Anthracyclines (doxorubicin, epirubicin, daunorubicin, and idarubicin) are highly effective in the treatment of solid tumors and hematologic neoplasms and avoiding their use due to potential cardiac effects may negatively affect prognosis. Anthracyclines can, however, cause irreversible cardiac damage and thus negatively affect the patient's prognosis.17

Several mechanisms of cardiac cell injury by anthracyclines are proposed based on animal studies and cell culture systems, and it is not yet clear which ones are at work in the clinical setting.20

Most of the proposed mechanisms involve oxidative stress induced by anthracyclines, which suggests the generation of reactive oxygen species (ROS) and lipid peroxidation of the cell membrane are responsible for the injury to cardiomyocytes (Figure 1).17

Figure 1.

adapted from Gottlieb, R.A. and Mehta, P.K.

Cardio-Onoclogy: Principles, Prevention and Management.

Caption: ROS - oxygen free radical species; Cyt. C - Cytochrome C.

(0.2MB).

However, there is considerable variability among patients in their susceptibility to anthracyclines. While many tolerate anthracyclines at standard doses without long-term complications, treatment-related cardiotoxicity may occur soon after the first dose in some patients.17

The mechanisms of doxorubicin's therapeutic effects on cancer cells include: generation of oxygen free radicals, to become interspersed with DNA, leading to inhibition of macromolecule synthesis, DNA binding, as well as DNA damage achieved by inhibition of topoisomerase IIB, and induction of apoptosis by inhibition of topoisomerase II.16

The first step in the process is the entry of the drug into the myocardial cell.

The proposed mechanism for the cardiotoxicity of doxorubicin is increased oxidative stress, demonstrated by increased levels of ROS and lipid peroxidation. Within the cell, the first mechanism is the formation of iron complexes and the production of oxygen free radicals that cause impaired mitochondrial function (Figure 1).16

Several mitochondrial enzymes such as NADH dehydrogenase, cytochrome P-450 reductase, and xanthine oxidase are involved in the generation of oxygen free radicals. Doxorubicin also increases superoxide formation by activating endothelial nitric oxide (NO) synthase.16

In addition to the formation of oxygen free radicals induced by the quinone portion of anthracyclines, oxidative stress that occurs via induction of NO synthase, forms NO and peroxynitrite, and this mechanism is associated with nitration and inactivation of key enzymes in the heart, namely myofibrillar creatine kinase.20

The oxygen free radicals produced by doxorubicin metabolism in cardiomyocytes can subsequently cause cell death through apoptotic pathways initiated by activation of caspase-9 and caspase-3, which leads to the opening of the mitochondrial membrane by altering the permeability of the transition pores and subsequent release of cytochrome C into the cytosol (Figure 1).16

Anthracyclines also cause compromise in membrane assembly and binding and in mitochondrial creatine kinase enzyme activity.20

Another mechanism of mitochondrial injury from doxorubicin may be through injury to the genome of mitochondria by interfering with topoisomerase IIβ activity.16

In the heart, as in other tissues, anthracyclines intersperse with nucleic acids and prevent the synthesis of DNA, RNA, and proteins. Some transcription regulatory proteins that appear important in regulating specific cardiac genes are particularly susceptible to the action of anthracyclines. The impaired synthesis of myofilament proteins, associated with accelerated myofilament degradation in the presence of anthracyclines, leads to a negative balance of sarcomeric proteins: the so-called “cardiac sarcopenia”.20

Anthracyclines also induce alterations in adenylate cyclase and adrenergic function, as well as abnormalities in calcium ion utilization, all critical processes in the dynamic regulation of cardiac function.20

The pathway to cardiomyocyte apoptosis also seems to undergo changes in the balance between cytoprotective and cytotoxic pathways: immediately after doxorubicin exposure, there is evidence that there is an initial positive regulation of the expression of the antiapoptotic proteins, Bcl-XL and Bcl-2, followed by decreases in their expression. This suggests that increasing the expression of Bcl-XL or Bcl-2 could protect against doxorubicin-induced cardiotoxicity.16

Cardiomyocyte death is thus determined by the balance between cytotoxic pathways and cytoprotective pathways. Understanding these cytoprotective pathways may provide insights into new possibilities to decrease anthracycline toxicity.16

The various mechanisms seem to contribute to progressive loss of myofibrils and cell death of cardiomyocytes by apoptosis and by necrosis with clear cell loss, thus leading to “heart muscle loss” (Figure 2).

Figure 2.

Mechanism of anthracycline toxicity.

Adapted from Esquivias G.B., Asteggiano R. Cardiac Management of Oncology Patients, Clinical Handbook for Cardio-Oncology.

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The main RISK FACTOR for developing HF is the cumulative dose of anthracyclines.17,21

It is estimated that more than half of the patients who have taken anthracyclines will develop cardiac changes in the subsequent six years and are five times more likely to have HF than patients not treated with these drugs.21

In addition to the cumulative dose, there are other risk factors for antracycline toxicity (Table 1).

Fluoropyrimidines (5-Fluoruracil and capecitabine) are antimetabolites that inhibit thymidylate synthase, preventing the production of thymidine and uracil, with subsequent inhibition of DNA and RNA synthesis, stopping the growth and division of rapidly dividing cells such as tumor cells.16

Capecitabine is the prodrug of 5-Fluoruracil (5-FU) and is administered orally, while 5-FU is administered intravenously. 5-FU is the third most commonly used chemotherapeutic agent in solid malignancies across the world, and the second most common chemotherapeutic drug associated with cardiotoxicity, after anthracyclines.

5-FU cardiotoxicity, manifested as coronary vasospasm, can occur with a wide dose range and it is dependent on the schedule and the route of administration. In general, risk appears higher with infusional regimens as opposed to bolus regimens: with bolus regimens, incidence of cardiotoxicity is lower.

There are predisposing factors for coronary vasospasm by fluoropyrimidines:

• •

  pre-existing coronary heart disease;

• •

  genetic deficit of dihydropyrimidine dehydrogenase;

• •

  folic acid supplementation.

Histological lesions found include classic ischemic lesions and direct cytotoxic lesions.

The mechanism of toxicity is related to induction of endothelial injury with reduction of NO synthase and subsequent coronary vasospasm and cytotoxic injury of the endothelium with possible induction of thrombosis.16 The mechanism of coronary vasospasm is completely reversible. The clinical expressions of these lesions are:

• •

  typical angina;

• •

  acute myocardial infarction;

• •

  arrhythmias, including ventricular tachycardia secondary to ischemia,

The incidence of myocardial ischemia varies considerably and can be as high as 10%, depending on the dose, schedule, and administration route.17

Electrocardiographic monitoring is essential for both the prevention and immediate diagnosis of toxicity. Once it has appeared, immediate discontinuation and replacement with another CT agent is indicated whenever possible.

While symptoms persist, treatment involves administering calcium channel antagonists such as verapamil and nitrates that are active against coronary spasm.16

Alkylating agents (cyclophosphamide, ifosfamide, busulfan, and other nitrogen mustards) are capable of alkylating different molecules (proteins, RNA, DNA) through an alkylating reaction with their alkyl groups.16 Cyclophosphamide and nitrogen mustards undergo complex modifications in the body that are responsible for their activation and inactivation and with consequent therapeutic and toxic activity. Alkylating agents differ in chemical structure, pharmacology, specific action, and clinical use (mainly in hematology and central nervous system cancer).

Toxicity is dose related, with the total dose of a single therapeutic cycle being more important than the cumulative dose. Concomitant use of anthracycline and RT increases the risk of cardiac toxicity.16

Heart failure has appeared in 7% to 28% of patients treated with cyclophosphamide, and there are a wide range of clinical manifestations of cardiotoxicity with this agent, varying from asymptomatic pericardial effusions to myopericarditis and HF.22

The anatomopathological features of alkylating agent toxicity consist of a framework of hemorrhagic myocarditis, edema, and cellular necrosis, with specific changes evident in the small intramural structures of the coronary arteries. The origin of these changes is an endothelial injury with microemboli and intracapillary lesions.16

Vinca alkaloids (vincristine, vinblastine) and taxanes (paclitaxel, docetaxel) are the two main groups of anti-microtubule agents, but their mechanisms of action are completely different: vinca alkaloids prevent microtubule formation, while taxanes prevent microtubule disassembly. In both, the cell cycle stops, leading to apoptosis.16

Paclitaxel can induce bradyarrhythmias and conduction defects directly through actions on the Purkinje system or indirectly through its transport vehicle. When used in combination with doxorubicin, paclitaxel appears to increase the cardiotoxicity of doxorubicin by altering its pharmacokinetics and increasing the formation of its major metabolite.16 Paclitaxel causes sinus bradycardia, auriculo-ventricular block, ventricular extrasystole, and ventricular tachycardia. Vinca alkaloids can cause angina, changes in the electrocardiogram, myocardial ischemia, and acute myocardial infarction.16

Cardiac events related to vinca alkaloids are more likely to occur in women than in men.16

The clinical presentation of Prinzmetal's angina and the reversible electrocardiogram sometimes described have led to the hypothesis of coronary spasm-induced ischemia.16

There is an increased risk of ischemic complications in patients with coronary artery disease or who have undergone previous thoracic RT.

Platinum compounds, when given in high doses, can cause HF and pericarditis.16 Higher plasma levels of cisplatin and carboplatin may result in decreased creatinine clearance and potentially lead to increased toxicity.16

Nephrotoxicity, seen in up to 35% of patients receiving cisplatin, can cause hypomagnesemia and hypokalemia, increasing the risk of cardiac arrhythmias.16

Patients of advanced age, after previous treatment with anthracyclines or with previous mediastinal irradiation, are at greater risk of cardiac toxicity from platinum.16

Monoclonal antibodies are directed against cancer cell antigens such as CD52, VEGF, HER, CD20, HER2 and BCR-ABL tyrosine kinase (TK). A common type of toxicity is caused by a huge release of cytokines that can also lead to anaphylactic shock. The main class effects appear to be hypertension (HT) and heart failure (HF).16

The precise mechanism involved in monoclonal antibody-induced cardiac dysfunction is not fully understood but is completely different from that of anthracyclines and may be secondary to a sequential mechanism of cellular stress (Figure 3).

Figure 3.

Cardiotoxic Activity of Monoclonal Antibodies.

Adapted from Esquivias G.B., Asteggiano R. Cardiac Management of Oncology Patients, Clinical Handbook for Cardio-Oncology.

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Since the approval of trastuzumab, several agents have entered the therapeutic arsenal, including small molecule TK inhibitors. It is difficult to make broad generalizations about these agents, because they generally have different targets within kinase enzymes.23

Tyrosine kinase enzymes are the key that allow for modulation of a variety of signaling pathways involved in the regulation of many important cellular functions. TK inhibitors act on specific pathways in neoplastic tissues that are influenced by the positive regulation of kinase enzymes.

Each molecule has, however, a specific toxicity profile due to the blocked receptors. It seems that the most problematic are agents that target VEGF and VEGF receptors. These agents are usually associated with severe systemic arterial disease, HT and ischemic events. The development of LVSD in these patients may be related to transient contraction impairment or increased afterload. Of most concern in this group are the non-selective agents, including sunitinib and sorafenib, because these drugs can affect up to 50 different kinases in addition to the target. Because these off-target kinases can play important roles in the heart and vasculature, the risk of toxicity is significant. As a result of its non-specific nature, it is difficult to give general recommendations on how to monitor patients receiving these agents.24

On the other hand, each of these drugs can have specific toxicity according to its specific cellular target.

Thus, it can be seen that:

• -

  VEGF inhibitors can lead to vascular rarefaction and damage to NO production, which in turn leads to HT;

• -

  in the case of HER2 pathway inhibitors, it is precisely the inhibition of this pathway in cardiomyocytes that seems to be responsible for the cardiotoxicity that appears with these drugs, such as trastuzumab and pertuzumab. In fact, the HER2 signaling pathway has an important protective, growth-promoting and antiapoptotic function at the cardiomyocyte level and is inhibited by these drugs. This toxicity is particularly aggravated by prior treatment with anthracyclines: the oxidative stress induced by anthracyclines leads to cell necrosis, but also to positive regulation of compensatory mechanisms by the HER2 pathway. If this is inhibited by monoclonal antibodies (mainly trastuzumab), the possibility of recovery is greatly reduced.16 The administration time between anthracyclines and trastuzumab probably has a crucial role in this toxicity (Figure 4).16

  
  

  Figure 4.

  Mechanisms of sequential toxicity anthracyclines/trastuzumab.

  Adapted from Esquivias G.B., Asteggiano R. Cardiac Management of Oncology Patients, Clinical Handbook for Cardio-Oncology.

  (0.32MB).

In these cases, it is clear that the most important risk factor for toxicity is prior administration of anthracyclines.