Clinical and Translational Radiation Oncology 24 (2020) 29–33 Contents lists available at ScienceDirect Clinical and Translational Radiation Oncology journal homepage: www.elsevier.com/locate/ctro Original Research Article Low dose anti-inflammatory radiotherapy for the treatment of pneumonia by covid-19: A proposal for a multi-centric prospective trial M. Algara a,1, M. Arenas b,1, J. Marin c, I. Vallverdu d, P. Fernandez-Letón e, J. Villar f, G. Fabrer g, C. Rubio h, A. Montero h,⇑,1 a Department of Radiation Oncology, Hospital del Mar, Autonomous University of Barcelona, Spain b Department of Radiation Oncology, University Hospital Sant Joan de Reus, Rovira iV irgili University, Tarragona, Spain c Intensive Care Unit, Hospital del Mar, Barcelona, Spain d Intensive Care Unit University Hospital Sant Joan de Reus, Universitat Rovira I Virgili, Tarragona, Spain e Department of Radiation Physics, University Hospital HM Sanchinarro, Madrid, Spain f Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain g Department of Geriatric and Palliative Care, University Hospital Sant Joan de Reus, Rovira i Virgili University, Tarragona, Spain h Department of Radiation Oncology, University Hospital HM Sanchinarro, Madrid, Spain a r t i c l e i n f o a b s t r a c t Article history: Background: COVID-19 is a highly contagious viral infection with high morbidity that is draining health Received 18 May 2020 resources. The biggest complication is pneumonia, which has a serious inflammatory component, with no Revised 6 June 2020 standardized treatment. Low-dose radiation therapy (LD-RT) is non-invasive and has anti-inflammatory Accepted 12 June 2020 effects that can interfere with the inflammatory cascade, thus reducing the severity of associated cyto- Available online 15 June 2020 kine release and might be useful in the treatment of respiratory complications caused by COVID-19. Study design and methods: This multicentric prospective clinical trial seeks to evaluate the efficacy of Keywords: bilateral lung LD-RT therapy as a treatment for interstitial pneumonia in patients with COVID-19 for COVID Radiotherapy improving respiratory function. Pneumonia This prospective study will have 2 phases: I) an exploratory phase enrolling 10 patients, which will assess the feasibility and efficacy of low-dose lung irradiation, evaluated according to an increase in the PaO2/FiO2 ratio of at least 20% at 48–72 h with respect to the pre-irradiation value. If a minimum efficiency of 30% of the patients is not achieved, the study will not be continued. II) Non-randomized comparative phase in two groups: a control group, which will only receive pharmacological treatment, and an experimental arm with pharmacological treatment and LD-RT. It will include 96 patients, the allo- cation will be 1: 2, that is, 32 in the control arm and 64 in the experimental arm. The primary end-point will be the efficacy of LD-RT in patients with COVID-19 pneumonia according to an improvement in PaO2/FiO2. Secondary objectives will include the safety of bilateral lung LD-RT, an improvement in the radiology image, overall mortality rates at 15 and 30 days after irradiation and characterizing anti- inflammatory mechanisms of LD-RT by measuring the level of expression of adhesion molecules, anti- inflammatory cytokines and oxidative stress mediators. Trial registration: ClinicalTrial.gov NCT-04380818 https://clinicaltrials.gov/ct2/show/NCT04380818? term=RADIOTHERAPY&cond=COVID&draw=2&rank=4. Ó 2020 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Background being a drain on health resources, which is causing a blockage of almost the entire world health system. Most of the patients devel- COVID-19 is a viral disease originated by a single-stranded RNA oped pneumonia with a serious inflammatory component, the so- virus of the Coronaviridae family and is characterized by being called cytokine release syndrome or cytokine storm syndrome highly contagious, having a non-negligible morbidity rate and (CSS), which in some cases can lead to acute respiratory distress syndrome (ARDS) and death from respiratory failure. According to Chinese experience, 81% of the clinical cases were mild in nature ⇑ Corresponding author. with an overall fatality rate of 2.3%, while a small subgroup of 5% E-mail address: angel.monteroluis@gmail.com (A. Montero). suffered respiratory failure, septic shock, and multiple organ 1 These three authors contributed equally to this job. https://doi.org/10.1016/j.ctro.2020.06.005 2405-6308/Ó 2020 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 30 M. Algara et al. / Clinical and Translational Radiation Oncology 24 (2020) 29–33 failure leading to death in half of these cases, suggesting that it is irradiation also lowers the levels of NO, iNOS, L and E selectins, within this group that the opportunity to save lives exists if appro- ROS, TNF- a or IL-beta 1 secretion together with an increase in pro- priate measures are taken [1]. Clinical observations suggest that duction and expression of anti-inflammatory cytokines, such as when the immune response is unable to effectively control the anti-inflammatory cytokine TGF-b1 and of apoptosis mediators virus, as in older people with a weakened immune system, the such as NF-jB. This anti-inflammatory effect of LD-RT was greatest virus spreads more efficiently, causing lung tissue damage, which at 48 h after irradiation and was lost after 72 h [6–10]. All of these activates macrophages and granulocytes and leads to the massive changes result in a local anti-inflammatory environment that release of pro-inflammatory cytokines responsible of associated would explain the clinical effects of LD-RT by reducing inflamma- ARDS [2]. tion and alleviating threatening-life symptoms and could be an There appear to be two distinct but overlapping pathological option to consider for the symptomatic relief of COVID-19 associ- subsets, the first triggered by the virus itself and the second, by ated pneumonia [11–13]. This type of treatment is non-invasive the host response. In the first stage patients will benefit from drug and therefore, a priori, and can be used for all types of patients. therapy directed against the virus and use of anti-inflammatory With this objective, we designed a pragmatic clinical protocol to therapy might not be necessary and might even lead to viral repli- evaluate the efficacy of low-dose lung irradiation as an adjunctive cation although its usefulness in advanced stages might be ques- treatment in interstitial pneumonia in patients with COVID-19. tionable. In the second stage of established lung disease, viral multiplication and localized inflammation in the lung is the norm. 2. Methods During this stage, patients develop viral pneumonia, with a cough, fever, and possibly hypoxia, producing chest radiograph images or 2.1. Study hypothesis computed tomography with bilateral infiltrates or ground glass opacities. Blood tests reveal an increase in lymphopenia along with Bilateral low-dose lung irradiation with a low dose of 0.5 Gy in a transaminitis. Markers of systemic inflammation might be some- single fraction or 1 Gy in 2 separate fractions 48–72 h after the first what elevated. It is at this stage that the majority of COVID-19 depending on the response might interfere with the inflammatory patients would need to be hospitalized for close observation and cascade and reduce the severity of cytokine release, improve treatment. If hypoxia occurs, patients are likely to progress to patient oxygenation, and decrease the risk of fatal evolution and requiring mechanical ventilation, and in that situation, the use of death in patients with symptomatic COVID-19 pneumonia. anti-inflammatory therapies, such as corticosteroids, might be helpful and might be used judiciously. A minority of patients with 2.2. Protocol design COVID-19 will progress to the third and most severe stage of the disease, which manifests as a syndrome of extra-pulmonary sys- Adult patients with COVID-19 with at least moderate to severe temic hyper-inflammation. A CSS occurs, involving a considerable pneumonia that warranted hospitalization will be considered for release of pro-inflammatory cytokines: interleukin (IL) -2, IL-6, this protocol. We propose to include those patients with moderate IL-7, IL-12, the stimulatory factor of granulocyte colonies, macro- to severe dyspnoea, respiratory frequency  30/min, oxygen satura- phage inflammatory protein 1-a, TNF-a, ferritin, and D-dimer are tion with supplemental O2 supply (SpO2) < 92%, PaO2/FiO2 ratio or significantly elevated in those patients with a more severe disease PaFiO2 ratio [the ratio between the blood pressure of the oxygen [3]. To date, there has been no a standardized treatment for such a (partial pressure of oxygen, PaO2) and the percentage of oxygen sup- hyper-inflammatory state. The only treatment options are those plied (fraction of inspired oxygen, FiO2)] < 300 mmHg. Where cases aimed at the side effects caused by the virus, such as inflammation are impossible to determine, PaFiO2, SaO2/FiO2 or SaFiO2 (percent- and pulmonary ARDS. Suppression of the pro-inflammatory mem- age of oxyhaemoglobin saturation in capillary arterial bers of the IL-1 and IL-6 family has been shown to have a therapeu- blood) < 315 mmHg will be used instead. We will also consider pres- tic effect in many inflammatory diseases, including viral infections ence of lung infiltrates > 50% within 24 to 48 h or patients with lab- [3,4]. Corticosteroids are used because of their known ability to oratory abnormalities such as C-reactive protein (CRP) > 100 mg/L, modulate a variety of involved cytokines and apparently being D-dimer > 1500 ng/ml, IL-6 > 40 IU or suspected cytokine release effective in reducing immune-pathological damage. Other treat- syndrome, all consistent with a more severe disease. ments that have shown to be effective are the use of cytokine inhi- This prospective, multicentre study was conceived in 2 phases: bitors, such as the monoclonal anti-human interleukin (IL)-6 an exploratory phase, which will include 10 patients, in order to receptor antibody, tocilizumab (IL-6 inhibitor) or anakinra (IL-1 assess the feasibility and efficacy of bilateral lung LD-RT, bearing receptor antagonist) [4,5]. The lack of a highly effective specific in mind that if there is no improvement in PaFiO2/ SaFI02 in at treatment together with the possible failure in the supply of com- least 30% of patients the study will not be continued, and a second monly used drugs because of the great demand, makes it necessary comparative phase in two groups, a control group, which will only to investigate new anti-inflammatory therapies. receive pharmacological treatment, and an experimental one LD-RT has an anti-inflammatory effect, which might be useful in receiving pulmonary LD-RT. This second phase will include 96 the treatment of respiratory complications of COVID-19. The anti- patients, the allocation will be 1: 2, that is, 32 in the control arm inflammatory efficacy of LD-RT has been proven in clinical studies and 64 in the experimental arm. This number has been calculated and there have been several experimental models, both in vitro and by accepting an alpha risk of 0.05 and a beta risk of a 0.2 in a two- in vivo. The radiobiological mechanisms that support this claim are sided test, to find as statistically significant a proportional differ- becoming increasingly known. Unlike high-dose radiation therapy, ence, expected to be of 0.2 in the control group and 0.5 in the which induces the production of pro-inflammatory cytokines in experimental group, with a drop-out rate of 10%. immune and endothelial cells, LD-RT (0.5–1.5 Gy) acts on cells involved in the inflammatory response, producing anti- 2.3. Objectives inflammatory effects. These effects include the inhibition of interactions between leukocytes and endothelial cells, a decrease The primary end-point will be to evaluate the efficacy of low- in the production of endothelial adhesion molecules, a decrease dose pulmonary irradiation as an adjunctive treatment in intersti- in the mediators of inflammation and a lower expression of tial pneumonia in patients with COVID-19 by improving the pro-inflammatory cytokines. As well as promoting the induction PaFiO2 by 20% measured 48–72 h after treatment with respect to of macrophage and polymorphonuclear apoptosis low-dose baseline pre-irradiation measurement. The secondary objectives M. Algara et al. / Clinical and Translational Radiation Oncology 24 (2020) 29–33 31 include assessing the safety of bilateral pulmonary LD-RT, evaluat- Table 1 ing the improvement of the radiological image, overall mortality Inclusion and exclusion criteria of patients with COVID-19 pneumonia. rates at 15 and 30 days after irradiation and characterizing anti- Inclusion Criteria 18 years old inflammatory mechanisms of LD-RT by measuring level of expres- Moderate or severe pneumonia sion of adhesion molecules, anti-inflammatory cytokines and Not candidate for Intensive Care Unit (ICU) <8 days of symptom on-set oxidative stress mediators Standard Medication Hydroxychloroquine or chloroquine 2.4. Patient selection Azithromycin Antivirals Corticosteroids All patients with moderate to severe COVID-19 pneumonia will Anti-IL-6 (tocilizumab) be evaluated by a multidisciplinary board (including different spe- Signed Informed Consent cialties such as Internal Medicine, Pneumology, Infectious Dis- Exclusion Criteria Pregnancy eases, Geriatrics, Intensive Care and Radiation Oncology) to White cell count below 1000/ml determine the benefit of their inclusion in the study. Unable to understand the study Decline to participate in the study Inclusion criteria (Table 1) are: patients over 18 years old with moderate to severe COVID-19 pneumonia as previously described, with <8 days of symptom onset and currently receiving standard will define the PTV and the dosimetry plan will be carried out. medication for COVID-19 at appropriate doses (which would Meanwhile, two radiotherapists wearing PPE will place the patient include, among others, hydroxychloroquine (or chloroquine), azi- in the linear accelerator (linac) coach. At the end of the treatment, thromycin, antivirals, corticosteroids, or anti-IL-6 (tocilizumab)) patients will be removed from the unit by radiotherapists, again and patients who are not candidates for admission to the Intensive equipped with the appropriate PPE, and will be returned to their Care Unit (ICU) due to age, concomitant diseases or general condi- room. The treatment will be carried out on the same linac to a time tion. All patients must read and sign an informed consent docu- schedule in order to avoid the risk of contagion to other patients. ment prior to inclusion. Those patients not meeting inclusion After the completion of the treatment, the treatment room and criteria, those with white cell count below 1000/ml in analytical linac will be decontaminated according to the established protocol. determination within 24 h prior to inclusion, pregnant or those unable to understand purpose of the study will not be enrolled. 2.6. Statistical analysis 2.5. Treatment procedure Through descriptive statistics, the normality of the distributions will be determined and the test will be chosen for comparisons Fig. 1 gives the study flowchart. CT Simulation will be carried between groups. The prospective nature of these comparisons will out on all patients using a simple and repositionable immobiliza- be taken into account. For the probability of mortality and toxicity tion device (pillow and leg wedge) exclusive to COVID-19 patients. calculations the Kaplan-Meier method will be used. In comparisons The volume of both lungs will be determined as CTV, which will be between two groups, we will use the Mann-Whitney U test for increased by 5 mm in all directions, except the superior-inferior non-parametric data and the Student’s t-test for parametric data. which will be 10 mm. Planning will aim to achieve a homogeneous Comparisons among multiple groups will be made by the distribution in the area to be treated that meets ICRU criteria of Kruskal-Wallis test or by ANOVA. The diagnostic accuracy of the between 95% and 107% of the prescribed dose of 0.5 Gy in single analysed parameters will be studied using ROC curves. Multivari- fraction or 1 Gy in two fractions 48–72 h apart (D95%  95% pre- ate analyses will include the PLDSA and the VIP, calculated using scribed dose and Dmax  107% prescribed dose). The heart will the MetaboAnalyst program. In the case of multiple comparisons, be considered an organ at risk and the dose will be established, the results will be interpreted according to a previously designated although given the ultra-low doses this is not necessary for critical False Discovery Rate value. For the analysis of results, software organs beyond the ALARA principle (As Low As Reasonably Achiev- programs such as SPSS, GraphPad Prism 6.0, MIX 2.0, ‘‘R” able https://www.cdc.gov/nceh/radiation/alara.html). All patients (https://cran.r-project.org/) and the Ingenuity Pathway Analysis will receive a single dose of 0.5 Gy and in the case of non- (IPA) will be used. For more complex statistics, which mainly efficacy and at the discretion of the researcher another 0.5 Gy dose include the integration of metabolic and biochemical data, existing will be repeated 48–72 h later. The patient will be followed up in analysis and specific ‘‘R” packages will be required. the hospital unit, measuring the PaFiO2/ SaFI02 and taking clinical data at 6, 24, 48 and 72 h and on days + 4 and + 7, and a control 2.7. Ethical aspects chest CT will also be carried out on days + 7 and + 30. Blood deter- mination of lymphocytes and mediators of inflammation (CRP, D- No financial compensation is foreseen for volunteer partici- dimer, ferritin and LDH) will be determined on days + 1, +4 pants, there will be no healthy volunteers and all subjects included and + 7 and later depending on the evolution of the condition must present the SARS-CoV-2 infection. This project will be carried (Table 2). Treatment-related acute adverse events will be assessed out in accordance with national and international guidelines, the according to CTCAE v5.0. basic principles of protection of human rights and dignity as stated For the preparation and administration of the irradiation, all in the Declaration of Helsinki (64th General Assembly, Fortaleza, necessary measures will be followed to guarantee the safety of Brazil, October 2013), and according to the regulations in force. patients and staff regarding the risk of SARS-CoV-2 transmission, The treatment, communication and transfer of the personal data following the regulations and instructions of each centre. On the of the study subjects will be processed and notified as necessary day of treatment, two technicians with the appropriate personal for the purposes of the study and in accordance with Regulation protective equipment (PPE) will place the patient according to (EU) 2016/679 of the European Parliament and the Council of April the protocol of the Radiation Oncology Department in order to 27, 2016 Data Protection (RGPD). The results of this study will be carry out the planned radiotherapy CT. The radiation oncologist published regardless of whether they are positive, negative or will verify the correct positioning (using a planar or tomographic inconclusive. The study has been approved by the Institution image) and the treatment will be carried out from the CT console. Research Board of each centre and is registered in ClinicalTrials.- Subsequently, the lungs will be delimited, a radiation oncologist gov, NCT-04380818. 32 M. Algara et al. / Clinical and Translational Radiation Oncology 24 (2020) 29–33 Fig. 1. Study flowchart. Table 2 Chronogram and monitoring plan. Procedures Selection Day 0 6h 12 h Day 1 Day 2 Day 4 Day 7 Day 30 Inclusion Criteria X Informed Consent signature X Medication X X X PAFIo2/SAFIO2 X X X X X X X X X Chest CT X X X Blood determinations X X X X X X Blood samples X X X X Irradiation X X* Adverse effects X X X X X X *When needed. 2.8. Status of the study 3. Discussion Phase I of the study is currently ongoing and patients are being Radiotherapy has been used for more than a century in the recruited. treatment of pneumonia, especially interstitial and atypical. In a M. Algara et al. / Clinical and Translational Radiation Oncology 24 (2020) 29–33 33 review by Calabrese et al., LD-RT to the lungs has demonstrated with its low acute and late toxicity profile, it is an option that could good response rates and resolution of symptoms. The authors be considered for patients with COVID-19 pneumonia. reviewed 15 studies covering 863 cases of bacterial pneumonia (lobular and bronchopneumonia), interstitial, and atypical pneu- Declaration of Competing Interest monia that were effectively treated with low-dose X-rays, improv- ing symptoms, increasing cure rates, and reducing mortality. The The authors declare that they have no known competing finan- mechanism by which X-ray treatment acts on pneumonia involves cial interests or personal relationships that could have appeared the induction of an anti-inflammatory phenotype that leads to a to influence the work reported in this paper. rapid reversal of clinical symptoms, facilitating resolution of the disease. Treatment was most effective when irradiation was Acknowledgement administered 6 to 14 days after the clinical onset of the disease. After 14 days, the successful response rate decreased by approxi- To the Spanish Group for Clinical Research in Radiation Oncol- mately 50%. The authors’ conclusion is that LD-RT offers excellent ogy - Spanish Society of Radiation Oncology (GICOR-SEOR 2020) potential as a treatment for interstitial pneumonia, especially for extraordinary grant for radiation research during COVID-19 to when used during the early stages of the disease [14]. The group cover the cost of legal insurance for the clinical trial. of Calabrese et al. reviewed the results published for >37,000 patients treated in the first half of the 20th century with LD-RT (be- References tween 0.3 and 1.5 Gy total) for different benign diseases character- ized by inducing inflammatory states, including both degenerative [1] Ge H, Wang X, Yuan X, et al. The epidemiology and clinical information about COVID-19 [published online ahead of print, 2020 Apr 14]. Eur J ClinMicrobiol and infectious disorders. The authors justify that the success of LD- Infect Dis 2020:1–9. https://doi.org/10.1007/s10096-020-03874-z. RT is directly related to the hyper-inflammatory state and to the [2] Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines anti-inflammatory effect of radiation at low doses. The authors (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS- CoV- 2): anti-inflammatory strategies pii: 1. J Biol Regul Homeost Agents 2020 conclude that a total dose in the range of 0.3–1 Gy probably Mar;34(2). https://doi.org/10.23812/CONTI-E. induces the expression of an anti-inflammatory phenotype that [3] Siddiqi Hasan K, Mehra Mandeep R. COVID-19 illness in native and can reduce inflammation and pain and promote tissue recovery immunosuppressed states: a clinical–therapeutic staging proposal. J. Heart Lung Transp 2020;39(5):405–7. https://doi.org/10.1016/j.healun.2020.03.012. in most subjects, although it should not be surprising that a per- [4] Russell B, Moss C, George G, et al. Associations between immune-suppressive centage of patients did not respond equally well [15]. and stimulating drugs and novel COVID-19—a systematic review of current Recently, in a 2020 publication, Dhawan et al. propose a total evidence. Ecancermedicalscience 14: 1022. https://doi.org/10.3332/ ecancer.2020.1022. dose of 0.3–0.5 Gy in the thoracic region for patients with [5] Zhang Wen, Zhao Yan, Zhang Fengchun, Wang Qian, Li Taisheng, Liu Zhengyin, COVID-19 in the acute phase of the disease, when cytokines Wang Jinglan, Qin Yan, Zhang Xuan, Yan Xiaowei, Zeng Xiaofeng, Zhang increase, and for those who present a moderate or severe clinical Shuyang. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical situation (‘‘cytokine storm”). According to those authors, the theo- immunologists from China. Clin Immunol 2020;214:108393. https://doi.org/ retical basis that would justify the use of LD-RT in patients with 10.1016/j.clim.2020.108393. COVID-19 rests on the fact that inflammation mediators triggered [6] Rödel F, Frey B, Manda K, et al. Immunomodulatory properties and molecular by COVID-19 initiate the cascade that leads to a hyper- effects in inflammatory diseases of low-dose x-irradiation. Front Oncol 2012. 2: 120. Published 2012 Sep 25. doi:10.3389/fonc.2012.00120. inflammatory state, the so-called ‘‘cytokine storm”, ultimately [7] Arenas M, Sabater S, Hernández V, et al. Anti-inflammatory effects of low-dose responsible for the rapid and extensive damage to the lungs and radiotherapy. Strahlenther Onkol 2012;188(11):975–81. other organs. The well-known anti-inflammatory phenotype [8] Arenas M, Gil F, Gironella M, et al. Time course of anti-inflammatory effect of low-dose radiotherapy: correlation with Epub 2007 Nov 26. induced by LD-RT is expected to decrease the intensity and severity [9] Torres L, Antelo G, Árquez, M, Arenas M. Low-Dose radiation therapy for of COVID-19 pneumonia [12]. benign pathologies. Rep Pract Oncol Radiother. 2020. Mar–Apr; 25(2):250–4. As with any other clinical protocol, both strengths and weak- doi: 10.1016/j.rpor.2020.02.004. Epub 2020 Feb 22. [10] Lödermann B, Wunderlich R, Frey S, et al. Low dose ionising radiation leads to nesses can be found when considering the use of LD-RT for a NF-jB dependent decreased secretion of active IL-1b by activated COVID-19 pneumonia. We are fully aware that the use of LD-RT macrophages with a discontinuous dose-dependency. Int J Radiat Biol does not replace any of the treatments currently in use and that 2012;88(10):727–34. [11] Kirkby C, Mackenzie M. Is low dose radiation therapy a potential treatment for it should not be recommended for all COVID-19 patients, but it COVID-19 pneumonia?. Radiother Oncol 2020. https://doi.org/10.1016/j. could be considered for those patients in a more critical condition radonc.2020.04.004. and when other treatment options have failed, are not indicated or [12] Dhawan G, Kapoor R, Dhawan R, et al. Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory it is not possible to access them quickly and easily. An additional distress syndrome (ARDS). Radiother Oncol 2020. https://doi.org/10.1016/j. advantage of this treatment would be that, unlike vaccines and radonc.2020.05.002. pharmacological treatments that depend on the stock, radiother- [13] Lara Pedro C, Burgos Javier, Macias David. Low dose lung radiotherapy for apy devices are always available for the treatment of patients with- COVID-19 pneumonia. The rationale for a cost-effective anti-inflammatory treatment. Clin Trans Radiat Oncol 2020;23:27–9. https://doi.org/10.1016/j. out being subject to fluctuations according to higher demand. But ctro.2020.04.006. on the other side, one of the aspects that has sometimes prevented [14] Calabrese EJ, Dhawan G. How radiotherapy was historically used to treat researchers from using LD-RT for the treatment of benign diseases pneumonia: could it be useful today? Yale J Biol Med. 2013;86(4):555–70. Published 2013 Dec 13. has been the risk of late complications, especially the development [15] Calabrese E, Dhawan G, Kapoor R, Kozumbo W. Radiotherapy treatment of of secondary cancers. Studies into the safety of LD-RT for the treat- human inflammatory diseases and conditions: Optimal dose. Hum Exp Toxicol ment of benign non-tumour pathology have all concluded that the 2019;38(8):888–98. https://doi.org/10.1177/0960327119846925]. [16] Jansen JTM, Broerse JJ, Zoetelief J, et al. Estimation of the carcinogenic risk of risk of presenting complications attributable to irradiation is extre- radiotherapy of benign diseases from shoulder to heel. Radiother Oncol mely low at the doses suggested in the present study [16–19]. 2005;76(3):270–7. In conclusion, there is a broad metabolic and immunological [17] Trott R, Kamprad F. Estimation of cancer risks from radiotherapy of benign diseases. Strahlenther Onkol 2006;182(8):431–6. basis that would justify the use of LD-RT in COVID-19 patients, [18] Mazonakis M, Damilakis J. Cancer risk after radiotherapy for benign diseases. mainly in the most advanced stages of the disease when it could PhysicaMedica: Eur J Med Phys 2017;42:285–91. be effective by acting as a powerful anti-inflammatory agent [19] Trott KR, McKeown SR, Hatfield P, et al. Radiotherapy for benign disease; assessing the risk of radiation-induced cancer following exposure to against the cascade of pro-inflammatory cytokines, and together intermediate dose radiation. Br J Radiol 2015;88:20150405.