Clinicians and regulators have increasingly expressed an interest in better understanding potential cardiovascular complications in cancer patients. This is driven largely by the fact that cancer patients are now surviving longer due to improved therapeutic options such as targeted therapies (e.g., immune checkpoint inhibitors, ICI), some of which may have associated cardiac toxicities1.
Cancer treatment-induced cardiac toxicities may include arrhythmias, hypertension, heart failure, cardiomyopathy, myocarditis, etc. And, as discussed in previous blogs clinical monitoring approaches include electrocardiograms, blood pressure, blood cardiac markers and imaging including echocardiography, molecular imaging techniques including PET or MUGA scans and cardiac imaging with CT or MRI.
Regulators are on Board
Regulatory agencies have expressed a common safety concern regarding all immune modulators, especially interleukin-based PDL1 inhibitors’ effects on immunoglobulins and interleukin 2 which has been shown to affect the myocardium. They have been requesting pharmaceutical companies address safety monitoring for potential cardiovascular toxicities2. In fact, following two halted clinical trials involving pembrolizumab, the FDA stated:
“The FDA has informed multiple investigators who have ongoing clinical trials using PD1/PD-L1 oncology drugs in combination with immunomodulatory agents or in hematologic malignancies combined with other classes of drugs whether their trials must be temporarily stopped to allow for modifications or must be permanently stopped.”2
Assessing Myocarditis with Echo
Myocarditis is a loosely-used term that refers to heart inflammation – typically diagnosed when patients present to the intensive care unit (ICU) with fever and generalized malaise together with profound left systolic ventricular dysfunction with cardiac ejection fractions (EF) markedly decreased in the range of 10- 15 %. This condition occurs in 1.14% of subjects treated with ICI (median time of onset 34 days after starting ICI treatment)3.
Although these subjects can be followed with a variety of imaging modalities such as cardiac MRI, echocardiography is the primary assessment tool since these critically ill patients are often connected to pumps and catheters which are contraindicated or make cardiac MRI more difficult.
Additionally, echocardiography is the most cost-effective cardiac imaging technique and can be conducted at the bedside in the ICU. Echo is well suited to assess myocardial damage, acknowledging that it is nonspecific, however, there are more specific techniques such as tissue Doppler and longitudinal strain which improve diagnostic performance.
When patients present acutely with myocarditis, transthoracic echocardiography is the standard for the initial diagnosis along with blood biomarkers (e.g., cardiac troponins and other enzymes) or cytokines as markers for cardiac damage and inflammation.
Planning the Protocol
During protocol and safety monitoring plan development, sponsors should consider whether they need to assess all of the enrolled patients or only the subset of patients experiencing deterioration in cardiac status. Clearly defining the protocol-required cardiac assessments and measurement parameters to be obtained during the echocardiogram will inform the clinical team to understand the patients’ clinical course and inform decisions on treatment adjustments which may be necessary to maintain or restore normal cardiac function.
The American Society of Echocardiography (2015) and more recently the European Cardiac Society created specific recommendations and management algorithms to direct therapy or interventions and provide details on cardiac ultrasound function measurements which include EF and more importantly myocardial longitudinal strain.
They recommend designing clinical protocols to include the assessment of systolic and diastolic function, determination of valvular abnormalities, and measurement of longitudinal strain with the latter modality being essential to determining the impact of myocardial damage post therapy.
Assessments should be performed with echo collected at baseline to establish cardiac performance and during follow up to determine the impact of any myocardial damage post therapy. The challenge for the industry is to identify the subject at risk and monitor therapeutic agent-induced cardiac damage.
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- Douglas B. Johnson, MD; Sunandana Chandra, MD; Jeffrey A. Sosman, MD Immune Checkpoint Inhibitor Toxicity in 2018, JAMA Insights Clinical Update, October 23/30, 2018, Volume 320, Number 16, 1702-1703
- Julie R. Brahmer, Christina Lacchetti, Bryan J. Schneider et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36:1714-1768