Radiation therapy considerations during the COVID‐19 Pandemic: Literature review and expert opinions

COVID-19 is an unprecedented pandemic that has already reached over 2 million confirmed cases globally, with at least 140,000 deaths as reported by the World Health Organization (WHO) as of April 16, 2020 1 . More than 662,000 cases have been reported in the United States with more than 29,000 deaths2 . The overall crude mortality rate now stands at 6.6% (may possibly be lower due to under-testing and under-reporting of total confirmed cases), and is highly dependent on age group, comorbidities, and the locoregional resources medically1 . A report from the United States presented age-stratified COVID-19 associated hospitalization rates among 1,482 patients during March 1-28, 2020, highlighting an alarmingly high rate of 74.5% at age > 50 years with underlining medical conditions3 . Based on a data summary report provided by New York City Health, as of April 14, 2020, the shares of a total of 6839 deaths reached 0.04%, 4.5%, 23.1%, 24.6%, and 47.7% for the age groups of 0-17, 18-44, 45-64, 65-74, and 75+ years old4 . All data suggest that adults at a more advanced age group are facing higher morbidity and mortality risks.

expectedly, the availability of healthcare resources has been significantly compromised. [11][12][13] Radiation oncology departments are not immune to these challenges especially from resource limitation such as PPE and risk/fear of staff exposure impacting day-to-day practices.
Hence, the feasibility of delivering quality assured RT during the pandemic has been called into question leading to the theme of this debate. Through a series of arguments below, we emphasize that cancer care cannot stop and RT is integral to cancer care during the pandemic which is unfortunately expected to last for an extended duration. As such emphasis of institutional policies should be to establish stringent infection control measures to safely treat both COVID-19 positive and negative cancer patients, while ensuring safety of staff and providers.

2.A | Cancer care cannot stop
While the pandemic has clearly impacted the world in more ways than one could have possibly imagined, a demon that cannot be ignored is cancer. Per WHO data, cancer resulted in an estimated 9.6 million deaths in the year 2018 accounting for 1 in 6 deaths. 14 This translates to 800,000 deaths per month, a number much higher than the current pandemic. The stake is high for the cancer patients who by virtue of their immunocompromised state are at a higher risk of contracting and suffering serious complications from COVID-19 infection. [15][16][17][18][19] At the same time, patients have an equally challenging fight at hands with the cancer itself which in many cases may be a more urgent problem. Untreated high-grade brain tumors, advanced head and neck (HN), lung, esophageal, hepato-biliary-pancreatic, and hemato-lymphoid malignancies can result in death in a period of few months or with severe symptomatic progression clinically. These patients may not have the luxury to wait 2-4 months, which is the period that may be needed for a nation to move past the COVID-19 surge activity with subsequent reduction in patient burden. History supports this need to continue cancer care without interruption. In an analysis of the National Cancer Database for impact of hurricane disaster, the longer radiation treatment duration in patients affected by a hurricane disaster (66.9 vs. 46.2 days; P < 0.001) was correlated with significantly worse overall survival. 20 The adjusted relative risk for death increased with increasing length of the disaster declaration. The fact is that cancer care must simply go on uninterrupted! 2.B | Radiotherapyeven more important during pandemic Furthermore, many oncological guidelines are recommending changes in practices for systemic therapy and surgery to minimize immune-compromising effects or adding comorbidities which could predispose to serious complications during the pandemic. 21 In a nationwide analysis in China, undergoing chemotherapy or surgery was correlated with a higher risk of clinically severe COVID-19 events in cancer patients than not receiving chemotherapy or surgery (75% vs 43%, P = 0·0026). 16 Incidentally, the one treatment modality which can be safely delivered with relatively less impact on systemic immune system is radiotherapy. With nearly 50-60% patients with cancer ultimately needing RT in their lifetime, 22,23 in the setting of deferred chemotherapy and surgery, RT may play an even more important role in management of many cancers. Syndrome epidemics. 27 As such, in response to the current pandemic, a number of guidelines are now published providing recommendations for practice changes to optimize use of resources and maximizing patient and personnel safety in radiation oncology clinics. [28][29][30][31][32] Major institutions have released operational guidance regarding practice of RT during the pandemic. [33][34][35][36][37][38][39] It is proposed EDITORIAL | 7 that use of appropriate PPE both by patients and RT personnel along with effective patient/staff screening at the entrance point to the clinic will help reduce spread of the infection between asymptomatic patients and staff.

2.D | Quality assured radiotherapy during pandemic
While the pandemic is not expected to have significant impact on a clinic's ability to complete pretreatment patient-specific quality assurance (QA) and machine QA, the need to follow stringent infec-  patients who need extensive care. In times like these, should radiation oncology departments truly distance themselves from providing care to patients for whom in other situations we debate with our other oncology colleagues regarding the strong merit in offering RT? This is even more relevant in this pandemic where a vast majority of the patients can be infectious while being entirely asymptomatic. 40 Hence, outside of universal testing, there is no feasible way to accurately assess the prevalence of infection in general population which can continue to transmit infection. Does that then justify pursuing a discriminatory approach for the patients who have been tested positive?
It is important to note that while we support treatment of all patients, we recognize that some triage measure during the COVID-19 pandemic is necessary guided by each local institution/region's burden of the pandemic. It is evident that radiation oncology is a discipline of interdisciplinary care with multiple members working together to deliver safe RT for our patients. Should a clinic be in a situation where staff availability is significantly crippled, then it will be imperative to initiate cutbacks by delaying initiation of therapy Owing to multiple factors including immunocompromised status, frequent use of hospital and medical facilities, needs for sustained contact with their healthcare givers and providers, cancer patients are more likely to be infected or coinfected by COVID-19, and, more critically, compared to the general population, they are at a much higher risk of having a severe event (ICU admission, intubation, or death; 39% vs. 8%, P < 0.001). 16 In fact, the most important factor leading to morbidity, as one Chinese study mentioned, 46 is known exposure to an infectious source (regardless of cancer type). Similarly, the Italian data also pointed that older age, cancer, and past smoking history were risk factors for death; 20.3% of their COVID-19 deaths were with active cancer. 47,48 In the absence of any proven vaccine or medication, prevention and mitigation are our only weapons in slowing down the spread of the coronavirus, and consequently preventing and averting death for everyone in the community including our cancer patients and also their healthcare givers. In early April, COVID-19 already overtook "cancer" and also "heart disease" (1,641 and 1,774 persons daily on average, respectively), and became the #1 cause of death (reaching even more than 2,000 persons daily on selected days) in our country. 49 As a result, a significantly conservative approach should be strongly employed and evaluated by each medical institution, in evaluating every cancer patient who will need to be evaluated for a course of radiotherapy; we may not be able to afford a "cookie-cutter," one policy-for-all approach in the face of this unusual pandemic globally. For each individual patient, considerable time should be spent in discussing whether the treatments can be safely postponed by 1-2 months (e.g., a patient with a resected craniopharyngioma), or if alternative therapy (initiating hormonal therapy or active surveillance now for prostate cancer), or a different schedule of radiotherapy (SBRT or hypofractionated treatments) can be used, regardless of their COVID-19 status. The postponing or shortening of the anticipated RT treatments is a balance of benefits and risks from possible cancer progression, vs. the increased risks and safety burdens for both our patients and also staff ourselves.
The Spanish College of Nursing suggested that up to one third of all nurses in Spain, or 70,000 of them, may have been infected by COVID-19; 30% of the surveyed nurses mentioned that they had symptoms 50 ; a CDC report 5 documented that over 9,000 healthcare providers were already infected by COVID-19, which was 19% of the data whereas the healthcare worker status was also reported - increasingly more prevalent now); further guidelines that are more appropriate for our own specialty will also need to be developed in the future.
For patients with confirmed COVID-19 infections, a detailed laboratory-based study 51 showed that viral shedding peaked on or 2-3 days before the onset of symptoms, and the viral load gradually declined as the patient became more symptomatic and sicker; a small period of RT delay, even for 1-2 weeks, can go a long way in decreasing the infection risks to others. For the patient, in most situations, delayed or interrupted radiotherapy treatments can still be more beneficial, especially considering that the patient may be symptomatic or having life-threatening respiratory issues by COVID-19, in addition to the side effects that radiotherapy may bring (consider "nonmaleficence" as a medical ethics issue). The safety and increased risks of infections toward other patients and staff by needlessly having a COVID-19 patient in the radiotherapy department must also be considered (consider "parity," "distributive justice," and "social justice" as medical ethic principles). The burden of justification, as mentioned above, is very high for deciding COVID-19+ patients should be routinely treated with radiotherapy. In an actively deteriorating COVID-19 patient, radiotherapy should be withheld (consider if EDITORIAL | 9 "beneficence" will become negligible or absent, or if continuing RT may even become harmful); 70-80% of patients who end up on a ventilator due to COVID-19 will eventually die as a result based on current reports.
There will be much written about the pandemic, its impact on radiotherapy, and what courses of action are best. But at the most local level, every department will have to wrestle with the following:  Could we designate and safely staff enough of these centers, in a short enough time frame to be helpful? And in terms of patients getting to the treatment location, there are so many considerations: Is it close enough to population centers? Would we really want COVID-19 positive patients to leave their homes, potentially with an increased use of public or private transit? What will happen when they are so ill they become inpatients, either from their cancer, comorbidities, or COVID-19? Would an outpatient department be willing to treat exclusively positive patients? If we did cluster these patients into selected centers, the previously voiced concerns about air exchanges and cleaning/sanitization come ever more into focus. All of the above is based on the idea that centers can and would be able to accept patients mid-treatment, from centers with disparate technology, dissimilar techniques, and unique workflows. That is not at all a certainty or possibility in a majority of metropolitan cities in America. Only if so many fractions were already complete? To emphasize this final rhetorical question, the idea of stopping a course of treatment mid-stream is even more logistically and emotionally challenging than simply never starting. Viable alternative pathways and the ability to defer radiotherapy may evaporate incrementally with which each successfully delivered fraction. We know that under ideal conditions, the guiding principle is to "exert all efforts to retain the planned irradiation schedule" to avoid accelerated repopulation, but in all practicality we are pessimistic that it can be fully executed and accomplished. 54 The RT treatment delivery team is complex, specialized, highly trained, strictly regulated, and not easy to replace. The loss of any staff member to sickness may be unavoidable now that community transmission is more prevalent (and inevitable), but introducing the known COVID-19+ patient into the department puts everyone at additional risk. Physicians from other disciplines cannot simply take a refresher course and become a clinically competent radiation oncologist. Physicists from high energy laboratories cannot review a few online presentations and safely QA the treatment plans and treatment machines needed for radiation delivery. Routinely, there is no spare pool of radiation therapists at one's center to upskill or repurpose. As of the time of publication, the authors are not aware of any emergency purviews for credentialing radiation workers, including physicists and physicians, from outside of our specialty; this is a different situation for letting family physicians or surgeons temporarily run intensive care units due to staff shortage. As a result, over a number of highly hypothesized scenarios, we can see that the burden of treating COVID+ patients can be high; in fact, it may easily overcome the benefit-to-risk ratio which, of course, is well-intended by all parties. The leadership for each individual radiotherapy center must make highly individualized decisions that are suitable for their own needs and beliefs on this controversial issue.