C 9741
Marc L. Citron, MD
Clinical Professor of Medicine
Albert Einstein College of Medicine
CALGB Breast Committee
C 9741
CALGB: John Carpenter, Donald Berry,
Constance Cirrincione, Clifford Hudis, Eric
Winer, David Hurd, James Holland,
Barbara Smith, Carolyn Sartor, Eleanor
Leung, Richard Schilsky, Hyman Muss,
Larry Norton. ECOG: William Gradishar,
Nancy Davidson. NCCTG: Edith Perez,
James Ingle. SWOG: Silvana Martino,
Robert Livingston. NCI: Jeffrey Abrams
C 9741-CALGB 9741
A Randomized Trial of
Dose Dense vs. Conventionally
Scheduled and Sequential vs.
Concurrent Combination
Chemotherapy as Post-Operative
Adjuvant Treatment of NodePositive Primary Breast Cancer
C 9741
• Dose Density: Administration of
drugs with a shortened intertreatment interval.
• Sequential Therapy: Application of
treatments one at a time rather
than concurrently
C 9741 Trial Design: Sequential
ATC
• Based on Hudis et al.
Doxorubicin 90 mg/m2
(JCO,1999. 17: 1118)
Paclitaxel 250 mg/m2 Cyclophosphamide 3.0 gm/m2
9 cycles, 14 day intervals, G-CSF supported
C 9741:
• Doxorubicin reduced to 60mg/m2
• Paclitaxel reduced to 175mg/m2
• Cyclophosphamide reduced to 600mg/m2
CALGB 9344 Adjuvant Study
N=3,170
Node+
Statification:
Premenopausal &
Postmenopausal
R
A
N
D
O
M
I
Z
E
P4
A60 C  4
A75 C  4
A90 C  4
No P
A = Doxorubicin (doses shown)
C = Cyclophosphamide (600 mg/m2)
P = Paclitaxel (175 mg/m2 – 3 hour infusion)
ER+ or PR+ patients received Tamoxifen  5 y
C 9741: Trial Design
(I) Sequential:
A q 3 wk  T q 3 wk C q 3 wk
(II) Sequential: +filgrastim
A q 2 wk T q 2 wk C q 2 wk
(III) Concurrent:
AC q 3 wk T q 3 wk
(IV) Concurrent:+ filgrastim
AC q 2 wk T q 2 wk
INTERGROUP C9741
2X2 Factorial Design q 2 wk +Filgrastim
SEQUENTIAL
q 3 wk
24 weeks
36 weeks
SEQ Q2
SEQ Q3
16 weeks
24 weeks
CONCURRENT
CON Q2
doxorubicin 60 mg/m2
cyclophosphamide 600 mg/m2
paclitaxel 175 mg/m2 over 3 hours
CON Q3
C 9741: Eligibility Criteria
• Stage: T0-3, N1-2, M0
• Primary Surgery:
Lumpectomy + axillary dissection or
MRM with clear margins
• Labs: ANC > 1000/µl
platelets > 100,000/µl
bilirubin = normal
• Other: Normal CXR & EKG
C 9741: Endpoints
• Primary: Disease-free survival
(DFS) Defined as date of study to
Local or distant recurrence
Or death without relapse
• Secondary:
Overall survival (OS)
Toxicity
C 9741: Statistics
• 2 X 2 factorial design:
- Dose density: 2 weeks vs. 3 weeks
- Treatment: concurrent vs. sequential
• Target accrual = 1584 pts in 22 mos.
• First planned analysis at 3 years after
complete accrual
• Provided 90% power to detect a
33% reduction in hazard
for either main effect
C 9741: Methods
•Radiation:
–After completion of
chemotherapy
–Per institutional
guidelines
C 9741: Tamoxifen
• Recommended 20mg per day
starting within 12 weeks of
completion of chemotherapy
• Premenopausal patients with ER+
cancers and all postmenopausal
patients irrespective of receptor
status
C 9741: Results
• 2005 pts accrued 9/97 & 3/99
• Increased number to
compensate for faster than
expected accrual
• 32 pts did not receive therapy
• 1973 pts evaluable & analyzed
First Protocol-Specified Analysis
MEDIAN FOLLOW-UP 36 MONTHS
600
500
EVENTS RELAPSE
OR
DEATH
515
400
300
315
200
100
0
CALGB 8541
C 9741
Patient Characteristics
N=
484
493
501
495
I
II (G-CSF)
III
IV (G-CSF)
No. Nodes+
1-3
4-9
≥10
Premenopausal
59%
29%
12%
50%
59%
29%
12%
48%
60%
28%
11%
49%
59%
29%
11%
48%
Postmenopausal
48%
51%
50%
50%
Patient Characteristics
N=
I
484
II
493
III
501
IV
495
ER-
34%
35%
33%
32%
Tumor > 2cm
60%
55%
58%
58%
Lumpectomy
33%
35%
37%
37%
Pre- got tam
66%
66%
62%
64%
Post- got tam
74%
76%
73%
78%
Disease-FreeDisease-Free
Survival
by
Density
Survival
1.0
By Density
0.8
0.2
0.4
0.6
q3
0.0
Proportion Disease-Free
q2
0
1
2
3
Years From Study Entry
q 2 wks
q 3 wks
N= 988
N= 985
Events= 136
Events= 179
4
Overall Survival
Overall Survivalby Density
1.0
By Density
0.2
0.4
0.6
q3
0.0
Proportion Surviving
0.8
q2
0
1
2
3
Years From Study Entry
q 2 wks
q 3 wks
N= 988
N= 985
Events= 75
Events= 107
4
Multivariate Cox Proportional
Hazards Model: DFS (N=1892)
1.00
RISK RATIO
0.90
1.00
1.00
0.93
0.80
0.74
0.70
0.60
0.50
0.40
0.30
P=0.58
P=0.010
0.20
0.10
0.00
Seq vs. Con
q 3 vs. q 2 wk
Multivariate Cox Proportional
Hazards Model: OS (N=1892)
1.00
RISK RATIO
0.90
1.00
1.00
0.89
0.80
0.69
0.70
0.60
0.50
0.40
0.30
P=0.48
P=0.013
0.20
0.10
0.00
Seq vs. Con
q 3 vs. q 2 wk
Estimated Annual Hazards:
Q 3wk and Q 2wk
.10
Q 3wk
.08
.06
Q 2wk
.04
.02
.00
0
1
2
Yrs
3
4
Hazard Ratio: Q3wk to Q2wk
1.0
.75
.50
.25
.00
0
1
2
Yrs
3
4
Major Toxicities
No. Treated
I
II
III
IV
Seq q 3 Seq q 2 Con q 3 Con q 2
488
493
501
495
No. Data
Granulocytes < 0.5/ul
Febrile Neutropenia
Hospitalized
99
24%
3%
96
3%
2%
101
43%
5%
101
9%
2%
Red Cell Transfusion
Platelet Transfusion
Neurologic: Severe
Sensory Loss or
Motor Weakness
0%
0%
1.9%
2%
0%
1.9%
3%
0%
3.9%
13%
0%
4.5%
Secondary AML/MDS: % by year
Year
1
2
3
9741
0.051%
0.11%
0.18%
9344
0.13%
0.15%
0.17%
In 9741, incidence of AML/MDS does not
appear to be influenced by filgrastim
(slightly higher in q 3-week regimens)
Dose Reductions
REGIMEN
I
II
III
IV
During
A
7%
5%
3%
3%
C
1%
3%
5%
5%
T
1%
7%
4%
5%
Summary (I)
36 Months Median Follow-Up
• Primary Endpoint: Dose-dense
treatment associated with a 26%
proportional reduction in relapse
(p=0.010)
• 4- year DFS was 82% for dosedense and 75% for the every
three-week regimens
Summary (II)
36 Months Median Follow-Up
• Secondary Endpoint: Dose dense
treatment associated with a 31%
proportional reduction in mortality
(p=0.013)
• 3-Year OS was 92% in the dosedense and 90% in every 3-week
regimens
Summary (III)
• No impact for sequentially or
concurrent treatment
• Grade 4 granulocytopenia
(<500/µl) was more frequent on
the q 3-week regimens
• Toxicities were acceptable
Conclusions (I)
• Improved DFS and OS warrant
this communication
• Advantages of dose density were
not accompanied by increase in
toxicity
• Baseline granulocyte count of
1000/µl is safe for administering
chemotherapy
Conclusions (II)
Caveats:
• Additional follow-up needed to
confirm survival benefit
• Maximum follow-up only 5 years &
treatment-related patterns of
recurrence and toxicity may
emerge
• Filgrastim adds cost
Conclusions (III)
• Results consistent with
mathematical models of tumor
kinetics
• Mathematical concepts may
be applied to other drugs and
diseases
Acknowledgements
CALGB: John Carpenter, Donald Berry,
Constance Cirrincione, Clifford Hudis, Eric
Winer, David Hurd, James Holland,
Barbara Smith, Carolyn Sartor, Eleanor
Leung, Richard Schilsky, Hyman Muss,
Larry Norton. ECOG: William Gradishar,
Nancy Davidson. NCCTG: Edith Perez,
James Ingle. SWOG: Silvana Martino,
Robert Livingston. NCI: Jeffrey Abrams
C 9741
Marc L. Citron, MD
Clinical Professor of Medicine
Albert Einstein College of Medicine
CALGB Breast Committee