In an earlier blog, we discussed the role of various imaging modalities for monitoring and assessing the negative cardiovascular impact (e.g., cardiotoxicity) of some cancer treatments. Here, we delve deeper into potential treatment-related cardiovascular (CV) issues and present practical approaches that sponsors should consider when creating drug development plans. This includes defining CV risks and incorporating appropriate imaging endpoints into clinical study protocols.
Over the past four decades, clinical data has shown that cancer treatments ─ such as anthracyclines and radiation ─ can cause a variety of cardiovascular and cardio-metabolic complications1,2,3 (See table, below).
With the introduction of new, targeted anticancer treatments we now have a better understanding of the relationship between pharmacogenomics and cardiac risk factors (e.g., diabetes, hypertension, atherosclerotic heart disease, hyperlipidemia, etc.) as well as the impact they have on potential cancer drug-related (or combination therapy) cardiotoxicities.
In 2017, the American Society of Clinical Oncologists (ASCO) published the clinical practice guidelines, “Prevention and Monitoring of Cardiac Dysfunction” for monitoring cancer patients at increased risk of developing cardiac dysfunction and recommended strategies to minimize and monitor risks before, during and after treatment.4 This CV risk stratifying approach is applied in the echocardiography imaging surveillance recommendations within the package insert for the targeted therapy trastuzumab.5 Other classes of new oncology drugs in development ─ i.e.,kinase inhibitors and other immunotherapies─ have been associated with CV toxicities such as hypertension, cardiomyopathy, vascular events, arrhythmias and myocarditis,1 and are currently the subject of great scientific and clinical interest.
Experienced and knowledgeable clinical development teams understand and apply the evolving body of clinical research and therapeutic-level recommendations from professional societies and regulatory bodies into clinical trial designs to monitor for the above defined cardiac sequalae. Regulatory bodies and sponsors have applied these expert recommendations to offer a personalized medicine approach for the assessment of CV toxicity.
Monitoring CV related endpoints across different patient cohorts (based on pre-study risk assessments) typically includes the following (not an exhaustive listing):
- Collection of ECGs
- Blood pressure monitoring
- Assessment of cardiac function (e.g., LVEF via 2D or 3D echocardiography; recommended by ASCO and endorsed by other societies)
- MUGA (multi-gated acquisition scans)
- Cardiac MRI (or CT)
- Other cardiac biomarkers (e.g. troponin, inflammatory markers)
The goal here, of course, is to understand baseline risks and identify patients at a higher risk for developing post-treatment cardiac dysfunction. Part 1 of this series reviewed advanced 2D and 3D echocardiographic imaging techniques and included a description of cardiac strain analysis. These techniques have been shown to provide reproducible measurements over time to detect changes in myocardial function. Further, we discussed the diagnostic utility of using Cardiac MRI for the diagnosis of myocarditis as outlined in the “Lake Louise Criteria,” and elaborated on the related imaging protocol standards, reporting terminology and imaging diagnostic criteria.
Successful drug development starts with having a thorough understanding of the safety and efficacy profile, including anticipated toxicities, and incorporates an understanding of regulatory precedents (approvals and rejections). In terms of CV risks, this should include appropriate quantitative or qualitative imaging and non-imaging assessments. The study team develops recommendations for monitoring frequency based on an understanding of the drug’s mechanism of action, intended patient population(s), drug toxicity profile, and review of prior clinical or non-clinical data.
As suggested in FDA’s Guidance for Clinical Trial Imaging Endpoint Process Standards an appropriate level of standardization and harmonization of non-imaging and imaging CV data should be collected across all investigative sites. These efforts will result in the generation of high quality CV data that may be used by the treating oncologists and cardiologists for future patient management decisions, and will provide robust clinical study data with which to seek regulatory approval.
Need to improve data quality and patient recruitment/retention in your upcoming oncology trial? Check out this infographic to learn how ERT’s proven, purpose-built imaging solution supports a range of modalities — from echocardiograms to ECGs.
- Blaes, AH, Thavendiranathan, P, Moslehi J. Cardiac Toxicities in the Era of Precision Medicine: Underlying Risk Factors, Targeted Therapies, and Cardiac Biomarkers; 2018 ASCO Educational Book (Print ISSN: 1548-8748 38; Electronic ISSN: 1548-8756) published by the American Society of Clinical Oncology, Inc. (“ASCO”), volume 38, p764-774
- Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) Eur Heart J. 2016 Sep 21;37(36):2768-2801.
- Curigliano, G, Mayer EL, Burstein, HJ, Winer EP, Goldhirsch A. Cardiac Toxicity From Systemic Cancer Therapy: A Comprehensive Review; Progress in Cardiovascular Diseases 53 (2010) 94–104
- Armenian SH,Lacchetti C, Barac A, Carver J, Constine LS et al. Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline; J Clin Oncol. 2017Mar10;35(8):893-911
- Trastuzumab package insert https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/trasgen020900LB.htm