Transcript CALGB 9741 - Projects In Knowledge

CALGB 9741
A Randomized Trial
of Dose-Dense vs Conventionally Scheduled
and Sequential vs Concurrent Combination
Chemotherapy as Postoperative Adjuvant
Treatment of Node-Positive Primary Breast
Cancer
Citron M, et al. J Clin Oncol. 2003;21:1431-1439.
C9741—Protocol
2X2 Factorial Design
q2wk + Filgrastim
q3wk
SEQUENTIAL
24 wk
“Seq Q2”
36 wk
“Seq Q3”
16 wk
“Con Q2”
24 wk
“Con Q3”
CONCURRENT
Doxorubicin 60 mg/m2
Cyclophosphamide 600 mg/m2
Paclitaxel 175 mg/m2 over 3 h
With Permission from Citron M, et al. J Clin Oncol. 2003;21:1431-1439.
C9741—Major Toxicities
Seq q3
Seq q2
Con q3
Con q2
No. treated
484
493
501
495
No. with detailed data
103
101
104
104
Granulocytes < 0.5/µL
24%
3%
43%
9%
Febrile neutropenia,
hospitalized
3%
2%
6%
2%
Red cell transfusion
0%
3%
4%
13%
Platelet transfusion
0%
0%
0%
0%
Neurologic: severe
sensory loss or motor
weakness
5%
5%
7%
5%
Citron M, et al. J Clin Oncol. 2003;21:1431-1439 Erratum published in J Clin Oncol,
2003;21:2226.
C9741—Disease-Free Survival by Dose Density
Disease-Free Survival
By Density
1.0
Proportion Disease-Free
q2
0.8
q3
0.6
q2wk
q3wk
0.4
N = 988
N = 985
Events = 136
Events = 179
0.2
RR = 0.74; P = .010
0.0
0
1
2
Years from Study Entry
With permission from Citron M, et al. J Clin Oncol. 2003;21:1431-1439.
3
4
Cox Model—Retrospective Analysis of Dose
Density (q2) Therapy by ER Status in C9741
0.9
0.8
0.81
Risk Ratio
0.7
0.68
0.6
0.73
0.66
0.5
0.4
0.3
0.2
ER+
ER+
ER-
ER-
0.1
0
DFS
ER = estrogen receptor; DFS = disease-free survival; OS = overall survival
Courtesy of Marc Citron, MD.
With permission from C. Hudis, MD.
OS
Disease-Free Survival
C9741—DFS by Dose Density
at Median 5-Year Follow-up
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
q2wk
q3wk
Q2 n = 988 Events = 230
Q3 n = 984 Events = 278
0
1
2
3
P = .012
4
Year
Hudis C, et al. 2005 San Antonio Breast Cancer Symposium. Abstract 41.
With permission from C. Hudis, MD.
5
6
7
Disease-Free Survival
C9741—DFS by ER Status and Dose
Density at 5-Year Median
1.0
0.9
ER+ q2wk
ER+ q3wk
0.8
0.7
0.6
ER- q2wk
ER- q3wk
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
Year
ER+ q2 n = 636 Events = 126
ER+ q3 n = 639 Events = 133
P = NS
ER- q2 n = 336 Events = 99
ER- q3 n = 327 Events = 127
P = .014
ER = estrogen receptors
With permission from Hudis C, et al. 2005 San Antonio Breast Cancer Symposium. Abstract 41.
Dose-Dense ChemotherapyInduced Pulmonary Toxicity
Courtesy of Marc Citron, MD.
Accelerated vs Standard FEC Regimen
GONO-MIG1 Protocol
FEC14 = q2wk (w/G-CSF) for 10 wk
FEC21 = q3wk for 15 wk
F = fluorouracil 600 mg/m2
E = epirubicin 60 mg/m2
C = cyclophosphamide 600 mg/m2
Accrued N = 1214
10.4 yr median follow-up
359 events
Venturini M, et al. J Natl Cancer Inst. 2005;97:1724-1733.
Accelerated vs Standard FEC Regimen
GONO-MIG1 Results
No significant differences in:
• Event-free survival
- HR for FEC14/FEC21 = 0.88, 95% CI (0.71–1.08) P =.219
• Risk of death
- HR for FEC14/FEC21 = 0.87, 95% CI (0.67–1.13) P = .293
Toxicity
FEC14
FEC21
Asthenia
36%
29%
Anemia
38%
19%
Bone pain
33%
4%
Leukopenia
12%
45%
FEC = fluorouracil, epirubicin, cyclophosphamide; HR = hazard ratio.
Venturini M, et al. J Natl Cancer Inst. 2005;97:1724-1733.
GONO-MIG1—Accelerated FEC Provides
No Significant Benefit for HER2 Negative
EFS
OS
HER2 negative
HER2 negative
100
90
90
82%
80
91%
80
81%
70
60
50
40
FEC21
30
% SURVIVAL
70
% Event Free
92%
100
60
50
40
FEC21
30
20
20
HR = 0.91 (0.65–1.27)
P = .57
10
FEC14
0
HR = 0.79 (0.49–1.28)
p = .34
10
FEC14
0
0
No. at risk
1
2
3
4 5
Years
6
7
8
9 10
FEC14 320 309 286 266 235 179 105 52 16
FEC21 308 297 281 247 227 178 107 52 16
0
No. at risk
1
1
2
3
4 5
Years
6
7
8
FEC14 320 318 314 308 297 244 161 92 31
FEC21 308 307 303 296 286 233 160 92 37
9
10
1
GONO-MIG1 = Gruppo Oncologico Nord-Ovest-Mammella Intergruppo; FEC = fluorouracil, epirubicin, cyclophosphamide;
EFS = event-free survival; OS = overall survival.
With permission from Del Mastro L, et al. Br J Cancer. 2005;93:7-14.
GONO-MIG1—Accelerated FEC Showed Trend
Toward Benefit for HER2 Positive
EFS
HER2 positive
OS
HER2 positive
100
100
FEC21
90
FEC21
78%
80
80
70
FEC14
Survival (%)
Eent Free (%)
70
60
63%
50
90%
90
40
75%
FEC14
60
50
40
30
30
20
20
HR = 0.54 (0.27–1.11)
P = .092
10
HR = 0.59 (0.25–1.37)
P = .22
10
0
0
0
1
2
3
4 5
Years
6
7
8
9 10
50 44 39 33 27 15 10
48 41 32 31 23 16 7
1
No. at risk
No. at risk
FEC14 50
FEC21 53
0
5
2
FEC14
FEC21
50 50
53 52
2
3
4 5
Years
50 47 46
47 45 42
6
7
8
39 23 14
33 20 9
5
4
9
10
GONO-MIG1 = Gruppo Oncologico Nord-Ovest-Mammella Intergruppo; FEC = fluorouracil, epirubicin, cyclophosphamide;
EFS = event-free survival; OS = overall survival.
With permission from Del Mastro L, et al. Br J Cancer. 2005;93:7-14.