(3)
Cardiology Department, Mauriziano Hospital, Turin, Italy
Cardiotoxicity is the most common complication of cancer therapy. Knowledge of the potential cardiac effects related to the use of different chemotherapy or radiotherapy and the assessment of cardiovascular risk factors is becoming relevant.
In this section, we summarize the issue that a clinician has to ask himself before the beginning of the therapy. He has to evaluate if the therapy proposed has a cardiac toxicity and how frequently it may occur and if the patient has risk factors related to the treatment or individual cardiovascular risk factors.
The answer to these questions allows the patient to complete a life-saving therapy minimizing cardiac damage.
The question “Is the patient a good candidate for chemotherapy or radiotherapy?” is one of the first that can arise to a cardiologist during a consultation regarding a patient before the beginning of a cancer therapy.
Cancer therapy had certainly improved the quality of life and survival of oncologic patients, but cardiac side effects and toxic effects still represent a substantial drawback of chemotherapy [1, 2].
This statement summarizes the best answer to the question:
The good candidate is the patient who can complete the therapy minimizing the possibility of developing the cardiotoxic effects.
Cardiotoxicity depends on many different factors related to the treatment itself or to individual risk.
The issues that have to be evaluated are:
1.
Does the proposed therapy have a cardiac toxicity?
2.
How frequent can be a complication related to the use of a specific drug?
3.
Does the patient present specific risk factors for cardiac toxicity and mainly for that specific cancer therapy?
4.
Do I have to look for further information on the cardiac risk?
Has the therapy propose a cardiac toxicity?
The following statement is the first point to keep in mind in the evaluation of a specific clinical situation:
Knowing the risk of chemotherapy-induced cardiovascular complications can help to reduce cardiotoxicity.
As shown in Chap. 2, each chemotherapeutic agent has a different incidence and a different kind of cardiac event, and it is necessary to consider several factors.
The dose of the drug administered during each session, cumulative dose, schedule of delivery, way of administration, combination of drugs administered, and interval of administration of these drugs are some important drug-related factors.
Early identification of patients who are at risk for cardiotoxicity should be a primary goal for oncologists in the development of personalized cancer therapy.
From a practical point of view, consider drugs with potential cardiac toxicity, dose, side effects, risk, and potentially, prevention strategies (Table 5.1).
Table 5.1
Cancer therapy: dose, side/toxic effects, risk factors, and possible prevention strategy
Chemotherapy agents | Dose | Frequency | Cardiotoxicity | Note |
|---|---|---|---|---|
Anthracyclines | ||||
Doxorubicin | >450 mg/m2 | Frequent | CHF and LVD | Consider risk factors for toxicity |
Daunorubicin | >600 mg/m2 | Frequent | Consider cardio protective strategies | |
Epirubicin | >800 mg/m2 | Relatively frequent | ||
Idarubicin | >100 mg/m2 | Relatively frequent | ||
Mitoxantrone | >160 mg/m2 | Relatively frequent | ||
Alkylating agents | ||||
Cyclophosphamide | >100–120 mg/kg | Relatively frequent | CHF | |
Uncommon | Pericarditis/myocarditis | High doses | ||
Isofosfamide | >12.5 g/m2 | Relatively frequent | CHF | Consider doses and concomitant anthracyclines |
Relatively frequent | Arrhythmias | |||
Cisplatin | >400 mg/m2 | Relatively frequent | Hypertension | |
Relatively frequent | CHF | Consider concomitant anthracyclines and chest XRT | ||
Uncommon | Cardiac ischemia | |||
Busolfan | >600 mg | Uncommon | Endomyocardial fibrosis | |
Uncommon | Cardiac tamponade | |||
Mitomycin C | >30 mg/m2 | Relatively frequent | CHF | Consider doses, concomitant anthracyclines, chest XRT |
Antimetabolites | ||||
5-fluorouracil | Relatively frequent | Cardiac ischemia | Consider CAD, prior chest XRT, concomitant cisplatin therapy; rate and doses | |
Capecitabine | Uncommon | Cardiac ischemia | Consider CAD | |
Cytarabine | Uncommon | Pericarditis | ||
Uncommon | CHF | |||
Microtubule-targeting agents | ||||
Paclitaxel | Relatively frequent | Arrhythmias and conduction disorders | ||
Uncommon | Hypotension | Consider possible CHF if given with doxorubicin | ||
Vinca alkaloids | Relatively frequent | Cardiac ischemia | Increased risk with CAD or prior chest XRT | |
Signaling inhibitors | ||||
Anti-HER2 | ||||
Trastuzumab | Relatively frequent | CHF and LVD | Uncommon as a single agent. Consider concomitant cyclophosphamide, anthracyclines, and/or paclitaxel; prevention: decrease anthracyclines dose, increase time between anthracyclines and trastuzumab | |
Lapatinib | Uncommon | CHF and LVD | ||
Angiogenesis inhibitors/anti-VEGF | ||||
Bevacizumab | Frequent | Hypertension | Consider preexisting hypertension. Prevention: optimal treatment of preexisting high blood pressure | |
Relatively frequent | CHF | |||
Relatively frequent | Thromboembolic complications | |||
Sunitinib | Frequent | Hypertension | ||
Relatively frequent | QT prolongation | |||
Relatively frequent | CHF and LVD | |||
Sorafenib | Frequent | Hypertension | ||
Relatively frequent | QT prolongation | |||
Uncommon | CHF and LVD | |||
Uncommon | Cardiac ischemia | |||
BCR-ABL inhibitors | ||||
Imatinib | 300 mg/day | Very frequent | Edema | |
Uncommon | CHF | |||
Relatively frequent | Pericardial effusion | |||
Dasatinib | Uncommon | QT prolongation | ||
Nilotinib | Uncommon | QT prolongation | ||
Vandetanib | Uncommon | QT prolongation | ||
Other drugs | ||||
Thalidomide | Uncommon | Edema | ||
Uncommon | Thromboembolic complications | |||
Relatively frequent | Bradycardia | |||
Hypotension | ||||
Arsenic trioxide | Very frequent | QT Prolongation | Prevention: maintain normal electrolytes, avoid drugs prolonging QTc | |
Tamoxifen | Uncommon | Thromboembolic complications | ||
How frequent can be a complication related to the use of a specific drug?
The frequency of toxic effects of chemotherapy is very different for several agents. It can be extremely rare or very high, ranging from 0.2 for lapatinib to 48 % of doxorubicin treatment at very high dosages.
In Table 5.2 is shown the incidence of cardiovascular complications and risk factors.
Table 5.2
Chemotherapeutic agent associated with cardiovascular complication
Drugs | Risk rate | |
|---|---|---|
Cardiac dysfunction | Doxorubicin 400 mg/m2 | 7–26 % |
Doxorubicin 550 mg/m2 | 18–48 % | |
Epirubicin | 0.9–3.3 % | |
Idarubicin | 5–18 % | |
Liposomal anthracyclines | 2 % | |
Mitoxantrone >150 mg/m2 | 2.6 % | |
Cyclophosphamide | 7–28 % | |
Docetaxel | 2.3–8 % | |
Trastuzumab | 2–8 % | |
Lapatinib | 0.2–1 % | |
Sunitinib | 10–28 % | |
Imatinib | 0.5–1.7 % | |
Bevacizumab | 1.7–3 % | |
Myocardial ischemia | 5 Fluorouracil | 7–10 % |
Capecitabine | 3–9 % | |
Paclitaxel | 1–5 % | |
Docetaxel | 1.7 % | |
Bevacizumab | 0.6–1.5 % | |
Sorafenib | 3 % | |
Thromboembolism | Cisplatin | 18 % venous |
Thalidomide | 27 % venous | |
Vorinostat | 5–8 % venous | |
Erlotinib | 3.9–11 % venous | |
Bevacizumab | 12 % arterial | |
Hypertension | Bevacizumab | 4–35 % |
Sunitinib | 6.8–21.5 % | |
Sorafenib | 16–42 % |
Does the patient have specific risk factors for cardiac toxicity and for that specific cancer therapy?
Every patient has an intimate level of risk, due to many different factors that can be summarized in three levels (1): genetic (2), generic cardiovascular risk factors, and (3) every kind of overt cardiovascular disease.
The knowledge of genetic predisposition to develop side effects after chemotherapy is only in its beginning, and it has to be improved largely before to become a routine clinical practice. Probably in a not so far future, the notions of pharmacogenomics can be applied to this field.
Screening of baseline risk factors makes patients less vulnerable to cardiovascular injuries and, as a consequence, less subject to chemotherapy or radiotherapy toxic effects.
The evaluation of risk cardiovascular factors of a candidate to chemotherapy includes high blood pressure, diabetes mellitus, total and LDL cholesterol, obesity, and smoking habits [3–5].
Table 5.3 shows what are the objectives of cardiovascular prevention and, for each risk factor, what the recommended values are.
Table 5.3
What are the objectives of CVD prevention?
No smoking |
BMI <25 kg/m2 and avoidance of central obesity |
BP <140/90 mmHg |
Total cholesterol ≤190 mg/dL |
LDL cholesterol ≤115 mg/dL |
Blood glucose ≤110 mg/dL |
However, the physician can use the common accepted risk chart for estimated risk of cardiovascular disease, as those published by European Society of Cardiology enclosed in the 2012 Guideline on Prevention [6].
The patient may be classified to be at:
1.
Very high risk:
Documented CVD such as previous myocardial infarction, ACS, coronary intervention (PCI, CABG), and diabetes mellitus (type 1 or type 2) with one or more CV risk
Severe chronic kidney disease
Calculated SCORE ≥10 %
2.
High risk:
When present, a markedly elevated single risk factor such as familial dyslipidemias and severe hypertension and diabetes mellitus (type 1 or type 2) but without CV risk factors or target organ damage
Moderate chronic kidney disease
A calculated SCORE of ≥5 and 10 % for 10-year risk of fatal CVD
3.
Moderate risk:
When the calculated risk SCORE is ≥1 and 5 % at 10 years. Many middle-aged subjects belong to this category. This risk is further modulated by factors mentioned above.
4.
Low risk:
When the calculated risk SCORE is 1 % and free of qualifiers that would put them at moderate risk
The determination of the specific total risk of the patient leads us toward a more aggressive evaluation of the patient, like the prescription of deeper investigation analysis, prevention measures like a more stringent arterial pressure control or metabolic control, and therapies that theoretically have preventive effects of possible toxicity (dexrazoxane, ACE inhibitors, or beta-blockers).
Does the patient have a specific risk related to specific cancer therapy?
In clinical practice, the knowledge of risk related to specific cancer therapy allows to decide the treatment strategy.
The specific aspects of toxic effects of each chemotherapeutic drug have been described in Chap. 2.
However, the amount of knowledge on every drug can be not so easy to apply into clinical practice, and it has to be summarized and to be schematized.
In Table 5.4 are shown the predisposing factors related to specific chemotherapeutic agents.
Table 5.4
Risk factors for the development of cardiotoxicity
Anthracycline | |
Prior anthracycline use | Cardiovascular disease and their predisposing factors are the most important factors to assess the treatment strategy |
Prior mediastinal irradiation | Higher vulnerability to anthracycline toxicity is observed in children, particularly in girls |
Genetic predisposition | |
Preexisting heart disease | Also, elderly with associated comorbidities have a higher risk of cardiotoxicity |
Female gender | |
Age (children or elderly) | |
Combination with other chemotherapy | |
Alkylating agents | |
Elderly patients | Cyclophosphamide and cisplatin had these predisposing factors, but for isofosfamide consider electrolyte disturbances [9] |
Prior anthracyclines | |
Antimetabolites | |
Coexisting coronary disease | As described in other chapters, the mechanism is yet unknown and seems to be related to endothelial dysfunction and coronary artery vasospasm [10] |
Risk cardiovascular factors | |
Prior mediastinal irradiation or chemotherapy | |
Microtubule-targeting agents | |
Coexisting heart disease | Consider paclitaxel used in combination with anthracyclines that enhances their cardiotoxicity [12] |
Dyselectrolytemia [12] | |
HER2-targeted agents | |
Coexisting cardiovascular disease | The best recognized agent associated with a relatively high risk of cardiac complications is trastuzumab |
Risk factors (coronary disease, hypertension, diabetes, hyperlipidemias, and obesity) | |
Old age | |
Prior cardiotoxic treatments (including mediastinal irradiation and chemotherapy) | |
VEGF-targeted agents | |
Preexisting hypertension | These drugs can worsen preexisting hypertension or can develop new hypertension |
Age over 65 years | |
Previous arterial thromboembolic events | |
Others drugs | |
Bradycardia | |
QT prolongation | Thalidomide, consider ECG baseline bradycardia |
Do I have to look for further information on the cardiac risk?
Susceptibility to the development of cardiotoxicity of any kind and its severity is determined by the interaction between genetic and multifactorial factors.
Other issues have to be considered.
1.
Age is one of the main issues: children cancer survivors may develop late complications also many years after the chemo- or radiotherapeutic treatment; older ages are otherwise at higher cardiovascular risk and, as a consequence, to higher risk related to cancer therapy.
2.
Sex is a second important factor: men and women have independent differences in risk of cardiotoxicity. Premenopausal women are less likely than men of the same age to develop atherosclerosis. After menopause, the levels of protective hormones drop, and therefore, the rate of atherosclerosis in women rapidly increases.
3.
The tendency of the patients to discontinue physical activity can be considered a new cardiovascular risk factor. Effectively, many subjects after cancer therapy are inclined to become sedentary leading to an increase of the body weight and to develop depression [17]. Encouraging exercise training may be effective because it has demonstrated the effect on cardiovascular reserve, modification of individual metabolic risk factors and hypertension, and overall reductions in CVD mortality.
4.
If depression develops, an adequate pharmacological and psychological support has to be considered to improve the quality of life and the compliance to healthy lifestyle rules.
5.
History of previous radiotherapy also plays an important role. Many cancer patients receive radiotherapy with or without chemotherapeutic agents. Most clinical data reported that mediastinal irradiation can lead to the development of acute and chronic cardiac effects [18]. The extent of cardiotoxicity depends mainly on the radiation dose, the area of the heart exposed, and the particular technique applied [19]. The association between radiotherapy and chemotherapy such as anthracycline generally may increase cardiac injury.
6.
A previous chemotherapy in the same way represents for the patient that has to be submitted to a new treatment a heavy risk factor that can lead to contraindication of the therapy.
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