key: cord-0939386-3mthqts8
authors: Matuschek, Christiane; Fischer, Johannes C.; Combs, Stephanie E.; Fietkau, Rainer; Corradini, Stefanie; Zänker, Kurt; Bölke, Edwin; Djiepmo-Njanang, Freddy-Joel; Tamaskovics, Balint; Fischer, Joachim E.; Stuschke, Martin; Pöttgen, Christoph; Förster, Robert; Zwahlen, Daniel R.; Papachristofilou, Alexandros; Ganswindt, Ute; Pelka, Rainer; Schneider, E. Marion; Feldt, Torsten; Jensen, Björn Erik Ole; Häussinger, Dieter; Knoefel, Wolfram Trudo; Kindgen-Milles, Detlef; Pedoto, Alessia; Grebe, Olaf; van Griensven, Martijn; Budach, Wilfried; Haussmann, Jan
title: Measures of infection prevention and incidence of SARS-CoV-2 infections in cancer patients undergoing radiotherapy in Germany, Austria and Switzerland
date: 2020-09-10
journal: Strahlenther Onkol
DOI: 10.1007/s00066-020-01681-1
sha: 14828b5a2a59824d734342009bbd56a66a7234cd
doc_id: 939386
cord_uid: 3mthqts8

PURPOSE: COVID-19 infection has manifested as a major threat to both patients and healthcare providers around the world. Radiation oncology institutions (ROI) deliver a major component of cancer treatment, with protocols that might span over several weeks, with the result of increasing susceptibility to COVID-19 infection and presenting with a more severe clinical course when compared with the general population. The aim of this manuscript is to investigate the impact of ROI protocols and performance on daily practice in the high-risk cancer patients during this pandemic. METHODS: We addressed the incidence of positive COVID-19 cases in both patients and health care workers (HCW), in addition to the protective measures adopted in ROIs in Germany, Austria and Switzerland using a specific questionnaire. RESULTS: The results of the questionnaire showed that a noteworthy number of ROIs were able to complete treatment in SARS-CoV‑2 positive cancer patients, with only a short interruption. The ROIs reported a significant decrease in patient volume that was not impacted by the circumambient disease incidence, the type of ROI or the occurrence of positive cases. Of the ROIs 16.5% also reported infected HCWs. About half of the ROIs (50.5%) adopted a screening program for patients whereas only 23.3% also screened their HCWs. The range of protective measures included the creation of working groups, instituting home office work and protection with face masks. Regarding the therapeutic options offered, curative procedures were performed with either unchanged or moderately decreased schedules, whereas palliative or benign radiotherapy procedures were more often shortened. Most ROIs postponed or cancelled radiation treatment for benign indications (88.1%). The occurrence of SARS-CoV‑2 infections did not affect the treatment options for curative procedures. Non-university-based ROIs seemed to be more willing to change their treatment options for curative and palliative cases than university-based ROIs. CONCLUSION: Most ROIs reported a deep impact of SARS-CoV‑2 infections on their work routine. Modification and prioritization of treatment regimens and the application of protective measures preserved a well-functioning radiation oncology service and patient care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00066-020-01681-1) contains supplementary material, which is available to authorized users.

The coronavirus disease 2019 (COVID-19) outbreak has become one of the greatest challenges for modern societies, economies and medicine. By now, most countries in the world have been affected by this pandemic viral infection [1] [2] [3] [4] [5] [6] [7] .

The SARS-CoV-2 infection poses a significant threat to cancer patients as they can be more susceptible to the pathogenic complications associated with the infection compared to the general population [2] . Patients with malignant tumors are generally older and affected by additional comorbidities [8] . Furthermore, oncological treatments including chemotherapy, radiotherapy and the use of additional systemic agents might be associated with lymphopenia and result in an impaired immune response to viral infections [9] . Additionally, cancer fever and other nonspecific symptoms may mask the signs of early COVID-19 infections.

Early reports from China suggested an increased incidence of COVID-19 in patients with active cancer and ma-jor complications (such as the need for mechanical ventilation or death) might be 3-4 times higher in this population [10] . Reports from Italy confirmed that at least 16.5% of all deceased cases had in retrospect a history of cancer within the last 5 years [11] .

Radiation oncology institutes (ROIs) present a unique challenge at the present time. Immune compromised patients with life-threatening diseases must visit these facilities daily to receive their treatment, being exposed to caregivers and fellow patients who can be asymptomatic carriers of the disease. Caregivers including radiation therapy technicians (RTTs), nurses, physicians and physicists have a higher incidence of exposure to the virus and contribute to further spreading the disease among coworkers and families. The RTTs generally meet about 30-50 patients per linear accelerator per day.

This work aims to quantify the incidence of COVID-19 in these departments, to measure and analyze the countermeasures taken by ROIs to decrease the risk of infection for both patients and healthcare workers (HCW), and to evaluate changes in treatment policy during the pandemic.

We invited all registered ROIs of the German Society for Radiation Oncology (DEGRO) (n = 292) and the Austrian Society for Radiation Oncology (ÖGRO) (n = 16) to participate in an anonymous online survey on the COVID-19 outbreak and its clinical implications in their institutions. A link to the questionnaire was embedded in E-mail messages sent between 26 and 27 April 2020. Additional invitations were sent on 5-7 May 2020 to all registered ROIs of the Swiss Society for Radiation Oncology (SRO, SSRO) (n = 37). The number of ROIs is based on the DIRAC database of the International Atomic Energy Agency (IAEA) [12] .

The questionnaire was designed to capture the specific numbers of COVID-19 infections of both patients and caregivers and to report what measures were taken to prevent COVID-19 infections. The web-based online survey was conducted using the SurveyMonkey tool (Sur-veyMonkey.com LLC, San Mateo, CA, USA; http://www. surveymonkey.com). Overall, the questionnaire consisted of 25 questions: 6 addressing how many patients and staff were infected, 9 screening procedures as well as the use of personal protective equipment (PPE) and other prevention strategies, and 10 investigated changes in oncological treatments and follow-ups due to the pandemic. The characteristics of ROIs were investigated with four questions, and an open field one was placed at the end ( Table 1 ). The 

The datasheet from SurveyMonkey was adapted by eliminating double, truncated or implausible entries. For statistical analysis, ordinal entries were transformed to continuous scale values, e.g. for numbers of employees or change of policies "4-6" into mean value of the range (5) . Changes in treatment and follow-up policy were factorized to sum 100%. Several hypotheses were formulated prior to the data analysis. We hypothesized: 1) a decrease in the number of patients treated in ROIs during the pandemic, 2) the type of ROI and the presence of positive SARS-CoV-2 results in the patients caused changes in treatment protocols, such as the use of fewer fractions, postponement or omission of radiation treatment (RT).

To clarify whether changes in radiation policy were contingent on the presence of the infection and the specific institution, the 19 variables describing this policy (curative, palliative, benign, chemotherapy and systemic therapy) were analyzed using principle component analysis for dimensionality reduction. Components with an eigenvalue >1 in all subgroups were included, resulting in 5 relevant components. The maximum distance of the factors was calculated. The highest 10% of the distances were further compared.

German COVID-19 incidences were taken from the Robert Koch Institute (RKI) accessed on 22 May 2020 [13] . The Austrian incidence of the infection was obtained from https://coronavirus.datenfakten.at/, while for the Swiss https://covid-19-schweiz.bagapps.ch/de-2.html was used, including the absolute numbers obtained as of 22 May 2020.

The pooled results of the questionnaire were reported in a descriptive form with total and relative numbers, means, and standard deviation. Statistical analysis was performed using Student's t-test for normally distributed data or by rank comparing or dichotomous statistics with p-values below 0.05 considered statistically significant.

Analysis was conducted in R (R core team, Auckland, New Zealand) and using IBM SPSS Statistics for Windows, Version 22.0. Released 2013 (IBM Corp, Armonk, NY, USA [14] ).

The questionnaire was open from 26 April until 22 May 2020. Nearly two thirds of the answers were provided within the first 2 days. Tables 2, 3 and 4 show the number of responding institutions distributed by country and type of ROI. After exclusion of double entries, 106 answers to the questionnaire were analyzed, with 83, 13 and 10 responses from Ger- Of the 106 ROIs, 24 reported a total of 46 SARS-CoV-2 positive patients. Notably, only two centers reported more than two infected patients (18 in one and 5 cases in the other) during radiotherapy. Most asymptomatic or oligosymptomatic patients (76.7%) continued their treatment with a break in RT of less than 1 week. Many centers with symptomatic patients stopped therapy or added a break for more than 1 week. Only 3 centers continued therapy in 10 patients either without a break or with 1 for less than 1 week. Most symptomatic cases continued their therapy (68.8%). The HCW tested positive in 16 ROIs (16.5%) with a similar distribution among the spectrum of roles.

As shown in Table 5 50.5% of the ROIs screened their patients for SARS-CoV-2 with questionnaires being the The question of how ROIs adapted their therapeutic regimens during the pandemic is addressed in Fig. 2 . In patients with curative intentions, 68.4% of the centers did not alter the treatment plan. When RT schedules were changed, the centers usually adopted a moderate hypofractionation (18.1%) with little use of ultra-hypofractionation (7.6%) or postponement of therapy (5.3%). When treating patients with a palliative intent, more centers switched to shorter protocols (42.1%). Most of ROIs postponed or omitted RT for benign indications (88.1%).

Concurrent chemotherapy was administered as scheduled in 90.8% of cases. Some ROIs modified their usual strategies (6.0%) with omissions of chemotherapy in 3.2% of cases. Additional systemic treatments were administered as scheduled (92.1%), with some modifications (5.0%) or omissions (2.9%).

Follow-up visits were done via telephone (43.6%) or postponed (42.2%). Videochat was rarely offered within routine follow-up (0.5%). Fig. 3 shows that Austrian (n = 13; p = 0.024) and German (n = 77; p < 0.001) ROIs treated significantly less cases after the beginning of the pandemic compared to before, whereas Swiss institutions did not report a reduction of case load (n = 9; p = n. s.). We further analyzed the impact of the SARS-CoV-2 incidence per 1000 patients in the German institutions on change of patient cases per ROIs. As all comparisons showed significant reductions, the incidence did not seem to affect the caseload. The drop in patients also appeared to be independent of the type of ROI and . 3 Comparison of mean number of patients treated per ROI per day before and during the pandemic separated by country, incidence, type of ROI and occurrence of positive cases. Bar denotes median, the box the first interquartile range (IQR, 50%), whiskers 1.5 IQR of the box. Outliers, when present, are marked as circles (more than 1.5 IQR out of the box) or as stars (more than 3 IQR out of the box) whether or not the ROIs reported positive patients; however, the differences did not reach statistical difference for the university hospitals. Fig. 4a -e shows the analysis of changes in therapeutic strategy to shorter treatment schedules, postponement or omission of radiation therapy by type of ROI and whether the institution reported positive patients.

We detected that curative schedules were more likely to stay unchanged, whereas moderate or ultra-hypofractionated treatment regimens were applied more in patients with palliative concepts. Postponing RT was more common in curative cases, in contrast to omission of RT in palliative situations. Moreover, we detected a tendency for non-university ROIs to change their RT-schedules compared to university clinics in curative and palliative cases. Fig. 5a -d demonstrated the changes in patients treated with a curative intend. Here the majority of ROIs reported mainly no changes or a switch to mild hypofractionation. The occurrence of SARS-CoV-2 cases did not affect the change in patients treated with curative intent. Fig. 6a -c shows the impacts on SARS-CoV2 on the follow-up concepts. Positive COVID-19 cases did not affect the changes in whole sample; however, non-university clinics with positive patients reported significantly more changes to follow-up visits by telephone.

The analysis of this online survey provides a cross-sectional assessment of ROIs in three European countries between the end of April and the end of May 2020, during the COVID-19 pandemic. The estimated cumulative COVID-19 incidence (0.56%) in ROIs is slightly higher than in the general [15] [16] [17] [18] [19] [20] [21] . In March 2020, ARO, DEGRO and the professional association for radiation oncology during the COVID-19 pandemic (https://www.degro.org/stellungnahme-der-aro-degro-unddes-berufsverbandes-zur-strahlentherapie-waehrend-dercovid-19-pandemie) released a statement with suggestions on the treatment of patients suspected of SARS-CoV-2 infection. These recommendations were in agreement with the current recommendations of the German RKI and local hygiene commissions. These documents highlight the need to maintain the safety of both patients and HCWs by avoiding or rescheduling treatments if the risk of being infected with COVID-19 outweighs the benefit of treatment, and shortening therapies as much as possible. Proper PPE seems to reduce the transmission of the virus and protects HCWs [22, 23] .

The American (ASTRO), European (ESTRO), Japanese (JASTRO) and the members of the Swiss (SRO SSRO) societies of radiation oncology published the results of similar surveys. Despite some regional differences, changes in clinical practice parallel the spread of COVID-19 in different countries. American centers appear to have implemented stricter screening procedures (98% screen patients and 91% HCW) compared to their European counterparts (82% screen patients and 60% HCW; our data: 51% screen patients and 23% HCW). Of the ASTRO centers 69% suffered from PPE shortage compared to 48% of ESTRO centers (our data 34.9%). The use of telemedicine was higher for ASTRO (89%) than ESTRO (72%) surveys. The number of patients wearing a mask differed between the sur-veys: ASTRO 83%, JASTRO 50.5%, SRO SSRO 59%, and our data 93%. Similarly, our results, a decline in referrals seemed to have affected institutions worldwide as 85% of American and 60% of the European centers reported reduced number of patients.

Kuderer et al. reported the largest analysis of cancer patients infected with SARS-CoV-2 [24] . Fever, cough, fatigue/malaise and dyspnea were the most common symptoms and the crude death rate was estimated at 13%. Patients with active cancer had odds ratio 5.2 times higher for death compared to patients in remission or no evidence of disease. Concomitant systemic therapy, however, had no statistically significant influence on survival, non-cytotoxic (OR = 1.04) and cytotoxic effects (OR = 1.47), suggesting that omission of systemic therapy is probably unnecessary and should be strongly weighed against the potential benefits. Patients with solid tumors, often treated with radiation therapy, may be less at risk than patients with hematological malignancies. This finding is supported by Lee et al. who reported that patients undergoing any systemic anticancer treatment during the last 4 weeks including cytotoxic chemotherapy (OR = 1.18) and radiotherapy (OR = 0.65) had no increased risk of death according to an univariate and a multivariate analysis [25] . In contrast, Achard et al. reported an increased mortality after chemotherapy (OR 3.51) with no effect of radiotherapy [26] .

Evidence for drastically higher mortality among SARS-CoV-2-positive cancer patients undergoing active therapy is controversial as data showing an increase are mostly retrospective and hampered by confounding factors. Specifically, radiation therapy as a cancer treatment modality is not linked to higher mortality from COVID-19; however, there is growing evidence on the additional harm from the K COVID-19 infection in untreated malignant diseases with an increased morbidity and mortality [27, 28] . It appears to be critical for health care providers to maintain a functioning structure to treat other diseases. Especially, tumortreatment often requires timely diagnosis and the participation of different medical departments.

Our survey shows that most of the curative treatment protocols were not affected by COVID-19, with infected cancer patients being able to continue their treatments, which demonstrated an intact infrastructure of the responding ROIs. This is in contrast with how other countries responded to similar scenarios. For example in Italy, in areas severely affected by the pandemic, the recommendations have been to postpone all non-urgent therapy and cancel palliative radiotherapy when other alternative protocols are equally effective [15] . Nonetheless, treatment of SARS-CoV-2 patients has been proven to be challenging as well as time and resource intensive. Centers have to secure transportation of the infected patients to the ROIs, allow specific time slots on the machines and perform specific training to the treatment staff. Hygiene measures as well as constant ventilation of the treatment rooms have also to be considered.

Similar to our experience, the Swiss survey reported an increase of hypofractionation, even though with a lower percentage compared to ours (5-18% and 25.6-42.1%, respectively) [29] . It will be interesting to see whether ROIs will continue using the shorter treatment protocols, especially for curative treatments of breast or prostate cancers. In these sites, the use of moderate hypofractionated or ultrahypofractionated regimens might still be lower compared to countries like the United Kingdom or Canada. One could speculate that some of these modifications in protocols will remain in practice as found to have improved patient outcome with less toxicity than anticipated.

We acknowledge several limitations of our survey. It reflects only a certain interval within the timeframe of the pandemic. The number of responding centers was limited, with a 31% response rate. This is comparable to 23.3% of the JASTRO survey [30] . Some parts of the raw data had to be transformed into continuous variables to allow statistical analysis, which might introduce bias. The number of COVID-19 cases is probably underreported as neither broader PCR nor antibody testing was performed at the time of the survey. Asymptomatic, yet infectious cases could have been present, but not detected [31, 32] .

This survey might be considered as a starting point for future studies. Comparative studies (ROI vs. general population or ROI vs. other organizations with increased patient contact) would add additional medical information on this topic. Data could be collected on the medical and financial repercussions of prevention strategies in different ROIs, or at the regional or national level, on the assessment of risky behavior and their consequences, with the identification of the responsible factors.

This survey demonstrated a significant effect of the COVID-19 pandemic on the responding ROIs, with implementation of safety measures and changes of their treatment protocols. The ROIs were able to perform curative treatments and persisted to mainly continue radiotherapy to SARS-CoV-2 positive patients. The study also aims to raise awareness to new clinical needs to cope with COVID-19 infections in the future.

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