A search of the literature did not find strong phase III evidence for use this regimen in the neoadjuvant setting. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The reference committee was most strongly influenced by the phase II CALGB 40603 trial.r
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Sikov et al.r |
No |
Yes |
- |
Observational studies |
- |
N/A |
- |
- |
Case series |
- |
N/A |
- |
- |
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
v.3 2015 |
No |
- |
Not recommended outside of a clinical trial setting |
BCCA |
- |
N/A |
- |
|
CCO |
- |
N/A |
- |
|
ESMO |
2015r |
Yes |
No doses |
Increased pCR in triple negative tumours, particularly those carrying BRCA 1/2 or RAD mutations |
The CALGB 40603 trial was a randomised, open-label phase II study used a 2 x 2 factorial experimental design to evaluate the impact of adding carboplatin and/or bevacizumab to standard neoadjuvant chemotherapy (NACT) on achieving pathological complete response (pCR) in patients with triple-negative breast cancer (TNBC).rr
A total of 443 patients with stage II to III TNBC were randomly assigned to receive one of the following 4 arms:
1. Sequential weekly paclitaxel x 12 -> dose dense doxorubicin and cyclophosphamide x 4 every 2 weeks with filgrastim.
2. Weekly paclitaxel x 12 -> dose dense doxorubicin and cyclophosphamide x 4 every 2 weeks with filgrastim; with concurrent bevacizumab x 9 every 2 weeks.
3. Concurrent weekly paclitaxel x 12 and carboplatin x 4 every 3 weeks -> dose dense doxorubicin and cyclophosphamide x 4 every 2 weeks with filgrastim.
4. Concurrent weekly paclitaxel x 12 and carboplatin x 4 every 3 weeks -> dose dense doxorubicin and cyclophosphamide x 4 every 2 weeks with filgrastim; with concurrent bevacizumab x 9 every 2 weeks.
Schema of CALGB 40603
© Journal of Clinical Oncology 2015
Between May 2009 and August 2012, 443 patients were randomised: Arm 1 (N=115), Arm 2 (N=113), Arm 3 (113) and Arm 4 (113).
The primary end point was pCR in the breast. (NB: pCR as a valid surrogate endpoint for long-term clinical benefit, such as disease-free survival (DFS) and overall survival (OS), is still an area of contention).
Secondary end points were pCR breast/axilla, treatment delivery, treatment-related toxicities, residual cancer burden, conversion from clinically node-positive to pathologically node-negative status, and conversion from BCS-ineligible to BCS-eligible status after treatment.
Efficacy
Specifically addressing carboplatin, efficacy was reported in two forms:
- Carboplatin-containing regimens (Arms 3 and 4) vs. non-carboplatin regimens (Arms 1 and 2).
- Individual pCR rates for each arm.
The addition of carboplatin significantly increased the pCR breast rate (60% vs 46%, OR 1.76; p=0.018) as well as pCR breast/axilla (54% vs 41%, OR 1.71; p=0.0029).
Individually, Arm 3 (chemotherapy backbone + carboplatin) had a pCR rate of 53% compared with 42% in Arm 1 (chemotherapy backbone alone), though statistical analysis was not performed on this comparison.
(A) Pathologic complete response (pCR) breast (ypT0/is); (B) pCR breast/axilla (ypT0/is N0)r
© Journal of Clinical Oncology 2015
Toxicity
Carboplatin-containing regimens (Arm 3 and Arm 4) were associated with a significantly greater incidence of grade 3 to 4 neutropenia (56% and 67% respectively) compared to non-carboplatin regimens (Arm 1 and Arm 2, 22% and 27% respectively). Growth factor support was used only during the ddAC cycles of the study protocol.
Thrombocytopenia was also more frequent in the carboplatin arms (20% (Arm 3), 26% (Arm 4) vs. 4% (Arm 1), 3% (Arm 2)).r
Other toxicities were relatively evenly matched.
Treatment-related toxicityr
(Grade 3/4) |
Arm 1: Control (%) |
Arm 3: Control + Carboplatin (%) |
Leukopenia |
12 |
13 |
Neutropenia |
22 |
56 |
Thrombocytopenia |
4 |
20 |
Anaemia |
0 |
4 |
Febrile neutropenia |
7 |
12 |
Nausea |
4 |
3 |
Vomiting |
2 |
2 |
Mucositis |
2 |
1 |
Diarrhoea |
0 |
2 |
ALT elevation |
0 |
0 |
Hypokalaemia |
3 |
6 |
Peripheral neuropathy |
2 |
7 |
Fatigue |
10 |
10 |
Pain |
3 |
3 |
Note: Bold font indicates significant difference in incidence compared with other treatment arms.
Patients assigned to carboplatin were more likely to miss > 2 doses of weekly paclitaxel (36% vs. 16%).
Because of treatment delays and toxicities, only 80% of patients assigned to carboplatin received all four planned doses.r