Cancer Therapy and Exercise Intolerance: The Heart Is But a Part: JACC: CardioOncology State-of-the-Art Review

Abstract

The landscape of cancer therapeutics is continually evolving, with successes in improved survivorship and reduced disease progression for many patients with cancer. Improved cancer outcomes expose competing comorbidities, some of which may be exacerbated by cancer therapies. The leading cause of disability and death for many early-stage cancers is cardiovascular disease (CVD), which is often attributed to direct or indirect cardiac injury from cancer therapy. In this review, the authors propose that toxicities related to conventional and novel cancer therapeutics should be considered beyond the heart. The authors provide a framework using the oxygen pathway to understand the impact of cancer treatment on peak oxygen uptake, a marker of integrative cardiopulmonary function and CVD risk. Peripheral toxicities and the impact on oxygen transport are discussed. Consideration for the broad effects of cancer therapies will improve the prediction and identification of cancer survivors at risk for CVD, functional disability, and premature mortality and those who would benefit from therapeutic intervention, ultimately improving patient outcomes.

Keywords: cardiorespiratory fitness; cardiotoxicity; cardiovascular; exercise; hematology; metabolic; oncology; skeletal muscle function.

Graphical abstract

Central Illustration

Multifactorial Contributors and Cardiorespiratory System Impact in Cancer Survivors That Drive Exercise Tolerance Multiple factors can contribute to poor exercise tolerance in cancer survivors. Cancer therapeutics can interact with patient cardiovascular risk factors including age, physical inactivity, comorbidities, genetic risk, and inflammation, as well as the cancer itself to potentially affect multiple steps of the oxygen pathway and limit exercise tolerance. Taking a more holistic approach to consider factors that can be affected by treatment beyond the heart provides new opportunities to treat exercise intolerance and could lead to reduced cardiovascular risk,^,,, hospitalizations, and fatigue and better quality of life (QOL) for cancer survivors. CVD = cardiovascular disease; DC = dissociation curve; VD = physiological dead space; Vo₂peak = peak oxygen consumption; V/Q = ventilation/perfusion; VT = tidal volume.

Figure 1

Overview of Cancer Therapy–Induced Skeletal Muscle Toxicity Skeletal muscle dysfunction can occur because of the combined and independent effects of cancer-targeted therapies and patient factors in patients with cancer. Several pathways involving mitochondrial and myocyte dysfunction likely contribute to skeletal muscle dysfunction in patients with cancer. There is growing evidence that skeletal muscle dysfunction is multifactorial and can lead to exercise intolerance and increase the risk for heart failure. ROS = reactive oxygen species.