key: cord-0773835-zmosa9f2
authors: Sanmamed, N.; Alcantara, P.; Cerezo, E.; Gaztañaga, M.; Cabello, N.; Gómez, S.; Bustos, A.; Doval, A.; Corona, J.; Rodriguez, G.; Duffort, M.; Ortuño, F.; de Castro, J.; Fuentes, M.; Sanz, A.; López, A.; Vazquez, M.
title: Low dose radiotherapy in the management of covid19 pneumonia (LOWRAD-Cov19). Preliminary report
date: 2020-11-26
journal: Int J Radiat Oncol Biol Phys
DOI: 10.1016/j.ijrobp.2020.11.049
sha: e7d27dda2b495eaa29e30947deae10f900b76ec4
doc_id: 773835
cord_uid: zmosa9f2

INTRODUCTION Low-Dose Radiation (LD-RT) has demonstrated to have anti-inflamatory effect and, preliminary results suggest it is feasible to treat COVID-19 pneumonia. MATERIAL AND METHODS We conducted a prospective single arm phase I-II clinical trial enrolling patients ≥ 50 years-old COVID-19 positive, at phase II or III with lung involvement at imaging study and oxygen requirement. Patients received 100 cGy to total lungs in a single fraction. Primary outcome was radiological response using severity and extension score on baseline CT, at day 3 and 7 after LD-RT. Secondary outcomes were toxicity using CTCAE v5, duration of hospitalization, blood work evolution and oxygen requirements using SatO2/ FiO2 index (SAFI), at day 3 and 7 after LD-RT . RESULTS Nine patients were included. Median age was 66 (IQR 57-77). Severity score was stable or decreased in the third CT but no statistically significant (p=0.28), however, there were statistically significant changes in the extension score (p=0.03). SAFI index significantly improved 72 hours and 1 week after LD-RT (p=0.01). Inflammatory blood parameters decreased one week after RT compared with baseline, only LDH decreased significantly (p=0.04). Two patients presented grade 2 lymphopenia after RT and another worsened to grade 4 being its baseline grade 3. Overall, the median number of days of hospitalization was 59 days (range 26-151). After RT the median number of days in hospital was 13 days (4-77). With a median follow-up after RT of 112 days (105-150), seven patients were discharged and two patients died, one due to sepsis and the other with severe baseline COPD from COVID-19 pneumonia. CONCLUSIONS Our preliminary results show that LD-RT was a feasible and well-tolerated treatment, with potential clinical improvement. Randomized trials are needed to establish whether LD-RT improves severe pneumonia.

Post-mortem analysis in series of COVID-19 infected patients has shown diffuse 33 alveolar damage with inflammatory infiltrate present wich compromise gas exchange. 1 34 Radiation therapy administered at low doses (LD-RT) has anti-inflammatory properties 35 such as lowering levels of pro-inflammatory cytokines (e.g IL-1a) or inhibiting leukocyte 36 recruitment. 2, 3, 4, 5 In addition to its anti-inflammatory effect, LD-RT was used for 37 pneumonia in the first half of the 20th century with several reports suggesting 38 . 6, 7 Preliminary results have shown potential efficacy that 0.5 Gy LD-RT is feasible in 39 8 patients with COVID-19 pneumonia. 40

Taking into account the low risk of toxicity and the potencial benefit of LD-RT, 41

we conducted a prospective phase I-II study to evaluate the radiological and clinical 42 efficacy of LD-RT in patients with SARS-CoV-2. Herein we report preliminary results. 43

Patients ≥ 50 years-old COVID19 positive confirmed by PCR with lung involvement at 47

imaging study (chest X-ray, chest CT or PET-CT) and oxygen requirement, previous 48 provision of written informed consent, were enrolled onto a prospective single arm 49 phase I-II clinical trial at a single institution (NCT-04420390). This study was approved 50 by our institutional research ethics board. 51

Patients in phase II (lung phase, patients develop a viral pneumonia, with cough, fever, 52 ) or phase III (hyper-inflammatory and hypoxia defined as PaO2/FiO2 < 300 mm Hg 53 phase, the disease manifests as an extrapulmonary systemic hyperinflammation 54 ) 9 were syndrome, C-reactive protein, ferritin, and D-dimer are significantly elevated 55 eligible. Exclusion criteria includes severe comorbidities that could hamper the 56 radiation treatment, such an impossibility to hold supine position. 

The primary outcome was radiological response. Patients underwent three thoracic 71

CTs: simulation CT, and days 3 and 7 after RT. Image analysis was performed by two 72 experienced thoracic radiologist (>10 years experience) and a second year radiology 73 resident using the institutional digital database system (IMPAX 6.5.33, Agfa-Gevaert 74 N.V.). In order to rate the COVID-19 lung involvement two scores described by Chung 75 et al. were used. 10 Oxygen requirement was measured using SatO2 / FiO2 index (SAFI) 11, 12 previous to RT, 88 72 hours, and a week after (normal SAFI index> 315, mild respiratory failure <300, and 89 severe <200). Blood tests including ferritin, blood cell count, C-reactive protein, d-90 dimer and LDH were performed before RT; 24, 48 and 72 hours after RT, then every 2 91 days until normal levels. 

From April to June 2020, 9 patients consented and were treated with 100 cGy to both 108 lungs on the same day as enrollment. Patient characteristics are summarized in Table  109 1. Median age was 66 (IQR 57-77). Details about RT are included in supplementary 110 Radiologically, there was no significant differences in severity score, however 147 there was a statistically significant improvement on the extension score by one week 148 (p = 0.03). Although radiological changes were modest, clinically there was a significant 149 improvement in SAFI 72 hours after RT (p=0.01). One week after, only 1 patient 150

This rapid continued with SRF, 3 MRF and 5 recovered normal SAFI index (p=0.01). 151 clinical improvement allowed patients to be discharged with a median of 13 days. 152

Patients were treated after a median of 52 days admitted, mainly because the 153 referral criteria to consider LD-RT was after another antiCOVID treatment failed. 154

According to Calabrese, LD-RT earlier than day 14 may be more effective, 14 al. 15 studied lymphocytes radiosensitivity and concluded that 2 Gy is the lethal dose 160 required to reduce the surviving fraction of lymphocytes by 50%. In our study we 161 administered 1Gy and, although lymphopenia can be produced by RT, COVID19 162 infection itself or the use of some drugs such as steroids can also contribute to it. 163 A risk of radiation-induced heart disease has been described at a dose of 1Gy, 164

with an increased risk of major coronary events of 7.4% for each Gy of mean heart 165 dose. 16 The mean dose to the heart in our study was 0. However, the small number of patients and the short follow-up are important 174 limitations. Furthermore, the heterogeneity of the medical treatments previously 175 received by patients and the absence of randomization with a control group makes 176 difficult to really know the extent of improvement due to LD-RT. 177

Our preliminary results show that LD-RT was a feasible and well-tolerated 178 treatment, with potential clinical improvement. A randomized trial with longer follow-179

up is needed to determine if LD-RT provides benefit in this setting. 180 

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