LOW DOSE RT FOR SEVERE COVID?

The first study to suggest benefit from low-dose radiotherapy for severe COVID-19–induced pneumonia involved only 10 patients with this condition, but the results were so promising that two larger randomized trials are now underway.

"RESCUE-119 was a trial based on the hypothesis that low-dose radiation therapy may help eliminate the stormy cytokine release and unchecked edema in hospitalized COVID-19 patients," said Mohammed Khan, MD, PhD, Winship Cancer Institute of Emory University, Atlanta, Georgia.

"We found patients had a quicker improvement in their time to clinical recovery with low-dose radiation therapy compared to controls, and this was significant even in this small cohort of patients," he said.

Khan was speaking at a special press briefing held during the virtual American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting.

A total of 20 patients were involved in the trial. Ten patients were treated with low-dose radiotherapy; 10 others, who served as control patients, were treated with the best supportive care and COVID-directed therapies. The control patients were matched for age and comorbidities. All these patients were hospitalized and were oxygen dependent, Khan noted. In addition, for all patients, serial x-rays demonstrated consolidation and damage in the lung.

The intervention consisted of whole-lung low-dose radiotherapy delivered at a dose of 1.5 Gy.

The first five patients were assessed at an interim endpoint of 7 days to confirm the safety of the procedure. Subsequently, a total of 10 patients were treated with radiotherapy and were followed to day 28.

The main study endpoints were time to clinical recovery, determined on the basis of the patient's being taken off oxygen; and improvement, evidenced on either serial x-rays or by inflammatory biomarkers.

The median time to clinical recovery was almost three times faster for the patients who received low-dose radiotherapy, at a median of 3 days; for control patients, the median was 12 days (P = .048).

"We also saw a trend towards getting patients out of hospital sooner," Khan added. The mean time to hospital discharge was 12 days for the patients who received low-dose radiotherapy, compared with 20 days for control patients (P = .19).

Only one patient required intubation after receiving low-dose radiotherapy, whereas 4 of 10 control patients required some sort of intubation (P = .12), he noted.

Investigators also saw improvements on serial x-rays in 9 of 10 patients treated with low-dose radiotherapy, compared with only four patients in the control group. There was also a significant improvement in delirium among the low-dose radiotherapy group compared with control patients (P < .01). Before receiving low-dose radiotherapy, C-reactive protein (CRP) levels increased by 22% per day. After receiving the 1.5-Gy radiation treatment, there was a sharp reduction in CRP levels (P < .01). (CRP), as well as in lactate dehydrogenase levels (P = .03).

Overall survival, however, did not differ between the two treatment groups; 90% of both groups were alive at day 28.

"By focally dampening cytokine hyperactivation, LD-RT [low-dose radiotherapy] may improve COVID-19 outcomes through immunomodulation," Khan explained.

VENTED and PRE-VENT Trials

These results from the small RESCUE-119 trial led to the launch of two larger phase 2 trials, the VENTED and the PRE-VENT trials, noted Arnab Chakravarti, MD, professor and chair of radiation oncology, the Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

To be enrolled in the VENTED trial, patients will have had to have received mechanical ventilation. They will receive at least one dose of ultra-low-dose bilateral whole-lung radiotherapy, with the option of receiving a second dose. The primary objective is 30-day mortality rate. "The hypothesis is that low-dose thoracic radiation will decrease inflammation and improve outcomes for these intubated COVID-19 patients," Chakravarti explained.

The PRE-VENT trial will explore low-dose thoracic radiotherapy for hospitalized patients with severe respiratory compromise who have not yet been intubated. Two doses of low-dose radiotherapy will be tested and compared. The primary study objective is to determine which of the two doses appears to be the most efficacious, Chakravarti noted.

"The ultimate question to which we remain agnostic is whether the potential benefits of low-dose radiation therapy outweigh the risks," he said.

Low-dose radiotherapy is readily available in most countries, unlike the newly developed COVID-19 drugs, which are only available in the developed world, he noted.

"This creates a bit more economic equity in terms of COVID-19 treatment," he commented.

In addition, it may offer a therapeutic option that could be useful in the future, "as low-dose radiation therapy does not discriminate against various viruses that may cause another pandemic," he commented. It could offer "a stopgap measure where we don't have to shut down society completely, which, as we have all witnessed, can cause tremendous financial and social unrest."

Reasonable Question

Whether or not radiotherapy has value for the short-term management of severe pulmonary inflammation caused by COVID-19 is a reasonable question to evaluate in clinical trials, commented discussant Ramesh Rengan, MD, PhD, professor and chair, Department of Radiation Oncology, University of Washington School of Medicine, Seattle.

He noted that inflammatory cells are highly sensitive to radiation, and low-dose radiotherapy has been used effectively in other inflammatory conditions, such as arthritis. Indeed, before the discovery of antibiotics, low-dose radiation was used with reasonable efficacy to treat pneumonia.

"The pneumonia associated with this viral infection is a bit unique in that what happens is the infection triggers an inflammatory cascade — the so-called cytokine storm — that essentially overwhelms the lungs, thereby leading, unfortunately, to mortality," Rengan noted. "So a big focus of our energy is how to stop this inflammatory cascade from occurring," he said.

Corticosteroids are currently the only therapeutic intervention that has shown any mortality benefit in COVID-19, he pointed out.

The question now being asked is, "can we suppress inflammation specifically within the lung?" Rengan continued. The main problem with radiotherapy is that it has different effects on various tissues, both immediately and over the long term.

"The immediate benefit that we will likely see from these studies is the immediate sterilization of inflammatory cells," he said. However, injury to normal lung tissue from low-dose radiotherapy could lead to inflammation weeks or months later, and this could contribute to the disease burden and increase the risk of dying.

Rengan also noted that there are some very real practical concerns about offering radiotherapy to COVID-19 patients, including potential COVID-19 transmission to vulnerable cancer patients.

Nevertheless, Rengan felt that the results to date are very important and that ongoing trials will provide important new information about the long-term impact of this particular treatment in high-risk patients.

"This is a race to the bottom — we are trying to find the lowest possible dose of radiation therapy that we can deliver to sterilize these inflammatory cells without creating any harm to the surrounding tissue," he said.

"It also brings radiation oncologists into the fight against this deadly disease," he added.

Rengan has received honoraria from Novocur and has served as a consultant to AstraZeneca.

American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting: Abstract LBA 8. Presented October 27, 2020.

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