Open access Original research ESMO Management and treatment adapted recommendations in the COVID-19 era: Lung cancer Antonio Passaro ‍ ,1 Alfredo Addeo ‍ ,2 Christophe Von Garnier,3 Fiona Blackhall,4 David Planchard,5 Enriqueta Felip,6 Rafal Dziadziuszko,7 Filippo de Marinis,1 Martin Reck,8 Hasna Bouchaab,9 Solange Peters9 To cite: Passaro A, Addeo A, ABSTRACT Since the beginning of the outbreak of Von Garnier C, et al. ESMO The COVID-19 pandemic, characterised by a fast COVID-19, the oncology community has been Management and treatment and global spread during the first months of 2020, under pressure to protect cancer patients and adapted recommendations in the COVID-19 era: has prompted the development of a structured set of ensure their treatment.4 5 This complex task Lung cancer. ESMO Open recommendations for cancer care management, to required brings with it an emotional struggle 2020;5:e000820. doi:10.1136/ maintain the highest possible standards. Within this as we balance the desire to cure or treat our esmoopen-2020-000820 framework, it is crucial to ensure no disruption to essential patients, with the fear of losing them from oncological services and guarantee the optimal care. This is a structured proposal for the management of lung infection.6 Received 5 May 2020 cancer, comprising three levels of priorities, namely: tier Several worldwide leading professional Revised 20 May 2020 1 (high priority), tier 2 (medium priority) and tier 3 (low organisations, including the European Society Accepted 20 May 2020 of Medical Oncology (ESMO), have worked priority)—defined according to the criteria of the Cancer Care Ontario, Huntsman Cancer Institute and Magnitude of to implement and share knowledge about Published online Clinical Benefit Scale. the importance of preventative/measures to 23 June 2020 The manuscript emphasises the impact of the COVID-19 maximise their support to our patients.4 7 pandemic on lung cancer care and reconsiders all steps Deciding whether to offer, postpone or from diagnosis, staging and treatment. even cancer or not treatments to patients, These recommendations should, therefore, serve as has become a crucial recurrent dilemma for guidance for prioritising the different aspects of cancer lung cancer oncologists.4 8 Different cancer care to mitigate the possible negative impact of the COVID-19 pandemic on the management of our patients. treatments require careful specific, individual As the situation is rapidly evolving, practical actions are assessment and consideration: for instance, required to guarantee the best patients’ treatment while chemotherapy may cause transient immune protecting and respecting their rights, safety and well-­ suppression, immunotherapy or tyrosine being. In this environment, cancer practitioners have great kinase inhibitors may trigger inflammatory responsibilities: provide timely, appropriate, compassionate lung changes, mimicking and worsening and justified cancer care, while protecting themselves pulmonary symptoms.9 These inflammatory and their patients from being infected with COVID-19. In lung damage scenarios that are routinely case of shortages, resources must be distributed fairly. faced in the contest of lung cancer care Consequently, the following recommendations can be could potentially lead to a poorer outcome applied with significant nuances, depending on the time in case of concomitant COVID-19 disease. and location for their use, considering variable constraints imposed to the health systems. An exceptional flexibility is However, oncologists should weigh the risk required from cancer caregivers. of death for patients with lung cancer due to COVID-19, with the negative impact on their prognosis due to disruption of their cancer © Author (s) (or their INTRODUCTION care.9 10 Oncologists should not ignore the employer(s)) 2020. Re-­use The coronavirus disease 2019 (COVID-19), risk of observing a bimodal peak of cancer permitted under CC BY-­NC. No characterised by a respiratory tract infec- patients dying: the imminent spike of those commercial re-­use. Published by BMJ on behalf of the tion caused by the severe acute respiratory falling victim to COVID-19 and the latent toll European Society for Medical syndrome coronavirus 2 (SARS-­CoV-2) virus, on those experiencing an excess of cancer-­ Oncology. to date has caused more than one million related mortality, whose treatments were For numbered affiliations see confirmed cases worldwide.1 This pandemic de-­intensified, delayed or cancelled. end of article. has forced all the healthcare stakeholders Considering that the duration of this Correspondence to to urgently reorganise the management of pandemic is difficult to foresee, patient Dr Antonio Passaro; patients with COVID-19, prioritising per decisions have to be made by multidisci- ​Antonio.​Passaro@​ieo.​it value resources and therapeutic strategies.2 3 plinary teams. A multifactorial risk/benefit Passaro A, et al. ESMO Open 2020;5:e000820. doi:10.1136/esmoopen-2020-000820 1 Open access evaluation, including the magnitude of the epidemic in to ensure the safest conditions for the health workforce, the country, the local healthcare structure resources and the proper provision of personal protective equipment, the infection risk to the individual, must be carried out.11 the testing strategy for healthcare personnel, patients In the present work, we report the ESMO recommenda- and communities are essential and developed in parallel, tions for diagnosis, treatment and follow-­up for patients conditioned by the local situation over time. Of note, affected by lung cancer during the COVID-19 pandemic. population-­based strategies and policies need to consider These recommendations should be used as guidance to the most vulnerable communities explicitly for COVID-19 prioritise the various aspects of cancer care and to miti- infection and complications—cancer patients being first gate the potential harm due to COVID-19 epidemic on among them.13 14 Recently, the TERAVOLT registry patients with lung cancer. revealed that patients with thoracic malignancies are less likely to be admitted to the intensive care unit and are at increased risk of prolonged hospitalisation and mortality, METHODOLOGY FOR THE SELECTION OF PRIORITY rising to 33% in this series, from COVID-19 infection. INTERVENTIONS Univariate analyses revealed that the presence of chronic The present manuscript reports the consensus of an obstructive pulmonary disease was associated with a risk international panel of thoracic malignancies experts in of hospitalisation and death. A multivariate analysis is that the management of lung cancer. It is proposed to guide no patient treatments or cancer-­related factors were asso- healthcare professionals treating lung cancer patients ciated with a higher risk of death.15 during the COVID-19 pandemic. The expert consensus-­ based recommendations are not intended to replace the current guidelines but slightly adapt them to the evolving PRIORITIES FOR LUNG CANCER PATIENTS circumstances and constraints imposed by the COVID-19 Outpatients visit priorities pandemic, using a value-­based framework to set priori- The COVID-19 pandemic has been placing unprece- ties. The experts have formulated all the adaptations and dented pressure on health systems worldwide. To respect prioritisations via teleconferences and email discussions. social distancing and to apply the overall public health With the aim to provide a framework for the response measures for the mitigation of SARS-­CoV-2 spread outpa- of the medical community to COVID-19, ESMO has estab- tient cancer services should be reinforced and reorgan- lished guide for clinicians, defining three levels of prior- ised. This must occur balancing; first, the risks for cancer ities regarding therapeutic interventions, namely: tier 1 patient to contract COVID-19 during investigations and (high priority), tier 2 (intermediate priority) and tier 3 treatments and, second, the care providers’ capacity. (low priority)—informed by the Ontario Health Cancer In the outpatient setting, prioritisation is guided by Care Ontario framework of resource-­prioritisation and by the magnitude of benefit. Clinical situation and quality the ESMO Magnitude of Clinical Benefit Scale (MCBS), of care should remain unchanged for the prioritised a public health tool intended to support the uptake of interventions. medical interventions in oncology.12 13 For example, all treatment plans for patients with Overall, the prioritisation has been developed to incor- cancer must be discussed in a multidisciplinary setting as porate both the information on the value-­based prioritisa- it has significant prognostic implications. Thus, while the tion and clinical cogency of the responses. format may change (eg, videoconferencing), the prin- ►► Tier 1 (high priority): patient’s condition is imme- ciple of multidisciplinary shared care is non-­negotiable.16 diately life-­threatening, clinically unstable and/or A quick triage for possible symptoms of COVID-19 the magnitude of benefit qualifies the intervention composed of a rapid questionnaire and temperature as high priority (eg, significant overall survival gain check should be put in place before entering any hospital and/or substantial improvement of the quality of life premises. (QoL)); To minimise the risk of exposure, outpatient visits ►► Tier 2 (medium priority): patient’s situation is non-­ should be reorganised: established patients with symp- critical but delay beyond 6 to 8 weeks could potentially toms or patients with high suspicion of new lung cancer impact the overall outcome and/or the magnitude of must be handled within standard pathways, ensuring benefit qualifies for intermediate priority; protective measures are in place (eg, hand hygiene, phys- ►► Tier 3 (low priority): patient’s condition is stable ical distancing recommendations and use of personal enough allowing services to be delayed for the dura- protective equipment requested).17 tion of the COVID-19 pandemic and/or the interven- Although hospital admission should be minimised, all tion is non-­priority based on the magnitude of benefit the new cases with suspicion of clinical stage III or meta- (eg, no survival gain with no change or reduced QoL). static, both for non-­small cell lung cancer (NSCLC) or The clinical guidance defined by ESMO must be inter- small cell lung cancer (SCLC), or the appearance of preted and used in the broader context of local and disease-­related symptoms (eg, dyspnoea, cough, chest international health system strategies and aligned to the pain, haemoptysis and so on) should keep the standard Global Norms of WHO, the lead public health agencies work-­up as per standard guidelines, without undue delay and health technical governmental boards. Interventions (high priority) (table 1). 2 Passaro A, et al. ESMO Open 2020;5:e000820. doi:10.1136/esmoopen-2020-000820 Open access Table 1 Outpatient visit priorities High priority Medium priority Low priority New diagnosis or suspicion of invasive New diagnosis or suspicion of localised Patients visits for psychological support lung cancer with either: lung cancer of clinical stage I (convert to telemedicine) ►► Disease-­related symptoms (dyspnoea, pain, hemoptysis and so on) ►► Suspicion of clinical stage III or metastatic NSCLC or SCLC Survivorship visits Follow-­up for patients at high risk of Follow-­up for patients at low/ relapse intermediate risk of relapse Visits for treatment administration Established patients with new problems Postoperative patients with no or symptoms from treatment - convert as complications - convert as many visits as many visits as possible to telemedicine possible to telemedicine visits visits NSCLC, non-­small cell lung cancer; SCLC, small cell lung cancer. All non-­priority outpatient appointments may be the appointments at least postponed by a few weeks or converted to the telemedicine platform, evaluating the months depending on the local situation. priority on a clinical need basis. Telemedicine suits best Furthermore, as reported by the National Health the non-­urgent situations for established patients without Service (NHS) of England guidelines for the manage- new complaints as well as patients on long-­term follow-­up ment of non-­COVID-19 patients, alternative methods to with low/intermediate risk of relapse. In asymptomatic monitor and review patients receiving systemic therapies patients on follow-­up, radiological investigation can be should be explored. Nevertheless, slots for follow-­ up delayed unless new symptoms occur (medium priority). imaging within the first 6 months of lung cancer treat- For some of the patients on active treatment, whenever ment or in case of possible progression disease at any possible, the consultations should be shifted to telemed- point in time should remain unchanged (high priority). icine and blood tests performed at home. Overall, in the It is highly recommended that all patients suspicious for context of oncology care, telemedicine might represent lung malignancy could have priority access to diagnostic a valuable tool to implement, but it should not entirely imaging (eg, CT scan, positron emission tomography replace standard practice. scan) (high priority). Whenever this was not feasible in The patient-­ centred care model requires addressing a local hospital, a transfer to a cancer hub should be of all patient’s needs and as such, psychosocial supports considered. must be assured and converted to telemedicine or other web-­based platforms if possible. LUNG CANCER SURGERY During the COVID-19 pandemic, the capacity of thoracic IMAGING surgery has been significantly reduced and access to the The role of imaging in lung cancer remains crucial for intensive care unit after elective surgery might have been diagnosis and disease management. As recommended by restricted. Due to these restrictions, setting up a priority-­ the Centers for Disease Control and Prevention (CDC)17 framework for lung cancer surgery is essential. guidance and endorsed by the American College of Radi- The multidisciplinary team plays an essential role to ologist (RCR),18 prioritising and safeguarding the health- prioritise different lung cancer surgical procedures while care resources is essential. Hence outpatient appoint- preserving the highest possible standards. Once again, ments and or imaging for non-­critical patients, including risk/benefit ratio, including not only patients and disease a non-­ urgent diagnostic or image-­ guided procedure, aspects19 but also alternative treatment modalities such should be postponed and rescheduled (low priority) as (chemo)radiation therapy for high volume disease (table 2). or stereotactic ablative radiotherapy T1-­T2N0 tumours, Radiologists should closely work with their referring should be carefully explored (table 3).20 21 thoracic oncologists to review and reschedule such During the COVID-19 outbreak, keeping at bay the exams, based on patient’s priorities, prognosis and symp- perioperative morbidity and mortality due to cancer or to toms (low priority). SARS-­CoV-2 infection should be a common goal. However, Similarly, considering the risk-­benefit ratio lung cancer lung cancer is usually characterised by fast-­ growing screening protocol with low-­ dose CT scan should be behaviour; therefore, a rapid surgical assessment must be temporarily withheld during the pandemic peak or prioritised and carried out in particular if a delay could Passaro A, et al. ESMO Open 2020;5:e000820. doi:10.1136/esmoopen-2020-000820 3 Open access Table 2 Imaging priorities for lung disease High priority Medium priority Low priority ►► Patients with significant respiratory Follow-­up imaging for high/intermediate Follow-­up imaging for high/intermediate symptoms and/or other clinically risk of relapse in a year after completion risk of relapse more than one year after relevant chest, cancer-­related of radical treatment completion of radical treatment. or treatment-­related symptoms. In patients with new respiratory symptoms such as dyspnoea, cough with or without fever, a CT scan is recommended Standard staging work-­up for suspected Standard staging work-­up for early lung Follow-­up imaging after radical treatment invasive cancer of unknown stage or cancer (stage I) in low-­risk of relapse scenario. stage II/III/IV Biopsies for suspicious nodules or mass Biopsies for suspicious nodules or for suspected invasive cancer of stage or mass for suspected invasive cancer of stage III/IV unknown stage or stage I/II Established patients with new problems or symptoms from treatment Evaluation of active treatment response Evaluation of active treatment response in the first 6 months of treatment or if beyond 6 months of treatment if stable/ suspicion of progression at any time controlled situation point Follow-­up of nodules of incidental finding Follow-­up of nodules of incidental finding with either: with either: 3 3 ►► Solid nodule 50 to 500 mm ►► Solid nodule <50 mm ►► Pleural-­based solid nodule ►► Pleural-­based solid nodule 5 to 10 mm <5 mm ►► Partially solid nodule with a non-­solid ►► Partially solid nodule with a non-­solid component of ≥8 mm component of <8 mm ►► Known VDT 400 to 600 days ►► Non-­solid nodule <8 mm ►► Benign morphology ►► Known VDT>600 days Pre-­planned imaging evaluation per Lung cancer screening can be deferred clinical trial protocol until the COVID-19 pandemic resolves - it is reasonable for patients in the general population to defer screening low-­dose CT, a deferral that is not likely to have an impact on overall survival. VDT, volume doubling time. compromise the surgical outcome (high priority).22 High A to C, from high to low priority, respectively. Therefore, priority must also be given to specific palliative surgical the selection and prioritisation of the medical treatments approaches as thoracentesis or stent insertion, in case of at these stages require prudence and long-­term vision as significant symptoms and in order to improve QoL and overall survival remains the most relevant endpoint. patients’ prognosis.23–25 Adjuvant platinum-­ based doublet chemotherapy, in Surgical indications must be individualised, and all resected stage I to III of NSCLC, showed an absolute decisions should be shared with the patients and their benefit in survival at 5 years of about 5% to 6%.22 Since caregivers: assessing preference and managing expecta- systemic treatments do not increase early mortality rates tions while informing on the pros and cons of any plan after surgery, tolerability and treatment adherence are in the context of the COVID-19 crisis remains crucial.26 critical factors for the optimum timing of chemotherapy in the COVID-19 era. Considering the risk of SARS-­CoV-2 EARLY STAGE NON-SMALL CELL LUNG CANCER infection related to peri-­surgical and post-­surgical time Improving outcomes in the curative setting of early stage and different chemotherapy aspects (eg, immunosup- remains a major therapeutic challenge in lung cancer pressive state), the role of adjuvant chemotherapy at the management. present time should be reconsidered, based on a priority According to the ESMO-­MCBS,13 pharmacological inter- scale that includes mainly the relative survival benefit and ventions in the curative setting are scored A, on a scale from functional comorbidities (table 4). 4 Passaro A, et al. ESMO Open 2020;5:e000820. doi:10.1136/esmoopen-2020-000820 Open access Table 3 Surgical oncology priorities for lung disease High priority Medium priority Low priority Drainage =/- pleurodesis of pleural effusion, pericardial effusion, tamponade risk Evacuation of empyema-­abscess T2N0 tumours naïve from treatment or after Discordant biopsies likely to be Discordant biopsies likely to be benign induction chemotherapy malignant Resectable T3/T4 tumours naïve from treatment or after induction chemotherapy Resectable N1/N2 disease naïve from Operable pure GGO nodule (T1a) treatment or after induction chemotherapy Operable NSCLC with T1AN0 (alternative if no surgical capacity available is stereotactic radiotherapy; surgery is preferred) Diagnostic procedure as mediastinoscopy / Diagnostic work-­up and/or resection Diagnostic work-­up and/or resection of all other thoracoscopy / pleural biopsy / endoscopy of nodules of incidental finding with nodules of incidental finding including too: / transthoracic investigations for diagnostic/ either: ►► Solid nodule >500mm3 and known VDT >600 staging workup ►► Solid nodule >500 mm3 days ►► Pleural-­based solid nodule >10 (alternative if no surgical capacity available is mm stereotactic radiotherapy) ►► Solid component >500 mm3 in partially solid nodule ►► Known VDT <400 days ►► New solid component in pre-­ existing non-­solid nodule (alternative if no surgical capacity available is stereotactic radiotherapy) GGO, ground-­glass opacity; NSCLC, non-­small cell lung cancer; VDT, volume doubling time. The risk-­benefit ratio of adjuvant chemotherapy should infection related to chemotherapy-­induced immunosup- be thoroughly discussed with patients. The indication pression, adjuvant chemotherapy should be proposed in should be strongly considered in the presence of nega- fit and young patients (≤65 years), with resected T3/T4 tive prognostic features (eg, lymphovascular infiltration, or in case of pN2 disease. pathological lymph node invasion), while it should be Similarly, neoadjuvant chemotherapies should be given withheld in frail, elderly patients with significant comor- top priority, as reported by NHS clinical guide for the bidities. On the other hand, despite the risk of SARS-­CoV-2 management non-­ coronavirus, in patients with cancer Table 4 Medical oncology priorities: early stage disease High priority Medium priority Low priority Concomitant chemo-­radiotherapy for SCLC limited disease stage I/II Neoadjuvant chemotherapy (enabling deferral of surgery by 3 months) in clinical stage II Medical follow-­up between two cycles should Adjuvant chemotherapy in T2B-­T3N0 or Adjuvant chemotherapy in stage T1A-­ be performed only if necessary and by pN1 disease should be discussed with T2BN0 with negative prognostic features telephone patients considering clinical features and (lymphovascular infiltration, …) prognosis Delivery of adjuvant chemotherapy in T3/4 or N2 disease for young (age ≤65/70 years old)* and fit patients Laboratory check between two cycles should Adjuvant chemotherapy for elderly be performed only if necessary and at home if (older than 65 years old) and patients possible with important comorbidities should be discussed and possibility omitted G-­CSF use if febrile neutropenia risk evaluated more than 10% to 15% *Defined elderly age according to local guidance. G-­CSF, granulocyte colony-­stimulating factor; SCLC, small cell lung cancer. Passaro A, et al. ESMO Open 2020;5:e000820. doi:10.1136/esmoopen-2020-000820 5 Open access Table 5 Medical oncology priorities: locally advanced disease Low High priority Medium priority priority Concomitant chemo-­radiotherapy for SCLC limited disease stage III Concomitant or sequential chemo-­radiotherapy for inoperable NSCLC Stage III Starting consolidation durvalumab (within 42 days) Neoadjuvant chemotherapy in clinical stage III Medical follow-­up between two cycles should be performed only if necessary and by telephone G-­CSF use if febrile neutropenia risk evaluated more than 10% to 15% Laboratory check during treatment should be performed only if necessary and at home if possible G-­CSF, granulocyte colony-­stimulating factor; NSCLC, non-­small cell lung cancer; SCLC, small cell lung cancer. requiring acute treatment. This approach applies poten- might potentially outweigh the number of deaths from tially to all patients suitable for a surgical approach with SARS-­CoV-2 in the next years.11 curative intent, in particular, in young and fit patients According to the MCBS, the priority interventions in without comorbidities. In adjuvant or neoadjuvant the advanced setting are scored 3, 4 or 5, in a descending platinum-­ based chemotherapy, the use of granulocyte scale for value, from 5 to 1.12 For such, the magnitude of growth factors should be considered to avoid and mini- benefit and the expected treatment benefits should guide mise neutropenia and its related risk of hospitalisation, the clinical indications and support treatment decisions. possibly beyond the usual recommendations.27 28 In order to limit cancer-­related mortality, in patients with a new diagnosis of metastatic NSCLC, all standard options for first-­line systemic therapy should be envisaged LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER unaltered, including chemotherapy, immunotherapy, The management of stage III of NSCLC is notably chal- tyrosine kinase inhibitors and different combinations. lenging during the COVID-19 pandemic, considering This approach aims to improve prognosis, cancer-­related that the need to optimise and prioritise the appropriate symptoms and QoL and should be prioritised whenever combination, time and sequence of multiple treatment possible. The same holds true for second-­line treatments modalities, potentially lead to an increased risk of expo- in patients with symptomatic, progressive disease, whereas sure within hospitals to SARS-­CoV-2.29 delaying the treatment could compromise patient's Given the significant curative potential, the treat- survival (high priority) (table 6). ment for a patient with stage III NSCLC should receive In both settings, when the chosen treatment for clinical high priority. These apply to neoadjuvant treatment in or biological criteria is chemotherapy, the use of G-­CSF potentially resectable stage IIIA and to concomitant or has to be considered if risk of febrile neutropenia is above sequential chemoradiation (CT/RT) in stage IIIA/IIIB/ >10% (high priority). This is not anticipated to impact on IIIC, both supported by the use of granulocyte colony-­ the specific COVID-19 risk but could reduce significantly stimulating factor (G-­CSF) as previously proposed. Simi- risk of neutropenic sepsis hence number of hospital larly, as for patients with disease control after CT/RT admissions for neutropenic sepsis. treatment, the subsequent use of durvalumab as consoli- Based on pharmacokinetic modelling and exposure-­ dation therapy should be guaranteed within 42 days after response analyses, immune checkpoint inhibitors (ICIs) CT/RT completion, without any planned delay (table 5). schedule should be modified/delayed to reduce clinical A durvalumab infusion every 4 weeks instead of the visit, using 4-­weekly nivolumab 480 mg30–34 or 6-­weekly standard every 2 weeks should be considered, where pembrolizumab 400 mg35–37, instead of the standard allowed from National Regulatory Agency (high priority). 2-­weekly or 3-­weekly, when appropriate and where allowed from National Regulatory Agency (high priority). METASTATIC NON-SMALL CELL LUNG CANCER For patients on ICI for more than 12/18 months, The definition of a homogeneous prioritisation algorithm delaying the subsequent cycle, omitting some cycles or in the metastatic setting is complex. In the clinical land- generally expanding intervals should be considered.37–40 scape of active treatments known to improve quality of Discontinuation of ICIs after 2 years should be discussed, life and survival in a very aggressive malignancy, evidence-­ keeping in mind the lack of prospective evidence about based treatment approaches should retain priority optimal treatment duration in lung cancer. even during the pandemic. Nowadays, the COVID-19 The role of tyrosine kinase inhibitors (TKIs) in outbreak represents an immediate threat to patients with oncogene-­ driven NSCLC must continue unaltered, NSCLC, but the possible disruption of cancer services unless clinical situations require discontinuation (high 6 Passaro A, et al. ESMO Open 2020;5:e000820. doi:10.1136/esmoopen-2020-000820 Open access Table 6 Medical oncology priorities: metastatic lung disease High priority Medium priority Low priority First-­line treatment including, chemo, Start second-­line and beyond-­line Discontinuation of ICIs after 2 years of chemo plus IO, IO alone or TKIs to improve chemotherapy or IO in asymptomatic treatment should be suggested prognosis, cancer-­related symptoms and QoL patients, in absence of threatening disease (volume/location). Start second-­line chemotherapy or IO in Consider when feasible, oral For patients ongoing with ICIs having symptomatic and progressive disease chemotherapy treatment instead of stopped due to toxicity, resuming patients. intravenous (etoposide, vinorelbine) to might be delayed in absence of reduce hospital visits disease progression Start second-­line TKI in progressive disease Medical follow-­up between two cycles Postpone antiresorptive therapy patients. should be performed only if necessary (zoledronic acid, denosumab) that is and by telephone urgently for hypercalcaemia G-­CSF use has to be considered if despite Blood check during treatment should optimal dose modification, a risk of febrile be performed only if necessary and at neutropenia is >10% home if possible ICIs scheduled cycles may be modified/ For patients ongoing with ICIs from delayed to reduce clinical visits (for instance, more than 12/18 months, delaying using 4 weekly or 6 weekly dosing instead the next cycle and omitting some of 2 weekly or 3 weekly for selected agents scheduled cycles or generally enlarged when appropriate (where allowed from intervals should be considered National Regulatory Agency) G-­CSF, granulocyte colony-­stimulating factor; ICI, immune checkpoint inhibitors; IO, immune-­oncology; QoL, quality of life; TKI, tyrosine kinase inhibitors. priority). A drug home delivery service should be insti- for metastatic disease, or in patients with limited disease, tuted if possible for patients receiving oral TKIs to ensure treated concurrently with chest radiotherapy. G-­ CSF similar drug access during the pandemic and unchanged support is strongly indicated for patients who have a high care, while limiting access to hospital hence reducing the or medium risk of febrile neutropenia (high priority) exposure to SARS-­CoV-2 (tables 5 and 6). Home delivery service should be considered even in Starting second-­line therapy in a symptomatic and/ the case of oral chemotherapy treatments, which are or platinum-­ refractory patient should be extensively preferred to the corresponding intravenous formula- discussed with the patient, weighing risk/benefit ratio. tions, when available, such as etoposide or vinorelbine, The administration of prophylactic cranial irradia- when clinically needed to reduce hospital admissions tion (PCI) should be potentially deferred in patients (medium priority). with limited stage, and replaced by MRI surveillance in Extra caution is required by systemic treatments that are patients with extensive disease SCLC. less likely to impact overall survival or quality of life. A full explanation and assessment of risk/benefit ratio should be discussed with the patient on a case-­by-­case basis. RADIATION ONCOLOGY In this emergency scenario, a temporary withdrawal The priority remains to guarantee that all curative of some interventions could be contemplated. Antire- treatments are unaffected by the COVID-19 pandemic. sorptive bone-­ protective therapy (zoledronic acid, Recently the Royal College of Radiologist has issued denosumab), not deemed urgent for malignant hyper- guidelines on “Reduced fractionation in lung cancer calcaemia, should be withheld unless deliverable in the patients treated with curative-­intent radiotherapy during community or at the patient’s home (low priority). the COVID-19 pandemic”.41 They highlight the impor- tance of discussing alternative dose-­fractionation sched- SMALL CELL LUNG CANCER ules of radiotherapy techniques. Timing and ability to SCLC treatment has always represented a challenge for implement changes to dose/fractionation schedules the thoracic oncologist, considering the tumour aggres- will vary depending on resources and technology avail- siveness, the rapid growth and early spread to distant able and current capabilities. The objective is to identify metastases, sometimes associated with paraneoplastic reduced-­ fractionation and curative-­ intent radiotherapy syndromes. regimes in lung cancer, assess their evidence base and As in the non-­COVID-19 clinical setting, the treatment provide organs-­at-­risk dose constraints. The aim is first to of SCLC should always be prioritised in patients suitable reduce hospital visits and exposure to SARS-­CoV-2 and to to receive first-­line chemotherapy with or without ICIs increase radiotherapy unit capacity for operable patients Passaro A, et al. ESMO Open 2020;5:e000820. doi:10.1136/esmoopen-2020-000820 7 Open access Table 7 Radiation oncology priorities for lung disease High priority Medium priority Low priority Radiotherapy for inoperable stage II to III cancers, with SABR - SBRT for stage I cancers contraindications for chemotherapy. Concomitant (preferred) chemo-­radiotherapy for Adjuvant PORT for R1 resection, Adjuvant PORT N2 R0, if indicated inoperable NSCLC Stage II/III. - if indicated in NSCLC could be in NSCLC should be discussed considered at the end of adjuvant and if retained considered at the chemotherapy or delayed up to 3 end of adjuvant chemotherapy months from surgery or delayed up to 3 months from surgery Concomitant (preferred) chemo-­radiotherapy for SCLC PCI in limited SCLC after PCI in extensive stage SCLC after limited disease chemotherapy chemotherapy should be replaced by MRI active surveillance Superior vein cave obstruction or significant haemoptysis, spinal cord compression or any threatening lesion amenable to radiation therapy NSCLC, non-­small cell lung cancer; PCI, prophylactic cranial irradiation; PORT, post-­operative radiation therapy; SABR, stereotactic ablative radiotherapy; SBRT, stereotactic body radiotherapy; SCLC, small cell lung cancer. with lung cancer who may not be able to have surgery PCI in limited-­ stage SCLC could be considered after during this pandemic. chemotherapy (medium priority). Furthermore, ESTRO-­ASTRO has issued some recom- mendations on how to adapt radiotherapy for lung cancer in the COVID-19 pandemic pointing out that all COVID-19 AND ITS IMPACT ON LUNG CANCER RESEARCH efforts should be made not to compromise the prognosis Strict measures to limit the virus spread have affected clin- of lung cancer patients by departing from guideline-­ ical cancer research centres that decreased their activity recommended radiotherapy practice.42 due to quarantine, working in shifts and lack of supplies. For instance, the adjuvant post-­ operative radiation In some of these centres it was necessary to make deci- therapy (PORT) for radically resected pN2 NSCLC sions of interrupting or even permanently stopping some should be discussed and eventually performed at the end trials in order to preserve the accuracy of endpoint eval- of adjuvant chemotherapy or eventually delayed up to 3 uation and the protocol adherence. While clinical and months from surgery (low priority) (table 7). The same translational research is crucial for providing the best therapeutic approach with PORT, in R1 resection, could care for cancer patients, many centres faced the need to be considered at the of adjuvant therapy or delayed up to modify programmes and adapt them to the new situation. 3 months from surgery (medium priority). Difficulties in trial conduction and monitoring may lead For inoperable or locally advanced stage II to III lung to specific and potentially critical protocol deviations. cancers, the radiation, alone or with concurrent or Despite this rapid evolution of the COVID-19, there is a sequential chemotherapy, should be delivered given the strong need to respect several important aspects. First, all curative potential (high priority). At the same time, palli- patients on trials should be ascertained a safe continu- ative radiotherapy should not be denied or delayed in life-­ ation of protocol treatments. Second, all efforts should threatening or highly symptomatic clinical conditions, be made to protect patients by minimising unnecessary as superior vena cava obstruction, spinal cord compres- visits to cancer unit. Patients must consent to pursue their sion, significant dyspnoea, bleeding or bone pain (high experimental trial care in the evolving COVID-19 situa- priority). Palliative RT with a single fraction or two frac- tion after having been adequately informed about risk/ tions could be considered as an alternative to longer frac- benefit ratios. tionation whenever possible. Nonetheless, the clinical trial investigating specific The curative treatment for stage I lung cancer should treatment for COVID-19 have been prioritised, following be given with stereotactic body radiotherapy. In very early the absolute clinical need.43 44 stage I patients, this treatment may be delayed in order to In lung cancer research, enrolling or treating patients protect the patient by limiting hospital access during the in trials with target therapy or ICIs should be prioritised, pandemic peak (medium priority). A single fraction of while reducing, if feasible, visits and planned hospital 30 to 34 Gy should be considered depending on tumour admission according to sponsors and clinical investigators. location. To withdraw optional trial procedure and to allow flexi- As far as SCLC is concerned, MRI surveillance should bility in visits, imaging assessments and laboratory checks be preferred to PCI for extensive-­stage SCLC in order to should be considered via protocol amendments as neces- reduce the number of visits (low priority); alternatively, sary. Trials with a placebo arm should be suspended until 8 Passaro A, et al. ESMO Open 2020;5:e000820. doi:10.1136/esmoopen-2020-000820 Open access the pandemic resolves, as exposing patients to the risk of Twitter Antonio Passaro @apassaroMD SARS-­CoV-2 in this context would be difficult to justify Contributors AP and SP developed the first outline, based on the ESMO To properly manage clinical trials during the COVID-19 recommendations already published online and developed with AA, CvG and HB. AP and SP coordinated the authors’ contributions, engaged for competencies and pandemic, the leading regulatory agencies such as the US expertise in the management of lung cancer. All the authors were involved in writing Food and Drug Administration (FDA) and the European and, when the first draft had been developed, all the authors refined the contents Medicines Agency (EMA) have issued guidelines and with feedbacks and comments, incorporated by AP, AA and SP. All the authors recommendations for a safe delivery of the study medi- approved the final draft before the submission. While the authors are affiliated to different institutions for cancer research and care, the perspectives expressed in cations and a structural information on changes and the present paper should not be intended to mirror the societal and institutional protocol deviations.45 46 positions. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-­for-­profit sectors. Competing interests AP: honoraria for consulting, advisory role or lectures from CONCLUSION AstraZeneca, Agilent/Dako, Bristol-­Myers Squibb, Eli Lilly, Merck Sharp & Dohme The COVID-19 has put a strain on the global health- and Roche Genentech. AA: honoraria for consulting, advisory role from AstraZeneca, care system leading to an unprecedented modification Bristol-­Myers Squibb, Merck Sharpe & Dohme, Takeda, Pfizer, Roche Genentech of patient care and access to health services. During this and Boehringer Ingelheim. CvG: honoraria for consulting, advisory role or lectures from AstraZeneca, Boehringer Ingelheim, GSK, Mundipharma, Novartis, Pfizer, pandemic, maintaining cancer care has represented PneumRx et Pulmonx. FB: honoraria for consulting, advisory role or lectures from a challenge that has required careful weighing of the AstraZeneca, Abbvie, Bayer, Roche Genentech, Pfizer, Cell Medica, Celgene, Takeda. COVID-19 risk and the optimal oncological standards.47 DP: honoraria for consulting, advisory role or lectures from AstraZeneca, Bristol-­ The oncology community has been forced to adapt Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche Genentech, Samsung Honoraria: cancer care and identify new strategies and priorities to AstraZeneca, Bristol-­Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, ensure the highest possible therapeutic standards for our Novartis, Pfizer, prIME Oncology, Peer CME, Roche. EF: advisory role or speaker’s patients. Following the WHO indications, the develop- bureau from AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, ment of a framework to provide clear guidance on health- Bristol-­Myers Squibb, GSK, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, prIME Oncology, Roche care priorities, to support and enable decision-­making Genentech, Samsung, Springer, Takeda, Touchime. Board: Grifols, independent when resources need to be rationed and cautiously allo- member Research funding: Fundación Merck Salud, Grant for Oncology Innovation cated. Any possible modification of a treatment schedule EMD Serono. RD: honoraria for consulting, advisory role or lectures from from should entail a multidimensional assessment adapted to AstraZeneca, Roche, Pfizer, Novartis, Seattle Genetics, Foundation Medicine, Bristol-­ Myers Squibb, Takeda. FdM: honoraria for consulting, advisory role or lectures local resources, comprising clinical and tumour char- from AstraZeneca, Boehringer Ingelheim, Bristol-­Myers Squibb, Celgene, Merck acteristics, therapeutic objective and the potential risks Sharp & Dohme, Novartis, Roche Genentech, Takeda and Pfizer. MR: honoraria for associated with COVID-19 infection. consulting, advisory role or lecture from Amgen, AstraZeneca, BMS, Boehringer-­ The ESMO clinical recommendations for lung cancer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Samsung. Support for clinical research from BMS. HB: honoraria for consulting, advisory role or lecture for management are, in this context, a guide to ensure and AstraZeneca, Bristol-­Myers Squibb, Merck Sharp & Dohme, and Roche Genentech. maintain high-­quality standards for our patients. SP: received education grants, provided consultation, attended advisory boards, Unfortunately, to date, robust data are lacking to guide or provided lectures for Abbvie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, adjustments to standard-­ of-­ care in patients with lung Blueprint Medicines, Boehringer Ingelheim, Bristol-­Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F Hoffmann-­La Roche, Foundation Medicine, Illumina, cancer. Individualised treatment strategies and close Janssen, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, follow-­up are needed to reduce the gaps of COVID-19 Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody, from whom she in our patients and to improve evidence-­based approach has received honoraria (all fees to institution). and policies during this pandemic. Patient consent for publication Not required. Useful and updated information can be found at Provenance and peer review Commissioned; internally peer reviewed. https://www.​ e smo.​ o rg/​ g uidelines/​ c ancer-​ p atient-​ Data availability statement No data are available. m a n a g e m e n t - ​ d u r i n g - ​ t h e - ​ c o v i d - ​ 1 9 - ​ p a n d e m i c /​ Open access This is an open access article distributed in accordance with the lung-​cancer-​in-​the-​covid-​19-​era Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-­commercially, Author affiliations and license their derivative works on different terms, provided the original work is 1 Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan, Italy properly cited, any changes made are indicated, and the use is non-­commercial. 2 University Hospital of Geneva Department of Oncology, Geneva, Switzerland See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. 3 Department of Pulmonary Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland ORCID iDs 4 Division of Cancer Sciences, University of Manchester & The Christie NHS Antonio Passaro http://​orcid.​org/​0000-​0002-​7575-​3870 Foundation Trust, Manchester, UK Alfredo Addeo http://​orcid.​org/​0000-​0003-​0988-​0828 5 Department of Medical Oncology, Thoracic Unit, Gustave Roussy, Villejuif, France 6 Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain 7 Department of Oncology and Radiotherapy, Gdanski Uniwersytet Medyczny, Gdansk, Poland REFERENCES 8 1 Guan WJ, ZY N, Hu Y, et al. 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