Clinical Challenges: Monitoring Cardiotoxicity From Cancer Treatment

Although cardiac biomarkers are increasingly used to monitor the development of cardiomyopathy and other effects of potentially cardiotoxic cancer treatments, clinicians still lack answers regarding how often they should test patients and which biomarkers to choose.

A blood test that can reliably catch cardiac dysfunction before clinical signs or symptoms appear has the appeal of potentially averting irreversible damage due to cardiovascular toxicity related to cancer treatment. With early diagnosis, the cancer treatment course could be altered and preventive strategies initiated so that anthracycline chemotherapy's myocardial damage may be reduced, for instance, or the early-stage harm from trastuzumab (Herceptin) targeted therapy be treated.

C-reactive protein (CRP), NT-proBNP, and troponin are commonly used for monitoring cardiac injury, but other biomarkers are under investigation for detecting cardiotoxicity early across a broad range of cancers and cancer treatment protocols. These include microRNAs and interleukin-6, myeloperoxidase, Galectin-3, and growth differentiation factor-15.

Firm thresholds for an abnormal value will need to be established before any candidate biomarker has clinical utility, however.

"For the most part, in virtually all patients with cancer who are undergoing contemporary cancer treatment with potentially cardiotoxic therapy, a baseline lipid panel, CRP, NT-proBNP (or BNP) and troponin (I or T) should strongly be considered. This is especially true if they are at high or very high risk for the development of cardiovascular adverse events," according to cardio-oncology specialist Daniel Lenihan, MD, of Saint Francis Healthcare System in Cape Girardeau, Missouri.

He acknowledged that important questions in cardio-oncology remain unanswered, as evidenced by the many ongoing clinical trials in the field.

"One challenge is that certain cardiac biomarkers have been demonstrated to be very important in specific areas like breast cancer, multiple myeloma, AL [amyloid light chain] amyloidosis, and in patients being treated with immunotherapy; however, cardiac biomarkers are not universally helpful in every patient in every cancer," Lenihan told MedPage Today.

This may come down to the cardiotoxicities varying widely across common tumor therapies, running the gamut from left ventricular dysfunction to hypertension to thrombosis to atrial fibrillation.

Another major challenge for serial monitoring of cardiotoxicity is that the interval of when to perform the biomarker testing is not well established. After a biomarker is established for a certain type of cancer patient, what is the best interval for cost-effective and clinically helpful repeat testing?

American and European societies offer some preliminary guidance to clinicians and patients. But given the low level of available evidence, there are conflicting recommendations that leave clinicians without a consensus strategy for the diagnosis and management of cardiotoxicity.

For instance, the European Society of Cardiology's 2016 expert consensus statement said that anthracycline recipients may be considered for at least one cardiac biomarker test at baseline, then proceed with a round of high-sensitivity troponin I checks with each cycle of anthracycline-containing chemotherapy.

The European Society for Medical Oncology guidelines from 2020, however, suggested that baseline biomarker tests should be reserved for selected anthracycline recipients with pre-existing cardiovascular disease and those taking high-dose anthracyclines.

Ultimately, "whether NT-proBNP or troponin or both should be done at certain intervals during therapy has to be individualized and done in cooperation with the cancer treatment team," Lenihan urged.

The right course of action when biomarkers suggest cardiomyopathy or other ill effects from cancer treatment may also be different for each person.

"A point to emphasize is that there needs to be active dialogue between the cardio-oncology team and the cancer treatment team in order to make the best decision for the specific patient," according to Lenihan. "In general, a cardiac biomarker that is abnormal before or during cancer therapy is a great marker of cardiovascular risk for adverse events, but it does not tell the clinician exactly what to do about the finding. This is where it is imperative that active collaboration is occurring."

One option would be routine primary cardioprotection for patients who are at particularly high risk based on their baseline biomarker results prior to cancer treatment. For example, one study recently found that patients with early-stage HER2-positive breast cancer had better cardiotoxicity-free survival when taking either lisinopril or carvedilol during treatment with trastuzumab.

"In patients at high or very high risk for developing cardiovascular adverse events, there is certainly evidence that specific cardiac medications are beneficial and provide cardioprotection," Lenihan commented.

Nevertheless, the use of beta-blockers, ACE inhibitors, and angiotensin II receptor blockers to prevent cardiotoxicity is controversial because of the limited data. Dexrazoxane, an iron-chelating agent, remains the only FDA-approved cardioprotective drug for preventing anthracycline-induced cardiac harms.

Lenihan cautioned that routine prophylactic therapy is currently not warranted for people at low risk for cardiovascular adverse events, namely people taking lower-dose cancer therapies who have no heart disease or elevated cardiac biomarkers before anticancer treatment.

Preclinical experiments suggest primary prevention may work in some patients free of cardiovascular risk factors -- yet like many questions in cardio-oncology, a definitive answer is likely years away.

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