The ongoing coronavirus disease 2019 (COVID-19) pandemic is associated with increased morbidity and mortality worldwide. To manage the pandemic, significant restrictions have been imposed on daily life, prompting discussion of related mental health issues.1

Numerous studies have reported that most patients who died as a result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had underlying medical conditions. Hence, complications are more likely to occur in people with comorbidities than in those without the disease. The U.S. Centers for Disease Control and Prevention states that “People of all ages with certain underlying medical conditions are at an increased risk of developing severe illness from COVID-19.”2 Decreased immune function in patients with malignant tumors and suppression of the systemic immune system by antitumor treatments such as radiation, chemotherapy, or surgery make patients with tumor more susceptible to being infected by SARS-CoV-2 than are patients without tumor.3 Cancer accounts for 5.6% of deaths in patients with COVID-19.4 Vaccines are a promising solution for minimizing the problems of patients with cancer threatened by new virus strains.5 A 6% decrease in the detection rate of all types of tumors has been reported during the COVID pandemic compared with the pre-COVID era and also a 16% reduction in brain cancer diagnosis was reported.6 In addition, expression of SARS-CoV-2 receptors (ACE2 [angiotensin-converting enzyme 2], CTSL [cathepsin L], and TMPRSS2 [type II transmembrane serine protease]) is significantly increased in many tumor types, which increases viral entry into cells and the likelihood of SARS-CoV-2 infection in patients with cancer. Therefore, patients with cancer have proved to be a particularly vulnerable group.7,8

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, accounting for 16% of all primary brain and central nervous system tumors.9 GBM is found almost exclusively in the brain but can also occur in the brainstem, cerebellum, and spinal cord.10 GBM is one of the deadliest types of cancer in adults and has a poor prognosis.11 No specific risk factors have been identified. GBM is diagnosed by imaging studies such as computed tomography (CT) and magnetic resonance imaging (MRI) and treated by maximal surgical excision followed by chemoradiation. High suspicious indicators may lead to early diagnosis.12 Incidence is higher in males than in females and in whites than in other ethnic groups.13 A cohort study in France showed that the rate of patients with diffuse glioma as a result of COVID-19 infection was 39% and is higher than in the general population (29%).14 However, the concurrent morbidities were 59% in gliomas versus 22% in the general population.

In this review, we discuss the relationship between coronavirus and GBM in terms of mortality, tumorigenesis, alterations in chemotherapy and radiotherapy approaches, diagnostic changes in GBM during the COVID-19 pandemic, hospitalization, infection of GBM cells with COVID-19, necessary training, and the effectiveness of vaccines.

Cancer is responsible for 5.6% of deaths in patients with COVID-19.4 Among patients with cancer infected with SARS-COV-2, lung cancer is the most frequent, followed by gastrointestinal cancer and breast cancer.15 This higher risk could be attributed to chronic immunosuppression, underlying medical conditions, and chemotherapy. Therefore, both infection and subsequent complications are expected to be higher among patients with cancer.3 Patients with cancer are at higher risk of death, intensive care unit admission, developing severe symptoms, and the probability of requiring invasive mechanical ventilation.15 Yu et al.16 reported that the incidence of COVID-19 infection is higher among patients with cancer, and patients with non-small-cell lung cancer are at the top of the list. An early Italian study showed that 20.3% of patients who died as a result of COVID-19 infection had active cancer.17 We did not find any articles in the literature that reported specifically on GBM.

The development of a malignancy is rarely caused by an isolated incident and results from the accumulation of mutagenic events over a long period. COVID-19 infection alters the immune responses, and proinflammatory cytokines such as interleukin 1 (IL-1), IL-6, IL-8, and tumor necrosis factor α are the main players of the immune response during the infection.18 These cytokines are also considered tumorigenesis. Another mechanism by which COVID-19 may increase the risk of cancer development is T-cell depletion and activation of oncogenic pathways such as JAK-STAT (Janus kinase signal transducer and activator of transcription), MAPK (mitogen-activated protein kinase), and Nk-κB (nuclear factor κ-light-chain-enhancer of activated B cells).18,19 In addition, hypoxia, which is caused by inflammation or virus-induced ACE2 depletion, leads to oxidative stress and subsequent malignant alterations.18 COVID-19 infection via immunosuppression, oxidative stress, downregulation of tumor suppressor protein, and hyperinflammatory responses may play a role in promoting cancer development in patients.

The diagnosis of cancer was reported to decrease in 2020 by the first wave of COVID-19 infection in several countries.20 The overall reduction in the diagnosis of new patients with cancer during the pandemic was about 6%. The decrease was higher in prostate cancer (26%), colon cancer (24%), and breast cancer (19%).6 In Belgium, a 44% decrease in cancer diagnosis in 2020 compared with 2019 was observed and the reduction was higher in older patients and patients with skin cancer.21 In a study in Spain, from March to September 2020, a 34% reduction in cancer diagnosis was seen.22 In the setting of brain cancer, a 16% reduction in the diagnosis of new cases was observed.6 We did not find any articles in the literature that reported specifically on GBM.

Corticosteroid application and immunosuppression as a result of anticancer treatment predispose patients with cancer to more severe infectious diseases and a poorer prognosis. The mortality of patients with cancer caused by COVID-19 infection was reported to be 28%–29%.23,24 Chavez-MacGregor et al.25 reported that the mortality in those without recent cancer treatment was 5% and in those who have recently received cancer treatment, it was 7.8%, compared with 1.6% for those without cancer. Mehta et al.26 reported a 28% mortality rate as a result of COVID-19 in patients with cancer. These investigators also reported that the mortality was 25% in patients with solid tumors and 37% in patients with hematologic malignancy, 55% in patients with lung cancer, 38% in patients with colorectal cancer, and 14% in patients with breast cancer. Lozano-Sanchez et al.14 reported that the mortality of patients with diffuse glioma as a result of COVID-19 infection was 39%, which was higher than in the general population (29%).

As with other medical conditions, the management of GBM underwent special alterations in visiting regimes, diagnosing, and subsequent perioperative courses. The importance of this experience and the protocols during a pandemic is that besides the COVID pandemic, the human race is at ongoing risk of encountering new pandemics. At the time of admission, safety matters must constantly be noticed, such as any influenza symptoms, reverse transcription polymerase chain reaction for the COVID-19 test, and a thorough epidemiologic description of the patient regarding COVID-19. Medical staff should be instructed to wear extra personal protective equipment such as face shields and N95 masks and to practice physical distancing and thorough hand hygiene.27 These steps all should be performed in a gray area specified for outpatients in case their COVID condition is not yet determined. Areas that require this strategy are deciding whether a patient necessitates immediate action or the treatment can be postponed and how we can suggest excellent care and minimize infection risk. The initial step is the selection of patients.28 The importance of imaging studies is well known regarding neuro-oncology patients in both therapeutic and diagnostic approaches, so it remains essential that the radiology centers remain available for outpatient tasks even during the pandemic.29 There should be a protocol in radio-oncology and radiology centers that lessens the number of patients in waiting zones and the time spent at the facility.29 Also, medical centers should be able to provide patients with masks and other personal protective devices.29 Although brain CT is performed for planning the radiation therapy (RT) protocol, a chest CT analysis should be obtained to efficiently isolate patients with COVID-19, even in asymptomatic cases. Those with equivocal results were instantly quarantined, and a nasopharyngeal swab test was obtained. The radiology chamber should be disinfected after every patient.28 A nasopharyngeal swab test with a concurrent chest CT scan should be performed for every surgical candidate to obtain a preeminent identification of COVID virus infection. MRI is more appropriately used in critical cases, especially in the follow-up period. Its application in patients with a satisfying molecular profile and stable conditions can be argued separately. Besides, diagnoses and doctors' visits that can be performed via telemedicine should be considered to reduce the burden of patient transport on society; also, these patients are a sensitive group, and this strategy can be effective for them and allow hospital resourses to be used only when necessary.27

Because of neurologic manifestations of COVID-19 infection and alterations in brain MRI of patients with a mild infection, the interaction of the virus and central nervous system cells has been explored. By damaging the choroid plexus epithelium, disruption occurs in the blood-brain barrier. Cortical astrocytes, neural progenitor cells, glial cells of the cortex, and brain organoids are cells that can be infected by SARS-CoV-2.30 Previous studies have shown that coronavirus receptors, including ACE2, TMPRSS2 (type II transmembrane serine protease), and DPP4 (dipeptidyl-peptidase 4), play an important role in virus entry.31 ACE2 is the main surface receptor for SARS-COV-2.32 The expression of ACE2 may play a role in the ability of the virus to infect cells. Smirnova et al.30 reported that expression of the ACE2 receptor is correlated with the permissiveness of the cells but it is not the sole factor. These investigators also reported that interferons (IFNs) may play an important anit-SARS-CoV-2 role. The highly permissive GBM GBM6138 cell line is incapable of type I IFN production, whereas GBMb4114 significantly produces IFN-β. These investigators also showed that nonpermissive cells were capable of IFN-β production.

In addition, the expression of ANPEP (alanyl aminopeptidase) and ENPEP (glutamyl aminopeptidase) by GBM acts as a binding receptor for SARS-COV-2 and increases the risk of COVID-19 infection.31 The upregulation of ANPEP and ENPEP is associated with poor survival of GBM and both are present in endothelial cells of the blood-brain barrier, which facilitates the entry of SARS-CoV-2 cells entry into the brain.31 Bielarz et al.33 reported that GBM cells are susceptible to SARS-COV-2 infection, and the virus can invade the cells without excreting a major cytopathic effect on either neuronlike morphology or functional glutamate uptake and without apoptosis.33 They also showed that the virus can infect GBM U87-MG and U37-MG cells33 Vanhulle et al.32 showed that GBM cells expressed high levels of ACE2 and cathepsin B, along with lower TMPRSS2 and cathepsin L levels, which make the GBM cells fuse to the virus. These investigators showed that GBM cells can replicate the SARS-COV-2 virus actively.

Introducing COVID-19 vaccines played a pivotal role in the management of the pandemic globally. In early 2020, scientists hypothesized that vaccines could cause increased immunity and prevent infection; therefore, the race for the production of a specified vaccine for COVID-19 was started.34 On December 2020, the United Kingdom approved the first vaccine, and since then, many different types of vaccines have been introduced.35 A worldwide survey conducted in late 202136 showed that 84.5% of patients with diagnosed brain cancer (mostly GBM) and 89.9% of their caregivers received COVID-19 vaccines. According to statistics,36 the vaccination rate among patients with a brain tumor was higher than in the general population in the United States and United Kingdom. No major side effects developed in patients with a brain tumor, but both localized and systematic minor side effects were observed. The rate of development of minor side effects was lower in these patients compared with the general population.36 The most common minor side effects were pain in the arm, fatigue, headache, and muscular pain. Nonlive vaccines, such as COVID-19, are assumed to be safe in patients undergoing chemotherapy, but the optimal immune response may not be achieved.37 This decreased antibody response to the vaccine indicates that additional vaccination is required in patients with cancer.38,39

The optimum treatment regimen in patients with GBM before the pandemic was maximal safe resection and, then, the treatment was completed with parallel chemoradiotherapy and monthly adjuvant temozolomide (TMZ).27,40 Regarding GBMs, the objectives of neurosurgical interventions are to achieve cytoreduction, lessen the mass effect, and attain tissue for histologic and molecular identification.41 The neurosurgical application should still be considered a priority because of its immense impact on the patient's survival directly perpetuated by the maximum extent of resection. The extent of resection is demonstrable within 48 hours after surgery with neuroimaging techniques. The goal of the surgery must be to resect the tumor entirely or to perform at least an 80% resection, because the proportion of the resected tumor is correlated with a higher survival.42,43

Awake craniotomy is a pivotal technique in the setting of maximal safe resection. Although transmission of COVID-19 has not been reported during an awake craniotomy, theoretically, the risk is higher. Nevertheless, the patient is awake and talking, so it is contemplated to use nonawake approaches. Consequently, the predictive features of the patient should be judiciously assessed to choose the optimal therapeutic strategy.42

In younger patients in relatively good condition, postponing the excision of the tumor leads to an increased risk of weakening the neurologic grade, survival, and quality of life. Besides, surgery provides doctors with neoplastic tissue helpful in molecular and histologic analyses, such as O6-methylguaine-DNA methyltransferase (MGMT) status. In uninfected patients, surgery should be avoided in the recurrence of high-grade gliomas (HGGs) positioned in eloquent zones, and there is an increased risk of complications and prolonged hospitalization.44

In the case of surgery, procedures should be conducted using the minimum number of staff, medical students, or trainees. This recommendation is to lessen the contamination risks and preserve personal protective equipment. Also, during intubation and extubation, the minimum number of staff should be present in the operating room. Intraoperative neuromonitoring, frozen section diagnoses, and tissue banking procedures should be used only in essential cases to decrease staff exposure. Adaptation to the logistics of operating room equipment is reported in the literature as a way to lessen SARS-CoV-2 transmission. Using a supplementary tent microscope cover and isolation of the patient throughout aerosol-generating procedures, such as endoscopic endonasal procedures in lesions at the skull base, create physical impediments, which can safeguard the personnel of the operating room.

During the COVID-19 pandemic, it is better to postpone adjuvant therapy for asymptomatic patients diagnosed with tumors assumed to have a slow rate of growth, such as mutation of isocitrate dehydrogenase and low-grade astrocytoma. In contrast, in those with HGGs, delaying adjuvant treatment poses a greater risk than does infection with COVID-19.44

In the RT setting, 3 strategies (postponing RT, replacing RT, and shortening the duration of RT) are applied to minimize exposure to COVID-19.27 Six weeks of daily RT is the traditional regime for managing HGGs. However, hypofractionation has become popular during the pandemic and should be applied in elderly patients or those with poor performance.44 Roa et al.45 reported that RT by 60 Gy in 30 fractions over 6 weeks, which is considered the standard protocol, is inferior to short-course RT (40 Gy in 15 fractions over 3 weeks) in patients older than 60 years because of their similar overall survival (OS), quality of life (assessed by Karnofsky Performance Status), and corticosteroid requirement. Malmstrom et al.46 reported that in elderly patients, application of TMZ (200 mg/m2 on days 1–5 of every 28 days for 6 cycles) has similar outcomes to hypofractionated RT (34 Gy as 3.4 Gy fractions over 2 weeks) and both are superior to standard RT (60 Gy over 6 weeks). Minniti et al.47 performed a clinical trial on elderly patients. These investigators concluded that performing standard RT concurrent with TMZ has similar OS (12 vs. 12.5 months) and progression-free survival (5.6 vs. 6.7 months) to short-course RT and TMZ. Perry et al.34 showed that the application of TMZ along with short-course RT has better outcomes than short-course RT alone in OS (9.3 vs. 7.6 months) and median progression-free survival (5.3 vs. 3.9 months). For patients younger than 65 years with good performance status and MGMT methylated tumors, still with the ongoing pandemic, the traditional standard RT (60 Gy in 30 fractions over 6 weeks) is recommended.44

TMZ is considered the preferred chemotherapeutic agent in the management of GBM.27 Wicket al.48 compared the outcomes of TMZ chemotherapy and RT and concluded that TMZ alone had similar results to RT alone in elderly patients diagnosed with GBM. These investigators also showed that patients with MGMT promoter methylation had better outcomes by application of TMZ than RT. Hegi et al.49 showed that the combination of TMZ and RT is superior to RT alone in those with a methylated MGMT promoter (OS, 21.7 vs. 15.3 months). Stupp et al.50 showed that RT (60 Gy over 6 weeks) in combination with 1 concurrent treatment (75 mg/m2) of TMZ and the following 6 cycles (150–200 mg/m2) improved OS by 2.5 months and 37% of reduction in mortality. These investigators also showed that by applying TMZ, the risk of developing hematologic disorders such as severe neutropenia and thrombocytopenia increases. So, chemotherapy complications, such as lymphopenia, predispose patients to more severe COVID-19 infection; therefore, the advantages and disadvantages must be evaluated before the application of TMZ.44 In the setting of the ongoing pandemic, TMZ is recommended in those with MGMT hypermethylation, according to previous studies that have shown the superiority of TMZ to RT.44,49 In contrast, because RT and TMZ have similar outcomes in those with no methylation, TMZ should be avoided.49 The application of chemotherapy must be evaluated based on the facts such as molecular profile, patient's profile, and local COVID condition.

The application of corticosteroid medication in neuro-oncologic patients during the COVID pandemic is a complex subject. Numerous patients with GBM require corticosteroid application to lessen the neurologic effects of cerebral edema.51 The antiproliferative effects of corticosteroids may adversely act as a protective agent for malignant cells during the chemotherapy or radiation period and subsequently decrease survival.52,53 The application of corticosteroids in the management of COVID-19 infection remains controversial. Corticosteroids are helpful in refractory septic shock or a hyperinflammatory state caused by the virus.54 Several studies have shown that the application of steroids such as methylprednisolone (1–2 mg/kg/day), dexamethasone (6 mg/day), or prednisolone (40 mg/day) has beneficial outcomes in COVID-19 infection.55,56 In contrast, as a result of the inhibition of providing a proper immune response, these steroids are associated with delayed viral clearance and increased intensive care unit mortality.57, 58, 59 In the setting of HGGs, the lowest dose of corticosteroids compatible with symptom control must be administered.27