In Reply to Welsh et al.

To the Editor:

We appreciate the comments¹ regarding our article “Lung Cancer and Heart Disease Risks Associated with Low-Dose Pulmonary Radiotherapy to COVID-19 Patients With Different Background Risks.”² It is indeed true that the effects of very low radiation doses are uncertain, and epidemiologic evidence at these very low doses is limited. However, the pulmonary and cardiac doses relevant to pulmonary radiation therapy for patients with COVID-19 are not in that “very low” dose range. Specifically, the pulmonary and cardiac doses are very similar to the prescription dose, typically in the range from 0.5 to 1.5 Gy²—and we summarize here evidence that these values are in the organ dose range where we have significant epidemiologic data.

Considering first radiation-induced cancer, at very low doses it is true that potential risks remain uncertain. The dose above which there is clear epidemiologic evidence of increased risk is often termed the “minimal significant dose” (MSD).³ Among atomic bomb survivors, the estimated MSD, both for cancer incidence and for cancer mortality, is 0.15 Gy.³ Of course, there are uncertainties associated with risk estimates derived from atomic bomb survivors, but the fact that the risk estimates for both radiation-induced cancer incidence and radiation-induced cancer mortality—which derive from entirely different databases—are very similar suggests that these MSD estimates are realistic. Recent data from a large study (N = 259,350) of nuclear workers also yields a similar estimated MSD of ∼0.2 Gy for radiation-induced cancer.⁴

Turning to radiation-induced circulatory disease, as recently summarized,⁵ there has long been statistically significant evidence for increased risks in the 0.5 to 1.5 Gy (and greater) organ dose range (eg, among atomic bomb survivors,⁶ nuclear workers,⁷ and Chernobyl emergency workers⁸). In fact, a large combined study (N = 77,275) of patients from the Massachusetts and Canadian fluoroscopy cohorts provides clear evidence of increased radiation-induced circulatory disease mortality, even at doses less than 0.5 Gy.⁹

In summary, our motivation was to enable realistic benefit-risk analyses for low-dose pulmonary radiation therapy for patients with COVID-19. Our overall conclusion was that the balance is generally favorable, but attention should be paid to high-risk groups such as smokers and individuals with high baseline risks of circulatory disease. The dose range of interest here is considerably greater than the MSDs for both radiation-induced cancer and radiation-induced circulatory disease, so we are able to rely on epidemiologic data without needing to speculate about mechanisms.