Letter to the editor regarding “Lack of supporting data make the risks of a clinical trial of radiation therapy as a treatment for COVID-19 pneumonia unacceptable”

To the Editor

We read with great interest the paper by Kirsch et al. entitled “Lack of supporting data make the risks of a clinical trial of radiation therapy as a treatment for COVID-19 pneumonia unacceptable”. The authors make valid points that merit serious consideration, but in the setting of an ongoing pandemic without effective therapies, the recommendation against carefully designed clinical trials is understandable but not the only valid point of view.

Because of the almost complete lack of pre-existing immunity to COVID-19, the pandemic overcame most of the health systems facing it and causing the rapid saturation of the available intensive care units beds (ICU) in many countries [1]. Early published series show high mortality among patients admitted to the ICU and in older hospitalized patients [2], [3]. Almost all of the current therapies in clinical trials other investigators selected because of possible preclinical or clinical efficacy in diseases other than COVID-19 in the hopes something might work [4].

Many of us in the global radiation oncology community independently raised the possibility of using low doses of thoracic radiation therapy based upon historical data suggesting benefit in pneumonia and its ongoing use in the treatment of non-neoplastic disease [5], [6]. COVID-mediated hyper-inflammatory response arises typically in the lungs, due to the difficulty of the immune system in eradicating the virus, as it happens in primary hemophagocytic lymphohistiocytosis [7]. Is it possible that older data from the pre-antibiotic era might be worth reviving, given the possibility that a local treatment may work for other types of pneumonia?

The authors minimize the past clinical observations published in well-respected peer-reviewed journals, focusing heavily on cautious interpretations by the authors rather than the data. By today’s standards, these papers are Level III evidence, the “weakest form of study design, but they may be the only available or practical information in support of a therapeutic strategy, especially in the case of rare diseases or when the evolution of the therapy predates the common use of randomized study designs in medical practice..” [8].

We agree with the authors that it is essential to conduct rigorous preclinical testing of low dose radiation therapy. We hope they agree that this research as a critical priority given the ongoing pandemic. Most preclinical data for pharmacologic strategies come from non-COVID-19 data. With old but relevant clinical data and research suggesting anti-inflammatory effects of radiation at very low doses that may affect key inflammatory cells involved in the hyper-inflammatory host response to COVID-19 [9], we do not agree that preclinical studies are require for radiation therapy and should be treated differently than the other therapies being tested.

The authors correctly raise concerns about cardiac disease and second malignancy as a late effect of radiation therapy. The very low doses (35–100 cGy) being considered for clinical trials fall in an unknown area for quantifying risk. Assuming whole body radiation exposure risks from atomic bombs or space exploration equate to risk from a single very low dose is a cognitive leap, particularly when the validity of the LNT hypothesis at very low doses is uncertain with modern techniques [10]. With thorough informed consent, it is a reasonable late risk for older patients balanced against a potential reduction in COVID-19 related morbidity or mortality within weeks. If we routinely offer many cancer patients treatment to lower recurrence rates without a survival benefit with a higher risk of late effects, it should be reasonable to offer to patients on protocol.