Transcript Late cardiotoxicity

Anthracycline – induced cardio toxicity :Cardio toxicity is a well recognized side effect of anthracycline
treatment that limits the total amount of drug administered and can
cause heart failure in some patients.
1-Mechanism of cardiotoxicity .
2-Protection against the cardiotoxicity of anthracyclines .
3-Strategies to reduce the cardiotoxicity of anthracyclines
1- Mechanism of cardiotoxicity :The cardiotoxicity of the drug has been attributed to a large number of
effects, including apoptosis , alterations in iron homeostasis, deregulation of
calcium homeostasis both in the sarcoplasmic reticulum and in the
mitochondria, and mitochondrial dysfunction.
However, the common trigger of these events appears to
be linked to an oxidative stress caused by the production
of reactive oxygen species (ROS).
Figure 1. Apoptosis hypothesis for the cardiotoxicity of anthracyclines. Apaf-1,
Apoptotic protease activating factor-1; TNF/FAS-R, tumor necrosis factor/Fas receptor.
Generation of ROS by anthracyclines :The chemical structure of anthracyclines consists of a tetracycline moiety
containing a quinone and a conjugated amino sugar residue (Figure 2).
In the cellular environment,
anthracyclines might undergo redox activation* through their interaction
with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen (O2)
as an electron acceptor, returning to the parent compound which is then
available for a new redox cycle.
This reaction leads to the formation of superoxide anion (O2−), which, in aerobic
conditions, can be produced in substantial amounts.
Driven by superoxide dismutases (SOD), or spontaneously in acidic pH,
superoxide anion is converted into hydrogen peroxide (H2O2) which,
in the presence of traces of transition metals such as iron or copper, will
be converted to the very reactive oxidizing species , hydroxyl radical
(OH) .
ODFR, oxygen-derived free radicals
Clinical features of anthracycline cardiotoxicity :The damage to the heart that occurs after anthracycline therapy can be
categorized as :
Early cardiotoxicity:
happening during anthracycline treatment or in the first year after its
completion, which manifests as non specific ST-segment and T-wave
abnormalities .
Late cardiotoxicity:
happening at least 1 year after the completion of anthracycline
treatment, which is cumulative, dose-related and can result in congestive
heart failure and left ventricular dysfunction.
Clinical presentation
The clinical presentation of anthracycline-induced toxicity can be divided into:
acute or subacute
early onset chronic
progressive
cardiotoxicity
late onset chronic
progressive
cardiotoxicity
heart damage that
develops
immediately after
the infusion of the
drug or within
a week of therapy
a depression of
myocardial function
which occurs during
the treatment or within
the first yearafter
treatment
this occurs at least
1 year after the end
of treatment.
Late on effects can
occur up to 20 years
after completion of
anthracycline therapy
Table 1. Risk factors for anthracyclines-related cardiotoxicity
RISK FACTORS
EFFECTS
Abnormal cardiac function
Higher risk for chronic cardiac dysfunction.
Hypertension is the only factor can potentiate cardio toxic
effects.
Cumulative dose
The most significant risk factor for cardiac dysfunction
Age
Younger age predisposes to greater cardiotoxicity
Length of infusion
Infusions do not differ from bolus modality in children.
Sex
Females are more vulnerable.
RISK FACTORS
EFFECTS
Black race
Higher risk of early clinical cardiotoxicity
Trisomy 21
Higher risk of early clinical cardiotoxicity
Length of follow-up
A longer follow-up increases the risk of cardiotoxicity .
Additional treatment
(cyclophosphamide,
bleomycin, vincristine or
mitoxantrone)
Predispose to cardiotoxicity
Irradiation
Concomitant mantle irradiation is a predisposing factor
Recent studies have not observed increased CHF in breast
cancer patients who received radiation therapy in combination
with a standard dose of doxorubicin (60 mg/m2) given for four
cycles
RISK FACTORS
Taxanes &
trastuzumab
EFFECTS
the incidence of cardiac toxicity increased when
cumulative doxorubicin doses exceeded 360 mg/m2
This is thought to be the result of taxanes stimulating the
conversion of doxorubicin to the more potent cardiotoxic
metabolite doxorubicinol inside human myocardium, and
potentiating anthracycline-induced cardiotoxicity, especially at
high, cumulative anthracycline doses.
Slow infusion of paclitaxel and doxorubicin or increased
time between doxorubicin and paclitaxel treatment
decreased cardiotoxicity.
When combined with paclitaxel, the cumulative
doxorubicin dose should not exceed 360 mg/m2.
Cumulative dose :Early retrospective studies from the 1970s demonstrated that anthracycline
toxicity and heart failure were dose-related,
with the incidence of complications increasing sharply when the cumulative
dose exceeded 550 mg/m2 of body surface area.
The incidence of heart failure was approximately 4% when the cumulative
dose was between 500 and 550 mg/m2,
but increased to 18% when the dose was increased to 551–600 mg/m2
and to as much as 36% when the total dose was at least 601 mg/m2
The prognosis of the cardiomyopathy, once developed, is grave, and it is
difficult to predict which individuals will develop heart failure on a case-by case
basis.
Children treated with anthracycline can develop cardiotoxicity even
when exposed to cumulative doses well below that believed to be safe
in adults .
Give Low Doses More Often
Giving low doses of an anthracycline more frequently reduces the peak plasma
concentration without decreasing the overall total dose.
This decreases the risk of cardio-toxicity without affecting the cytotoxicity
of the anthracycline.
Mucositis and cardiac toxicity are related to the peak plasma concentration.
1- toxicity can be reduced by administering lower, more frequent
doses.
2-The use of prolonged infusion schedules may also reduce toxic peak
concentrations, although this can be cumbersome, is expensive and requires a
central venous access device to administer the drug safely.
3-Antitumour efficacy and myelosuppression appear to depend on the
cumulative dose administered and are therefore not diminished by altering the
administration schedule to give lower doses at more frequent intervals.
Strategies to reduce cardiotoxicity of anthracyclines
•Changing the process of administration to one of continuous
infusion .
•Reducing the total cumulative dose to <400 mg/m2 .
•Using liposome-encapsulated anthracyclines .
•Reducing the amount of free iron by the use of dexrazoxane
(however, this compound is not recommended at the beginning of
treatment, because of the possibility that it could diminish the effect of
anticancer agents)
•Lessening the production of ROS with N-acetyl cysteine, coenzyme
Q10, or a combination of anti-oxidant vitamins. Other cardioprotective
agents such as l-carnitine, probucol, and deferoxamine are being
investigated
•Finally, an appropriate treatment of early and late cardiac
events is necessary, to slow down the evolution of
anthracycline-induced cardiotoxicity.
•Early dysfunction such as arrhythmias and pericarditis is treated with
antiarrhythmic agents and aspirin.
•For late dysfunction, angiotensin-converting enzyme inhibitors and βblockers form the basis of treatment.
Angiotensin-converting enzyme inhibitors have been shown to slow the
progression of left ventricular dysfunction in patients undergoing high-dose
chemotherapy,
early treatment with enalapril seemed to prevent the development of late
cardiotoxicity and the occurrence of adverse clinical events
Dexrazoxane
• is a catalytic inhibitor of the topoisomerase II enzyme that is used as a detoxifying
agent to prevent the effect of anthracyclines.
•used
to protect the heart against the cardiotoxic side effects of anthracycline
•
•dexrazoxane chelat iron , but the precise mechanism by which it protects the heart is
not known.
• brand name Totect.
•The recommended regimen for dexrazoxane is 1000 mg/m2 (maximum,
2000 mg) given on days 1 and 2, and followed by a dose of 500 mg/m2
(maximum, 1000 mg) on day 3.
•-Because compromised renal function can increase exposure to
dexrazoxane, the dose should be reduced by 50% in patients with
creatinine clearance values of less than 40 mL/minute.
The FDA warns that dexrazoxane is cytotoxic and has an
additive effect with anthracycline-containing cytotoxic
therapy, thereby increasing the risk for leukopenia,
neutropenia, and thrombocytopenia. Reversible elevations
of liver enzymes may also occur. Therefore, monitoring of
blood counts and liver enzymes is advised.
FDA approved dexrazoxane intravenous (IV) injection for the treatment of
extravasation resulting from IV anthracycline chemotherapy.
An Antidote to Adriamycin Cardiotoxicity?
The animal study tested whether probucol, a lipid-lowering drug with strong
antioxidant properties, offers any protection.
Researchers in Canada studied four groups of rats that received
•adriamycin alone (25 animals),
• adriamycin plus probucol (25),
• probucol alone (12), or no therapeutic agents (12) over a two-week period.
The probucol was started two weeks before adriamycin treatment.
Adriamycin
alone
Adriamycin plus
probucol (25)
Probucol alone (12), or
no therapeutic agents
No. of died
rats
23% of the rats
died
None
None
Cardio- toxicity
developed
evidence of
cardiomyopathy,
including ascites
Hemodynamically
Hemodynamically stable
Agent
stable
The antitumor
effects of
adriamycin
no difference