Dataset Information

Low-dose whole-lung radiation for COVID-19 pneumonia: Planned day 7 interim analysis of a registered clinical trial.

ABSTRACT:

Background

Individuals of advanced age with comorbidities face a higher risk of death from coronavirus disease 2019 (COVID-19), especially once they are ventilator-dependent. Respiratory decline in patients with COVID-19 is precipitated by a lung-mediated aberrant immune cytokine storm. Low-dose lung radiation was used to treat pneumonia in the pre-antibiotic era. Radiation immunomodulatory effects may improve outcomes for select patients with COVID-19.

Methods

A single-institution trial evaluating the safety and efficacy of single-fraction, low-dose whole-lung radiation for patients with COVID-19 pneumonia is being performed for the first time. This report describes outcomes of a planned day 7 interim analysis. Eligible patients were hospitalized, had radiographic consolidation, required supplemental oxygen, and were clinically deteriorating.

Results

Of 9 patients screened, 5 were treated with whole-lung radiation on April 24 until April 28 2020, and they were followed for a minimum of 7 days. The median age was 90 years (range, 64-94 years), and 4 were nursing home residents with multiple comorbidities. Within 24 hours of radiation, 3 patients (60%) were weaned from supplemental oxygen to ambient air, 4 (80%) exhibited radiographic improvement, and the median Glasgow Coma Scale score improved from 10 to 14. A fourth patient (80% overall recovery) was weaned from oxygen at hour 96. The mean time to clinical recovery was 35 hours. There were no acute toxicities.

Conclusions

In a pilot trial of 5 oxygen-dependent elderly patients with COVID-19 pneumonia, low-dose whole-lung radiation led to rapid improvements in clinical status, encephalopathy, and radiographic consolidation without acute toxicity. Low-dose whole-lung radiation appears to be safe, shows early promise of efficacy, and warrants further study.

Lay summary

Researchers at Emory University report preliminary safety outcomes for patients treated with low-dose lung irradiation for coronavirus disease 2019 (COVID-19) pneumonia. Five residents of nursing or group homes were hospitalized after testing positive for COVID-19. Each had pneumonia visible on a chest x-ray, required supplemental oxygen, and experienced a clinical decline in mental status or in work of breathing or a prolonged or escalating supplemental oxygen requirement. A single treatment of low-dose (1.5-Gy) radiation to both lungs was delivered over the course of 10 to 15 minutes. There was no acute toxicity attributable to radiation therapy. Within 24 hours, 4 patients had rapidly improved breathing, and they recovered to room air at an average of 1.5 days (range, 3-96 hours). Three were discharged at a mean time of 12 days, and 1 was preparing for discharge. Blood tests and repeat imaging confirm that low-dose whole-lung radiation treatment appears safe for COVID-19 pneumonia. Further trials are warranted.

SUBMITTER: Hess CB

PROVIDER: S-EPMC7748390 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Low-dose whole-lung radiation for COVID-19 pneumonia: Planned day 7 interim analysis of a registered clinical trial.

Hess Clayton B CB Buchwald Zachary S ZS Stokes William W Nasti Tahseen H TH Switchenko Jeffrey M JM Weinberg Brent D BD Steinberg James P JP Godette Karen D KD Murphy David D Ahmed Rafi R Curran Walter J WJ Khan Mohammad K MK

Cancer 20200928 23

<h4>Background</h4>Individuals of advanced age with comorbidities face a higher risk of death from coronavirus disease 2019 (COVID-19), especially once they are ventilator-dependent. Respiratory decline in patients with COVID-19 is precipitated by a lung-mediated aberrant immune cytokine storm. Low-dose lung radiation was used to treat pneumonia in the pre-antibiotic era. Radiation immunomodulatory effects may improve outcomes for select patients with COVID-19.<h4>Methods</h4>A single-institutio ...[more]

PMID: 32986274

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Project description:PurposePhase 1 clinical trials have established low-dose, whole-lung radiation therapy (LD-RT) as safe for patients with coronavirus disease 2019 (COVID-19)-related pneumonia. By focally dampening cytokine hyperactivation, LD-RT may improve disease outcomes through immunomodulation.Methods and materialsPatients with COVID-19-related pneumonia were treated with 1.5 Gy whole-lung LD-RT, followed for 28 days or until hospital discharge, and compared with age- and comorbidity-matched controls meeting identical disease severity criteria. Eligible patients were hospitalized, severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) positive, had radiographic consolidations, and required supplemental oxygen but had not rapidly declined on admission or before drug therapy or LD-RT. Efficacy endpoints were time to clinical recovery, radiographic improvement, and biomarker response.ResultsTen patients received whole-lung LD-RT between April 24 and May 24, 2020 and were compared with 10 control patients blindly matched by age and comorbidity. Six controls received COVID-19 drug therapies. Median time to clinical recovery was 12 days in the control cohort compared with 3 days in the LD-RT cohort (hazard ratio 2.9, P = .05). Median time to hospital discharge (20 vs 12 days, P = .19) and intubation rates (40% vs 10%, P = .12) in the control and LD-RT cohorts were compared. Median time from admission to recovery was 10 versus 13 days (P = .13). Hospital duration average was 19 versus 22.6 days (P = .53). Average hospital days on supplemental oxygen of any duration was 13.1 versus 14.7 days (P = .69). Average days with a documented fever was 1 versus 4.3 days (P = .12). Twenty-eight-day overall survival was 90% for both cohorts. The LD-RT cohort trended toward superior rates of improved radiographs (P = .12) and delirium (P < .01). Statistically significant reductions were observed in numerous hematologic, cardiac, hepatic, and inflammatory markers.ConclusionsA prospective cohort of predominantly elderly hospitalized patients with COVID-19-related pneumonia were recovered to room air quicker than age- and comorbidity-matched controls, with trending or significant improvements in delirium, radiographs, and biomarkers, and no significant acute toxicity. Low-dose, whole-lung radiation for patients with COVID-19-related pneumonia appears safe and may be an effective immunomodulatory treatment. Larger prospective randomized trials are needed to define the efficacy of LD-RT for COVID-19.

Project description:Purpose/Objective(s) The mortality of the SARS-CoV-2 virus (COVID-19) has been associated with a pulmonary inflammatory response resulting in hypoxemia and rapid clinical decline. Recent work has indicated a potential therapeutic window for treatment to prevent ventilator-dependence thereby reducing mortality. PREVENT is an ongoing prospective multicenter Phase II randomized controlled trial where patients hospitalized with COVID-19 pneumonia are randomized to ultra-low dose radiation therapy (RT) versus control. This study is registered at clinicaltrials.gov, NCT04466683. The following is a description of the inpatient onboarding process of the center contributing the largest number of patients to this trial. Materials/Methods COVID-19 hospital admissions from the previous day were attained by the clinical research manager each morning, screened for eligibility, and then sent to the designated radiation oncologist who further delineated from this list. Common exclusion criteria were: 1. Oxygen saturation > 96% on room air, 2. Age < 50, 3. > 9 days from initial COVID-19 symptomatology. From this list, HIPAA-compliant text message contact was made with infectious disease, critical care, and nursing staff with reciprocal discussion of the trial protocol and approval for consulting the patient. Subsequently, a virtual consult was made with the patient, with witnessed informed consent obtained via telephone and in person by our research associate. Patients randomized to RT were treated within 24 hours of consent. Simulation and treatment were performed on a linear accelerator with one personal protective equipment-protected therapist moving in and out of the treatment room, and a second therapist manning the console. On-site dose calculation was performed by physics, after which the radiation oncologist approved the fields prior to treatment delivery. Simulation and treatment were performed without a computer plan; therapists underwent several practice sessions prior to treating patients on trial. Results Between August 28, 2020 and October 6, 2020, the first 10 enrolled patients on this multicenter trial were randomized and treated at our institution; no research staff member nor radiation oncology clinical team member contracted COVID-19 while employing this protocol. Conclusion This represents the first published protocol to address efficient and safe recruitment of COVID-19 patients for a radiation oncology trial. Despite the procedural hurdles of conducting a trial in the midst of a pandemic, the combination of recruitment efficiency (> 2 patients/week) and safety to the research and clinical teams (no COVID-19 infections) of this protocol has allowed for the PREVENT trial to make substantial progress in meeting recruitment goals (n = 100). This onboarding process serves as a model in conducting recruitment of COVID-19 patients for clinical trials, and is worthy of emulation at additional centers.

Project description:BackgroundLow dose radiation therapy (LDRT) has been used for non-malignant conditions since early 1900s based on the ability of single fractions between 50-150 cGy to inhibit cellular proliferation. Given scarcity of resources, poor access to vaccines and medical therapies within low and middle income countries, there is an urgent need to identify other cost-effective alternatives in management of COVID-19 pneumonia. We conducted a pilot phase Ib/II investigator-initiated clinical trial to assess the safety, feasibility, and toxicity of LDRT in patients with severe COVID-19 pneumonia at the Aga Khan University Hospital in Nairobi, Kenya. Additionally, we also assessed clinical benefit in terms of improvement in oxygenation at day 3 following LDRT and the ability to avoid mechanical ventilation at day 7 post LDRT.MethodsPatients with both polymerase chain reaction (PCR) and high-resolution computer tomogram (HRCT) confirmed severe COVID-19 pneumonia, not improving on conventional therapy including Dexamethasone and with increasing oxygen requirement were enrolled in the study. Patients on mechanical ventilation were excluded. Eligible patients received a single 100cGy fraction to the whole lung. In the absence of any dose limiting toxicity the study proposed to treat a total of 10 patients. The primary endpoints were to assess the safety/feasibility, and toxicity within the first 24 hours post LDRT. The secondary endpoints were to assess efficacy of LDRT at Day 3, 7, 14 and 28 post LDRT.ResultsTen patients were treated with LDRT. All (100%) of patients were able to complete LDRT without treatment related SAE within the first 24 hours post treatment. None of the patients treated with LDRT experienced any acute toxicity as defined by change in clinical and respiratory status at 24hr following LDRT. Majority (90%) of patients avoided mechanical ventilation within 7 days of LDRT. Four patients (40%) demonstrated at least 25% improvement in oxygen requirements within 3 days. Six patients (60%) were discharged and remained off oxygen, whereas four progressed and died (1 due to sepsis and 3 in cytokine storm). Median time to discharge (n = 6) was 16.5 days and median time to death (n = 4) was 11.0 days. Patients who ultimately died showed elevated inflammatory markers including Ferritin, CRP and D-dimers as compared to those who were discharged alive.ConclusionLDRT was feasible, safe and shows promise in the management of severe COVID-19 pneumonia including in patients progressing on conventional systemic treatment. Additional phase II trials are warranted to identify patients most likely to benefit from LDRT.

Dataset Information

Low-dose whole-lung radiation for COVID-19 pneumonia: Planned day 7 interim analysis of a registered clinical trial.

Background

Methods

Results

Conclusions

Lay summary

Publications

Low-dose whole-lung radiation for COVID-19 pneumonia: Planned day 7 interim analysis of a registered clinical trial.

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