Late Cardiac Toxicity After Anthracyclines and Radiotherapy for Lymphoma-A Regression Analysis of Dose-Response

Late cardiac toxicity after radiation therapy and/or systemic therapy with anthracyclines for lymphomas is a serious concern. To estimate the risks with different treatment combinations, reliable estimates of the dose-response relationships are needed. We performed a literature-based regression analysis of long-term cardiac events after lymphoma treatment. The objective was to identify dose-response relationships for anthracycline and radiotherapy regarding congestive heart failure (CHF), ischemic heart disease (IHD), and valvular heart disease (VHD). We included papers published January 2000-December 2022 with data on long term cardiac outcomes in lymphoma patients, radiation doses to the heart, and anthracycline doses. Papers without dose/response information were excluded. We identified six eligible papers including 22,916 patients. The excess relative risk (ERR) of CHF for anthracyclines per 100 mg/m2 (corresponding to 2 cycles of ABVD or CHOP chemotherapy) was 92% (CI: 74%-101%), and for radiotherapy per Gray (Gy) of mean heart dose it was 6.1% (CI: 4.4%-7.6%). Corresponding numbers for the other endpoints were: IHD: No effect of anthracyclines, ERR = 4.4%/Gy (CI: 2.7%-6.1%) and VHD: ERR = 25%/100 mg/m2 (CI: 13%-37%) and ERR = 10%/Gy (CI: 6%-13%). Data agree with a linear no threshold dose-response relationship for related endpoints, that is, there are no "safe" lower doses of either anthracyclines or radiotherapy. Late cardiac toxicity risks for all three endpoints can be assessed in each patient by a combined estimate from the cumulative doses of anthracyclines and radiation to the heart. This estimate can guide future treatment allocation in lymphoma patients.