key: cord-0861434-6nxy2yqz
authors: Kirsch, David G.
title: Radiation Therapy as a Treatment for COVID-19?
date: 2020-07-23
journal: Int J Radiat Oncol Biol Phys
DOI: 10.1016/j.ijrobp.2020.07.025
sha: 15d27c9c185a1fefd05738195997369a96620035
doc_id: 861434
cord_uid: 6nxy2yqz

nan

In this issue of the Red Journal, Ameri and colleagues report the interim results of 5 patients with COVID-19 treated on a clinical trial in Teheran, Iran with 0.5 Gy single-fraction whole lung radiation therapy 1 . The patients (age 60-84) enrolled with oxygen saturation ranging from 74% to 89% and received radiation therapy at a median of 2 days after admission. One patient died, one patient withdrew consent 3 days after radiation therapy, and the other 3 patients were followed to discharge 5 to 7 days after radiation therapy. The patient discharged 7 days after radiation therapy still required oxygen supplementation at home. The authors report that 4 patients showed signs of clinical recovery as defined by changes in oxygen saturation and temperature within one day after radiation therapy. However, the average absolute improvement in oxygen saturation one day after radiation therapy appears to be only 3% across these 4 patients, and only 2 of the 4 patients had a baseline temperature greater than 37.7 0 C. This is the first published, peerreviewed prospective study of patients with COVID-19 pneumonia treated with radiation therapy. These results should be considered in the context of contemporary outcomes for hospitalized COVID-19 patients that require oxygen support, anticipated future developments in the management of symptomatic COVID-19, and within the historical studies of radiotherapy for pneumonia.

COVID-19 is caused by the recently discovered SARS-CoV-2 coronavirus. Standard of care for COVID-19 is rapidly evolving and is being defined by rigorous, well-powered randomized controlled clinical trials. For example, in a randomized trial of the antiviral agent remdesivir or placebo that included 421 COVID-19 patients receiving oxygen but no ventilation, 50% of these patients recovered within 6 to 9 days with a recovery rate ratio of 1.47 (95% confidence interval 1.17-1.84) favoring the remdesivir arm 2 . In the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, which is a platform trial in the United Kingdom comparing several different treatments, the preliminary results of the comparison of dexamethasone versus usual care have been posted to a pre-print server prior to peer review 3 . In 3,383 patients receiving oxygen without mechanical ventilation, dexamethasone reduced deaths from 25% to 21.5% (RR 0.80, 95% CI 0.70 to 0.92). These clinical trials not only established dexamethasone and remdesivir as effective treatments for hospitalized COVID-19 patients requiring oxygen, but they also provide a framework for evaluating short-term outcomes of radiotherapy to the lungs as a treatment for COVID-19 pneumonia in patients with decreased oxygen saturation. Patients in the clinical trial from Tehran were treated according to national guidelines 4 , but did not receive steroids or remdesivir. From the perspective of the results of the large, prospective clinical trials of remdesivir and dexamethasone, survival to discharge in 3 out of 4 evaluable patients with a mean time to discharge of 6 days 1 appears to be within the expected range for COVID-19 patients requiring oxygen in the absence of radiotherapy. This trial tested whether plasma with neutralizing antibodies to SARS-CoV-2 from survivors of COVID-19 improved outcome for patients hospitalized with COVID-19. This study was terminated early because COVID-19 infection was successfully controlled in Wuhan and therefore the study was underpowered. However, patients randomized to receive convalescent plasma showed a trend to decreased mortality: 15.7% vs. 24% (P=0.3). Among 55 patients with severe disease that did not require mechanical ventilation, which was defined as tachypnea (respiratory rate >30 breaths/min) or hypoxia (oxygen saturation <93% on room air or arterial partial pressure of oxygen/fraction of inspired oxygen <300), mortality was 0% in the patients randomized to convalescent plasma vs. 9.1% in the control arm (P=NS). Although larger clinical trials of convalescent plasma are needed to definitively test this therapy, these results suggest that neutralizing antibodies are a promising approach for treating hypoxic patients with COVID-

Clinical trials are currently testing neutralizing monoclonal antibody cocktails to determine if they can provide passive immunity to patients with symptomatic COVID-19 7 . If these clinical trials are successful, because of enhanced safety and the ability to scale up production, monoclonal antibody cocktails would likely supplant convalescent plasma as a treatment for hospitalized COVID-19 patients on supplemental oxygen. Our cancer patients routinely receive monoclonal antibodies, such as trastuzumab, rituximab, or pembrolizumab. There are already several monoclonal antibodies approved by the FDA to treat infectious diseases, such as respiratory syncytial virus, anthrax, and Clostridioides difficile 7 . Therefore, in the future it is conceivable that hypoxic COVID-19 patients will be infused with highly effective neutralizing antibodies when they are admitted to the hospital. In this scenario, it is unlikely that 0.5 Gy whole lung radiation therapy with its risks of carcinogenesis and circulatory disease 8,9 would become a major part of the anti-COVID-19 armamentarium.

The clinical trial from Amiri and colleagues builds on historical data where radiation therapy was used to treat pneumonia. The initial report of using thoracic radiotherapy to treat pneumonia was published in 1905 by Musser and Edsall at the University of Pennsylvania in Philadelphia 10 . One patient with unresolved pneumonia reportedly derived benefit from 4 daily doses of X-rays.

Musser and Edsall stated that "one case proves nothing, but this result is sufficiently suggestive to encourage further trial in other cases of unresolved pneumonia." Indeed, Edsell and Pemberton published a follow-up paper claiming that X-ray therapy improved the outcome of two additional patients with pneumonia 11 . When the devastating outbreak of H1N1 influenza occurred in 1918 causing approximately 20,000 deaths in Philadelphia, the medical system was overwhelmed and many patients with respiratory distress were not able to receive supplemental oxygen 12 . Just as some radiation oncologists today are conducting clinical trials of radiotherapy for COVID-19 pneumonia, it is interesting to speculate whether these early pioneers in Philadelphia also used X-rays to treat patients suffering from pneumonia during the influenza pandemic. There are no reports of X-rays being used to treat patients in respiratory distress during the 1918 pandemic. As data accumulates from clinical trials of radiotherapy for COVID-19, it will be important to not only publish the short-term outcome of survival from COVID-19 as reported here by Ameri and colleagues, but also to follow survivors over the years ahead and report any late effects, such as lung cancer and cardiovascular events 8, 9 . As we face the urgent challenge to devise novel treatments for COVID-19, we are fortunate to be able to rely on an exceptional foundation of science built up over the past century since the 1918 influenza pandemic. With currently available antivirals and steroids, the likelihood of effective monoclonal antibodies for SARS-CoV-2 in the not too distant future, the potential for effective vaccines, and given the risks of late effects from whole lung irradiation 8, 9 , it is unlikely that radiation therapy will be used outside of clinical trials to treat COVID-19.

Low-dose Whole-lung Irradiation for COVID-19 Pneumonia: Short Course Results

for the ACTT-1 Study Members. Remdesivir for the Treatment of Covid-19 -Preliminary Report

COVID-19 in Iran, a comprehensive investigation from exposure to treatment outcomes

These Scientists Raced to Find a Covid-19 Drug. Then the Virus Found Them

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial

Monoclonal Antibodies for Prevention and Treatment of COVID-19

Lack of supporting data make the risks of a clinical trial of radiation therapy as a treatment for COVID-19 pneumonia unacceptable

Low dose radiation therapy for COVID-19 pneumonia: is there any supportive evidence?

A study of metabolism in leukaemia, under the influence of the xray

The use of the x-rays in unresolved pneumonia

Influenza in 1918: recollections of the epidemic in Philadelphia