Brazilian cardio-oncology: the 10-year experience of the Instituto do Cancer do Estado de Sao Paulo

The profile of a patient with cardiotoxicity reflects a younger population with fewer risk factors and predominant breast cancer. This population analysis suggests that the cardiac complications found in these patients resulted from cancer therapy. Patients in this group had a lower left ventricular ejection fraction, despite presenting fewer comorbidities.

Care in this outpatient clinic is focused on all forms of cardiotoxicity (ventricular dysfunction, myocardial ischaemia, hypertension, arrhythmias); however, the vast majority is related to anthracycline and trastuzumab cardiotoxicity, which lead to ventricle dysfunction. The largest Brazilian study conducted in our institution estimated the incidence of anthracycline-related cardiotoxicity in breast cancer patients to be approximately 14% [5].

The concept of cardiotoxicity has changed over the years. Initially, only the ejection fraction drop was valued as a criterion. The I Brazilian Cardio-Oncology Guideline of the Brazilian Society of Cardiology [6], coordinated by the ICESP and InCor teams, redefined cardiotoxicity as follows: 1) cardiomyopathy with reduced left ventricular ejection fraction (LVEF), 2) heart failure (HF) symptoms, 3) HF-associated signs such as S3, tachycardia or both; 4) reduction in LVEF compared to a baseline of at least 5% to less than 55% with concomitant signs or symptoms of HF, or reduction in LVEF in the range of at least 10% to less than 55% without signs or concomitant symptoms. In recent years, the programme has incorporated the currently accepted definition of cardiotoxicity as a drop-in ejection fraction of at least 10% absolute points to values below 50% [7]. The standard treatment involves angiotensin-converting-enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs) associated with beta blockers (BBs) and spironolactone. The maintenance of chemotherapy can be considered in this scenario but with cardiac imaging monitoring and biomarkers. There is not an exact definition as to when chemotherapy should be halted – this decision should preferably be made alongside the assistant team (oncologist or haematologist) [7].

One of the key tools for deciding how to select the cardioprotection strategy for a certain patient is based on a complete clinical history and complete physical examination, the identification of cardiovascular (CV) risk factors, biomarker analysis, and an evaluation of the potential risk of cardiotoxicity [8]. It is also important to discuss with the cancer team the type of chemotherapy to be administered, its dose and its potential cardiovascular toxicities. Following this initial approach, optimization of CV risk factors and previous CV conditions should be achieved following its specific therapeutic goals [7, 8].

The incidence of cardiovascular risk factors is high in this population. The median age was 66 (58–74) years, which shows that most of the patients attended are elderly. Age is an isolated risk factor and contributes to the development of CVD and cancer. The risk for CVD doubles with each decade of life, and it is estimated that 70% of new cancer cases occur in individuals over 55 years of age [9, 10].

The prevalence of hypertension in our population is high, with approximately 60% of patients exhibiting hypertension. The treatment for hypertension in oncological patients must follow the recommendations from current guidelines [11, 12]. The main objective of antihypertensive treatment for oncological patients aside from reducing cardiovascular risk is to enable them to receive antineoplastic treatment at maximum doses and ultimately derive benefits from neoplasm control.

Cardiac arrhythmia is another frequent complication with oncological patients, since it can be a side effect to different drugs [13, 14]. Aside from antineoplastic therapy, it is necessary to be cautious about a series of factors present in oncological patients that can contribute to this exponential incidence, such as electrolyte disorders, hypothyroidism, advanced age, and concomitant use of drugs that prolong QTc. These conditions must be treated and corrected for all patients who will initiate chemotherapeutic treatment [7].

The main drugs related to prolonged QT are arsenic trioxide and tyrosine kinase inhibitors. When these drugs are administered, a basal electrocardiogram must be repeated periodically during chemotherapy. The discontinuation of chemotherapy is recommended when QTc prolongation is > 500 ms or there is an increase of more than 60 ms in basal QTc [7, 15, 16].

Supraventricular arrhythmia is also relatively frequent in oncological patients, where atrial fibrillation (AF) is most commonly noticed [14]. In our cohort, the prevalence of atrial fibrillation was 8.74%. Elevated incidence of AF is acute in scenarios of post-procedures, and the treatment in these cases is indicated [17].

The incidence of thromboembolism (VTE) phenomena in cancer patients is high, and VTE is the second leading cause of mortality in these patients [18]. For patients with documented thromboembolic events, full dose anticoagulation could be conducted for those with platelet counts > 50,000/mm³, with no associated coagulation disorders [19]. Coagulation in patients with active neoplasms and/or ongoing chemotherapy treatment can be performed, preferably with low molecular weight heparin, avoiding the use of warfarin in this context [19].

Recent published studies have tested the efficacy and safety of direct-acting oral anticoagulants (DOAC) for VTE treatment and prophylaxis in cancer patients. The results show that DOACs are viable alternatives, as long as they are used with caution in patients who are taking drugs with high drug interactions or have gastrointestinal tumours or severe renal dysfunction [20‐22]. In ICESP, the use of a DOAC (rivaroxaban) was regularized in 2018 and is regularly provided to patients with indication of its use.

Another important complication in cancer patients is coronary artery disease (CAD). Approximately 15% of all patients had documented CAD on their first visit to ICESP. The definition of CAD treatment in oncology patients must be performed quickly to avoid intermission or interruption of oncological disease treatment. The decision between clinical or invasive treatments (percutaneous or surgical) must follow current protocol recommendations and be decided upon preferably only after clinical consultation with the entire team (cardiologist, haematologist, oncologist and surgeons).

The high mortality rate observed in this patient cohort reflects the complexity and severity of these patients in long-term follow-up. CVD and cancer are the leading causes of death worldwide. The corresponding estimates for total cancer deaths in 2007 are 7.6 million (approximately 20,000 cancer deaths a day). In 2018, the corresponding estimated cancer deaths were 9.5 million higher (approximately 26,000 cancer deaths a day). By 2040, the projected 16.3 million cancer deaths will be simply due to the growth and ageing of the population [10].

In ICESP, there is a high volume of cancer surgery. In our cohort, we observed a high prevalence of cardiovascular risk factors in this group of patients. The most frequent tumour types evaluated in this patient group were gynaecological/urological and gastrointestinal tumours. Evidence suggests that patients undergoing surgery for a cancer indication have a substantially increased risk of fatal pulmonary embolism compared to that in patients undergoing surgery for benign disease [23]. The risk of bleeding in cancer patients is also elevated and multifactorial and is a complication of several surgical procedures [24].

The risk of perioperative complications depends on the clinical condition of the patients before surgery, prevalence of comorbidities, urgency, magnitude, type and duration of the surgical procedure. Each surgery provokes a different level of surgical stress [25]. The most difficult aspect in the perioperative evaluation of these patients would be time. The scheduled oncological surgery does not fit an urgent situation, but it also cannot be considered totally elective. If surgery is delayed, the tumour may grow, and the cancer staging may change. Thus, oncological surgery can be classified as “time sensitive”, with the best results if performed between 1 and 6 weeks after indication [26].

The evaluation aims to minimize the risks through an individualized evaluation that integrates the risk factors with the surgical stress of the planned procedure. In this way, the cardiovascular risk can be estimated with the opportunity to administer medications, coronary interventions when necessary, and planning of the most suitable surgical and anaesthetic techniques. Among the main cardiovascular complications observed in patients under cancer treatment, the most common are HF, myocardial ischaemia, hypertension, arrhythmia and thromboembolism [26].