Neuro-Oncologic Care During the COVID-19 Pandemic

Introduction

Neuro-oncology is a multidisciplinary specialty dedicated to caring for those faced with neoplasms in the nervous system. Neuro-oncologists are often fellowship-trained neurologists or medical oncologists. The bulk of care is directed at primary brain tumors of which the majority have no cure and limited effective treatments, metastatic cancer to the brain and spine, central nervous system (CNS) lymphoma, and complications of cancer or cancer treatment such as paraneoplastic syndromes and drug toxicities. Neuro-oncologists manage patients with primary CNS tumors from suspicion of diagnosis through end-of-life to survivorship. Neuro-oncologic care requires a coordinated effort by neurosurgeons, oncologists, radiation oncologists, neurologists, nurses, supportive services, and others. As COVID-19 takes the health-care system hostage, those faced with cancer are left with deviations in care and a greater need for supportive services while providers strive to maintain clinical operations in a time of previously unforeseen hazards and limited resources. Health-care providers, patients, and caregivers are scrambling to redesign health services during the pandemic resulting in new paradigms and opportunities to improve such as dependence on video visits from home upending traditional access to care barriers (yet introducing new barriers), decentralized access to specialized resources through isolated non-COVID-19 health centers, and reliance on subspecialty clinics to reduce emergency room and intensive care unit (ICU) utilization.

The risks of COVID-19 in vulnerable neuro-oncologic populations necessitate a balancing act of resource restrictions, mitigation of COVID-19 risks to patients and providers through the lens that every health-care contact is an infection risk, observation of altered therapy-related comorbidities, and potential undertreatment of incurable and devastating diseases. If at all possible, standard of care (SOC) guidelines should be followed; however, this may not be feasible during a pandemic. Neuro-oncologists have an additional responsibility to advocate within the health system for prioritization of resources including ICU beds and operating room access for this population with the largely incurable disease but also tremendous variability in outcomes that may result in many years of high-quality life with appropriate interventions.

Oncologic care reorganization is a dynamic and evolving process dictated by local circumstances. Treatment plans may be altered to reduce exposure to COVID-19 environments, de-escalate dependence on hospital resources, and prevent anticipated complications of anticancer therapy in the setting of potential COVID-19 infection. In health systems that have multiple hospitals or regional federations of hospitals isolating non-COVID-19 cancer services to dedicated centers may reduce exposure. Our core neuro-oncologic services are anchored at the quaternary hospital with radiologic imaging, multidisciplinary subspecialty clinics, supportive services, and clinical trial staff in one location to facilitate an efficient patient experience. As hospital resources shifted toward COVID-19 management we decentralized operations. Clinical trial and routine oncologic care were provided at a smaller non-COVID-19 satellite center, video visits for nonessential care were used, we redesigned clinical trial protocols to maximize safety, and we obtained MRI imaging at a satellite center distant from COVID-19 caring facilities which reduced patient exposure. Neuro-oncology teams are typically small and may have only one or two providers within each subspecialty in a hospital or geographic region, thus efforts to limit exposure among the care team are also necessary to ensure the preservation of the program.

Brain tumors and CNS metastatic cancer have always been emotionally isolating conditions due to disease sequelae and social stigma but in the COVID-19 world where patients are undergoing brain surgery, chemotherapy, and treatment in isolation from family and friends—feelings of isolation and despair have increased. Behavioral health and supportive oncological resources for patients and caregivers need to be escalated and distance-based solutions such as virtual platforms of communication must be utilized. Caregivers for those faced with a neuro-oncologic condition are caring for someone with possible cancer, neurologic deficits that limit mobility or communication, executive function impairments, socioeconomic stressors, and mental health concerns. Increasing burden is placed on caregivers during COVID-19 due to social distancing practices, escalated emotional stressors, and fear of virus exposure that limits engagement with home care providers, therapists, and social support services. Clinicians should screen for caregiver health and provide resources to address emotional support and other caregiver needs.

Anticipated risks between COVID-19 and disease-modifying agents such as immunotherapies and chemotherapies need to be factored into treatment recommendations. There is a void of high-level evidence for direction; however, international consensus recommendations are available in neuro-oncology to provide guidance. Adjustment toward less toxic therapies and reduced hospital exposures are common recommendations. Alkylating chemotherapy with temozolomide (TMZ) or lomustine is SOC treatments for many primary brain tumors that often cause lymphopenia. In the general population, lymphopenia has been used to predict the severity of COVID-19 outcomes. The relationship between chemotherapy-induced lymphopenia, brain tumors, and COVID-19 infection outcomes has yet to be elucidated. Immunotherapy agents that manipulate the immune system as a disease treatment are commonly used in solid tumors that are metastatic to the brain (melanoma, non-small cell lung cancer, renal carcinoma, others) and represent an active area for primary brain tumor clinical trials. Severe cases of COVID-19 are marked by a hyperinflammatory immune response and complications of immune-related adverse events, therefore agents such as checkpoint inhibitors that carry a rare risk of immune-related adverse events such as pneumonitis, or agents disrupting cytotoxic lymphocytes and natural killer cells which facilitate the body’s control of a viral infection may pose uncertain additional risks during the COVID-19 pandemic.

Advocating for Patients in Resource-Limited Settings

Prospective multidisciplinary cancer conferences (MCC) or tumor boards are a standard in neuro-oncology and should continue during the COVID-19 pandemic. Virtual technologies such as video conferencing provide an opportunity to reduce patient and provider exposure to COVID-19 which can also result in reduced barriers to MCC participation and perhaps a wider breadth of expertise at the meeting. MCCs should also be used to stratify therapy and exposure risk for patients with COVID-19. If there is a need to ration scarce resources in your institution (mechanical ventilation, operating room access) then this forum may be an effective way to document neuro-oncologic specific factors informative to your institution’s ethical framework for rationing.

Comprehensive neuro-oncology MCCs often include social work support and supportive oncology representation that provide important insight into barriers to care and health outcome disparities that need to be considered, particularly during COVID-19, a disease that disproportionately impacts specific communities. For example, does your recommendation for 6 weeks of radiation therapy change if the patient is taking a city bus to their appointments, or lives in assisted living that requires 14-day quarantine after each health system encounter? What is the health-related quality of life impact of these decisions? Guidance by a patient and patient-advocate advisory board when rendering treatment recommendations in this new health landscape is needed.

Primary Brain Tumors

The most common malignant primary brain tumor is glioblastoma (GBM) which is an incurable tumor with an average survival of less than 2 years despite the best available treatment. Glioblastoma is a World Health Organization (WHO) Grade IV glioma. It is conceivable that social distancing restrictions may be in place for the remainder of a person’s life who is diagnosed with a GBM. The majority of gliomas have no cure and are treated with maximal safe resection followed by external beam radiation therapy (EBRT) typically delivered in 30 fractions over 6 weeks with additional chemotherapy. GBM SOC treatment includes oral TMZ alkylating chemotherapy concurrently with EBRT followed by adjuvant TMZ and a wearable tumor treatment field device that utilizes alternating low-frequency electric fields to disrupt mitosis. Low-grade gliomas (LGGs), such as WHO grade II oligodendroglioma and astrocytoma, may also receive a fractionated course of EBRT followed by combination chemotherapy with Procarbazine, Lomustine, and Vincristine that has demonstrated median overall survival exceeding a decade in clinical trials. Given the favorable long-term survival in the LGG population consensus recommendations during COVID-19 encourage MCC review to consider delayed therapy and/or surgery in some patients.

The average age of GBM diagnosis is 64 years and many GBM patients have additional comorbidities—thus this group faces significant morbidity from their primary disease as well as from COVID-19. Early reports revealed that people with advanced age and a cancer diagnosis have poorer outcomes when infected with COVID-19. Optimal GBM treatment for elderly or frail patients is an ongoing debate. There is a rationale to support hypofractionated radiation therapy, such as a 15 fraction 40 Gy course of EBRT with or without TMZ that may result in reduced virus exposure for this vulnerable population. For advanced age patients, the benefits of TMZ chemotherapy are dependent on O6 methylguanine-DNA methyltransferase ( MGMT ) DNA repair methylation status, which influences whether or not to include TMZ in the treatment. Epigenetic silencing of this DNA repair pathway results in improved response to alkylating chemotherapies such as TMZ. However, there is minimal to no benefit of TMZ in MGMT unmethylated elderly patients, which is even less appealing when considered in the context of additional COVID-19 risks. In elderly patients with poor performance status who do not have MGMT methylation, omitting TMZ should be considered. For elderly patients with poor performance status harboring favorable MGMT promoter methylation, one may consider using TMZ alone without EBRT, depending on additional factors such as COVID-19 risk and comorbidities. This therapeutic complexity is compounded by COVID-19, however simulation models are being presented to provide some insight into the relationship between COVID-19 exposure risks, comorbidities, EBRT fractionation regimens, and the historical landscape of elderly GBM trial data to guide decision making and quantify relative risk.