ABSTRACT
Purpose/Objective(s): Low-dose radiotherapy (LD-RT) is a well-established treatment for multiple human inflammatory conditions. Whole-lung LD-RT may be effective in COVID-19-related pneumonia. Materials/Methods: Patients hospitalized with COVID-19-related pneumonia receiving supportive care, glucocorticosteroids, and/or remdesivir were administered LD-RT treatment of 0.5 or 1.5 Gy to the bilateral lungs on a prospective, combined phase I/II, multi-site, single-institution trial. Patients were followed for 28 days or until discharge and compared to controls blindly matched by age, comorbidity, duration of symptoms, and disease severity. Eligible patients were confirmed by SARS-CoV-2 positive PCR, unable to wean from oxygen at enrollment, and had radiographic consolidations. Patients were enrolled into 5 cohorts stratified by treatment variables and severity of illness: LD-RT alone vs. LD-RT with concurrent drug therapies, non-intubated vs. intubated status, and low (1.5 Gy) vs. lower (0.5 Gy) radiation dose. Qualitative aims were to establish safety and explore efficacy. Quantitative endpoints were continuous, categorical, and time-to-event, and included clinical recovery, intubation, radiographic changes, and biomarker responses. Intubation endpoints are reported for all cohorts using the log-rank test and Kaplan-Meier method. Results: Outcomes of 80 patients were available for analysis at study closure. In total, 40 of 70 planned patients (57% trial enrollment) received whole-lung LD-RT between April 24 and December 7, 2020 and were compared to 40 matched controls. Cohorts 1&2: Ten non-intubated patients received 1.5 Gy without concurrent COVID-directed drug therapies (10 of 10 planned, 100% cohort enrollment) and were compared to matched controls. Intubation rates were 40% in controls compared to 10% following LD-RT (P = 0.11). Cohort 3: One intubated patient received 1.5 Gy (1 of 20 planned, 5% cohort enrollment). Cohort 4: Twenty separate non-intubated patients received 1.5 Gy with concurrent dexamethasone/remdesivir (20 of 20 planned, 100% cohort enrollment) and were compared to matched controls. Intubation rates were 32% in controls compared to 14% following LD-RT (P = 0.09). Cohort 5: Nine patients received 0.5 Gy with concurrent drug therapies (9 of 20 planned, 45% cohort enrollment) and were compared to matched controls. Zero controls required intubation compared to 11% following LD-RT (P = 0.32). Among all non-intubated patients and matched controls combined (n = 78), mechanical ventilation was required in 28% of controls compared to 12% following LD-RT (reduced 57%, P = 0.05). The trial was prematurely closed due to observed reproducibility of efficacy. A randomized trial is now ongoing. Conclusion: In the first, prospective, phase I/II trial of radiotherapy for COVID-19-related pneumonia, a single treatment of whole-lung LD-RT reduced intubation rates by 57% compared to controls in patients receiving supportive care with or without drug therapies (P = 0.05).
ABSTRACT
Low-Dose Radiation Therapy (LD-RT) is an emerging treatment option for patients with COVID-19 related pneumonia. Infectivity of the SARS-CoV-2 virus complicates incorporation of LD-RT into existing radiation oncology clinics. The first phase I/II trial of LD-RT for COVID-19-related pneumonia implemented novel operational protocols to address risk of infection and respiratory events. Patients were transported from hospital rooms to linear accelerators and treated with 0.5 Gy or 1.5 Gy using pre-planned, two-dimensional treatments prepared using diagnostic x-rays and caliper measurements. Workflows were revised over time to balance infection risks with implementation burden. Between April 24 and December 7, 2020, fifty-two patients were enrolled and forty were treated. The end-to-end process comprised 16 distinct teams and > 120 cooperating staff members (> 50 core radiation oncology staff). The trial was operationalized at two hospitals at the onset of the COVID-19 pandemic, prior to vaccine availability. Teams included trial leadership/screening (n > 4), inpatient floor staff (n > 10), clinical trials staff and coordinators (n = 8), transport (n = 2), radiation therapists (n > 20), respiratory therapists (n = 5), radiation nursing (n > 7), ICU nursing (n = 4), rapid response teams (n = 4), medical physics (n > 4), dosimetry (n > 3), infection prevention (n > 3), environmental services (n > 6), security (n = 7), lab personnel (n = 1), and physicians from radiation oncology (n = 7), infectious diseases (n = 2), pulmonary/critical care medicine (n = 2), anesthesia (n = 2), and internal medicine (n > 20) [total > 120]. All non-intubated patients were transported by a multi-disciplinary team, consisting of a physician, nurse, transporter, infection prevention specialist, and (when needed) a respiratory therapist. Treatments occurred after normal clinic hours, were initiated by team huddles, check lists, and included personal protective equipment supervision at multiple time points. Transport routes were 880 to 1760 feet (0.33 miles) one-way, with 1 to 3 elevator banks and required 20-35 minutes for round-trip transport and treatment. Oxygen supplementation in non-intubated patients ranged from 2 to 15 L/min. One intubated patient was transported with a portable ventilator and accompanying ICU staff. There were no code-level events during transport. No patient-facing staff contracted COVID-19 from trial activities. Workflow burden was successfully reduced and protocols relaxed over time with increased staff experience. Whole-lung low-dose radiation therapy (LD-RT) for COVID-19-related pneumonia was successfully incorporated into existing workflows at a major academic university. Forty patients were treated with no code-level events, and no staff contracted the virus during eight months of trial accrual. Instructional materials and implementation check lists are provided. [ABSTRACT FROM AUTHOR] Copyright of International Journal of Radiation Oncology, Biology, Physics is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
ABSTRACT
Introduction: Individuals with advanced age and comorbidities face risk of death from COVID-19, especially onceventilator-dependent, precipitated by an immune cytokine storm in the lungs. Lymphocytes, a mediator of cytokinestorms, are exquisitely sensitive to ionizing radiation. Low doses of radiation therapy (LD-RT) were used to treatinfectious processes during the first half of the 20th century, including pneumonia. It is conceivable that focalimmunosuppression with LD-RT may reduce pulmonary inflammation associated with COVID-19 pneumonia. Methods: The Radiation Eliminates Storming Cytokines and Unchecked Edema as a 1-day Treatment for COVID-19 (RESCUE 1-19) trial explores safety and efficacy of single-fraction, low-dose, whole-lung radiation forhospitalized, oxygen-dependent patients with COVID-19 pneumonia (Clinical Trial NCT04366791 ). Patients had tobe hospitalized with a positive COVID-19 nasopharyngeal swab, have radiographic pneumonic consolidations, require oxygen supplementation, and be clinically deteriorating (i.e., mentation, oxygenation, dyspnea). Patientsreceived a single-fraction dose of 1.5 Gy to the bilateral lungs. The primary endpoint was safety, measured by apreplanned stopping rule. We utilized an established clinical scale to define clinical recovery, the Glasgow ComaScale (GCS), an established radiographic ARDS scale, and 27 serologic biomarkers. Results: Between April 23-28, 2020, nine candidates were evaluated. Of these, one died before enrollment, one didnot meet severity criteria, and seven enrolled. Of these, two were intubated before LD-RT (one died), and fivereceived LD-RT. Median age was 90 (range 64-94). Four had been admitted from nursing homes with COVID-19outbreaks. Comorbidity burden was high. Four were African American and one was Caucasian. Four were female.Median oxygen requirement at the time of LD-RT was 3 L/min (range 1.5-6). Median duration of prehospitalizationsymptoms was 4 days (range 1-7). LD-RT was delivered on median hospital day 5 (range 2-8). Three patientsreceived azithromycin prior to enrollment. During a 14-day observation period, no patients experienced acutetoxicity. Four patients (80%) clinically recovered, 3 within 24 hours, without evidence of COVID symptomexacerbation. Mean time to recovery was 35 hours. Median GCS rose from 10 (range 9-15) to 14 (range 13-15) athour 24. Serial x-rays showed improved or stable disease in 4/5 patients. At day 7, 4/5 patients had 85-92% of allbiomarkers either improve or remain normal. At day 14, all patients were alive, 3 had returned to their nursinghomes (mean time to discharge 12 days), and a 4th was pending discharge. Conclusion: Five hospitalized, oxygen-dependent, and clinically deteriorating patients received low-dose, whole-lung radiation and experienced no acute toxicities. 80% returned to room air at a median time of 1.5 days. Noworsening of the cytokine storm was observed in 4 of 5 patients. Low-dose lung radiation appears safe and meritsfurther evaluation.