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

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) .

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.

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 EFFECTS

Taxanes & trastuzumab

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 .

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.

Give Low Doses More Often

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 β-blockers 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

• 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.

Dexrazoxane

•

•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.

FDA approved dexrazoxane intravenous (IV) injection for the treatment of extravasation resulting from IV anthracycline chemotherapy.

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.

•-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.

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.

Agent 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

stable Hemodynamically stable

The antitumor effects of

adriamycin no difference