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Address for correspondence: Takashi Ishikawa, MD, PhD, Breast Oncology and Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
Neuropathy was significantly less frequent and less severe with eribulin than paclitaxel.
•
The pCR rate was higher with paclitaxel (29.8%) than with eribulin (20.7%, P = .289).
•
Three-year DFS was equivalent (paclitaxel: 86.0%, eribulin: 89.7%, P = .561).
Abstract
Objective
Neoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel.
Methods
In this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis.
Results
One hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E.
Conclusion
Neuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy.
Neoadjuvant chemotherapy (NAC) is actively administered to breast cancer patients, partly because response to NAC is a valuable indicator of the requirement for additional treatment.
According to the Japanese Breast Cancer Registry, which is based on the National Clinical Database, 10% of 90,232 Japanese breast cancer patients without distant metastasis received NAC in 2017.
The choice of chemotherapy regimen is dependent on the clinical status of the patient and their tumor subtype. NAC agents with proven efficacy include anthracyclines and taxanes such as paclitaxel, but they are associated with several side effects including neuropathy. Chemotherapy-induced peripheral neuropathy is a severe and dose-limiting adverse effect of neurotoxic chemotherapeutic agents and can lead to discontinuation of treatment in serious cases.
Paclitaxel targets microtubules, which are involved in neuronal function, and thus induces peripheral neuropathy in approximately 60-70% of patients administered paclitaxel for cancer treatment.
Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states.
Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomized study.
However, there are limited reports about the efficacy of eribulin for early breast cancer. In the HOPE study, promising antitumour activity of eribulin as NAC was observed in patients with triple-negative breast cancer who had received paclitaxel and doxorubicin.
The clinical benefit of eribulin-based treatment as NAC in triple-negative breast cancer was further compared with that of paclitaxel in another phase II study, demonstrating pCR rates of 65% and 45%, respectively.
Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial.
Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9.
A randomized phase II study of sequential eribulin versus paclitaxel followed by FAC/FEC as neoadjuvant therapy in patients with operable HER2-negative breast cancer.
and eribulin was not as effective as paclitaxel. However, these trials did not focus on neuropathy, a possible advantage of eribulin. We performed a NAC study to determine if sequential administration of eribulin followed by anthracycline induced less peripheral sensory and motor neuropathy than paclitaxel followed by anthracycline and compared patient-reported neuropathy outcomes for more than 4 years. Our findings will enable clinicians to select alternative treatment strategies for early-stage breast cancer patients suffering from paclitaxel-induced neuropathy.
Materials and Methods
Study Design
This randomized, prospective, unblinded phase II study was conducted by Japan Organization Neoadjuvant Innovative Experts (JONIE), which was established to perform clinical trials and improve breast cancer treatment. This study compared eribulin with paclitaxel for 12 weeks, followed by 4 cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Registration was from December 3, 2013 to April 13, 2016, and the study was performed from December 25, 2013 to December 31, 2020. Patients were randomly assigned to receive eribulin (group E) or paclitaxel (group P) as the first agent by computer random-based allocation, and the registration number was sent from the data center. The allocated treatment was not concealed from the physicians or the patients. Patients who received any other treatment were removed from the study. HER2+ patients were administered trastuzumab. Stratification factors were estrogen receptor (ER), HER2, and menopausal status, and they were centralized at the data center (Department of Medical Informatics of Niigata University Medical and Dental Hospital). HER status was assessed in accordance with the 2013 American Society of Clinical Oncology and/or College of American Pathologists clinical practice guidelines,
Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.
while hormone receptor status was determined by the presence of 1% or more estrogen receptor-positive cells. The study protocol (UMIN000012817) was approved by the institutional review board of Tokyo Medical University on December 25, 2013 (approval number: SH2588) and subsequently by all participating institutions. Written informed consent was obtained from all participants prior to study inclusion.
Patient Eligibility
The inclusion criteria of this study were: stage II–IIIb hormone receptor-positive and HER2-negative breast cancer and stage Ic–IIIb triple-negative or HER2-positive breast cancer; Eastern Cooperative Oncology Group performance status of 0–1; aged over 20 years; and diagnosed with invasive breast cancer via core-needle biopsy before treatment. Exclusion criteria were: pregnancy; breastfeeding; or bilateral breast cancer (synchronous or asynchronous).
Treatment
Patients received either 4 cycles of eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle (group E) or weekly paclitaxel 80 mg/m2 for 12 weeks (group P), followed by 4 cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) every 21 days, and crossover was not permitted. Treatment was discontinued if progressive disease or unacceptable toxicity was noted. Dose reductions (P from 80 to 70 mg/m2 and E from 1.4 to 1.1 mg/m2) were permitted according to the grade of toxicity. Prophylactic granulocyte colony-stimulating factor was permitted depending on the grade of neutropenia. Patients were withdrawn from the study if they had Grade 4 non-hematological toxicity, progression while undergoing chemotherapy, or a treatment delay of 16 days due to toxicity.
Surgery was planned after completion of the stratified treatment and evaluation of the tumor. Mastectomy or breast-conserving surgery (BCS) and axillary staging was performed at the discretion of the surgeon and patient. Postoperative radiation and adjuvant therapy was administered according to the attending physician's judgement or patient preference. The stopping criteria were as follows: 1) clear clinical exacerbation of breast cancer after the start of treatment and the efficacy is determined to be progressive disease (PD); 2) protocol treatment cannot be continued due to adverse events (AEs) ((i) grade 4 non-hematological toxicity; (ii) start of the next course of chemotherapy is delayed for 3 weeks or more due to an AE; (iii) the provisions for discontinuing protocol treatment in the Treatment Change Criteria are met; (iv) an allergic reaction/hypersensitivity of grade 3 or higher develops during weekly paclitaxel); 3) the patient withdraws consent or wishes to discontinue the study; 4) the patient is found to be ineligible after the start of treatment; and 5) the investigator determines that it is difficult to continue the protocol treatment.
Assessment of safety
AEs were assessed before treatment with eribulin or paclitaxel and FEC on the day of administration. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0)
Feasibility and validity of the Patient Neurotoxicity Questionnaire during taxane chemotherapy in a phase III randomized trial in patients with breast cancer: N-SAS BC 02.
a validated patient-reported questionnaire on neuropathy. The scoring definitions of PNQ are detailed in Table 1; patients subjectively responded to each item, and the mean scores of PNQ were calculated by averaging the collected data. PNQ was collected not only from baseline, during the intended chemotherapy, and after the administration of FEC, but also at 6 months and at 1, 2, 3, and 4 years after surgery.
Clinical response was radiologically assessed prior to surgery as complete response (CR), partial response (PR), stable disease (SD), and PD in accordance with the Response Evaluation Criteria in Solid Tumors version 1.1.
Pathological response was assessed post-surgery using hematoxylin–eosin-stained tissue samples prepared from tissue sections of primary tumors at each participating institution. Pathological complete response (pCR) was defined as no invasive residual tumor tissue in the breast. Non-invasive breast residual and infiltrated lymph nodes were permitted, as used by the National Surgical Adjuvant Breast and Bowel Project (ypT0/is ypN0/+).
The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27.
The primary endpoint was the incidence of grade 1 or higher peripheral sensory neuropathy (PSN) and peripheral motor neuropathy (PMN) according to CTCAE. This was evaluated every 3 weeks for a total of 8 times during the treatment prior to surgery. Secondary endpoints were pCR, clinical response (CR+PR), BCS, AEs, PNQ, and disease-free survival (DFS).
Statistical analysis
The planned sample size was 230 cases based on the assumptions that the proportion of grade 1 or higher neuropathy in group P would be 30% and that of group E would reduce the proportion to 50%. Thus, we estimated that 105 patients would be required to detect this difference with a power of 80% and a 2 sided α of 0.05. According to an estimated dropout rate of approximately 10%, the target enrolment was set at 230 patients (115 per group).
Patients who received the protocol treatment (4 cycles of eribulin (E) or weekly paclitaxel 12 times (P), followed by 4 cycles) were included in the efficacy analysis. Those who received at least 1 dose of either regimen were included in the safety analysis.
For the primary endpoint, PSN and PMN rates were compared between the groups using Fisher's exact test. The secondary endpoints of clinical response rates and BCS rates were compared between the groups using the Fisher's exact test. PSN, PMN, and PNQ were also compared using Fisher's exact test. DFS was estimated using the Kaplan–Meier method and was compared between the groups using the log-rank test when the sample size was considered sufficient.
All analyses were performed using IBM SPSS Statistics Version 26 (IBM Corp., Armonk, NY, USA). A P value of < .05 was considered significant.
Results
Patient characteristics
One hundred and twenty-one participants were recruited from 10 participating institutions and registered between December 2013 and April 2016. Patients were randomized to group E (n = 60) and group P (n = 61) (Table 2). Three patients in group P were excluded before the protocol treatment. Two patients withdrew consent, and 1 could not start the protocol by the scheduled date because they were undergoing treatment for subclavian vein thrombus associated with central venous access port placement. Thus, safety was analyzed in 60 patients from group E and 58 from group P. Efficacy could not be evaluated in 3 patients. One patient in group E discontinued treatment because of a grade 3 allergic reaction to the initial treatment, 1 in group E refused surgery, and 1 in group P dropped out of the study because she required treatment for deterioration of diabetes during chemotherapy and could not undergo the protocol treatment. Overall, 115 patients (58 from group E and 57 from group P) completed the treatment and were evaluated for efficacy (Figure 1).
Table 2Baseline Characteristics.
Group E
Group P
(n = 60)
(n = 58)
Age (years)
Median
53.5
53
Minimum, maximum
28, 69
27, 67
ECOG PS
0
59 (98.3%)
58 (100%)
1
0 (0%)
0 (0.0%)
NA
1 (1.7%)
0 (0.0%)
Menopausal status
Pre
29 (48.3%)
27 (46.6%)
Post
31 (51.7%)
31 (53.4%)
Clinical T stage
T1
7 (11.6%)
7 (12.0%)
T2
45(75.0%)
38 (65.5%)
T3
2 (3.3%)
5 (8.6%)
T4
6 (10.0%)
8 (13.7%)
Nodal status (clinical)
Negative
22 (36.7%)
28 (48.3%)
Positive
35 (58.3%)
29 (50.0%)
NA
3 (5.0%)
1 (1.7%)
Histological type
Ductal
56 (93.3%)
53 (91.3%)
Lobular
1 (1.7%)
1 (1.7%)
Other
1 (1.7%)
0 (0.0%)
NA
2 (3.3%)
4 (6.9%)
Histological grade
1
4 (6.7%)
4 (6.9%)
2
46 (76.7%)
38 (65.5%)
3
10 (16.7%)
16 (27.6%)
Oestrogen receptor
Positive
37 (61.7%)
38 (65.5%)
Negative
23 (38.3%)
20 (34.5%)
HER2 status
Positive
20 (33.3%)
20 (34.5%)
Negative
40 (66.7%)
38 (65.5%)
ECOG PS = Eastern Cooperative Oncology Group performance status; NA = not available.
Incidences of PSN and PMN according to CTCAE ver.4.0. are shown in Table 5 and 6, respectively. PSN was consistently lower in group E than in group P after week 6, while PMN in group E was significantly lower at weeks 9, 12, and 15 (Figure 2).
Figure 2Incidences of grade 1 or higher peripheral sensory neuropathy (A) and peripheral motor neuropathy (B) according to CTCAE ver.4.0.
PNQ item 1 (sensory) and item 2 (motor) grades for the scheduled times are shown in Figure 3, Figure 4, respectively. PNQ item 1 (sensory) was consistently lower in group E after week 7, while item 2 (motor) in group E was consistently lower, although not significant (Figures 3 and 4). These findings indicate that the incidence and severity of peripheral neuropathy was significantly lower in patients who received eribulin compared with those who received paclitaxel.
Figure 3Mean scores (line graph) of PNQ item 1 (sensory) and number of cases with a score of 4 or 5 (bar graph). Error bars indicate standard deviation.
pCR rates were 20.7% in group E and 29.8% in group P, and there was no significant difference between them (P = .289; Table 3). There were no cases of pCR in the breast but with residual cancer in the lymph nodes.
Table 3Clinicopathological Effects and Type of Surgery.
The overall clinical response rate was significantly lower in group E (55.2%; CR, 6.9% and PR, 48.3%) than in group P (77.2%; CR, 8.8% and PR, 68.4%; P = .017; Table 3). The rates of BCS were 56.9% in group E and 52.6% in group P (P = .710; Table 3). Thus, paclitaxel demonstrated better pCR and clinical response rates than eribulin, but BCS rates were better in patients who received eribulin.
Safety
AEs are summarized in Table 4. Four (6.7%) patients in group E had febrile neutropenia, which was not experienced by patients in group P, although this was not significantly different. Moreover, neutropenia and leukocytopenia over grade 3 were significantly more frequent in group E. However, rash, nail disorder, and allergic reaction were significantly more frequent in group P.
Table 4Adverse Events.
Group E (n = 60)
Group P (n = 58)
Adverse event
Total
Grade 3 or 4
Total
Grade 3 or 4
P value (Total)
P value (Grade 3 or 4)
n (%)
n (%)
n (%)
n (%)
All adverse events
60 (100%)
16 (26.7%)
58 (100%)
2 (3.4%)
1.000
<0.001
Peripheral sensory neuropathy
40 (66.7%)
0 (0.0%)
54 (93.1%)
3 (5.2%)
<0.001
0.116
Peripheral motor neuropathy
16 (26.7%)
0 (0.0%)
28 (48.3%)
0 (0.0%)
0.022
1.000
Leukopenia
14 (23.3%)
6 (10.0%)
9 (15.5%)
0 (0.0%)
0.355
0.028
Neutropenia
20 (33.3%)
15 (25.0%)
14 (24.1%)
1 (1.7%)
0.313
<0.001
Febrile neutropenia
4 (6.7%)
4 (6.7%)
0 (0.0%)
0 (0.0%)
0.119
0.119
Alopecia
55 (91.7%)
0 (0.0%)
56 (96.6%)
0 (0.0%)
0.439
1.000
Nausea
18 (30.0%)
0 (0.0%)
15 (25.9%)
0 (0.0%)
0.684
1.000
Vomiting
2 (3.3%)
0 (0.0%)
5 (8.6%)
0 (0.0%)
0.268
1.000
Constipation
18 (30.0%)
1 (1.7%)
20 (34.5%)
0 (0.0%)
0.695
1.000
Diarrhoea
7 (11.7%)
0 (0.0%)
10 (17.2%)
0 (0.0%)
0.440
1.000
Increased ALT
4 (6.7%)
0 (0.0%)
1 (1.7%)
0 (0.0%)
0.365
1.000
Increased AST
4 (6.7%)
0 (0.0%)
2 (3.5%)
0 (0.0%)
0.680
1.000
Stomatitis
11 (18.3%)
0 (0.0%)
13 (22.4%)
0 (0.0%)
0.651
1.000
Dysgeusia
9 (15.0%)
0 (0.0%)
8 (13.8%)
0 (0.0%)
1.000
1.000
Decreased appetite
16 (26.7%)
0 (0.0%)
13 (22.4%)
0 (0.0%)
0.671
1.000
Fatigue
30 (50.0%)
0 (0.0%)
33 (56.9%)
0 (0.0%)
0.467
1.000
Hand-foot syndrome
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
1.000
1.000
Nail disorder
3 (5.0%)
0 (0.0%)
11 (19.0%)
0 (0.0%)
0.023
1.000
Rash
6 (10.0%)
0 (0.0%)
21 (36.2%)
0 (0.0%)
<0.001
1.000
Pigmentation
0 (0.0%)
0 (0.0%)
1 (1.7%)
0 (0.0%)
0.492
1.000
Pyrexia
8 (13.3%)
0 (0.0%)
4 (6.9%)
0 (0.0%)
0.363
1.000
Arthralgia
6 (10.0%)
0 (0.0%)
10 (17.2%)
0 (0.0%)
0.291
1.000
Headache
7 (11.7%)
0 (0.0%)
11 (19.0%)
0 (0.0%)
0.313
1.000
Oedema
4 (6.7%)
0 (0.0%)
7 (12.1%)
0 (0.0%)
0.358
1.000
Allergic reaction
2 (3.3%)
1 (1.7%)
9 (15.5%)
0 (0.0%)
0.028
1.000
Hepatic failure
0 (0.0%)
0 (0.0%)
1 (1.7%)
1 (1.7%)
0.492
0.492
Significant associations are marked in bold.
ALT = alanine aminotransferase; AST = aspartate transaminase.
The median relative dose intensity (RDI) for eribulin in group E was 98.9% (25.0%-102.8%) and for paclitaxel in group P was 99.2% (12.5%-100.2%); the RDI for epirubicin was 94.5% (0%-100.0%) in group E and 95.4% (0%-130.6%) in group P. The number of patients with an RDI of 85% or more was 49 (81.7%) for eribulin and 48 (80.0%) for epirubicin in group E, and 53 (91.4%) for paclitaxel and 48 (82.8%) for epirubicin in group P. Thus, while RDI was similar between the 2 groups, the incidence of grade 3 or higher neutropenia and leukocytopenia was significantly higher in patients who received eribulin.
Disease-free survival
Median follow-up of group E and group P was 54.2 and 51.4 months, respectively, and there was no significant difference between group E and group P (P = .561, Figure 5). Thus, no greater survival benefits were observed between eribulin and paclitaxel.
NAC is 1 of the preferred treatment strategies for early breast cancer because it has various advantages including improved breast conservation and enhanced assessment of tumor response. However, several side effects are associated with neoadjuvant agents such as paclitaxel. We conducted this prospectively registered multicenter study with patient-relevant outcomes to explore whether eribulin followed by an anthracycline confers fewer side effects than paclitaxel, with emphasis on grade 1 or higher peripheral neuropathy. To our knowledge, this is the first prospective randomized controlled trial comparing eribulin and paclitaxel focusing on neuropathy. A significant difference in PSN was observed between eribulin and paclitaxel. However, the trial review committee of the JONIE group halted this trial because a similar study at MD Anderson had closed early due to lower pCR rates that crossed a futility stopping boundary in the eribulin group.
A randomized phase II neoadjuvant (NACT) study of sequential eribulin followed by FAC/FEC-regimen compared to sequential paclitaxel followed by FAC/FEC-regimen in patients (pts) with operable breast cancer not overexpressing HER-2.
pCR rates in the current study indicated that the efficacy of eribulin was lower than that of paclitaxel, affecting prognosis.
Neuropathy should be evaluated if taxane is administered as the control because neuropathy accompanying taxanes causes severe long-term damage to quality of life, and there is currently no effective standard therapy.
Thus, it is important to alleviate neuropathy from adjuvant chemotherapy, which occurs in certain patients, most of whom are survivors. Neuropathy was evaluated as 1 of several AEs in 2 previous trials, but to our knowledge there have been no prospective randomized controlled trials comparing neuropathy caused by eribulin with that of paclitaxel.
Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9.
A randomized phase II study of sequential eribulin versus paclitaxel followed by FAC/FEC as neoadjuvant therapy in patients with operable HER2-negative breast cancer.
In this study, the frequency and severity of neuropathy were significantly better in group E than group P. PNQ was evaluated for 4 years, and PSN was significantly better in group E. Some patients suffered from severe neuropathy (PNQ score 4 or 5; interfering with activities of daily living) in group P, which continued for several years, consistent with previous reports.
It remains unclear as to why some patients have long-term severe neuropathy in perioperative chemotherapy, but a previous report indicated that neuropathy induced by paclitaxel in Japanese breast cancer patients was associated with older age and a polymorphism in the ABCB1 transporter.
Therefore, paclitaxel alternatives should be considered, of which eribulin could be a candidate.
Our study showed a significant difference in the response rate on imaging but no significant difference in pCR between patients who received paclitaxel or eribulin (29.8% and 20.7%, respectively; P = .289). This contrasts with the findings of the MD Anderson trial,
A randomized phase II neoadjuvant (NACT) study of sequential eribulin followed by FAC/FEC-regimen compared to sequential paclitaxel followed by FAC/FEC-regimen in patients (pts) with operable breast cancer not overexpressing HER-2.
in which pCR was 27% in the paclitaxel group and 5% in the eribulin group. These differences may be because of the low number of cases receiving eribulin in the MD Anderson trial.
A randomized phase II neoadjuvant (NACT) study of sequential eribulin followed by FAC/FEC-regimen compared to sequential paclitaxel followed by FAC/FEC-regimen in patients (pts) with operable breast cancer not overexpressing HER-2.
Another study comparing eribulin with paclitaxel in combination with anthracycline was performed by the National Surgical Adjuvant Breast and Bowel Project (NSABP).
Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9.
Although the prognosis was not reported, they also revealed a lower pCR rate of 17% for eribulin compared with 26% for paclitaxel (not significant). Although there was no significant difference in the pCR rate between eribulin and paclitaxel followed by anthracycline, the efficacy for early breast cancer was commonly lower in the eribulin arm in the 3 trials. Nonetheless, the differences between the results of these previous studies and the current study are marked. One explanation is that they were conducted in different patient populations and the differences could be attributed to pharmacoethnicity, but there is currently no reported evidence of such differences for eribulin. Furthermore, while the US Food and Drug Administration endorses pCR as a surrogate endpoint for breast cancer to enable acceleration of drug approval, a systematic review of pCR as a surrogate endpoint for DFS and overall survival in randomised trials for neoadjuvant therapy of early breast cancer questioned its reliability and suggested that it was not robust as a primary endpoint.
Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomized clinical trials of early stage breast cancer: systematic review and meta-analysis.
Hence, the use of pCR to assess efficacy may be misleading, and a future study examining the effect of neoadjuvant eribulin on other equivalent endpoints should be considered. Thus, caution should be exercised when comparing pCR rates between studies.
Regarding prognosis, despite there being several more patients with nodal metastases in group E at baseline, the Kaplan–Meier curve was superior in group E in this study, although not significant. However, according to Lim et al., DFS and overall survival was better for paclitaxel, but this was also not significant.
A randomized phase II study of sequential eribulin versus paclitaxel followed by FAC/FEC as neoadjuvant therapy in patients with operable HER2-negative breast cancer.
Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9.
A randomized phase II study of sequential eribulin versus paclitaxel followed by FAC/FEC as neoadjuvant therapy in patients with operable HER2-negative breast cancer.
. Hematological toxicity was also more frequent and more severe in group E than group P in this study, and several patients had febrile neutropenia, which must be treated seriously. Nonetheless, eribulin caused fewer allergic reactions, and thus may represent a treatment option for patients who cannot tolerate paclitaxel.
There are several limitations of this study. The number of enrolled patients did not reach the planned sample size, and thus the statistical interpretation of the data was limited. Furthermore, the trial was stopped early, and hence the analyses of the prespecified endpoints are underpowered. The evaluation of neuropathy is subjective and thus has the potential to introduce bias, particularly because the study was not blinded. In addition, eribulin induced more severe hematological events than paclitaxel, and therefore the choice to administer eribulin would need to be justified on a patient-by-patient basis in consideration of these effects. Furthermore, this study, as well as the MD Anderson trial
A randomized phase II neoadjuvant (NACT) study of sequential eribulin followed by FAC/FEC-regimen compared to sequential paclitaxel followed by FAC/FEC-regimen in patients (pts) with operable breast cancer not overexpressing HER-2.
Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology).
The patients of both groups underwent FEC; it is unlikely to affect the outcome, but the effect cannot be completely ruled out. FEC was used in this study; however, if eribulin was administered instead of paclitaxel, epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC) which provides comparable efficacy with FEC, would be applied. Nonetheless, a strength of this study is that there were notable differences in the AEs between eribulin and paclitaxel.
Since eribulin did not show higher efficacy, it is difficult to reimburse insurance as a preoperative treatment as single administration; however, it may be useful in combination with immuno-oncology drugs
In conclusion, eribulin resulted in less frequent and less severe peripheral neuropathy than paclitaxel. While eribulin was not more effective than weekly paclitaxel, and it conferred more frequent and more severe hematological AEs than paclitaxel, eribulin could be an alternative to weekly paclitaxel in perioperative chemotherapy. Future studies should focus on analyzing a subgroup of early-stage breast cancer patients with neuropathy to assess non-inferiority with regards to efficacy using alternative endpoints to pCR, and to confirm the neuropathy outcome. A subgroup analysis of such a study should also be conducted to determine if efficacy observations are dependent on ethnic background.
Clinical Practice Points
•
Only 2 randomized phase II trials compared eribulin with paclitaxel as NAC, and eribulin was not as effective as paclitaxel. However, these trials did not focus on neuropathy, a possible advantage of eribulin. Paclitaxel is associated with severe neuropathy, leading to treatment discontinuation. Eribulin, like paclitaxel, targets microtubules and has demonstrated improved survival of metastatic breast cancer with less neuropathy. This study investigated whether eribulin induces less neuropathy than paclitaxel in NAC for early breast cancer.
•
Eribulin treatment resulted in less frequent and less severe neuropathy than paclitaxel. Peripheral sensory neuropathy and peripheral motor neuropathy were significantly lower at week 6 and at weeks 9, 12, and 15, respectively, in patients who received eribulin compared with those who received paclitaxel. Furthermore, 4 year PNQ evaluation revealed that peripheral sensory neuropathy was lower in patients who received eribulin compared with those who received paclitaxel. And eribulin accompanied fewer allergic reactions, while it conferred more frequent and more severe hematological AEs than paclitaxel.
•
Eribulin was not more effective than weekly paclitaxel. pCR rates were 20.7% and 29.8% (P = .289) in patients who received eribulin and paclitaxel, respectively, while clinical response was 55.2% and 77.2%, respectively (P = .017), and 3 year DFS was similar between both groups, at 89.7% and 86.0%, respectively (P = .561).
•
Eribulin could be an alternative for patients who cannot tolerate paclitaxel because of neuropathy or allergic reactions. Nonetheless, the choice to administer eribulin would need to be justified on a patient-by-patient basis in consideration of the possibility of less effectiveness.
Author Contributions
D.M. designed this phase 2 trial. K.N., T.I., K.N., D.M., Y.H., A.T., J.H., M.H., M.M., T.K, M.S., N.K., and T.I. were the site investigators who recruited patients, contributed to patient care, and collected patient data. K.A. was the bioinformatician who managed the data center and analyzed and summarized the acquired data statistically. T.I. guided the initial drafting of the manuscript, and K.N. drafted, refined, and edited the manuscript. T.I., D.M., and Y.H. reviewed the manuscript. All authors had full access to the study data, contributed to the revision and approval of the manuscript, and participated in the decision to submit the manuscript for publication.
Data Availability
The data underlying this study were collected and analyzed at the Department of Medical Informatics, Niigata University Medical and Dental Hospital, Niigata, Japan. Data will be shared on request to the corresponding author with the permission of JONIE.
Ethics Approval
The study complied with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research of the Ministry of Health, Labor, and Welfare of Japan. The study protocol (UMIN000012817) was approved by the institutional review board of Tokyo Medical University on December 25, 2013 (approval number: SH2588) and subsequently by all participating institutions.
Disclosure
The authors declare that they have no potential conflicts of interest.
Acknowledgments
We thank H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. This study was self-funded by each facility. Data management, English proofreading, and posting costs were supported in part by a grant from JONIE.
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