Practice recommendations for lung cancer radiotherapy during the COVID-19 pandemic: An ESTRO-ASTRO consensus statement



## A b s t r a c t
Background: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic. Methods: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC. Results: In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is https://doi.org/10.1016/j.radonc.2020.04.001 0167-8140/O 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). q The Editors of the Journal, the Publisher and the European Society for Radiotherapy and Oncology (ESTRO) cannot take responsibility for the statements or opinions expressed by the authors of these articles. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. For more information see the editorial ''Radiotherapy & Oncology during the COVID-19 pandemic", Vol. 146, 2020. generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided. Conclusion: This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic. After the outbreak of the coronavirus SARS-CoV-2 (COVID-19) in Wuhan, China, in December 2019 [bib_ref] Early transmission dynamics in Wuhan, China, of novel coronavirusinfected pneumonia, Li [/bib_ref] , the disease rapidly became a global pandemic. Infection rates peaked and began to decline in some Asian countries by March 2020, but Europe and the US are now among the most affected regions [bib_ref] Facing Covid-19 in Italy -Ethics, Logistics, and Therapeutics on the Epidemic's Front..., Rosenbaum [/bib_ref]. Most COVID-19 infections are characterized by only mild symptoms of fever and cough; however, there is a high risk of severe pulmonary infection and death, in particular for the elderly and populations with comorbidities such as diabetes, hypertension and cardiopulmonary diseases [bib_ref] Clinical Characteristics of Coronavirus Disease 2019 in China, Guan [/bib_ref]. Cancer patients have been reported to be at increased risk of mortality [bib_ref] Risk of COVID-19 for cancer patients, Xia [/bib_ref]. Therefore, many countries have implemented strategies to reduce the risk of spread, aiming to slow-down or ''flatten" the infection rate of the coronavirus and to stay within the capacity of the healthcare services, especially intensive care units.
The pandemic mitigation strategies of most countries also apply to medical care in general and to oncology in particular, and include reduction of elective services, a focus on remote visits (e.g. telemedicine and video), and use of personal protective equipment. However, most health authorities maintain emergency services (e.g. for accidents) and services for diagnosis and treatment of severe diseases such as cancer. These dramatic developments related to COVID-19 are associated with challenges for the practice of radiation oncology [bib_ref] COVID-19 outbreak in northern Italy: first practical indications for radiotherapy departments, Filippi [/bib_ref] [bib_ref] Running a Radiation Oncology Department at the time of coronavirus: an Italian..., Krengli [/bib_ref] , especially for radiotherapy of lung cancer patients, who represent one of the highest-risk groups, with high risks of death from both cancer and COVID-19 illness.
It may be challenging for radiation oncologists to continue to follow accepted practice guidelines, given these limitations, and delivering standard therapies may even become inappropriate. There are two potential scenarios that may unfold, with different radiation practice patterns [bib_ref] Individualized treatment recommendations for lung cancer patients at different stages of treatment..., Zhao [/bib_ref].
In a first (early) pandemic scenario, sufficient resources are still available to deliver radiation or multimodality treatment. This is sometimes referred to as the ''contingency standard of care". However, suppression strategies aiming to slow down the virus spread may also impact the practice of lung cancer radiotherapy due to: a) the need for suppression of the coronavirus and, therefore, the need to minimize the travel of patientsand exposure of our radiotherapy staff [bib_ref] COVID-19: protecting health-care workers, Lancet [/bib_ref] ; b) an altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection when repeatedly leaving their home and traveling to radiotherapy treatment and simultaneously being treated with thoracic radiotherapy. For example, a patient who contracts COVID-19 during a visit for radiation is at a high risk of morbidity and death due to that visit. In this scenario of the COVID-19 pandemic, standard-of-care practice of curative or palliative radiotherapy for lung cancer might require adaptations and lead to treatment recommendations that are outside current guidelines [bib_ref] Managing COVID-19 in the oncology clinic and avoiding the distraction effect, Francesco [/bib_ref].
In a second (later) pandemic scenario, radiotherapy resources may not be available in sufficient quantity for treatment of all patients. A severe shortage of radiotherapy resources may result from sickness or home-quarantine of our department staffing. Service or repair of radiotherapy software and hardware might be restricted or unavailable by radiotherapy vendors. These issues would require the allocation of resources and triage of patients [bib_ref] Fair allocation of scarce medical resources in the time of Covid-19, Emanuel [/bib_ref] , in addition to the potential need to make changes to lung cancer radiotherapy prescriptions. This phase is sometimes referred to as the ''crisis standard of care".
In this setting of the COVID-19 pandemic, hypofractionation is an attractive treatment option, one that is actively being discussed within the radiotherapy community on social media platforms such as Twitter and theMednet. However, the results of such ad hoc discussions do not address the needs of our radiotherapy community in an optimal way. Individual opinions may not be clinically appropriate and might expose cancer patients to potential harm from suboptimal radiotherapy practice. On the other end of the spectrum, adoption of appropriate hypofractionation might be low if that practice is outside of international guidelines and not endorsed by recognized experts and professional societies, yet such guidelines often take many months to develop.
In this practice recommendation, which is endorsed by the European Society for Radiotherapy and Oncology (ESTRO) and the American Society for Radiation Oncology (ASTRO), an international group of experts in lung cancer radiotherapy aims to rapidly provide guidance about the potential need to adapt the practice and fractionation of radiotherapy for lung cancer in the current COVID-19 pandemic.

# Methods
On March 22nd, 32 experts in lung cancer radiotherapy were invited to participate in this project, 16 European and 16 US/Canadian experts. By March 24th, 97% had agreed, and a replacement was found for the single invitee who was unavailable, to keep the total at 32 with a balance between groups. All invited participants are co-authors of recent national and international lung cancer practice guidelines or principal investigators of lung cancer clinical trials. A modified Delphi process was used to establish consensus about whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic. Surveys were circulated to all individual participants using the online survey tool SurveyMonkey. All respondents agreed to participate in a rapid Delphi process, with 24 h to complete each round and successive rounds starting 24 h after the closure of the previous round.
Two scenarios of the COVID-19 pandemic were assessed, both of which were already occurring in some geographical regions: d Early pandemic scenario 1 -risk mitigation: In this scenario, we asked if respondents would recommend changes to standard practice during the early phase, considering these challenges:
The altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient traveling and exposure of our radiotherapy staff.
d Later pandemic scenario 2 -reduced radiotherapy resources: In this scenario, we asked respondents to consider how their above recommendations from scenario 1 would change if a lack of radiotherapy resources prevented some patients at their centre from receiving radiation treatment.
Six common lung cancer cases were assessed for both pandemic scenarios . For all six, we assumed a patient with average / standard characteristics for the lung cancer population. The standard treatment for each case was provided, consistent with guideline-recommended radiotherapy according to current versions of the National Comprehensive Cancer Network (NCCN), ESTRO, ASTRO and European Organization for Research and Treatment of Cancer (EORTC) guidelines.
The questions for the first round of the Delphi process are shown in . All responses were analyzed and consolidated by two investigators (MG and DAP). A threshold of 66% for agreement or disagreement was required for each item to reach consensus and a threshold of 80% for strong consensus. For questions voting on prioritizing the cases, the results of the vote are presented without necessarily achieving consensus. In the second and third rounds, participants received the results and summary of comments from prior rounds, and were asked to vote again on items that had not reached 66% agreement. New questions were constructed (by MG and DAP) in order to gain clarification or to raise issues noted in the comments from participants. Following the third round, any items still lacking consensus were not considered a recommendation, but some important issues raised by a large minority of respondents are reflected below.

# Results
A total of three Delphi rounds were conducted. Surveys remained open for 24 h and response rates were 29/32 (March 23rd, round 1), 31/32 (March 25th, round 2) and 30/32 (March 27th, round 3).
Early phase of the COVID-19 pandemic: risk mitigation Question: Would you recommend postponing the initiation of treatment by 4-6 weeks?
In the early phase of the COVID-19 pandemic, decisions on delay of treatment depended on the clinical case [fig_ref] Table 3: Recommendations regarding postponement of treatment [/fig_ref]. There Questions in the first round of the Delphi process.
Early pandemic scenario 1 -risk mitigation

## All cases
Do you recommend that physicians change their radiotherapy practice to address the challenges in this early phase of the COVID-19 pandemic? (i.e. risks due to multiple visits, susceptibility of lung cancer patients to COVID-19 morbidity/mortality) All cases Would you recommend postponing the initiation of treatment by 4-6 weeks? All cases Would you recommend hypofractionating beyond your usual fractionation? Case 1-3
Would your answers to questions #2 and #3 above change if the tumor was mutation positive (EGFR or ALK) or PD-L1 positive (i.e. >50%)? Please rank the six cases in order of priority, starting with the highest-priority case, in the setting of reduced resources Overall
If you were to triage patients for treatment, in the setting of reduced RT resources, please provide up to 5 factors that you would use to decide who gets treatment, in order of importance The six lung cancer cases described, including the diagnosis and the presumed standard guideline-recommended therapy. , answers on postponement were balanced and we asked for factors influencing the decision whether or not to postpone. There was strong consensus that tumor growth rate (87%) should be used in the decision-making process and some support for these other factors (33-66%): patient preference, solid component vs GGO, patient performance status, T1 vs T2, current and future status of pandemic.
For case 5 (PCI SCLC) we asked about regular contrast-enhanced cranial MRI follow up as an alternative to PCI: this strategy was supported by 46% without reaching consensus.
Question: Would you recommend hypofractionating beyond your usual fractionation?
In the early phase of the COVID-19 pandemic, there was consensus not to universally change radiotherapy practice to more hypofractionated regimens (table 4). There was consensus or strong consensus not to change to more hypofractionated approaches in case 3 (PORT NSCLC), case 4 (LS SCLC) and case 5 (PCI SCLC). In contrast, there was strong consensus to change to more hypofractionation in case 6 (palliative NSCLC).
If a decision was made for hypofractionation beyond standard fractionations, there was strong consensus for using a single fraction SBRT of 30-34 Gy in case 1 (stage I NSCLC). In case 6 (palliative NSCLC), palliative regimens in 5 fractions, 2 fractions and a 1 fraction all had similar support.
For case 2 (stage III NSCLC), we further differentiated fractionations based on whether the patient was treated with radiotherapy only, with sequential radiochemotherapy or concomitant radiochemotherapy. There was strong consensus that hypofractionated radiotherapy is appropriate in radiotherapy alone or sequential radiochemotherapy; however, there was consensus against hypofractionation in concomitant radiochemotherapy . Various fractionations were considered as appropriate, with total doses between 50 Gy and 66 Gy delivered in 15-30 fractions.
Question: An operable patient with stage I NSCLC is referred to you by a thoracic surgeon because timely access to surgery is not available due to surgical capacity issues. Would you treat with SBRT?
Surgical capacities might become especially at risk because of the strong need for intensive care and ventilators in patients with severe COVID-19 infection. We therefore addressed a situation where an operable patient with stage I NSCLC is referred to radiation oncology by a thoracic surgeon because timely access to surgery is not available due to surgical capacity issues: it was asked whether treatment with SBRT would be offered. There was a 100% consensus to offer SBRT.
Question: Which multi-modality strategies would you consider as reasonable in order to address the challenges in this early phase of the COVID-19 pandemic?
This question was asked for the curative stage III NSCLC (case 2) only. It was explicitly described that the patient does not have any contraindications against the guideline recommended standard-ofcare concomitant radiochemotherapy. Concurrent radiochemotherapy achieved strong consensus as the preferred treatment strategy. Radiotherapy alone, chemotherapy followed by radiotherapy and chemotherapy followed by radiochemotherapy were not considered as reasonable treatment strategies by >33% of participants.
We also asked if respondents would recommend against any standard concurrent chemotherapy agents (e.g. cisplatinetoposide, cisplatin-vinka alkaloid, cisplatin-pemetrexed, carboplatin-paclitaxel, or carboplatin monotherapy), and there was no consensus to recommend against any of these. The carboplatin-paclitaxel regimen was chosen as a regimen of concern most often (by 37% of respondents), potentially due to risks of myelosuppression and/or pneumonitis. [bib_ref] Randomized phase III trial of single versus fractionated thoracic radiation in the..., Bezjak [/bib_ref] 17 Gy in 2 Fx (37%)8-10 Gy in 1Fx (33%) [bib_ref] Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or..., Medical [/bib_ref] Question: Would your multi-modality treatment strategy change if the tumor was mutation positive (EGFR or ALK) or highly PD-L1 positive (i.e. > 50%)? (Cases 1-3) There was strong consensus (96%) not to change the treatment strategy for case 1 (stage I NSCLC) and almost consensus (64%) for case 3 (PORT NSCLC).
For case 2 (stage III NSCLC), we asked about induction strategies to postpone the start of radiotherapy for the populations described in this question, although these are not yet evidence-based treatment options. There was limited support but no consensus to consider induction EGFR-targeting TKI for EGFR mutated NSCLC or induction ALK-targeting TKI for NSCLC with ALK rearrangement (38%); induction chemo-IO for cancers highly PD-L1 positive was not supported (17%).
For case 3 (PORT NSCLC) we asked about EGFR/ALK targeting TKIs and about immune-checkpoint inhibition (chemotherapy) as options to postpone radiotherapy or as alternatives to radiotherapy (although these are not yet evidence-based treatment options): none of these strategies was supported by >25% of the participants.

## Question: handling of covid-19 positive patients?
There was consensus in all cases to postpone initiation of radiotherapy until the patient becomes asymptomatic and the test for COVID-19 becomes negative [fig_ref] Table 6: Recommendations on delay or interruption of treatment in COVID-19 positive patients [/fig_ref]. When patients are diagnosed as COVID-19 positive during radiotherapy treatment, there was consensus to interrupt radiotherapy until the patient becomes asymptomatic and the test for COVID-19 is negative in cases 3, 5 and 6 whereas opinions were evenly split for the cases with curative radiotherapy at the time of primary diagnosis (cases 1, 2 and 4).
For case 2 (stage III NSCLC) and case 4 (LS SCLC) with longer radiotherapy treatments, the following factors were described as relevant in the decision-making process of whether or not to interrupt radiotherapy in patients diagnosed as COVID-19 positive: COVID-19 related symptoms, symptoms of lung cancer, and infection with COVID-19 near the end of treatment.
Later phase of the COVID-19 pandemic: lack of radiotherapy resources and need for patient triage For the later phase of the COVID-19 pandemic with potentially reduced radiotherapy resources, we addressed the questions whether further hypofractionation or postponement of radiotherapy for COVID-19 positive patients would be considered as reasonable and how to prioritize and triage patients. Results are summarized in. For case 3 (PCI SCLC) there was strong consensus (83%) for regular contrast-enhanced cranial MRI follow up instead of PCI. Availability of MRI may, however, be limited during a pandemic situation. Recommended hypofractionation regimens based on availability/use of concurrent and sequential radiochemotherapy, or radiotherapy alone.
Would you consider hypofractionated radiotherapy as appropriate? [bib_ref] Precision hypofractionated radiation therapy in poor performing patients with non-small cell lung..., Westover [/bib_ref] 60 Gy in 20 Fx (27%) [bib_ref] Image guided hypofractionated 3-dimensional radiation therapy in patients with inoperable advanced stage..., Osti [/bib_ref] 60-66 Gy in 24-30 Fx (2.2-2.75 Gy/day) (23%) [bib_ref] Randomised trial of sequential versus concurrent chemoradiotherapy in patients with inoperable non-small..., Belderbos [/bib_ref] 55 Gy in 20 Fx (13%) [bib_ref] SOCCAR: a randomised phase II trial comparing sequential versus concurrent chemotherapy and..., Maguire [/bib_ref] None (3%) Sequential radiochemotherapy
Yes: 97% (strong consensus) No: 3% 60-66 Gy in 24-30 Fx (2.2-2.75 Gy/day) (27%) [bib_ref] Randomised trial of sequential versus concurrent chemoradiotherapy in patients with inoperable non-small..., Belderbos [/bib_ref] 55 Gy in 20 Fx (27%) [bib_ref] SOCCAR: a randomised phase II trial comparing sequential versus concurrent chemotherapy and..., Maguire [/bib_ref] 60 Gy in 15 Fx (23%) [bib_ref] Precision hypofractionated radiation therapy in poor performing patients with non-small cell lung..., Westover [/bib_ref] 60 Gy in 20 Fx (20%) Regarding postponement or interruption of treatment for COVID-19 positive patients during scenario 2, since the consensus in Scenario 1 was to postpone and interrupt in all situations, it was concluded that treatment would be postponed/interrupted until the patient recovers and is COVID-19 negative in Scenario 2 as well, since it is a more extreme example. [fig_ref] Table 8: Prioritization of lung cancer patients and factor for triaging of patients [/fig_ref] shows the ranking of cases based on relative priority, their perceived priority relative to all other types of cancer cases, and the top 5 factors recommended in order to triage patients in a setting where not all patients can receive radiotherapy due to capacity shortages.

## Prioritization of cases and triage of patients

# Discussion
This Delphi process was able to achieve consensus in many important aspects of lung cancer radiotherapy in the current COVID-19 pandemic. A total of 32 international experts in lung cancer radiotherapy completed 3 rounds of a consensus-building process and addressed six common lung cancer cases within the context of two different scenarios of the COVID-19 pandemic. Beyond detailed recommendations shown above, the following three take-home messages should be considered in lung cancer radiotherapy.
First, in a risk-mitigation pandemic scenario where radiotherapy resources remain available, efforts should be made to not compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. Second, in that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients should be considered to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. Third, in a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors included potential for cure, relative benefit of radiation, life expectancy, and performance status.
This joint ESTRO-ASTRO practice recommendation aims to provide rapid, pragmatic and balanced guidance in common clinical scenarios of radiotherapy for lung cancer. Practitioners must use their clinical judgement when considering how these consensus statements apply to their individual clinical practice. These consensus statements are not absolute clinical practice recommendations. Clinical decisions should take into account all clinical factors, and in some settings the consensus recommendations may not be appropriate. The decision-making process will be influenced by various stakeholders (governments, health care authorities, hospital and university administration), will be restricted by logistical and financial aspects, will need to follow the appropriate legal frameworks, and will need to be put into political and cultural context. The ability to implement hypofractionation may depend on departmental resources available (e.g. physicist).
This ESTRO-ASTRO practice recommendation used methodologies that are established quality indicators for regular consensus and guideline processes [bib_ref] Methods for the guideline-based development of quality indicators-a systematic review, Kotter [/bib_ref] : the practice recommendation was officially endorsed by the ESTRO and ASTRO societies, a sufficiently large group of international experts in lung cancer radiotherapy contributed to this recommendation, the modified Delphi process started with open questions aiming to comprehensively collect the knowledge and opinions of all participants and consensus was established by follow-up rounds of feedback and voting. A systematic review was not part of the practice recommendation due to time constraints, and especially due to a lack of evidence for pandemic situations.
All co-authors therefore encourage practitioners to consider the results of this ESTRO-ASTRO practice recommendation on whether and how to adapt radiotherapy for lung cancer to the COVID-19 pandemic. Finally, we want to express our gratitude to all colleagues of all professions and disciplines who continue delivering optimal cancer care in serious situations such as now -take care of yourselves as well as your patients.

## Estro disclaimer
ESTRO cannot endorse all statements or opinions made on the guidelines. Regardless of the vast professional knowledge and scientific expertise in the field of radiation oncology that ESTRO possesses, the Society cannot inspect all information to determine the truthfulness, accuracy, reliability, completeness or relevancy thereof. Under no circumstances will ESTRO be held liable for any decision taken or acted upon as a result of reliance on the content of the guidelines. The component information of the guidelines is not intended or implied to be a substitute for professional medical advice or medical care. The advice of a medical professional should always be sought prior to commencing any form of medical treatment. To this end, all component information contained within the guidelines is done so for solely educational and scientific purposes. ESTRO and all of its staff, agents and members disclaim any and all warranties and representations with regards to the information contained on the guidelines. This includes any implied warranties and conditions that may be derived from the aforementioned guidelines. PORT NSCLC Low/very low (68% consensus) 5. Performance Status 6.
SCLC PCI Low/very low (81% consensus) *The six cases were ranked, with 6 points given for a #1 ranking, 5 points for #2, etc, and the average number of points was determined. The average scores, in order of ranking as listed in the table, were 5.2, 4.9, 4.1, 3.0, 2.1 and 1.7, respectively. **Respondents were asked to prioritize each case as very high, high, average, low, or very low, corresponding to quintiles of priority (e.g. very high = top 20%, very low = bottom 20%), compared to all types of cancers treated in their department. Adjacent categories were combined to determine consensus.

## Astro disclaimer
Disclaimer and Adherence: American Society for Radiation Oncology (ASTRO) guidelines present scientific, health, and safety information and may reflect scientific or medical opinion. They are available to ASTRO members and the public for educational and informational purposes only. Commercial use of any content in this guideline without the prior written consent of ASTRO is strictly prohibited. Adherence to this guideline does not ensure successful treatment in every situation. This guideline should not be deemed inclusive of all proper methods of care or exclusive of other methods reasonably directed to obtaining the same results. The physician must make the ultimate judgment regarding therapy considering all circumstances presented by the patient. ASTRO assumes no liability for the information, conclusions, and findings contained in its guidelines. This guideline cannot be assumed to apply to the use of these interventions performed in the context of clinical trials. This guideline is based on information available at the time the task force conducted its research and discussions on this topic. There may be new developments that are not reflected in this guideline and that may, over time, be a basis for ASTRO to revisit and update the guideline.
[table] Table 3: Recommendations regarding postponement of treatment. Would you recommend postponing the initiation of treatment by 4-6 weeks? [/table]
[table] Table 4: Fractionation recommendations. [/table]
[table] Table 6: Recommendations on delay or interruption of treatment in COVID-19 positive patients. [/table]
[table] Table 8: Prioritization of lung cancer patients and factor for triaging of patients. Prioritization of lung cancer patients Top 5 factors for triaging patients across all radiotherapy cases Rank Case* Relative Priority Compared All Other Types Cancer Cases in Department** [/table]