The evidence for this regimen comes from the BCIRG 006 trial.r,rr This multicentre phase III randomised trial compared the following 3 regimens:
- 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of docetaxel (AC-T) (n=1073)
- 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of docetaxel plus 12 months of trastuzumab (AC-TH) (n=1074)
- 6 cycles of docetaxel and carboplatin plus 12 months of trastuzumab (TCH) (n=1075)
From April 2001 through March 2004, a total of 3222 women with HER2-positive, node positive or high risk node negative, breast cancer were enrolled into the study for adjuvant treatment.
The primary endpoint of the study was disease-free survival (DFS) and secondary endpoints were overall survival (OS), global safety and cardiac safety.
Only 33 patients (3.1%) in the control group (AC-T) crossed over to receive trastuzumab leaving 96.9% available for the DFS, OS and safety comparison analysis.r
Efficacy
At a median follow up of 10.3 years, both trastuzumab arms were superior to AC-T.r
|
AC-T |
AC-TH |
TCH |
DFS at 10 years (%)
HR (95% CI)
p-value vs AC-T |
67.9
1
|
74.6
0.72 (0.61 - 0.85)
p<0.0001 |
73
0.77 (0.65 - 0.90)
p=0.0011 |
OS at 10 years (%)
HR (95% CI)
p-value vs AC-T |
78.7
1
|
85.9
0.63 (0.51 - 0.79)
p<0.0001 |
83.3
0.76 (0.62 - 0.93)
p=0.0075 |
DFS in patients with lymph node metastases (%)
HR (95% CI)
p-value vs AC-T |
62.2
1 |
69.6
0.72 (0.61 - 0.87)
p<0.001 |
68.4
0.75 (0.63 - 0.90)
p=0.0018 |
DFS and OS were not statistically different between the two trastuzumab-containing arms (TCH and AC-TH). There was a difference of only 10 DFS events between these arms at 10 years.r The two trastuzumab-containing arms were also equivalent for the higher risk node-positive patients.
Toxicity
The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-TH compared with TCH. There were no cardiac related deaths reported in this study at the time of the 10 year efficacy and long term safety analysis.r
9 cases of acute leukaemia were reported, 6 in the AC-T arm, 2 in the AC-TH arm and 1 in the TCH arm.r
Toxicities (grade 3/4) r |
AC-T
n=1050
(%) |
AC-TH
n=1068
(%) |
TCH
n=1056
(%) |
Neutropenia |
63.5 |
71.6 |
66.2* |
Febrile neutropenia |
9.3 |
11.0 |
9.6 |
Anaemia |
2.3 |
3.0 |
5.4* |
Thrombocytopenia |
1.6 |
2.1 |
6.1* |
Arthralgia |
3.2 |
3.3 |
1.4* |
Myalgia |
5.2 |
5.1 |
1.8* |
Fatigue |
7.0 |
7.2 |
7.2 |
Stomatitis |
3.5 |
2.9 |
1.4* |
Diarrhoea |
3.0 |
5.6 |
5.4 |
Nausea |
5.9 |
5.7 |
4.8 |
Vomiting |
6.2 |
6.7 |
3.5* |
Irregular menses |
27.0 |
24.5 |
26.7 |
Neuropathy-sensory (all grades) |
48.8 |
50.1 |
36.1* |
Neuropathy-motor (all grades) |
5.2 |
6.4 |
4.3* |
Congestive heart failure
(NYHA grade 3 or 4) |
0.7 |
2.0 |
0.4* |
> 10% reduction in LVEF |
11.4 |
18.7 |
9.2* |
Leukaemia |
0.6 |
0.2 |
0.1# |
* statistically significant difference between the group receiving AC-TH and the group receiving TCH
# Acute leukaemia occurred 20 months after treatment with CHOP for B-cell lymphoma