Diapositiva 1

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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 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-based regimen ?

• Three-drug regimens
• CAF gt CMF Tam (INT 0102)
• CEF gt CMF (NCIC-CTG)
• Sequential regimen
• E ? CMF gt 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 Generation Trials 31000 pts
• Comparing taxane/anthracycline to
  non-taxane/anthracycline
• Sequential (anthra followed by taxane)
• Combination
• Second Generation Trials 25000 pts
• Comparing taxanes in both arms
• Sequential
• Combination
• With Herceptin

Nowak AK et al. Lancet Oncol 5 37280, 2004
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Randomized Trials of Adjuvant Chemotherapy with
Taxanes
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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 al JCO 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
RRdeath?18
NONE
A 60 75 90 mg/m2
Recommended TAM if HR() after chemoRx
Median follow-up 69.0 months
Henderson et al JCO 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 (lt1) and
six (lt1) 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 et al, 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 lt 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 women after chemotherapy
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PACS-01characteristics 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-fluoroura
cil 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
P0.09
P1.0
During and posttreat
P.03
P.63
P.09
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Comments

• Cardiac toxicity data are controversial most of
  the trials dont 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 ?
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Adjuvant Chemotherapy Options
Trastuzumab if HER-2 positive
adapted from Piccart et al. (2005)
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Anthracyclines may not be necessary in adjuvant
therapy of breast cancer ?
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Slamon SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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BCIRG 006, SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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Slamon BCIRG 006, SABCS 2006
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TC vs AC
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TC vs AC
Jones S. et al. JCO 2006
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TC vs AC results I
Jones S. et al. JCO 2006
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TC vs AC results II
Jones S. et al. JCO 2006
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TC vs AC toxicity
Jones S. et al. JCO 2006
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Conclusion 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 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

• Stop Here

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MAIN TOXICITY
????????
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Best Use of Taxanes / Anthracyclines

• When should we offer a Taxane-regimen ?
• Which Taxane Paclitaxel ? Docetaxel ?
• Which Regimen Sequential A(C)?T, Combined AT ?
• Which Antracycline regimen (CEF ?)
• Which Schedule 3 Weekly, Weekly ?
• Which Patients ? Role of Predictive Factors

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Adjuvant Taxanes 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 gt50 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 ???
Slamon BCIRG 006, SABCS 2006
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?????
Slamon BCIRG 006, SABCS 2006
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Adjuvant Chemotherapy Options
Trastuzumab if HER-2 positive
CMF ? TAXANES ?
adapted from Piccart et al. (2005)