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Endocrine-Related D Raghavan et al. COVID-19 and endocrine- 27:9 R357–R374 Cancer related cancer management REVIEW Management changes for patients with endocrine-related cancers in the COVID-19 pandemic

Derek Raghavan, Antoinette R Tan, E Shannon Story, Earle F Burgess, Laura Musselwhite, Edward S Kim and Peter E Clark

Departments of Solid Tumor Oncology, Endocrinology, and Urologic Oncology, Levine Cancer Institute, Charlotte, North Carolina, USA

Correspondence should be addressed to D Raghavan: [email protected]

Abstract

Substantial management changes in endocrine-related malignancies have been Key Words required as a response to the COVID-19 pandemic, including a draconian reduction in ff standard operating the screening of asymptomatic subjects, delay in planned surgery and radiotherapy for procedures primary tumors deemed to be indolent, and dose reductions and/or delays in initiation ff pathways of some systemic therapies. An added key factor has been a patient-initiated delay in ff COVID-19 the presentation because of the fear of viral infection. Patterns of clinical consultation ff adrenal cancer have changed, including a greater level of virtual visits, physical spacing, masking, staffing ff breast cancer changes to ensure a COVID-free population and significant changes in patterns of family ff prostate cancer involvement. While this has occurred to improve safety from COVID-19 infection, the ff thyroid cancer implications for cancer outcomes have not yet been defined. Based on prior epidemics ff chemotherapy and financial recessions, it is likely that delayed presentation and treatment of high-grade ff targeted therapies malignancy will be associated with worse cancer outcomes. Cancer patients are also at increased risk from COVID-19 infection compared to the general population. Pandemic management strategies for patients with tumors of breast, prostate, thyroid, parathyroid and adrenal gland are reviewed. Endocrine-Related Cancer (2020) 27, R357–R374

Introduction

The COVID-19 pandemic has required substantial the world population at large and, in particular, its changes in the management of cancer, with decisions political leadership and the medical profession have being predicated on a careful risk–benefit analysis. It has been unprepared for a viral onslaught of this magnitude been necessary to balance the relative merits of speed and intensity. This has been compounded by lack of and intensity of anti-cancer therapy vs the potential risks transparency about the onset of the infection in Wuhan, of viral infection, particularly for patients with reduced China, the extraordinarily swift global pace of spread, the immune profiles or specific cardio-pulmonary toxicity severity of medical management issues for around 5–15% from anti-cancer treatments. In all situations, the keynote of patients, the impact and prevalence of asymptomatic of management has been to maximize the safety of carriers, and the global inexperience in pandemic care patients, their caregivers and healthcare workers. (Zhu et al. 2020). Despite important warnings about the rising The initial cases were reported in Wuhan, China, risks of pandemics in the 21st century (Gates 2018), in December 2019, and by March 2020 a pandemic was

-20-0229 Endocrine-Related D Raghavan et al. COVID-19 and endocrine- 27:9 R358 Cancer related cancer management declared by the World Health Organization. The speed safety of patients, their families or caregivers, and the of global spread has been facilitated by transmission by healthcare workers involved in their care (see Table 1). contact and aerosolized droplets (with a potential dwell Early in the current pandemic, the leadership of time of 2–4 h in the air and longer on surfaces), with the Levine Cancer Institute, a 25-site academic-hybrid, symptoms that can arise 2–14 days or longer after exposure multidisciplinary cancer institute in three states, which (Zhu et al. 2020), often with an asymptomatic spread. The sees more than 17,000 new cases per year and has more symptoms are quite characteristic, including fever, cough, than 200,000 patient encounters annually, developed a fatigue, sputum production, dyspnea, chills, loss of taste strategy of cancer management with this key criterion and smell, and myalgia predominating. However, there is in mind. The available literature was reviewed, tumor- a considerable similarity to the common cold, influenza specific teams considered each tumor type and modified and allergic diatheses, confounding the precision of their standard approaches where appropriate, and a series diagnosis (Lauer et al. 2020, Zhu et al. 2020). of conference calls and webinars were held internationally The specific situation of the patient with cancer in the to gain experience from those with earlier exposure to the present (COVID-19 pandemic) environment is a mixture COVID-19 virus. The intent was to minimize the risks of of hyperbole and substance, with the former being drawn viral exposure, predicated on social/physical distancing, predominantly from the popular press and television delay or reduction of the intensity of treatment where outlets. Early reports from China and Italy have suggested possible, with aggressive testing for viral antigens while that cancer patients are more likely to become infected attempting not to impair cancer treatment outcomes. and are at high risk for severe clinical complications, Our general approach to pandemic cancer care has been such as the need for ventilation, intensive care unit documented in detail (Raghavan et al. 2020). admission, or death (Liang et al. 2020, Onder et al. 2020, Yu et al. 2020). A review of patients hospitalized at Wuhan University showed that hospital-acquired viral Viral testing parameters transmission accounted for around 40% of admitted ‘Patient under investigation’ (PUI) testing parameters have patients (Wang et al. 2020). been defined for our overall healthcare system, which With this background, clinicians have moved includes around 40 hospitals that are responsible for swiftly to refine treatment paradigms for patients with 12 million encounters annually. These include influenza- a range of cancers, including approaches to screening like illness (ILI) (fever >38°C (100.4°F), subjective fever, plus in asymptomatic patients, the timing of surgery or chills, cough or dyspnea), a domicile in long-term care or radiotherapy, and the management of advanced prison, plus one added risk factor (immunocompromised, disease. In view of the relative paucity of published lung disease (including asthma or COPD), or major information, we have assessed the strategy of treatment vascular episode or inability to give a history). Recently, it in our multidisciplinary tumor conferences, predicated has been shown that loss of the sensation of taste and/or on a review of the available literature and lessons learned smell is strongly associated with COVID-19, although from prior pandemics, and have created paradigms of this is less reliable in patients receiving radiotherapy to treatment aimed at maximizing the safety of patients. the oropharynx or chemotherapy. The implementation This overview is focused on COVID-19 management of of COVID-19 testing is predicated on the availability common endocrine-related cancers. of testing kits, and this continues to cause widespread variation internationally of measured new case rates.

General considerations Standardized management procedures

During the HIV, SARS and Zika virus epidemics, principles As previously reported, keystones of overall cancer of management were developed for large populations management, focused on risk–benefit analysis with beset with these viruses, given that each one had spread an emphasis on safety from viral infection and relatively rapidly and without specific vaccines or active optimal survival from cancer, have included (Raghavan treatments being available. These approaches, crafted et al. 2020): initially from first principles, have been applied to the current pandemic, despite relatively scant published •• virus-adapted consideration of risk/benefit ratio of information. The key approach has been to ensure the diagnostic and treatment options;

Table 1 General parameters of pandemic management for patients with endocrine-related cancers.

Parameters Pre-treatment During treatment After departure Medical imperatives Risk–benefit analysis Pre-screening for risk Temperature check and risk Re-assess aims vs. toxicity vs. (telephone) questionnaire on arrival response vs. COVID-19 •• Prognosis of tumor Careful evaluation Review approach to aims and environment •• Intercurrent disease expectations of treatment Emphasis on virtual follow up visits •• Risk factors for CO- •• General Psychological support as – medical, social and psychological VID-19 •• COVID-19 unusually high-stress period issues •• COVID-19 positive? •• Cancer prognosis compounded by COVID-19 Structured approach to safe •• Access to testing? Establish clear aims and Physical/social distancing in phlebotomy and blood tests expectations of treatment clinic, infusion center, Nurse navigators Choosing wisely principles radiation unit, diagnostic Connection with nurse centers navigators Timing of treatment Delay visits/Rx if safe Review the use of repeated Rx Assess for symptoms of progressive Clear communication of (radiation, systemic Rx) if CA if Rx delayed •• Surgery? reasons for plan COVID-19 phase changes Careful assessment and •• Radiation? Discussion of options documentation of treatment •• Systemic? Consent document including toxicity vs. symptoms of COVID-19 b •• Adjuvant? COVID-19 rationale – important for timing of next Rx •• Neoadjuvant?b •• Observation? Triaging Timing/delay of treatment Virtual follow-up increased Use of virtual consultation Thoughtful planning re follow-up scans and their timing Staffng considerations Staffing rotations – on/off Masking/social distancing of Virtual follow-up increased Reduce patient facing by staff increased virtual visits Personal protection equipment Patient-focused issues Education and Standard pre-arrival operating Reinforcement of principles Follow-up education communication procedures and telephone Nurse navigators pre-check Virtual follow-up visits to cover •• Cancer-focused Access to nurse navigators COVID-19 safety protections •• COVID-focused Printed and electronic materials •• Treatment impact and complications •• Reason for no visitors policya Importance of masking Educational materials Staff education and standard Follow-up education and social distancing Web access to information operating procedures Role of nurse navigators Signage Reinforcement aExcept specific indications – end of life, ICU, physical assistance needed, and children – visitors must be screened for symptoms/exposures/travel. bFor example, use of adjuvant rather than neoadjuvant chemotherapy if there is no significant difference in cancer outcome (=delay chemo). Rx, treatment.

•• emphasis on clear, proactive communication for white-board or paper modifications of standard patients, families and staff regarding virus-adapted operating procedures and protocols can be distributed changes in management, rules regarding social and to all staff and provide a reasonable alternative as long physical distancing policies, reduction of visitors for as they are current and accurate (Table 2); inpatients and outpatients, and so on; •• restructuring of social support via nurse navigators, •• assurance of symmetrical and instant communication social workers and ancillary staff; of COVID-19-specific alterations in standard treatment •• physical/social distancing via reduced non-urgent algorithms, using a system of computerized pathways clinic visits and with increased physical spacing in (Electronically Accessible or EA Pathways), predicated clinics; physical spacing is supported by structured on whatever evidence is available and/or first data (Chu et al. 2020); principles in the context of COVID-19 (Fig. 1); for •• increased use of virtual consultation when consistent systems without this level of electronic sophistication, with patient safety and need;

Figure 1 Electronically accessible pathway for breast cancer in COVID-19 pandemic.

•• alterations to staffing with 14-day rotations of success of treatment, risks of cancer and its treatment mixed teams of physicians and advanced practice vs COVID-19, and effectiveness of available treatment; professionals to ensure a reservoir of non-COVID- •• delay of surgery or radiotherapy for lower risk, indolent infected staff at all times; malignancies; •• universal masking of patients and staff, with patient- •• replacement of intravenous by oral medications where facing staff wearing scrubs whenever possible, and possible; added Personal Protective Equipment (PPE) for high- •• use of hormonally active medications in preference to risk situations; N95 or equivalent masks appear to cytotoxics where feasible and appropriate; provide added protection compared to routine surgical •• tumor-specific approaches have been applied to the masks (Chu et al. 2020); use of adjuvant and neoadjuvant treatment strategies, •• application of a conceptual framework (Hanna et al. usually predicated on likelihood of response and 2020, Raghavan et al. 2020) addressing goals and likely potential patterns of toxicity, as outlined subsequently;

Table 2 Suggested triage of newly diagnosed well-differentiated thyroid cancer during COVID-19 pandemic (white-board model).

Initial follow up when routine care ATA risk category Clinical features Surgery Radioactive iodine delayed Low Confined to gland, central neck May delay with increased Not indicated 6–12 weeks low-volume metastases surveillance Intermediate Minor extrathyroidal Delay not recommended May possibly be delayed 6–12 weeks extension, larger volume up to 3–6 months metastases High Gross extrathyroidal extension, Delay not recommended Delay not recommended 4–6 weeks distant metastases

•• careful review of potential COVID-19 issues relating to Conversely, in phase III, where all resources are routed to targeted therapies and immunoactive agents; urgent management of COVID-19 cases and ventilator •• maintenance of all aspects of supportive oncology, and ICU capacity have been exhausted, only extremely including careful attention to pain management, urgent, immediately life-threatening cases are considered psychosocial support, cancer rehabilitation, much of (Bartlett et al. 2020). which can be achieved by virtual visits, depending on The route of surgery (open vs laparoscopic) and the acuity of the service being provided; COVID-19 antigen status are important determinants •• consideration of establishing a separate ‘COVID-19 and have been reviewed in various position papers, such positive’ unit for large volume clinical practices as the joint statements from specialty surgical societies when numbers of infected cancer patients increase (Bartlett et al. 2020, Francis et al. 2020). A particular dramatically; for smaller clinical teams, physical source of debate has been the strengths and drawbacks separation, masking, and so on of infected patients are of open vs laparoscopic surgery. For example, in normal reasonable alternatives; circumstances, the surgical approach to prostatectomy •• explicit discussion of new COVID-19-related risks of has shifted largely to minimally invasive/robotic-assisted procedures (or of associated delay) with documentation laparoscopic approaches (Alemozaffar et al. 2015). Several of consent. studies have demonstrated viral particles in surgical smoke, and such particles may be more prevalent and As our mission at Levine Cancer Institute is to be a aerosolized within the pneumoperitoneum required for cancer center ‘without walls’, our standard operations laparoscopic surgery (Johnson & Robinson 1991, Capizzi prior to the pandemic, across 25 sites, has involved et al. 1998, Hensman et al. 1998, Kwak et al. 2016, Zheng extensive use of electronic communication (including et al. 2020), leading to the controversy. The absence of tumor conferences, grand rounds, meetings of tumor- data specific to coronavirus particles has meant the specific teams), with linked and standardized treatment American College of Surgeons and other surgical societies programs predicated on our Electronically Accessible have generally left the decision to individual surgeons Pathways. In retrospect, it appears that this has to choose the appropriate surgical approach to any facilitated considerable agility during the early phases given case, with recommendations on how to minimize of the pandemic, which may explain the relatively low the release of aerosolizing particles and appropriate use volumes of COVID-19 infected cancer patients at our of PPE (https://www.facs.org/covid-19/clinical-guidance/ institution to date. elective-case).

Cancer surgery Clinical trials

In most cancer centers, surgical departments have adhered Clinical trials have been severely impacted by the to a universal overall strategy for cancer surgery, defined COVID-19 pandemic, specifically with regard to activation, by the projected urgency of need compared to the safety enrollment and ongoing conduct. The safety of patients of the patient and surgical staff (Bartlett et al. 2020, Francis and clinical trials staff remains crucially important, and et al. 2020; https://www.asge.org/home/joint-gi-society- thus accrual to many trials has been suspended, with the message-covid-19). ‘Non-essential surgery’ is generally use of virtual technology wherever feasible for follow-up delayed, both to prevent unnecessary exposure and to and for patients who remain on active treatment trials. conserve surgical and PPE resources, as well as ICU and At our institution, each disease section reviewed their surgical beds in case of need for pandemic management. respective clinical trial portfolios, maintaining in ‘active The American College of Surgeons and Society of Surgical status’ studies for which alternative treatment options Oncology have defined three phases of COVID-19 acuity, were unavailable (and with a reasonable likelihood of reflecting the extent of community-wide medical resource therapeutic response). Registry, specimen collection, utilization (and inverse availability of resources, such as and non-urgent patient treatment studies have been PPE and hospital/ICU beds). In phase I, the least intensive temporarily suspended to avoid added patient and staff with the least intrusion into standard availability of exposure. Similarly, during the crisis, new cancer trials have resources, a lower bar is set for cases eligible for surgery not been opened because of risk–benefit considerations (as discussed below in tumor-specific sections) (Bartlett and, most particularly, the uncertainty of patient benefit et al. 2020). Phase II reflects intermediate levels of acuity. in early phase trials. Most tumor types have standards of

https://erc.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/ERC-20-0229 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 10:19:44PM via free access Endocrine-Related D Raghavan et al. COVID-19 and endocrine- 27:9 R362 Cancer related cancer management care in place, and the default position has predominantly centers, such as Wuhan, New York City and Venice at been to adhere to those. the peak of the pandemic, again because of risk–benefit Wherever possible, adherence to active and ongoing considerations and lack of availability of resources. Much clinical trial protocols has been maintained, especially of this type of surgery is completed at ambulatory surgical for responding patients, but when patient safety has centers rather than in the inpatient operative setting. dictated variation from protocol, the deviation is reported Analogous to the treatment of other cancers during accordingly. Where patients have continued treatment the pandemic, the rationale for modifications in the on cancer trials, data management and research nursing multidisciplinary management of breast cancer is staff and the trial monitors from many sponsoring extensive. The goals include an assurance that the long- organizations have leveraged virtual visits and electronic term clinical outcomes are optimized, the risk of exposure documentation wherever possible. among patients and staff is minimized, protecting patients from significant immunosuppression, and preserving vital resources within a healthcare system. Although minimal definitive evidence is available on how Breast cancer to best treat breast cancer patients during the COVID-19 The management of breast cancer is at the forefront of pandemic, several organizations including the COVID-19 modern oncology, with very carefully defined pathways Pandemic Breast Cancer Consortium and European of treatment that are stage-specific,and which represent Society for Medical Oncology (ESMO) have issued position a detailed understanding of the biology of this disease, papers to assist healthcare providers (Dietz et al. 2020, including the interplay of hormone receptors, genetic De Azambuja et al. 2020). mutations, a well-defined range of biological characteristics and prognostic and predictive determinants (Harbeck & Surgery Gnant 2017, Waks & Winer 2019). One of the defining features of breast cancer management is the very well Recommendations have been published by several developed and interactive communication systems and organizations including the Society of Surgical Oncology advocacy networks that have been developed by and and the American College of Surgeons regarding the for breast cancer patients and survivors, and these have management of breast cancer surgeries (Bartlett et al. 2020, provided extensive accurate (and sometimes inaccurate) Curigliano et al. 2020; https://www.facs.org/-/media/files/ information for their constituents. This constitutes a covid19/guidance_for_triage_of_nonemergent_surgical_ relatively unique added demand for informed decision procedures_breast_cancer.ashx). The underlying principle making in the COVID-19 era, as compared with the during the COVID-19 crisis as with surgical approaches populations dealing with many other tumor types. with other cancers is to perform surgery in patients In line with the risk–benefit analyses that have likely to have ‘survivorship compromised’ if surgery characterized medical management during the is not performed within the ensuing 3 months. These pandemic, all routine screening (mammography, CT are highlighted as follows. For ductal carcinoma in situ scans, ultrasounds) of asymptomatic women have been (DCIS), it is recommended that surgery be deferred for discontinued (Dietz et al. 2020, Tasoulis et al. 2020, 3–5 months. For ER-positive DCIS, endocrine treatment Viale et al. 2020), reasoning that the increased risks of can be given during the delay, until surgery can be exposure to COVID-19 are greater than the likely benefit performed. For stage I and II hormone-receptor (HR) of immediate, early diagnosis. However, for patients positive, HER2-negative breast cancer, surgery can be presenting with symptoms (breast mass, new dimpling, deferred for several months and neoadjuvant endocrine cutaneous inflammation of the breast, etc), appropriate therapy can be given until surgery is possible. medical management is routinely initiated, with either For larger, stage III HR-positive and HER2-negative face-to-face or virtual consultation, followed by diagnostic breast cancer, this strategy can also be applied to tests if indicated. downstage the tumor and improve the possibility of For patients with clinically localized breast masses and breast conservation (Spring et al. 2016). For triple-negative a positive core needle biopsy, most surgical practices have breast cancer and HER2+ breast cancer, presenting with moved to achieve early complete resection, especially in clinical ≥T2 and/or ≥N1 disease, the standard approach the early phases of the pandemic, as defined by specialty is neoadjuvant chemotherapy and should continue to surgical societies. This has not been practicable in crisis be utilized. Upfront surgery for these two breast cancer

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With regards to reconstructive cancer center, reducing the risk of immunosuppression surgery, it is recommended that autologous reconstructions when possible, and switching therapy to oral agents, if be postponed during the pandemic. Implant-based an equivalent formulation is available. For example, the reconstruction at the time of mastectomy could still be backbone chemotherapy regimen given in the adjuvant reasonable to perform depending on resources and the and neoadjuvant setting is composed of an anthracycline severity of the COVID-19 threat. Prophylactic surgery for and taxane. If a patient is receiving weekly intravenous asymptomatic high-risk patients is currently viewed as paclitaxel, consideration can be given to dose-dense being of low priority. (every 2 weeks) intravenous paclitaxel so that fewer visits are needed. This regimen does require an injectable Radiation growth factor agent to be given more than 24 h after the administration of chemotherapy. If feasible, we have Several groups have published guidelines on radiation encouraged self-injection of pegfilgrastim or biosimilar, at therapy for breast cancer during the COVID-19 pandemic home. Another example is the modification of monthly (Coles et al. 2020, De Azambuja et al. 2020, Dietz et al. leuprolide acetate in premenopausal women receiving 2020). Radiation is commonly delivered after surgery adjuvant endocrine therapy to 3-monthly formulation of and chemotherapy. Depending on the circumstances, the the LHRH analogue, in order to reduce the frequency of sequencing of surgery, systemic therapy, and radiation visits (Kendzierski et al. 2018). If patients have not had may be modified during the pandemic. For example, in previous ovarian function breakthrough on an every patients with HR-positive, HER2-negative breast cancer 3-month suppression schedule, then these patients can be who need both adjuvant chemotherapy and radiation, switched to every 3-month leuprolide acetate injections. consideration could be given to giving radiation before At our institution, we have opted to check hormone levels chemotherapy without resulting in the compromised at the second injection point and if not suppressed, then outcome (Bellon et al. 2005). This could be helpful if switch patients to a monthly injection. immunosuppressive chemotherapy is to be avoided but then has to be balanced with the frequency of facility visits and the risk of exposure this would impose. For Early stage disease adjuvant therapy, hypofractionated, shorter regimens For a patient with an early stage hormone receptor (42.6 Gy in 16 fractions or 40 Gy in 15 fractions) in the (HR)-positive, HER2-negative breast cancer, a common adjuvant setting should be considered when feasible and approach is proceeding to upfront surgery. During this approach results in similar safety and efficacy to the pandemic, consideration has been given to offer conventional fractionation (Whelan et al. 2010, Haviland neoadjuvant endocrine therapy to a clinical stage I or et al. 2013). In order to reduce exposure of patients and II HR-positive, HER2-negative breast cancer if there will staff, the boost can be omitted in patients >50 years of age be a deferral of definitive surgery by 3 months or more with HR+ and/or small HER2+ breast cancers. If necessary, (Dietz et al. 2020). This approach can be reasonably radiation can be postponed up to 3 months for high-risk applied to tumors with low genomic assay scores, low- patients and up to 6 months for low-risk patients (Van grade tumors, and invasive lobular disease. However, Maaren et al. 2017). Typical settings in which to consider several factors should be weighed in this scenario of the omission of radiation therapy (in which survival is upfront NET vs upfront surgery, including the risk of the not affected) could include (1) patients aged ≥ 65 with tumor enlarging with a delay in surgery, potential added an early stage, HR+, HER2-negative, node-negative, grade burden on hospital resources, and the risk of exposure 1–2 breast cancer, provided that the patient agrees to to SARS-CoV-2. Genomic evaluation of a HR-positive, take endocrine therapy (Hughes et al. 2013, Kunkler et al. HER2-negative invasive breast cancer can be obtained 2015) and (2) after excision of a low-to-intermediate grade to help guide initial decisions regarding neoadjuvant ER-positive DCIS. systemic therapy during the pandemic. An Oncotype

DX Breast Recurrence Score is traditionally sent on the Advanced disease resected breast cancer. The Society of Surgical Oncology For patients with metastatic disease, the sites of suggests that, if a clinician desires genomic testing such involvement, symptoms and pace of the disease should as Oncotype DX to decide between endocrine therapy govern management. In general, the modifications in and chemotherapy, testing can be sent on the core metastatic breast cancer treatment during the COVID-19 biopsy. It is important to emphasize that sending a core crisis include using less myelosuppressive regimens when biopsy represents untreated breast tissue and is optimal feasible, increasing the interval between staging scans to send this type of tissue for Oncotype Dx testing; especially without symptoms of progressive disease, this avoids the concern that endocrine treatment alters and lengthening the interval between other monitoring mRNA expression levels used to calculate the Recurrence assessments such as ejection fraction on anti-HER2 Score. Core biopsy specimens have been shown to therapy. Based on risks and preferences, thoughtful produce Recurrence Score results highly concordant with consideration could be given to decreasing regimen resection specimens (Anderson et al. 2009). If endocrine intensity, moving away from weekly dosing schedules, therapy is deemed appropriate, the patient can be treated and delaying the timing of infusions, when appropriate. with neoadjuvant agents for at least 3–6 months and Patients who are symptomatic or who are in early line then proceed to surgery. For postmenopausal patients treatment, where published data show improved clinical with HR-positive, HER2-negative early breast cancer outcomes in the metastatic setting, should proceed. For who may have just had surgery during the height of the example, there should be early use of first-line treatment pandemic and need chemotherapy, it may be safe to delay of a HER2-positive metastatic breast cancer with a chemotherapy for more than 3 months and to administer taxane, trastuzumab and pertuzumab, as this clearly endocrine therapy as a bridge in such patients. provides improved overall survival (Swain et al. 2013). In patients with low-risk HER2-positive breast cancer, For patients receiving later lines of salvage treatment, consideration can be given to shorten the duration of it may be reasonable to discuss drug holidays or best adjuvant trastuzumab to less than 12 months, based supportive care. on data from the Phare and Persephone prospective As noted previously, elderly patients and those randomized trials, both of which showed that 6 months with comorbidities are at higher risk for COVID-19 of adjuvant trastuzumab was not inferior to 12 months infection and death, and for those with low burden of of trastuzumab (Earl et al. 2019, Pivot et al. 2019). In HR-positive, HER2-negative metastatic disease (absence patients who have been receiving ongoing adjuvant anti- of visceral disease) receiving treatment in the first- HER2 targeted therapy, an infusion can be postponed by line setting, consideration could be given to starting 6–8 weeks (De Azambuja et al. 2020). For ejection fraction endocrine therapy initially and postponing the start of monitoring in patients receiving anti-HER2-treatment, a cyclin-dependent kinase (CKD) 4/6 inhibitor because follow-up echocardiogram can be performed at 4-month these agents cause myelosuppression and occasional intervals and then deferred in the absence of symptoms. pneumonitis. On a case-by-case basis, it may also be Patients with triple-negative breast cancer can only be appropriate to avoid or delay the addition of other effectively treated with chemotherapy, and for those with targeted therapy that is usually paired with aromatase a higher risk of relapse, their adjuvant and neoadjuvant inhibitors, such as everolimus (induced immune- treatment should not be delayed. In patients who are suppression) and alpelisib (risk of diabetes). Risks and receiving adjuvant zoledronic acid every 6 months, this benefits of this approach should be discussed with this can be deferred during the height of the pandemic. vulnerable population (Bartlett et al. 2020). For patients Patients presenting with locally advanced breast cancer with bone metastases, it is reasonable to minimize such are at greater risk of local progression, with ulceration or supportive agents as denosumab or zoledronic acid, cutaneous involvement, or early dissemination, and this especially if this is the only reason to enter the infusion situation requires greater urgency of management. In center. However, more active management is mandated these situations, treatment results in substantial benefit, in the setting of hypercalcemia. Modifications could in all breast tumor types, namely triple-negative, HER2- include delay or lengthening of treatment interval positive, and high-risk HR-positive, Her2-negative, and to give intravenous bisphosphonates, for example, should not be postponed. every 3 months.

Prostate cancer Urology, and the British Association of Urological Surgeons (Kokorovic et al. 2020, Mejean et al. 2020; https://caunet. Even before the onset of COVID-19, the management of all org/wp-content/uploads/2020/04/BAUS-Oncology- stages of prostate cancer has been somewhat controversial, COVID-19-Prostate.pdf), and a collaborative position largely because of the heterogeneity of the disease and its paper on radiotherapy for prostate cancer in the COVID-19 time course, the broad availability of therapeutic options, pandemic (Zaorsky et al. 2020). These recommendations and the impact of strong specialty-specific biases about have involved structured studies of evidence-based optimal care (Raghavan 2013, Bill-Axelson et al. 2018, literature. Mostly, patients presenting with symptoms Raghavan 2018, Gillessen et al. 2020). suggestive of prostate cancer are being deferred for While there has been varied opinions about the in-person visits, diagnostic work-up and biopsies for 3–4 utility of screening of asymptomatic subjects prior to the months, allowing the pandemic to ebb. pandemic (Raghavan 2013), the onslaught of COVID-19 While active surveillance, with serial measurement has closed down virtually all cancer screening activities, of PSA and appropriate imaging protocols, has been predicated on a cost–benefit analysis of risk to patients practiced increasingly in recent years (Bill-Axelson et al. and staff vs the potential low yield of early diagnoses per 2018), especially for good- and, perhaps, intermediate- number of subjects screened. This has applied to men risk tumors (i.e. well and moderately differentiated with who might otherwise have been screened for prostate PSA less than 10 ng/mL), most recommendations have cancer with measurement of prostate-specific antigen suggested avoidance of routine clinical visits and tests, (PSA). Randomized trials have failed to show an overall so functionally this has not been a treatment option that survival benefit from PSA screening for asymptomatic is in use in the COVID-19 pandemic (Kokorovic et al. Caucasian males (Schroder et al. 2012, Raghavan 2013), 2020, Mejean et al. 2020; https://caunet.org/wp-content/ and while the urological community has continued uploads/2020/04/BAUS-Oncology-COVID-19-Prostate. with variants of screening (sometimes targeted at pdf). There has been general consensus that definitive specific subpopulations), those activities have been surgery should be delayed, particularly for well- and discontinued during the pandemic and supported by moderately differentiated tumors, provided the delay is recommendations from relevant professional societies less than around 3 to less than 6 months, for the reasons (Kokorovic et al. 2020, Mejean et al. 2020; https://caunet. enumerated previously (Kokorovic et al. 2020, Mejean org/wp-content/uploads/2020/04/BAUS-Oncology- et al. 2020). A similar delay of definitive radiotherapy for COVID-19-Prostate.pdf). In the past, substantial good-risk tumors has been proposed by a multi-center concern has been expressed that delays in screening consensus group of radiation oncologists (Zaorsky et al. lead to worse outcomes for cancers of breast, colon and 2020), based on published data on the outcomes of lung, but the situation is much less well defined in the radiotherapy for good-risk disease. context of prostate cancer. However, the same consensus group has proposed Of course, the asymptomatic screening situation is the use of neoadjuvant androgen deprivation therapy different from a specific investigation of symptoms, such (ADT) for patients with unfavorable intermediate-risk as the sudden onset of dysuria, reduced urinary stream, and poor-risk localized and locally advanced prostate perineal pain or features that may suggest new metastatic cancer (Zaorsky et al. 2020). This group has provided a disease (bone pain, features of spinal cord compression broader generic structure, the RADS framework (Remove and non-metastatic features of advanced malignancy). In visits, Avoid radiation, Defer radiation and Shorten this situation, the clinical decision process is required and radiation) for pandemic management. Arising from this would usually lead to the consultation (patient facing or framework, it has been specifically recommended to virtual) and appropriate investigation and management avoid brachytherapy during the pandemic because of its (Kokorovic et al. 2020). need for anesthesia, PPE and increased risk of viral spread For patients with early stage prostate cancer, with a (Zaorsky et al. 2020). There is an extensive literature that positive biopsy and negative clinical staging tests, there supports the use of combined modality hormones and are no published data to drive management during either surgery (Messing et al. 1999) in the setting of locally the pandemic, beyond general guidance issued by extensive disease or nodal metastases or radiotherapy professional societies, such as the Canadian Urological (Bolla et al. 2010) for high risk, clinically non-metastatic Oncology Group and Canadian Urological Association, prostate cancer, and thus these recommendations seem the Cancer Committee of the French Association of very reasonable.

For patients with high-risk localized or locally laboratory-confirmed COVID-19 infection, showed that advanced prostate cancer, several urological groups patients suffering from cancer have a greater risk of have recommended the use of radical prostatectomy if COVID-19 infection than patients without cancer, but COVID-surge conditions are not current (with the hope also that males being treated with androgen-deprivation of rapid treatment, admission and discharge prior to therapy (ADT) had a substantially lower risk of the onslaught), or the use of neoadjuvant ADT to delay COVID-19 infection than for patients with other cancers. surgery (or definitive radiotherapy) Kokorovic( et al. Men receiving ADT also showed lower rates of infection 2020, Mejean et al. 2020; https://caunet.org/wp-content/ than other non-cancer patients; furthermore, patients uploads/2020/04/BAUS-Oncology-COVID-19-Prostate. with prostate cancer receiving ADT had lower infection pdf). There are no defined guidelines for charting a rates than prostate cancer patients not treated with course of treatment in the uncertain environment of ADT. Extending this theme, Stopsack et al. (2020) have a post-surge situation (i.e. after an initial surge when a recently proposed the investigation of specific inhibitors second COVID-19 surge is anticipated at an uncertain of TMPRSS2 and inhibition of the androgen signaling axis future time); that decision should be made, based on as anti-COVID-19 treatment. population demographics, the clinical experience in the For patients relapsing after standard ADT, or after initial surge, and the predictive analytic studies that are salvage therapy with enzalutamide or equivalent second- available for that specific geographical region. In general line hormonal blocking therapies, the pace of the disease terms, a period of ADT of 6 months or even somewhat and clinical context should dictate the pattern of care. longer would be reasonable in this clinical setting unless One of the commonest presentations is asymptomatic serial PSA measurements or the clinical findings suggested rising PSA levels, and this should not constitute an failure of ADT to achieve remission. indication for salvage treatment during the pandemic For patients presenting with metastatic prostate (we would contend that treatment at this clinical-stage is cancer, initial ADT is the usual standard of care (Crawford palliative, and it is difficult to palliate an asymptomatic et al. 1989). More recently, it has been shown that the patient). novel compounds abiraterone acetate (Ryan et al. 2013) However, for symptomatic patients in whom the or enzalutamide (Davis et al. 2019) (or analogs) add symptoms cannot be controlled by conventional palliative significantly to the survival impact of ADT, both for therapy, a clinical decision should be made, balancing good-risk and poor-risk metastatic disease. As abiraterone the risks of myelosuppression vs the potential impact acetate is administered with corticosteroids, it would seem of COVID-19. From first principles, the use of docetaxel wise to use enzalutamide or apalutamide as the added at a reduced dose (around 50 mg/m2, thus reducing the component during the pandemic (Kokorovic et al. 2020, risk of myelosuppression) is a reasonable option, given Mejean et al. 2020). The dose of corticosteroids is only the paucity of dose–response data supporting the use low, but there is the variability of immunosuppression in of the conventional dose of 70–75 mg/m2. For patients association with these agents in the elderly. Sweeney and with the bone-dominant disease, another appropriate colleagues also reported that initial docetaxel added to option is radium-223, which is highly active against ADT improves survival for poor-risk metastatic prostate bone metastases from prostate cancer without causing cancer significantly (Sweeney et al. 2015), but during significant myelosuppression. This will place the Nuclear the pandemic we have focused treatment on ADT plus Medicine staff at some potential risk, and appropriate enzalutamide or apalutamide as initial therapy for poor- physical distancing and PPE should be implemented for risk metastatic disease, thus avoiding extra clinic visits them. We have delayed the use of bone-stabilizing agents, and the risks of myelosuppression. such as bisphosphonates, during the pandemic to reduce One unanticipated aspect of androgen deprivation the frequency of clinic visits and monitoring. therapy has been the assertion that it may be protective The key issue is that there are many treatment against COVID-19. Glowacka et al. (2011) reported that options for patients with prostate cancer, some of which the transmembrane serine protease 2 (TMPRSS2), one may even afford protection against COVID-19 per se, and of the more frequently altered genes associated with management decisions should be taken based on careful prostate cancer, has a significant role enabling cellular risk–benefit calculation, with transparent discussion with invasion by the coronavirus by activating spike protein patients and their caregivers that defines the aims and and that it reduces the antiviral antibody response. expectations of treatment. Consent documents should Montopoli et al. (2020), in a review of 4532 males with be modified to reflect the impact of COVID-19 on the

https://erc.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/ERC-20-0229 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 10:19:44PM via free access Endocrine-Related D Raghavan et al. COVID-19 and endocrine- 27:9 R367 Cancer related cancer management decision process and selection of treatment and that this to hospitals with COVID-19 (Dai et al. 2020). If confirmed, has been explained in detail to the patient. further research would be necessary to ascertain whether this is a coincident finding due to the high prevalence of thyroid cancer or whether there are tumor-, patient-, or treatment-specific factors conveying increased Cancers of thyroid and parathyroid vulnerability (Dai et al. 2020). In this setting, pre-treatment The disruption of adult cancer treatment protocols during staging is vital, and each step must be considered in the COVID-19 pandemic has necessitated a temporary the context of comorbidities and risk of serious disease realignment of thyroid nodule and thyroid cancer care. should the patient become infected. Although knowledge Prior to the onset of the pandemic, there was a growing of genetic signatures has not been formally incorporated consensus that many patients were either under or over- into published guidelines, the field is far enough along to treated for thyroid neoplasms. This culminated in the be of clinical utility, and many centers, including ours, publication of guidelines formalizing risk stratification now routinely submit specimens for mutational testing for thyroid nodule evaluation and biopsy, as well as and incorporation into treatment planning (Seib & Sosa thyroid cancer, under the auspices of the American 2019, Prete et al. 2020). Thyroid Association (ATA) (Haugen et al. 2016). These The primary treatment of thyroid cancer is surgical, guidelines contain vocabulary and template readily and it is relevant that the first reported physician fatality adaptable for triage purposes during the pandemic. due to COVID-19 in Wuhan, China, was that of an Several national societies also have provided guidance for otolaryngologist. This has contextualized the management physicians and reassurance for patients (Puig-Domingo considerations for cancers of the thyroid and parathyroid, et al. 2020; http://www.thyroid.org/covid-19/coronavirus- especially as it has been reported that head and neck frequently-asked-questions/; https://www.aace.com/ surgery is associated with high COVID-19 infection recent-news-and-updates/aace-position-statement- rate and associated deaths (Chan et al. 2020). Patients coronavirus-covid-19-and-people-thyroid-disease). with differentiated thyroid cancer, clinically projected Most thyroid nodules are benign and malignant by ATA classification to have low risk for recurrence ones usually tend to grow slowly. Nodules without pre-operatively, may safely delay the initial procedure highly suspicious ultrasound characteristics (as classified without a negative effect on prognosis. This includes most by ATA or Thyroid Imaging, Reporting and Data patients with metastatic disease to local cervical nodes, Systems or TIRADS) generally can be observed and fine- found in the majority of patients with classic papillary needle aspiration biopsy for diagnosis delayed pending cancer, the most frequent subtype (Haugen et al. 2016). resolution of the pandemic. Patients not appropriate for Those considered to have ATA intermediate risk for the delay in diagnosis include those with clinical evidence recurrence (and possibly some with ATA high risk disease) of aggressiveness such as recent-onset hoarseness may have a delay in surgery, after weighing of individual (indicating infiltration of the recurrent laryngeal nerve) risk of tumor aggressiveness. Factors to consider include or a rapidly enlarging mass, imaging demonstrating both patient vulnerabilities and local prevalence of suspected invasion of local structures, or large suspected COVID-19 in the community or hospital. Patients nodal metastases (Haugen et al. 2016, Grani et al. 2019). with a rapidly progressive disease by history or clinical In cases where biopsy renders an indeterminate result findings, large or invasive neck metastases, distant (Bethesda Classes III-V), ultrasound characteristics can metastatic disease, or suspected de-differentiated tumor guide surveillance, often with repeat imaging at 3–6 should proceed to surgery if possible. Priority for urgent months rather than immediate repeat biopsy or surgical intervention is placed on the need for control of high- removal (Cibas & Ali 2017, Persichetti et al. 2018). Further volume neck disease and airway protection. risk stratification of nodules by mutational analysis is a An algorithm for urgent surgical intervention recently validated strategy, and consideration should be has been proposed at Stanford University for locally given to holding a sample at the initial biopsy for genetic aggressive papillary, medullary and anaplastic thyroid sequencing rather than having the patient return for an cancer and includes parathyroidectomy when there is additional biopsy requiring a separate encounter with the deteriorating renal function (Topf et al. 2020). These cases medical system (Nikiforov et al. 2019). will require extra precautions in the operating room as Preliminary data from China have listed thyroid noted previously and especially during procedures such as cancer as a frequent diagnosis among patients admitted tracheostomy which may generate aerosolized particles.

In addition, consideration has been given to the estimated necessary for up to several days. Although this has yet to transmission risk for operations on specific cancers. Thus, be reported, should the patient become infected during low risk operations (with no mucosa involved in the this time frame, the need for radiation safety precautions surgery), including thyroidectomy, parathyroidectomy, for health workers in the vicinity of the patient would and neck dissection, have generally been given a higher complicate the ability to deliver care. If appropriate priority than transoral procedures which have a higher infection control is in place and given the relatively short associated risk to staff (Givi et al. 2020, Kowalski et al. period of radiation isolation, this is anticipated to be a 2020, Schwartz et al. 2020, Topf et al. 2020). rare, but possible, scenario (Sisson et al. 2011). It is generally accepted that patients with ATA low External beam radiotherapy (ERBT) is employed risk disease do not benefit additionally from ablation with infrequently in thyroid cancer, with the main exceptions radioactive iodine (RAI) (Haugen et al. 2016). After surgical being recurrent invasive neck disease, typically in older recovery, these patients are ideal candidates for virtual patients, and localized treatment of bone metastases. follow-up until the pandemic infection curve is favorable Unless there is an imminent threat to the airway, and routine follow-up can be resumed. Post-surgically, consideration may be given to postponing EBRT to the neck some patients with ATA intermediate and possibly even in the setting of a rising pandemic threat, given potential ATA high risk for recurrence, who are candidates for radiation effects to the upper airway and esophagus (Tam radioactive iodine for adjunctive or therapeutic treatment, et al. 2017). For patients deemed candidates for systemic may also safely delay therapy for weeks and perhaps therapy with FDA-approved multikinase inhibitors, with months without significant effect on prognosis Scheffel( the goal to extend progression-free survival, optimal et al. 2016). Of particular concern, in this context, is timing for initiation is often a challenge as even advanced that most RAI protocols utilize human recombinant metastatic disease tends to be slow to progress. Tyrosine TSH and require no fewer than four separate face-to- kinase inhibitors exhibit varied immunomodulatory face encounters with medical personal, including two and immunosuppressive effects and substantial toxicity. intramuscular injections 24 h apart followed by I-131 oral In some cases, these interventions may be deferred dosing 24 h later, and then whole-body scanning at 5–7 when in a highly infectious environment. The role of days. The need for repeated patient exposures to medical immunotherapy in thyroid cancer is emerging and could staff must, therefore, be balanced against the perceived be considered within research protocols, although most of benefits of treatment. Older protocols requiring thyroid these have been suspended during the pandemic (Naoum hormone withdrawal may enable fewer staff encounters et al. 2018). but possibly may have severe consequences if patients The prognosis of anaplastic thyroid carcinoma has contract an infection while clinically hypothyroid. Our historically been so poor that, until recently, treatment general approach to mitigating risk has been to utilize our plans consisted predominantly of airway management usual protocols for RAI with human recombinant TSH in and palliation, with a median survival of 5 months. ATA intermediate- and high-risk categories while delaying Cytotoxic chemotherapy rarely was associated with a therapy by up to a few weeks in patients without the significant anti-tumor effect. However, a combination clinically aggressive disease, until the risk of COVID-19 inhibition of the BRAF gene has recently been shown to transmission is reduced (Table 2). improve substantially the response rate and progression- Pathologically aggressive subtypes, such as Tall Cell free survival after 1 year (Subbiah et al. 2018). Once again, variant, which confer increased rates of residual disease the risk of serious side effects and the vulnerability of the and recurrence, should be promptly treated when feasible patient to viral infection must be weighed against the (Shi et al. 2016). Invasive neck disease with suspected likelihood of long-term remission. residual microscopic remnants and treatable metastatic The options available for patients with relapsed and lung disease are examples of cases which also warrant metastatic cancer of the parathyroid gland are much proceeding directly to RAI as long as enhanced infection more limited, and depending on the sites and speed of control protocols are in place. Myelosuppression related to relapse, include palliative radiotherapy or cytotoxic I-131 is minimal, subclinical, transient, and not likely to chemotherapy, with agents such as cisplatin, the taxanes, confer additional immunosuppressive risk to the patient and doxorubicin showing occasional anti-cancer effect; (Silberstein et al. 2012). However, in the period after RAI risk–benefit analysis will often result in referral to hospice, treatment, isolation protocols for radiation exposure are particularly for the elderly patient. Targeted therapeutics

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It is not uncommon for the Pre-treatment staging is routinely employed based on perceived risk of residual and/or recurrent thyroid initial indications of tumor aggressiveness on imaging and cancer to be significantly modified by the biology of the by the presence of hormonal secretory syndromes. Excess disease as the patient advances through care. Therefore, secretion of cortisol and steroid precursors (resulting in patients assessed initially as low risk should not have Cushing’s syndrome or subclinical hypercortisolism), their treatment postponed indefinitely. In those cases characteristic of the majority of these tumors, results in a where delay is necessary, short interval follow-up can state of immunosuppression and patient vulnerability to be employed, ranging from neck ultrasound performed overwhelming infection. The mortality in these patients in the office to cross-sectional imaging surveillance of can be presumed to be high in the setting of concurrent suspected metastatic disease. Once again, for this pattern infection with COVID-19 (Dekkers et al. 2013). of care, the respective risks and benefits for patients and Because resection is the only chance for cure in staff need to be factored into the decision process. ACC, surgery should not be delayed at the stages when complete resection is possible (stage I and II), although this approach may have to be delayed during an escalating or crisis phase of the pandemic. For the best chance at Adrenal carcinomas complete R0 resection, open adrenalectomy is considered In similar fashion to the malignancies discussed standard when ACC is suspected (https://www.nccn.org/ previously, carcinoma of the adrenal gland is a protean professionals/physician_gls/pdf/neuroendocrine.pdf). condition with widely variable speed of progression, However, the effect of the choice of surgical procedure which can be localized, locally extensive or occasionally on disease clearance and long-term prognosis has become metastatic. Incidentally discovered adrenal masses with controversial as laparoscopic procedures have increased low density on pre-contrast CT (Hounsfield units <10) in recent years. Uncertainty regarding the role of are usually benign and can be observed if non-functional laparoscopic adrenalectomy in ACC has arisen due to the on hormonal assessment and not large (Schieda & possible risk of peritoneal seeding (Autorino et al. 2016). Seigelman 2017). Biopsy of indeterminate or suspicious Additional concerns have arisen during the pandemic in adrenal masses is generally contraindicated due to low this context (see previous discussion), therefore, open diagnostic yield and risk of peritoneal seeding (Williams resection remains the preferred option for patients with et al. 2014). Surgical resection is recommended when high suspicion of ACC during the COVID-19 pandemic. the diagnosis is not obvious by clinical presentation For patients with completely resected tumors, the and imaging, the main exception being when biopsy benefit of adjuvant treatment with radiation to the confirmation of a metastatic focus from a non-adrenal adrenal bed and/or mitotane has not been defined and is primary would change therapeutic course. Screening for the subject of ongoing trials (Bedrose et al. 2020). In the pheochromocytoma should always precede either biopsy setting of the COVID-19 pandemic, there seems little place or resection, to avoid the risk of crisis. Pheochromocytomas for adjuvant therapies without proven substantial survival also require the immediate initiation of the benefit. For patients suffering from hypercortisolism adrenergic blockade and prompt resection, due to the who are not candidates for surgery, cortisol blockers unpredictable risk of life-threatening adrenergic crisis and inhibitors of steroidogenesis are the mainstays of (Stewart & Story 2017). therapy. Mitotane is also employed therapeutically for The success of strategies for risk mitigation during its adrenolytic activity with the goal of stabilization the pandemic for patients with adrenal lesions remain of progressed, recurrent, or metastatic disease. It is not poorly defined, but a strategy can be determined using generally associated with myelosuppression. Due to its experience from other solid tumors combined with an long half-life, mitotane can be dose escalated without understanding of the unique features of adrenocortical the immediate need for measurement of blood levels if carcinoma (ACC). In areas of low viral prevalence or as reasonably tolerated. Patients experiencing significant

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Therefore, temporary dose-reduction with less frequent Especially when circumstances change on an almost daily in-person visits and laboratory work is a reasonable basis, our experience during the COVID-19 pandemic has option during periods of impaired access to routine care, demonstrated the value of an integrated, multidisciplinary with telemedical support. Patients on long-term mitotane approach with all the support that brings, not only for therapy are almost universally adrenally insufficient as a our vulnerable patients but for the physicians who care consequence. The required block-and-replace strategy with for them. oral steroids is complex even under normal circumstances. In a pandemic setting, it is a challenge to keep follow-up visits at a minimum while avoiding the risk of adrenal insufficiency on the one hand and iatrogenic Cushing’s Summary syndrome with immunosuppression on the other (Terzolo The COVID-19 pandemic has created a complicated set et al. 2014). It is noteworthy that COVID-19 infection of issues for patients with endocrine-related cancers, may disrupt the hypothalamic–pituitary–adrenal axis, wherein patients, families and healthcare workers are causing functional hypoadrenalism, and it is known that potentially placed at increased risk. Protection for all COVID-19 may localize to the adrenals (Pal 2020). participants is crucial, both by reducing risks of virus When metastatic adrenal carcinoma has progressed exposure and by maintaining active treatment algorithms despite mitotane, cytotoxics only have modest additional commensurate with optimal cancer survival. Physical/ utility. For the COVID-19 pandemic, cisplatin is probably social distancing, extensive use of virtual consultation, the most appropriate single agent, given an objective a careful review of the risk–benefit of treatment (and its response rate of 20–30%, of which about half are urgency), and modification of therapeutic approaches to sustained for more than 6–12 months, and only modest reduce patient-facing contact whenever feasible and safe dose-dependent myelosuppression. Other options, such are important elements of the strategy of pandemic cancer as paclitaxel, gemcitabine and etoposide are all associated care. Meticulous strategies of communication to patients, with significant myelosuppression, although one benefit families and staff are essential to make these changes of etoposide is its availability as an oral medication. as palatable as possible. In addition, modifications of Although multi-agent chemotherapy may have a small Tumor Board functions must be implemented, leveraging response benefit, its use is not recommended during the electronic technology to allow the virtual presentation of COVID-19 pandemic due to greater myelosuppression pathology and radiology and discussion of complex cases, and lack of overall survival benefit compared to single- a particularly important aspect of cancer center function agent cytotoxic therapy (Fassnacht et al. 2012). In this given the uncertainties that surround the interface of setting, risk–benefit analysis is crucial, and we do not COVID-19 and cancer. We have summarized the strategies use cytotoxics for metastatic adrenal cancer that is stable employed to maintain the quality and safety of care for or only slowly progressive. These recommendations patients with early, locally advanced and metastatic are made from first principles, as we are unaware cancers of breast, prostate, thyroid and adrenal, in each of any published data to guide the management of case focusing on maintaining the best outcomes with metastatic adrenal tumors in the COVID-19 pandemic least morbidity and risk. (Megerle et al. 2018). During this uncertain time, compounded by the relative infrequency of these tumors, patient and family Author contribution statement engagement in decision-making regarding goals of care Each author has contributed equally to the manuscript, including should be especially emphasized. Frequent video or phone accumulation of data and literature review, writing, editing, and review of contact when office visits are reduced can be immensely the manuscript. Dr Raghavan acted as editor of the entire work in addition to the roles aformentioned. reassuring and should be considered a vital part of the palliative strategy. Individualizing care for patients with rare and complex tumors is imperative, and therefore Declaration of interest some forum for review of these cases is encouraged, even The authors declare that there is no conflict of interest that could be if not within an academic setting. Access to a tumor perceived as prejudicing the impartiality of this review.

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Received in final form 5 June 2020 Accepted 15 June 2020 Accepted Manuscript published online 30 June 2020