key: cord-0754457-qhnbbzo5
authors: Thomson, David J.; Palma, David; Guckenberger, Matthias; Balermpas, Panagiotis; Beitler, Jonathan J.; Blanchard, Pierre; Brizel, David; Budach, Wilfred; Caudell, Jimmy; Corry, June; Corvo, Renzo; Evans, Mererid; Garden, Adam S.; Giralt, Jordi; Gregoire, Vincent; Harari, Paul M.; Harrington, Kevin; Hitchcock, Ying J.; Johansen, Jorgen; Kaanders, Johannes; Koyfman, Shlomo; Langendijk, J. A.; Le, Quynh-Thu; Lee, Nancy; Margalit, Danielle; Mierzwa, Michelle; Porceddu, Sandro; Soong, Yoke Lim; Sun, Ying; Thariat, Juliette; Waldron, John; Yom, Sue S.
title: Practice recommendations for risk-adapted head and neck cancer radiotherapy during the COVID-19 pandemic: an ASTRO-ESTRO consensus statement
date: 2020-04-14
journal: International journal of radiation oncology, biology, physics
DOI: 10.1016/j.ijrobp.2020.04.016
sha: cb5c033ae6972c3016c0bcc434270b05ef6e7227
doc_id: 754457
cord_uid: qhnbbzo5

Abstract Introduction Due to the unprecedented disruption of health care services by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC), in a time of heightened risk for patients and staff, and of limited resources. Methods A panel of international experts from ASTRO, ESTRO and select Asia-Pacific countries completed a modified rapid Delphi process. Questions and topics were presented to the group, and subsequent questions developed from iterative feedback. Each survey was open online for 24 hours, and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (≥80%) and agreement (≥66%) were extrapolated from the RAND methodology. Two pandemic scenarios: early (risk mitigation) and late (severely reduced radiotherapy resources) were evaluated. The panel developed treatment recommendations for five HNC cases. Results In total, 29/31 (94%) of those invited accepted, and after a replacement 30/30 completed all three surveys (100% response rate). There was agreement or strong agreement across a number of practice areas including: treatment prioritisation, whether to delay initiation or interrupt radiotherapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation dose-fractionation schedules and use of chemotherapy in each pandemic scenario), management of surgical cases in event of operating room closures, and recommended adjustments to outpatient clinic appointments and supportive care. Conclusions This urgent practice recommendation was issued in the knowledge of the very difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health during the COVID-19 pandemic. The aim of this consensus statement is to ensure high-quality HNC treatments continue, to save lives and for symptomatic benefit.

In total, 29/31 (94%) of those invited accepted, and after a replacement 30/30 completed all three surveys (100% response rate). There was agreement or strong agreement across a number of practice areas including: treatment prioritisation, whether to delay initiation or interrupt radiotherapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation

The coronavirus (SARS-CoV-2) outbreak is considered a global pandemic by the World Health Organization. 1 Most infected people develop a mild respiratory illness, but based on an early census from the U.S. Centers for Disease Control, 20-30% of persons aged ≥ 45 years require hospital admission, and fatality rates range from 10-17% in persons aged ≥ 85 years, 3-11% among persons aged 65-84 years, and 1-3% among persons aged 55-64 years. 2 Those with cancer or receiving treatment for cancer are at enhanced risk of serious morbidity, including the need for ventilator support or death (HR 3.56, [95% CI, 1.65 to 7.69]). 3 The pandemic has strained cancer services, with routine outpatient appointments cancelled, elective surgeries postponed and resources diverted to the front line.

For the oncology clinician wishing to offer palliative systemic therapies there is a Hobson's choice: a high symptom burden from the cancer without treatment or an increased risk of a more imminent death from SARS-CoV-2 infection resulting from the exposure and stress of therapy. For curative-intent treatments, there are parallel and specific challenges facing the head and neck (HN) oncologist: (i) operating room closures, with increased requirement for nonsurgical treatments, (ii) an altered risk-benefit ratio of chemotherapy and radiotherapy due to increased susceptibility for SARS-CoV-2 infection, (iii) a need to suppress coronavirus spread by minimizing travelling of patients for daily treatments and the exposure of hospital and radiotherapy staff, and (iv) a shortage of radiotherapy resources due to staff sickness or leave for family care entailing allocation of resources and triage of patients. The use of hypofractionated radiotherapy (radiation schedules that are shorter overall but give a larger dose per treatment) could help address the latter two concerns, but these regimens may be unfamiliar to many radiation oncologists, and there is a risk of inappropriate application if these fall outside current international guidelines.

Due to this unprecedented disruption of health care services by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC), in a time of heightened risk for patients and staff, and of limited resources.

With endorsement of the ASTRO and ESTRO executive committees, a panel of international experts was identified to provide practice recommendations for HNC during the COVID-19

pandemic. Panellists were nominated in equal numbers from the two societies with select representation from a few affected Asia-Pacific countries. A modified rapid Delphi process was used to develop consensus recommendations. A systematic literature review was not performed due to the urgency and lack of information on the conduct of cancer treatment related to the COVID-19 pandemic. The organizers (DT, SY, DP, MG) presented the initial topics and questions to the group by electronic survey and subsequent questions were developed based on iterative feedback from the panellists. Questions were not asked again after agreement was reached. Each survey was open online for 24 hours and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (≥80%) and agreement (≥66%) were extrapolated from RAND methodology. 4 Two scenarios, both of current and global relevance to the COVID-19 pandemic, were evaluated:

• Early COVID-19 pandemic scenario 1 -risk mitigation, given the potential for: (i) patient and/or staff infection due to repeat hospital visits, (ii) risk of more serious infection in those receiving radiotherapy and/or chemotherapy, and (iii) negative impact on strained healthcare resources from the management of the expected severe toxicities associated with intensive chemo-radiotherapy.

• Later COVID-19 pandemic scenario 2 -severely reduced radiotherapy resources: the additional consideration of a lack of resources, whereby some patients are unable to receive radiotherapy. 

In total, 29/31 (94%) of those invited accepted, and after a replacement nomination by ESTRO, 30/30 completed all three surveys (100% response rate). In the respective rounds, there were 80, 35 and five questions, taking on average a total of 73, 25 and five minutes to complete. The list of questions and panellists' responses are included in Appendix 1.

Panellists were asked if certain cases should be postponed in either the early or late pandemic scenario. There was strong agreement (for cases of OP-, OP+, LX, HXpal, OC+) or agreement (GLOT) not to postpone the initiation of HNSCC radiotherapy by more than 4-6 weeks in both the early and late scenarios. For OC-in the late scenario, there was no consensus.

Panellists were then asked to prioritise the cases. Compared to all other types of cancer within one's department requiring radiotherapy, there was strong agreement that OP-, OP+, and LX were very high (top 20%) or high (top 20-40%) priority. On average, GLOT and OC+ were also deemed high priority, while HXpal was of average (40-60%) priority. OC-was lower priority, and some (23%) would omit radiotherapy in case of severely limited radiotherapy capacity.

In a situation of severely reduced resources, we further asked for these cases to be ranked in order of treatment priority against each other. These were ranked by the panel from high to low as: OP+, OP-, LX, OC+, GLOT, HXpal, OC-. To further understand the trade-offs between treatment urgency and clinical priority, we asked respondents to set a policy by which a group of 20 patients would be treated before the other group could start. In this situation of policy determination, panellists prioritised LX over OP-(62%), OC+ over HXpal (63%), and HXpal over GLOT (73%).

Panellists were finally asked to prioritise factors that would matter most in starting radiotherapy either within the next one week or next 2-3 weeks. These rankings are shown by the highest to lowest weighted average from top to bottom (Figures 1a-b) . In both scenarios of early and late pandemic, the three factors of active SARS-CoV-2 infection, symptomatic benefit, and potential for cure (as opposed to the specific % likelihood of cure) were the most important in triage for radiotherapy over the next one week (Fig. 1a) . With an additional week or two of time before starting, active SARS-CoV-2 infection fell to the second highest weighted position behind symptomatic benefit (Fig. 1b) .

Do not postpone the initiation of HNSCC radiotherapy by 4-6 weeks 

In the case of a patient testing positive for SARS-CoV-2 infection, there was strong agreement (OP, GLOT, OC) or agreement (LX, HXpal) to delay the initiation of radiotherapy until the patient had recovered. However, for all cases there was initially agreement not to interrupt radiotherapy (except for HXpal, where a single fraction could be used). We therefore sought to better understand the recommendation not to interrupt radiotherapy, and the interaction of this decision with SARS-CoV-2 symptom severity and timing during radiotherapy.

Panellists were instructed to assume that appropriate personal protective equipment (PPE) would be available and best practices would be implemented, such as treating the patient at the end of the day in a designated vault, limiting exposure by utilizing minimal staff and properly sanitizing the vault.

Under assurance of these conditions, for patients testing positive with mild symptoms (cough but normal activity level), 63% of the panel voted to continue radiotherapy, 17% would only interrupt in the first or second week of radiotherapy, and 20% would interrupt in any week of radiotherapy until the patient recovered. In other words, there was strong agreement to continue radiotherapy in those with SARS-CoV-2-related mild symptoms who had completed more than two weeks of treatment. On the other hand, there was also strong agreement among panellists to interrupt radiotherapy in any SARS-CoV-2+ patient demonstrating more severe symptoms (cough, chest pain, and trouble breathing at rest requiring oxygen support) until the patient had fully recovered. Different centers reported varying policies on deciding when a SARS-CoV-2+ patient would be able to return including repeat negative testing as well as 10-14 day waiting periods.

For the minority who would interrupt radiotherapy even for mild symptoms, the top stated reasons included: (i) concern for worsening the patient's respiratory and general condition, (ii) increased likelihood of emergency admission and/or need for feeding tube insertion and (iii) risk of infecting other patients and staff. A few panellists expressed that protection of staff and other patients should be prioritised over treatment of a single patient, if unavailability of resources would endanger the many for the one. 

For each case, we asked participants to provide their center's standard radiotherapy dosefractionation and how (if at all), this would be varied for scenarios of risk mitigation or severely restricted radiotherapy capacity ( Of note, most panellists (63%, near-agreement) stated they did not consider induction chemotherapy to be a standard treatment for LX. A few (10%) supported induction as a standard treatment and a minority (27%) supported its consideration as a temporizing measure in times of pandemic. There was in the end a majority (63%) recommending against use of induction chemotherapy in either of the pandemic scenarios. Several panellists expressed concern about the SARS-CoV-2-specific risk that could be incurred from an extended period of myelosuppression.

In scenario 1, risk mitigation: In response to this question, a few panellists commented that they would not wait more than 2-3 months for surgery. Therefore, for oral cavity cancers, where primary radiotherapy is less effective and more toxic, we specifically asked what amount of time would be acceptable for a patient to wait for operating room availability rather than starting radical (chemo-)radiotherapy.

A: Oral Tongue SCC, Wait up to 4 weeks

A few practitioners commented that in these conditions they might wait longer such as 12 or 6 weeks, respectively, to obtain surgery for these two cases.

Where faced with operating theatre closures and no capacity for HNC surgery:

( 

During the pandemic, there was strong agreement to modify the routine weekly in-person (face to face, in the same room) on-treatment reviews for patients receiving radiotherapy. There was also agreement to change the usual practice of conducting all new patient consultations in person. For both situations, there was no consensus approach, as some (23%) had stopped inperson reviews altogether and others had reduced the frequency of in-person visits, replacing them with telephone (50%) or video (26%) consultations. A few panellists commented on concomitant reduction of dental, nutrition, or speech pathology services.

Panel members were in strong agreement not to increase the use of prophylactic placement of percutaneous endoscopic gastrostomy (PEG) feeding tubes; some commented that interventional radiology services were unavailable due to pandemic and PEG use was actually decreased. Over half (53%) of the panellists were no longer performing aerosol-generating procedures within the radiotherapy department (tracheostomy care, airway suctioning, flexible fiberoptic nasopharyngoscopy, nasogastric tube insertion).

Where possible, reduce in-person (face to face, in the same room) consultations and replace with telephone or video for:

Routine weekly on-treatment reviews Strong agreement

The aim of this ASTRO-ESTRO practice recommendation was to provide urgent support for clinicians faced with managing HNC during the COVID-19 pandemic. There are a number of substantial recommendations, structured around typical cases in distinct pandemic scenarios, but treatment decisions in the real world must take into account all of the clinical factors relevant at the time. These decisions are informed by local and national policies, and must be made within political, financial and regulatory frameworks. On a practical level, the ability to implement hypofractionated radiotherapy schedules will depend on the circumstances of the particular radiotherapy department, and the capability and capacity to do so (for example, knowledge of altered fractionation, critical structure dose constraints, and dosimetrist and physicist resources).

In the early, risk-mitigation scenario, neither the potential benefits of using hypofractionated radiotherapy to reduce frequency of patient attendance, nor the omission of concomitant chemotherapy to reduce risk of immunosuppression or treatment complications, were deemed sufficient justification to alter standard practices for locoregionally advanced HN cancer. However, our scenarios described a patient fit for a combined-therapy regimen. Patient-specific factors (such as age, fitness, comorbidities) were not addressed in this study. It has been recognized that the benefit of concomitant chemotherapy decreases with increasing age (especially for those >60 years' old). 5 Therefore, for older patients or those with comorbidities who are at higher risk of more serious SARS-CoV-2 infection, 6 and for whom concomitant chemotherapy will have less benefit, the use of chemotherapy should be restricted.

In the later scenario of severely reduced capacity (where some patients would need to go without radiotherapy), there was strong support for hypofractionated radiotherapy. For early larynx cancer (T1N0), 50 Gy / 16f was most commonly recommended, 7, 8 and there are data for 55 Gy / 20f in T2N0 disease. 9, 10 There is limited evidence to support the use of hypofractionated radical radiotherapy over 4-5 weeks for locoregionally advanced disease, but panellists suggested schedules including: 55 Gy / 20f, 11, 12, 13, 14 62.5-64 Gy / 25f, 15, 16 and 54 Gy / 18f. 17, 18 Most would not use concomitant chemotherapy in this setting, and there was agreement to restrict concomitant chemotherapy to schedules of ≤ 2.4 Gy / f. While there are data to support the use of concomitant platinum chemotherapy with higher doses per fraction, 12, 13, 15 panellists expressed reservations about the potential lack of benefit (for example, no apparent local control or overall survival advantage from the combination of chemotherapy with accelerated radiotherapy), 19, 20 However, when further tested as direct trade-offs choosing whether to start groups of 20 patients over the others, there were two areas of divergence. First, in these larger-scale policy terms, it was agreed HXpal should be prioritised over GLOT with the rationale that: (i) the treatment course could be delivered expediently by a single radiation fraction (note the increase from 4% to 30% of panellists who would use a single fraction in these late pandemic circumstances), which would result in important symptomatic benefit, and (ii) GLOT could wait for a period of time to start radiotherapy without risk of significant progression or change in the chance of cure. This approach is in keeping with the earlier finding where postponement of GLOT by 4-6 weeks was acceptable to more than 20% of panellists. Second, the majority (62%) now agreed LX should be treated before OP-. This was important to prevent potential airway obstruction (i.e., for symptomatic benefit), where both cases had a similar chance of cure. This preference was consistent with our finding that symptomatic benefit and chance of cure were two of the top three factors for panellists in determining which group of patients should start treatment within a week or 2-3 weeks in the face of severely reduced radiotherapy capacity. In terms of factors conditioning whether to initiate radiotherapy, the third most important factor was SARS-CoV-2 status, which reflects the strong agreement to delay the start of treatment in patients testing positive for SARS-CoV-2 infection.

An unfortunate consequence of the COVID-19 pandemic is the closure of operating rooms, due to a lack of protective equipment to counteract increased exposure risk, and redeployment of anesthesiologists and ventilators to critical care. There was consensus that HNC cases normally managed by primary surgery should generally be treated with radical (chemo-)radiotherapy rather than have no treatment. However, for cancers of the oral cavity, where radiotherapy is less effective and more toxic than surgery, there was agreement that waiting for up to 8 and 4

weeks for surgery was acceptable for T1-2 cancers and T3-4 cancers, respectively, with close clinical surveillance every few weeks to monitor for clinical progression.

A major effect of the COVID-19 pandemic is a shift in the risk-benefit ratio which typically governs HNC management. In the face of severely reduced resources, unaccustomed tradeoffs may become necessary with the consequence of being forced to consider treatments that could carry a higher risk of late effects (hypofractionation) or could be suboptimal (without chemotherapy, nonsurgical), to ensure safety and therapeutic benefit for the greatest number of persons. These newly developed practice recommendations provide a global consensus and basic harmonisation of approach in the face of limited clinical data to direct these difficult, unfamiliar decisions. One tangible benefit already achieved was the rapid sharing and comparison of hypofractionation schedules considered "acceptable" by global HNC experts in times of extreme crisis such as COVID-19.

This urgent practice recommendation was issued in the knowledge of the difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health from SARS-CoV-2

infection. The aim of this consensus statement is to ensure that high-quality HNC treatments continue, to save lives and for symptomatic benefit. The process was unusual in that several members of this panel participated even as they continued to deliver treatments facing serious personal risks to themselves. This statement attempts to address the immediate impacts of the COVID-19 pandemic on HNC clinical practice; an understanding of future consequences (impacts on clinical research and scientific advance, health care systems' financial standing, health and psychological consequences for practitioners and patients) will require continued attention.

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SCC: squamous cell carcinoma; Gy/f: Gray/fraction; % of panellists in agreement with dose/fraction range, followed by listing of the most commonly cited schedules arranged by % of panellists giving that response (latter does not add up to 100%). *Panellists called this schedule "quad shot" but the exact schedule can vary; the most common version is 3.7 Gy given twice daily for 2 days, repeated for 3 cycles.