Dr. Fauci Briefs Radiation Oncologists on Impact of COVID-19

x-ray; radiology: x-ray; radiologyThe current epidemic of COVID-19 in the United States will get worse before it gets better, Anthony Fauci, MD, Director of the National Institute of Allergy and Infectious Diseases, told a special session of the ASTRO 2020 Annual Meeting. He gave an overview of infectiousness of COVID-19, and presented the latest facts and figures on the virus and its impact on cancer patients and radiologists responsible for treating them. Reiterating that the damage from COVID-19 is much worse than the common cold, Fauci said fewer patients have been visiting hospitals for non-COVID medical emergencies, and this reluctance to visit medical establishments may have “devastating” future consequences, as peer-reviewed publications have estimated approximately 10,000 excess deaths from breast and colorectal cancers in the near term. He also discussed the uncertainty surrounding aerosol transmission of the virus, but that bars, gyms, coffee shops, indoor restaurants, and religious gatherings remain risky locations for spreader events. In addition, racial disparities in COVID-19 outcomes are particularly troubling, Fauci noted. He assured attendees that panels of experts are meeting regularly to develop treatment guidelines and that, to date, there are several promising treatments including remdesivir, dexamethasone, and three promising families of vaccines in trials. His presentation ended with contact information for preventcovid.org, a site where individuals can express interest in joining clinical trials. COVID-19 Pneumonia Mohammad K. Khan, MD, PhD, DABR, FACRO, Associate Professor of Radiation Oncology at Emory University's Winship Cancer Institute, presented findings from a clinical trial that found low-dose radiation can significantly help reduce hospital stays and the number of days requiring supplemental oxygen, as well as other benefits for patients, all of which are especially important during the current pandemic. Last June, the first results of low-dose radiation therapy (LD-RT) for COVID-19 pneumonia were made publicly available by researchers at Emory. Another study, from Iran, examined five COVID-19 patients who were hospitalized and receiving supplementary oxygen for pneumonia. All were treated with a single fraction of 0.5 Gy whole-lung irradiation. Both trials had encouraging results, with 80 percent response rates. Since then, other similar trials of low-dose radiotherapy have started in the U.S. and elsewhere. “This research has sparked a lively debate in the field,” said ASTRO President Laura Dawson, MD, FRCPC, FASTRO, Professor of Radiation Oncology at the University of Toronto, who moderated a panel session at ASTRO on how RT practice might be changing as a result of the current crisis. “Results from published trials show the potential of LD-RT, but not a definite benefit, as these small studies have not been randomized. Also, the potential for adverse long-term effects of this approach cannot be forgotten.” Khan, from Winship Cancer Institute, presented results from the RESCUE-1-19 clinical trial. “RESCUE-1-19 was based on the hypothesis that LD-RT may help eliminate storming cytokines and unchecked edema in hospitalized COVID-19 patients,” he explained. “This was the first LD-RT trial in the world.” The trial examined COVID-19 patients who were hospitalized and required supplemental oxygen and was comprised of two phases. In Phase I, the team treated five patients with 1.5 Gy whole-lung LD-RT, with a pre-planned day-7 interim safety analysis. By day 7, four of these patients exhibited significant clinical improvements and overall survival was 100 percent. The time to clinical recovery (no longer needing oxygen or being discharged from hospital) was 1.5 days, suggesting a possible benefit of LD-RT without significant toxicity. Following this finding, the team obtained approval to treat five more patients as part of a Phase II trial to assess the efficacy of LD-RT. These 10 patients' outcomes were compared against 10 other patients who were age and comorbidity matched. At day 28, the median time to clinical recovery was 3 days in the LD-RT group versus 12 days in the control group. Patients also left the hospital earlier (12 days vs. 20 days) and had lower intubation rates (10% vs. 40%) compared with the controls. “LD-RT seems to suggest a statistically significant improvement in time to clinical recovery, at least in this cohort,” noted Khan. Ultra-Low-Dose Radiation Arnab Chakravarti, MD, who is leading two ongoing trials examining ultra-low-dose thoracic radiation for COVID-19 patients at Ohio State University Comprehensive Cancer Center, presented findings demonstrating the effectiveness of ultra-low-dose whole lung radiation in critically ill patients with COVID-19 pneumonia. All patients in the study had been mechanically ventilated and were treated with at least one dose of 80 cGy to whole thorax bilaterally, with the option for a second dose. “Our hypothesis here is that low-dose thoracic radiation will decrease inflammation and improve outcomes for these intubated COVID-19 patients,” said Chakravarti. The trial's primary objective is to evaluate the 30-day mortality rate after whole-lung LD-RT. The secondary objectives are primarily to assess the feasibility, safety, and tolerability of this approach. The second study is a multisite trial called PREVENT, which includes hospitalized COVID-19 patients who have severe respiratory compromise but are not yet intubated. The trial is currently running at several U.S. institutions with more sites scheduled to join shortly, including sites in other countries. Step one involves patients randomized to receive either 35 cGy LD-RT, 100 cGy LD-RT, or standard-of-care treatment. After interim dose selection, step two will compare patients treated with the preferred dose against the control group. The primary objectives are to determine which dose level is most efficacious and whether LD-RT at this dose is of clinical benefit. Secondary objectives include assessing the cost of care and patients' quality-of-life. “The ultimate question, to which we remain agnostic as a study team, is whether the potential benefits of LD-RT outweigh the risks,” emphasized Chakravarti. He noted that, prior to launching these trials, the team had heard of institutions globally who were looking to treat patients using this LD-RT regimen off-protocol. “That drew a lot of concern from our study community and that was the rationale behind launching these two studies,” he explained. Severe Pulmonary Inflammation LD-RT might also prove useful in clinically managing severe pulmonary inflammation from COVID-19, said Ramesh Rengan, MD, PhD, of the University of Washington School of Medicine. “The question that we are wrestling with, with these studies, is whether or not LD-RT may have some value in short-term clinical management of the severe pulmonary inflammation rendered in patients due to COVID-19,” he said. In COVID-19, the viral infection triggers an inflammatory cascade—the cytokine storm—that overwhelms the lungs and can lead to respiratory failure, he explained. Currently, the only way to stop this is by using corticosteroids. But as inflammatory cells are highly sensitive to radiation, and LD-RT has historically been used to effectively treat inflammatory diseases, could LD-RT be used instead to suppress inflammation specifically within the lung? he wondered. Representing the National Cancer Institute, Deborah Citrin, MD, a senior investigator in the Radiation Oncology Branch, also discussed the potential benefits and concerns of treating COVID-19 patients using LD-RT. “Low-dose radiation can have not just killing effects on these immune cells, but can change the way that some cells function,” she said, noting that it can reduce the oxidative burst produced by macrophages that can damage lung tissue, as well as stopping the growth of fibrocytes, the cells that make scar tissue and leads to lung fibrosis. However, she also said this is new territory and must be approached with caution, for example long-term, downstream secondary inflammation. “One of biggest concerns is the risk of long-term toxicity,” Citrin noted. “In patients who are extremely ill, we have to balance the risk of injury or death from the virus, but we also need to consider the risk of long-term damage to the heart or lungs. We know that even at 1 Gy, there is a risk of cancer or cardiac damage.” Kurt Samson is a contributing writer.

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