Journal of Radiation and Cancer Research

EDITORIAL
Year
: 2021  |  Volume : 12  |  Issue : 2  |  Page : 39--40

Early indications of clinical trials direct toward need of research for successful low-dose radiation therapy for COVID-19 pneumonia


Badri Narain Pandey 
 Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India

Correspondence Address:
Dr. Badri Narain Pandey
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra
India




How to cite this article:
Pandey BN. Early indications of clinical trials direct toward need of research for successful low-dose radiation therapy for COVID-19 pneumonia.J Radiat Cancer Res 2021;12:39-40


How to cite this URL:
Pandey BN. Early indications of clinical trials direct toward need of research for successful low-dose radiation therapy for COVID-19 pneumonia. J Radiat Cancer Res [serial online] 2021 [cited 2021 Sep 22 ];12:39-40
Available from: https://www.journalrcr.org/text.asp?2021/12/2/39/318946


Full Text



Coronavirus disease (COVID-19) as a global pandemic engulfed >3 million lives around the world.[1] The multiple waves of the disease, not only added tremendous pressure on the health infrastructure but also severely affected the economic activities, especially in developing countries like India. Severe acute respiratory syndrome coronavirus 2, the causative agent of the pandemic, poses serious clinical challenges through damage of several critical organs, especially the lungs. Infected host cell releases damage-associated molecular patterns (such as adenosine triphosphate (ATP) and nucleic acids), which when gets recognized by the surrounding epithelial cells, endothelial cells, and alveolar macrophages, generate excessive amount of pro-inflammatory cytokines/chemokines. Such inflammatory condition of “cytokine storm” results in damage to lung cells associated with mortality of COVID-19 patients through acute respiratory distress syndrome (ARDS), sepsis, pneumonia and respiratory failure.[2],[3] To overcome the pathogenesis due to inflammatory response, various strategies have been explored including the application of anti-inflammatory agents (such as corticosteroids and fingolimod). In addition, the antagonists for cytokines (such as tocilizumab an interleukin-6 receptor blocker, mavrilimumab, gimsilumab, lenzilumab affect action of granulocyte-macrophage colony-stimulating factor through binding) are also being evaluated to mitigate the harmful effects of the elevated cytokines.[4]

In this direction, several publications appeared advocating low-dose radiation therapy (LDRT) for the treatment of pneumonia/ARDS in COVID-19 patients using gamma/X-ray irradiation of lungs in the range of 0.3-1.5 Gy.[3],[5] LDRT for the treatment of pneumonia/ARDS is based on the known anti-inflammatory effect of low-dose irradiation, which was further supported by the evidences generated in the early twentieth century for the treatment of bacterial infection and pneumonia using low-dose therapy. Despite some apprehensions, several clinical trials were initiated globally for the application of LDRT for pneumonia in Covid-19 patients.[6] The outcome of a few clinical trials has been published recently, which, however, created more confusion than consensus about LDRT. A preliminary result from Sanmamed et al.[7] using nine patients after administering 0.1 Gy dose to total lungs suggested LDRT as feasible and well-tolerated treatment modality. The study showed radiological improvement while surveillance computed tomography after 7 days of LDRT. Improved clinical recovery and response rate were observed in another clinical trial after whole lung irradiation with 0.5 and 1 Gy.[8] The outcome could be questioned due to the lack of control cohort in these clinical trials. In another clinical trial by Hess et al.[9] showed improved median time to clinical recovery, i.e. 3 days for LDRT (1.5 Gy to bilateral lungs) cohort than 12 days in the control cohort. This study also showed that LDRT cohort trended toward superior rates of improved radiographs and anti-inflammatory (such as C-reactive protein and lactate dehydrogenase)/immune-modulatory (reduction in monocytes and neutrophil-lymphocytes ratio) biomarkers. This study suggested LDRT to be safe without any acute toxicity. The weaknesses of these clinical trials were overcome by a randomized double-blinded clinical trial,[10] which, however, concluded that whole-lung LDRT failed to improve clinical outcomes in critically ill patients requiring mechanical ventilation for COVID-19 pneumonia.

Even though many clinical trials are still ongoing, the outcome of a few clinical trials provides an overview of LDRT and the underlying challenges. A few points become clear from these clinical trials (i) there is a need for more randomized double-blinded control trials with more number of patients; (ii) LDRT may work in a window of radiation dose, dose fraction and interval, which need to be optimized; and (iii) age of patients, stage of infection, comorbidity conditions and history of other therapies seem to play a role in the outcome of LDRT and hence need to be considered in future clinical trials. General apprehensions prevailed among clinicians (about risk of cardiac problem and cancer incidence after low dose radiation) are much more than saving human lives through low dose radiation in health crisis situation. Many barriers in clinicians' attitude toward application of LDRT in Covid 19 patients were brought out recently.[11] The logistic issue in hospital set up particularly the risk of transmission of disease to non-Covid patients is highly valid, which, however, could be worked out to save the fragile Covid-19 patients without much treatment options left. Lack of data to prove benefit versus risk of LDRT is another barrier in the attitude of the clinicians, which upto some extent could be overcome by a positive vibrance of a few clinical trials of LDRT. However, the failed outcome of a clinical trial again puts a question mark about LDRT.

The confidence of clinicians needs to be supported through strong backing of mechanistic insights obtained from in vivo and preclinical models. There is also a dare need to optimize the window of radiation dose/dose rate, frequency/intervals of radiation doses, age groups of patients, and stage of infection. A recent workshop with multidisciplinary participants favored exploration of LDRT for COVID-19 in both human clinical trials and animals.[12] It would be of utmost importance that an extensive low-dose research in the coming days would facilitate overcoming the barriers in the mind of clinicians and researchers.

Whatever outcome would be of future/ongoing clinical trials of LDRT in COVID-19 patients, it would strengthen and shape the future low-dose radiation biology research. A positive outcome would build a confidence in the clinicians to adopt a rather orphan mode of therapy. As blessings in disguise, the negative results would put challenges before radiation researchers to discover the unexplored shores of low-dose radiation biology for exploiting it for the betterment of mankind.

References

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3Pandey BN. Low-dose radiation therapy for coronavirus disease-2019 pneumonia: Is it time to look beyond apprehensions? Ann Thoracic Med 2020;15:199-207.
4Cyranoski D. Profile of a killer: The complex biology powering the coronavirus pandemic. Nature 2020;581:22-6.
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6U.S. National Library of Medicine, COVID-19 and Low dose Radiation Therapy Clinical Trial; 2020. Available from: https://clinicaltrials.gov/ct2/results?cond=Covid-19&term=low+dose+radiation+therapy&cntry=&state=&city=&dist. [Last accessed on 2021 June 10].
7Sanmamed N, Alcantara P, Cerezo E, Gaztañaga M, Cabello N, Gómez S, et al. Low-dose radiation therapy in the management of coronavirus disease 2019 (COVID-19) pneumonia (LOWRAD-Cov19): Preliminary report. Int J Radiat Oncol Biol Phys 2021;109:880-5.
8Ameri A, Ameri P, Rahnama N, Mokhtari M, Sedaghat M, Hadavand F, et al. Low-dose whole-lung irradiation for COVID-19 pneumonia: Final results of a pilot study. Int J Radiat Oncol Biol Phys 2021;109:859-66.
9Hess CB, Nasti TH, Dhere VR, Kleber TJ, Switchenko JM, Buchwald ZS, et al. Immunomodulatory low-dose whole-lung radiation for patients with coronavirus disease 2019-related pneumonia. Int J Radiat Oncol Biol Phys 2021;109:867-79.
10Papachristofilou A, Finazzi T, Blum A, Zehnder T, Zellweger N, Lustenberger J, et al. Low-dose radiation therapy for severe COVID-19 pneumonia: A randomized double-blind study. Int J Radiat Oncol Biol Phys 2021 (In press). [doi: 10.1016/j.ijrobp.2021.02.054].
11Hanna CR, Robb KA, Blyth KG, Jones RJ, Chalmers AJ. Clinician attitudes to using low-dose radiation therapy to treat COVID-19 lung disease. Radiat Oncol Biol 2021;109:886-90.
12Prasanna PG, Woloschak GE, DiCarlo AL, Buchsbaum JC, Schaue D, Chakravarti A, et al. Low-dose radiation therapy (LDRT) for COVID-19: Benefits or risks? Radiat Res 2020;194:452-64.