All signs are detectable with physical examination:

The clinical scenarios of acute cardiotoxicity are:

ECG, Doppler echocardiography, and markers of cardiac damage (troponin T and I, natriuretic peptides) can help in the diagnosis.

Acute clinic toxicity expressions during administration of anthracycline are usually chest pain due to myopericarditis or palpitations due to sinus tachycardia, paroxysmal supraventricular/ventricular tachycardia, and premature atrial and ventricular beats.

Acute left ventricular dysfunction is a rare manifestation but may be reversible (Fig. 6.1).

In addition all anthracyclines can prolong QT (QTc) [4].

Acute manifestations are usually chest pain, angina or myocardial infarction, palpitations due to cardiac arrhythmias, and less frequently heart failure [5, 6] (Fig. 6.2).

The most common acute cardiotoxicity of this group is due to cyclophosphamide that is less potent than etoposide during stem cell mobilization [7]. It appears as a myopericarditis more frequent at high doses, with acute/subacute heart failure usually responding to medical treatment. This event is uncommon (<10 %), transient, and reversible. Palpitations due to supraventricular arrhythmias and atrial fibrillation may occur [8, 9] (Fig. 6.3).

Acute clinic toxicities during cisplatin infusion are usually palpitations and chest pain due to acute myocardial ischemia or occasionally to myocardial infarction. Dyspnea due to heart failure and electrolyte disturbances may occur [8–10] (Fig. 6.4).

Most data on cardiac toxicity that have been collected for paclitaxel show uncommon finding (0.5 %) of palpitations due to important cardiac arrhythmias (atrial fibrillation 0.23 %, ventricular tachycardia/fibrillation 0.26 %). This compound may cause dyspnea, dizziness, or syncope due to sinus bradycardia and atrioventricular and bundle branch blocks that however often may be completely asymptomatic [8, 9] (Fig. 6.5).

Ixabepilone showed acute fatal cardiotoxicity in a case report [11]. The same goes for vandetanib [12].

Only at experimental level, inhibitors of angiotensin II are effective in preventing Adriamycin acute cardiotoxicity preventing ROS formation at intracellular level. In fact, some natural compounds are promising in protecting rat hearts from anthracycline acute myocardial damage: dexrazoxane, schisandrin B [8], ocotillo [9], ginkgo biloba extract [10], and chrysin [11]. Those compounds are promising, but no controlled trials have tested their efficacy in a clinical evidence-based setting.

All attempts to prevent acute cardiotoxicity should be done: we expect some effects from certain drugs that are discussed before and we are trying to treat toxicity as soon as possible to avoid permanent damage. If heart failure develops, we should treat it with beta-blockers, ACE inhibitors, and diuretics. If arrhythmias are present, the treatment depends according to the type of rhythm disorder. If the scenario is that of an acute coronary syndrome, we can use guidelines to drive our therapy.

In this section possible late complications of a potentially cardiotoxic therapy will be evaluated and related signs and symptom will be analyzed.

In the last decades, cancer therapy has improved the quality of life and survival of the patients, but the late cardiac complications are becoming more and more relevant.

The specificity of these complications depends on the type and on the eventual combination of drugs for the therapy used.

For some treatments as many as one half of patients surviving may develop left ventricular systolic dysfunction with or without heart failure later in life due to the cardiotoxic effects of chemotherapy [12].

In early stages the lack of clinical heart failure may reflect the activation of compensatory mechanisms in the heart and in the body, but when the symptoms develop generally there is a brisk increase in mortality and a significant morbidity [13, 14].

Additionally, radiotherapy induces cardiovascular toxicity in all the cardiac structures: myocardium, pericardium, coronary artery, valve, and conduction tissue.

However, the late effects of anticancer therapy may have many different aspects due to the possibility of the contemporary presence of more than one of these damages and as a result of synergic impact from different therapy.

In clinical practice, appropriate recognition of potential cardiac complications related to chemotherapy or radiotherapy is warranted, but it is possible to have several signs and symptoms of combined cardiac injury that sometimes are not distinguishable from other cardiovascular diseases.

Therefore, in evaluating patients with history of oncological treatment, a close attention to the manifestation of a cardiac disease is needed.

CMR is the gold standard in the evaluation of left ventricular dysfunction. Its main limitation is the cost and should be reserved to the patients in whom echocardiographic quality is not optimal.

One of the most frequent cardiovascular complications of chemotherapy and radiotherapy is cardiomyopathy, which may become clinically relevant even years after treatment.

The most important information comes from the pediatric population cancer survivors having a long life expectancy. In adults the development may be multifactorial and general cardiovascular risk factors have to be added to the effect of the anticancer therapy, with a net balance difficult to evaluate.

It is well known how several chemotherapy agents may lead to the development of LV dysfunction [19]. Anthracyclines play a major role among the anticancer drugs in use, and their cardiotoxic effects have been studied from many years [20, 21]. Other classes have also been identified to cause significant cardiac toxicity, including alkylating agents, tyrosine kinase inhibitors, antimicrotubule agents, and monoclonal antibody as shown in the previous chapters.

The cardiotoxic expression of systolic dysfunction may range from subclinical damage to signs and symptoms of overt heart failure.

At baseline the clinical approach consists of the following:

During chemotherapy the clinical approach is as follows:

After conclusion of chemotherapy, the clinical approach is as follows:

For a schematic clinical point of view, see Fig. 6.8.

Many cardiac imaging tools may be helpful at baseline and during and after the chemotherapy for the diagnosis of cardiac damage.

ECG may add additional diagnostic information in detecting cardiotoxicity because it is sometimes associated with rhythm disturbance, heart block, or ischemic changes.

Echocardiography is a widely used method for the measurement of LVEF, but it is limited by suboptimal image and inter- and intra-observer variability [19, 20].

Diastolic dysfunction detected by Doppler pulsed analysis and DTI often precedes alterations of systolic dysfunction but has no predictive value later [21].

Global longitudinal strain is a parameter for early detection of systolic dysfunction and is predictive of late LVEF decrease [23].

Radionuclide ventriculography or multiple-gated acquisition scan (MUGA) has been validated as an accurate and reproducible method for LVEF estimation, but exposes patients to ionizing radiation [24, 25].

Cardiac MRI is considered the gold standard for volume and LVEF determination¸ but the higher costs limit its use. MRI has to be considered when measure of LVEF is controversial or quality image of echocardiography is inadequate [26].

Nowadays, the effort of cardiologists and oncologists is to find out early systolic dysfunction improving the survival of cancer patients especially for systolic dysfunction [27].

Every coronary risk factor has a powerful impact on prognosis of patients with cancer treated with chemotherapy or radiotherapy. Hypertension is one of the most important of these risk factors. This can be a preexisting condition or may also develop during some specific chemotherapy. It is of paramount relevance to treat actively the first condition and to prevent the second.

The high prevalence of hypertension across the world implies that several cancer patients, especially those at older ages, have essential hypertension at the time of diagnosis of cancer; in fact hypertension is the most common comorbidity in patients with malignancy (37 %) [28]. But the relation between cancer and hypertension is not only a coincidence; there are four aspects involved in that relation.

Firstly, in 1975, Dyer et al. reported a positive association between high blood pressure and cancer mortality in a cohort of 1,233 Chicago gas company male employees [29]. Furthermore, there are literature references supporting a link between hypertension and cancer; however, a mechanism for this association has not been defined. A meta-analysis including a very large prospective sample size from seven European population-based cohorts with virtually complete capture of cancer cases showed that elevated BP was statistically significantly associated with cancer incidence in men and with cancer mortality in men and women, as well as with several specific cancers. In that study, cancer risk increased linearly with increasing BP levels, and for both cancer incidence and mortality, the association was stronger for men than for women. Among men, the absolute 20-year risk of cancer incidence or mortality at age 50 years was 1–2 % points higher with hypertensive systolic or diastolic BPs compared with men with normal BP [30].

Secondly, the relation of hypertension and cancer with risk factors is real. Salt intake contributes to hypertension and is implicated as a causal factor in gastric cancer. Analogously, heavy alcohol consumption contributes to both increased blood pressure and many malignancies. Another powerful risk factor for hypertension is obesity, reinforced by a Swedish study that found independent dose–response relations between body mass index and the risk of renal-cell cancer and between diastolic and systolic blood pressure and the risk of renal-cell cancer, with a greater risk observed in men with an even slightly higher body mass index or blood pressure than in their counterparts with lower values [31]. Because increased consumption of fat results in an increase in both weight and blood pressure and has also been implicated as a risk factor for some forms of cancer, dietary fat may explain the correlation between blood pressure and cancer. Similarly, low socioeconomic status simultaneously confers an increased risk of high blood pressure, certain cancers, and exposure to known carcinogens (e.g., alcohol and tobacco).

Thirdly, blood pressure regulation is modulated not only by risk factors but also by another key players that include the dopamine-1 receptor (D1R), G protein-coupled kinase type 4 (GRK4), and c-Myc, all found in renal proximal tubule cells. Some of them play a role in cancer development, such as c-Myc that also regulates GRK4 in the breast cancer cell line MCF7.

Finally, hypertension prevalence before chemotherapy is around 30 %, and that is similar in the general population, but there is a relation between hypertension and cancer treatment. HT is a recognized effect of antimetabolite purine analogs such as clofarabine; natural agent vinca alkaloids such as vinblastine and vincristine; taxanes such as paclitaxel and docetaxel; anti-small molecule tyrosine kinase such as dasatinib, imatinib, lapatinib, sorafenib, sunitinib, and pazopanib; monoclonal antibody such as bevacizumab; hormones such as prednisone; and antiandrogens such as abiraterone acetate [32, 33]. Table 6.2 shows the most described prevalence [34–42].

The association between cancer and hypertension is a growing problem considering the high prevalence of both conditions. Among chemotherapeutic drugs, anti-VEGFs are the most frequently involved in a rise of blood pressure levels, mainly through the decrease in NO synthesis. Regarding the relationship between antihypertensive agents and risk of cancer development, many studies have been conducted, leading to conflicting results. However, the most recent studies have denied an increased risk of cancer in patients receiving antihypertensive drugs [43]. The control of a de-novo hypertension or worsened pre-existing hypertension control after initiation of an anticancer treatment may indicate many possible underlying mechanisms: endothelial dysfunction associated with decreased bioavailability of nitric oxide and increased endothelin production vascular and kidney, increased vascular tone, vascular rarefaction (decreased microvessel density), and glomerular renal thrombotic microangiopathy with high structural and functional changes that lead to hypertension and proteinuria, glomerular lesions, or more often, secondary concerned itself hypertension treatment. In the absence of a single dominant mechanism, most of them are usually present [44–46]. In almost all cases, glomerular or vascular involvement or worsening of previous damages explains the appearance of hypertension and hence the importance of assessing renal abnormalities (creatinine clearance, proteinuria, hematuria) and markers of hemolytic anemia or thrombocytopenia.