Cardiotoxicity Monitoring in Patients With Cancer: Focus on Safety and Clinical Relevance

With advances in detection, stratification, and treatment, an increasing number of patients are surviving long after a cancer diagnosis. An aging population, the potentially cardiotoxic effects of certain cancer therapies, and an increase in cancer survivors have led to a significant overlap between cardiovascular (CV) disease and cancer.¹ Oncologists face many challenges while caring for patients with cancer with a significant burden of CV risk factors or CV disease and more so those who develop antineoplastic therapy–related CV toxicity.² Also, the rapidly increasing number of novel cancer therapies with a wide spectrum of potential CV toxic effects has led to the rapid growth of a subfocus in cardiology, termed cardio-oncology or onco-cardiology, to provide support to our oncology colleagues and usher patients safely through cancer therapy and into survivorship.³ The long-term goal of this collaborative effort is to minimize the risk of cancer therapy–related CV toxicities and to improve overall survival and the quality of life in survivorship.¹ Noninvasive imaging remains the backbone not just for screening and surveillance but also for the diagnosis, risk stratification, and guidance on the management of cancer therapy–related CV toxicities. The timely review by Stone et al⁴ in this issue of the journal describes the role of various imaging techniques in screening and surveillance of cancer therapy–related cardiac dysfunction (CTRCD) and also discusses the timing and frequency of suggested surveillance techniques.

As detailed by the authors, it is important to recognize that CTRCD is a spectrum from mild asymptomatic myocardial injury, typically an elevated troponin, to subclinical left ventricular systolic dysfunction, a decline in global longitudinal strain (GLS) or ejection fraction (EF), or overt heart failure. Although numerous studies have assessed CV toxicities, particularly CTRCD in patients with cancer undergoing various types of cancer therapies, given the lack of uniformity in defining such CV toxicities as well as a different set of definitions used in clinical trials and clinical practice, it is often difficult to make a direct comparison of the effectiveness of the surveillance method and management strategies, emphasizing the need for uniform definitions across the board. This implies that the current diagnostic evaluation and management approach for CTRCD is not a one-size-fits-all strategy, particularly in light of the rapidly evolving landscape of cancer therapeutics. Therefore, we commend the authors for consolidating existing knowledge of CV imaging strategies, serum biomarkers, and clinical practices for the surveillance of CTRCD as related to a myriad of cancer therapies.

As the authors note, most of the current recommendations are specific to anthracyclines and human epidermal growth factor receptor 2 inhibitors, whereas guidance for monitoring novel cardiotoxic therapies such as Tyr kinase inhibitors, proteasome inhibitors, BRAF and MEK inhibitors, immune checkpoint inhibitors (ICIs), and chimeric antigen receptor (CAR) T-cell therapy is still emerging as our understanding of the potential cardiac effects evolves.

The authors note the potential role of myocardial GLS as a more sensitive marker for early detection and surveillance of cardiotoxicity as compared with EF. Although the technology to measure GLS and the value of measuring it routinely are evolving, it is important to note the practical challenges related to the accurate acquisition and analysis of serial GLS measurements, the lack of familiarity with GLS among clinicians, and the ambiguity in its interpretation in the clinical context.^5-7 For example, from an oncologist's viewpoint, it can be difficult to interpret a baseline or interval change in GLS when deciding whether to proceed with a specific cancer therapy and whether cardioprotective strategies should be employed. At present, no cancer therapy should be withheld based on an isolated reduction in GLS. These questions about the clinical application of GLS are a current critical area of research.⁸ The authors also describe the role of cardiac magnetic resonance (CMR) imaging as the gold standard when echocardiography yields inaccurate or diverging results. A CMR study can measure EF and can measure GLS, but the real value lies in tissue characterization using parametric mapping and late gadolinium enhancement. Although there are several forthcoming clinical trials such as the PREFECT study (ClinicalTrials.gov identifier: NCT03543228) and the PROACT study (ClinicalTrials.gov identifier: NCT03862131) aiming to validate magnetic resonance imaging–based segmental MyoStrain for the individualized prediction and detection of early and subclinical cardiac dysfunction,^9-11 to date, its role in clinical practice, especially in a community setting, may be restricted because of limited availability and the need for expertise. There are data on the value of tissue characterization in basic and clinical studies of patients treated with traditional cytotoxics, but similarly, these are developing.¹² Although evolving imaging techniques empower us to assess cardiac function accurately and detect even subclinical cardiac dysfunction, further prospective studies are needed to determine clinically relevant thresholds for changes in these emerging CV imaging parameters and to see whether acting upon such early subclinical abnormality has any impact on clinically meaningful outcomes. An additional point that is important to consider is that most imaging-based research studies have focused on the left ventricle, whereas the presence and prognostic implications of concomitant or isolated right ventricle dysfunction in patients receiving cardiotoxic regimens are equally important but often ignored and need to be better studied.^13-15

The authors also discuss the role of troponin and natriuretic peptides in the setting of traditional chemotherapy and emerging immunotherapy regimens to detect early cardiac injury and guide its management. The exact timing of serial measurements and the interpretation of abnormal findings in these serum biomarkers is yet to be determined, and it is also relevant to emphasize that their frequent changes in common clinical scenarios other than cardiotoxicity such as severe infections or anemia make their application in cardio-oncology more challenging. Additionally, novel biomarkers such as myeloperoxidase, C-reactive protein, interleukin-6, absolute lymphocyte count, neutrophil/lymphocyte ratio, Galectin-3, soluble ST2, and growth differentiation factor-15 are also currently under investigation for detecting acute and chronic cardiotoxicity with increased specificity.^16,17 There is also room to expand this research area by highlighting cutting edge studies exploring genetic predisposition to CTRCD via the use of patient-specific human-induced pluripotent stem cells, genome-wide association studies, and expression profiles, including microRNAs, proteomics, and metabolomics.^18,19 These are exciting future directions holding great promise as novel tools in the development of personalized medicine in cardio-oncology. In the future, a multimodality approach integrating several circulating biomarkers along with imaging and clinical data can help inform clinical decision making and minimize the need for modification or early discontinuation of potentially life-saving or life-sustaining cancer treatments.

Finally, immunotherapy has become a cornerstone of contemporary cancer treatment, and it is helpful to highlight the emerging evidence that expands our understanding of the significant implications of its CV toxicities.^7,20-22 Although the key concepts concerning the characterization and detection of adverse events because of ICIs and CAR-T were outlined in this review, the landscape of immunotherapy is rapidly changing, and it is evident that our knowledge of the implications of altering the immune system is still modest.^23-26 Recent studies show that the incidence of a wide range of serious CV toxicities associated with CAR T-cell therapy has been underestimated, that a sustained risk extends months after receiving immunotherapy, and that there is a link between ICIs and the incidence of accelerated atherosclerotic plaque inflammation and CV events.^20,21,27,28 As the applications of immunotherapy continue to expand from late-stage disease to the adjuvant and neoadjuvant setting, the clinical significance of its associated cardiotoxicity is likely to increase. Long-term prospective studies and large registries will be needed to inform the detection and treatment of adverse CV events associated with immunotherapy.

As comprehensively stated in this review article, knowledge translation from guidelines and close collaboration between cardiologists and oncologists will be crucial for providing comprehensive oncological care while improving CV outcomes for patients with cancer. This gives support to the notion that has been long accepted by oncologists that cancer survivorship starts at the time of cancer diagnosis. Although our understanding and ability to perform routine surveillance for CTRCD have improved, its net clinical benefit and cost-effectiveness remain to be studied. We must continue to be vigilant about how we use information, particularly findings of undetermined clinical significance. Although cancer therapy–related CV toxicities are a real concern, we may have to learn to be comfortable with permissive CV toxicity and remember not to put the cart (concern about potential CV toxicity) before the horse (cancer treatment).

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at DOI https://doi.org/10.1200/OP.21.00075.

AUTHOR CONTRIBUTIONS

Conception and design: Giselle A. Suero-Abreu, Sarju Ganatra, Tomas G. Neilan

Collection and assembly of data: Giselle A. Suero-Abreu

Data analysis and interpretation: Giselle A. Suero-Abreu

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Cardiotoxicity Monitoring in Patients With Cancer: Focus on Safety and Clinical Relevance

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