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Finding Cancer Therapies Without Cardiotoxicity

Lasting cardiac damage from cancer therapy can be devastating. Thanks to powerful new therapies, many people are surviving cancers that were once believed to be fatal. We are now seeing, however, that the off-target effects of these cancer therapies can have deadly repercussions, such as heart failure, cardiac arrhythmia, thrombosis, heart attack, severe hypertension, Q-T prolongation, or other serious illnesses.

The primary goal of cancer treatment is to eradicate and prevent the recurrence of cancer, thereby prolonging life. And the modern drug and radiation therapies have done just that: Improvements in the efficacy of modern treatment are demonstrated by the approximately 14 million cancer survivors in the United States alive today who owe their lives, in part, to chemotherapy and radiation treatments.

Nonetheless, cancer survival gains have revealed an unintended consequence of therapy: An increased incidence of cardiovascular injury. Studies have shown that after recurrence and second malignancies, cancer treatment–related cardiotoxicity is the third leading cause of treatment-associated mortality in survivors of pediatric and adolescent cancers. The incidence of treatment-induced heart damage in pediatric survivors of cancer increases over time, and can develop even three decades after therapy.

In adult patients, cardiotoxicity is drug-dependent, and depending on the type of cardiac condition, incidence can be as high as 50 percent. Five- to ten-year male survivors of adult cancer have reported heart problems to be the most common post-treatment issue, while in women survivors it is the third most reported problem, following arthritis and osteoporosis.

The acute effects of cancer treatment primarily impact the vascular system, specifically leading to hypertension, vasospasm, and thrombosis (including venous thromboembolic disease and rupture of arterial plaques). Late effects include long-term toxicities that generally involve structural cardiovascular changes, including atherosclerosis, valvular heart disease, and conduction system disease.

Chemotherapy-induced cardiomyopathy often occurs during active treatment, but it can have a delayed onset, too. With cancer patients living longer (in part because of treatment advances) it has become increasingly important to address these adverse events. Little is known, however, about the pathogenic cardiovascular mechanisms associated with cancer treatment, and even less about how to optimally prevent and manage the short- and long-term cardiovascular complications that could lead to improved patient safety and clinical outcomes.

Biomarkers may represent one of the most cost-effective and minimally invasive means for diagnosing and monitoring cardiac injury following cancer therapy. Ongoing studies are investigating the potential of known cardiac biomarkers to detect asymptomatic, cancer treatment-related, cardiac damage, as well to predict the cumulative effects of initial injury or loss of cardiac muscle cells. High-sensitivity troponin is considered the biomarker of choice for the detection of cardiac injury.

The early and non-invasive detection of cancer therapy-induced cardiac tissue injury will not only help to optimize cancer treatment, but it will also provide much-needed insight into cardio-protective interventions. Researchers are now using ultrasound-based devices, such as 3D echocardiography, strain rate imaging, and tissue Doppler imaging, to assess cardiovascular dysfunction.

Cardiac magnetic resonance imaging (CMRI) methods are also being developed and tested for cardiac toxicity assessment. As research continues, CMRI and the further identification of clinical, genetic, and biomarker risk factors will allow for the stratification of patients at low to high risk for cancer treatment-induced cardiotoxicity. It’s expected that this will lead to improved treatment and monitoring options and safer cancer therapy without compromising the patient’s survival.

In addition, several clinical trials are exploring various strategies for preventing or reducing the cardiovascular changes induced by cancer therapies. The beta-blocker carvedilol is being investigated as a possible therapy that could prevent—or even reverse—damage to the hearts of young adults who received high-dose anthracyclines, chemotherapeutic antibiotics that inhibit enzyme topoisomerase II, including doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin. Statin drugs are also being tested to see whether they can prevent the cardiotoxic effects seen in lymphoma and breast cancer patients receiving anthracycline treatment.

To assess the potential of novel drugs for heart toxicity in the coming years, drug testing may include lab tests involving animals, or cells from humans engineered to artificially express heart-related genes. Palo Alto-based researchers are now using stem cell-derived heart cells from volunteers to develop a cardiac safety index that may be used to determine how toxic tyrosine kinase inhibitors are to the human heart.

While more than two dozen of these drugs are currently used to treat a variety of cancers, some can cause irregular heartbeats or heart failure. Thus, this new index will not only help the pharmaceutical industry identify drugs that cause heart-related side effects during the drug development process, but it will also help the Food and Drug Administration during the review and approval process.