COVID-19, Cancer, and Consequences: Where Are We Now?

The coronavirus pandemic

The world is in the midst of a global pandemic that represents a monumental and terrifying threat unseen in the modern era and far exceeding in scope and scale other dangerous epidemics seen in recent years. Originally detected in Wuhan China, the highly contagious nature of the virus and our increasingly global connectedness led many to fear a coming global pandemic. The severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2) and the associated clinical disorder coronavirus disease 2019 (COVID-19) were first identified in the United States in a traveler from China in Washington State in late February 2020 with the first COVID-19 death in the United States reported a few weeks later. When investigators at the University of Washington were allowed to test for the virus, it was apparent that there was already community spread, notably among the most vulnerable. The virus has now been documented on every continent except Antarctica and in well over 100 countries. The World Health Organization (WHO), multiple countries including the United States and several states within the United States have declared the outbreak a Public Health Emergency.

Now in Mid-September 2020, there are 28 million confirmed cases of COVID-19 globally and nearly 1 million deaths with these numbers expected to continue their climb in the coming weeks and months. Data from the countries most severely affected suggest that COVID-19 impacts most dramatically the elderly and other “vulnerable” populations with serious comorbid medical conditions. While continuing to rise steeping in some regions, the growth curve has begun to level off in others depending on several factors including efforts to curtail contact (social distancing) or wearing of masks in public areas to reduce spread to others. However, since the vast majority of the population lack immunity and remain at risk, continued spread with periods of rapid resurgence following lessening of public health restrictions have been commonly seen. Devastating additional waves of spread are being observed that may greatly worsen with anticipated lethal consequences during the upcoming seasonal flu in the fall and winter. While the majority of individuals with documented infection have had mild to moderate symptoms not requiring hospitalization, many more vulnerable individuals based on age, other demographic risk factors as well as major medical comorbidities, have developed more serious and life-threatening complications requiring hospitalization, intensive care unit (ICU) care, or even mechanical ventilation. Overall, while the ability to spread the virus appears to be present in all infected individuals, including those without symptoms, the likelihood of severe or fatal outcomes is more heavily concentrated in vulnerable individuals including the elderly, certain sociodemographic groups and those with serious underlying medical conditions including patients with cancer.

The coronavirus and cancer

One of the first reports of COVID-19 among 18 patients with cancer in China reported that they experienced a greater risk of severe COVID-19 with major complications such as acute respiratory distress syndrome (ARDS) compared to patients without cancer (1). Although a number of case reports and small series of patients with cancer and COVID-19 have subsequently been reported. Published literature on the impact of coronavirus spectrum infections in patients with cancer has remained limited until recently.

It has become apparent that patients with cancer are exceptionally vulnerable to COVID-19 and to more severe forms of the disease likely due to older age, underlying comorbidities, immunosuppressant therapies and the cancer itself (2,3). In an article by Knisely et al. in this issue of Cancer Investigation, the authors present a systematic review of studies reporting the clinical presentation of patients with cancer infected by one of the coronaviruses (4). A rigorous literature search was conducted through April 20, 2020, identifying 19 studies with a total of 110 patients of which two-thirds were patients with COVID-19. Titles and abstracts were independently reviewed and full text screening was undertaken of eligible publications. Standard data abstraction methods were utilized and verified, and formal quality assessment was undertaken and independently scored. The investigators observed that cancer patients infected with the severe acute respiratory syndrome (SARS or SARS-CoV-1), Middle-Eastern Respiratory Syndrome (MERS) virus and SARS-CoV-2 were found to be at greater risk for serious complications and mortality. Among the 12 studies including 73 patients with cancer with COVID-19, the most common malignancies were cancers of the lung (40%), breast (11%) and colorectum (11%). Patients were commonly recently postoperative (30%) or receiving current or recent systemic cancer therapy (27%) while 16% were in remission. The majority of patients (86%) had a laboratory diagnosis of SARS-CoV-2 as well as abnormal chest imaging. Severe COVID-19 was observed in 44% of patients with 28% requiring mechanical ventilation, 28% admitted to the ICU and 12% with ARDS. Overall, COVID-19 was associated with a 27% fatality rate among patients with cancer with 73% either discharged or still hospitalized.

Importantly, overall data quality of the reviewed studies was poor and patient numbers low prompting the authors to conclude that clear recommendations must await results from ongoing large cohort studies and eventual controlled clinical trials. While admitting that their data are early and limited, the authors raise concern that patients with cancer may be more susceptible to severe disease and more likely to experience serious complications than the general population. The authors acknowledged two larger studies examining impact of COVID-19 among patients with cancer published following the cutoff date for their systematic review. These included a study of 69 patients with lung cancer and COVID-19 receiving checkpoint inhibitors reporting a 23% ICU admission rate and 24% fatality rate and a study of 218 COVID-19 positive patients with cancer with a fatality rate of 28% (5,6). Nevertheless, with such limited numbers and poor data quality early in the COVID-19 pandemic, major professional organizations have struggled to provide firm guidance on the management of patients with cancer with or without confirmed SARS-CoV-2 infection in midst of the pandemic (7–10). The authors note that the true case fatality rate in patients with cancer and COVID-19 remains uncertain due to likely publication bias, the inability to perform appropriate risk adjustment and the need to better estimate the true denominator as most studies only included patients with severe symptoms requiring hospitalization. The authors conclude by acknowledging that results from even larger cohort studies will be needed to stratify risk by phase of treatment and other factors to adequately inform practicing oncologists and their patients in the midst of the continuing COVID-19 pandemic.

Where are we now?

As the SARS-CoV-2 crisis emerged and the pandemic rapidly expanded both globally and exponential, many disease-specific registries and both retrospective and prospective cohort studies emerged to rapidly gather information on COVID-19 and its impact on vulnerable populations including cancer. While not intended to substitute for controlled clinical trials, such registries are perfectly adapted to rapid learning in nearly real time to provide urgently needed knowledge in a crisis situation (11). One of the earliest and largest of these registries with cancer and confirmed COVID-19 emerged out of social media crowdsourcing efforts among oncologists eager to rapidly learn more about the risk of COVID-19 among patients with cancer and its impact on clinical outcomes (12). The COVID-19 and Cancer Consortium (CCC19) collects de-identified data on patients, aged 18 years and older, with active or previous history of malignancy and with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using an online data entry tool to collect retrospective and prospective clinical data rapidly and at scale. The consortium now comprises more than 120 institutions in the United States, Canada, South America and Europe.

The initial results from the Consortium on approximately 1000 eligible patients with cancer and COVID-19 were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) 2020 with a simultaneous publication in The Lancet (13). The most common malignancies were breast (21%) and prostate (16%) cancer, 43% had measurable cancer, while 39% were on active cancer treatment. One or more COVID-like symptoms were reported in 96% of patients. The primary study outcome of 30-day all-cause mortality which was significantly associated with increased age, male sex, smoking status, number of comorbidities, ECOG performance status and active cancer after partial adjustment in multivariable logistic regression analysis. Secondary outcomes included: hospitalization (50%), supplemental oxygen (44%), ICU admission (14%), and mechanical ventilation (12%) and composite severe illness (26%).

In a more recent updated analysis of the CCC19 Registry with more than 2000 patients with cancer and laboratory-confirmed SARS-CoV-2 infection, 30-day all-cause mortality was 16%, hospitalizations 60% and a composite of severe COVID-19 outcomes of 29% with a median followup of 30 days (14). Mortality varied by cancer type from a low for cancers of the thyroid (2%) and breast (8%) to a high for lymphoma (22%) and lung cancer (26%). Additional factors now independently associated with increased 30-day mortality were black race, and hematologic malignancies. While persistent unmeasured confounding was considered likely making assessment of specific COVID-19 therapies very challenging, the results were considered consistent with the majority of reported observational studies as well as emerging prospective controlled clinical trials. The anti-viral drug remdesivir was mostly reported in the context of a randomized clinical trial in a relatively small number of patients but was available to only half as many black patients as white patients with cancer and COVID-19. Overall, among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with both general risk factors and those unique to patients with cancer.

Several additional registry studies of patients with cancer and COVID-19 have been reported across a wide range of cancer types as well as geographic and healthcare settings. These include the UK Coronavirus Cancer Monitoring Project (UKCCMP) published in the same issue of The Lancet (15), the Teravolt study of patients with lung cancer (16), and a recent multicenter retrospective cohort from the Italian Hematology Alliance of patients with hematological malignancies (17). Despite the numerous and critically important limitations of observational studies, the need to rapidly establish methods for urgently gathering as much reliable information as possible in times of a public health crisis are clear. Although, randomized controlled trials will be needed to definitively establish safe and effective therapies for COVID-19, registries have provided therapeutic leads and identified numerous risk factors for serious and potentially life-threatening complications in patients with cancer and COVID-19 being considered for COVID-19 therapies. Such information is essential to informed clinical decision making and should be shared and discussed by clinicians with their patients to inform the best options for each patient over time. Such information may also be of great value in discussions whether to accelerate end-of-life planning in the most vulnerable or seriously ill.

Despite the growing number of expanding registries and a number of prospective clinical trials evaluating a range of therapies of potential value for COVID-19, important clinical questions related to the optimal management of cancer patients at risk for or infected with SARS-CoV-2 remain. As the pandemic continues with no definite end in sight, the impact on delays in diagnosis, evaluation and treatment of patients with cancer grows along with concerns about increasing risk of advanced cancer at diagnosis and greater risk for disease recurrence in those whose treatment was severely interrupted (18). Professional organizations are increasing offering recommendations for approaches for safely continuing optimal cancer treatment in the midst of the pandemic. The National Comprehensive Cancer Network (NCCN) has offered interim guidelines for cancer supportive care during the pandemic with recommendations for broader use of available supportive care approaches (19). More aggressive use of cancer supportive care in the times of crises or when patients are at uniquely high risk for infection or treatment-related complications is critically important to enabling patients with active malignancy to receive and remain on optimally effective and potentially curative cancer therapy (20,21).

Nicole M. Kuderer
Guest Editor
Gary H. Lyman
Editor-in-Chief
[email protected]

Disclosure statement

NMK reports personal fees from Celldex, Invitae, BeyondSpring, BMS, Janssen and Total Health outside of the submitted work.

GHL reports personal fees from G1 Therapeutics, Partners Healthcare, Mylan, Invitae, Samsung Bioepis, BeyondSpring and research funding to Institution from Amgen outside of the submitted work.