Anthracycline-based and taxane-based therapies are frequently used as preoperative systemic treatments for patients with locally advanced disease at presentation.rr The incorporation of a sequential taxane following an anthracycline has improved patient outcomes in the neo/adjuvant setting.r Some studies have shown that the addition of weekly paclitaxel after an anthracycline-based regimen is associated with reduction in risk of relapse.rr While most adjuvant and neoadjuvant trials have typically incorporated a taxane after the anthracycline-based regimen on the basis of historical precedent, there is some data to suggest that administering the taxane before the anthracycline may be more effective.rr It is the consensus of the eviQ reference committee that either order of administration is acceptable.
The combination of doxorubicin and cyclophosphamide followed by paclitaxel has been used successfully in the adjuvant setting. (Link to ID 4113 Breast adjuvant/neoadjuvant AC (DOXOrubicin and CYCLOPHOSPHamide) three weekly followed by PACLitaxel weekly overview). In the neoadjuvant setting the combination of AC followed by paclitaxel (or vice versa) has been used as the control arm in phase II studies.rr However, a search of the literature did not find any strong phase III clinical trial evidence for use of paclitaxel given before or after AC in the neoadjuvant setting, despite this combination being considered a standard of care. Whilst there have been some phase III trials that have shown efficacy of the addition of paclitaxel, this has been in combination with other anthracycline-based regimens (e.g.EC, FEC, FAC).rrr
The expert reference panel supported publication of this protocol on the basis of the information summarised below. The committee was most strongly influenced by the extensive use of this regimen in the adjuvant setting.
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trial |
Abraham, et al. 2015r
(NSABP foundation study FB-9) |
Yes
(control arm) |
Yes
(paclitaxel given before AC) |
Paclitaxel q1w x 12 cycles, OR
Eribulin 1.4 mg/m2 day 1 and 8, q3w x 4 cycles,
followed by
AC q3w x 4 cycles |
|
Saura et al. 2013r |
Yes
(control arm) |
Yes
(AC given before paclitaxel) |
AC q3w x 4 cycles
followed by either:
ixabepilone 40 mg/m2 q3ws x 4 cycles, OR
paclitaxel 80 mg/m2 q1w x 12 cycles |
Phase III trial |
Earl et al. 2014r
(Neo-tAnG0) |
Yes |
No |
Paclitaxel 175 mg/m2 q2w +/- gemcitabine 2000 mg/m2 q2w x 4 cycles followed by EC q3w x 4 cycles
OR
Same drugs/dose as above but given in the reverse order |
|
Green et al 2005r |
Yes |
No |
Paclitaxel q1w x 12 cycles OR paclitaxel q3w x 4 cycles
followed by
FAC (standard doses) q3w x 4 cycles |
Retrospective analysis |
Alvarez et al. 2010r
(MD Anderson study) |
Yes |
No |
FAC/FEC followed by paclitaxel
vs.
paclitaxel followed by FAC/FEC |
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN guidelines |
V2. 2017 |
Yes |
No doses stated |
- |
CCO |
Feb 2017 |
Yes |
Yes
(AC given before paclitaxel) |
Adjuvant/neoadjuvant protocol
AC q3w followed by paclitaxel q1w +/- trastuzumab |
BCCA |
Aug 2016 |
Yes |
Yes
(paclitaxel given before AC) |
Neoadjuvant protocol
Paclitaxel q1w followed by AC q3w |
ESMO clinical practice guidelines |
2015 |
Yes |
No doses stated |
Primary (neoadjuvant) systemic therapy:
Sequential regimen of anthracyclines and taxanes
is recommended for the vast majority of patients |
Efficacy
A summary of the evidence supporting the effect of this protocol is below.
Study |
Results |
No. of patients |
Pathologic complete response (pCR) |
Clinical
objective
complete response |
Partial response
and/or
stable disease |
Conclusion |
NSABP foundation study (FB-9)r |
Paclitaxel followed by AC
(control arm) |
n = 19 |
5 (26%) |
1 (5%) |
16 (88%) |
Substitution of eribulin for
paclitaxel did not suggest
increased pCR |
Eribulin followed by AC
(treatment arm) |
n = 30 |
5 (17%) |
4 (13%) |
21 (70%) |
Saura et al. 2013r |
AC followed by paclitaxel
(control arm) |
n = 144 |
25.2% |
48 (32.7%) |
66 (44.9%)
17 (11.6%) |
No significant difference
in efficacy between the
two arms |
AC followed by ixabepilone
(treatment arm) |
n = 145 |
24.3% |
41 (27.7%) |
79 (53.4%)
14.(9.5%) |
In the retrospective analysis from the M.D. Anderson Cancer Center group, data from 1414 patients treated in the neoadjuvant setting were used to compare the results among patients treated with paclitaxel followed by fluorouracil, doxorubicin, and cyclophosphamide (FAC)/FEC (n = 226) with those of patients treated with the reverse sequence of FAC/FEC followed by paclitaxel (n = 1188). The corresponding rates of pathologic complete responses (pCR) with the two sequences were 20.9% and 12.4% (P = 0.04). In multivariate analysis, after adjustments for period of diagnosis, age, clinical stage, hormone-receptor status, grade, and lymphovascular invasion, the sequence with the anthracycline first was associated with a higher risk of relapse (HR = 1.49; P = 0.01) but not death (HR = 1.28; P = 0.17).r
Toxicity
In the NSABP FB-9 trial both the weekly paclitaxel and eribulin regimens were well tolerated, with only one grade 3 event (diarrhoea) and no grade 4 events reported in the paclitaxel arm. AC was well tolerated following both the weekly paclitaxel and eribulin regimens. Grade 3/4 toxicities associated with the AC component of the regimen were mainly haematologic (neutropenia and febrile neutropenia).r
Treatment-related toxicities reported in the paclitaxel-AC arm of the NSABP FB-9 trialr
|
NSABP FB-9r |
Adverse event |
Paclitaxel (n= 19) |
AC (after paclitaxel) (n= 19) |
Grade 2 |
Grade 3 |
Grade 4 |
Grade 2 |
Grade 3 |
Grade 4 |
Neutropenia |
2 (10.5%) |
0 |
0 |
0 |
3 (15.8%) |
6 (31.6%) |
Febrile neutropenia |
0 |
0 |
0 |
0 |
1 (5.3%) |
0 |
Fatigue |
3 (15.8%) |
0 |
0 |
0 |
1 (5.3%) |
0 |
Nausea |
2 (10.5%) |
0 |
0 |
NR |
N/R |
NR |
Vomiting |
2 (10.5%) |
0 |
0 |
NR |
N/R |
NR |
Constipation |
2 (10.5%) |
0 |
0 |
NR |
N/R |
NR |
Diarrhoea |
2 (10.5%) |
1 (5.3%) |
0 |
NR |
N/R |
NR |
Stomatitis |
0 |
0 |
0 |
0 |
1 (5.3%) |
0 |
Sensory neuropathy |
2 (10.5%) |
0 |
0 |
NR |
NR |
NR |