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