Clinical and Translational Oncology https://doi.org/10.1007/s12094-020-02401-y EDITORIAL Low‑dose radiation therapy: could it be a game‑changer for COVID‑19? A. Montero1 · M. Arenas2 · M. Algara3 Received: 13 April 2020 / Accepted: 12 May 2020 © Federación de Sociedades Españolas de Oncología (FESEO) 2020 It is only afterwards that a new 81% of the clinical pictures were mild in nature with an over- idea seems reasonable. To begin with, it usually seems all case fatality rate of 2.3%, while a small subgroup of 5% unreasonable had respiratory failure, septic shock, and multi-organ failure -Isaac Asimov - leading to death in half of these cases. Some patients with COVID-19 disease may experience a cytokine release syn- drome (SLC) caused by a systemic inflammatory response At the beginning of December 2019, the first cases of a new that occurs when large numbers of leukocytes (neutrophils, acute respiratory syndrome, of extraordinary contagious- macrophages, and mast cells) are activated and release large ness, began to be described in the city of Wuhan, the capital amounts of proinflammatory cytokines (interleukin (IL)-6, of Hubei province, in central China. New virus, a severe IL-10, interferon (IFN), monocyte chemoattractant protein-1 acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (MCP-1), granulocyte–macrophage colony-stimulating fac- thus far unknown in the human species, was identified as tor (GM-CSF), tumor necrosis factor α (TNF-α), IL-1, IL-2, the causative agent. Since then, humanity has witnessed a IL-8). Clinical observations suggest that when the immune rapid spread of this RNA virus throughout the world, being response is unable to effectively control the virus, as in older recognized by the World Health Organization (WHO) as a people with a weakened immune system, the virus would pandemic on March 11, 2020. As of 12th April 2020, over spread more efficiently, causing lung tissue damage, which 1 614,951 cases and nearly 100,000 deaths are reported would activate macrophages and granulocytes and would worldwide [1]. The consequences of the coronavirus dis- lead to the massive release of proinflammatory cytokines. ease (COVID-19) have been quickly noticed, being Spain This pulmonary hyperinflammation would be associated is one of the countries where the infection has shown the with SARS, which has been described as the main cause of most virulence, putting our national health care system at an COVID-19 mortality [2]. There are two distinct but over- imaginable stress and with evident risk of collapse in case lapping pathological subsets, the first triggered by the virus of uncontrolled outbreaks. itself and the second, the host response. Although in the COVID-19 is a respiratory disease caused by this coro- first stage patients will benefit from drug therapy directed navirus that produces significant morbidity and mortality. against the virus, its usefulness in advanced stages may be The most frequent symptoms are fever, dry cough, asthenia, questionable. Similarly, the use of anti-inflammatory therapy expectoration, dyspnea, sore throat, headache, arthromyal- applied too early may not be necessary and may even cause gia, among others. Some patients develop pneumonia that viral replication. In the second stage of established lung dis- can lead to respiratory failure or severe acute respiratory ease, viral multiplication and localized inflammation in the syndrome (SARS). According to the Chinese experience, lung is the norm. During this stage, patients develop viral pneumonia, with a cough, fever, and possibly hypoxia, chest * A. Montero radiograph images, or computed tomography with bilateral angel.monteroluis@gmail.com infiltrates or ground glass opacities. Blood tests reveal an increase in lymphopenia, along with transient elevation 1 Oncología Radioterápica, Hospital Universitario HM of transaminases. Systemic inflammation markers may be Sanchinarro, Madrid, Spain elevated, but not markedly. It is at this stage that the major- 2 Oncología Radioterápica, Hospital Universitario Sant Joan de ity of COVID-19 patients would need to be hospitalized for Reus, Universitat Rovira I Virgili, Reus, Spain close observation and treatment. If hypoxia occurs, patients 3 Oncología Radioterápica, Hospital de la Esperanza, Parc are likely to progress to requiring mechanical ventilation, de Salut del Mar, Universitat Autónoma de Barcelona, Barcelona, Spain and in that situation, the use of anti-inflammatory therapy 13 Vol.:(0123456789) Clinical and Translational Oncology may be helpful and may be used judiciously. A minority (membrane-bound IL-6 receptor (mIL6R) and soluble IL-6 of patients with COVID-19 will progress to the third and receptor (sIL6R)) and inhibit signal transduction. Russell most severe stage of the disease, manifesting as a syndrome et al. have recently published a systematic review of current of extra-pulmonary systemic hyperinflammation. At this evidence for treatment with immunosuppressants, cytotoxic stage, systemic inflammation markers will be elevated and chemotherapy, steroids, TNF-α blockers, IL-6 block, Janus COVID-19 infection causes a decrease in helper, suppressor, kinase inhibitors (JAK), block IL-1, mycophenolate, tacroli- and regulatory T cells. [3]. mus, anti-CD20 and CTLA4-Ig. After reviewing 89 studies, Currently, there is no effective treatment capable of treat- the authors’ conclusion is that low doses of prednisolone ing SARS-CoV-2, and the only treatments are those aimed and tacrolimus may have beneficial effects on COVID-19, at the side effects caused by the virus, such as inflamma- as well as that IL-6 levels are associated with the severity tion and pulmonary fibrosis, recognized as the first causes of pulmonary complications, although there is no evidence of death. Chloroquine/hydroxychloroquine treatment has regarding the beneficial impact of IL-6 inhibitors on the demonstrated some efficacy for COVID-19. The results of course of COVID-19 disease [7]. the study by Chen et al. from Wuhan University, showed In the constant and incessant search for treatments against improvement in those COVID-19 patients who were admin- COVID-19, it has been suggested that low-dose radiation istered hydroxychloroquine versus placebo in addition to therapy (LD-RT) could play a role for their anti-inflamma- standard treatment with oxygen therapy, antivirals, antibi- tory effects. The dose is below 1% of doses used for cancer otics, immunoglobulins, or corticosteroids and also hydroxy- treatment and the range between 0.3 and 0.7 Gy. LD-RT chloroquine could transmit some protection against worsen- has been used for more than a century in the treatment of ing of the disease [4]. Likewise, Gautret et al. observed a pneumonia, especially interstitial and atypical. In the review possible synergistic effect of the combination of hydroxy- by Calabrese et al., low doses of radiation to the lungs were chloroquine and azithromycin, although the authors also found to be associated with good response rates and resolu- warn against a possible unwanted risk effect in relation to tion of symptoms. The authors reviewed 15 studies including the severe prolongation of the QT interval induced by the 863 cases of bacterial pneumonia (lobular and bronchopneu- association of the two drugs [5]. Despite the encouraging monia), interstitial, and atypical pneumonia that were effec- results, both studies have limitations in relation to a small tively treated with low-dose X-rays, improving symptoms, sample size, short follow-up, lack of group control and a increasing cure, and reducing mortality. The mechanism not inconsiderable percentage of patients abandoned the by which X-ray treatment acts on pneumonia involves the studies but have established the most widely used treatment induction of an anti-inflammatory phenotype that leads to today to deal with SARS-CoV-2 infection. However, a recent a rapid reversal of clinical symptoms, facilitating resolu- systematic review by Pacheco and Riera on the efficacy of tion of the disease. Treatment was most effective when irra- chloroquine or hydroxychloroquine in COVID-19 patients diation was administered 6–14 days after the clinical onset concluded that according to the data from the two avail- of the disease. After 14 days, the successful response rate able studies, and of their limited methodological quality, the decreased by approximately 50%. The authors’ conclusion efficacy and safety of chloroquine or hydroxychloroquine is that LD-RT offers excellent potential as a treatment for treatment in COVID-19 patients is still uncertain and that interstitial pneumonia, especially when used during the early its regular use should not be recommended until further evi- stages of the disease [8]. dence is available [6]. Suppression of the proinflammatory The anti-inflammatory effects of LD-RT have been members of the IL-1 and IL-6 family has been shown to confirmed in several experimental models, both in vitro have a therapeutic effect in many inflammatory diseases, and in vivo and in clinical studies. The radiobiologi- including viral infections. Suppression of IL-1β by IL-37 cal mechanisms that support this claim are increasingly in an inflammatory state induced by COVID-19 may have known. Unlike high-dose radiation therapy that induces a therapeutic effect in this pathology. Overall, there appear the production of proinflammatory cytokines in immune to be some positive results for the use of corticosteroids in and endothelial cells, paradoxically LD-RT (0.5–1.5 Gy) viral infections such as SARS-CoV-2. Corticosteroids are acts on cells involved in the inflammatory response, used because of their known ability to modulate a variety producing anti-inflammatory effects. The mechanisms of involved cytokines (including IL-1, IL-6, IL-8, IL-12, that explain these anti-inflammatory effects are due to a and TNFα). Several human studies found that corticosteroid decrease in polymorphonuclear cells to endothelial cells seemed effective in reducing immunopathological damage. and the induction of apoptosis, a decrease in the expres- Another treatment that has been shown to be effective is sion of adhesion molecules (selectins (P-, L-, E-), ICAM, the monoclonal anti-human IL-6 receptor antibody, toci- VCAM), a decreased production of nitric oxide (NO), lizumab (used in the treatment of rheumatoid arthritis). It increased activation of nuclear factor kappa-beta (NK- can specifically bind the two forms of the IL-receptor 6 KB), and increased production of cytokines by endothelial 13 Clinical and Translational Oncology cell and immune cells (IL-10, transforming growth factor Currently, only ICU admittance can recover patients anti-inflammatory cytokine β1 (TGF- β 1)) [9–13]. All of severely afflicted by COVID pneumonia. Severely diseased these changes result in a local anti-inflammatory environ- COVID-19 patients with pre-existing comorbidities and ment that would explain the clinical effects of LD-RT. The older patients represent a gap in the current clinical prac- evidence obtained from laboratory studies demonstrated tice because they usually are not considered candidates to the maximum anti-inflammatory effect of radiotherapy in aggressive manoeuvres. Ultra LD-RT to both lungs could be the environment with doses of 0.3–0.7 Gy per fraction [9, an option for these patients with COVID-19 pneumopathy 10]. Likewise, in vitro experiments showed that the anti- by decreasing the inflammatory storm while contributing to inflammatory effect of LD-RT was greatest at 48 h after reduce the overload of the health system, especially in ICU. irradiation and was lost after 72 h justifying the interval We are convinced that the possibility of having a treatment of at least 48 h between the administrations of consecutive that is not subject to fluctuations in its acquisition, with low radiation therapy fractions [8–13]. cost and available in many centers without the need for a Choosing the right time to administer LD-RT in COVID- high financial investment should also be considered under 19 patients is challenging. It is at the beginning of the the current circumstances of the COVID-19 pandemic. proinflammatory phase that the use of anti-inflammatory treatments such as corticosteroids and cytokine inhibi- tors tocilizumab (IL-6 inhibitor) or anakinra (IL-1 recep- tor antagonist) seems to be justified. Presumably, it is in Compliance with ethical standards this phase where LD-RT to both lungs could be effective by acting as a powerful anti-inflammatory agent against the Conflict of interest The authors have declared no conflicts of interest. cascade of proinflammatory cytokines [2]. There are several Ethical approval This article do not contain any studies with human advantages associated with the use of LD-RT as proposed: participants or animals performed by any of the authors. radiotherapy treatment units are available and the procedure for the proposed treatment is optimized to simplify its devel- Informed consent For this type of study formal consent is not required. opment as much as possible. Furthermore, the objective of this treatment is pragmatically designed to be used in a seg- ment of patients with limited treatment alternatives and who References in the current situation are not candidates for mechanical ventilation measures and intensive care units (ICU). 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