European Journal of Cancer 86 (2017) 385e393
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Original Research
Phase II, multicentre, randomised trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine as first-line chemotherapy in patients with HER2-negative metastatic breast cancer Yeon Hee Park a,1, Seock-Ah Im b,1, Sung-Bae Kim c, Joo Hyuk Sohn d, Keun Seok Lee e, Yee Soo Chae f, Ki Hyeong Lee g, Jee Hyun Kim h, Young-Hyuck Im a, Ji-Yeon Kim a, Tae-Yong Kim b, Kyung-Hun Lee b, Jin-Hee Ahn c, Gun Min Kim d, In Hae Park e, Soo Jung Lee f, Hye Sook Han g, Se Hyun Kim h, Kyung Hae Jung c,*, Korean Cancer Study Group (KCSG) a
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, North Korea b Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University, College of Medicine, Seoul, North Korea c Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, North Korea d Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, North Korea e Center for Breast Cancer, National Cancer Center, Goyang, North Korea f Kyungpook National University Medical Center, Daegu, North Korea g Chungbuk National University Hospital, Cheongju, North Korea h Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, North Korea Received 10 August 2017; received in revised form 13 September 2017; accepted 1 October 2017
KEYWORDS Metastatic breast cancer; Eribulin;
Abstract Background: Paclitaxel plus gemcitabine (PG) combination chemotherapy is a preferred chemotherapeutic regimen for patients with metastatic breast cancer (MBC). Eribulin mesylate is a halichondrin non-taxane inhibitor of microtubule dynamics. A recent pooled analysis with eribulin showed improved overall survival (OS) in various MBC patient
* Corresponding author: Division of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, North Korea. Fax: þ82 2 3010 6961. E-mail address:
[email protected] (K.H. Jung). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.ejca.2017.10.002 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
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Paclitaxel; Gemcitabine; Chemotherapy
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subgroups pretreated with anthracycline and taxane. Furthermore, eribulin may have less neurotoxicity than paclitaxel. Patients and methods: This study was a prospective randomised phase II, open-label, two-arm, multicentre study comparing eribulin plus gemcitabine (EG) with PG chemotherapy as a firstline treatment for patients with human epidermal growth factor receptor 2-negative MBC. We hypothesised that EG chemotherapy would not be inferior to PG chemotherapy. The primary end-point was progression-free survival (PFS), which was estimated to be 70% at 6 months for each arm. The secondary end-points were as follows: OS, neuropathic scale, toxicity and clinical benefit rate. Results: A total of 118 patients (median age: 50, 24e66) were enrolled between March 2015 and March 2016 and were randomly assigned to PG (n Z 59) or EG (n Z 59) chemotherapy. The mean number of metastatic sites was 3 (range 1e8). The 6-month PFS rates for both arms were 72% for EG and 73% for PG (P Z 0.457). There was no significant difference in OS between the two groups (not reached versus 21.2 months, P Z 0.2234). The median number of chemotherapy cycles for both groups was 10 for EG and 8 for PG (range 2e32). Clinical benefit rates were 44% for EG and 49% for PG. Major toxicities were neutropenia and neurotoxicity. Grade II or above neurotoxicity was more common with PG than with EG (13.6% for EG versus 45.8% for PG, P < 0.0001). Conclusion: EG chemotherapy had similar clinical benefits to PG chemotherapy in terms of PFS but less neurotoxicity. Trial registration: KCSG BR13-11; ClinicalTrials.gov, NCT02263495. ª 2017 Elsevier Ltd. All rights reserved.
1. Introduction Breast cancer (BC), the most frequent malignancy in women, is a global problem and a leading cause of cancer mortality worldwide including Korea [1,2]. Metastatic BC (MBC) continues to be an incurable disease with a poor prognosis and a median 5-year survival of only 23e26% [1,3]. Effective long-term management of MBC poses significant clinical challenges. Taxanes, such as paclitaxel and docetaxel, are a cornerstone treatment across multiple lines of therapy to improve survival duration and palliate symptoms while minimising toxicity and maintaining quality of life (QoL) for patients with MBC. Eribulin mesylate is a non-taxane inhibitor of microtubule dynamics and is in the halichondrin class of antineoplastic drugs. Eribulin has a novel mode of action that is distinct from those of other tubulin-targeting agents, inhibiting the microtubule growth phase without affecting the shortening phase and causing tubulin to be sequestered into non-productive aggregates [4e6]. A recent pooled analysis showed an improvement in survival when eribulin was used with anthracycline in various subgroups of MBC patients pretreated with taxane [7]. Preclinical studies have found that eribulin combines synergistically with gemcitabine to induce tumour regression in non-small cell lung cancer xenografts [8,9]. Eribulin plus gemcitabine (EG) combination may be a potentially new regimen for early-line therapy in patients with MBC.
The phase III trial of paclitaxel and gemcitabine (PG) combination versus paclitaxel alone proved that gemcitabine added to paclitaxel is an effective therapy for women with BC who have previously received anthracyclines [10]. PG combination chemotherapy is one of the preferred chemotherapeutic regimens for patients with MBC and was found to be an appropriate maintenance chemotherapy regimen with survival benefits and a feasible toxicity profile in a large phase III Korean Cancer Study Group (KCSG) study [11]. Although there is no direct evidence that eribulin has a better neurotoxic profile than taxane, eribulin tended to show less neurotoxicity compared with ixabepilone in a phase II trial [12]. Chemotherapy-induced neurotoxicity is a significant problem in patients treated with taxane. Although there is no direct evidence that eribulin has a better neurotoxicity profile than taxane, there is some indirect evidence. Wozniak et al. conducted a mouse study to compare the neuropathy-inducing propensity of three drugs: paclitaxel, ixabepilone and eribulin mesylate [12]. Paclitaxel and ixabepilone, at their respective maximal tolerable doses, produced significant deficits in caudal nerve conduction velocity, caudal amplitude and digital nerve amplitudes as well as moderate to severe degenerative pathologic changes in dorsal root ganglia and the sciatic nerve. In contrast, eribulin mesylate produced no significant deleterious effects on any nerve conduction parameter measured and caused milder, less frequent effects on morphology. The toxicity of eribulin is no
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worse than that of paclitaxel. Therefore, EG may be less neurotoxic than PG. Based on this rationale, we aimed to conduct a randomised phase II study comparing EG chemotherapy with PG chemotherapy as first-line chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)-negative MBC. 2. Patients and methods 2.1. Eligibility criteria Women with histologically confirmed metastatic or recurrent BC were eligible for the study. Both premenopausal and postmenopausal women with measurable and/or non-measurable lesions, who were candidates for chemotherapy and who had no prior history of chemotherapy in the metastatic setting were eligible. Patients were eligible for the study if it had been at least 12 months since completion of prior chemotherapy, even if they had received an anthracycline- or taxanecontaining regimen as neoadjuvant or adjuvant therapy. Patients who had received hormonal therapy in an adjuvant and/or metastatic setting were eligible, but hormonal therapy was terminated before randomisation. Patients who had received radiation to less than 25% of their bone marrow and had recovered from the acute toxic effects of the treatment were eligible. Additional requirements included the following: aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0e2; adequate bone marrow, renal and liver function and absence of other concurrent or previous malignant neoplasms, with the exception of adequately controlled in situ uterine carcinoma and/or cutaneous basal cell carcinoma. The exclusion criteria were prior chemotherapy for MBC, clinically detectable brain parenchymal and/or leptomeningeal metastases, prior treatment with gemcitabine, grade II or higher peripheral neuropathy, other severe medical conditions and being HER2 positive. 2.2. Study design This study is a multicentre, randomised phase II, openlabel study of the KCSG (KCSG-BR13-11, NCT02263495). Patients were randomly assigned, in a 1:1 ratio, to either the EG or PG chemotherapy arm. Patients were accrued from eight institutes in Korea. Sub-investigators were members of the Breast Cancer Subcommittee in the KCSG. Randomisation numbers and treatment allocation were assigned by central randomisation. Patient numbers were chronologically assigned within each centre as patients were enrolled in the study. All patient numbers across the study were unique. Chemotherapy was started within 14 days after randomisation. The stratification factors for
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randomisation were prior neoadjuvant/adjuvant taxane therapy and hormonal receptor (HR) status (HR positive versus HR negative) (Fig. 1A). EG chemotherapy comprised eribulin 1.0 mg/m2 intravenous (i.v.) administration on days 1 and 8, and gemcitabine 1000 mg/m2 administered as a 30-minute i.v. infusion on days 1 and 8, and every 21 days thereafter. The doses of the EG regimen are based on a phase I trial of EG combination chemotherapy [13]. PG chemotherapy comprised paclitaxel 175 mg/m2 i.v. administration on day 1 and gemcitabine 1250 mg/m2 administered as a 30-minute i.v. infusion on days 1 and 8, and every 21 days thereafter. The patients were randomised to the chemotherapy until disease progression, development of unacceptable toxicity or withdrawal of consent. Hormonal therapy for patients with HR-positive MBC was not allowed in either group of patients after randomisation before disease progression. The study was conducted in full accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki and was approved by the institutional ethics committees of each hospital and the KCSG institutional review board. The ClinicalTrials.gov identifier number was NCT02263495. Written informed consent was obtained from each participant. 2.3. Study evaluation The pre-study clinical evaluation included a physical examination; vital signs with performance status; chest X-ray; computed tomography scans of the chest, abdomen and pelvis and a bone scan. Blood chemistry results and complete blood counts were obtained for every treatment cycle. Radiographic studies were performed every 6 weeks. Toxicity was assessed on the first day of each cycle. Overall survival (OS) was measured from the date of randomisation to the date of death from any cause, with censoring of the last visit date. Progression-free survival (PFS) was calculated from the date of randomisation to the documented date of disease progression or the last visit date. Disease response was assessed according to the Response Evaluation Criteria in Solid Tumours, (version 1.0) [14,15]. The duration of the response was measured from the time of chemotherapy to the date of disease progression. PFS and the duration of response were assessed by investigators. Toxicity was assessed at the end of each cycle using National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 4.0. The neuropathic scale was evaluated using a Functional Assessment of Cancer Therapy (FACT) for taxane QoL assessment (Korean version) [16]. 2.4. Dose modifications On the planned day of therapy, if the absolute neutrophil count was less than 1.5 109/L and/or the platelet
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Fig. 1. (A) Treatment scheme. (B) CONSORT flow diagram. EG, eribulin plus gemcitabine; PG, paclitaxel plus gemcitabine, HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer, PFS, progression-free survival; OS, overall survival; QoL, quality of life.
count was less than 100 109/L, chemotherapy was delayed for up to 3 weeks to allow sufficient time for recovery. If treatment could not be started after 3 weeks, the patient was removed from the study. Any patient who required a dose reduction continued to receive the reduced dose for the remainder of the study. Any patient who had two dose reductions and experienced a level of toxicity that would cause a third dose reduction was discontinued from the study therapy. Once reduced, no dose escalations were allowed in this study.
2.5. Statistical methods The primary end-point was PFS after randomisation. This was to demonstrate that the first-line treatment of EG chemotherapy was not inferior to PG in terms of PFS in patients with MBC. Secondary end-points included OS, neuropathic scale, toxicity, response duration, objective response rate and clinical benefit rate. We hypothesised that the PFS of the EG arm would not be inferior to that of the PG arm. The 6-
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Table 1 Patients’ characteristics between EG and PG arm. Characteristics
EG (%) (n Z 59)
PG (%) (n Z 59)
P value
Median age (range) ECOG PS 0 1 2 Menopausal status Pre Post Unknown IDC versus others HR positive HR negative HER2 positive Number of metastatic sites 1 2 3 Metastatic sites Distant lymph nodes Lung haematogenous Lung lymphangitic Liver Bone Pleura Others Visceral metastases Prior neoadjuvant chemotherapy Prior adjuvant chemotherapy Anthracycline Taxane Prior adjuvant endocrine therapy Palliative endocrine therapy before EG and PG chemotherapy
50 (27e65)
50 (24e65)
0.484 (T-test)
25 (42.4) 30 (50.9) 4 (6.8)
26 (44.1) 31 (52.5) 2 (3.4)
0.704
26 (44.1) 26 (41.1) 7 (11.9) 47 (79.7) 45 (76.3) 14 (23.7) 0
26 (44.1) 30 (50.8) 3 (5.1) 50 (84.7) 46 (78.0) 13 (22.0) 0
0.515
12 (20.3) 24 (40.7) 23 (39.0)
13 (22.0) 20 (33.9) 26 (44.1)
0.746
34 (57.6) 13 (22.0) 13 (22.0) 27 (45.8) 34 (57.6) 7 (11.9) 10 (16.9) 44 (74.6) 16 (27.1) 29 (49.2) 20 (33.9) 16 (27.1) 29 (49.2) 20 (33.9)
35 (59.3) 12 (20.3) 14 (23.7) 28 (47.5) 34 (57.6) 11 (18.6) 2 (3.4) 42 (71.2) 11 (18.6) 32 (54.2) 22 (37.3) 18 (30.5) 35 (59.3) 25 (42.4)
0.852 0.822 0.827 0.854 1.000 0.306 0.029 0.836 0.273 0.580 0.701 0.684 0.268 0.343
0.470 0.359
EG, eribulin plus gemcitabine; PG, paclitaxel plus gemcitabine; IQR, interquartile range; IDC, invasive ductal carcinoma; HR positive; HR negative.
month PFS rate for each arm was expected to be 70%. With 80% power and 10% one-sided type I error, and considering a 10% drop-out rate, we calculated that 112 patients were needed at the time of randomisation. The non-inferiority margin was 13%. All randomised patients were included in the efficacy analysis according to the intent-to-treat principle, and patients who received at least one dose of study medication were evaluated for safety. PFS and OS were estimated using the KaplaneMeier method and were compared with the log-rank test. Analyses of treatment effects were adjusted for covariates selected before the analysis using a multivariate Cox proportional-hazards model with stratification according to the visceral disease, age, menopausal status, performance status, number of metastatic sites, prior adjuvant taxane therapy, disease response and HR status. Differences were considered to be statistically significant at a P value of less than 0.05 in a two-tailed test.
3. Results 3.1. Patient characteristics A total of 118 patients were enrolled from eight centres in Korea from March 2015 to March 2016 and were randomly assigned to either EG chemotherapy (n Z 59) or PG chemotherapy (n Z 59) (Fig. 1B). The baseline characteristics of the patients were similar between the two groups (Table 1). The median ages of the two groups were 50 years, and about half of the patients were premenopausal women. The number of HRpositive patients was 45 (76.3%) in the EG arm and 46 (78.0%) in the PG arm. Twenty-nine (49.2%) patients in the EG and 32 (54.2%) patients in the PG group had received adjuvant chemotherapy (P Z 0.461). Adjuvant endocrine therapy had been administered to 29 (49.2%) patients in the EG arm and 35 (59.3%) patients in the PG arm who were HR positive. Palliative hormonal
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Fig. 2. (A) Progression-free survival (PFS). (B) Overall survival (OS). (C) Forest plots (PFS analysis). EG, eribulin plus gemcitabine; PG, paclitaxel plus gemcitabine; CI, confidence interval.
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Table 2 Toxicities. Adverse event, n (%)
Neutropenia Thrombocytopenia Anaemia Neuropathy Azotaemia AST ALT Nausea Vomiting Constipation Diarrhoea Alopecia
All grade
Grade IIIeIV
EG (n Z 59) (%)
PG (n Z 59) (%)
P value
EG (n Z 59) (%)
PG (n Z 59) (%)
P value
56 (94.9) 35 (59.3) 51 (86.4) 36 (61.0) 7 (11.9) 33 (55.9) 39 (66.1) 39 (66.) 22 (37.3) 5 (8.5) 10 (16.9) 44 (74.6)
50 (84.7) 31 (52.5) 50 (84.7) 54 (91.5) 3 (5.1) 25 (42.4) 28 (47.5) 30 (50.8) 18 (30.5) 7 (11.9) 10 (16.9) 38 (64.4)
0.13 0.46 0.79 <0.0001 0.32 0.14 0.041 0.093 0.44 0.54 NAy 0.23
34 (57.6) 8 (13.6) 5 (8.5) 0 1 (1.7) 0 0 1 (1.7) 1 (1.7) 0 0 NA
40 (67.8) 6 (8.5) 2 (3.4) 1 (1.7) 0 0 0 2 (3.4) 2 (3.4) 0 0 NA
0.25 0.56 0.44 NAa NAa NAa NAa NAa NAa NAa NAa NAa
EG, eribulin plus gemcitabine; PG, paclitaxel plus gemcitabine; AST, aspartate aminotransferase; ALT, alanine aminotransferase. a NA; not accessible.
therapy had been administered to 20 (33.9%) patients before enrolment in the EG group and 25 (42.4%) patients in the PG group because of metastasis. 3.2. Dose administration A total of 735 cycles of EG chemotherapy (median 10 cycles) and 590 cycles of PG chemotherapy (median eight cycles) were received by 118 patients after randomisation. The median dose intensity of eribulin was 0.898 mg/m2/week (89.8% of the expected dose; interquartile range (IQR), 0.811e0.950 mg/m2/week) in the EG arm. The median dose intensity of paclitaxel was 167.7 mg/m2/week (95.8% of the expected dose; IQR, 142.1e175.0 mg/m2/week) in the PG arm. The median dose intensity of gemcitabine was 901 mg/m2/week (90.1% of the expected dose; IQR, 819e960 mg/m2/ week) in the EG group and 1150 mg/m2/week (92.0% of the expected dose; IQR, 1072.5e1200 mg/m2/week) in the PG group. 3.3. Efficacy analysis The overall response and disease control rate of the study in 118 patients was 48.9% for EG and 44.1% for PG chemotherapy. The PFS rate at 6 months, which was the primary end-point of this study, between the two arms was 72% and 73%, respectively (hazard ratio Z 0.84, 95% confidence interval [CI], 0.53e1.33; P Z 0.457; Fig. 2A). The median PFS in the PG arm tended to be longer than in the EG group (median PFS 12.6 months for PG versus 9.6 months for EG) without statistical significance. The median OS appeared to be longer in the PG group than in the EG group without statistical significance (not reached versus 21.2 months) (hazard ratio Z 0.57; 95% CI, 0.23e1.45; P Z 0.240; Fig. 2B). There was no difference between the two arms, except for in HR status: a longer PFS was observed in patients receiving PG chemotherapy with an HR-negative
subtype than in those with an HR-positive subtype (95% CI, 0.10e0.78; P Z 0.014; Fig. 2C). The reasons for discontinuing the study drugs in the absence of progression differed between the two groups (Fig. 1B). Early discontinuation by physician/patient discretion was more prominent in the PG arm than in the EG arm (23% versus 6.5%). Eighty patients, 37 of 46 patients (80.4%) in the EG arm and 33 of 51 patients (64.7%) in the PG arm experienced disease progression. The median number of chemotherapy cycles of both groups was 10 for EG and 8 for PG (range 2e32). 3.4. Toxicity analysis Table 2 shows the drug-related NCI-CTC toxicities in each patient observed. There is no difference between the two groups in haematologic toxicity of all grades: neutropenia (94.9% for EG versus 84.7% for PG, P Z 0.13), thrombocytopenia (59.3% for EG versus 52.5% for PG, P Z 0.458) and anaemia (86.4% for EG versus 84.7% for PG, P Z 0.793). The rate of grade III or higher neutropenia was similar between the two arms (57.6% for EG versus 67.8% for PG, P Z 0.253). Neurotoxicity was the most common nonhaematologic toxicity (76.3%). Neuropathy of all grades was observed more frequently in the PG arm than in the EG arm: all grades (61.0% for EG versus 91.5% for PG, P < 0.0001) and grade II or more (13.6% for EG versus 45.8% for PG, P < 0.0001). Neuropathic scale results evaluated using FACT for taxane QoL assessment will be reported in a separate article. 4. Discussion In this randomised phase II study, the PFS of patients receiving EG chemotherapy as a first-line treatment for MBC was comparable with that of those receiving PG chemotherapy, which was the primary end-point. As
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anticipated, the EG arm had less severe neurotoxic effects compared with those receiving PG chemotherapy (Table 2) though the design does not allow a formal comparison between the two groups of treatment. Noninferiority (NI) trials are almost exclusively performed in phase III setting. However, the NI question might already be relevant in phase II setting in several settings: treatment optimisation in diseases or investigation of cytostatic agents or rare diseases or try to establish a reduced dose for frail patients [17]. We use this design anticipating a phase III NI trial. The significant increase in objective responses from PG compared with paclitaxel alone in the phase III study, together with the benefits observed in patients with poor visceral disease prognosis, supports its firstline use when a reduction in tumour burden is needed [10]. In addition, a KCSG study showed that PG was appropriate as a maintenance chemotherapy regimen with survival benefits and a feasible toxicity profile [11]. Based on these two trials [10,11], the schedule of paclitaxel was 175 mg/m2 every three weeks. However, the PG regimen has been associated with serious neurotoxicity, which is the main reason for discontinuing chemotherapy without disease progression. When considering the benefits and harms, our study results support the use of both the EG regimen and PG chemotherapy in daily practice. Despite the encouraging results, there are some caveats in this study. First, this study is a randomised phase II study using a NI margin, which reveals good but insufficient evidence for NI and requires further evidence [18]. We are aware that it is not a confirmative study result. Next, although there is no statistical difference, there are some results suggesting that PG is better than EG (Fig. 2B and C). These results are particularly noticeable in the HR-negative MBC subgroup (hazard ratio 0.28, 95% CI; 0.10e0.78, Fig. 2C) in spite of the higher number of chemotherapy cycles in EG (10) than in PG (8) chemotherapy. This finding suggests the need for a phase III study. EG may not be as effective as PG chemotherapy though it resulted in less serious neurotoxicity. The reason PG is so well in the referred study [10] is because the target population is different. The population of anthracycline pretreated versus non-pretreated is different (95% for ref. 10 versus 36% for this study). Nonetheless, it is essential to know that patients with MBC are a heterogeneous group, and the therapeutic strategies differ depending on subtypes and the circumstances of the individual patient [19]. For this reason, our study excluded patients with HER2-positive MBC; trastuzumab in combination with cytotoxic chemotherapy is recommended as the first-line treatment in this case [20]. Most importantly, for patients with HR-positive disease, endocrine therapy is the standard first-line therapy and should be considered
initially, except for patients with compromising organ function or requiring rapid response. Recent data have shown that in practice, a high percentage of patients with HR-positive MBC receive chemotherapy as firstline therapy [21,22]. Eventually, nearly all patients with MBC will require chemotherapy, particularly patients with HR-negative or hormone-resistant disease. Obviously, about half of the patients in our study were young and premenopausal. More than 60% of the patients had received adjuvant endocrine therapy previously. Approximately 40% of the patients had received palliative endocrine therapy before enrolment (Table 1). Moreover, about 75% of the patients had visceral diseases (lymphangitic pulmonary metastases and/or hepatic metastases). Over three-quarters of the patients had two or more metastatic sites. These findings necessitate cytotoxic chemotherapy for patients with HRpositive MBC. The treatment regimen, duration, sequence and order of palliative chemotherapy are major challenges yet to be defined for MBC patients who are candidates for chemotherapy. In this regard, our study suggests a promising new combination chemotherapy option with a favourable toxicity profile. EG chemotherapy may be a good therapeutic alternative to PG in patients with MBC who receive palliative chemotherapy. There is still a need to assess its optimal duration, which may lead to better long-term outcomes. In conclusion, our results show that EG chemotherapy has a clinically meaningful activity with a more favourable neurotoxic profile compared with PG chemotherapy in the PFS of patients with MBC. Funding None declared. Conflict of interest statement None declared.
Acknowledgements This study was supported by Eisai Korea Inc. (supplied eribulin), Dong-A ST Co., Ltd. (supplied gemcitabine), and Shamyang Biopharmaceuticals (supplied paclitaxel). This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1720150). Presented in part at the 53rd Annual Meeting of the American Society of Clinical Oncology, June 2e6, 2017, Chicago, IL. The authors thank Young Lan Hong and Sinae Kim of the A-CRO team in AMC for data management support and the study coordinators from each institute.
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