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Dr. Filip Ionescu (hematology-oncology fellow at Moffitt Cancer Center in Tampa, FL), Dr. Teodora Donisan (cardiology fellow at the Mayo Clinic in Rochester, MN and CardioNerds House Thomas chief), Dr. Sarah Waliany (internal medicine chief resident at Stanford University in Palo Alto, CA), Dr. Dinu Balanescu (internal medicine chief resident at Beaumont Hospital in Royal Oak, MI) and Dr. Amit Goyal (structural interventional cardiology fellow at the Cleveland Clinic, in Cleveland, OH and CardioNerds Co-Founder), discuss the cardiotoxicities of common cancer treatments with Dr. Susan Dent, a medical oncologist and one of the founders of the field of Cardio-Oncology. Using the recently published ESC Guidelines on cardio-oncology, they cover cardiovascular risk stratification in oncology patients, pretreatment testing, as well as prevention and management of established cardiotoxicity resulting from anthracyclines, trastuzumab, and fluoropyrimidines. They touch on the unique aspects of cardio-oncology encountered in patients with breast cancer, rectal cancer, and lung cancer, who are frequently the recipients of multiple cardiotoxic treatments. Audio editing by CardioNerds Academy Intern, student doctor Chelsea Amo Tweneboah.

Access the CardioNerds Cardiac Amyloidosis Series for a deep dive into this important topic.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan. 

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Pearls • Notes • References • Production Team

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Pearls and Quotes – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Oncologist Perspective with Dr. Susan Dent

1. Formal cardiovascular risk stratification must be performed prior to initiating a potentially cardiotoxic anticancer treatment regimen. Considering both drug toxicity and patient-related factors (e.g., age, smoking, hypertension etc) is important. 
2. Anthracyclines affect the cardiomyocyte in complex ways which lead to a largely irreversible cardiomyopathy. All patients should have a pretreatment echocardiogram and ECG. 
3. Trastuzumab cardiotoxicity, by contrast, is more like stunning the myocardium, which manifests as a reversible decrease in left ventricular ejection fraction which generally normalizes upon discontinuation of the drug. 
4. The treatment of chemotherapy-induced cardiomyopathy should involve interdisciplinary discussions and shared decision making with the patient. Beyond guideline-directed medical therapy of heart failure with reduced ejection fraction, management can include temporarily holding or permanently discontinuing the offending agent. 
5. Fluoropyrimidine-associated cardiotoxicity manifests as cardiac ischemia from coronary vasospasm. A 5FU infusion is essentially a stress test as it tends to unmask clinically silent atherosclerosis. 

Show notes

1. What is the basic pretreatment assessment of any oncology patient who is to receive a potentially cardiotoxic regimen? 

Awareness and management of the cardiovascular toxicity of oncology treatments are of paramount importance to be able to deliver treatment safely and to achieve maximal efficacy guided by an expert multidisciplinary team. Thanks to Dr. Dent and her colleagues’ work, this year we have seen the publication of the first Cardio-Oncology guideline (1). Perhaps the most important recommendation is that cancer patients about to start a cardiotoxic regimen should undergo formal cardiovascular risk stratification by considering both the adverse profile of the planned treatment and patient-related factors (e.g., preexisting heart disease, hypertension, smoking). High-risk patients may be referred early to a cardio-oncologist who can anticipate and mitigate toxicities. In addition to risk stratification, specific treatment modalities may require additional imaging and biochemical testing as outlined next. 

2. How does anthracycline-induced cardiotoxicity present and what are the risk factors to consider? 

Anthracycline-induced cardiotoxicity generally manifests as a permanent decrease in left ventricular ejection fraction (LVEF) caused by direct toxic effect of the cytotoxic chemotherapy on the cardiomyocytes. The risk factors for developing anthracycline-induced cardiotoxicity are cumulative anthracycline dose, advanced age, pretreatment low-normal LVEF, prior cardiovascular disease, as well as other established cardiovascular risk factors (e.g., hypertension, diabetes, obesity, smoking).  

3. What is included in the work-up of a patient about to begin an anthracycline-containing regimen? 

All patients who are about to received anthracyclines require a baseline echocardiogram, ideally with global longitudinal strain, and an electrocardiogram. For patients who are at moderate-to-high risk of developing cardiomyopathy, B-type natriuretic peptide and Troponin can also be helpful for monitoring.  

4. How is established anthracycline-induced cardiotoxicity typically managed? 

When a decrease in LVEF below 50% is detected, management usually involves holding the anthracycline and repeating imaging. At this point, discussion with a cardio-oncologist about the initiation of ACC/AHA guideline-directed medical therapy (GDMT) is warranted. If there is improvement in the LVEF with this approach, the decision to rechallenge is nuanced and often part of a multidisciplinary and shared decision-making process with the patient.  

5. What are some proven strategies to prevent or mitigate anthracycline-induced cardiotoxicity? 

In the case of a rechallenge, two ways to mitigate the risk of cardiac damage are using liposomal doxorubicin, which is a less cardiotoxic anthracycline formulation, and co-administration of dexrazoxane, which is the only FDA-approved cardioprotectant for use in this setting. 

6. What is trastuzumab and how does the cardiotoxicity associated with its use differ from that caused by anthracyclines? 

Trastuzumab is a monoclonal antibody directed against the HER2 receptor molecule expressed on breast cancer cells. The actual mechanism of trastuzumab-associated cardiotoxicity is not clear, but it appears to be more akin to myocardial stunning and is generally reversible. If it occurs, a decrease in LVEF appears early and for most patients withholding the drug is effective in reversing the effect.  

7. How is trastuzumab-associated cardiotoxicity managed? 

For those patients with a nadir LVEF < 50%, there is evidence to support the efficacy of GDMT. For those with an LVEF decrease in the 40-49% range, trastuzumab can be continued concomitantly with GDMT and close monitoring of LVEF. In cases with severe LVEF decrease <40%, the decision to continue or rechallenge becomes more complicated and always should involve a multidisciplinary discussion of the risks and benefits of either approach. Depending on the goal of treatment (curative in the adjuvant setting or palliative in the metastatic setting), the actual predicted benefit and whether the cardiac function recovers with GDMT, trastuzumab could potentially be restarted.  

8. How do novel antibody drug conjugates that contain trastuzumab differ in their cardiotoxicity profile from the naked antibody? 

In recent years we have seen the advent of antibody drug conjugates (T-DM1, T-DXd) which in addition the antibody directed against HER2 (trastuzumab) also carry a cytotoxic payload (2). While the experience with these newer agents is still limited, early data suggest these are no more cardiotoxic than trastuzumab. However, the impact of long-term, sequential exposure to these agents on cardiovascular outcomes is unknown. 

9. What are fluoropyrimidines and how does fluoropyrimidine-associated cardiotoxicity manifest clinically? 

Fluoropyrimidines are analogs of nucleic acid bases which inhibit synthesis of DNA and RNA. These are some of the most widely use anticancer drugs and examples include 5-fluorouracil (5FU) and capecitabine (an oral prodrug of 5FU). Fluoropyrimidine-associated cardiotoxicity presents primarily with cardiac ischemia caused by coronary vasospasm or endothelial damage, although these are not the only mechanisms by which these drugs can damage the cardiovascular system (3). This is a phenomenon which typically occurs early in therapy after 1-2 cycles and its incidence varies greatly with the mode of administration, occurring in >10% of patients treated with a 5FU infusion (or continuous capecitabine) versus in 3-5% of those who receive the 5FU as a bolus.  

10. What is the management of fluoropyrimidine-associated cardiotoxicity? 

Rechallenge is possible in select patients who take active part in the decision-making process and who are deemed to derive substantially larger benefits than risks from continuing. When done, rechallenges usually take place in an inpatient setting with close monitoring and co-administration of calcium channel blockers and nitrates. 

11. Is it possible to rechallenge patients with ischemic symptoms induced by fluoropyrimidine treatment? 

Generally, presentations are clinically apparent with symptoms of ischemia and management necessarily includes holding the drug and performing an ischemic work-up which may require invasive testing such as coronary angiography. If there is a clear temporal association with fluoropyrimidine use and ischemic symptoms, a multidisciplinary discussion on whether treatment should be continued is warranted.  

12. What is unique about the cardiotoxicity of oncology therapy in lung cancer patients? 

Lung cancer patients are the perfect storm for cardiotoxicity. The prevalence of smoking is very high in this particular cohort which correlates with preexisting cardiovascular disease. Furthermore, radiation to the chest, tyrosine kinase inhibitors (TKIs) targeting EGFR or ALK, and immune checkpoint inhibitors are frequently part of the treatment schema and have defined cardiovascular toxicities (4). As such, these patients are very likely to benefit from cardiology consultation and optimization of cardiovascular risk factors prior to initiating cancer therapy. 

13. What is the cardiovascular toxicity of TKIs? 

These systemic treatments were initially developed for metastatic disease but are now making their way into the adjuvant setting. These drugs can maintain efficacy for a long time which translates into prolonged exposure and cardiovascular side effects such as hypertension and QT prolongation.  

14. What is the cardiovascular toxicity of immune checkpoint inhibitors? 

Immune checkpoint inhibitors can cause hyperactivation of the immune system resulting in immune attack of normal structures, such as the myocardium. While immune-mediated myocarditis is uncommon (1-2%), it can be very severe with mortality rates approaching 50%, underlining the importance of early recognition and treatment. 

References – Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Oncologist Perspective with Dr. Susan Dent

1. Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS): Developed by the task force on cardio-oncology of the European Society of Cardiology (ESC). European Heart Journal. Published online August 26, 2022:ehac244. doi:10.1093/eurheartj/ehac244 

2. Dent SF, Morse A, Burnette S, Guha A, Moore H. Cardiovascular Toxicity of Novel HER2-Targeted Therapies in the Treatment of Breast Cancer. Current Oncology Reports. 2021;23(11). doi:10.1007/s11912-021-01114-x 

3. Sara JD, Kaur J, Khodadadi R, et al. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1758835918780140. doi:10.1177/1758835918780140 

4. Kunimasa K, Kamada R, Oka T, et al. Cardiac Adverse Events in EGFR-Mutated Non-Small Cell Lung Cancer Treated With Osimertinib. JACC: CardioOncology. 2020;2(1):1-10. doi:10.1016/j.jaccao.2020.02.003