key: cord-0900429-22jygucv
authors: Ganesan, Govindaraj; Ponniah, Sasipriya; Sundaram, Vivek; Kumar Marimuthu, Praveen; Pitchaikannu, Venkatraman; Chandrasekaran, Manikandan; Thangarasu, Janakiraman; Kannupaiyan, Gunasekaran; Ramamoorthy, Prabhu; Thangaraj, Brindha; Sasipriya Govindaraj, Harshavardhanan; Vaishnavi Raguram, Shree
title: Whole lung Irradiation as a Novel treatment for COVID-19: Final Results of the Prospective Randomized trial (WINCOVID trial)
date: 2021-12-25
journal: Radiother Oncol
DOI: 10.1016/j.radonc.2021.12.024
sha: be90deca4cfe5e94844da3a3cbfd839ac49cb1e0
doc_id: 900429
cord_uid: 22jygucv

BACKGROUND AND PURPOSE: The ability of Low dose radiotherapy (LDRT) to control the unprecedented cytokine release associated with COVID-19 pathogenesis has been an area of widespread research since the COVID pandemic. It has not been studied adequately whether the anti-inflammatory effect of LDRT provides additional benefit when used concurrently with steroids amongst other standard pharmacologic therapy. MATERIAL AND METHODS: 51 RT-PCR positive COVID-19 patients were recruited between November 2020 and July 2021. 34 patients were allotted to receive 0.5Gy single session LDRT along with standard pharmacologic therapy while 17 patients received standard pharmacologic therapy alone. All had SpO2<94% on room air, respiratory frequency > 24/min and SpO2/FiO2 (SF) ratio between >89 but <357. All patients underwent a baseline CT scan. They were followed up for 28 days during when serial SF ratio, blood biomarkers (CRP, Serum ferritin, IL-6), Absolute lymphocyte count (ALC), repeat CT scan were performed at pre-defined time points. RESULTS: LDRT showed a statistically significant early improvement in oxygenation, an early time to clinical recovery, early hospital discharge and better radiological resolution compared to control group. There was no statistically significant difference between the two groups with respect to ALC or blood biomarkers at any of the measured time points. The 28-day mortality rate did not show statistically significant difference between the two groups. CONCLUSION: LDRT can be considered for selected oxygen-dependent moderate to severe COVID-19 patients for rapid relief of respiratory distress. It can be safely combined with standard pharmacologic treatment in such patients for added clinical benefit.

 First prospective, randomized trial comparing LDRT+ pharmacological therapy vs pharmacological therapy alone for moderate to severe COVID-19  Significant improvement in SF ratio leading to earlier, rapid relief from severe respiratory distress in LDRT group  Quicker time to clinical recovery, fewer days to hospital discharge and better radiological resolution in LDRT group  No significant difference in 28-day mortality rate, blood biomarkers response or incidence of significant lymphopenia between the groups  LDRT could be useful as an adjunctive treatment in selected moderate to severe COVID-19 patients ABSTRACT BACKGROUND AND PURPOSE The ability of Low dose radiotherapy (LDRT) to control the unprecedented cytokine release associated with COVID-19 pathogenesis has been an area of widespread research since the COVID pandemic. It has not been studied adequately whether the anti-inflammatory effect of LDRT provides additional benefit when used concurrently with steroids amongst other standard pharmacologic therapy.

MATERIAL AND METHODS 51 RT-PCR positive COVID-19 patients were recruited between November 2020 and July 2021. 34 patients were allotted to receive 0.5Gy single session LDRT along with standard pharmacologic therapy while 17 patients received standard pharmacologic therapy alone. All had SpO2<94% on room air, respiratory frequency > 24/min and SpO2/FiO2 (SF) ratio between >89 but <357. All patients underwent a baseline CT scan. They were followed up for 28 days during when serial SF ratio, blood biomarkers (CRP, Serum ferritin, IL-6), Absolute lymphocyte count (ALC), repeat CT scan were performed at pre-defined time points.

LDRT showed a statistically significant early improvement in oxygenation, an early time to clinical recovery, early hospital discharge and better radiological resolution compared to control group. There was no statistically significant difference between the two groups with respect to ALC or blood biomarkers at any of the measured time points. The 28-day mortality rate did not show statistically significant difference between the two groups.

LDRT can be considered for selected oxygen-dependent moderate to severe COVID-19 patients for rapid relief of respiratory distress. It can be safely combined with standard pharmacologic treatment in such patients for added clinical benefit.

The emergence of new variants leading to outbreaks, slow vaccination rates, growing costs of pharmacological therapies, shortage of beds and supplemental oxygen in hospitals are some of the challenges faced by several countries across the world in the fight against COVID-19 pandemic. The probability of future outbreaks cannot be entirely ruled out, especially in densely populated countries.

There remains a need for a widely available, non-toxic, cost-effective treatment approach for patients with moderate to severe COVID-19.

Low dose radiotherapy (LDRT) is being evaluated across many institutions around the world as an anti-inflammatory/immunomodulatory approach against moderate to severe COVID-19. There has been recent advancement in understanding the underlying mechanism of action of LDRT. Calabrese et al proposed that the clinical benefit from LDRT was derived from various subcellular effects mediated by activation of nuclear factor erythroid 2-related transcription factor (Nrf-2)resulting in anti-oxidant responses and subsequent polarization shift of macrophages from pro-inflammatory (M1) to anti-inflammatory (M2) phenotype.

This could not only help in resolving inflammation, but also in suppressing the cytokine storm, promoting tissue repair thereby preventing COVID-19 related mortality. 1 As per our preliminary observations, LDRT appeared to be a promising modality for selected patients with moderate to severe COVID-19. 2 In this manuscript, we discuss the final results from our single-institutional experience in treating COVID-19 patients with low dose whole-lung radiotherapy. Registry of India (CTRI/2020/10/028597), available at www.ctri.nic.in.

The study was done toevaluate bilateral whole lung LDRT using a Linear Accelerator (6 MV), as a treatment for interstitial pneumonia in patients with moderate to severe COVID-19.It was conducted in 2 phases:

1. an initial exploratory phase enrolling 10 patients, which assessed the feasibility and efficacy of low-dose whole lung irradiation, evaluated according to an increase in the SpO2/FiO2 ratio of at least 20% at 48 hours with respect to the preirradiation value. Only upon achieving this minimum pre-defined improvement in at least 30% of patients treated, did the study proceed to the next phase 2. Randomized comparative phase in two groups: i) a control group, which received pharmacological treatment only, and ii) an experimental LDRT arm with pharmacological treatment and LDRT. It included 51 patients, the allocation was2:1, that is, 34 in the LDRT arm and 17 in the control arm. Computer based random sequences were generated and no blinding was done.

The flowchart of study design is shown in Figure 1 .

All patients with moderate to severe COVID-19 pneumonia were evaluated by a multidisciplinary board (including specialties such as Radiation Oncology, Internal Medicine, Pulmonology, Critical Care and Anesthesia) to determine the benefits and risks of their inclusion in the study.

1. Adult patients above the age of 40 with RT-PCR proven COVID-19 with fewer than 14 days of symptom onset that warranted hospitalization and currently receiving pharmacological therapy for COVID-19 at appropriate doses as per national standard COVID-19 management recommendations And 2. Patients with moderate to severe dyspnea requiring oxygen support(Nasal Cannula/Simple face mask/Venturi mask/non-rebreathermask/High flow nasal cannula/CPAP) with respiratory frequency ≥ 24/min, oxygen saturation on room air SpO2< 94% and SpO2/FiO2 ratio >89 and <357.

And/or 3. laboratory abnormalities such as C-reactive protein>100 mg/L or D-dimer>1000 ng/ml or IL-6>50 IU or suspected cytokine release syndrome (Criteria 1 and 2 were mandatory and 3 was optional) were assessed using the Log Rank test. A two-sided p value less than 0.05 was considered to be statistically significant. 

Upon conclusion of the initial exploratory phase in 10 patients at 1 month followup, we found that LDRT was well tolerated. Clinical profile and baseline parameters of these 10 patients are tabulated in table 1 and 2 respectively. The predefined efficacy criteria of "minimum 20% improvement in SF ratio in at least 30% of the patients at 48h"was achieved, as50% of treated patients fulfilled this (Table 3) . SF ratio distribution of these 10 patients is depicted using a boxplot in Within and between group comparisons are tabulated in tables 6 and 7 respectively and depicted using a boxplot in figure 4 .

Incidence of lymphopenia was compared between the groups by monitoring serial absolute lymphocyte counts at baseline, day 1, day 3, day 7 and day 14 and no statistically significant reduction was found at the measured time points (Table 8) .

Inflammatory and immunological response biomarkers such as CRP, Serum ferritin and IL-6 were compared based on their baseline, day 3, day 7 and day 14 values between the groups. There was no statistically significant difference with respect to any of the biomarkers ( Table9 This is represented using a Kaplan Meier curve in Figure 6 . We observed speedy clinical recovery and an earlier hospital discharge for patients who underwent LDRT compared to the control group. This meant better availability of beds for other needy patients and conservation of oxygen supplies for the hospital. Notably, a major part of patient recruitment happened during the times of acute oxygen crisis in our country.

Radiological assessment was done using the scoring criteria proposed by Li et al. 6 Three out of five patients in the LDRT group who died, had a baseline CT severity score of ≥20. LDRT may be of limited use in these patients and upcoming clinical trials could consider the same while devising selection criteria.

At 28 days of follow-up, the all-cause mortality rate was 14.7% in the LDRT group and 23.5% in the control group. The clinical characteristics of the patients who died is represented in table 13. It is noteworthy that the percentage of co-morbid patients in LDRT group (85%) was markedly higher compared to the control group (59%). Also, the overall median baseline CT severity score was worse for the Risk-benefit balance needs to be assessed and discussed with the patient before irradiating relatively younger female patients with smoking history and in those with several cardiac risk factors as the EAR % may be higher for this sub-group. In our study, neither female smokers nor pre-existing cardiac co-morbidity cases were part of the patient population.

Several published preliminary results have shown favorable outcomes with the use of LDRT for COVID-19 with negligible side effects. 2, 5, [9] [10] [11] But some clinicians in the radiation oncology community continue to be hesitant on usage of this approach, quoting lack of robust data, feasibility and logistic issues. 12 These barriers need to be overcome for LDRT to be studied under a large scale multiinstitutional research setting worldwide.

This prospective, randomized study is not without its limitations. It utilized a 2:1 allocation ratio for statistical comparison between the intervention and control group. Although this is scientifically not validated, this allocation has been selected for better patient recruitment and gathering additional safety profile of LDRT.

Remdesivir, tocilizumab, Pirfenidone, Vitamin C and zinc were used for patients in both groups in addition to 'standard pharmacologic treatment' according to physician's discretion. Notably, there were several revisions to guidelines about the best use of these pharmacological drugs throughout the duration in which this trial was conducted. This had resulted in varying number of patients receiving these drugs between the two groups and some patients not receiving the drugs, which may have influenced the outcome.

This prospective, randomized trial shows that addition of LDRT to pharmacological treatment hastens clinical recovery and time to hospital discharge compared to pharmacological treatment alone in selected moderate to severe COVID-19 patients. This was achieved by improvement in oxygenation and is backed by radiological resolution of pneumonia in majority of patients treated, in the absence of limiting side effects. The all-cause mortality rate was lower in the LDRT group compared to the control group, although this was not statistically significant. These findings need to be further validated by larger samples and longterm follow-up.

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Captions for figures Figure 1 Flowchart of study design Figure 2 Flow diagram of "Randomized comparative phase" study participants Figure 3 Boxplot showing distribution of SpO 2 /FiO 2 (SF) ratio in "Initial Exploratory phase" patients (n=10) Figure 4 Boxplot showing SF ratio: Within and Between group comparison Figure 5 Kaplan Meier Curves for survival at 28 days post-admission in LDRT (n=34) and control groups (n=17) Figure 6 Kaplan Meier Curves for Time to Clinical Recovery in LDRT (n=34) and control groups (n=17) Figure 7 Kaplan Meier Curves for Time to hospital discharge in LDRT (n=34) and control groups (n=17) Baseline to Day 14 -4(-5, -2.75) -2(-3, -1) 0.011 * Statistically significant at p <0.05 Table 13 . Clinical Characteristics of patients who died

NRF2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): novel mechanistic considerations

Whole lung Irradiation as a Novel treatment for COVID-19: Interim Results of an Ongoing Phase 2 trial in India

Biomarkers associated with COVID-19 disease progression. Critical reviews in clinical laboratory sciences

Association of elevated inflammatory markers and severe COVID-19: A meta-analysis

Could pulmonary low-dose radiation therapy be an alternative treatment for patients with COVID-19 pneumonia? Preliminary results of a multicenter SEOR-GICOR nonrandomized prospective trial (IPACOVID trial)

The clinical and chest CT features associated with severe and critical COVID-19 pneumonia. Investigative radiology

The risk of induced cancer and ischemic heart disease following low dose lung irradiation for COVID-19: estimation based on a virtual case

Lung Cancer and Heart Disease Risks Associated with Low-Dose Pulmonary Radiotherapy to COVID-19 Patients with Different Background Risks

Immunomodulatory low-dose whole-lung radiation for patients with coronavirus disease 2019-related pneumonia

Low-dose whole-lung irradiation for COVID-19 pneumonia: short course results

Low-dose radiation therapy in the management

Preliminary report

Clinician attitudes to using low-dose radiation therapy to treat COVID-19 lung disease

The Authors would like to acknowledge the following people for their inputs and 

The authors declare that there has been no significant financial support from any fund source(s) that could have influenced the outcome of the study. 

The authors declare that there is no conflict of interest