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.

Trial registration: ClinicalTrials.gov NCT00943423.

FIG 1.

Distribution of mean doses in Gy to cardiovascular structures for PET-negative patients receiving radiotherapy and for whom dosimetry was completed (n = 144). (A) Whole heart, showing those with mediastinal involvement (dark blue) and those without (light blue). (B) Common carotid arteries. PET, positron emission tomography.

FIG 2.

Predicted cardiovascular mortality for PET-negative patients receiving radiotherapy for whom radiation dosimetry was completed (n = 144). (A) Predicted cumulative risks of mortality from heart disease or stroke for the general population, for patients receiving ABVD chemotherapy alone, and for patients receiving ABVD plus IFRT. Cumulative risks allow for the competing risk of noncardiovascular causes of death. (B) Predicted absolute excess risk of mortality from heart disease or stroke for patients receiving ABVD plus IFRT compared with patients receiving ABVD alone, by disease category. (C) Predicted absolute excess risk of mortality from heart disease for patients receiving ABVD plus IFRT compared with patients receiving ABVD alone, by categories of mean whole heart dose in Gy. To achieve comparability across categories, predictions for each category assume all 144 patients received the average radiation dose in that category. (D) Predicted absolute excess risk of mortality from stroke for patients receiving ABVD plus IFRT compared with patients receiving ABVD alone, by categories of mean bilateral common carotid artery dose in Gy. To achieve comparability across categories, predictions for each category assume all 144 patients received the average radiation dose in that category. ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; IFRT, involved field radiotherapy; PET, positron emission tomography.

FIG 3.

Predicted 30-year absolute excess risk of radiation-related heart disease or stroke for PET-negative patients who received radiotherapy and for whom dosimetry was completed (n = 144). Mortality is indicated by orange lines and incidence by black lines. (A) Individual absolute excess risks. Dotted line corresponds to the median excess risk (ie, average of patients ranked 72 and 73 of 144), which was 0.26% for mortality and 3.61% for incidence. (B) Population average absolute excess risks. Dotted line corresponds to population average for irradiated patients if 50% of PET-negative patients with the lowest predicted risks were irradiated. This group of irradiated patients has 0.11% average excess risk for mortality and 1.79% for incidence. PET, positron emission tomography.

FIG 4.

Predicted cardiovascular disease incidence for PET-negative patients receiving radiotherapy and for whom radiation dosimetry was completed (n = 144). (A) Predicted cumulative risks of incident heart disease or stroke for the general population, for patients receiving ABVD chemotherapy alone, and for patients receiving ABVD plus IFRT. Cumulative risks allow for the competing risk of noncardiovascular causes of death. (B) Predicted absolute excess risk of incident heart disease or stroke for patients receiving ABVD plus IFRT compared with patients receiving ABVD alone, by disease category. (C) Predicted absolute excess risk of incident heart disease for patients receiving ABVD plus IFRT compared with patients receiving ABVD alone, by categories of mean whole heart dose in Gy. To achieve comparability across categories, predictions for each category assume all 144 patients received the average radiation dose in that category. (D) Predicted absolute excess risk of incident stroke for patients receiving ABVD plus IFRT compared with patients receiving ABVD alone, by categories of mean bilateral common carotid artery dose in Gy. To achieve comparability across categories, predictions for each category assume all 144 patients received the average radiation dose in that category. ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; IFRT, involved field radiotherapy; PET, positron emission tomography.