Whole-lung low-dose radiation therapy led to quicker recovery from COVID-19–related pneumonia in hospitalized and oxygen-dependent patients compared with matched controls treated with best supportive care and physician’s choice of anti–COVID-19 therapy, according to the results of a small trial.¹ All trial findings, including the effect on proinflammatory markers, favored the use of low-dose radiation therapy in hospitalized patients with severe pneumonia.

However, cautioned lead authors Clayton B. Hess, MD, MPH, and Mohammad K. Khan, MD, PhD, of Winship Cancer Institute at Emory University, Atlanta, this is only a preliminary signal. “Remember what happened with small trials of hydroxychloroquine,” Dr. Khan noted during the virtual edition of the 2020 American Society for Radiation Oncology (ASTRO) Annual Meeting.

Clayton B. Hess, MD, MPH

Mohammad K. Khan, MD, PhD

“Multiple phase I studies have shown that low-dose radiation therapy is safe as a treatment for serious COVID-19–related pneumonia. By focally dampening hyperactivation, low-dose radiation therapy may improve COVID-19 outcomes through immunomodulation. Our study was a single-arm, phase II trial to investigate the potential efficacy of low-dose radiation therapy for COVID-19–related pneumonia,” Dr. Hess explained.

At least 15 other prospective international and domestic trials are currently evaluating low-dose radiation therapy in this setting.

Study Details

A total of 50 patients were screened, and 13 met the eligibility requirements for trial enrollment. All patients were hospitalized, had COVID-19–related pneumonia, had radiographic consolidation, were on supplemental oxygen, and had not been treated with any COVID-19–directed drugs. “We enrolled only patients with severe COVID-19–related pneumonia, who were dependent on oxygen supplementation,” Dr. Hess stated.

Patients were treated with 1.5 Gy of whole-lung radiation therapy between April 24 and May 24, 2020, and followed for 28 days. The 10 patients on study were retroactively compared with 10 controls who were severely ill with COVID-19–related pneumonia and had been enrolled on separate prospective trials. Controls were blindly matched by age and comorbidity burden and required to meet the same disease severity criteria. Efficacy endpoints included the time to clinical recovery, radiographic improvement, and serologic biomarker response. The investigators also measured intubation rates, survival, hospital duration, oxygen duration, and time from admission to recovery.

“By focally dampening hyperactivation, low-dose radiation therapy may improve COVID-19 outcomes through immunomodulation.”

— Clayton B. Hess, MD

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The time to clinical recovery was defined similarly to the ACTT-1 trial, as the number of days between the first intervention and the first day where a patient experienced either hospital discharge or weaning off supplemental oxygen to room air. “We tightened the ACTT-1 trial’s initial definition of recovery to require 12 consecutive hours off oxygen,” Dr. Hess noted.

The time of intervention was defined for enrolled patients as the day low-dose radiation therapy was initiated; for matched controls, it was the first administration of COVID-9–directed drug or supportive care. Of 10 matched controls, 6 were treated with best supportive care plus COVID–directed drugs and 4, with best supportive care alone.

Study Findings

At baseline, the radiation cohort and controls had similar characteristics, with the exception of age and Glasgow Coma Scale (GCS) score. The radiation cohort had a mean age of 78 vs 75 for controls (P = .06). A severe GCS score was more prevalent in the radiation cohort, whereas a mild GCS score was more prevalent in matched controls at the time of intervention: 5 vs 1 and 5 vs 9, respectively.

At baseline, 70% of all patients had hypertension, 30% had diabetes, 25% had dementia, and 20% had pulmonary embolism or deep vein thrombosis. The median duration of symptoms prior to hospital admission was 6.5 days for both groups. There were no differences in blood gas levels between the groups. Anti-COVID therapy was started on day 4.5 in the radiation cohort and on day 2 in controls.

The time to clinical recovery was statistically superior in the low-dose radiation therapy cohort: median of 3 days vs 12 days for matched controls (P = .05). The time to hospital discharge was halved by low-dose radiation therapy: 12 days to 24 days for matched controls (numerically superior but not statistically significant).

Other Endpoints

Most other endpoints numerically favored low-dose radiation therapy but were not statistically significant. The rate of intubation following intervention was 10% following radiation compared with 40% in controls. The 28-day survival rate was 90% for both cohorts. The median duration of hospital stay was shortened by 10 days following low-dose radiation therapy (26 days to 16 days). The duration of total oxygen supplementation was 9 days with low-dose radiation therapy compared with 13 days for controls.

At hour 24, the median GCS score was 2.5 points higher in the low-dose radiation therapy cohort compared with controls (P < .01). The total clinical recovery time from admission was 10 days in low-dose radiation therapy cohort compared with 12 days in controls (not statistically significant).

The cohort average radiographic severity of acute respiratory distress syndrome (ARDS) trended downward in the group that received low-dose radiation therapy, whereas it fluctuated in controls. The proportion of patients with a radiographically improved ARDS scale score by day 21 was 90% compared with 57% in controls.

COVID-19–related laboratory markers rapidly improved in the cohort receiving low-dose radiation therapy compared with matched controls. Inflammatory markers, such as C-reactive protein and lactate dehydrogenase, fell more rapidly in patients given low-dose radiation therapy. Ferritin levels and erythrocyte sedimentation rate trended downward more quickly after low-dose radiation therapy.

Creatinine kinase levels significantly improved after low-dose radiation therapy, whereas troponin levels stayed low after low-dose radiation therapy and increased in controls. The same pattern was observed with hepatic, and certain clotting, and immune markers, all favoring low-dose radiation therapy for a beneficial effect.

“Low-dose radiation therapy for COVID-19–related pneumonia appears safe and may be an effective immunomodulatory treatment. Confirmatory trials are needed.”

— Clayton B. Hess, MD

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“A cohort of hospitalized patients with COVID-19–related pneumonia treated with low-dose radiation therapy had faster recovery than age- and comorbidity-matched controls who received best supportive care alone or with COVID drug therapies. Low-dose radiation therapy may hasten recovery and discharge, prevent intubation, improve delirium, radiographs, and multiple categories of disease markers with no acute toxicity. Low-dose radiation therapy for COVID-19–related pneumonia appears safe and may be an effective immunomodulatory treatment. Confirmatory trials are needed,” Dr. Hess told the audience.

A total of 20 additional hospitalized patients with COVID-19–­related pneumonia have been treated with low-dose radiation therapy plus steroids and remdesivir at Emory. Analysis of these patients is ongoing. A phase III randomized trial has started accrual to compare low-dose radiation therapy vs physician’s choice of COVID-19 therapy in hospitalized patients with COVID-19–related pneumonia.

Of note, “no study-related staff has contracted COVID-19 during this study,” Dr. Hess said. 

DISCLOSURE: Dr. Hess and Dr. Khan reported filing a provisional patent and cofounding CureRays Inc.

REFERENCE

1. Hess CB, Buchwald ZD, Stokes WA, et al: Immunomodulatory low-dose whole-lung radiation for patients with COVID-19-related pneumonia. 2020 ASTRO Annual Meeting. Abstract LBA8. Presented October 27, 2020.