key: cord-0938520-oug6agsj
authors: Papachristofilou, Alexandros; Finazzi, Tobias; Blum, Andrea; Zehnder, Tatjana; Zellweger, Núria; Lustenberger, Jens; Bauer, Tristan; Dott, Christian; Avcu, Yasar; Kohler, Götz; Zimmermann, Frank; Pargger, Hans; Siegemund, Martin
title: Low dose radiation therapy for severe COVID-19 pneumonia: a randomized double-blind study
date: 2021-03-05
journal: Int J Radiat Oncol Biol Phys
DOI: 10.1016/j.ijrobp.2021.02.054
sha: 2256bf9c0b21eed60ed2918b1a66e1f988c8c7b5
doc_id: 938520
cord_uid: oug6agsj

Purpose The morbidity and mortality of patients requiring mechanical ventilation for coronavirus disease 2019 (COVID-19) pneumonia is considerable. We studied the use of whole-lung low dose radiation therapy (LDRT) in this patient cohort. Methods and Materials Patients admitted to the intensive care unit (ICU) and requiring mechanical ventilation for COVID-19 pneumonia were included in this randomized double-blind study. Patients were randomized to 1 Gy whole-lung LDRT or sham irradiation (sham-RT). Treatment group allocation was concealed from patients and ICU clinicians, who treated patients according to the current standard of care. Patients were followed for the primary endpoint of ventilator-free days (VFDs) at day 15 post-intervention. Secondary endpoints included overall survival, as well as changes in oxygenation and inflammatory markers. Results Twenty-two patients were randomized to either whole-lung LDRT or sham-RT between November and December 2020. Patients were generally elderly and comorbid, with a median age of 75 years in both arms. No difference in 15-day VFDs was observed between groups (p = 1.00), with a median of 0 days (range, 0-9) in the LDRT arm, and 0 days (range, 0-13) in the sham-RT arm. Overall survival at 28 days was identical at 63.6% (95%CI, 40.7-99.5%) in both arms (p = 0.69). Apart from a more pronounced reduction in lymphocyte counts following LDRT (p < 0.01), analyses of secondary endpoints revealed no significant differences between the groups. Conclusions Whole-lung LDRT failed to improve clinical outcomes in critically ill patients requiring mechanical ventilation for COVID-19 pneumonia.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral cause of the coronavirus disease 2019 (COVID- 19) pandemic. Although symptoms of COVID-19 are mild to moderate in the vast majority of cases, some patients present with severe illness, which may quickly deteriorate to acute respiratory distress syndrome (ARDS) or end-organ failure (1, 2) . The mortality of critically ill patients requiring intensive care unit (ICU) admission remains considerable, with global ICU mortality rates of 30-40% in most geographical regions (3) .

Respiratory failure from ARDS is the leading cause of mortality in patients with . Viral pneumonia can induce a hyperinflammatory syndrome characterized by a cascade of cytokine activation, overwhelming systemic inflammation, and multiorgan failure (5) . In addition to direct viral damage, this excessive host immune response is thought to play a key role in the pathophysiology of lung injury in COVID-19, characterized by diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis (6, 7) . Evidence of hyperinflammation has led to the use of glucocorticoids in patients with severe COVID-19, an approach supported by findings of the randomized RECOVERY trial, which demonstrated that dexamethasone reduces mortality in patients requiring supplemental oxygen or invasive mechanical ventilation (7) . Remdesivir, an antiviral agent, has also been shown to shorten the time to recovery in hospitalized patients with COVID-19 pneumonia (8) . However, since remdesivir and other repurposed antiviral drugs appear to have little or no effect on overall mortality, the World Health Organization J o u r n a l P r e -p r o o f has recommended against their use based on results of the multinational Solidarity trial (9) . Therefore, despite improvements in survival seen in ICU patients (10) , the clinical management of COVID-19 remains largely supportive, and additional improvements remain desirable for critically ill patients requiring intensive care.

One novel approach which has been suggested is the use of whole-lung low dose radiation therapy (LDRT) to treat COVID-19 pneumonia. This unconventional use of ionizing radiation is based on its anti-inflammatory and immunomodulatory effects, which have been well established in preclinical models. These effects are the likely mechanism by which low doses of x-rays were historically effective in treating various forms of pneumonia in the first half of the 20 th century (11). Due to the limited treatment options for COVID-19 pneumonia, several clinical trials of LDRT have been initiated, using radiation doses in the range of 0.3 -1.5 Gy (12). Initial experiences have suggested that LDRT is a feasible and well-tolerated treatment, which appeared to be associated with a reduction of inflammation and possibly bearing signs of clinical improvement in these small single-arm studies (13) (14) (15) (16) . However, due to the lack of prospective controls, the efficacy of LDRT in the treatment of COVID-19 remains unknown. We therefore performed a randomized double-blind study of whole-lung LDRT in patients with severe COVID-19 pneumonia requiring mechanical ventilation.

Study design and participants XXXXXXXXXXX (NCTXXXXXXXX) was a randomized double-blind phase II trial conducted at the XXXXXXXXXX XXXXXXXX of XXXXX in XXXXX, XXXXXXXXXXX.

Patients with COVID-19 related pneumonia requiring mechanical ventilation were included. The lower age limit for male and female patients was 40 and 50 years, respectively, with exclusion of pregnancy required in women of childbearing potential.

No other exclusion criteria were applied. The trial was approved by the Ethics Committee of XXXXXXXXXXXX XXX XXXXXXX XXXXXXXXXXX.

Patients with a confirmed SARS-CoV-2 infection requiring intensive care were screened for eligibility by three sub-investigators present on the ICU. The presence of COVID-19 related pneumonia was identified based on clinical and radiological findings, including ground glass opacities and other typical characteristics observed in thoracic computed tomography (CT) imaging (1, 17) . All patients were dependent on mechanical ventilation, applied using an endotracheal tube following endotracheal intubation (ETI), or using face masks for continuous or intermittent non-invasive ventilation (NIV). Informed consent was granted by the legal representatives of the patients prior to trial inclusion, and deferred consent was later obtained from recovering patients. The aim was to carry out the study intervention within 72 hours after onset of mechanical ventilation.

Patients were randomly assigned with a 1:1 ratio to either whole-lung LDRT or sham irradiation (sham-RT). No stratification criteria were applied. Randomization was performed on the Castor EDC platform (Castor, Hoboken, USA), using variable block sizes of 4, 6 and 8 patients. The two principal investigators (PIs) in the radiation oncology department, who carried out the randomization, as well as one medical physicist, responsible for quality assurance, were aware of the group allocation. All other investigators remained blinded for the duration of the study. This included the J o u r n a l P r e -p r o o f entire ICU treatment team, who continued to treat patients in accordance with local standards, without any involvement by the two study PIs.

The study procedure was performed in compliance with hospital-wide measures for Figure E1 . A set of SSD-specific monitor unit calculations was prepared, although all patients were ultimately treated using the prespecified SSD of 110 cm, which appeared adequate in all cases. We performed no patient-specific simulation, dosimetry, or image-guidance, thereby limiting the unattended in-vault time to 1-2 minutes. After treatment, patients were transported back to the ICU, completing the study procedure within a total out-of-ICU time of less than 20 minutes.

The primary endpoint was the number of ventilator-free days (VFD) at day 15, calculated form the day of intervention (day 0). VFDs were defined as the number of days a patient was alive and free of mechanical ventilation. Patients who died before day 28 were assigned zero VFDs (18) . VFDs at 15 days were assumed at 3.93 days J o u r n a l P r e -p r o o f with standard of care, based on unpublished in-house data of COVID-19 patients admitted to the ICU in spring 2020. We hypothesized that LDRT would increase VFDs to 10 days, which required randomization of 22 patients to detect superiority of LDRT with a power of 90%, a significance level of 5%, and a standard deviation of 4.36 days (based on in-house data). Exploratory secondary endpoints, based on routinely conducted measurements, included: changes in PaO2/FiO2 ratio (Horowitz index), measured from baseline (day 0) compared to the lowest observations within 24 hours (day 1) and on subsequent days; overall survival at day 15, 28; and levels of inflammatory markers up to day 15. Baseline comorbidity assessment was performed using the Charlson comorbidity index (CCI), based on pre-existing conditions prior to SARS-CoV-2 infection (19) . The Simplified Acute Physiology Score (SAPS II), a predictor of hospital mortality, was calculated within 24 hours after ICU admission (20) . ARDS severity was defined according to Berlin criteria based on the lowest PaO2/FiO2 ratio measured on treatment day (prior to the intervention) (21) . Continuous and categorical data were compared using two-tailed Wilcoxon rank sum test and Fisher's exact test, respectively. A p-value <0.05 was considered statistically significant. Overall survival was calculated using the Kaplan-Meier method, calculated from the day of intervention. All statistical analyses were performed using RStudio (v.1.3.1093; Boston, USA). Twenty-two patients were enrolled, randomized and treated per protocol. The characteristics of these patients are summarized in Table 1 The patterns of COVID-19 treatment were overall similar between groups ( Table 1) .

All patients (100%) received standard of care with dexamethasone, which was initiated a median of 3.5 days (range, 1-12) prior to the study intervention, and given for a median of 10 days (range, 5-11) total. Remdesivir was given to 50% of patients for a median of 5 days (range, 5-6), and three patients (14%) received experimental drugs (canakinumab, conestat alfa) as part of ongoing clinical trials. At the time of study intervention, patients had been mechanically ventilated for a median of 2 days (range, 0-2) by way of ETI (59%) or NIV (41%). The proportion of patients managed with ETI was 73% in the LDRT group, and 45% in the sham-RT group. SAPS II scores were a median of 52 and 43, respectively, in the LDRT and sham-RT arms.

The study intervention occurred after a median of 0 days (range, 0-3) following patient enrollment, with most patients being treated in supine position (86%). The procedure was executed without incident in all cases, and no noticeable adverse events were observed in the hours and days following the intervention.

Individual outcomes for the primary endpoint are visualized in Figure E4) . The statistical difference remained when two patients in the LDRT group, who had marked lymphocytosis at baseline due to known chronic lymphocytic leukemia, were excluded from the analysis (p < 0.01). Otherwise, no significant difference in the reduction of inflammatory markers was observed between groups. Similarly, no significant differences were seen in oxygenation changes within 24 hours (LDRT vs. sham-RT: median PaO2/FiO2 change +5 vs. +9, p = 0.49), nor in serial longitudinal measurements, which were limited due to the low number of (alive) patients still on ventilator (data not shown).

Despite global efforts to improve outcomes in patients hospitalized with COVID-19, the mortality rates remain high in patients requiring mechanical ventilation. We now report on, to the best of our knowledge, the first randomized investigation of wholelung LDRT in this patient population. In our study, whole-lung LDRT failed to improve VFDs compared to sham-RT, suggesting a lack of clinical benefit in critically ill patients requiring mechanical ventilation for COVID-19 pneumonia.

We used a primary endpoint of VFDs, a composite outcome measure commonly reported in ARDS trials (18) , and based our statistical power calculation on ICU data J o u r n a l P r e -p r o o f gathered during the early phase of the COVID-19 pandemic. The observed outcomes were worse than predicted, which is likely a consequence of patient selection for our study, which enrolled elderly and comorbid patients with poor or uncertain prognosis.

In addition, changes in ICU admission practice likely increased the average case severity, as non-critical patients are now routinely treated in the dedicated COVID-19 ward. We acknowledge that our initial hypothesis was optimistic in regards to the magnitude of improvement with whole-lung LDRT. However, we were looking for a clear clinical benefit, which would justify potential risks for patients and staff related to the procedure, and which would reflect the rapid symptom reversal described in historical series of x-ray therapy for pneumonia (11), and in some early experiences of LDRT use for COVID-19 pneumonia (13) (14) (15) (16) . Our study was not powered to detect small differences in outcomes, which would require a larger sample size. However, as we failed to detect any meaningful signal in primary and secondary endpoints, it appears questionable whether larger studies in similar cohorts are warranted unless more robust (preclinical) data become available.

We chose a simple approach to deliver whole-lung LDRT due to the clinical priorities in these critically ill patients. In particular, we did not perform patient-specific (CTbased) treatment planning, and we decided against using more sophisticated radiotherapy techniques, which could be used to achieve a more favorable dose distribution (22). Rather, we optimized our workflow to minimize the risk of unexpected events while outside the ICU (23, 24) . This included treating patients in their hospital beds to eliminate the need for patient transfer, and using simple setup and delivery techniques to reduce treatment times. Since we used only one photon beam, the prescribed dose of 1 Gy was not delivered homogeneously to the lungs.

Rather, the lungs were irradiated with a spectrum of anti-inflammatory doses in the J o u r n a l P r e -p r o o f range of approximately 0.5 -1.0 Gy, which is comparable to other ongoing studies (12, 25). Since we did not perform serial CT imaging, we were unable to quantify radiological responses in different areas of the lung, and correlate changes to the dose distribution. Furthermore, due to the simple technique used, LDRT was also delivered to parts of the liver and spleen, as well as axillary, supraclavicular and upper abdominal lymph nodes. The impact of irradiating these regions in the context of systemic hyperinflammation remains unknown.

The doses used in clinical trials of LDRT are highly unlikely to cause any deterministic side effects, such as radiation pneumonitis or fibrosis. However, there is a risk of radiation-induced cardiac disease and a stochastic risk of cancer induction (26) (27) (28) , which led us to introduce a lower age limit in our study. The long-term risks appeared to be of little concern in our patients, considering their age and risk of early mortality from COVID-19 pneumonia. However, the ratio of risk to potential benefit appears less favorable in younger patients, as well as in less critical patients in earlier phases of SARS-CoV-2 infection. Based on historical data, LDRT may be most effective in treating interstitial pneumonia when delivered early (29) , and similar assumptions could be made for COVID-19 pneumonia based on the pathogenesis of ARDS (12). Although we enrolled patients as soon as possible after onset of mechanical ventilation, the lack of effect could therefore be attributed to the advanced stage of COVID-19 pneumonia in our cohort. In addition, the use of dexamethasone as a standard of care could have masked anti-inflammatory effects of LDRT in our patients, most of whom already had lymphopenia at study entry, reflecting a severe clinical course (30, 31) . The latter can be further complicated by an array of extrapulmonary manifestations of COVID-19 (32), which are unlikely to be affected by LDRT, and which add another dimension of complexity to these patients. The main strengths of our study are its randomized and double-blind design, the swift accrual period of 2 months, and the patient-centered clinical endpoint. Main weaknesses are the small sample size, and possibly the inclusion of only patients requiring mechanical ventilation. The latter was a consequence of our decision to J o u r n a l P r e -p r o o f focus on critically ill patients, for whom the ratio of risk to potential benefit appeared most favorable, which is relevant considering the experimental nature of our study.

Although the baseline characteristics were overall similar in both groups, the impact of random differences has to be considered when interpreting our results. This includes a higher proportion of patients managed with ETI, and a numerically higher rate of comorbidities, in the LDRT group. The influence of these and other factors, such as the number of ventilator days prior to the intervention, could not be studied due to the small sample size. However, since these small imbalances would not have changed the overall outcome of our study, we believe that future efforts would need to explore a different approach than reported here. This could, at least in theory, involve the use of a different LDRT regime and technique, or application in earlier clinical stages of COVID-19 pneumonia.

In conclusion, whole-lung LDRT failed to improve clinical outcomes in critically ill 

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of 22 patients randomized to either whole-lung LDRT or sham irradiation. Data are presented as number (percentage) of patients unless indicated otherwise. Abbreviations: ARDS, acute respiratory distress syndrome. BMI, body mass index. CCI, Charlson comorbidity index. COVID-19, coronavirus disease 2019. LDRT, low dose radiation therapy

75 (54-84) 75 (69-82) SexMale 10 (91%) 7 (64%) Female 1 (9%) 4 (36%) BMI (kg/m 2 ), median (range) 24 Table 2 : Summary of changes in inflammatory markers and pulmonary function (PaO2 / FiO2 ratio) after whole-lung low dose radiation therapy (LDRT) and sham irradiation (sham-RT). Median values are based on alive patients for whom observations were available. Reductions in inflammatory markers were measured as relative reduction from baseline to the lowest value observed until 15 days or death. With the exception of a more pronounced relative reduction in lymphocyte counts after LDRT, analyses of secondary outcome parameters did not reveal significant differences