Cardiac dose-volume analysis of 9,411 patients with registry data for cardiovascular disease and overall survival.

Abstract Background and purpose Radiation therapy (RT) to the thorax poses risks of radiation-induced cardiotoxicity, potentially increasing cardiovascular diseases (CVD) incidence. Advances in RT strive to minimize these risks by reducing heart radiation dose exposure. This study integrates detailed 3D dosimetry on individually delineated hearts with registry-based outcome data to assess the impact of radiation dose on cardiovascular morbidity and overall survival (OS) across multiple cancer types. It also examined the influence of patient-specific factors on cardiotoxicity risk and survival outcomes. Materials and methods We analyzed data from 9,411 patients receiving RT at Rigshospitalet between 2009 and 2020 for breast, esophageal, lymphoma, and lung cancers. Cumulative incidence of CVD and death in the presence of competing risks was calculated with the Aalen-Johansen estimator. The impact of radiation dose and patient characteristics on ischemic heart disease (IHD) onset and OS were assessed using Kaplan-Meier and Cox Proportional-Hazards Models. Results Higher mean heart dose (MHD) was associated with poorer OS in breast and lung cancer patients (Hazard ratio 2.8 and 1.2), but no significant relationship was found between MHD and IHD. Established cardiac risk factors (age, sex, and existing IHD) outweighed cardiac dose as a risk factor for subsequent cardiac events for all diagnoses. The risk of death was greater than subsequent CVD, especially in esophageal and lung cancers (cumulative incidence 60% versus 17% and 60% versus 14%), despite comparatively high heart doses. Conclusion The study demonstrates that risk of death from primary cancer is of far greater concern than risk of subsequent cardiac events from cardiac radiation dose exposure in the range achievable with contemporary RT techniques, especially for lung and esophageal cancer patients. Further sparing of the heart should not be prioritized at the expense of adequate treatment of the index cancer. Highlights - Age and existing heart disease far outweighed heart dose as predictors of ischemic heart disease - Overall survival is not a useful surrogate for cardiac toxicity in dose-response studies due to confounding by disease stage - With modern RT techniques, the excess absolute risk attributable to radiotherapy is so small that a statistically significant dose-response could not be observed even in 9,411 patients - For most patients, good quality contemporary radiotherapy is sufficient to limit heart toxicity as a clinically relevant concern ### Competing Interest Statement We report institutional research and teaching contracts with Brainlab, Varian, and ViewRay. ### Funding Statement This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 801199. The authors acknowledge support from Kirsten and Freddy Johansen's award and National Cancer Institute (Grant No. P30 CA 134274-04). SMB was supported by funds through the Maryland Department of Health's Cigarette Restitution Fund Program. IRV and JP received research funding from Varian Medical Systems. IRV and JP are supported by Danish Cancer Society (Grant No. R231-A13976). This work is supported by Danish National Research Foundation (DNRF) grant number 126 (PERSIMUNE). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Danish National Committee of Health Research Ethics (NVEK) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data produced in the present study are available upon reasonable request to the authors.