Hypertensive Cardiotoxicity in Cancer Treatment-Systematic Analysis of Adjunct, Conventional Chemotherapy, and Novel Therapies-Epidemiology, Incidence, and Pathophysiology

Abstract

Cardiotoxicity is the umbrella term for cardiovascular side effects of cancer therapies. The most widely recognized phenotype is left ventricular dysfunction, but cardiotoxicity can manifest as arrhythmogenic, vascular, myocarditic and hypertensive toxicities. Hypertension has long been regarded as one of the most prevalent and modifiable cardiovascular risk factors in the general population, but its relevance during the cancer treatment journey may be underestimated. Hypertensive cardiotoxicity occurs de novo in a substantial proportion of treated cancer patients. The pathology is incompletely characterized-natriuresis and renin angiotensin system interactions play a role particularly in conventional treatments, but in novel therapies endothelial dysfunction and the interaction between the cancer and cardiac kinome are implicated. There exists a treatment paradox in that a significant hypertensive response not only mandates anti-hypertensive treatment, but in fact, in certain cancer treatment scenarios, hypertension is a predictor of cancer treatment efficacy and response. In this comprehensive review of over 80,000 patients, we explored the epidemiology, incidence, and mechanistic pathophysiology of hypertensive cardiotoxicity in adjunct, conventional chemotherapy, and novel cancer treatments. Conventional chemotherapy, adjunct treatments, and novel targeted therapies collectively caused new onset hypertension in 33-68% of treated patients. The incidence of hypertensive cardiotoxicity across twenty common novel therapies for any grade hypertension ranged from 4% (imatinib) to 68% (lenvatinib), and high grade 3 or 4 hypertension in < 1% (imatinib) to 42% (lenvatinib). The weighted average effect was all-grade hypertension in 24% and grade 3 or 4 hypertension in 8%.

Keywords: cancer; cardio-oncology; cardiotoxicity; hypertension; tyrosine kinase inhibitors.

Figure A1

Search terms for conventional, adjunct and novel cancer therapies: Twenty novel (biological and tyrosine kinase inhibitor) cancer treatments known to cause > 5% new incidence of all grade hypertension, and adjunct treatments were selected by consensus; imatinib was included for historical comparison as the earliest approved oral tyrosine kinase inhibitor. The range of cancer therapies were searched against the terms “hypertension”, “cardiotoxicity”, and “cancer”. Inclusion criteria were articles published from 1990 to 2020 in English. Randomized control trials (RCT) including landmark phase 2b/3 studies, observational clinical studies, such as cohort, case-control and cross-sectional studies, as well as meta-analyses and systematic reviews including at least 250 treated patients were included.

Figure 1

Pathophysiology of cancer therapies leading to hypertension. Outline of the pathophysiology of cancer therapies leading to hypertension. Cancer therapies can have various impacts on the systemic vascular resistance and cardiac output which ultimately has an effect on the blood pressure. BP: Blood pressure, CO: Cardiac output, SVR: Systemic vascular resistance.

Figure 2

Cancer therapies causing hypertension and their subsequent effects ranging from target-organ damage to final common pathway of end-stage disease [64]. Multiple therapies in cancer have hypertensive effects. This has profound implications on the renal, cardiac and central nervous system. Over time, this can lead to end organ damage and subsequent death. (mTOR: mammalian Target of Rapamycin, TKI: tyrosine kinase inhibitors, VEGF: Vascular Endothelial Growth Factor, TIA: Transient ischemic attack).

Figure 3

Graph showing incidence of hypertensive cardiotoxicity (high grade versus all grade) with various novel cancer therapies. Incidence is ordered from highest to lowest for all grade hypertension; the bar for all is a weighted average calculation across all novel drug types in our analysis.