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CINBO Consorzio Interuniversitario Nazionale per la Bio-Oncologia. Highlights in the Management of Breast Cancer. “Taxanes vs Anthra-containing chemotherapy in the treatment of early-BC and the issue of cardiac toxicity”. Rome, May 25-26, 2007. Vincenzo Adamo

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CINBO

Consorzio Interuniversitario

Nazionale per la Bio-Oncologia

Highlights in theManagement of

Breast Cancer

“Taxanes vs Anthra-containing chemotherapy in the treatment of early-BC and the issue of cardiac toxicity”

Rome, May 25-26, 2007

Vincenzo Adamo

Oncologia Medica e Terapie Integrate A.O.Universitaria, Policlinico “G. Martino” Messina


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from Lancet ‘98

to Oxford 2000


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CMF and node positive Patients

RFS

HR 0.71, p.005

OS

HR 0.79, p.04

Median Follow up 28.5 yrs

G. Bonadonna,BMJ, Jan 2005


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Crown J. Ed. Book, ASCO 2004


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EBCTCG OVERVIEW 2005 AND ISSUE SYSTEMIC CHEMOTHERAPY

TO CONFIRM

  • To need of adjuvant chemotherapy for early breast cancer

  • A superiority of antrhaciclynes based regimens in adjuvant setting

The Lancet Vol 365 May 14, 2005


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Single-Agent Chemotherapy vs Not and Polychemotherapy vs Not

from the EBCTCG (2005)


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Anthravs otherregimens

5 yr of recurrence

from the EBCTCG (2005)


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Which Anthracycline-basedregimen ?

  • Three-drug regimens

    • CAF>CMF ± Tam(INT 0102)

    • CEF>CMF(NCIC-CTG)

  • Sequential regimen

    • E  CMF > CMF(NEAT-SCTBG BR9601)

  • Two-drug regimens

    • AC = CMF TAM(NSABP B-15, B-23)

    • EC and hEC = CMF(Belgian trial)


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ROLE OF TAXANES IN ADJUVANT SETTING

“Taxanes (Paclitaxel and Docetaxel) with significant antitumoral activity in metastatic disease have been evaluated in the adjuvant setting, and their inclusion can further modify the natural history of the disease by reducing the risk of recurrence and death”

Buzdar AU, et al. editorial JCO2007


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ROLE OF TAXANES IN ADJUVANT SETTING

  • First GenerationTrials: 31000 pts

    • Comparing taxane/anthracycline to non-taxane/anthracycline

      • Sequential (anthra followed by taxane)

      • Combination

  • Second GenerationTrials: 25000 pts

    • Comparing taxanes in both arms

      • Sequential

      • Combination

      • With Herceptin

Nowak AK et al. Lancet Oncol 5: 372–80, 2004



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NSABP B28

N= 3060 N+ pts

P 225mg/m2(3 h)

C 600 mg/m2

NONE

A 60 mg/m2

Recommended

TAM if HR(+)

with chemoRx

Median follow-up

64.8-64.4 months

Mamounas et alJCO 2005


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NSABP B28: Toxicity

*cardiac dysfunction either during or subsequent to therapy

°acute myelogenous leukemia ormyelodysplastic syndrome

**AC: pulmonary embolism in one, congestive heart failure in two, sepsis in one, and seizure in one; AC and PTX: coronary artery disease in one, pulmonary embolism in one.


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CALGB 9344

RR: recurrence

17%

N= 3121 N+ pts

P 175 mg/m2(3 h)

C 600 mg/m2

RR: death

18%

RR:death18%

NONE

A 60= 75= 90 mg/m2

Recommended

TAM if HR(+)

after chemoRx

Median follow-up

69.0 months

Henderson et alJCO 2003


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CALGB 9344: Toxicity

There was no difference in incidence of cardiotoxicity between those who did and those who did not receive paclitaxel.

CHF was observed during active protocol therapy in four (<1%) and six (<1%) pts and during post treatment follow-up in 23 (1%) and 27 (2%) pts randomly assigned to CA alone and CA plus paclitaxel, respectively.

°including high dose of Doxorubicin


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E2197 Trial

Goldstein L,PASCO ’05 abs 512


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E2197:Results I

Goldstein L, PASCO ’05 abs 512


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E2197:Results II

Goldstein L, PASCO ’05 abs 512


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E2197: Toxicity

Goldstein L,PASCO ’05 abs 512


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BCIRG001

Adaptated 26° SABCS 2003


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BCIRG001: post Chemotherapy Treatment

Adaptated 26° SABCS 2003


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BCIRG001: characteristics of the pts and the tumors

Martin M et al N Engl J Med 352; 22, 2, 2005


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Analysis of Survival Rates in the

two Study Groups

Martin M et al N Engl J Med 352; 22, 2, 2005


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Risk Reduction for Disease-free Survival in the Main Subgroups

Martin M et al N Engl J Med 352; 22, 2, 2005


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BCIRG001: toxicity

Martin M et al N Engl J Med 352; 22, 2, 2005


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MDACC TRIAL

Buzdar AU, et al. Clinical Cancer Research 2002


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MDACC TRIAL: Results

ER- pts

RFS all pts

ER+ pts

Buzdar AU etal, Clinical Cancer Research 2002


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MDACC TRIAL: toxicity

Buzdar AU, et al. Clinical Cancer Research 2002


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PACS-01

Stratified on:

Center

 Age: < or  50

 N: 1-3;  4

6 FEC-100: ARM A

Fluorouracil 500 mg/m² d1

Epirubicin 100 mg/m² d1

Cyclophosphamide 500 mg/m² d1

6 cycles every 21 days

S

U

R

G

E

R

Y

R

3 FEC-100/3 Docetaxel: ARM B

3 cycles of FEC 100 every 21 days

followed by

3 cycles of Docetaxel 100 mg/m² d1

every 21 days

Radiotherapy delivered within 4 weeks after the last chemotherapy cycle

 Tamoxifen 20 mg/day for 5 years prescribed in hormone-receptor positive

post-menopausal womenafter chemotherapy


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PACS-01:characteristics of pts and tumors

Roché H et al J Clin Oncol 2006


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PACS-01: RESULTS

DFS

OS

Roché H et al J Clin Oncol 2006


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PACS-01: DFS in different subgroups(Forest plot analysis)

Roché H et al J Clin Oncol 2006


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PACS-01:Toxicity

Roché H et al J Clin Oncol 2006


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ECTO Study

Gianni L, et al, Clin Cancer Res 2005


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Patient characteristics and results

Gianni L, et al. Clin Cancer Res 2005


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Main toxicities

Gianni L, et al. Clin Cancer Res 2005


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NCIC CTG MA.21

q 3 w

Pts

N+

or

N-

HRisk

q 3 w

q 2 w

Primary end point: relapse free survival (RFS)

Secondary end-points: overall survival, toxicity and QoL

Burnell M et al. Breast Cancer Res Treat. Abs 53, 2006


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NCIC CTG MA.21: Schedules

CEF = oral cyclophosphamide/epirubicin/5-fluorouracil; AC-T =doxorubicin/cyclophosphamide and paclitaxel; EC-T = epirubicin/cyclophosphamide and paclitaxel;

from medscape: Update on Adjuvant Chemotherapy in BC H McArthur & C Hudis, 2007   


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NCIC CTG MA.21: Results

2104 patients enrolled Dec-2000-April 2005

global test of significance


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NCIC CTG MA.21

However, both the CEF and dose-dense EC-T regimens were associated with increased rates of febrile neutropenia,TVE, and delayed cardiotoxicity compared with AC-T.


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Randomized Trials of Adjuvant Chemotherapy with Taxanes

* parameter after 4 years of follow up


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Cardiac Toxicity

P=0.09

P=1.0

During and posttreat

P=.03

P=.63

P=.09


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Comments

  • Cardiac toxicity data are controversial: most of the trials don’t include a careful cardiac monitoring before, during and after the treatments

  • Many trials demostrate that Anthracyclines and Taxanes are the most active cytotoxic drugs for the treatment of breast cancer also as adjuvant chemotherapy.

  • However the advantages obtained by this combination must be carefully balanced against potential risks, particularly in the adjuvant setting.


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Mechanisms and types of Cardiotoxicity Associated with different therapeutic modalities

by Brian R, et al, Ed Boock ASCO 2007


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Who need Adjuvant Chemotherapy ? different therapeutic modalities


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Adjuvant Chemotherapy Options different therapeutic modalities

Trastuzumab if HER-2 positive

adapted fromPiccart et al. (2005)



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Slamon breast cancer ?SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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“BCIRG 006”, breast cancer ? SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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Slamon “BCIRG 006”, breast cancer ? SABCS 2006


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TC breast cancer ?vs AC


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TC breast cancer ?vs AC

Jones S. et al. JCO 2006


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TC breast cancer ?vs AC: results I

Jones S. et al. JCO 2006


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TC breast cancer ?vs AC: results II

Jones S. et al. JCO 2006


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TC breast cancer ?vs AC: toxicity

Jones S. et al. JCO 2006


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Conclusion: breast cancer ?Thirty-one years ago, the original AC regimen was reported. Now, there is a superior nonanthracycline regimen, TC.

At 5 years, TC was associated with a superior DFS and a different toxicity profile compared with AC.

Jones S. et al. JCO 2006


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High Risk Patient breast cancer ?

provocative new scenarious

HR negative

Node neg/pos

HER2 negative

Topo II positive

HR negative

Node neg/pos

HER2 positive

Topo II negative

HR negative

Node neg/pos

HER2 positive

Topo II positive

HR negative

Node neg/pos

HER2 negative

Topo II negative

FEC

FEC docetaxel

Taxanes(carbo) +

Trastuzumab

FC(caelyx)C +

Trastustumab

Taxanes +

Cyclophosphamide


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The End breast cancer ?

Stop Here


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MAIN TOXICITY breast cancer ?

????????


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Best Use of Taxanes / Anthracyclines breast cancer ?

  • When should we offer a Taxane-regimen?

  • Which Taxane:Paclitaxel ? Docetaxel ?

  • Which Regimen: Sequential A(C)T, Combined AT ?

  • Which Antracyclineregimen:(CEF ?)

  • Which Schedule:3 Weekly, Weekly ?

  • Which Patients ?: Role of Predictive Factors


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Adjuvant Taxanes : breast cancer ?which data from randomized trials

  • Adjuvant taxanes improve DFS

    (Level 1 evidence ?)

    2 positive trials(CALGB 9344, BCIRG 001)

    1 negative trial ( NSABP B-28),but:

    TAM concomitant to chemotherapy

    TAM to all pt >50 years old

  • Adjuvant Taxanes do not improved OS:

    longer follow-up

    waiting for ongoing trials results

  • Adjuvant taxanes increase toxicity


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Togliere ??? breast cancer ?

Slamon “BCIRG 006”, SABCS 2006


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????? breast cancer ?

Slamon “BCIRG 006”, SABCS 2006


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Adjuvant Chemotherapy Options breast cancer ?

Trastuzumab if HER-2 positive

CMF ? TAXANES ?

adapted fromPiccart et al. (2005)


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