key: cord-0770366-75e3373k
authors: Boettcher, Adeline N.; Hammoud, Dima A.; Weinberg, Jason B.; Agarwal, Prachi; Mendiratta-Lala, Mishal; Luker, Gary D.
title: Cancer Imaging and Patient Care during the COVID-19 Pandemic
date: 2020-11-13
journal: Radiol Imaging Cancer
DOI: 10.1148/rycan.2020200058
sha: 45421c55bf318537f60d155086e51f4bc30903e5
doc_id: 770366
cord_uid: 75e3373k

Patients with cancer have been negatively impacted during the coronavirus disease 2019 (COVID-19) pandemic, as many of these individuals may be immunosuppressed and of older age. Additionally, cancer follow-up or imaging appointments have been delayed in many clinics around the world. Postponement of routine screening exams will result in delays in new cancer diagnoses. Clinics are continuing to monitor and adapt their appointment schedules based on local outbreaks of COVID-19. Studies on COVID-19 in patients with cancer are limited, but consistently indicate that this population is at risk for more severe COVID-19 illness. Data from recent studies also suggest that pediatric patients with cancer have a lower risk of severe COVID-19 illness compared to adults. Certain features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection detected by lung, brain, and gastrointestinal imaging may confound radiologists’ interpretation of cancer diagnosis, staging, and treatment response. Lastly, as clinics begin to re-open for routine appointments, protocols have been put in place to reduce SARS-CoV-2 exposure to patients during their visits. This review details different perspectives on the impact of the COVID-19 pandemic on patients with cancer and on cancer imaging.

The coronavirus disease 2019 pandemic is currently (as of September 1, 2020) affecting 188 countries with 25.8 million confirmed cases and 858,000 deaths worldwide (1) .

Throughout 2020, COVID-19 outbreaks have emerged in different geographical areas at different times and have resulted in varying stay-at-home orders and business closures. Responses to COVID-19 also included closure of many cancer clinics, and hence postponed or cancelled patient appointments (2) resulting in a decrease in new cancer diagnoses and a delay in treatments.

Patients with known cancer, suspected cancer, or at risk for cancer are particularly vulnerable during this pandemic for two main reasons: (a) postponement of screening or treatment followup appointments negatively impacts long-term outcomes and (b) these individuals have a higher risk for more severe COVID-19 illness because of age and immunosuppression (3) (4) (5) .

During the early period of the pandemic (spanning from March to May 2020), many institutions developed guidelines on how to safely resume patient imaging appointments.

Additional guidelines have been published for determining routes of care for different types of cancer (6) (7) (8) . More recently, many institutions or groups of care systems have implemented marketing campaigns to encourage persons to re-enter the health care system for elective procedures, such as mammography and lung cancer screening (9) . Although plans were specifically designed to mitigate potential for viral transmission, there will still likely be many individuals who will choose not to reschedule appointments during this year (and potentially into 2021) due to fears of becoming infected with severe acute respiratory syndrome coronavirus 2 I n p r e s s 5 cancer, which is higher than the population incidence of cancer (0.29%). The same study also demonstrated that patients with cancer were at a higher risk for developing severe events (admittance to an intensive care unit, ventilation, or death) from COVID-19 illness (39%; 7 of 18) than those without cancer (8%; 125 of 1572) (13) . Another study from New York City (5) , which included 218 individuals with a diagnosis of COVID- 19 or immunotherapy were not associated with an increased case fatality rate in this group of patients (5) .

Increased mortality and morbidity were also observed in another study which included 928 patients (mean age 66 years; interquartile range, [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] with COVID-19 and cancer (14) . In this study, older age (per 10 77, 9.77) were all associated with an increased 30-day mortality due to . In another study, Warner et al reviewed 1018 patients with COVID-19 and cancer, in which 30-day mortality and severe illness were significantly higher than that of the general population, and tumor type or type of cancer therapy were not significant factors for mortality I n p r e s s 6 (14) . Another recent study by Rini et al, which included 2749 patients with COVID-19 and cancer, demonstrated high rates of mortality, approaching 16% at 30 day follow-up, with increased risk of intensive care unit admission an intubation (15) . This rate of mortality from COVID-19 in patients with cancer was higher than the global 1-5% mortality rate from COVID-19 for an unselected general population (16) .

In contrast, numerous studies have concluded that pediatric patients have lower risk for infection with SARS-CoV-2 and less severe manifestations of disease compared to adults (17) .

Children are approximately 50% less susceptible to infection, comprising less than 5% of total infections, with approximately 20% or fewer developing clinical symptoms (18, 19) . In the United States, children represent approximately 22% of the population but less than 2% of SARS-CoV-2 infections, and only 5% of infected children require hospitalization (20) . A study in Switzerland reported similar findings (21) . Some of these statistics may change as schools reopen in the Fall of 2020 (22) .

Kettering Cancer Center determined that children in New York City with cancer did not have increased risk for infection or severity of COVID-19 as compared with children without cancer (23) . Reasons underlying why children typically do not experience more severe manifestations of COVID-19 remain unclear. One hypothesis is that healthier blood vessels in children as compared with adults, particularly adults with underlying cardiovascular disease, protect against complications of COVID-19 related to thrombosis (24) . However, following SARS-CoV-2 infection, a small proportion of children develop multisystem inflammatory syndrome in children (called I n p r e s s 7 As the number of infected individuals increases worldwide, and with longer follow-up data, long-term assessments of patients with cancer that have tested positive for SARS-CoV-2 are being initiated in a clinical trial called COVID-19 in Cancer Patients Study (NCCAPS, ClinicalTrial Identifier: NCT04387656). The main objectives of this clinical trial are to characterize different factors related to COVID-19 and cancer outcomes, such as other comorbidities, demographics, and types of cancer treatments (26) . This study also aims to assess how cancer treatments were modified in response to the SARS-CoV-2 infection. Lastly, images from recruited participants will be collected, and thus this clinical trial will enable clinicians to gain a better understanding of confounding imaging findings between cancer, treatment response, and SARS-CoV-2 infection.

The impact of the pandemic resulting in government mandated shut-downs, shortages of personal protective equipment, insufficiencies of healthcare organizations, social distancing mandates, and generalized fear and anxiety of the public, essentially led to a near complete halt in all outpatient elective activity, including cancer screening and follow-up. Due to these modified activities, many diagnoses, initiation of treatment plans, modifications to treatment plans, and surgeries for resection did not occur during this time. Additionally, many clinical centers converted patients undergoing cancer therapy from intravenous to oral medications and/or to less aggressive regimens (monotherapy rather than combination therapies) to reduce risks of complications, hospitalizations, and visits to treatment facilities (9) . The long-term impacts on delayed cancer imaging and treatment, as well as delayed follow-up appointments, during this pandemic will not be evident for some time. recommended delaying screening studies such as screening mammograms, colonoscopy, and surveillance for lung cancer (29,30). Some experts proposed delaying screening for cervical and prostate cancer given that they are slow growing malignancies in which screening often aims to detect precancerous lesions, such that outcomes will likely be minimally affected (31,32).

However, delay in diagnosis of rapidly growing malignancies such as breast and lung cancer can result in adverse outcomes (33). An expert panel also developed consensus statement to guide clinicians on the management of lung cancer screening programs and previously detected lung nodules encompassing various scenarios (eg baseline and annual lung cancer screening, management of previously detected nodules stratified by risk, and management of clinical stage 1 non-small cell cancer [6] ). The consensus was to defer imaging and management in several situations, recognizing that individualized decisions may be necessary depending on patient preferences and other local factors.

In the United States, shut downs related to COVID-19 will result in a substantial backlog of screening evaluation, with a projected delay of more than 22 million screening tests for cancer and a 20% reduction in oncology visits (10) . Additionally, even as clinics reopen, patients may still choose to postpone appointments in fear of COVID-19. Avoidance of health care procedures due to COVID-19 is highlighted in one study in Italy that compared the rate of procedure and surgical refusal in women with breast cancer or suspected breast lesions before and after March Additionally, this study showed substantial reductions in breast (−89.2%) and colorectal cancer (−84.5%) screenings. (35). Early estimates from the National Cancer Institute suggest that there could be an excess of 10,000 deaths from breast and colorectal cancers due to altered appointment scheduling from the pandemic within the next 10 years (36) . Considering the lower overall mortality rate of COVID-19 compared to some cancers, such as breast, lung or prostate cancer, healthcare teams must formulate thoughtful mechanisms to circumvent prolonged delay in cancer diagnosis and treatment.

In addition to the delay in screening and clinic appointments, there is also a large impact on delayed treatment. Treatment options vary widely depending on cancer type, but can include surgical resection, chemotherapy, immunotherapy, radiation therapy, locoregional interventional therapies, or a combination of any of those therapies. With the delay in all 'elective non-essential surgeries', it is critical to identify which cancer-related surgeries are essential and which are not. Some modifications, such as the addition of radiation therapy to I n p r e s s 10 of tumor progression, although additional considerations include the potential added burden on hospital resources, case complexity, and risk of COVID-19 exposure (38, 39) . Nonetheless, neoadjuvant therapy, which requires multiple clinic visits and direct clinician-patient contact, or that is immunosuppressive, also adds potential risks for the patient that must be considered.

One confounding factor for cancer therapy is the use of immunotherapy for cancer treatment. Studies have shown that patients who receive corticosteroids while on immunotherapy have a lower overall response rate (7% versus 18%) and worse progression-free and overall survival than those not receiving steroids. Furthermore, in patients who stopped taking steroids 1-30 days before immunotherapy administration, there was intermediate reduction in progression free and overall survival compared to those on steroids (40) . This concept is important, as many emerging studies show that corticosteroids may improve outcomes for patients with severe manifestations of COVID-19 (41). Insufficient data exist to evaluate the effect of short term corticosteroid use in patients with cancer who are infected with SARS-CoV-2. Additional considerations are that immunotherapy can cause treatment-related pneumonitis, which can mimic the imaging appearance of COVID-19 infection (42) ( Figure 1 ). Frequent in-person visits are also necessary for medication administration. Thus, a tailored approach to treatment is necessary for these patients, after weighing the possible risks and benefits.

Most facilities in the United States and worldwide only continued interventional clinical trials for cancer that could provide direct benefit to participants, such as testing a new therapy 

Special attention will need to be given to those patients that are being screened for lung cancer or monitored for treatment responses. An expert consensus statement on reporting of chest CT findings related to COVID-19 has categorized the findings into negative, atypical, indeterminate, and typical appearance for COVID infection (6) . Typical features of COVID-19 on chest CT include peripheral bilateral ground-glass opacities (GGO) with or without consolidation or septal thickening (crazy paving), multifocal GGO with rounded morphology (with or without consolidation or crazy paving), and reverse halo sign (6, 48, 49) . CT has high sensitivity (> 95%) but low specificity (∼50%) for SARS-CoV-2 infection (49) (50) (51) . Asymptomatic individuals may still exhibit radiologic abnormalities in the lung (52, 53) , indicating that attention will be required in cases where patients may not have known they contracted COVID-19. However, it is also including abnormally high signal intensity lesions on FLAIR and diffusion weighted imaging in the mesial temporal lobes, brainstem, and thalami (71, 72) . Although the majority of those changes are not commonly confused with primary brain tumors or brain metastatic disease, there can be some similarities to MRI findings in patients presenting with immunotherapy-associated autoimmune and/or limbic encephalitis, with involvement of mesial temporal lobes and/or basal ganglia (76, 77) . Assessing the exact etiology of brain imaging findings in patients on immunotherapy and COVID-19 is thus warranted. I n p r e s s 16 The vascular system has been implicated as one of the primary targets of SARS-CoV-2 and causes of morbidity and mortality in patients with COVID-19 (78) . Recent reports now suggest that pulmonary embolism may be a large contributing factor to mortality from COVID-19 (79) .

Endothelial cells lining blood vessels express angiotensin-converting enzyme 2, the receptor for SARS-CoV-2, making these cells a target for infection (80) (81) (82) . Heart damage and arrhythmia, likely from viral infection, commonly occur in patients with COVID-19 (83) . COVID-19 greatly increases risk of blood clots, with pulmonary emboli detected by CT pulmonary angiography in 20-30% of patients (84) (85) (86) . In one case study, a 59-year-old man with metastatic lung cancer was suspected of having cardiac arrest secondary to pulmonary embolism with symptoms of 

While elevations of liver enzymes occur commonly in patients with COVID-19, reported at 40-43% in some studies (97) , available data suggest that clinically significant liver injury is rare I n p r e s s 19 aminotransferase levels, but rarely elevated total bilirubin (99) . However, liver injury likely occurs more frequent secondary to sepsis and systemic inflammatory response syndrome; drug toxicity from antipyretics, analgesics, antivirals, and other drugs (100-102); COVID-19-related hypercoagulation; or damage of bile duct cells (103) .

Microembolic changes from hypercoagulability may lead to abnormal geographic arterial hyperperfusion on arterial phase imaging, which normalize by the portal venous phase of imaging. However, despite the prevalence of liver function abnormalities detected in COVID-19 patients, clinically significant abnormal liver imaging findings are not typically seen in these patients. and multidisciplinary discussion can help prevent progression of cancer secondary to delayed treatment from the pandemic. As one example, Figure 5 depicts a patient for whom delay in care resulted in a clinically significant increase in the size of his tumors.

Groups of cancer centers and medical organizations have issued guidelines for managing cancer therapy and imaging during the pandemic (6). van de Haar et al gathered information I n p r e s s 20 from seven cancer centers about prioritization of cancer appointments and potential modifications to treatment regimens (9) . One recommendation was to consider de-escalating cytotoxic chemotherapy and other immunotherapies to minimize immunosuppression that might increase COVID-19 severity. Additionally, guidelines were proposed to determine the urgency of different appointments for prioritization. Clinics will need to be prepared for potentially rapidly increasing or decreasing capacity for the duration of this pandemic (9). (7), as well as gastrointestinal cancers (39) . Management of these patients is likely best made in a virtual multidisciplinary setting to ensure patients are receiving optimal care without affecting overall survival during this pandemic.

Care is also being taken with regards to minimizing the potential of SARS-CoV-2 exposure during appointments. The use of telehealth (ie, virtual visits) has expanded substantially over the course of the pandemic. However, different geographical regions may have limited access to resources that would facilitate these types of visits (106 This was pathologically proven to be lung adenocarcinoma. show diffuse ascending colon wall thickening, with submucosal edema and a featureless appearance (arrows) with stranding and nodularity in the peri-colonic fat (*). B, Contrastenhanced CT shows diffuse peritoneal and mesenteric nodularity (*) with ascites (blue arrows).

C, Coronal contrast-enhanced CT shows bilateral common deep vein thrombosis of the femur (arrows). These imaging findings demonstrate multiple intra-abdominal findings that can be seen with SARS-CoV-2 infection. These findings in particular, mimic that of metastatic cancer. The abnormality in the ascending colon also has the appearance of a colon cancer, with infiltration into the adjacent peri-colonic fat, peritoneal carcinomatosis and malignant ascites with deep vein thrombosis secondary to a hypercoagulable state which can be seen in cancer patients. and recommendation for microwave ablation of only the larger lesion was made. However, due to further delay in care secondary to the pandemic, the patient was scheduled 2 months later for microwave ablation. (E, F) Contrast-enhanced US performed prior to microwave ablation reveals clinically significant interval increase in size of both lesions. The largest lesion was greater than the 3.5 cm threshold for curative microwave ablation. However, imaging was performed after the patient was already under general anesthesia. After discussion with the ordering clinician, the decision was made to biopsy and treat both lesions. Post-ablation contrast-enhanced US shows adequate ablation zones with margins greater than 1 cm larger than the tumor size.

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