Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-Shorter; NCT02001506)

Abstract

Purpose

To determine whether six cycles of FEC3-D3 has a comparable efficacy to eight of AC4-D4.

Methods

The enrolled patients (pts) were clinically diagnosed with stage II or III breast cancer. The primary endpoint was a pathologic complete response (pCR), and the secondary endpoints were 3-year disease-free survival (3Y DFS), toxicities, and health-related quality of life (HRQoL).

Results

Among the 248 pts enrolled, one case was ineligible for screening; 10 discontinued treatment due to progressive disease (7 and 3 in the AC4-D4 and FEC3-D3 arms), 16 dropped out due to a withdrawal of consent, and 3 were unable to complete the study (2 and 1 in the AC4-D4 and FEC3-D3 arms). The 218 pts who completed the surgery were included in the current analysis. The baseline characteristics of these subjects were well balanced between the two arms. By ITT analysis, pCR was achieved in 15/121 (12.4%) pts in the FEC3-D3 arm and 18/126 (14.3%) in the AC4-D4 arm (P = 0.40). With a median follow up of 64.1 months, the 3-year DFS was comparable between the two arms (77.0% in FEC3-D3 vs. 74.9% in AC4-D4; P = 0.82). The most common adverse event (AE) was Grade 3/4 neutropenia, which arose in 27/126 (21.4%) AC4-D4 arm pts vs 23/121 (19.0%) FEC3-D3 arm cases. The primary HRQoL domains were similar between the two groups (FACT-B scores at baseline, P = 0.35; at the midpoint of NACT, P = 0.20; at the completion of NACT, P = 0.44).

Conclusion

Both NACT AC4-D4 and FEC3-D3 show comparable outcomes in terms of pCR, three-year DFS, toxicities, and QoL Shorter neo-adjuvant FEC3-D3 could be an alternative to AC4-D4 for stage II or III operable breast cancer.

Trial registration

ClinicalTrials.gov NCT02001506. Registered December 5,2013

https://clinicaltrials.gov/ct2/show/NCT02001506

Introduction

The previous national surgical adjuvant breast and bowel project (NSABP) B18 study[1] demonstrated that there was no significant difference in overall survival (OS) or disease free survival (DFS) between adjuvant and neoadjuvant chemotherapy, also confirmed in many subsequent studies[1-4]. Although has been no reported survival gain with neoadjuvant chemotherapy, it has been used to reduce the extent of local therapy or reduce delays in initiating therapy[1, 5-7]. In addition, some studies have confirmed that achieving a pathologic complete response (pCR) after neoadjuvant chemotherapy was significantly helpful in predicting long term survival outcomes[1-4]. Neoadjuvant chemotherapy has thus become a standard of care that can be considered in a locally advanced breast cancer.

The previous randomized NSABP-B27 study has reported a 90% overall clinical response rate after 4 cycles of AC followed by 4 cycles of docetaxel [8]. Three cycles of FEC (fluorouracil, epirubicin, and cyclophosphamide) followed by 3 cycles of docetaxel, compared to 6 cycles of FEC, in an adjuvant setting have also demonstrated a survival benefit[9]. Three cycles of FEC followed by 3 cycles of docetaxel (FEC3-D3) was a popular neoadjuvant chemotherapy regimen in Europe when this study was designed. Six rather than 8 cycles has an advantage in terms of a shorter treatment duration with lower toxicities and a higher compliance unless efficacy is compromised. Docetaxel can also be used at a dose of 75 mg/m² in each cycle considering the higher toxicity at the 100mg/m² dose for no benefit observed in previous studies [10, 11], and would be more feasible in a neoadjuvant setting in terms of a reduced toxicity and improved tolerance. However, there have been limited reports to date on whether efficacy is maintained, or quality of life (QoL) is reduced, when the number of treatment cycles is reduced. In our present study, we compared the degree of efficacy and QoL over the course of the neoadjuvant chemotherapy intervention in patients who underwent AC4-D4 or FEC3-D3 as a preoperative chemotherapy regiment for stage II or III breast cancer.

Patients And Methods

Study design and objectives

This was a randomized, prospective, parallel group, comparative phase 3 study conducted at Asan Medical Center, Seoul, Korea. The patient allocation is described in Figure 1. The primary outcome was pCR from a node-positive breast cancer treated with an FEC3-D3 or AC4-D4 neo-adjuvant chemotherapy regimen. Secondary outcomes included 3-year disease free survival (3Y DFS), quality of life (QoL), and the correlation between pCR and Ki-67 expression. pCR was defined as no evidence of invasive cancer in the breast or lymph nodes. Detailed descriptions of the study methodology and eligibility criteria are provided in the Supplementary Information.

Procedures

Three cycles of FEC followed by 3 cycles of docetaxel (FEC3-D3) were administered by intravenous injection every 3 weeks using the following dosages: 5-fluorouracil, 500 mg/m²; epirubicin, 100 mg/m²; cyclophosphamide, 500 mg/m²; and docetaxel 75 mg/m². Four cycles of AC followed by 4 cycles of docetaxel (AC4-D4) were also administered by intravenous injection every 3 weeks as follows: adriamycin, 60 mg/m²; cyclophosphamide, 600 mg/m²; and docetaxel, 75 mg/m². Mammography and breast ultrasounds were done at the midpoint (after the 3 cycles of FEC in arm A and 4 cycles of AC in arm B) and at the completion of the chemotherapy. Breast magnetic resonance(MR) was performed at baseline and before surgery. Surgery was undertaken within 6 weeks of the last round of chemotherapy. The administration of adjuvant chemotherapy, hormonal therapy and/or trastuzumab, and postoperative radiation was at the discretion of the treating physician.

Response and toxicity assessments

Response assessments were done using RECIST version 1.1. Averse events (AEs) were evaluated every 3 weeks (±1 weeks) using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Patients who had received at least one cycle of chemotherapy were included in toxicity assessment. A QoL assessment was conducted at the midpoint and at the completion of the chemotherapy using Functional Assessment of Cancer Therapy-Breast (FACT-B) version 4.0[12].

Statistical analysis

With a two-sided type Ι error of 0.05 and a power of 80%, we calculated that 252 pts were needed in each treatment group to enable the detection of non- inferiority of neoadjuvant FEC3-D3 compared to AC4-D4 with a pCR rate of 20% (non- inferiority margin of 10%). Considering a dropout rate of 10%, and 280 pts in each arm, a total of 560 patients per arm would be enrolled. Pts were randomized using the stratified block randomization method with the hormone receptor and Her2 expression status included as the stratification factors. The sample size was amended due to slower enrolment and competing trials. The revised statistical procedure was that all parameters would be analyzed using descriptive statistics i.e. without any statistical formal comparison. Disease free survival was calculated with the Kaplan-Meier method. Categorical variables were expressed as proportions and continuous variables as the mean ± SD. The Mann-Whitney U-test was used to compare differences between the treatment arms. The Friedman test was used to detect repeated measurement difference. Statistical analysis was done using SPSS version 23.0 (IBM Corp, Armonk, NY), and statistical significance was defined as a P value less than 0.05. The cut off value of the Ki-67 labeling index was determined by the AUC curve based on the values of the highest sensitivity and specificity.

Results

Baseline characteristics of the total cohort

In this present study, 247 patients diagnosed with stage II or III breast cancer between November 2012 and December 2015 were enrolled. These cases were randomly assigned (1:1) to an FEC3-D3 (n=121, 48.9%) or AC4-D4 (n=126, 51.1%) treatment arm. Subsequent to this enrollment, one patient was found to be ineligible for screening; 10 discontinued treatment due to progressive disease (7 in the AC4-D4 arm and 3 in the FEC3-D3 arm), 16 patients withdrew consent to participate (13 in the AC4-D4 arm and 3 in the FEC3-D3 arm), and 3 patients were unable to complete the study (2 in the AC4-D4 arm due to exceeding the limit of dose delay of 9 weeks and grade 3 peripheral neuropathy, and 1 patient in the FEC3-D3 arm due to a loss of consciousness of unknown etiology). Ten out of 247 patients (4.0%) experienced progression during the neoadjuvant chemotherapy. Two of them were unable to undergo surgery because they had a distant metastasis. The 218 remaining patients receiving surgery were included in our per-protocol analysis. The baseline characteristics were well balanced in terms of median age (48 vs 47), percentage of luminal type cases (68.4% vs 72.1%), and percentage of triple negative breast cancers (20.2% vs. 17.3%) between the FEC3-D3 (n=121) and AC4-D4 (n=126) arms. Clinical T2 (57.5% vs. 62.7%) and N1 (63.3% vs. 64.3%) stage tumors were also predominant in both arms (Table 1).

Pathologic complete response outcomes and correlations with the baseline Ki-67 labeling index

By intention-to-treat (ITT) analysis, pCR was achieved in 15/121 (12.4%) patients in the FEC3-D3 arm and 18/126 (14.3%) patients in the AC4-D4 arm (P=0.40). In the FEC3-D3 arm, 92/114 patients achieved a clinical response [4 complete responses (CR) and 88 partial responses (PR)] and among these cases, 15 patients (13.2%) achieved pCR. In the AC4-D4 arm, 95/104 patients achieved a clinical response (6 CR and 89 PR), among which 18 patients (17.3%) achieved pCR (Table 2). There was no significant difference between the 3YDFS and pCR in each arm even when analyzed by subtype (Table S2 in the Supplementary material). In the total patient cohort, a higher pCR rate was observed for a baseline Ki-67 labeling index of 55% or more. In terms of the treatment arm, the pCR rate and a Ki-67 labeling index ³55% were correlated in both groups. By subtype, the pCR rate was higher when the Ki-67 labeling index was ≥55% in the luminal B type cases.

Three-year disease-free survival outcomes

With a median follow up of 64.1 months, the 3Y DFS (77.0% in FEC3-D3 vs. D74.9% in AC4-D4) was comparable between the two arms (P=0.82; Fig. 2). Forest plots of the 3Y DFS for the subgroups in the per-protocol analysis are shown in Figure 3. In the subgroup analysis, there was no favorable regimen between FEC3-D3 and AC4-D4. Univariate and multivariate analyses of the associations between the clinicopathologic factors and 3Y DFS are summarized in Table S1 in the Supplementary material. For the 3Y DFS, ³55% of the baseline Ki-67 labeling index (HR 2.1, 95% CI, 1.03-4.40; P=0.04), and ³4 lymph node metastases at surgery (HR 1.9, 95% CI, 1.07-3.51; P=0.03) were independent predictive factors for the 3Y DFS. 

Toxicity and QoL assessments

The most common AE was a Grade 3/4 neutropenia [27/126 (21.4%) patients in the AC4-D4 arm vs. 23/121 (19.0%) patients in the FEC3-D3 arm]. The most common Grade 3/4 non-hematologic AE was hyperglycemia (4.0%). A dose modification was made in 25/121 (20.7%) patients in the FEC3-D3 arm and 37/126 (29.4%) in the AC4-D4 arm (P=0.09; Table 3). The QoL scores determined by FACT-B version 4 are listed in Table 4. The mean QoL values at baseline were 102.39, (standard deviation (SD), 17.50) vs.100.74 (SD, 16.72), at the midpoint of neoadjuvant chemotherapy were 85.24 (SD, 36.80) vs. 79.28 (SD, 38.62), and at the completion of chemotherapy were 75.71 (SD, 39.53) vs.70.73 (SD, 42.25) in the FEC3-D3 vs. AC4-D4 arm, respectively. In the FACT-B subgroups, emotional wellbeing (EWB) showed the lowest scores in both groups at baseline [FEC3-D3, 16.71 (SD, 4.81) vs. AC4-D4, 15.89 (SD, 4.79)]. Social wellbeing (SWB) had the lowest score in the FEC3-D3 arm [15.23 (SD,8.16)] ,whereas functional wellbeing (FWB) displayed the lowest score in the AC4-D4 arm [13.81 (SD, 7.61)] at the midpoint of the neoadjuvant chemotherapy. FWB was the lowest in both groups at the completion of chemotherapy [FEC3-D3, 12.83 (SD, 7.76) vs. AC4-D4, 12.72 (SD, 8.52)]. 

Discussion

FEC 3 followed by docetaxel 3 had been one of representative preoperative/adjuvant chemotherapy regimens specified in the NCCN guidelines up to 2017.[13-17]. Notably however, the FEC regimen was excluded from the NCCN guidelines after the NSABP-B36 trial[18]. In that study, six cycles of an FEC regimen did not show a superior efficacy to four AC cycles, but did show a higher toxicity. In our present study, no reduction in toxicity was confirmed in the FEC3-D3 arm which was consistent with findings of NSABP-B36 study in which duration of cycles were addressed. Since the NSABP-B27 report, the AC4-D4 regimen has become widely used. However, the 8 cycles of treatment in this protocol requires 6 months to complete, and there have been concerns regarding the reduction in patient compliance that is commonly related to a longer treatment duration. In addition, there is a reported QoL decrease due to increased exposure to anthracycline and taxane in the AC4-D4 regimen. Strategies to reduce the number of chemotherapy cycles has also been explored in another study[19].

In our present study, we observed no significant difference between the two treatment arms in terms of the pCR rate, although a numerically higher pCR rate was noted among the AC4-D4 cases. The pCR rate in our study was low compared to the 26.1% level reported in the NSABP-B27[8]. The pCR rate is known to be higher after neoadjuvant chemotherapy in the absence of HER2, estrogen receptor (ER) positivity and a lack of lymph node metastasis[20-23]. The difference between the pCR rate in our study series and that in the NSABP-B27 trial may have been due to the greater number of lymph node metastases in our present cohort [Neo-Shorter vs. NSABP-B27, 247/247 (100%) vs. 244/805 (30.3%)] and also the higher ER positivity [Neo-Shorter vs. NSABP-B27, 153/247 (62.0%) vs. 319/805 (39.6%)]. In the NSABP-B27 study, the pCR rate in the AC followed by taxane treatment group with ER positivity was 14.1%, comparable to the 17.3% rate found in our present series. In addition, our observed pCR rate was low compared to a prior Indian study with a similar design concept[19]. The difference in the pCR rate between our present study and the prior Indian report may also have been affected by differences in the proportion of triple negative breast cancers (TNBCs) and HER2-positive tumors, even though they had a similar clinical stage (neo-shorter vs. India, 29.8% vs. 49%). Also, in the study cohort from India, unlike our present series, HER2 2+ was considered to be negative without further HER2 in situ hybridization being conducted, which may have affected the findings.

Similar to previous studies, the higher Ki67 level among patients with the luminal type breast tumors in our present cohort was associated with a higher pCR. There was no significant correlation found between Ki-67 and the pCR rate in previous TNBC studies, or among these cases in our present study, which might reflect the heterogeneity of this disease[24]. However, there was a significant correlation found in our current analyses, in both treatment arms, between the pCR and a Ki 67 index that was equal to or more than 55%.

There was no significant difference in the 3Y DFS between our two study arms and further subgroup analysis indicated that neither regimen was more favorable. Multivariate analysis revealed that a ³55% baseline Ki-67 labeling index (HR 2.1, 95% CI,1.03-4.40; P=0.04), and ³4 lymph node metastases at surgery (HR 1.9, 95% CI, 1.07-3.51; P=0.03) were independent predictive factors for the 3Y DFS outcome. A previous study found that an age >50, higher T and N clinical stage, or tumor size >5 cm were independent risk factors for distant metastasis in TNBC[25]. Additionally, in a previous meta-analysis study by Salvo et al of hormone receptor-positive and HER2-negative breast cancers, it was confirmed that lymph-node positivity was an important factor for recurrence[26]. Our present results were consistent with the previously reported criteria for high-risk recurrence in TNBCs or hormone receptor-positive breast cancers. In terms of the 3Y DFS, the difference between our current study findings and those of the PCAS01 trial appears be an effect of the inclusion ratio of stage I lesions (neo-shorter: stage I, 0%, 3Y DFS, 77.0% vs. PACS01: stage I, 10.4%, 3Y DFS, 84.5%). Similarly, the 3Y DFS in the NSABP-B27 trial (5Y DFS, 71%) was comparable to that of the Neo-Shorter subjects treated with AC4-D4 (74.9%). The difference may be due to the presence of higher-risk patients in our current series, including those with more than 4 LN metastases [≥4LN metastases: neo-shorter vs. NSABP-B27, 85/247 (34.4%) vs. 114/752 (15.2%)].

There was no significant difference in the toxicities between our present study arms. In our current cohort, febrile neutropenia was within the 11-34% range reported in previous studies[9, 19]. In terms of QoL outcomes, there was also no significant difference between our two study groups. The FACT-B score, including all subfactors, showed a gradual decrease during chemotherapy. These differences indicated that the chemotherapy affected the QoL. At the treatment baseline, the EWB had the lowest score whereas the FWB score was the lowest at the completion of the chemotherapy. The lowest sub-factor before the start of the chemotherapy was the EWB, and this was likely related to the previously described prevalence of depression in breast cancer patients[27]. That prior study reported that upon a diagnosis of breast cancer, uncertainty about future disease progress, imagining of a poor situation by the patient, and fear of physical changes following treatment can cause depression. In our current investigation, it appeared that the EWB level before the start of chemotherapy was also influenced by the abovementioned factors. The lowest subfactor at the completion of chemotherapy was the FWB, likely because of the toxicity effects after these treatments. Interestingly, at the midpoint of treatment, the FEC3-D3 cases had the lowest SWB and AC4-D4 patients had the lowest FWB. The FWB was thus not the lowest in the FEC3-D3 group even in the middle of the chemotherapy. The cause of this might be associated with the decrease in anthracycline administration but further research is warranted. 

Limitations

Although the results of the TRYPHAENA trial were published in 2013[28], we were unable to use a HER2 blockade in our neoadjuvant setting, especially during study period, because of the reimbursement policy of the Korean National Health Insurance system for locally advanced breast cancer. Hence, 9.7% (24/247) of the cases included in our present study series had the HER2 subtype. In addition, only the 3Y DFS outcomes could be confirmed among our study patients because of the relatively short follow-up period. In this regard, continuous follow-up will be required to confirm any differences in the long-term outcomes in both arms.

Conclusion

There is no significant difference in terms of the pCR, 3Y DFS, QoL, or toxicity profiles between the shorter FEC3-D3 and longer AC4-D4 neo-adjuvant chemotherapeutic regimens for stage II or III operable breast cancers. The shorter FEC3-D3 could be therefore a viable alternative.

Declarations

Acknowledgements

This study was presented in part during the 2020 San Antonio Breast Cancer Symposium (SABCS) , 8-11 December 2020, San Antonio, USA.

Role of the funding source

This work was supported by a grant from the Sanofi-Aventis (Grant No.2012-0116)

Conflicts of interest

Hee-Jin Lee is founder of Neogene TC. Kyung Hae Jung has advisory roles at Astra-Zeneca, BIXINK, MSD, Novartis, Pfizer, Roche, Takeda and Everest Medicine. Sung-Bae Kim is a consultant on the advisory boards of Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, and Daiichi-Sankyo, and has received research funding from Novartis, Sanofi-Aventis, and DongKook Pharm Co., and owns stock in Genopeaks and NeogeneTC. No other authors have any conflicts of interest to declare in relation to this study.

Research involving human and animal participants

All of the enrolled human subjects in this study provided written informed consent to participate and to the publication of the findings.

Author contributions

All of the listed study authors contributed to this study in accordance with the International Committee of Medical Journal Editors (ICMJE) guidelines for authorship. All authors have read and approved the submitted version of the manuscript (and any substantially modified version that involves their contribution to the study). Each author has agreed to be personally accountable for their own contributions and to ensuring that any questions regarding the accuracy or integrity of any part of the work, even those areas in which the author was not personally involved, are appropriately investigated and resolved, and that this resolution is documented in the literature.

Availability of data and materials

All data and materials will be made available upon reasonable request.

Ethical approval and consent to participate

The Institutional Review Board (IRB) at our institution approved this study. All procedures involving human participants followed the ethical standards of the institutional and/or national research committee, and of the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors confirmed that our manuscript do not contains any individual person’s data.

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Tables

Table 1. Baseline characteristics of the study population

Abbreviations: AC4-D4, adriamycin and cyclophosphamide (4 cycles) followed by docetaxel (4 cycles); BCO,  Breast conserving operation; Dec, decreasing; FEC3-D3, fluorouracil, epirubicin, and  cyclophosphamide (3 cycles) followed by docetaxel (3 cycles); HER2, human epidermal growth factor receptor 2; MRM, modified radical mastectomy; NACT, neoadjuvant chemotherapy.

^aLuminal B-like: ER-positive (all red score ≥ 3) with high Ki-67 (≥15%) or ER-positive with HER2 positivity

^bHER2-positive: hormone receptor-negative with HER2 positivity (Her2/neu immunohistochemistry (IHC) 3+ or Her2/neu 2+ and fluorescence in situ hybridization (FISH)-positive) 

1) Three patients with stage I disease were included in the study because the stage of the contralateral breast was locally advanced.

2) Four patients with N0 stage disease were included in this study because the stage of the contralateral breast was locally advanced in 3 out of 4 patients and the others had T2 lesions.
 

Table 2. Efficacy determined by per protocol analysis

Abbreviations: AC4-D4, adriamycin and cyclophosphamide (4 cycles) followed by docetaxel (4 cycles); CI,  confidence interval; FEC3-D3, fluorouracil, epirubicin, and cyclophosphamide (3 cycles) followed by docetaxel (3 cycles); pCR, pathologic complete response.

Table3. Adverse events during the neoadjuvant chemotherapy

Abbreviations: AC4-D4, adriamycin and cyclophosphamide (4 cycles) followed by docetaxel (4 cycles); ALT,  alanine aminotransferase; AST, aspartate aminotransferase: FEC3-D3, fluorouracil, epirubicin, and cyclophosphamide (3 cycles) followed by docetaxel (3 cycles); FN, febrile neutropenia.

Table 4. Quality of life scores determined using Functional Assessment Of Cancer Therapy-B (FACT-B) version 4.0

Abbreviations: AC4-D4, adriamycin and cyclophosphamide (4 cycles) followed by docetaxel (4 cycles); BCS, Breast cancer subscale; EWB, Emotional wellbeing; FEC3-D3, fluorouracil, epirubicin, and cyclophosphamide (3 cycles) followed by docetaxel (3 cycles); FACT-B, Functional Assessment Of Cancer Therapy-B; FWB,  functional well-being; NACT, neoadjuvant chemotherapy; PWB, physical well-being; SD: standard deviation; SWB, social well-being.

^aU-test: the Mann-Whitney U-test was used to compare differences between the two treatment groups.

^bFriedman test: used to confirm whether a significant decrease in the QoL values occurred during the treatment period.