CALGB 9741 CALGB 9741 A Randomized Trial A Randomized Trial of Dose-Dense vs of Dose-Dense vs Conventionally Conventionally Scheduled Scheduled and Sequential vs Concurrent and Sequential vs Concurrent Combination Chemotherapy as Combination Chemotherapy as Postoperative Adjuvant Treatment of Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer Node-Positive Primary Breast Cancer Citron M, et al. J Clin Oncol. 2003;21:1431- 1439.
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CALGB 9741CALGB 9741
A Randomized TrialA Randomized Trialof Dose-Dense vsof Dose-Dense vs Conventionally ScheduledConventionally Scheduledand Sequential vs Concurrent Combination and Sequential vs Concurrent Combination Chemotherapy as Postoperative Adjuvant Chemotherapy as Postoperative Adjuvant
Treatment of Node-Positive Primary Breast Treatment of Node-Positive Primary Breast CancerCancer
Citron M, et al. J Clin Oncol. 2003;21:1431-1439.
q2wk + Filgrastim q3wk
24 wk “Seq Q2”
16 wk“Con Q2”
24 wk“Con Q3”
36 wk“Seq Q3”
C9741—Protocol
SEQUENTIAL
CONCURRENT
2X2 Factorial Design
With Permission from Citron M, et al. J Clin Oncol. 2003;21:1431-1439.
Doxorubicin 60 mg/m2
Cyclophosphamide 600 mg/m2
Paclitaxel 175 mg/m2 over 3 h
C9741—Major ToxicitiesC9741—Major ToxicitiesSeq 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.
C9741C9741——Disease-Free Survival by Dose DensityDisease-Free Survival by Dose Density
Years from Study Entry
Pro
port
ion
Dis
ease
-Fre
e
0 1 2 3 40.0
0.2
0.4
0.6
0.8
1.0
Disease-Free Survival By Density
q2wkq3wk
N = 988N = 985
Events = 136Events = 179
q 2
q 3
With permission from Citron M, et al. J Clin Oncol. 2003;21:1431-1439.
RR = 0.74; P = .010
Cox Model—Retrospective Analysis of Dose Cox Model—Retrospective Analysis of Dose Density (q2) Therapy by ER Status in C9741Density (q2) Therapy by ER Status in C9741
0.73
0.81
0.660.68
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
DFS OS
Risk RatioER+ER-
ER+ER-
ER = estrogen receptor; DFS = disease-free survival; OS = overall survivalCourtesy of Marc Citron, MD.With permission from C. Hudis, MD.
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7Year
C9741—DFS by Dose Density at Median 5-Year Follow-up
q2wk
q3wk
Dis
ease
-Fre
e S
urvi
val
Q2 n = 988 Events = 230Q3 n = 984 Events = 278
Hudis C, et al. 2005 San Antonio Breast Cancer Symposium. Abstract 41.With permission from C. Hudis, MD.
P = .012
C9741—DFS by ER Status and Dose Density at 5-Year Median
Dis
ease
-Fre
e S
urvi
val
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7
Year
ER+ q3wk
ER- q3wkER- q2wk
ER+ q2wk
ER+ q2 n = 636 Events = 126 ER- q2 n = 336 Events = 99ER+ q3 n = 639 Events = 133 ER- q3 n = 327 Events = 127
P = .014P = NSER = estrogen receptorsWith permission from Hudis C, et al. 2005 San Antonio Breast Cancer Symposium. Abstract 41.
Dose-Dense Chemotherapy-Induced Pulmonary Toxicity
Courtesy of Marc Citron, MD.
FEC14 = q2wk (w/G-CSF) for 10 wk
FEC21 = q3wk for 15 wk
Accrued N = 121410.4 yr median follow-up 359 events
F = fluorouracil 600 mg/m2
E = epirubicin 60 mg/m2
C = cyclophosphamide 600 mg/m2
Accelerated vs Standard FEC RegimenAccelerated vs Standard FEC RegimenGONO-MIG1 ProtocolGONO-MIG1 Protocol
Venturini M, et al. J Natl Cancer Inst. 2005;97:1724-1733.
Accelerated vs Standard FEC RegimenAccelerated vs Standard FEC RegimenGONO-MIG1 ResultsGONO-MIG1 Results
Toxicity FEC14 FEC21
Asthenia 36% 29%
Anemia 38% 19%
Bone pain 33% 4%
Leukopenia 12% 45%
No significant differences in:No significant differences in:
• • Event-free survival Event-free survival
- HR for FEC- HR for FEC1414/FEC/FEC2121 = 0.88, 95% CI (0.71–1.08) = 0.88, 95% CI (0.71–1.08) PP =.219 =.219
• • Risk of deathRisk of death
- HR for FEC- HR for FEC1414/FEC/FEC2121 = 0.87, 95% CI (0.67–1.13) = 0.87, 95% CI (0.67–1.13) PP = .293 = .293
FEC = fluorouracil, epirubicin, cyclophosphamide; HR = hazard ratio.Venturini M, et al. J Natl Cancer Inst. 2005;97:1724-1733.
HR = 0.79 (0.49–1.28) p = .34
Years109876543210
% S
UR
VIV
AL
100
90
80
70
60
50
40
30
20
10
0
FEC21
FEC14
HER2 negative
31 92161244297308314318320FEC14
No. at risk
3792160233286296303307308FEC21 1
HR = 0.91 (0.65–1.27) P = .57
Years
109876543210
% E
vent
Fre
e
100
90
80
70
60
50
40
30
20
10
0
FEC21
FEC14
HER2 negative
116 52105179235266286309320FEC14
No. at risk
1652107178227247281297308FEC21
EFS OS
81%
82%91%
92%
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 Provides No Significant Benefit for HER2 Negative
HR = 0.54 (0.27–1.11) P = .092
Years109876543210
Een
t Fre
e (%
)
100
90
80
70
60
50
40
30
20
10
0
FEC21
FEC14
HER2 positive
51015273339445050FEC14
No. at risk
FEC21 2 716233132414853
HR = 0.59 (0.25–1.37) P = .22
Years109876543210
Sur
viva
l (%
)
100
90
80
70
60
50
40
30
20
10
0
FEC21
FEC14
HER2 positive
51423394647505050FEC14
FEC21 4920334245475253
No. at risk
EFS OS
63%
78%
75%
90%
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 TrendToward Benefit for HER2 Positive
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