Note: Limited evidence is specific to the neoadjuvant setting.
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 and the phase III BrighTness trial.rr
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase III trial |
Loibl et al.r |
Yes |
|
- |
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.5 2021 |
Yes |
- |
- |
BCCA |
- |
N/A |
- |
- |
CCO |
- |
N/A |
- |
- |
ESMO |
2015r |
Yes |
No doses stated |
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 on achieving pathological complete response (pCR) in patients with triple-negative breast cancer (TNBC).rr
Between May 2009 and August 2012, 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 (N=115).
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 (N=113).
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 (N=113).
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 (N=113).
Triple negative was defined in the CALGB 40603 trial by ER and PR expression 10% or less, AND HER-2 negativity (i.e. IHC 0 to 1+ OR FISH ratio less than 2.0 if IHC 2+ or IHC not performed).
Schema of CALGB 40603r
© J Clin Oncol 2015
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 and overall survival, 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 breast conserving surgery (BCS)-ineligible to BCS-eligible status after treatment.
BrighTnessr
The BrighTNess study, a phase III trial evaluating the benefit of veliparib plus carboplatin in the neoadjuvant setting in stage II and III triple negative breast cancer. In this study, 55.6% of patients received dose dense AC, with G-CSF support given at the discretion of the clinician.
The study had 3 arms which included:
- Carboplatin (AUC 6 q3weekly) x 4 + paclitaxel (80 mg/m2 q1weekly) x 12 + veliparib (50 mg orally twice daily) followed by doxorubicin (60 mg/m2) + cyclophosphamide (600 mg/m2) q2weekly or q3weekly based on clinician discretion.
- Carboplatin (AUC 6 q3weekly) x 4 + paclitaxel (80 mg/m2 q1weekly) x 12 followed by doxorubicin (60 mg/m2) + cyclophosphamide (600 mg/m2) q2weekly or q3weekly based on clinician discretion.
- Paclitaxel (80 mg/m2 q1weekly) x 12 followed by doxorubicin (60 mg/m2) + cyclophosphamide (600 mg/m2) q2weekly or q3weekly based on clinician discretion.
EBCTCG meta-analysisr
A meta-analysis by the EBCTCG demonstrated a lower 10 year risk of recurrence with dose-intense chemotherapy compared with standard-schedule chemotherapy (28.0% vs 31.4%, relative risk (RR) 0.86, 95% CI 0.82 to 0.89; p<0.0001). Dose-intense chemotherapy was also associated with lower 10 year breast cancer mortality rates (18.9% vs 21.3%; RR 0.87, 95% CI 0.83 to 0.92; p<0·0001) and all-cause mortality (22.1% vs 24.8%; RR 0.87, 95% CI 0.83 to 0.91; p<0·0001).
Efficacy
CALGB 40603r
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
© J Clin Oncol 2015
BrighTnessr
In the subgroup analysis of BrighTNess, the comparison of dose dense AC (q2weekly) vs standard schedule AC (q3weekly) found pathological complete response rates to be similar between both groups.
|
pathological complete response (pCR)r |
Paclitaxel + carboplatin + veliparib |
Paclitaxel + carboplatin |
Paclitaxel |
Dose dense AC |
56% |
56% |
31% |
Standard schedule AC |
50% |
59% |
31% |
Toxicity
In the CALGB 40603 trial 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).r Growth factor support was used only during the ddAC cycles of the study protocol.
Thrombocytopenia was also more frequent in the carboplatin arms (Arm 3: 20%, Arm 4: 26% vs Arm 1: 4%, Arm 2: 3%).r
Other toxicities were relatively evenly matched.
Treatment-related toxcityr
(Grade 3/4) |
Arm 1: Sequential weekly paclitaxel + ddAC (%) |
Arm 3: Concurrent weekly paclitaxel and carboplatin + ddAC (%) |
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