Open access Review ESMO Management and treatment adapted recommendations in the COVID-19 era: Breast Cancer Evandro de Azambuja ‍ ‍ ,1 Dario Trapani,2 Sibylle Loibl,3 Suzette Delaloge,4 Elzbieta Senkus,5 Carmen Criscitiello,6 Philip Poortmans,7 Michael Gnant,8 Serena Di Cosimo,9 Javier Cortes,10 Fatima Cardoso,11 Shani Paluch-­Shimon ‍ ‍ ,12 Giuseppe Curigliano ‍ ‍ 13 To cite: de Azambuja E, Abstract all.1 While the response strategy to the global Trapani D, Loibl S, et al. ESMO The global preparedness and response to the rapid spread of COVID-19 must be immediately Management and treatment escalation to severe acute respiratory syndrome integrated into public health policy, these adapted recommendations coronavirus (SARS-­CoV)-2-­related disease (COVID-19) actions require non-­COVID-19 health prior- in the COVID-19 era: Breast Cancer. ESMO Open to a pandemic proportion has demanded the formulation ities to be urgently identified and defined to 2020;5:e000793. doi:10.1136/ of a reliable, useful and evidence-­based mechanism reshape health systems, which are struggling esmoopen-2020-000793 for health services prioritisation, to achieve the highest to meet the health demands in view of the quality standards of care to all patients. The prioritisation of high value cancer interventions must be embedded rapid spread of the pandemic.2 EdA and DT contributed equally. in the agenda for the pandemic response, ensuring that In oncology, the definition of essential no inconsistency or discrepancy emerge in the health services must be developed within a value Received 17 April 2020 framework for organisational and clinical planning processes. Revised 22 April 2020 Accepted 26 April 2020 The aim of this work is to organise health interventions decision making—as the clinical response for breast cancer management and research in a tiered to COVID-19 should never be developed framework (high, medium, low value), formulating a a latere, but integrated in the multisectoral scheme of prioritisation per clinical cogency and intrinsic approach, to pursue overarching commu- value or magnitude of benefit. The public health tools nity goals, while preserving the perspectives and schemes for priority setting in oncology have been of patient-­centred care.3 No response from used as models, aspiring to capture clinical urgency, the oncology community should be discon- value in healthcare, community goals and fairness, while respecting the principles of benevolence, non-­maleficence, nected from the broader healthcare priority autonomy and justice. setting mechanisms. A horizontal approach is We discuss the priority health interventions across the envisioned, engaging with the continuum of cancer continuum, giving a perspective on the role care and embracing the primary healthcare and meaning to maintain some services (undeferrable) sector to guide patients with cancer at home, while temporarily abrogate some others (deferrable). including effectively developing telemedicine Considerations for implementation and the essential link to systems. Globalisation has propelled the rapid pre-­existing health services, especially primary healthcare, spread of the disease, inundating healthcare are addressed, outlining a framework for the development systems, in particular, intensive healthcare of effective and functional services, such as telemedicine. capacities, thus necessitating the abrogation The discussion covers the theme of health systems strategising, and why oncology care, in particular breast of some health services of deferrable priority cancer care, should be maintained in parallel to pandemic as a key strategic approach. Therefore, inte- control measures, providing a pragmatic clinical model grated healthcare planning is the bedrock of within the broader context of public healthcare schemes. success in the preparation and response to © Author (s) (or their COVID-19—including oncology.4 employer(s)) 2020. Re-­use Introduction The need for value-­based priority setting permitted under CC BY-­NC. No mechanisms has been envisioned by the The global preparedness and response to the commercial re-­use. Published by BMJ on behalf of the rapid escalation of severe acute respiratory global agencies for public health, especially European Society for Medical syndrome coronavirus (SARS-­CoV)-2-­related when planning in health environments with Oncology. disease (COVID-19) at a pandemic propor- impaired availability or accessibility to essen- For numbered affiliations see tion has demanded the prompt develop- tial health resources, including epidemic end of article. ment of a reliable, applicable and evidence-­ outbreaks and disruptions of procurement Correspondence to informed mechanism for the priority-­setting chains and intermittent health service Professor Giuseppe Curigliano; of health services, to assure the attainment delivery—one of the global dividend of equi- ​giuseppe.​curigliano@​ieo.​it of the highest standards of quality care to table quality care between well-­resourced and de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 1 Open access resource-­constrained settings.5 In the era of COVID-19-­ related constraints and the need to meet the goals of popu- lation health against threats that challenge the resilience of the health systems as we know them, the development of clinical guidelines must embrace an evidence-­based mechanism to make choice, thus refusing the easy ways of perspectives or opinions approached per silos. The key to succeed in the management of cancer, when resources are limited or impaired by extraordinary events, is to define a methodology and create a value-­enhanced framework with the most salient cancer interventions—attaining the principles of benevolence, non-­maleficence, autonomy and justice.6 Contemporary oncology research and care models are sophisticated and resource intensive in many countries. However, the necessary restrictions posed by the public health interventions in the pandemic control demand a practical framework for resource prioritisation, main- Figure 1 Priority-­setting of the health interventions in taining high standards of quality cancer care while oncology during COVID-19. protecting patients from health-­related financial distress. Patients with cancer have been suggested as a more fragile population, namely more vulnerable to SARS-­ CoV-2 In the aim to provide a framework for the response infection, reporting poorer outcomes from COVID-19 of the medical community to COVID-19, the European for multicomorbid and/or older patients—cancer history Society for Medical Oncology (ESMO) has established a positioning as a possible independent prognostic risk guidance for clinicians, defining three levels of priorities factor.7 However, a general under-­ representation of regarding medical interventions, namely: tier 1 (high patients with cancer in the mixed series published to date priority intervention), tier 2 (intermediate priority) and limits any articulated dissertation. tier 3 (low priority)—informed by the Ontario Health In such an uncertain area of healthcare, the knowledge Cancer Care Ontario framework of resource-­prioritisation of protecting the vulnerable defines the needs for research and by the ESMO Magnitude of Clinical Benefit Scale implementation, addressing the spectrum of non-­ (MCBS), a public health tool intended to support the communicable diseases including cancer, as mandated uptake of medical interventions in oncology.9 10 by WHO in strategising the response to COVID-19 in the Overall, the prioritisation has been developed to incor- operational guidance for maintaining essential health services porate both the information on the value-­based prioritisa- during an outbreak. The mandate is to ensure the essential tion and clinical cogency of the interventions (figure 1). services to all, prioritising per value.8 ►► Tier 1 (high priority): patient’s condition is immedi- The trajectory of the present work aligns in parallel with ately life-­threatening, clinically unstable and/or the the WHO indications to ‘redirect chronic disease management magnitude of benefit qualifies the intervention as to focus on maintaining supply chains for medications and high priority (eg, significant overall survival (OS) gain needed supplies, with a reduction in provider encounters’— and/or substantial improvement of the quality of life approaching across the continuum of care and shaping (QoL)). a multidisciplinary dialogue across societies and diverse ►► Tier 2 (medium priority): patient’s situation is non-­ stakeholders.8 critical but delay beyond 6–8 weeks could potentially impact overall outcome and/or the magnitude of benefit qualifies for intermediate priority. Methodology for the selection of priority ►► Tier 3 (low priority): patient’s condition is stable interventions enough allowing services to delay for the duration of The present manuscript is the result of an international the COVID-19 pandemic and/or the intervention is panel of expert health providers in the management non-­priority based on the magnitude of benefit (eg, of breast cancer and is proposed to guide healthcare no survival gain with no change or reduced QoL). Of professionals treating patients with breast cancer during note, some interventions included in the tier 3 and the COVID-19 pandemic. The expert consensus-­ based considered safely deferrable should be re-­discussed recommendations are not intended to replace the current after 6–8 weeks, to re-­assess the priority and deliberate guidelines but rather adapt breast cancer care during the on the clinical cogency. COVID-19 pandemic, using a value-­based framework to The clinical guidance defined by ESMO must be inter- set priorities. All the adaptations and prioritisations have preted in the broader context of healthcare response to been formulated by the experts via teleconferences and the pandemic, and always linked to the Global Norms e-­mails discussions. of WHO, the lead public health agencies and health 2 de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 Open access technical governmental boards, for the definition of the Also, there should be a triage for possible symptoms strategies for the preparedness and response on popula- of COVID-19 prior to enter into the hospital premises. tions—including the interventions to ensure the safest The use of home-­based services should be considered as conditions for the health workforce, the proper provision much as possible while hospital procedures are still indi- of personal protective equipment, the testing strategy for cated for patients with cancer where delaying treatment healthcare personnel, patients and communities. Incon- may compromise cancer prognosis. For specific condi- sistencies of clinical guidelines developed outside the tions resulting from treatment-­ related toxicities, such global strategy and not in coordination with the strategic as febrile neutropenia13 with clinical and anamnestic population policies of pandemic control will inevitably adverse prognostic factors, a rapid clinical intervention harm communities, with the earliest impact being on the can make a difference in the prognosis as well as optimise most vulnerable patients—patients with cancer being first the treatment delivery plan, thus must be included in the among them.11 priorities.14 Accordingly, the safety monitoring of patients receiving Priorities for the management of breast cancer: oral treatments (eg, biological agents, endocrine agents reorganising the outpatient setting and sharing and chemotherapeutics) should be organised through a decisions quality system of telemedicine, assuring the requirements Meeting the community goals and perspectives of phys- for a patient-­centred connection with the oncologists and ical distancing and the overall public health measures the cancer nurses. All the non-­priority outpatient visits for the mitigation of SARS-­CoV-2 spread may necessitate may be shifted to the telemedicine platform. The tele- a reinforcement and reorganisation of the outpatient medicine delivery is best suited to non-­urgent situations setting. Triaging patients for fever and COVID-19-­related for established patients with no new complaints as well symptoms is mandatory and an entry checkpoint should as survivorship and follow-­up care of patients with cancer be considered by all healthcare facilities. and of people referred to high-­risk clinics (eg, BRCA In the outpatient setting, postsurgical haematoma and carriers) for preventive interventions. In asymptomatic infectious complications of surgical wounds may prompt patients, follow-­up exams can be delayed unless there are ambulatory clinical interventions, like a drainage or an symptomatic clinically emergent conditions. incision, to reduce the burden of serious, but preventable The patient-­centred model of care requires addressing complications from cancer interventions, applying the all of a patients care needs and as such, psychosocial priority criteria of clinical cogency. supports must be assured and may be converted to tele- Prioritisation is guided by magnitude of benefit, tumour medicine or other web-­based platforms. biology and stage together with clinical scenarios. Quality Although telemedicine has been recognised as an of care should remain unchanged for the prioritised inter- efficient delivery platform for deferrable healthcare ventions. For example, for the treatment planning of all services, limiting factors must be considered. Aspects of patients with cancer, a multidisciplinary board discussion legal frameworks and data protection regulations, along must be assured, as retaining a major prognostic signif- with the management of the workforce for tele-­health icance: thus while the format may change (eg, video- are of prominent interest. The consensus recognises the conferencing), the principle of multidisciplinary care is multiple legal and ethical issues, especially in the area of non-­negotiable12 (table 1). patient privacy and confidentiality—fostering the engage- Visits to hospital should be minimised and if neces- ment with the competent vertices for healthcare profes- sary, all protective measures should be taken (eg, phys- sionals, healthcare facilities and academic institutions, ical distancing recommendations and use of masks). communities, health managers and policy makers—to Table 1 Outpatient visit priorities for the management of breast cancer High priority Medium priority Low priority Postoperative unstable clinical scenario New diagnosis of non-­invasive cancer. Established patients with no new issues: (eg, haematoma, infection) Convert as many visits as possible to refer to telemedicine telemedicine visits. New diagnosis of invasive breast cancer (for multidisciplinary tumour board Survivorship follow-­up: refer to discussion: biology and stage will drive priority) telemedicine Breast cancer diagnosis during Postoperative visits in patients with no Follow-­up for patients at high risk of pregnancy complications breast cancer (BRCA carriers, etc) or patients at high risk of relapse On-­treatment patients with new symptoms or side effects (depending on severity Psychological support visits (convert to of symptoms/side effects, burden of progression, etc). Convert as many visits as telemedicine) possible to telemedicine visits. Intensify safety monitoring for those patients on oral chemotherapy or endocrine therapy plus biological agents de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 3 Open access develop a socially accountable infrastructure of cancer rethink the intersection of cancer care within the existing service delivery. A public health approach is essentially healthcare system. While providing clinical recommenda- endorsed, as the implementation of new service delivery tions for telemedicine, all the key elements of the health- models cannot be framed under a pure clinical indica- care contexture are to be included in the discussion, to tion but approached by multiple competent stakeholders. ensure that the clinical guidance is truly offering a valid In principle, telemedicine is envisioned as part of the alternative option for patients and not an ideal structure clinical service of the health personnel, thus accounted unfeasible on the pre-­existing community services. entirely in the clinical workload. Eventually, although Of note, it is of utmost importance that all medical and beyond the scope of the present work, sustainability, strategic decisions regarding a patient’s care programme financing, reimbursability and health impact of telemed- are made with careful consideration by a multidisci- icine must be accountable, on the longer term, to inspire plinary team and shared with the patient. An informed a durable set-­up of innovative paradigms of healthcare via consent process needs to be performed ensuring that the telehealth applications. From this angle, an assessment of patient fully understand the risks and benefits she/he can the baseline capacity and interim registration of the effi- expect from any medical intervention in the context of ciency of telemedicine should orient the entire process of the current public health crisis, with all its limitations. capacity building and, if appropriate, prompt the estab- lishment of the programmes. To date, the telemedicine model is interpreted across several applications and web-­ based platforms, within the national and local perimeters Priorities for the radiological and pathological of legal frameworks—variable across the settings, and a diagnosis of breast cancer definite optimum has not been defined in oncology, as data Understanding the implications of the delay in diag- are still warranted. While the efficiency of the prescrip- nosis and access to treatment of breast cancer cannot be tion of multiple treatment cycles (eg, several months entirely captured unless contextualised to the biology of endocrine therapy and target agents for patients of the cancer and patterns of clinical presentation, for with metastatic breast cancer) to reduce the healthcare example, the stage and the setting of care.15 All patients admissions is recognised, it may be critical to intersect presenting with a new breast lump with high suspicion of the cancer institution activity in a service delivery model malignancy or who have already undergone a screening based on a primary healthcare approach—engaging procedure with an imaging finding highly suspicious for with community-­ based healthcare providers, including malignancy (eg, BIRADS 5 at mammography) should be general practitioners and nurses.14 Overall, in the context promptly referred for tissue diagnosis and imaging and of oncology care, telemedicine is indeed a mechanism to pathology are to be designated as high priority (table 2). Table 2 Priorities for breast diseases: diagnostics and imaging High priority Medium priority Low priority Self-­diagnosis of breast lump or other Further diagnostic imaging Mammography-­based population screening and symptoms suggestive of malignancy for BIRADS 4 screening risk-­adapted breast screening programmes for mammogram in asymptomatic asymptomatic subjects (eg, MRI or ultrasound). subjects. Clinical evidence of locoregional relapse Image-­guided or clinically guided Patients with abnormal findings at screening with surgical radical approach feasible biopsy to ascertain a suspect of mammograms who can go to 6-­month interval (according to stage, histology and metastatic relapse. imaging (BIRADS 3). biological features of the disease) Pathology assessment (histopathology Initial metastatic workup In patients with early stage breast cancer, follow-­ or cytopathology) for abnormal (according to stage and biological up imaging, restaging studies, echocardiograms, mammograms or breast symptoms or a features) in patients with early ECGs and bone density scans can be delayed if symptomatic metastatic relapse stage invasive breast cancer. clinically asymptomatic. In patients with metastatic breast cancer, we recommend symptoms-­oriented follow-­up. Imaging, restaging studies, echocardiograms and ECGs can be delayed or done at lengthened intervals. Implement telemedicine follow-­up. Further diagnostic imaging for Echocardiograms in patients BIRADS 5 screening mammogram in with early stage invasive breast asymptomatic subjects cancer requiring with indication to anthracycline-­based or anti-­ HER2 treatment. BIRADS, Breast Imaging-­Reporting and Data System. 4 de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 Open access Similarly, patients experiencing locoregional disease surgery aims to understand how reasonably and for how recurrence of breast cancer can still pursue a radical long cancer surgery can be delayed, assuring the attain- intention for the treatment—with a combination of ment of the highest standards for quality care delivery. locoregional treatments, either surgery and/or radiation Once again, the question must take into account cancer therapy, and complemented with risk-­reducing medical biology, clinical presentation pattern, patients’ condi- therapies: targeted, endocrine or chemotherapy.16–18 In tions and preference (table 3).23 this setting, it becomes essential to share the clinical deci- The clinical cogency for intervention is dictated by sion, informed by the primary intention of the approach. the risk for serious complications or irreversible health Although often complex across a spectrum of clinical conditions, like for postsurgical breast cancer complica- presentations, some disease recurrence patterns are more tions. Where relatively simple surgical interventions can prone to radical approaches and, long-­lasting disease-­free determine a change in the natural process of a poten- intervals can be expected. Thus, based on clinical and tially adverse pathological condition at rapid evolution, pathological criteria, priority must be based on the inten- it represents a surgical priority. This also includes surgery tion of the care to identify the undeferrable cases, always complications demanding haemostatic procedures, inci- in a multidisciplinary assessment. sion, drainage or packing material insertion and certain Overall, histopathology diagnosis can have an imme- wound dressing. However, relatively more complex proce- diate impact and sometimes cannot be deferred to dures can sometimes still retain a priority, when inaction complete the differential diagnosis. For patients with is associated with potentially fatal outcomes (eg, for the symptomatic metastatic relapse, whenever the provision delay of adjuvant treatments).24 Several respected profes- of a treatment can be life-­ saving and/or significantly sional societies have proposed classifications of urgency/ modify the quality of life, a histopathology diagnosis will benefit/postponability.25 26 be included in the set of undeferrable health services. Based on the magnitude of benefit criteria, patients Besides the primary treatment intentions, the safe completing neoadjuvant chemotherapy-­based treatments delivery and safety monitoring of treatments may or, less commonly, progressing during such treatments, require specific imaging techniques. Commonly, patients should receive curative surgery with no postponement. under treatment with anthracyclines or anti-­ HER2 In situations in which this is absolutely impossible in agents require a regular assessment of cardiac function, terms of crisis healthcare resources, adding another cycle prompting treatment interruptions, dose-­reductions or of neoadjuvant therapy in patients responding well to cardio-­oncology interventions, where indicated.19 Simi- therapy may ‘protect’ the patient from the postponement larly, the ECG assessment for potentially arrhythmogenic of surgery. changes, including the QT tract prolongation, should be Primary surgery of low-­risk early breast cancer can safely considered in selected patients receiving some biological be postponed up to 12 weeks, based on experts’ opinion, agents or carrying specific comorbidities.20 Overall, the although no firm data exist, unless very aggressive tumour cardio-­oncology consultation could be reshaped in a risk-­ biology is present. In latter situations, neoadjuvant adapted scheme, adapting the monitoring intensity to the baseline risk of cardiac adverse events and the treatments treatment approaches may be considered anyway. For received. luminal-­like breast cancers, using appropriate preopera- During the pandemic outbreak, mammography-­based tive endocrine treatment might be an option for avoiding screening for breast cancer in asymptomatic women harm due to the delay of surgery in selected cases. The should be temporarily abrogated, as the risk-­benefit ratio psychological strain for patients who experience delays (risk of infection related to healthcare admissions for of their surgical procedures must not be underestimated, second-­level procedures vs lives saved by screening) is not and appropriate psychological support offered. predicted to be high during the pandemic and appoint- Surgery for in situ ductal carcinomas could be tran- ments may be postponed by a few weeks or months without siently deferred in some cases, and the use of endocrine disproportionate predicted harms. Similarly, imaging for therapy if hormone receptor positive may be considered. follow-­up of patients with early breast cancer and meta- Reconstructive procedures can/should be postponed, static patients may be delayed if necessary, with tailoring also because their perioperative morbidity risk is higher of radiological assessments per symptoms or other suspi- than that of standard breast surgery.27 cion of progression, as clinically assessed—while still As discussed above, patients experiencing locoregional preferring telemedicine for non-­priority complains and relapse should be discussed in a multidisciplinary setting interventions.21 to weigh the potential benefits of offering an immediate radical surgical excision with subsequent durable survival gain versus postponing surgery after a primary systemic Priorities for breast surgical oncology treatment. Cancer surgery is one of the cancer interventions bringing As for all the other clinical presentations, the discussion the greatest benefits for patients with cancer, princi- about surgical indications must be individualised. Of note, pally in the curative setting, resulting in gains in cancer all decisions must be shared with the patients, assessing survival.22 The priority-­setting framework of breast cancer the preference and expectations while informing on the de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 5 Open access Table 3 Priorities for breast disease: surgical oncology High priority Medium priority Low priority Breast cancer surgery complication with Clinically low-­risk primary breast cancer (eg, stage I/ Excision of bleeding or indication to incision and II ER-­positive/PR-­positive/HER2-­negative, low-­grade/ benign lesions drainage of a breast abscess and/or low proliferative index tumours). After multidisciplinary and duct excision haematoma tumour board discussion consider starting neoadjuvant/ (fibroadenomas, atypia, preoperative endocrine therapy according to menopausal papillomas). status and delay surgery. Complications of reconstructing surgery Discordant biopsies likely to be malignant. Surgery of non-­invasive (eg, ischaemia) breast cancer (in situ) except for extended high-­grade DCIS. Surgery in patients who have completed - Discordant biopsies neoadjuvant chemotherapy-­based likely to be benign. treatment (or, in exceptional cases, with progression of disease during neoadjuvant treatment) - - Immediate or delayed breast reconstruction with autologous tissue and/or implants. Surgery in patients with invasive cancer - Prophylactic surgery for for whom multidisciplinary tumour board asymptomatic high-­risk may decide, case-­by-­case, to proceed patients. with upfront surgery Excision of malignant recurrence (depending on phenotype and extent) Breast cancer surgery during pregnancy - - (multidisciplinary treatment should be individualised according to stage and biology) DCIS, ductal carcinoma in situ. threats and advantages of the adapted treatment plans in immediate radiation therapy should be initiated, in the context of the COVID-19 crisis. accordance with current clinical practice, in patients with acute spinal cord compression, symptomatic brain Priorities for breast radiation oncology metastases not improving with steroidal medication and The indications for radiation therapy in breast oncology any urgent irradiation with an expected impact in survival are wide, and must be interpreted in the multidiscipli- or a modifying effect on the risk of disabling sequelae nary care settings. According to clinical prioritisation, and/or quality of life (table 4). While the control of Table 4 Priorities for breast cancer: radiation oncology High priority Medium priority Low priority Palliative treatment of acute spinal Adjuvant postoperative radiation therapy for low-­ Elderly patients with low-­risk breast cancer cord compression, symptomatic brain risk/intermediate-­risk patients with breast cancer (aged >70 years, with low-­risk stage I ER-­ metastases, bleeding/painful inoperable (aged <65 years and stage I/II luminal cancer, ER positive/HER2-­negative breast cancer): breast masses or any urgent palliative positive regardless of nodal status or positive starting adjuvant endocrine therapy is radiation therapy, when control of symptoms margins). Use of hypofractionated regimens should recommended while postponing radiation cannot be achieved pharmacologically be considered to reduce hospital visits. Endocrine therapy. therapy can be started during the waiting interval. Carcinoma in situ. Patients already on radiation treatment - - Adjuvant postoperative radiation therapy - - for high-­risk patients with breast cancer (inflammatory disease at diagnosis, node-­ positive disease, triple-­negative or HER2-­ positive breast cancer, residual disease at surgery postneoadjuvant therapy, young age (<40 years) 6 de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 Open access breast mass-­related symptoms for fungating or bleeding or shortage of medicines for the supportive care.30 Opti- neoplasia can usually be obtained with supportive care mising the medical oncology service during COVID-19 interventions, including advanced wound dressings, means assuring the assignment of the treatments at the there may exist a need to provide surgery or radiation highest benefit to the eligible population, in the safest therapy for haemostasis or to alleviate pain due to inop- conditions and guaranteeing punctual monitoring erable breast masses for improving the quality of life for mechanisms for the adverse effects, implemented by patients with advanced disease. telemedicine systems and engaging with primary health- The optimisation of locoregional control and the care sectors—an effort of one health system working in improvement of survival define the priority of the inter- synchrony. ventions in radiation therapy. Thus, post-­operative radi- Decisions at national and institutional level can be ation therapy for high-­ risk patients (eg, inflammatory readily informed by public health tools of selection and breast cancer, node-­positive or high-­risk biology) should prioritisation of the medical interventions, including be scheduled as high priority, respecting the highest stan- the ESMO MCBS.10 According to the MCBS, the priority dards of quality for radiation therapy when proposing interventions in the curative setting are scored A, on a alternative (shorter) radiation regimens.28 Most patients scale from A to C, from high to low priority, respectively. are eligible for short-­ course treatments using hypo-­ While the score has been applied to a several novel fractionated schedules, being the treatment of choice. compounds for breast cancer treatment, mostly in the Accelerated partial breast irradiation should be proposed advanced setting, less scoring has been performed in for low-­ risk patients, when indicated and technically the early breast cancer setting, particularly with chemo- feasible, given available technology and the capacity of the therapy regimens, and this should be considered when centres. Also for this, shorter treatment courses should balancing risk and benefits.10 be favoured, including single dose intra-­operative elec- Patients with the highest risk breast cancers are to tron radiation therapy or up to 5 fractions of preferably be prioritised for systemic treatments (ie, either triple-­ external beam radiation therapy and not brachytherapy negative or HER2-­positive early breast cancer). Overall, as this implicates a second intervention and more intense adjuvant endocrine treatments are not expected to be hospital visits. Where the expected clinical benefit of irra- substantially changed, not impacting significantly on diation is very low, as in the older population with low-­ immune functions, while the monitoring for side effects risk breast cancer under adjuvant endocrine therapy, and treatment compliance could be readily performed deferral is possible or omission could even be considered via telemedicine. Of note, in case of SARS-­CoV-2 infec- in some circumstances.29 The aim is to maintain a balance tion in a patient with breast cancer taking tamoxifen, the between respecting COVID-19 restrictive measures such as hormone therapy should be suspended and preventive limiting number of contacts and physical distance, while measures against thrombosis proposed, given the high at the same time preventing jeopardising the outcomes of risk of thromboembolic events in patients with COVID-19 cancer interventions, considering that radiation therapy with severe disease, and the well-­known increased throm- usually requires a sometimes long series of treatments boembolic risk associated with tamoxifen.31 with repeated admissions to the institutions. This should For some patients, a neoadjuvant endocrine approach be an additional argument for applying the abundance could be considered, according to the current clinical of evidence in favour of the use of hypofractionation in recommendations, and possibly to delay the time to clinical practice. surgery in selected clinical presentations. This group encompasses patients with postmenopausal stage I cancers, low-­grade to intermediate-­ grade tumours and Priorities for breast medical oncology in the early lobular breast histology variants, deferring the surgery setting of care up to 6–12 months, as indicated in existing guidelines.32 The role of presurgical, perisurgical and postsurgical Aromatase inhibitors (AI) should be preferred. While for systemic therapies has evolved to become the backbone postmenopausal women neoadjuvant endocrine therapy of care in breast oncology, and over the last decade a is an established approach, this is not so for premeno- paradigm shift in systemic care has occurred, with the pausal women but may be considered on a case-­ by-­ tailoring of type and timing of care to tumour subtypes. case basis under these extenuating circumstances. All The delivery of systemic treatments usually demands a premenopausal women receiving an AI should receive resource-­intense effort of the health institutions, built LHRH (Luteinizing hormone-­ releasing hormone) around the patient, with optimal safety conditions— analogue. Monthly injections should be preferred but stating that the quality of medical oncology must attain in some cases (particularly women in their mid-­ late the highest standards, when priority interventions are 40s), one may discuss 3-­monthly formulation of LHRH established (table 5). analogue, in order to reduce patient visits. Overall, home-­ During pandemics, the disruption of the procurement based monthly administrations would be the preferred chain for medicines and the changed contexts of drug choice. The possibility to deliver treatments at home, selection can have an impact on the availability and including some antineoplastic agents (eg, subcutaneous accessibility of medicines, including irregular provision trastuzumab, LHRH agonists) is framed in the national de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 7 Open access Table 5 Priorities for breast cancer: medical oncology—early breast cancer High priority Medium priority Low priority Neoadjuvant and adjuvant chemotherapy For postmenopausal women with Follow-­up imaging, restaging studies, for patients with triple-­negative breast stage I cancers, with low-­intermediate echocardiograms, ECGs and bone cancer grade tumours, lobular breast cancers density scans can be delayed if patients Neoadjuvant and adjuvant chemotherapy endocrine therapy may be started first clinically asymptomatic or clinical signs in combination with targeted therapy while surgery can be delayed. of response in the neoadjuvant setting. for HER2-­positive patients with breast cancer Neoadjuvant and adjuvant endocrine therapy±chemotherapy for high-­risk ER-­ positive/HER2-­negative breast cancer as defined by current guidelines Completion of neoadjuvant For patients with low-­risk genomic - chemotherapy (with or without anti-­HER2 signatures/score prefer endocrine therapy) that has already been initiated therapy alone. Continuation of adjuvant capecitabine Ongoing adjuvant trastuzumab alone may - treatment in patients with high-­risk triple-­ be postponed by 6–8 weeks in patients negative breast cancer, and T-­DM1 in at high risk of complicated COVID-19 HER2-­positive patients with high-­risk infection. breast cancer Continuation of standard adjuvant endocrine therapy in premenopausal and postmenopausal setting. Use telemedicine to manage potential toxicity reported by patients Continuation of treatment in the - - context of a clinical trial, provided patient benefits overweight risks, with possible adaptation of procedures without affecting patient safety and study conduct. Regulatory agencies and sponsors may provide guidance on rules on study conduct during the pandemics and regional competencies in the matter of healthcare to escalate immunosuppressive supportive medications organisation and regulations on medicines—condi- (eg, steroids for premedication); the informed patient’s tioning the grades of operational flexibilities for the preference. In the midst of uncertainties of the impact of treatment delivery at the time of COVID-19.33 However, immune-­suppressive agents or steroids used for premed- any initiative for home-­based care should be built under ication at non-­immunosuppressive doses on the risk of the COVID-19 agenda, to ensure consistency with the SARS-­CoV-2 infection and COVID-19 outcome, the use physical distancing measures and protection of both the of these agents should be carefully evaluated. The use of patients and the workforce. granulocyte growth factors may be considered to mini- Moreover, for selected HER2-­ positive breast cancer, mise neutropenia. low-­risk or elderly patients with cardiovascular or other comorbidities adjuvant trastuzumab may reasonably be discontinued after 6 months instead of 12 months of treatment, according to clinical guidelines.34 Priorities for breast medical oncology in the Ongoing treatments should be fully completed, as any advanced and metastatic setting of care compromise in dose density and intensity may adversely The decision making for priority positioning in the meta- impact prognosis. For triple-­negative and HER2-­positive static setting is more complicated. In the clinical land- patients with breast cancer treated with neoadjuvant ther- scape of effective treatments that impact on the quality apies and not reaching a pathological complete response, of life and the survival, the best treatment approaches postneoadjuvant systemic treatments are highly recom- should be part of the health priorities (table 6). mended as they provide durable disease control and The health cogency criterion demands prompt cancer improved survival. treatments in patients where a delay can result in fatal The selection of the most appropriate schedules of outcomes. For example, patients experiencing cancer-­ chemotherapy will make considerations of at least three related treatment organ dysfunctions or at increased risk factors: the number of monthly admissions to the institu- of it, namely patients in visceral crisis, should be priori- tions, preferring 2-­weekly or 3-­weekly schedules; the need tised for the start of antineoplastic treatments. 8 de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 Open access Table 6 Priorities for breast cancer: medical oncology—metastatic breast cancer High priority Medium priority Low priority Early line chemotherapy, endocrine therapy, Second, third, beyond third-­line Bone agents therapy (zoledronic acid, targeted agents or immune-­checkpoint treatment when therapy may denosumab) that are not needed inhibitors likely to improve outcomes in provide clinical benefit and impact urgently for hypercalcaemia, or not metastatic disease (high priority to pertuzumab/ on outcome. needed for pain control and in patients trastuzumab plus chemotherapy in HER2-­ who are otherwise not in need for positive breast cancer). coming to the hospital (ie, receiving oral Consider also, discussing case-­by-­case in chemotherapy or endocrine therapy). multidisciplinary tumour board, endocrine Bone agents can be administered every therapy with CDK 4–6 inhibitors in ER-­positive/ 3 months. HER2-­negative breast cancer, chemotherapy plus atezolizumab in PD-­L1-­positive TNBC Visceral crisis Consider avoiding or delaying the If clinically asymptomatic follow-­ addition of mTOR inhibitors or up imaging, restaging studies, PIK3CA inhibitors (still not approved echocardiograms and ECGs can be in European Union) to endocrine delayed or done at lengthened intervals. therapy, particularly in elderly patients with comorbidities. Continuation of treatment in the context Consider, discussing case-­by-­ - of a clinical trial, provided patient benefits case, inclusion in a clinical trial, overweight risks, with possible adaptation of provided patient benefits overweight procedures without affecting patient safety and risks, with possible adaptation of study conduct. procedures without affecting patient Regulatory agencies and sponsors may provide safety and study conduct. guidance on rules on study conduct during the pandemics. mTOR, mammalian target of rapamycin; PD-­L1, programmed death-­ligand 1; PIK3CA, phosphatidylinositol-4,5-­bisphosphate 3-­kinase catalytic subunit alpha; TNBC, triple-­negative breast cancer. According to the MCBS, the priority interventions in considered in some cases, as to the choice of longer inter- the advanced setting are scored 3, 4 or 5, in a descending vals for intravenous bisphosphonates, for example, every scale for value, from 5 to 1.10 For such, the magnitude 3 months. Similarly, in late treatment lines, patients with of benefit and the expected treatment benefits should poorer prognosis and impaired functional status could guide the clinical indications. Early line chemotherapy, be considered for a best supportive care (BSC) approach endocrine therapy and targeted agents with higher and/or drug holiday periods—with consideration given MCBS score are of choice, and should be delivered in the for the benefits in terms of quality of life, while attaining to eligible population—for example, in the prescription of the highest standards of care: an early start of home-­based the double anti-­HER2 blockade plus chemotherapy as supportive care plan and the judicious referral of some first line for patients with HER2-­positive disease, where patients to BSC is a priority, overall, when the available ther- affordably accessible (MCBS score 4). apies are known to provide only a narrow benefit and they The use of immunotherapy (eg, atezolizumab) and may incur on the patient excessive of toxicity.35 Treatment CDK4/6 inhibitors and endocrine therapy (MCBS scores de-­escalation and/or maintenance with oral agents may be of 3–4), should be considered after a case-­by-­case discussion considered, although largely based on experts’ opinions. taking into account baseline risk factors of the patient and their functional status, along with considerations on the COVID-19 and its impact on cancer research disease pattern of spread and biology—to ensure a critical The continuation of treatment in the context of a clin- decision making by tailoring for the single patient, in accor- ical trial is valuable for cancer clinical research, provided dance with local practice and resource availability. In the patient benefits outweigh risks, with possible adaptation midst of uncertainty related to some immune-­modulating of trial procedures without affecting patient safety and agents with limited value in cancer treatment, avoiding or study conduct. delaying the addition of mTOR inhibitors to endocrine To date, the social distancing measures have partially therapy could be prudent, especially in multicomorbid frozen the preclinical laboratory-­based research in many older patients (MCBS score for everolimus: 2). countries, in response to the urgent need to prioritise the This means that the contingency plan during the services with an immediate role in COVID-19 response pandemic could result in the temporary withdrawal of and to serve community needs. Overall, the national and some interventions, or predefined safe delays. The use of regional regulatory agencies have formulated guidance oral bisphosphonate or subcutaneous denosumab can be for the management of patients enrolled in clinical trials, de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 9 Open access providing recommendations on the exploitation of the countries, providing global guidance and guidance for study procedures and the safe delivery of the study medi- local action. This means that the degree of SARS-­CoV-2 cations, including concrete information on changes and spread in a country dictates the type and intensity of the protocol deviations which may be needed in the conduct public health interventions and should also orient the of clinical trials to deal with extraordinary situations. In selection and prioritisation of the health interventions in such a context, protocol deviations are expected and oncology—with a tiered approach. some are justified, when not exposing patients to safety The perimeters and limits of this work should be inter- issues and facilitating procedural barriers or bureaucratic preted and adapted within the national and regional aspects of study procedures: a real moment to re-­think dispositions in terms of the ability towards health system the clinical trial conductions tout court.36 For instance, in reorganisation and reshaping of the existing model. Europe the recommendations of the European Medicines While some countries have interpreted a segregation Agency can be found at: https://www.​ema.​europa.​eu/​ model, and suggestions from WHO seems to propend en/​news/​guidance-​sponsors-​how-​manage-​clinical-​trials-​ more for the identification of a COVID-19 health pathway during-​ covid-​ 19-​pandemic In the USA, the Food and for prompt referral, policies can vary across countries, Drug Administration also released guidance on clinical related to the stage of the pandemic as well as the health research and COVID-19 (https://www.​fda.​gov/​media/​ sector specificities. 136238/​download). In such a complex setting, this clinical guidance for While avoiding a total distraction of the cancer research community from the goals and research questions and breast cancer management is intended to orient and slowing the progress in cancer care—research questions not decree local guidelines, and guide the development of immediate clinical interest for cancer and COVID-19 of action plans to maintain a quality cancer service, have been implemented, bridging the need to provide setting a minimal array of required interventions. Useful responses to patients with cancer and the advancement information can be found at https://www.​ esmo.​ org/​ of knowledge. guidelines/​ c ancer-​ p atient-​ m anagement-​ d uring-​ t he-​ Several ongoing trials are addressing the safety and covid-​19-​pandemic/​breast-​cancer-​in-​the-​covid-​19-​era trying to dissect the interplay of anticancer and antiviral immune responses. Generating quality evidence is now Author affiliations 1 Institut Jules Bordet and l’Université Libre de Bruxelles (U.LB), Brussels, Belgium the real priority, to enhance the clinical decision-­making: 2 European Institute of Oncology (IEO) IRCCS, Milan, Italy the observational series of the first waves are now expected 3 GBG Forschungs GmbH, Neu-­Isenburg, Germany to leave room for controlled studies, mechanistic expla- 4 Oncology, Gustave Roussy and Paris-­Saclay University, Villejuif, Île-­de-­France, nations and translational experiences, ensuring the France 5 best research at the service of the cancer and pandemic Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, response. There is an ongoing list of clinical trials testing Poland 6 European Institute of Oncology IRCCS, Milan, Italy different strategies in patients with COVID-19 and they 7 Iridium Kankernetwerk and University of Antwerp, Antwerp, Belgium can be found at http://www.​redo-​project.​org/​COVID-​ 8 Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria 19_​db-​summaries/ 9 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 10 IOB, Institute of Oncology, Quiron Group (Madrid & Barcelona); Vall d'Hebron institute of Oncology (VHIO) (Barcelona), Barcelona, Madrid, Spain 11 Conclusions Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, For cancer care, COVID-19 is presenting a challenging Portugal 12 Division of Oncology, Shaare Zedek Medical Centre, Jerusalem, Jerusalem, Israel period in medicine, demanding a re-­focus on the value 13 Department of Oncology and Hemato-­Oncology, University of Milano and and priorities of health interventions, including the European Institute of Oncology, IRCCS, Milano, Italy reshaping of cancer care—catalysing a review of value-­ based and patient-­ centred decision making. Setting Correction notice This paper has been updated since first published to correct priorities based on the intrinsic value of the interventions name of author 'Philip Poortmans'. about patients’ outcomes and ensuring simultaneously Twitter Evandro de Azambuja @E_de_Azambuja, Dario Trapani @darioT_ and population and societal benefits is the perspective in Michael Gnant @MichaelGnant which the response to COVID-19 has been designed. Acknowledgements The authors would like to thank ESMO for allowing the use of The priority-­setting mechanism that is envisioned the tables in this manuscript. aligns with the global, regional and national standards Contributors GC developed the first outline and coordinated the authors’ proposed in several work streams, including the develop- contributions, engaged for competencies and expertise in the management of breast cancer, development of adapted guidelines in special circumstances and ment and implementation of the MCBS scale, which is its methodology. GC and DT formulated the first draft to organise the authors’ based on patient-­related end points and aimed to provide work, and with EdA developed a draft zero. All the authors were involved in writing a statement and guidance on priority setting, to support and, when the first draft had been developed, all the authors refined the contents and enable decision making when resources need to be with feedbacks and comments, incorporated by GC, EdA and DT. All the authors approved the final draft before the submission. While the authors are affiliated to rationed and cautiously allocated. different institutions for cancer research and care, the perspectives expressed in WHO has defined differentiated preparedness and the present paper should not be intended to mirror the societal and institutional response plans, according to the disease spread in single positions. 10 de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 Open access Funding The authors have not declared a specific grant for this research from any 11 OECD. Tackling coronavirus (COVID–19). Contributing to a global funding agency in the public, commercial or not-­for-­profit sectors. effort. Available: https://www.​oecd.​org/​coronavirus/​en/ [Accessed 10 Apr 2020]. Competing interests GC has received honoraria from Pfizer, Novartis, Eli Lilly, 12 Kesson EM, Allardice GM, George WD, et al. Effects of Roche; fees for expert testimony and medical education from Pfizer and has multidisciplinary team working on breast cancer survival: participated in advisory boards for Pfizer, Roche, Eli Lilly, Novartis, Seattle Genetics, retrospective, comparative, interventional cohort study of 13 722 Celltrion. SD reports grants, institutional fees from Roche/Genentech, Pfizer, Puma, women. BMJ 2012;344:e2718. AstraZeneca, Novartis, Amgen, Sanofi, Eli Lilly, MSD, BMS, Daichi and non-­financial 13 Georges Q, Azoulay E, Mokart D, et al. Influence of neutropenia on support from Roche/Genentech, Pfizer, AstraZeneca. SDC has received fees for mortality of critically ill cancer patients: results of a meta-­analysis on medical education from Novartis and Pierre-­Fabre and is the recipient of the IG individual data. Crit Care 2018;22:326. 14 Carrera PM, Kantarjian HM, Blinder VS. The financial burden and 20774 of Fondazione AIRC. MG reports personal fees/travel support from Amgen, distress of patients with cancer: understanding and stepping-­up AstraZeneca, Celgene, Eli Lilly, Invectys, Pfizer, Novartis, Puma, Nanostring, Roche, action on the financial toxicity of cancer treatment. CA Cancer J Clin Medison, LifeBrain, all outside the submitted work; an immediate family member 2018;68:153–65. is employed by Sandoz. PP is medical advisor of Sordina IORT Technologies. ES 15 Caplan L. Delay in breast cancer: implications for stage at diagnosis has received honoraria from Amgen, AstraZeneca, Clinigen, Egis, Eli Lilly, Genomic and survival. Front Public Health 2014;2:87. Health, Novartis, Pfizer, Pierre-­Fabre, Roche, Sandoz, TLC Biopharmaceuticals 16 Anderson SJ, Wapnir I, Dignam JJ, et al. Prognosis after ipsilateral and travel support from Amgen, AstraZeneca, Egis, Novartis, Pfizer, Roche. FC has breast tumor recurrence and locoregional recurrences in patients consultancy role for Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-­ treated by breast-­conserving therapy in five national surgical Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, adjuvant breast and bowel project protocols of node-­negative breast cancer. J Clin Oncol 2009;27:2466–73. Merck-­Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-­Fabre, prIME 17 Waeber M, Castiglione-­Gertsch M, Dietrich D, et al. Adjuvant therapy Oncology, Roche, Sanofi, Samsung Bioepis, Seattle Genetics, Teva. EdA honoraria after excision and radiation of isolated postmastectomy locoregional and/or advisory board from Roche/GNE, Novartis, SeaGen and Zodiac; travel grants breast cancer recurrence: definitive results of a phase III randomized from Roche/GNE and GSK/Novartis; research grant to the institution from Roche/ trial (SAKK 23/82) comparing tamoxifen with observation. Ann Oncol GNE, AstraZeneca, GSK/Novartis and Servier. CC declares consultancy/advisory 2003;14:1215–21. role/speaker's bureau: Pfizer, Eli Lilly, Roche, Novartis. SP-­S discloses honoraria, 18 Wapnir IL, Price KN, Anderson SJ, et al. Efficacy of chemotherapy consultancy and speaker’s bureau: Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, for ER-­negative and ER-­positive isolated locoregional recurrence Nanostring. of breast cancer: final analysis of the CALOR trial. J Clin Oncol 2018;36:1073–9. Patient consent for publication Not required. 19 Curigliano G, Lenihan D, Fradley M, et al. Management of cardiac Provenance and peer review Not commissioned; externally peer reviewed. disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol 2020;31:171–90. Open access This is an open access article distributed in accordance with the 20 Americal College of Cardiology (ACC). Risk score for drug-­ Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which associated QTc prolongation. ventricular arrhythmia risk due to permits others to distribute, remix, adapt, build upon this work non-­commercially, Hydroxychloroquine-­Azithromycin treatment for COVID-19. Available: and license their derivative works on different terms, provided the original work is https://www.​acc.​org/​latest-​in-​cardiology/​articles/​2020/​03/​27/​14/​00/​ properly cited, any changes made are indicated, and the use is non-­commercial. ventricular-​arrhythmia-​risk-​due-​to-​hydroxychloroquine-​azithromycin-​ treatment-​for-​covid-​19 [Accessed 10 Apr 2020]. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. 21 Lafranconi A, Pylkkänen L, Deandrea S, et al. Intensive follow-­up for women with breast cancer: review of clinical, economic and patient's ORCID iDs preference domains through evidence to decision framework. Health Evandro de Azambuja http://​orcid.​org/​0000-​0001-​9501-​4509 Qual Life Outcomes 2017;15:206. Shani Paluch-­Shimon http://​orcid.​org/​0000-​0002-​6677-​2199 22 World Health Organization. Updated appendix 3 of the who global Giuseppe Curigliano http://​orcid.​org/​0000-​0003-​1781-​2518 Ncd action plan 2013-2020. Technical Annex 2017. 23 Harbeck N, Gnant M. Breast cancer. Lancet 2017;389:1134–50. 24 Robertson SA, Jeevaratnam JA, Agrawal A, et al. Mastectomy skin flap necrosis: challenges and solutions. Breast Cancer 2017;9:141–52. References 25 American College of Surgeons. COVID 19: elective case triage 1 Burki TK. Cancer guidelines during the COVID-19 pandemic. Lancet guidelines for surgical care. released March 2020, 2020. Available: Oncol 2020;21:629–30. https://www.​facs.​org/​covid-​19/​clinical-​guidance/​triage [Accessed 14 2 Emanuel EJ, Persad G, Upshur R, et al. Fair allocation of scarce Apr 2020]. medical resources in the time of Covid-19. N Engl J Med 2020. 26 Jiang Zefei LJ. Ten hot issues of breast cancer during the COVID-19 doi:10.1056/NEJMsb2005114. [Epub ahead of print: 23 Mar 2020]. pandemic. Recommendations by the Chinese Society of clinical 3 Ferguson NM, Laydon D, Nedjati-­Gilani G, et al. Impact of non-­ oncology breast cancer (CSCO bc) 2020. pharmaceutical interventions (NPIs) to reduce COVID-19 mortality 27 Gnant M. Challenges and controversies in breast surgery. Breast and healthcare demand. London: Imperial College London, 2020. Care 2019;14:185–7. 4 Baker T, Schell CO, Petersen DB, et al. Essential care of critical 28 Coles CE, Aristei C, Bliss J, et al. International guidelines on radiation illness must not be forgotten in the COVID-19 pandemic. Lancet therapy for breast cancer during the COVID-19 pandemic. Clin Oncol 2020;395:1253–4. 5 GBD 2016 Healthcare Access and Quality Collaborators. Measuring 2020;32:279–81. performance on the healthcare access and quality index for 195 29 Kunkler IH, Williams LJ, Jack WJL, et al. Breast-­Conserving surgery countries and territories and selected subnational locations: a with or without irradiation in women aged 65 years or older with early systematic analysis from the global burden of disease study 2016. breast cancer (prime II): a randomised controlled trial. Lancet Oncol Lancet 2018;391:2236–71. 2015;16:266–73. 6 Hanna TP, Evans GA, Booth CM. Cancer, COVID-19 and the 30 Linton T, Vakil B. Coronavirus is proving we need more resilient precautionary principle: prioritizing treatment during a global supply chains. Harvard business review, 2020. Available: https://​hbr.​ pandemic. Nat Rev Clin Oncol 2020;17:268–70. org/​2020/​03/​coronavirus-​is-​proving-​that-​we-​need-​more-​resilient-​ 7 Liang W, Guan W, Chen R, et al. Cancer patients in SARS-­ supply-​chains [Accessed 5 Apr 2020]. CoV-2 infection: a nationwide analysis in China. Lancet Oncol 31 Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated 2020;21:335–7. with decreased mortality in severe coronavirus disease 2019 patients 8 WHO. COVID-19: operational guidance for maintaining essential with coagulopathy [published online. J Thromb Haemost 2020. health services during an outbreak interim guidance, 2020. Available: 10.1111/jth.14817 (ahead of print, 2020 Mar 27). https://​apps.​who.​int/​iris/​handle/​10665/​331561 [Accessed 10 Apr 32 Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO 2020]. clinical practice guidelines for diagnosis, treatment and follow-­up. 9 Cancer Care Ontario. Identify priority problems and goals to Ann Oncol 2019;30:1674. improve the model of care. Available: file:///C:/Users/pc/Downloads/​ 33 Cocquyt VF, Martinez-­Mena CL, Martens MT, et al. Belis: safety and PEPPAToolkit_​Step4.​pdf [Accessed 10 Apr 2020]. tolerability of at home administration of trastuzumab (Herceptin) 10 Cherny NI, Dafni U, Bogaerts J, et al. ESMO-­Magnitude of clinical subcutaneous for the treatment of patients with her2-­positive early benefit scale version 1.1. Ann Oncol 2017;28:2340–66. breast cancer [abstract P4-21-17]. Cancer Res 2017;77. de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 11 Open access 34 Earl HM, Hiller L, Vallier A-­L, et al. 6 versus 12 months of adjuvant 36 Tarantino P, Trapani D, Curigliano G. Conducting phase 1 cancer trastuzumab for HER2-­positive early breast cancer (Persephone): clinical trials during the severe acute respiratory syndrome 4-­year disease-­free survival results of a randomised phase 3 non-­ coronavirus 2 (SARS-­CoV-2)-­related disease pandemic. Eur J Cancer inferiority trial. Lancet 2019;393:2599–612. 2020;132:8–10. 35 Cinausero M, Gerratana L, De Carlo E, et al. Determinants of Last-­line treatment in metastatic breast cancer. Clin Breast Cancer 2018;18:205–13. 12 de Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793