grade 1 and 2). However, we acknowledge that this may be partly due to underreporting (being retrospective in nature) and also varied patient perception of the importance of fatigue in this part of the world. Besides the incidence of peripheral neuropathy, the toxicity profile in this data set indicates that eribulin is well tolerated in our patients.
A majority of patients receiving treatment in our institution are not insured and do not have the financial wherewithal for expensive treatment options. Very few patients will be able to afford eribulin in the Indian population, which makes it all the more vital that we have some data from this population before embarking on such an expensive treatment option. This small data set is also an indirect indicator of the small number of patients who will eventually receive eribulin, outside of a clinical trial in India.
The main weakness of this study is the small sample size, the retrospective nature of the study, likely underreporting of subjective side effects such as fatigue and lack of uniform criteria for reporting side effects. These are expected lacunae in a single institution retrospective analysis.
The major strength of this analysis is its accurate representation of the cohort in the Indian population who will be eligible for eribulin, quite unlike the populations who are taken up for clinical trials. The results here are more likely to be indicative of expected usage, outcomes, and toxicities in a real world population.
This is one of the first data set on eribulin in India, and we hope this furthers our understanding of this molecule, which has already become an established part of the armamentarium against MBC in USA and Europe.
| » Conclusion|| |
Eribulin offers a relatively well-tolerated treatment option in heavily pretreated MBCs with meaningful clinical benefit and responses across most subgroups. However, experience with a larger cohort will make us wiser in using this molecule.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
American Cancer Society. Breast Cancer Facts & Figures 2011-2012. Atlanta: American Cancer Society, Inc.; 2011.
Cardoso F, Senkus-Konefka E, Fallowfield L, Costa A, Castiglione M; ESMO Guidelines Working Group. Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21 Suppl 5:v15-9.
El Saghir NS, Tfayli A, Hatoum HA, Nachef Z, Dinh P, Awada A. Treatment of metastatic breast cancer: State-of-the-art, subtypes and perspectives. Crit Rev Oncol Hematol 2011;80:433-49.
Dufresne A, Pivot X, Tournigand C, Facchini T, Altweegg T, Chaigneau L, et al
. Impact of chemotherapy beyond the first line in patients with metastatic breast cancer. Breast Cancer Res Treat 2008;107:275-9.
Guarneri V, Conte P. Metastatic breast cancer: Therapeutic options according to molecular subtypes and prior adjuvant therapy. Oncologist 2009;14:645-56.
Martín M, Ruiz A, Muñoz M, Balil A, García-Mata J, Calvo L, et al.
Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: Final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol 2007;8:219-25.
Possinger K, Kaufmann M, Coleman R, Stuart NS, Helsing M, Ohnmacht U, et al.
Phase II study of gemcitabine as first-line chemotherapy in patients with advanced or metastatic breast cancer. Anticancer Drugs 1999;10:155-62.
Martín M, Sánchez-Rovira P, Muñoz M, Baena-Cañada JM, Mel JR, Margeli M, et al.
Pegylated liposomal doxorubicin in combination with cyclophosphamide and trastuzumab in HER2-positive metastatic breast cancer patients: Efficacy and cardiac safety from the GEICAM/2004-05 study. Ann Oncol 2011;22:2591-6.
Fiegl M, Mlineritsch B, Hubalek M, Bartsch R, Pluschnig U, Steger GG. Single-agent pegylated liposomal doxorubicin (PLD) in the treatment of metastatic breast cancer: Results of an Austrian observational trial. BMC Cancer 2011;11:373.
Decatris MP, Sundar S, O'Byrne KJ. Platinum-based chemotherapy in metastatic breast cancer: Current status. Cancer Treat Rev 2004;30:53-81.
Blum JL, Barrios CH, Feldman N, Verma S, McKenna EF, Lee LF, et al.
Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2012;136:777-88.
Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al.
Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 2007;25:3407-14.
Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, et al.
Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007;25:5210-7.
Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, et al.
Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005;23:7794-803.
Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, et al.
The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 2005;4:1086-95.
Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, et al.
Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry 2010;49:1331-7.
Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al.
Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomised study. Lancet 2011;377:914-23.
Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, et al.
Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2015;33:594-601.
Pagani O, Senkus E, Wood W, Colleoni M, Cufer T, Kyriakides S, et al.
International guidelines for management of metastatic breast cancer: Can metastatic breast cancer be cured? J Natl Cancer Inst 2010;102:456-63.
Beslija S, Bonneterre J, Burstein HJ, Cocquyt V, Gnant M, Heinemann V, et al.
Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009;20:1771-85.
Gamucci T, Michelotti A, Pizzuti L, Mentuccia L, Landucci E, Sperduti I, et al.
Eribulin mesylate in pretreated breast cancer patients: A multicenter retrospective observational study. J Cancer 2014;5:320-7.
Aogi K, Iwata H, Masuda N, Mukai H, Yoshida M, Rai Y, et al.
A phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancer. Ann Oncol 2012;23:1441-8.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]