Global Cardio-Oncology Viewpoints ‘Contextualize’ ESC Guidelines

Now that the cardio-oncology community has had a few months to digest new practice guidelines from the European Society of Cardiology (ESC), clinicians around the world are chiming in on where they see both value and knowledge gaps in the broad and hefty document.  

As TCTMD reported at the time, the 133-page document was published and presented at the ESC Congress 2022. The recommendations were created by a multidisciplinary committee and cover definitions, diagnosis, treatment, and prevention of cancer therapy-related cardiovascular toxicity, as well as the management of CV disease caused directly or indirectly by cancer.

This month in JACC: CardioOncology, a range of solicited and unsolicited feedback provides some critical reactions to the recommendations.

“This is an effort to help contextualize the guidelines and to [add] perspective from members of the international community [about] how these guidelines apply to the clinical care of their patients across the globe,” said journal editor Bonnie Ky, MD (Hospital of the University of Pennsylvania, Philadelphia). “Guidelines are living documents, and they're meant to be dynamic and updated over time according to the evidence. So, in that sense, it is important to be able to have a healthy dialogue and discourse about them within the community.”

The guidelines were developed by ESC in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO), and the International CardioOncology Society (IC-OS).

Guidelines are living documents, and they're meant to be dynamic and updated over time according to the evidence. Bonnie Ky

One of the viewpoints, by Darryl P. Leong, MBBS, PhD, and Som D. Mukherjee, MD (both McMaster University, Hamilton, Canada), reviews the quality of the evidence, noting that of the 272 explicit recommendations in the guidelines, 76% were supported by level C evidence. Among Class I recommendations, only 3% were supported by level A evidence, with the majority supported by level C.

“This is only a superficial representation of the recommendations, and in many circumstances, expert opinion is all that may be required,” Leong and Mukherjee write. “However, the risk with Class I recommendations supported by Level of Evidence: C is that they may hinder research to address the limited existing evidence, because clinicians, ethics committees, and patients may be reluctant to trial strategies that run counter to the guidelines.”

Ky said she is hopeful that it will become a priority for researchers to generate new evidence for some of these recommendations with weak support. At the same time, she said, there needs to be a place for recommendations that may be based on level C, but are common sense and never likely to be tested in a randomized trial.

Patients With Active Cancer

Leon and Mukherjee also feel that the document’s massive size “is a two-edged sword,” noting that while its comprehensiveness across all pertinent areas of cardio-oncology make it an excellent reference for clinicians, “an important limitation of the document’s length is that the most important or robust recommendations may not be readily apparent among the many recommendations with limited supportive data.”

They also contend that the generalizability of the guidelines to patients with active, advanced cancer is limited.

In a similar vein, Joseph A. Sparano, MD, and Gagan Sahni, MD (both Icahn School of Medicine at Mount Sinai, New York, NY), note that while the 2022 guidelines encompass a broad spectrum of cancer therapeutics associated with cardiac effects, ranging from cytotoxic agents to newer therapies targeting immune checkpoints, there are areas of notable discordance between this document and prior guidelines. One issue they focus on is imaging surveillance with two-dimensional transthoracic echocardiography (TTE) in breast cancer.  

Both the 2022 ESC guidelines and 2016 guidelines from the American Society of Clinical Oncology (ASCO) recommend stratifying based on CV risk associated with the specific cancer therapy indicated and the individual’s baseline CVD history and risk factors.

But while the new ESC guidelines recommend surveillance with TTE at baseline and every 3 months during anti-HER2 therapy in all patients irrespective of risk, the 2016 ASCO guidelines recommend surveillance only in high-risk individuals, with clinical judgment and patient circumstances driving the frequency of TTE.

As Sparano and Sahni point out, the purpose of TTE is to confirm symptomatic cardiac therapy-related cardiac dysfunction and detect asymptomatic dysfunction that may trigger interrupting or withholding anti-HER2 therapy. As such, in breast cancer patients with low baseline CV risk receiving nonanthracycline anti-HER2 strategies, there is too low a likelihood of meeting criteria for interrupting anti-HER2 therapy and/or initiating cardioprotective therapy to justify the effort and expense of increased frequency of TTE monitoring.

“The ESC panel indeed recognized ‘gaps in the evidence’—we agree that substantial gaps exist and suggest that evaluation and validation of cardiac surveillance algorithms for the entire spectrum of anti-HER2 therapy be added as a knowledge gap and identified as a research priority,” Sparano and Sahni write.

A Global Perspective

According to Ky, the 2022 ESC guidelines and the reaction to them are signs of how the field of cardio-oncology has evolved, and where it is going as it continues to expand and advance the knowledge base. 

“These guidelines are stimulating conversation and discussion, identifying gaps in knowledge and thus motivating new science, and will ultimately lead to the generation of new evidence. All of this is critically important,” she said.

Also of importance is figuring out how the community can provide effective, inclusive, and accessible care not only in academic medical centers, but to communities and healthcare systems globally, particularly in the setting of resource constraints.  

“That’s another major issue that I think the guidelines do highlight. We have to think about and prioritize accessible cardio-oncology care for our patients,” Ky added.  

Kazuhiro Sase, MD, PhD (Juntendo University, Tokyo, Japan), and colleagues Mikio Mukai, MD, PhD (Osaka Prefectural Hospital Organization, Japan), and Yasuhiro Fujiwara, MD, PhD (National Cancer Center Hospital and the Pharmaceuticals and Medical Devices Agency, Tokyo, Japan), in a third viewpoint, highlight the personalized algorithms proposed by the new guidelines as one of their key strengths. These algorithms represent a paradigm shift from a drug-centric to a patient-centric approach, they note. Moreover, the guidelines break cancer therapy-related cardiovascular toxicity severity down into mild, moderate, and severe/very severe and provide definitions for its various types, including myocarditis, vascular toxicity, arterial hypertension, and cardiac arrhythmias.

Sase and colleagues note that Japan is no exception in having a limited availability of dedicated cardio-oncology services. As such, the guidelines do a good job of explaining “modern cancer therapies for cardiologists,” as well as “modern cardiology for oncologists,” they observe.

For example, the inclusion of a detailed protocol for immune checkpoint inhibitor-related myocarditis “is quite feasible for cardiologists who must support the completion of effective cancer therapies in understanding the overall benefit-risk analysis.” In another instance, the section on end-of-cancer therapy CV risk assessment should encourage oncologists to refer their eligible patients to cardiologists for education and support related to modifiable CV risk factors, they say.

One final viewpoint in this month’s issue drives home the view that there’s more work to be done to educate providers in this relatively new subspecialty, while also making the aims of these guidelines both realistic and financially supportable. Ronald M. Witteles, MD, and Sunil A. Reddy, MD (both Stanford University School of Medicine, CA), warn that the guidelines may overreach in what they expect of those providing cardio-oncology care, saying “our sense is that the percentage of providers who would currently be meeting the guideline recommendations is extremely small.”

Like others questioning low levels of evidence in the document, they predict that many of the recommendations likely won’t stand the test of time as supporting data shift and change.

“If the guidelines were to be followed as written, the monetary costs to patients and the healthcare system from non-evidence-supported imaging, laboratory testing, and therapeutic interventions would be enormous,” Witteles and Reddy write. “One must further consider the time and emotional costs to patients, who may get labeled with new ‘diseases’ that they do not truly have.”

_{Note: An earlier version of this story incorrectly abbreviated transthoracic echocardiography as TEE.}