anthracyclines in early breast cancer: patient perspectives and expert debate this program is...

Anthracyclines in Early Breast Cancer: Patient Perspectives and Expert Debate

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Early Days: Alkylating Agents and Antimetabolites In 1976, Bonadonna and colleagues from Milan, Italy,

reported that postoperative CMF improved DFS and OS in women with node-positive breast cancer

At the same time, the NSABP was evaluating adjuvant L-phenylalanine mustard and fluorouracil

In Scandinavia, Nissen Meyer was evaluating adjuvant cyclophosphamide



0 0.5 1.0 1.5

Entry Age andNodal Status

40-49 yrs

50-59 yrs

60-69 yrs

70+ yrs

Total

AllocatedPolychemo

AllocatedControl

Events/Women

Log RankO-E

Varianceof O-E

Ratio of Annual Event Rates Polychemo:Control

Polychemo Events

784/2480(31.6%)

1843/4880(37.8%)

1812/4886(37.1%)

158/570(27.7%)

4973/13776(36.1%)

Heterogeneity between 5 categories: 2 = 25.4; P = .000044

954/2391(39.9%)

2220/5143(43.2%)

2063/4967(41.5%)

209/610(34.3%)

5909/14019(42.1%)

-150.4

-196.8

-125.3

-8.6

-567.3

367.8

770.6

733.4

56.3

2095.2

< 40 yrs 376/960(39.2%)

463/908(51.0%)

-86.2 167.0 40% (SE 6)

34% (SE 4)

23% (SE 3)

16% (SE 3)

14% (SE 12)

23.7% (SE 1.9)reduction

2P < .00001

Polychemo Better Polychemo WorseTreatment effect 2P < .00001

2.099% or <I> 95% Cl

Polychemotherapy vs No Polychemotherapy: Recurrences

EBCTCG. Lancet. 2005;365:1687-1717.



Anthracyclines

FarmItalia Research developed these compounds in 1960s

Derivatives of soil microbe, Streptomyces peucetius (rhodomycin)

Daunomycin (R = CH3), doxorubicin (R = CH2OH)



Anthracyclines (cont’d)

Inhibition of DNA and RNA synthesis

– By intercalation between DNA base pairs

– Block DNA repair by inhibition of topoisomerase II

In the 1980s, RCTs were initiated to evaluate the role of anthracycline-containing adjuvant regimens



NSABP B-15: AC x 4 vs CMF x 6

> 1400 women with node-positive breast cancer

No difference in 3-year DFS (62% vs 63%)

No difference in 3-year OS (83% vs 82%)

Different toxicity profiles

Fisher B, et al. J Clin Oncol. 1990;8:1483-1496.



Epirubicin and Doxorubicin

O

O

OO

OCH3O OH

OH

OO

NH2

HOCH3 O

O

OO

OCH3O OH

OH

OO

NH2HO

CH3

Epirubicin Doxorubicin



Epirubicin and Doxorubicin Structural ConsiderationsFeature Consequence

Epirubicin has lower pKa than doxorubicin

More lipophilic and better able to penetrate cells

Glucuronidation of epirubicin and epirubicinol to inactive metabolites

Terminal half-life Epirubicin: 30 hours Doxorubicin: 45 hours



Doxorubicin:Epirubicin Dose RatiosWith Similar Toxicities Hematologic 1.0:1.2

Nonhematologic 1.0:1.5

Cardiac 1.0:1.8

Launchbury AP, et al. Cancer Treat Rev. 1993;19:197-228.



Node-positive,pre- and perimenopausal

patients with lumpectomy

or mastectomy from 1985-1993

(N = 710)

C 75 mg/m2 PO QD Days 1-14E 60 mg/m2 IV Days 1 and 8 every 4 weeks x 6* F 500 mg/m2 IV Days 1 and 8

C 100 mg/m2 PO QD Days 1-14 M 40 mg/m2 IV Days 1 and 8 every 4 weeks x 6 F 600 mg/m2 IV Days 1 and 8

*Plus prophylactic antibiotics.

NCIC CTG MA.5 Trial



Endpoint, %CEF

(n = 351)CMF

(n = 359)P Value

DFS 63 53 .009

OS 77 70 .03

Levine MN, et al. J Clin Oncol. 1998;16:2651-2653.

MA.5 Trial: 5-Year DFS and OS



Anthracycline Regimens vs CMF

Study Treatments N DFS, % OS, %

SWOG CAF vs CMF 2691 85 vs 82* 92 vs 90

Danish FEC60 vs CMF 1195 63 vs 58* 70 vs 65*

*Statistically significant (P < .05).



NIH Consensus Statement 2000

“Adjuvant chemotherapy regimens that include an anthracycline (such as doxorubicin or epirubicin) result in a statistically significant improvement in survival compared to nonanthracycline regimens”



Poole et al UK Trial (2006)

4 cycles of epirubicin every 3 weeks followed by 4 cycles of CMF vs 8 cycles of CMF alone

Median follow-up: 48 months

A priori specified combination of the results of NEAT and BR9601

Poole CJ, et al. N Engl J Med. 2006;355:1851-1862.



Copyright © [2006] Massachusetts Medical Society. All rights reserved. Poole CJ, et al. N Engl J Med. 2006;355:1851-1862.

UK Trial: Survival by Treatment

No. at RiskEpirubicin plus CMFCMF

11891202

11661172

10821044

851797

Years Since Surgery0 1 2 3 4 5

0

25

50

75

100

560521

293257

OS

(%

)

HR = 0.67; P < .001

82

75

95

92

Epirubicin plus CMFCMF



Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Levine MN, et al. J Clin Oncol. 2005;23:5166-5170.

HR = 0.80; P = .007

MA.5 Trial: 10-Year Recurrence-Free Survival—CEF vs CMF

No. at RiskCEFCMF

351359

212193

Years0 5 10

0

20

40

60

8480

10-Y

ear

Su

rviv

al R

ate

(%)

80

CEFCMF

100



MA.5 Trial: 10-Year OS—CEF vs CMF

HR = 0.85; P = .047

No. at RiskCEFCMF

351359

269253

Years0 5 10

0

20

40

60

98106

80

100 CEFCMF

10-Y

ear

Su

rviv

al R

ate

(%)

Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Levine MN, et al. J Clin Oncol. 2005;23:5166-5170.



EBCTCG: 15-Year Mortality

Reprinted from The Lancet, Vol. 365. pp1687-1717. © 2005, with permission from Elsevier.

Anthracycline Better

0.84 (SE 0.033)2P < .00001

Treatment effect 2P < .00001

0 0.5 1.0 1.5CMF Better

2.0

Anthracycline:CMFRatio of Annual Death Rates

Deaths/Women Anthracycline Deaths

Anthracycline CMF Log rank O-E Variance of O-E

(95% CI) (95% CI) -133.0 761.9

Total 1809/7228 2038/7243

(25.0%) (28.1%)



Summary

DFS and OS are improved with anthracycline-containing adjuvant chemotherapy compared with CMF

These data are robust as they are based on trials with 15 years of follow-up in > 15,000 women

Anthracycline-containing adjuvant chemotherapy is the standard



Adjuvant Chemotherapy of Primary Breast Cancer: What We Know Low-risk category

– ER(+), PR (+), axillary lymph nodes (-), Size<1 cm, histologic grade 1, or 1-2 cm hormone receptor-positive tumor with tubular or mucinous histologic types.



Ushering in a New Era: The Taxanes

Anthracyclines are still the backbone; taxanes are studied in sequence or concurrent

Perhaps because 4 cycles of AC every 3 weeks is not enough?

O

O

O

NH

OH

HO O

OH

OH

H H

OO

O

O

O

O

O

NH

OH

O O

OH

OH

OOO

O

O

H

O

DocetaxelPaclitaxel

O



Study N Treatments DFS, OS Improve With:

CALGB 9344[1] 3121 AC vs AC → T AC → T

CALGB 9741[2] 2005 AC → T: sched, comb Dose-dense AC → T

PACS 01[3] 1999 FEC vs FEC → Td FEC → Td

BCIRG 001[4] 1491 FAC vs Td AC Td AC

1. Henderson IC, et al J Clin Oncol. 2003;21:976-983.2. Citron ML, et al. J Clin Oncol. 2003;21:1431-1439.3. Roche H, et al. J Clin Oncol. 2006;24:5664-5671.4. Martin M, et al. N Eng J Med. 2005;352:2302-2313.

Trials Incorporating Taxane Therapy



Safety of Anthracyclines: Cardiotoxicity Clinical CHF is rare (< 1%)

In EBCTCG analysis, mortality from heart disease was 0.08% vs 0.06% per year[1]

Decrease risk by screening patients

Use safer anthracyclines, eg, epirubicin

1. EBCTCG. Lancet. 2005;365:1687-1717.



Safety of Anthracyclines: Leukemia

Leukemia is a rare event and typically occurs early in contrast to the late occurrence with alkylating agents

Leukemia occurs with most every chemotherapy agent



Risk vs Benefit of Anthracyclines in Preventing Breast Cancer

Benefits

Toxicity



Adjuvant Trastuzumab

Study Rx Efficacy Safety

B-31/9831[1]

(n = 3351)AC (Q3) → T(Q1)

AC → THDFS: HR = 0.48OS: HR = 0.67

Cardiac:4.1% vs 0.8%

HERA[2]

(n = 3387)Chemo*

Chemo* → HDFS: HR = 0.54

Cardiac:0.5% vs 0%

1. Romond EH, et al. N Engl J Med. 2006;353:1673-1684.2. Piccart-Gebhart MJ, et al. N Engl J Med. 2005;353:1659-1672.

*A/E + taxane in 30%, A/E alone in 70%.

↔



NSABP B-31: Cardiac Update

Rastogi P, et al. ASCO 2007. Abstract 513.

At 5 years, rate of cardiac events unchanged (3.8%)

Recovery in LVEF noted in patients who had clinically relevant declines

Symptoms of CHF resolved in most women but many remained on meds for LV dysfunction

None of 175 patients randomized to AC → TH who initiated trastuzumab after completing paclitaxel has developed a cardiac event



Summary

Adjuvant anthracyclines in > 40,000 women

15-year follow-up with anthracyclines

Dose and schedule of anthracyclines are important

Cardiac events are very rare

Avoidance of breast cancer deaths far outweighs toxicity



Summary (cont’d)

Trastuzumab adds significant benefit to anthracycline-based adjuvant chemotherapy

Serious cardiac toxicity was considerably higher in B-31/9831 than in HERA likely due to sequencing of trastuzumab relative to anthracyclines



What Evidence Is Required to Change Current Therapy? Require level 1 evidence:

“Beyond a reasonable doubt that the proposed new treatment is better than or as good as current treatment”

Large RCT showing a statistically significant difference

Adequately powered noninferiority trial

ACCP Guidelines. Chest. 2008;133:123S-121S.



What Methodologic Criteria Need to Be Satisfied? Results of the trial should be published in a peer-reviewed

journal

Sample size should be large enough to rule out a clinically important difference

Treatment should be safe

Results should be consistent over the long term

Results should be reproducible



BCIRG 006

3225 women with HER2-positive (FISH), high-risk, node-positive, or node-negative breast cancer

Randomized to

– AC x 4 → Td x 4 (ACT)

– AC x 4 → Td x 4 + trastuzumab x 1 year (AC → TH)

– Td Carbo x 6 + trastuzumab x 1 year (TCH)

Phase II data for Td Carbo regimen in metastatic disease



Slamon D, et al. SABCS 2006. Abstract 52.Years From Randomization

Dis

ease

Fre

e (%

)

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

83%

82%

AC → TH 1074 128

Arm Pts Events

TCH 1075 142

270

HR = 0.9 (0.7-1.2)

BCIRG 006: DFS—2nd Interim Analysis

AC → THTCH



US Oncology 9735

AC every 3 weeks x 4 vs Td C every 3 weeks x 4

HR = 0.67, P = .01 in favor of TC

AC every 3 weeks is not standard adjuvant chemotherapy

Standard therapy is DD ACT or CEF

Jones SE, et al. J Clin Oncol. 2006;24:5381-5387.



How Do These Studies Match Criterion?Criterion BCIRG 006 USO 9735

Completed and published Abstract J Clin Oncol 2006

Underpowered Yes (at this point) No

Safety ? Yes

Long-term follow-up No (3 years) No (5 years)

Reproducible No No



Criteria to Use to Choose a Regimen Based on Biomarkers Demonstrated prediction, not just association

Validated prospectively in large numbers of patients



+++++++

+++

Prediction

Not Amplified Amplified

0

20

40

60

80

100

OS

(%

)

Years6 8 100 2 4

0

20

40

60

80

100

OS

(%

)

Years6 8 100 2 4

++++ +++++++ ++++ +

++ +++++ ++ +

++ +++ ++ +

++ +++++++ +++++ + ++

++++++++++++++

+++++++++++++++ +++++

+++

++

++

+

++

++

+

+

++ ++++++

++++++

Interaction

++

+++

Bartlett JMS, et al. J Clin Oncol. 2008;26:5027-5035. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

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