Diapositiva 1

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Highlights in the Management of Breast
Cancer Rome, May 25-26, 2007
TAXANE- vs ANTHRACYCLINES-CONTAINING CHEMOTERAPY
IN THE TREATMENT OF EARLY BREAST CANCER AND THE
ISSUE OF CARDIAC TOXICITY
Dr, Salvatorelli Emanuela G. d Annunzio
University and Center of Excellence on
Aging Chieti
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Prior / concomitant RT Age Previous cardiac
disease Hypertension Other drugs
1
.
0
0
0
.
7
5
Cardiac Event Probability
0
.
5
0
0
.
2
5
DOX
0
.
0
0
mg/m2
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PHARMACODYNAMIC SYNERGISM
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1
.
0
0
0
.
7
5
Cardiac Event Probability
0
.
5
0
0
.
2
5
DOX
0
.
0
0
mg/m2
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TAXANES ?
TAXANES ?
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SYSTEMIC PHARMACOKINETIC SYNERGISM
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Gianni et al. J. Clin. Oncol. 1997
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INTRAMYOCARDIAL PHARMACOKINETIC SYNERGISM
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• Studies in cancer patients are limited by
  ethical or practical constraints to fine needle
  endomyocardial biopsies of sufficient number and
  size to characterize DOX metabolism accurately

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• Studies in cancer patients are limited by ethical
  or practical constraints to fine needle
  endomyocardial biopsies of sufficient number and
  size to characterize DOX metabolism accurately

• Interspecies differences in the expression and
  activity of the cytoplasmic reductases catalyzing
  DOXol formation limit the predictive value of
  animal models

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• IMPORTANCE OF A TRANSLATIONAL MODEL OF HUMAN
  HEART
• Obtain human myocardial samples
• Prepare thin strips
• Reconstitute the strips with DOX in human plasma
  (drug-protein binding) w/wo PTX and Cremophor EL
• Analyze the strips for the content and
  distribution of DOX, DOXol and taxane

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PTX STIMULATES DOXOL FORMATION IN
CYCLOHEXIMIDE-INHIBITED HUMAN MYOCARDIUM
Salvatorelli et al., J Pharmacol Expt Ther, 2007
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Kinetics of doxorubicinol formation and effects
of PTX
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DOX
Low Taxane
CS
AS

Reductase
TX
DOX
DOX
-
CS
High Taxane
AS
DOXOL
Reductase
Salvatorelli et al., J Pharmacol Expt Ther, 2006
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ABOUT SWITCHING TO DOCETAXEL?
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DOXORUBICIN
DOXORUBICINOL
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Kinetics of doxorubicinol formation and effects
of DCT
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A 75 mg/m2
A 60 mg/m2
A 60 mg/m2
Gianni et al. Clin Cancer Res 2005118715-8721
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GROUP A
S
TAC (75/50/500 mg/m2) x 6
GROUP B
FAC (500/50/500 mg/m2) x 6
S
Martin et al. N. Engl. J. Med. 2005
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DOCETAXEL
PACLITAXEL
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HOW TO PREVENT THE CARDIOTOXICITY OF DOX-TAXANE
COMBINATIONS ?
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• By increasing the interval between the
  administration of the two drugs (gt 4h)

• By replacing DOX with EPI

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EPIRUBICIN
EPIRUBICINOL
Salvatorelli et al., J Pharmacol Expt Ther, 2007
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EPIRUBICIN
EPIRUBICINOL
Salvatorelli et al., J Pharmacol Expt Ther, 2007
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Kinetics of epirubicinol formation and effects
of taxanes
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• By increasing the interval between the
  administration of the two drugs (gt 4h)

• By replacing DOX with EPI

• By replacing DOX with liposomal DOX

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LIPOSOME-ENCAPSULATED DOX FORMULATIONS

• Uncoated citrate-containing liposomal DOX
• Polyethyleneglycolcoated (Pegylated) liposomal
  DOX

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• Slow Release reduced peak levels of free drug

• Improved tumor targeting passive accumulation by
  enhanced permeability (leaky vasculature) and
  retention (EPR phenomenon) effect

• Limited cardiac partitioning too big to cross
  the normal vasculature of the heart

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Grade 3-4 cardiotoxicity ()
TAC
Caelyx
AT-CMF
DOCETAXEL
DOCETAXEL
PACLITAXEL
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CONCLUSIONS

• Doxorubicin-induced cardiotoxicty is determined
  by the cardiac level and reactivity of DOX and
  its secondary alcohol metabolite DOXol

• The observations that PTX increased DOXol
  formation in human myocardium helps to explain
  the cardiotoxic synergism between DOX and PTX at
  lower than expected cumulative doses of DOX when
  the two drugs are given almost concomitantly

• The fact that also DCT is able to modulate DOXol
  formation raises caution against combining DCT
  with cumulative doses of DOX higher than those
  adopted in available clinical studies

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• Switching from concomitant to sequential is a
  pharmacologically sound option to diminish the
  risk of DOXol formation and related cardiac
  events during the course of DOX-taxane regimens

• Combinations of taxanes with EPI appear devoid of
  cardiotoxic synergism, partly due to the
  intrinsic lower cardiotoxicity of EPI, but mainly
  due to the lack of modulation of EPIol formation
  by PTX or DCT.

• Liposomal formulations of DOX offer another
  option for improving the therapeutic index of
  DOX-taxane regimens