Low-dose radiotherapy for COVID-19 pneumonia and cancer: summary of a recent symposium and future perspectives.

The lessons learned from the Coronavirus Disease 2019 (COVID-19) pandemic are numerous. Low dose radiotherapy (LDRT) was used in the pre-antibiotic era as treatment for bacterially/virally associated pneumonia. Motivated in part by these historic clinical and radiobiological data, LDRT for treatment of COVID-19-associated pneumonia was proposed in early 2020. Although there is a large body of epidemiological and experimental data pointing to effects such as cancer at low doses, there is some evidence of beneficial health effects at low doses. It has been hypothesized that low dose radiation could be combined with immune checkpoint therapy to treat cancer. We shall review here some of these old radiobiological and epidemiological data, as well as the newer data on low dose radiation and stimulated immune response and other relevant emerging data. The paper includes a summary of several oral presentations given in a Symposium on "Low dose RT for COVID and other inflammatory diseases" as part of the 67th Annual Meeting of the Radiation Research Society, held virtually 3-6 October 2021.

An educational initiative to develop radiotherapy-specific teaching following the introduction of the oncology common stem year

Background: Following the GMC's Excellence by Design report on postgraduate curricula, the clinical oncology (CO) curriculum has been rewritten and includes a shared first year of training - the oncology common stem (OCS) - where medical oncology (MO) and CO trainees have the same curriculum including radiotherapy (RT) skills evidenced with DORPS (direct observation of radiotherapy planning skills) and acute oncology. Radiotherapy planning experience had suffered during the COVID-19 pandemic, with more planning happening remotely. It was realised that additional RT teaching was needed to support both the CO and MO trainees. Method(s): At the Kent oncology centre most MO and CO trainees are ST3 in their OCS year with little prior RT experience. As senior trainees we therefore designed teaching sessions suitable for junior trainees and performed an anonymised online survey after six months of initiation to assess the effectiveness and areas to improve on. Intervention(s): Dedicated 30-minute weekly RT teaching sessions were initiated following site-specific oncology teaching. The teaching programme included an introduction to radiotherapy physics, radiobiology, palliative planning and radical planning. Due to the ongoing COVID-19 pandemic, and cross-site location of trainees, the teaching was held on Microsoft Teams. Planning sessions were 'hands-on', with anonymised cases used to allow each trainee to participate in each case. Result(s): Eight of the ten trainees (80%) attending the teaching completed the survey, two MO trainees and six CO. All responders were ST3/4. Of the MO trainees 100% felt the teaching was 5/5 for usefulness and found the teaching was interesting and helped them meet their curriculum competencies. CO trainees all gave scores of 4/5 or more as to whether the teaching improved their understanding of radiotherapy, and the majority felt it improved their confidence in radiotherapy planning. All CO trainees felt it helped them meet their radiotherapy competencies. 7/9 found the practical planning sessions the most helpful. The majority of the registrars surveyed found that the allocated 30 minutes was sufficient (62.5%). Conclusion(s): The introduction of the oncology core stem by the royal colleges in 2021 has brought together the training of junior medical and clinical oncology registrars. These additional radiotherapy sessions have helped improve trainees' knowledge of RT, and helped them meet their curriculum competencies. We plan to continue to develop this teaching, alongside previously delivered on-the-job teaching, and will continue to evaluate to improve its effectiveness. Keywords: education, radiotherapy, training, OCS Copyright © 2022

Fukushima Daiichi Nuclear Power Station Accident From the Aspect of Radiation Biology and Risk Communication

Fukushima Daiichi Nuclear Power Station Accident in March 2011 caused a massive release of radionuclides, such as I-131, Cs-134 and Cs-137, to the atmosphere. To date, there are no documented health effects among Fukushima residents, which are directly attributable to radiation exposure from the accident. In addition, it is not likely that the incidence of solid cancer and leukemia increases to a discernible extent. Indeed a substantial increase of thyroid cancer is observed, but this is likely due to ultrasensitive screening procedures rather than radiation exposure. Nevertheless, there was increased public concern about the effects of radiation in human health since the accident. I have provided information and knowledge on radiation and its health effects to general public on request. I have been also engaged in scientific education in elementary schools or junior high schools. In 2020 and 2021 under COVID-19 situation, the classes in elementary schools or junior high schools were provided mainly online, where both demerits and merits of online classes were found. I would also briefly introduce recent research to analyze the effects of low dose/low dose-rate radiation on mutation frequency and spectrum in genome-wide.

Radiotherapy treatment interruptions during the Covid-19 pandemic: The UK experience and implications for radiobiology training.

Unintended treatment interruptions during a course of radiotherapy can lead to extended overall treatment times which allow increased tumour cell repopulation to occur. Extra dose may therefore be required to offset any loss of tumour control. However, the manner in which the extra dose is delivered requires careful consideration in order to avoid the risk of increased normal tissue toxicity. Radiobiological modelling techniques can allow quantitative examination of such problems and may be used to derive revised pattens of radiation delivery which can help restore a degree of tumour control whilst limiting the likelihood of excess normal tissue morbidity. Unintended treatment interruptions can occur in any radiotherapy department but the rapid spread of the Covid-19 pandemic caused a major increase in the frequency of such interruptions due to staff and patient illness and the consequent self-isolation requirements. This article summarises the radiobiological considerations and caveats involved in assessing treatment interruptions and outlines the UK experience of dealing with the new challenges posed by Covid-19. The world-wide need for more education programmes in cancer radiobiology is highlighted.

Dose-Effects Models for Space Radiobiology: An Overview on Dose-Effect Relationships.

Space radiobiology is an interdisciplinary science that examines the biological effects of ionizing radiation on humans involved in aerospace missions. The dose-effect models are one of the relevant topics of space radiobiology. Their knowledge is crucial for optimizing radioprotection strategies (e.g., spaceship and lunar space station-shielding and lunar/Mars village design), the risk assessment of the health hazard related to human space exploration, and reducing damages induced to astronauts from galactic cosmic radiation. Dose-effect relationships describe the observed damages to normal tissues or cancer induction during and after space flights. They are developed for the various dose ranges and radiation qualities characterizing the actual and the forecast space missions [International Space Station (ISS) and solar system exploration]. Based on a Pubmed search including 53 papers reporting the collected dose-effect relationships after space missions or in ground simulations, 7 significant dose-effect relationships (e.g., eye flashes, cataract, central nervous systems, cardiovascular disease, cancer, chromosomal aberrations, and biomarkers) have been identified. For each considered effect, the absorbed dose thresholds and the uncertainties/limitations of the developed relationships are summarized and discussed. The current knowledge on this topic can benefit from further in vitro and in vivo radiobiological studies, an accurate characterization of the quality of space radiation, and the numerous experimental dose-effects data derived from the experience in the clinical use of ionizing radiation for diagnostic or treatments with doses similar to those foreseen for the future space missions. The growing number of pooled studies could improve the prediction ability of dose-effect relationships for space exposure and reduce their uncertainty level. Novel research in the field is of paramount importance to reduce damages to astronauts from cosmic radiation before Beyond Low Earth Orbit exploration in the next future. The study aims at providing an overview of the published dose-effect relationships and illustrates novel perspectives to inspire future research.

Clinical application of time factor principles in radiotherapy in compensation of radiation series interruptions.

BACKGROUND: The time factor plays a key role in radiotherapy. The radiotherapy overall treatment time is one of the most important predictive factors in the treatment effectiveness and is associated with better local control and impact on the overall survival. The length of the time from the dia-gnosis to radical radiotherapy or from surgery to adjuvant radiotherapy or the use of alternative fractionation schemes shortening the total treatment time also play an important role. The prevention of prolongation of the radiation series remains a fundamental and well feasible way of applying the time factor in radiotherapy. PURPOSE: Interruption of radiotherapy usually occurs for technical reasons, due to factors at the patients side or for personnel reasons of the department. Standard procedures for the compensation for treatment breaks are part of the treatment protocols at radiotherapy departments. Possible risks of the discontinuation of radiotherapy are considered on the basis of the type and extent of the disease, the treatment intent and the condition of the patient, and the need of compensation for a break in the treatment is set. Patients are classified into three categories according to the above mentioned parameters. Compensation for the pause in radiotherapy is performed by calculating the equivalent dose in 2 Gy per fraction (EQD2); the preferred method of compensation is the one which enables observation of the planned total time of radiotherapy without extension. The benefit of local tumor control and the risk of increased acute or especially late toxicity should always be considered. In the current epidemiological situation, radiotherapy is often discontinued for COVID-19, and due to longer breaks in the treatment, it is necessary to combine multiple compensation methods in one patient.

COVID-19-Associated Pneumonia: Radiobiological Insights.

The evolution of SARS-CoV-2 pneumonia to acute respiratory distress syndrome is linked to a virus-induced "cytokine storm", associated with systemic inflammation, coagulopathies, endothelial damage, thrombo-inflammation, immune system deregulation and disruption of angiotensin converting enzyme signaling pathways. To date, the most promising therapeutic approaches in COVID-19 pandemic are linked to the development of vaccines. However, the fight against COVID-19 pandemic in the short and mid-term cannot only rely on vaccines strategies, in particular given the growing proportion of more contagious and more lethal variants among exposed population (the English, South African and Brazilian variants). As long as collective immunity is still not acquired, some patients will have severe forms of the disease. Therapeutic perspectives also rely on the implementation of strategies for the prevention of secondary complications resulting from vascular endothelial damage and from immune system deregulation, which contributes to acute respiratory distress and potentially to long term irreversible tissue damage. While the anti-inflammatory effects of low dose irradiation have been exploited for a long time in the clinics, few recent physiopathological and experimental data suggested the possibility to modulate the inflammatory storm related to COVID-19 pulmonary infection by exposing patients to ionizing radiation at very low doses. Despite level of evidence is only preliminary, these preclinical findings open therapeutic perspectives and are discussed in this article.

[Low dose radiotherapy for COVID-19 pneumopathy: Biological rationale and literature review]. / Radiothérapie de faible dose pour la pneumopathie covid-19 : rationnel biologique et revue de la littérature.

The world has now been facing the coronavirus disease 2019 (COVID-19) pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since over a year. If most of clinical presentations are benign, fragile patients are at greater risk of developing severe or fatal lung disease. Many therapies have been explored with very low impact on mortality. In this context, Kirkby et Mackenzie have published in April 2020 a report reminding the anti-inflammatory properties of low-dose radiotherapy (delivering less than 1Gy) and its use in the treatment of viral and bacterial pneumopathies before antibiotics era. Large in vivo and in vitro data have demonstrated the biological rationale and anti-inflammatory activity of low-dose radiotherapy in many pathologies. Over the past year, three phase I/II clinical trials have been published, as well as one randomized controlled trial, reporting the feasibility and the clinical and biological improvement of a 0.5 to 1Gy treatment dose to the entire lung. 13 other studies, including a randomized phase III trial, are currently ongoing worldwide. These studies may provide data in the effect of low-dose radiotherapy in the treatment of SARS-CoV-2 pneumonia. This article explains biological rationale of low-dose radiotherapy, and reports already published or ongoing studies on low-dose radiotherapy for SARS-CoV-2 pneumonia.

Resource-sparing curative-intent hypofractionated-accelerated radiotherapy in head and neck cancer: More relevant than ever before in the COVID era.

The incidence of head and neck squamous cell carcinoma (HNSCC) is increasing worldwide, with over three quarters of cases now diagnosed in low and middle-income countries (LMICs) with resource-constraints. Loco-regional recurrence remains the predominant pattern of failure mandating adequate local therapy for acceptable loco-regional control and survival. There is high-quality evidence that intensification of treatment by either by adding concurrent chemotherapy or by altering radiotherapy (RT) fractionation improves outcomes in the curative-intent management of loco-regionally advanced HNSCC. Even conservative estimates indicate that >50% of patients in LMIC are unlikely to get access to timely RT, which will only get compounded with the coronavirus disease (COVID)-19 pandemic. The radiation oncology community has been systematically testing altered fractionation schedules in several solid cancers (breast, lung, and head-neck), given the cost-effectiveness, convenience, and compliance to short-course RT regimens. Radiobiological modelling suggests that standard fractionation of 6-7 weeks in HNSCC can be compressed safely into a 4-week schedule to counter accelerated repopulation by increasing the dose per fraction and delivering 5 fractions per week which is currently being tested in the ongoing multicentric trial of hypo- vs normo-fractionated accelerated RT (HYPNO study). Herein, we discuss the radiobiological basis of curative-intent hypofractionated-accelerated RT schedule delivering 55 Gy in 20 fractions over 4 weeks in HNSCC followed by critical appraisal of the published literature on such regimens with concurrent systemic therapy and its inherent resource-sparing potential applicable across large parts of the world particularly in the context of the ongoing COVID-19 pandemic.

Rationale for the Use of Radiation-Activated Mesenchymal Stromal/Stem Cells in Acute Respiratory Distress Syndrome.

We have previously shown that the combination of radiotherapy with human umbilical-cord-derived mesenchymal stromal/stem cells (MSCs) cell therapy significantly reduces the size of the xenotumors in mice, both in the directly irradiated tumor and in the distant nonirradiated tumor or its metastasis. We have also shown that exosomes secreted from MSCs preirradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from nonirradiated mesenchymal cells, and also that proteins, exosomes and microvesicles secreted by MSCs suffer a significant change when the cells are activated or nonactivated, with the amount of protein present in the exosomes of the preirradiated cells being 1.5 times greater compared to those from nonirradiated cells. This finding correlates with a dramatic increase in the antitumor activity of the radiotherapy when is combined with MSCs or with preirradiated mesenchymal stromal/stem cells (MSCs*). After the proteomic analysis of the load of the exosomes released from both irradiated and nonirradiated cells, we conclude that annexin A1 is the most important and significant difference between the exosomes released by the cells in either status. Knowing the role of annexin A1 in the control of hypoxia and inflammation that is characteristic of acute respiratory-distress syndrome (ARDS), we designed a hypothetical therapeutic strategy, based on the transplantation of mesenchymal stromal/stem cells stimulated with radiation, to alleviate the symptoms of patients who, due to pneumonia caused by SARS-CoV-2, require to be admitted to an intensive care unit for patients with life-threatening conditions. With this hypothesis, we seek to improve the patients' respiratory capacity and increase the expectations of their cure.