This JCO Podcast provides observations and commentary on the JCO article "Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study" by Bates et al. My name is Joseph Carver, and I am the Chief of Staff at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, Pennsylvania. My specialty is cardio-oncology.

It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field. It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field. Total dose delivered does not reflect specific cardiac exposure. This has led to report the mean heart dose that is the percent cardiac volume within the radiation fields. For most treated patients, discovery of anthracycline cumulative dosing is easily abstracted and straightforward. For modern therapeutic radiation, however, historical mean heart dose or other cardiac dosimetric parameters have not been traditionally reported and may be more difficult to obtain. This has led to a lack of consensus about the cardiovascular risk when the total dose is <30 Gy,

In the article that accompanies this podcast, Bates et al1 enhance our understanding of the association between cardiac volume exposure to different radiation therapy doses and rates of serious cardiac conditions among long term survivors of pediatric cancer and reaffirms the association of cumulative anthracycline dose and subsequent risk for cardiomyopathy.

With data from the Childhood Cancer Survivorship Study, they determined the rates of self-reported grade 3-5 cardiac conditions as defined by Common Terminology Criteria for Adverse Events v4.03 in 24,214 >5-year survivors who were treated for a variety of cancers at a median age of 7 years. Evaluation occurred at a median follow-up of 20.3 years with a median attained age of 27.5 years. Late cardiac risk was compared to 5,046 untreated siblings. For each survivor, radiation fields were reconstructed on age-specific phantoms to calculate estimated mean heart dose and the percent of heart volume receiving at least 5 Gy (low dose) and 20 Gy (higher dose). Doxorubicin-equivalent doses were similarly abstracted.

Toxicity parameters were any cardiac disease, coronary artery disease and heart failure. They found a cumulative incidence of cardiac disease, 30 years from diagnosis of 4.8% (95% CI 4.3-5.2). There was a dose relationship between mean heart dose and all parameters. Both low-moderate doses (5-19.9 Gy) to a large volume of the heart (>50%) and higher doses (≥20Gy) to small cardiac volumes (0.1-29.9%) were associated with an increased risk of cardiac disease. Heart failure drove the risk of high doses to small volumes while CAD drove the risk of low doses to large volumes.

Similarly, they reconfirm the relationship between cumulative anthracycline dosing and any cardiac disease with an increased risk for those treated at a younger age (≤ 13 years of age). An increased relative risk for any cardiac disease was also present with any anthracycline exposure (0.1-<250 mg/m2: RR 1.7%, 95% CI 1.1-2.5) compared to siblings.

This study shows that low-moderate dose RT to a large volume of the heart and higher-dose RT to a small volume of the heart increase the risk of late cardiac disease. It also reconfirms the association of cumulative anthracycline dosing and cardiac risk, especially in patients who were treated at < 13 years). With a 4.8% risk for any cardiac toxicity at 30 years, the study provides an evidence-based long-term realistic risk estimate that can be part of pre-treatment conversations with patients and family as well as survivors.

What are the take-home points of this study?

In spite of modern techniques to deliver therapeutic radiation and avoid the heart, a "safe" cardiac dose has not been well-defined. Two large retrospective, phantom-based studies have shown an increased risk of coronary heart disease of 7.4% per 1 Gy MHD in breast cancer and lymphoma patients. These studies have not only alerted radiation oncologists to the potential risk of even "low" radiation doses to the heart but have also driven them to push RT planning algorithms to optimize one parameter, mean heart dose. The problem with this single metric is that two treatment plans with vastly different dose maps can have the same mean heart dose: 1) low dose spread out to a large volume such as in an intensity modulated radiotherapy plan; or 2) high dose to a small volume (that may include the left anterior coronary artery) with almost no dose to the rest of the heart such as in breast tangents or a proton therapy plan. Even with current image-driven treatment planning algorithms that prioritize a low mean heart dose, it is still possible to deliver higher doses of radiation to cardiac substructures. The results from this paper have major implications for treatment planning and delivery, informing us to be wary of low dose generic mean heart dose metrics and makes a case for universal adaptation of the quantification of structure-specific dose exposure and attention to the "low-dose cloud" in the rest of the heart.

For survivorship and surveillance, there are implications for guideline development evolving one step beyond binary "high risk/low risk" stratification to understand that any exposure to anthracyclines and/or therapeutic radiation is part of a continuum of risk: low risk is not no risk. This continuum informs health care providers to a proactive management approach for the late survivor population that includes aggressive management of cardiac risk factors present at initial evaluation and those that emerge over the decades of survivorship.

It is equally as important to reiterate that the late cardiac toxicity due to therapeutic radiation and anthracyclines pales in comparison to the risk associated with untreated traditional cardiac risk factors: (obesity, cigarette smoking, sedentary life style, diabetes, hypertension and the metabolic syndrome) and when they are present in this population, they magnify the 4.8% cardiac event risk defined by Bates.

This study also provides additional rationale for the field of cardio-oncology- for greater collaboration between medical and radiation oncologists and cardiologists at every step of the cancer treatment continuum.

I congratulate Bates and colleagues for this potentially paradigm changing contribution and am optimistic that further enhancements in radiotherapy planning and delivery will reduce late cardiac toxicity and improve survival.

This concludes this JCO Podcast. Thank you for listening.

The Heartbreak of Cancer Treatment: The Latest in Late Cardiac Toxicity

Journal of Clinical Oncology (JCO) Podcast

The Heartbreak of Cancer Treatment: The Latest in Late Cardiac Toxicity