Minimizing Cardiac Risks With Contemporary Radiation Therapy for Hodgkin Lymphoma

The association between chest radiation therapy (RT) for Hodgkin lymphoma (HL) and cardiac complications was first reported almost 50 years ago by Dollinger et al as a case report. Hancock et al from Stanford University subsequently established that the risk is related to doses to themediastinum. Since then, several studies have become available, focusing mostly on childhood and breast cancer survivors, connecting cardiac RT dose with the risk of cardiac morbidity and mortality. The methods of radiation dose estimation to the heart varied from study to study. They ranged from using the prescribed mediastinal dose as a surrogate, to averaging doses at several points in the heart, to measuring mean heart scatter doses in phantoms, and to estimating the dose from a reconstructed plan on a patient with a typical anatomy. The article by van Nimwegen et al, which accompanies this editorial, is an important, unique contribution to the HL survivorship literature. It focuses specifically on patients with HL treated mostly as adults. The authors used a previously validated methodology based on the cardiac contour on the simulation x-rays to determine the mean heart dose, which has been shown to closely estimate the dose calculated by modern-day computed tomography (CT)-based dosimetry. This study is the first to demonstrate a linear, no-threshold relationship betweenmean heart dose and development of coronary heart disease in survivors of HL. The results provide cardiac risk estimates for counseling treated patients, directing their follow-up care, and guiding mediastinal RT planning in newly diagnosed patients. Furthermore, the dose-effect relationship provides additional data aiding in the development of radiobiological models for predicting cardiac risk specific to adult patients with HL treated in the modern era. The role of RT in HL is an intensely debated topic, with recent data suggesting that elimination of RT in early-stage HLmay adversely affect disease control and survival. For patients with HL requiring mediastinal RT, findings from the study by van Nimwegen et al lend further support to our effort to limit cardiac doses to as low as reasonably achievable. In this study, mean heart doses of more than 20 Gy in more than half of the study population reflected the historical RT approaches for HL. Such high cardiac doses are rarely seen in the contemporary era, where mean heart doses in the single-digit range or even less than 5 Gy can often be achieved in patients receiving mediastinal RT for HL. The three principal strategies for reducing critical organ exposure include radiation dose reduction, radiation field/volume reduction, and use of modern RT planning and delivery techniques. For patients with early-stage HL and low-risk disease according to the GermanHodgkin Study Group (GHSG) criteria, the GHSG HD10 trial showed that the radiation dose can be safely de-escalated from 30 Gy to 20 Gy after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Although the GHSG HD11 trial did not support reducing RT dose to 20 Gy in patients with risk factors after ABVD chemotherapy, there are data showing that in some cases of early-stage, unfavorable HLwith complete metabolic response to adequate chemotherapy, doses of 20 to 24 Gy yield excellent long-term in-field control, suggesting that dose de-escalation can be considered in these patients, especially when doses to the heart and lung are unacceptably high because of the disease distribution. The second strategy of minimizing radiation exposure is RT field/volume reduction. The availability of more effective systemic therapy, modern staging and restaging imaging studies, and CT-based RT planning has now allowed RT for lymphoma to transform from extended-field RT (EFRT), mantle-field RT, and involved-field RT (IFRT) to involved-node/involved-site RT (INRT/ISRT). Up until the late 1980s to early 1990s, EFRT was commonly used in HL therapy. This required field matching, which has been shown to result in higher (up to 50% more than prescribed) total dose to the heart at the junction of the mantle and subdiaphragmatic fields and is associated with a significantly increased risk of subsequent coronary heart disease. Reduction from EFRT to mantle field is an improvement, but a standard mantle field is still associated with substantial radiation exposure to the heart. A dosimetric study on patients with earlystage HL showed a mean heart dose of 27.5 Gy with mantle field RT, compared with 7.7 Gy with INRT. The estimated 25-year absolute excess risk of cardiac disease was reduced from 9.1% to 1.4%, and cardiovascular mortality risk was reduced from 2.1% to 1%. Other dosimetric studies have compared IFRT with INRT, showing close to 50% reductions inmean heart doses with the field reduction. A final strategy to reduce critical organ exposure is employment of modern RT technology. The historical EFRT, mantle-field RT, and IFRT were all based on two-dimensional radiation planning, which relied on bony landmarks on plain films and inevitably resulted in unnecessary exposure of a large volume of normal tissue due to uncertainty in targeting. The current standards of ISRT/INRT are CT based, with far more accurate targeting and sparing of normal tissue. Additional new technology,