key: cord-0996525-gsy4vtlz
authors: Ameri, Ahmad; Ameri, Pooya; Rahnama, Nazanin; Mokhtari, Majid; Sedaghat, Meghdad; Hadavand, Fahimeh; Bozorgmehr, Rama; Haghighi, Mehrdad; Taghizadeh-Hesary, Farzad
title: Low-dose Whole-lung Irradiation for COVID-19 Pneumonia: Final Results of a Pilot Study
date: 2020-12-02
journal: Int J Radiat Oncol Biol Phys
DOI: 10.1016/j.ijrobp.2020.11.065
sha: 65a7d552b0e2b2b08b1be6f52ea06c6dd522a478
doc_id: 996525
cord_uid: gsy4vtlz

Introduction Radiotherapy (RT) -commonly employed in cancer management- has been considered as one of the potential treatments for COVID-19 pneumonia. Here, we present the results of the pilot trial evaluating low-dose whole-lung irradiation (LD-WLI) in patients with COVID-19 pneumonia. Methods Ten patients with moderate COVID-19 pneumonia were treated with LD-WLI in a single fraction of 0.5 or 1.0 Gy along with the national protocol. The primary endpoint was the improvement in SpO2. The secondary endpoints were the number of hospital/ICU stay days, the number of intubations after RT, 28-day mortality, and changes in biomarkers. The response rate (RR) was defined as a rise in SpO2 upon RT with a rising or constant trend in the next 2 days, clinical recovery (CR) included patients who were discharged or acquired SpO2≥93% on room air, and 28-day mortality rate was defined based on RT day. Results The median age was 75 years (80% male). Five, 1, and 4 patients received single 0.5Gy, two 0.5Gy, and single 1.0Gy LD-WLI, respectively. The mean improvement in SpO2 at days 1 and 2 after RT was 2.4% (±4.8%) and 3.6% (±6.1%), respectively, with improvement in 9 patients after 1 day. Five, 1, and 4 patients were discharged, opted out the trial, and died in hospital, respectively. Two of 5 discharged patients died within 3 days at home. Among discharged patients, the SpO2 at discharge was 81-88% in 3 and 93% in the other 2 patients. Overall, the RR and CR were 63.6% and 55.5%, respectively. The RR, CR, and 28-day mortality of single 0.5Gy- and 1.0Gy-WLI were 71.4 vs. 50% (p = 0.57), 60 vs. 50% (p = 0.64), and 50 vs. 75% (p = 0.57), respectively. Conclusion LD-WLI with a single 0.5 Gy or 1 Gy-fraction is feasible. A randomized trial with patients that do not receive radiation is required to assess efficacy of LD-WLI for COVID-19.

Since December 2019, the novel coronavirus disease , caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has led to global catastrophe. Based on historical evidence using radiation therapy (RT) for viral pneumonia, 1 lung irradiation has been proposed for COVID -19 pneumonia. 2, 3 The preliminary results in 5 patients were previously reported. 4 Herein, we report the results of the whole 10 patients treated with LD-WLI and compare the clinical outcomes of two applied RT regimens.

Patients aged > 60 years with COVID-19 [based on real-time polymerase chain reaction (RT-PCR) of SARS-CoV-2 RNA, antibody tests, or radiographic pneumonic consolidations] with moderate pulmonary involvement [defined as blood oxygen saturation level (SpO 2 ) ≤93% on room air or respiratory rate >30/min] were eligible. Details of evaluating the eligibility criteria have been previously described. 4 Briefly, peripheral blood SpO 2 was measured on room air within 1 hour before RT and in subsequent mornings using a pulse oximeter. The body temperature of patients was measured every morning using tympanic membrane thermometry. Likewise, c-reactive peptide (CRP), interleukin-6 (IL-6), ferritin, J o u r n a l P r e -p r o o f procalcitonin, and D-dimer were evaluated as the prognostic biomarkers of COVID-19. 5 The exclusion criteria were presented in the preliminary report. 4

Eligible patients were enrolled in a single-arm pilot trial (Clinical Trial Registration Number XXX). The protocol was approved by the Institutional Review Boards and ethics committee of XXX (XXX), and all patients declared written and verbal informed consent. The study design and details of the protocol for transportation of patients to the RT Department and details of LD-WLI have been described previously. 4

Briefly, in conjunction with the national protocol for COVID-19 pneumonia, 6 irradiation was delivered in a single fraction of 0.5Gy to both lungs via two opposed anteroposterior and posteroanterior open portals. The irradiation was extended to another 0.5Gy, after at least 3 days, based on the physician's discretion. Treatment with a single 1.0Gy-WLI was planned for 4 patients in the second phase of the pilot study. This decision was originated from the preliminary results of an ongoing study evaluating single 1.5Gy WLI. 7 Incidentally, no patient received dexamethasone, remdesivir, (hydroxy)chloroquine, or macrolides.

The primary endpoint was an improvement in SpO 2 . The secondary endpoints were the number of hospital/ICU stay days, the number of intubations after RT, 28-day mortality rate, and changes in CRP, IL-6, ferritin, procalcitonin, and D-dimer. To evaluate 28-day mortality, participants were contacted by telephone to confirm vital status at 28-days after lung radiation. The applied ferritin test kit could not measure amounts > 1600 ng/mL. Response rate (RR) was defined as improvement in SpO 2 on the first day after RT with increasing or constant trends for the next 2 days, and clinical recovery (CR) was defined as patients who were discharged from hospital or weaned off the supplemental oxygen with SpO 2 ≥93% on room air.

To examine and compare the effects of radiation dose on SpO 2 , CRP, and IL-6, the mixed-design analysis of variance (ANOVA) with time as between-subjects factor was performed. We tested the normality, homogeneity, and sphericity using the Shapiro-Wilk, Levene's, and Mauchly's tests. The comparison of RR, CR, 28-day mortality rate between the radiation doses were examined using Fisher's exact test. The statistical significance level was set to 0.05. All analyses were performed using IBM SPSS Statistics (version 26.0, Armonk, NY, USA, IBM, Corp.).

Between 21 May 2020 and 2 July 2020, 10 patients with moderate COVID-19 pneumonia received LD-WLI at the Clinical Oncology Department of XXX. Patients' demographics and baseline disease characteristics are summarized in Table 1 . The median age was 75 years (range 60-87 years) and 80% were male. All except 2 patients had comorbidities. Dyspnea was the predominant chief complaint (70%). All participants, except for 1 (patient #3), were positive for RT-PCR of SARS-CoV-2 RNA; patient #3 had the typical computed tomography (CT) features of COVID-19 pneumonia and elevated CRP. Initial physical examination revealed stable vital signs for all patients with the median SpO 2 of 80.5% (range 70-89%). All patients received O 2 supplement mainly (60%) via facial mask with reservoir bag.

Patients were allocated to receive WLI in 2 plans; (1) LD-WLI with a single-0.5Gy fraction (patients #1-5),

(2) LD-WLI with a single-1.0Gy fraction (patients #7, 8, 9, and 10) . Patient #6 experienced SpO 2 improvement within a day after 0.5Gy LD-WLI; After 6 days he developed clinical deterioration and received the second 0.5Gy. Patients were followed for 2-155 days (median 10 days). Within a day after RT, 9 (90%) and 6 (60%) patients demonstrated initial improvement in their SpO 2 (median: 2.5%, range: 1 to 10%) and body temperature (median: -0.45°C, range: -0.1 to -2.0°C). Despite the clinical J o u r n a l P r e -p r o o f improvement, patient #3 opted out of the trial on the 3 rd day after RT. Based on the telephone followup, patient #3 is fully recovered and alive. Overall, the RR and CR were 63.6% and 55.5%, respectively.

By including patient #3, overall CR improves to 60%. The mean magnitude of the improvement in SpO 2 at days 1 and 2 after RT was 2.4% (±4.8%) and 3.6% (±6.1%), respectively. In 0.5 and 1.0 Gy groups, the mean improvement in SpO 2 within 2 days was 6.1 vs. 0.25% (p = 0.95), respectively. The RR of single 0.5Gy-and 1.0Gy-WLI were 71.4% vs. 50% (p = 0.57), and CR rates of single 0.5Gy-and 1.0Gy-WLI were 60% vs. 50%, respectively (p = 0.64) (by including patient #6 twice in the RR who well responded to 2×0.5 Gy-fractions of WLI, and not including patient #3 in CR who left the trial). By including patient #3, CR of 0.5 Gy group improves to 66.7% (p = 0.54). The clinical course and outcomes are summarized in Tables 1 and 2. The median time to discharge was 6 days (range 2-14 days) for 5 patients. The remaining 4 patients experienced a decline in SpO 2 at median 2.5 th day (range 2 nd -3 rd day) and died at median 7 th day (range 3 rd -10 th day) (Figure 1-A) . Patient #5, 7, and 9 experienced SpO 2 ≥94% with supplementary O 2 and 81 to 88% on room air at discharge day. They were discharged on the 6 th , 2 nd , and 15 th days after irradiation with medical advice to receive O 2 supply at home due to hospital bed shortage. The remaining 2 (of 5 discharged) patients had SpO 2 of 93% at discharge. Patient #10 was the only case who experienced intubation with mechanical ventilation done on the 4 th day after RT. The laboratory tests following irradiation had diverse patterns (Figures 1 and 2) . Three of 5 discharged patients had a drop in CRP over 1-2 days after RT, while all patients who had died experienced a rise in CRP over the same period (Figure 1-C) . The mean magnitude (± SD) of the change in CRP over hospitalization in discharged vs. patients who died was -20. and accordingly after 2 days were 24.4 (± 59.2) vs. 82.1 (± 29.2) (p = 0.10), respectively. Following RT, IL-6 levels fell in all discharged patients after 1-3 days, while, rose within 2 days in 2 of 4 participants who died from COVID-19. (Figure 1-D) . The mean magnitude (± SD) of the change in IL-6 over hospitalization Considering RR of 80% and CR of 75%, the initial results of this trial addressed the potential efficacy of 0.5Gy-WLI in moderate COVID-19 pneumonia. 4 In this updated report, however, both RR and CR of 1.0Gy-WLI were 50%. In addition, the 28-day mortality rate of 0.5 Gy-WLI was less than 1.0 Gy group (50% vs. 75%). These findings may reflect the concept that doses < 1.0Gy have an anti-inflammatory effect, while, higher doses may exacerbate the pro-inflammatory response. 13 Several factors that may interfere with our results. Firstly, the mean age of 1.0 Gy-group was approximately 7 years older (71.6 vs 78.5 years) that may influence the RR and CR. Overall, 4 of 5 patients above 70 years old who received LD-WLI progressed to death, with one, who had no underlying medical condition, surviving to discharge. This finding suggests that the efficacy of LD-WLI in patients > 70 years is limited, but a randomized trial of LD-WLI would be needed to define whether there is any benefit. All 3 patients who were discharged in 0.5 Gy-group were 60-70 years, while 1 patient in 1.0 Gygroup was in this range of age who recovered from COVID-19. The effect of age on radiosensitivity and inflammation has been demonstrated. 15, 16 Secondly, data on body mass index and smoking were not evaluated. The effect of these 2 factors on the prognosis of COVID-19, inflammation, and radiosensitivity has been demonstrated. [17] [18] [19] Thirdly, according to the national guideline, patients who had SpO 2 <90% under non-invasive ventilation with FiO 2 >50% were indicated for the ICU admission, intubation, and mechanical ventilation. 6 Due to the limited ventilation facilities 1 out of the 8 indicated patients was intubated. This limitation may affect the clinical results of patients # 4, 6, and 8 as well as patients #5 and 7 who died after discharge. Fourthly, patients of 1.0 Gy-group were recruited on average 22 days later in the study. This may have faced them to a SARS-CoV-2 with more genetic mutations with possibly worse prognosis. 20 Although these limitations are important, this study is the first that has compared two radiation doses of WLI in patients with COVID-19 pneumonia.

The results of this trial may signal the feasibility of LD-WLI in patients with moderate COVID-19

pneumonia, but require further study in randomized, controlled trials. 

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