Cancer and cardiovascular diseases are currently the leading causes of mortality worldwide.
Accordingly, patients receiving oncological treatment have come to be seen as having an elevated risk of cardiovascular disease.
CO emerged as a result of the intersection between cardiovascular health and cancer treatment.
Although the field of CO is vast, with important windows of opportunity for action in the diverse phases of the oncological journey, the main challenge lies in the management of events throughout the active phase of antitumor treatment. The appropriate management of these cases is crucial, as it directly impacts not only cardiovascular, but especially oncological prognosis and survival.
These data, in conjunction with the development of antineoplastic treatments that have significantly increased patient survival rates, have directed the focus of attention to CO, which has become fundamental to ensuring excellence in oncological care.
We broadly define cardiotoxicity as any pathological alteration of the cardiovascular system induced by oncological treatment.
Although it has a broad spectrum of manifestations, the main types of cardiotoxic manifestations are presented in the form of the following two clinical syndromes: arrhythmias and chemotherapy-related cardiac dysfunction (CTRCD). Among these, systolic myocardial dysfunction has been the most impactful clinical presentation (due to its severity and risk), making CTRCD a near synonym of "cardiotoxicity." The antineoplastic medications most frequently associated with CTRCD are listed in
| Pharmacological class | Examples of agents | Indicated tumor types |
|---|---|---|
| Anthracyclines | Doxorubicin, epirubicin, daunorubicin, idarubicin, mitoxantrone | Breast, ovarian, lymphomas, and leukemias |
| Anti-HER therapies | Trastuzumab, T-DM1, pertuzumab, trastuzumab deruxtecan | Breast, gastric |
| Tyrosine kinase inhibitors | Sorafenib, sunitinib, pazopanib, afatinib, osimertinib, erlotinib | Renal carcinoma, hepatocellular carcinoma, lung cancer |
| Alkylating agents | Cyclophosphamide, ifosfamide | Lymphomas and leukemias, sarcomas |
| Immune checkpoint inhibitors | Pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab | Multiple indications, the main ones being: melanoma, bladder cancer, renal carcinoma, lung cancer, hepatocellular carcinoma |
| Proteasome inhibitors | Carfilzomib, ixazomib, bortezomib | Multiple myeloma |
| VEGF inhibitors | Bevacizumab, aflibercept | Colorectal cancer and renal carcinoma |
| MEK/BRAF inhibitors | Dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib | Melanoma |
BRAF: serine/threonine-protein kinase; CTRCD: chemotherapy-related cardiac dysfunction; HER: human epidermal growth factor; MEK: mitogen-activated protein kinase; T-DM1: ado-trastuzumab emtansine; VEGF: vascular endothelial growth factor.
The most widely accepted and internationally applied definition for CTRCD in clinical practice was standardized by the publication of the Cardio-Oncology Guideline of the European Society of Cardiology in partnership with the International Cardio-Oncology Society in 2016, which defines CTRCD as a drop in left ventricular ejection fraction (LVEF) of ≥ 10% (in relation to the pre-treatment value) in the presence of absolute values < 50%.
The main challenges of CO include the management of situations in which patients are exposed to a highly effective oncological treatment, but they progress with signs of cardiovascular toxicity. In this scenario, classically, a discussion takes place about whether to pause or suspend antineoplastic treatment, given that this was initially considered the most appropriate course of action. However, questions began to be raised when studies demonstrated that even brief and temporary suspension of oncological treatment resulted in a reduction in its efficacy.
The strategy of PC consists of maintaining the antitumor treatment underway when ventricular dysfunction is detected, without pauses or interruptions.
Literally speaking, the strategy of PC is indicated in cases of CTRCD during antitumor treatment. Nonetheless, it can also be applied to candidates who have elevated cardiovascular risk. In this situation, "non-ideal" conditions are tolerated in the name of obtaining a major oncological benefit. In both cases, what differentiates the approaches is the moment when the permissive strategy is instituted: during cancer treatment (in cases of established cardiovascular toxicity) or pre-treatment (in cases of high baseline cardiovascular risk).
The concept of PC assumes that, even in unfavorable cardiological scenarios, the oncological treatment of choice can be maintained as long as the cardiovascular risk is reduced to acceptable levels. It is believed that, in the absence of evidence that proves the benefit of suspending antitumor treatment, clinical optimization provides sufficient conditions to continue to offer the oncological regimen. This concept encourages care teams to change their stances, replacing reactive approaches (modifying or suspending chemotherapy regimens) with proactive approaches (aimed at reducing cardiovascular risk and enabling the continuation of the antitumor regimen). Ultimately, the aim is to achieve a residual cardiovascular risk that is outweighed by the benefits of cancer treatment.
The evidence supporting the PC approach is still scarce and has been published slowly, predominating in the scenario of HER2-positive breast cancer. It is important to underscore that PC is an exceptional approach and that eligible patients are not numerous on a daily basis; therefore, as is the case with rare diseases, it is not a condition that can easily be studied by robust clinical trials with large sample sizes.
| Author and year | Design | Population | Sample | Results |
|---|---|---|---|---|
| Nowsheen S. et al, 2018 |
Retrospective, case-control | Patients with HER-positive breast cancer exposed to trastuzumab |
20 cases with baseline LVEF < 53% 408 controls with LVEF ≥ 53% |
Group with LVEF < 53% at baseline did not show a higher risk of decreased LVEF |
| Lynce F. et al, 2019 |
Prospective, single-arm | Patients with HER-positive breast cancer candidates for T-DM1 or trastuzumab with or without pertuzumab |
31 patients with baseline LVEF between 40% and 49% All treated with BB and ACEI |
90% of patients completed the planned anti-HER treatment |
| Leong D. et al, 2019 |
Prospective, single-arm | Patients with HER-positive breast cancer candidates for trastuzumab |
20 patients with baseline LVEF between 40% and the lower limit or ≥ 15% drop in LVEF |
90% of patients received all planned cycles without interruptions |
| Khoury K. et al, 2021 |
Prospective, single-arm | Patients with HER-positive breast cancer candidates for T-DM1 or trastuzumab with or without pertuzumab |
23 cases from the original cohort (8 of them still in continuous anti-HER therapy for metastatic disease) Follow-up of 42 months |
Improvement in mean LVEF from 44.9% (beginning of the study) to 52.1% (end of study) 1 case of symptomatic heart failure |
| Zhou S. et al, 2023 |
Retrospective, cohort | Patients with HER-positive breast cancer exposed to trastuzumab |
51 patients managed with PC Follow-up of 3 years |
92% completed the treatment 6% suspended trastuzumab due to severe/symptomatic ventricular dysfunction |
ACEI: angiotensin-converting enzyme inhibitor; BB: beta blocker; HER: human epidermal growth factor; LVEF: left ventricular ejection fraction; T-DM1: ado-trastuzumab emtansine; PC: permissive cardiotoxicity.
These data, although they come from small, single-center, non-randomized studies, reveal the experience of groups who opted not to deprive patients of treatments that modified the natural history of their disease, resulting in a substantial increase in disease-free survival curves.
The PC approach has also been applied in other contexts in oncology. Examples include situations of re-exposure to treatment after episodes of vasospasm with 5-fluorouracil,
Cardiovascular imaging tools are essential when implementing the strategy of PC, because they allow for the progressive monitoring of cardiac function during cancer treatment.
Among cardiovascular imaging methods, echocardiography stands out as a non-invasive, widely available, and low-cost method, which facilitates regular, serial use in cardiotoxicity monitoring programs. This method's accessibility allows for frequent use for cardiovascular monitoring, making it possible to adjust the therapeutic strategy in real time, which maximizes the efficacy of oncological treatment without compromising patient safety. In this manner, echocardiography has proven to be a valuable resource for the dynamic management of cardiovascular risk in patients who will be exposed to potentially cardiotoxic therapeutic regimens.
Myocardial strain is a quantitative measure of deformation during the cardiac cycle, and it is a sensitive tool for detecting subclinical cardiac dysfunction (before LVEF is affected).
The strategy of PC has not been studied with sufficient methodological rigor to design protocols and guidelines based on scientific data. However, reports of successful experiences and studies conducted in the area
The concept of PC is applicable in cases of mild to moderate CTRCD (LVEF > 40%), provided that there are no severe symptoms (significant pulmonary congestion with worsening of the respiratory pattern; clinical, electrical, or hemodynamic instability; poor perfusion and/or signs of low output).
The strategy of PC applies to manageable cases of CTRCD (patients who have a window for the introduction of cardiovascular medications), always focusing on long-term cardiological safety.
It is mandatory to perform strict, regular monitoring of cardiac function during PC, preferably with the same professional and on the same device.
It is necessary to pre-define levels of cardiac dysfunction at which it is no longer safe to continue therapy. Routinely, continuation of PC is tolerated as long as LVEF is > 40%. This value varies according to LVEF at the beginning of PC, the magnitude of the drop in LVEF in relation to baseline, and the associated clinical repercussions.
The medical management of these cases should follow the recommendations of the current guidelines for the treatment of heart failure, respecting individual limitations related to the clinical/laboratory context of each case. Below, we will briefly discuss the medical management of CTRCD according to the most recent recommendations.
It is suggested that, initially, priority should be given to the introduction of drugs studied for heart failure that also have specific evidence of cardioprotection in patients with cancer, such as beta blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs). Carvedilol and enalapril are the medications with the highest number of favorable studies in CO, and they are the most commonly used medications in practice (although other BB and ACEI/ARB indicated for heart failure also have similar effects). The combination of BB and ACEI/ARB should be initiated at low doses, with progressive escalation up to the maximum tolerated doses. In the case of hypotension that limits concomitant initiation, each medication should be introduced individually; there is no defined order based on evidence, and the choice should be based on each case's characteristics and restrictions. Depending on the presence and degree of associated pulmonary congestion, the prescription of diuretics and/or mineralocorticoid antagonists may be indicated during this first stage of drug management. During a second stage, depending on the clinical response, functional class, presence (or absence) of residual symptoms, and tolerance (also related to laboratory alterations), it is possible to assess the need to add other first-line medications for the treatment of heart failure, with SGLT2 inhibitors and sacubitril/valsartan replacing ACEI or ARB.
The key points for implementing the strategy of PC are summarized in the Central Illustration.
The strategy of PC has numerous limitations, the main one being the lack of robust scientific evidence to support its use. A borderline context for its implementation is the presence of pre-treatment ventricular dysfunction, since further worsening of LVEF can result in significant impairment. In these cases, drug optimization should be even more immediate and aggressive, and the search for the best oncological outcome should respect the premises of cardiovascular safety. Finally, it is important to underscore that it is not considered appropriate to institute PC in cases that have therapeutic alternatives with similar efficacy or in cases where treatment is optional (a decision that should be delegated exclusively to the oncologist).
Gaps still abound in the literature regarding PC. They include the lack of studies that explore long-term cardiovascular outcomes, the lack of guidelines and standardized protocols for identifying safe levels of ventricular dysfunction to be tolerated, and the identification of specific risk predictors that could help individualize the PC approach.