ESC Cardio-Oncology Guidelines

I t is difficult to assign a precise date to the birth of the field of cardio-oncology. Although cardiac effects of anthracyclines have been known for decades, the field as we now know it truly emerged in the early to mid-2000s, largely in response to recognized cardiac toxicities from trastuzumab and vascular endothelial growth factor (VEGF) inhibitors. Since that time, the field has exploded, mirroring the exponential growth of new cancer therapeutics; toxicities grew from a focus on left ventricular dysfunction/heart failure to include vascular, electrophysiologic, pericardial, thrombotic, and valvular toxicities. How does one measure milestones of the maturation of the field? The very existence and growth of this journal is one; 15 to 20 years ago, it would have been hard to conceive that an entire JACC journal could be devoted to the field. In that context, the simultaneous publication and presentation of the new European Society of Cardiology (ESC) CardioOncology guidelines to a packed auditorium should be viewed as nothing less than a triumph—and as further evidence that the field of cardio-oncology has hit the mainstream. And a triumph these guidelines are. The numbers themselves are astounding: 30 international experts from 13 countries collaborated to put together a 133-page document (plus an additional 45-page supplement) with 837 references. The committee aimed to do no less than to cover the entire field of cardio-

I t is difficult to assign a precise date to the birth of the field of cardio-oncology. Although cardiac effects of anthracyclines have been known for decades, the field as we now know it truly emerged in the early to mid-2000s, largely in response to recognized cardiac toxicities from trastuzumab and vascular endothelial growth factor (VEGF) inhibitors.
Since that time, the field has exploded, mirroring the exponential growth of new cancer therapeutics; toxicities grew from a focus on left ventricular dysfunction/heart failure to include vascular, electrophysiologic, pericardial, thrombotic, and valvular toxicities.
How does one measure milestones of the maturation of the field? The very existence and growth of this journal is one; 15 to 20 years ago, it would have been hard to conceive that an entire JACC journal could be devoted to the field. In that context, the simultaneous publication and presentation of the new European Society of Cardiology (ESC) Cardio-Oncology guidelines 1 to a packed auditorium should be viewed as nothing less than a triumph-and as further evidence that the field of cardio-oncology has hit the mainstream.
And a triumph these guidelines are. The numbers themselves are astounding: 30 international experts from 13 countries collaborated to put together a 133-page document (plus an additional 45-page supplement) with 837 references. The committee aimed to do no less than to cover the entire field of cardio-oncology, including toxicities across every major class of cancer therapeutics, primary and secondary prevention strategies, diagnostic and therapeutic pathways-and more! The guidelines include 82 tables and 48 figures; the tables reviewing drug-drug and drug-food interactions alone would be a monumental achievement, and yet there is so much information in the guidelines that these are found in the supplemental material.
The writing and recommendations are clear, the tables/figures are direct and concise, and the comprehensive nature of the document is truly impressive. The overriding theme-that the goal of cardio-oncology is to maximize the safe administration of cancer therapies rather than to limit treatment with effective cancer therapies-is a laudable one. If health care providers or cancer patients have a question about anything cardio-oncology related, they will almost certainly find it addressed. This is even more impressive when one considers that these are the first such guidelines-meaning that all of the content had to be created from scratch, rather than building upon previous efforts. That is a tremendous achievement, and one which every member of the task force should take great pride in.
Where might the guideline authors have taken a different tact? It largely depends on the manner in which one views the purpose of guidelines. Should guidelines be more conservative in their recommendations-restricting their recommended diagnostic and treatment strategies to those areas with a solid evidence-base? Or, should guidelines be more aspirational-going out on a limb to make recommendations where the evidence base may not be there, but recommending practices that committee members believe are more likely than not to be a good idea. The ESC Cardio-Oncology guidelines clearly take the latter approach.
But is it a good idea? One of the most important roles for guidelines is to set the standard of care for a field. If guidelines are seen as overreaching, they run the risk of being ignored. A potential litmus test for any guideline recommendation can start with the question, "What percentage of providers currently meet what is being recommended?" If the number is <50%, most providers are by definition providing care below the "standard-of-care," a concept that is in and of itself an oxymoron. There are potential legal implications as well, with liability a real risk if a bad patient outcome occurs and a provider is seen as not having followed the "official guidelines" in diagnosis or management. For the ESC Cardio-Oncology guidelines, our sense is that the percentage of providers who would currently be meeting the guideline recommendations is extremely small. Is that okay? Are providers in the field that much behind the evidence, or does it mean that the guidelines have overreached? Our view is that it is the latter.
Consider the document's recommendations for biomarker screening: The guidelines recommend baseline cardiac troponin (cTn) and natriuretic peptide (NP) measurements for all patients treated with agents that have the potential to cause cancer therapy-related cardiovascular toxicity. This is despite the fact that, as the guideline authors concede, "the literature on the use of biomarkers for cancer therapyrelated cardiovascular toxicity risk stratification before cancer therapy is limited." 1 NP and cTn monitoring is recommended at baseline, every 3 months, and 12 months after therapy even in low-and moderate-risk HER2þ early breast cancer patients. 1 NP monitoring is recommended at baseline and every 4 months for the first year in moderate-risk patients receiving a VEGF inhibitor. 1 NP measurements are recommended every cycle for the first 6 cycles even in low-to moderate-risk patients receiving bortezomib, despite a lack of evidence that bortezomib treatment even predisposes to a higher risk of heart failure. 1,2 Cardiac biomarkers are recommended 12 months after completion of cancer therapy in asymptomatic moderate-risk patients (Class IIa) and even in asymptomatic low-risk patients (Class IIb).
How many oncologists meet these recommendations? Is there reasonable evidence to guide any of this?
Consider the troponin screening recommendations for immune checkpoint inhibitor (ICI) therapy. The guidelines recommend cTn measurements at baseline, before doses 2, 3, 4, and every 3 doses thereafter. 1 Our institution has more experience than most with cTn screening for ICI myocarditis, having performed one of the early studies testing such an approach. 3 Although we detected 3 early cases of myocarditis (1.4% of patients screened), we also learned the challenges of such a screening methodnot the least of which were both a high rate of false positives and the need to provide staffing to safely triage elevated troponin results whenever they resulted. Even as a group that advocates the potential of cTn screening, we recognize its challenges/limitations and do not believe the evidence basis is there to begin to make such a broad recommendation for the entire ICI-treated population.
Next, consider the imaging guidelines. Although we wish a more restrained path had been chosen when it comes to many of the recommendations, the ESC guidelines nevertheless represent a seminal moment in our field of cardio-oncology. They are a true triumph, and the writing committee who worked tirelessly to put them together deserve our respect, our praise, and our congratulations.

FUNDING SUPPORT AND AUTHOR DISCLOSURES
Dr. Witteles has participated in advisory boards for Pfizer, Alnylam, Ionis, Bridgebio, NovoNordisk, Janssen, Intellia, and AstraZeneca. Dr Reddy has reported that he has no relationships relevant to the contents of this paper to disclose.