Predicted Risks of Cardiovascular Disease Following Chemotherapy and Radiotherapy in the UK NCRI RAPID Trial of Positron Emission Tomography–Directed Therapy for Early-Stage Hodgkin Lymphoma

Abstract

PURPOSE The contemporary management of early-stage Hodgkin lymphoma (ES-HL) involves balancing the risk of late adverse effects of radiotherapy against the increased risk of relapse if radiotherapy is omitted. This study provides information on the risk of radiation-related cardiovascular disease to help personalize the delivery of radiotherapy in ES-HL. METHODS We predicted 30-year absolute cardiovascular risk from chemotherapy and involved field radiotherapy in patients who were positron emission tomography (PET)–negative following three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy within a UK randomized trial of PET-directed therapy for ES-HL. Cardiac and carotid radiation doses and chemotherapy exposure were combined with established dose-response relationships and population-based mortality and incidence rates. RESULTS Average mean heart dose was 4.0 Gy (range 0.1-24.0 Gy) and average bilateral common carotid artery dose was 21.5 Gy (range 0.6-38.1 Gy), based on individualized cardiovascular dosimetry for 144 PET-negative patients receiving involved field radiotherapy. The average predicted 30-year radiation-related absolute excess overall cardiovascular mortality was 0.56% (range 0.01%-6.79%; < 0.5% in 67% of patients and > 1% in 15%), whereas average predicted 30-year excess incidence was 6.24% (range 0.31%-31.09%; < 5% in 58% of patients and > 10% in 24%). For cardiac disease, the average predicted 30-year radiation-related absolute excess mortality was 0.42% (0.79% with mediastinal involvement and 0.05% without) and for stroke, it was 0.14%. CONCLUSION Predicted excess cardiovascular risk is small for most patients, so radiotherapy may provide net benefit. However, for a minority of patients receiving high doses of radiation to cardiovascular structures, it may be preferable to consider advanced radiotherapy techniques to reduce doses or to omit radiotherapy and accept the increased relapse risk. Individual assessment of cardiovascular and other risks before treatment would allow personalized decision making about radiotherapy in ES-HL.

Informing radiotherapy decisions in stage I/IIa Hodgkin lymphoma: modeling life expectancy using radiation dosimetry

“…Ours is the first model to evaluate this treatment choice using not only individual patient characteristics such as age, sex, and smoking status but, importantly, representative RT dosimetry based on 144 patients treated in a clinical trial. 16 Crucially, the model estimates the excess risks of late effects based on published dose-response relationships obtained from large cohorts of patients treated for HL. Another key strength of our model is the use of parameter inputs that are informed throughout by real data rather than assumptions or expert opinion.…”

“…For consistency, doses for all fields were calculated for a commonly used prescribed dose of 30 Gy. Doses for examples 1, 4, and 5 were calculated using the method published by Maraldo et al 18 Doses for examples 2 and 3 were constructed using cardiovascular doses from 144 patients in the RAPID trial, combined with the method by Maraldo et al 16,18 Full details of the derivation of dosimetry parameters are given in supplemental Methods. The MBD, MLD, MHD, and MDCCA doses from each example set are given in Table 3 .…”

Proton Therapy in Supradiaphragmatic Lymphoma: Predicting Treatment-Related Mortality to Help Optimize Patient Selection

“…Instead, risk predictions based on dose-response relationships derived by the best currently available followup studies of HL patients treated in the past combined with individual radiation doses received by patients treated with modern RT, can provide useful approximate results, and determine the potential risk reductions achievable with modern treatment approaches. 37 Our results are based on such predictions and there are uncertainties associated with these models, some of which can be quantified. Confidence intervals for the coefficients of the dose-response relationships are available (see Supplemental Table B3) and the impact of dose-reconstruction uncertainties on them has previously been evaluated and found to be small.…”

“…Instead, risk predictions based on dose–response relationships derived by the best currently available follow-up studies of patients with HL treated in the past combined with individual radiation doses received by patients treated with modern RT can provide useful approximate results, and determine the potential risk reductions achievable with modern treatment approaches. 37 …”

Cardiovascular Disease in Adult Cancer Survivors: a Review of Current Evidence, Strategies for Prevention and Management, and Future Directions for Cardio-oncology

“…While this technique is currently only evidenced in animal models [93,94], the ongoing ERIC-ONC trial [95] and RESILIENCE trial [96] may provide some evidence for the use of remote ischemic conditioning in human patients with cancer receiving anthracycline-based treatment. For those treated with thoracic radiation, the use of advanced radiation techniques such as stereotactic ablative radiotherapy and/or dose reductions may additionally be considered, although Cutter et al [97] suggest that individual risk assessment is required to determine whether this is appropriate. Similarly, proton therapy has been shown to be effective in reducing the cardiac impact of radiation [98].…”