Download Breast cancer adjuvant therapy

516 (32723)
Phase III trial comparing AC (x4)taxane (x4)
with taxane (x8) as adjuvant therapy
for node-positive breast cancer:
Results of N-SAS-BC02 trial (Japan)
T. Watanabe, M. Kuranami, K. Inoue,
N. Masuda, K. Aogi, H. Iwata, H. Mukai,
S. Tanaka, T. Yamaguchi, Y. Ohashi
Background
• Doxorubicin and cyclophosphamide (AC) x 4  paclitaxel x 4
is a standard regimen for postoperative chemotherapy.
• Rare but serious side effects (e.g., cardiac failure, secondary
leukemia) are major concerns with AC.
• AC cannot be used in some patients.
• Relative efficacy of docetaxel to that of paclitaxel needs to be
clarified.
Trial Design
ACP
R
A
N
D
O
M
I
Z
E
ADM 60 mg/m2
CPA 600 mg/m2
ACD
Paclitaxel 175 mg/m2
PTX
Docetaxel 75 mg/m2
DTX
 Pts with BCS received RT.
 Pts with ER(+) BC received
TAM or an AI for 5 yrs.
0
3
6
9
12 15
weeks
18
21
Primary objectives
 To compare disease-free survival (DFS) with
AC (x4)taxane (x4) vs. taxane (x8)
 To compare DFS with paclitaxel (x8) vs.
docetaxel (x8)
in node-positive breast cancer
Exploratory analyses
 To find subsets of patients who benefit from
additional treatment with AC
 Subsets:
 HER2 positive vs. HER2 negative or unknown
 ER positive vs. ER negative or unknown
Inclusion Criteria
• Stage I to IIIA invasive breast cancer
• Histologically involved axillary lymph nodes
• Age 18-75 years
• PS (ECOG) 0, 1
• No prior chemotherapy or endocrine therapy
• Adequate organ functions
• Written informed consent
Statistical Considerations
Hypothesis 1:
A taxane (x8) is not inferior to AC (x4)  a taxane (x4)
Hypothesis 2:
One of the taxanes is superior or equivalent to the other.
Planned N = 1200 (based on planned events (≥320) in
hypothesis 1)
a=0.05; 1-sided (non-inferiority); power (1-b) = 0.80
Patient accrual
• Between December 2001 and April 2006,
1060 patients were randomized at 84
institutions in Japan.
• Date of first analysis: June 15, 2008
Patient Disposition
Patients randomly assigned (n=1060)
ACP
263
ACD
265
PTX
267
DTX
265
Patients eligible for this trial (n=1060)
ACP
263
ACD
265
PTX
267
DTX
265
Patients analyzed for safety and efficacy (n=1044)
ACP
260
ACD
262
PTX
263
DTX
259
Patients completed protocol therapy (n=902)
ACP
227
ACD
226
PTX
228
DTX
221
Did not receive protocol therapy (n=16)
ACP
3
ACD
3
PTX
4
DTX
6
Did not complete protocol therapy (n=142)
ACP
33
ACD
36
PTX
35
DTX
38
Patient characteristics (1)
ACP
(n=260)
ACD
(n=262)
PTX
(n=263)
DTX
(n=259)
52.8±8.3
52.7±9.5
52.4±8.7
51.9±8.6
I
42
18
29
35
II A
95
115
102
103
II B
85
106
109
97
III A
38
23
23
24
<3 cm
168
167
167
165
≥3 cm
92
95
96
94
Age（mean±sd）
Stage
Pathological tumor size
Number of positive lymph nodes
1-3
154
158
156
154
4-9
63
61
64
64
10 -
43
43
43
41
Patient characteristics (2)
Estrogen Receptor
positive
negative
not tested
Progesterone Receptor
positive
negative
unknown
Type of surgery
Breast conserving surgery
Mastectomy
Others
HER2 (HercepTest®)
0
1+
2+
3+
unknown
ACP
ACD
PTX
DTX
147
110
3
144
116
2
147
111
5
144
112
3
107
149
4
122
138
2
109
147
5
113
142
4
121
135
4
121
140
1
122
139
2
121
136
2
85
76
24
35
40
77
68
26
36
55
91
63
29
35
45
90
61
27
34
47
Grade ¾ adverse events (%) (1)
Neutropenia
Leukopenia
Thrombocytopenia
Anemia
Febrile neutropenia
Elevated AST or ALT
Elevated bilirubin
Edema
Pleural effusion
Ascites
Body weight gain
Hair loss
Phlebitis (injection site)
Nail changes
ACP
17
3
0
0
5
2
0
0
0
0
0
0
0
0
ACD
18
5
0
0
11
1
0
1
0
0
0
0
0
0
PTX
2
0
0
0
0
2
0
0
0
0
0
0
0
0
DTX
6
2
0
0
8
0
0
11
0
0
0
0
0
0
Grade ¾ adverse events (%) (2)
Stomatitis
Nausea
Vomiting
Constipation
Diarrhea
Urinary urgency
Hematuria
Fatigue
Lacrimation
Rash, desquamation
Sensory neuropathy
Motor neuropathy
Joint pain (arthralgia)
Muscle pain (myalgia)
ACP
ACD
PTX
DTX
1
5
3
1
0
0
0
3
0
2
4
2
6
4
1
3
3
1
1
0
0
3
0
1
0
1
4
3
0
0
0
0
0
0
0
2
0
0
6
1
8
5
0
1
1
0
2
0
0
2
0
1
4
1
2
1
Disease-free Survival
100
Percent probability
90
80
70
：ACP
：ACD
：PTX
：DTX
60
50
～
～
0
0
1
2
3
Time from randomization （years）
4
Disease-free Survival
Summary of events (disease-free survival)
No. of pts
ACP
ACD
PTX
DTX
258
255
261
257
Hypothesis 1:
A taxane alone is not inferior to AC + a taxane
Hazard ratio
(AC + a taxane as standard)
1.26
99% CI
0.92 - 1.72
90% CI
1.03 - 1.53
p value
0.67
Hypothesis 2: Whether PTX or DTX is more effective
Hazard ratio
(PTX as standard)
0.81
99.5% CI
0.57 - 1.14
95% CI
0.64 - 1.03
p value
0.08
・Two confidence intervals are calculated for each endpoint, taking into account
multiplicity due to interim analysis.
・Final analysis will be planned number of events (>=320) are observed.
Percent probability
Disease-free Survival
100
100
90
90
80
80
70
70
60
60
50
～
～
： AC –>Taxane
： Taxane
：ACD+DTX
：ACP+PTX
50
Hazard ratio (99%CI)：1.26(0.92 – 1.72)
～
～
Hazard ratio (99.5%CI)：0.81(0.57 – 1.14)
0
1
2
3
4
Time from randomization （years）
0
0
0
1
2
3
4
Time from randomization （years）
AC Taxane vs. Taxane
Subset according to HER2
HER2 positive
HER2 negative/unknown
100
90
90
80
80
70
70
60
60
Percent probability
100
50
～
～
： AC Taxane
： Taxane
： AC Taxane
： Taxane
50
～
～
Hazard ratio (95% CI): 1.63(1.05 – 2.54)
0
Hazard ratio (95% CI): 1.13(0.85 – 1.50)
0
0
1
2
3
Time from randomization（years）
4
0
1
2
3
4
Time from randomization （years）
・Interactions between the response to AC and HER-2
positive/HER-2
negative/unknown status, P=0.17
AC Taxane vs. Taxane
Subset according to ER
ER negative
Percent probability
ER positive
100
100
90
90
80
80
70
70
60
60
：AC Taxane
：Taxane
50
～
50
～
～
Hazard ratio (95%CI)：1.32(0.90 – 1.95)
：AC Taxane
：Taxane
Hazard ratio (95%CI)：1.22(0.90 – 1.66)
0
0
0
1
2
3
4
Time from randomization （years）
0
1
2
3
4
Time from randomization （years）
Summary (1)
• Taxane (x8) is not demonstrated to be non-inferior to AC (x4)  a
taxane (x4) in the study group as a whole in terms of DFS.
• Docetaxel (75 mg/m2) is superior to paclitaxel (175 mg/m2) when
given every 3 weeks in terms of DFS.
• In the subset of HER2-positive patients, AC (x4)  a taxane (x4)
produced superior DFS than did a taxane (x8). This result was not
obtained in patients with HER2-negative or unknown tumors.
• For ER, there was no interaction with the addition of AC.
Summary (2)
• Regarding the incidences of adverse events:
–Nausea and vomiting were higher with AC (x4)  a taxane (x4)
than with taxane (x8) .
–Edema and febrile neutropenia were higher with docetaxel (75
mg/m2) than with paclitaxel (175 mg/m2) .
–Sensory neuropathy was higher with paclitaxel (175 mg/m2) than
with docetaxel (75 mg/m2) .
Conclusions
• AC can be omitted in certain subsets of patients with
postoperative breast cancer.
• When given every 3 weeks, docetaxel (75 mg/m2) improves
DFS in women with node-positive breast cancer as compared
with paclitaxel (175 mg/m2) .
• The expression of HER2 may be associated with a benefit
from the addition of AC.