Results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-18 trial demonstrated an increased likelihood of Breast Conservation Surgery (BCS) in breast cancer patients treated with a neoadjuvant anthracycline-based regimen.r Although the B-18 trial did not demonstrate a survival advantage in patients treated with preoperative chemotherapy, it established pathological complete response (pCR) as a prognostic marker for disease-free survival (DFS).
FEC-D has been successfully utilised in the adjuvant setting with eight-year follow-up data showing a 4% absolute benefit in DFS and 5% benefit in OS (Link to the evidence for adjuvant FEC-D).
A search of the literature did not find strong phase III evidence for use of FEC-D in the neoadjuvant setting. Ohno et alr and von Minckwitz et alr studied the efficacy of neoadjuvant (F)EC-D but in varying combinations with capecitabine.
There were three phase II trials directly studying neoadjuvant FEC-D.rrr The expert reference panel supported publication of the protocol on the basis of the information summarised below. The Japan Breast Cancer Research Group (JBCRG) 01 trial, published in 2008, was the largest study to date evaluating neoadjuvant chemotherapy in this patient populationrr where the Quasi-Pathologic Complete Response (QpCR – no invasive tumour or only focal residual cells) rate was 25%. Within 40 months median follow-up, 3-year DFS was estimated at 98% for patients with QpCR versus those without (89%, HR 0.38 [95% C.I. 0.09 – 0.84]). The overall clinical response rate was 75%. 85% of patients achieved breast conservation. HER-2 status and response to FEC were independent predictors of QpCR. Grade 3/4 neutropaenia was the common adverse event.
In order to achieve a higher pCR with an improved safety profile, the JBCRG-03 trial, published in 2011,r assessed the efficacy of the reverse sequence of the chemotherapy used in the JBCRG-01 trial, with 4 cycles of docetaxel (75 mg/m2 q3w) followed by 4 cycles of 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 q3w in patients with early-stage breast cancer. The primary endpoint was the pathological complete response (pCR) rate defined for the breast alone, assessed by a central review committee. Secondary endpoints included clinical response and safety. Of the 132 patients assessable for pathologic response, 23% experienced a pCR and 6% had a near pathological complete response (few remaining cancer cells), resulting in a QpCR of 29%. Clinical response rate following the initial docetaxel regimen was 64%. The overall clinical response rate was 79%. Breast-conserving surgery was performed in 79% of patients. More patients with triple-negative disease experienced a pCR (14/29, 48 %) versus those with other molecular subtypes. The safety profile was acceptable.
Note that all the phase II trials used 4 cycles of FEC and 4 cycles of docetaxel (75 mg/m2). Given that OS and DFS are essentially equivalent whether chemotherapy is given in the adjuvant or neoadjuvant setting, there are arguments for using either the 6 or 8 cycles of FEC-D.
Evidence for the “FEC” portion of the regime is provided by Mouret-Reynier et al,r where pCR rates were 15-25% depending on classifications.
Evidence for the “D” portion of the regime is provided by the NSABP B-27 trial. The addition of sequential docetaxel to AC doubled the pCR rate and increased the clinical complete response (cCR) rate but did not improve disease free survival (DFS) and overall survival (OS) compared to AC alone. (Link to the evidence for Breast neoadjuvant AC followed by docetaxel).
Source |
Study and year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase III trials |
Ohno et al. 2013r |
Yes |
No |
4 cycles of FEC (5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2, day 1 q3w) followed by 4 cycles of docetaxel 75 mg/m2 day 1 q3w +/- capecitabine 1650 mg/m2/day on day 1 to 14 |
|
von Minckwitz. 2010r |
Yes |
No |
4 cycles of EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2, day 1 q3w) followed by 4 cycles of docetaxel 100 mg/m2 day 1 q3w alone, in sequence with, or combined with capecitabine 1800 mg/m2/day on day 1 to 14 |
Phase II trials |
Toi et al. 2008r |
Yes |
No |
4 cycles of FEC (5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2, day 1 q3w) followed by 4 cycles of docetaxel 75mg/m2 day 1 q3w |
|
Iwata et al. 2011r |
Yes |
No |
4 cycles docetaxel 75 mg/m2 q3w followed by 4 cycles 5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 q3w in patients with early-stage breast cancer |
|
Focan et al. 2005r |
Yes |
No |
4 cycles of FEC 100 followed by 4 cycles of docetaxel |
|
Yao et al. 2012r |
Yes |
No |
6 cycles TEC (docetaxel 75 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2 + G-CSF), q3w |
Observational studies |
- |
- |
- |
|
Case series |
- |
- |
- |
|
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
v.1 2014 |
Yes |
N/A |
|
BCCA |
- |
- |
- |
|
CCO |
March 2014 |
Yes |
Yes |
3 cycles of FEC (5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2, day 1 q3w) followed by 3 cycles of docetaxel 100 mg/m2 day 1 q3w |
Efficacy
A summary of the evidence supporting the effect of this protocol is below.
|
Study |
No. of patients |
Effect |
pCR |
Iwata et alr |
135 |
23% |
Overall clinical response |
Iwata et alr |
135 |
Response rate (RR) 79%
(complete RR 21%, partial RR 57%) |
BCS* |
Toi et alr |
198 |
85% |
QpCR** |
Iwata et alr |
135 |
29% |
*BCS= Breast conservation surgery
**Quasi-pCR: complete disappearance of invasive carcinoma in the breast or only focal tumour cells remaining in the stroma in the removed breastr
Toxicity
A summary of the toxicities associated with this protocol are included in the table below. The most clinically significant toxicity for both parts of the treatment was myelosuppression. In the JBCRG-01 trial, G-CSF was administered at investigators' discretion in 10.5%, 8.2% and 9.4% of treatment cycles of FEC (part 1), docetaxel (part 2) and both (part 1 and 2) respectively.r For non-hematologic toxicities of any grade, rash, sensory neuropathy, oedema, muscle pain and joint pain occurred more frequently during docetaxel treatment than with FEC. Conversely, the frequency of gastrointestinal symptoms, such as nausea, vomiting and anorexia, was higher with FEC.r
Grade 3/4 toxicity r |
FEC % (n=198) |
Docetaxel % (n=194) |
Importance for prescribing |
Neutropenia |
44 |
35 |
Critical |
Febrile neutropenia |
20 |
7 |
Critical |
Leukopenia |
35 |
30 |
Critical |
Thrombocytopenia |
1 |
1 |
Important |
Anaemia |
1 |
0 |
Important |
AST/ALT |
2 |
1 |
Not important |
Nausea |
6 |
1 |
Not important |
Vomiting |
5 |
1 |
Important |
Diarrhoea |
1 |
0 |
Important |
Constipation |
0 |
1 |
Not important |
Fatigue |
1 |
1 |
Not important |
Arthralgia/Myalgia |
0 |
1 |
Important |
Neurotoxicity |
0 |
1 |
Important |
Cardiotoxicity |
NR |
NR |
Critical |
FEC = fluorouracil, epirubicin, cyclophosphamide; NR = not reported