INTRODUCTION
The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has wholly
changed healthcare worldwide, including the care of neuro-oncology patients with high-grade
gliomas. In this review, current recommendations for the treatment of high-grade gliomas
during the pandemic are presented to guide clinical practice. COVID-19 pandemic will
require individual centers to shift their focus and resources to allocate patients
and provide a safe environment. It will also demand physicians to employ clinical
care in different manners and to an interdisciplinary extent.
Current publications provide mostly a framework of evidence-based care to prolong
overall survival and progression-free survival. Each health service should manage
resources to avoid the potential for undertreatment of cancer. During the current
pandemic, neuro-oncology treatment decisions will challenge clinicians, surgeons,
and hospitals, and the best efforts to deliver treatment should prevail.
High-grade gliomas comprise a heterogeneous group of aggressive and incurable tumors,
usually requiring maximal safe surgical resection, radiotherapy, and chemotherapy
as an upfront treatment to reach the best overall survival and progression-free survival.
COVID-19 pandemic broke the traditional workflow employed during neuro-oncology therapy
in many centers. Glioblastoma patients are usually offered the standard treatment
protocol established since 2005 (Stupp protocol). Still, aged patients or patients
with poor performance status may benefit from hypofractionated protocols or even monotherapy
with radiotherapy or temozolomide. Molecular changes like O-6-methylguanine-DNA methyltransferase
(MGMT) promoter methylation and Isocitrate dehydrogenase (IDH) mutation should be
used to stratify best treatment among older patients.
Here, a group of Brazilian neuro-oncology experts gathered together to suggest treatment
approaches during the COVID-19 pandemic in Brazil.
GLIOBLASTOMA
Glioblastoma is currently treated according to EORTC-NCIC (Stupp protocol), where
maximal safe resection is followed by concurrent chemo-radiotherapy (CRT) and six
cycles of adjuvant chemotherapy with temozolomide[1] ([Figure 1]). Patients with MGMT promoter methylation status reached better overall survival
than unmethylated ones, with about 50% longer median survival for those treated with
temozolomide[2],[3]. Aged patients generally have a worse prognosis and are less tolerant to toxicities.
Still, a recent study demonstrated that hypofractionated radiotherapy (40Gy/15 fractions
of 2.67Gy over three weeks) is as effective as the standard 60Gy over six weeks. The
association of temozolomide showed better overall survival when compared to radiotherapy
alone[4]. Treatment with either temozolomide or radiotherapy alone is an option, mainly for
those with poor performance status, and it should be guided by MGMT promoter methylation
whenever possible[5].
Figure 1 EORTC-NCIC protocol (Stupp protocol).
Neurosurgery
Maximal safe resection is recommended for glioblastoma, and since it offers a benefit
in overall survival (OS) and quality of life (QOL), it should be considered a priority[6],[7]. Surgery also makes histological and molecular analysis possible, which might inform
treatment decisions.
When admitting neuro-oncological patients, some safety issues should always be considered,
such as active screening for flu symptoms, reverse transcription polymerase chain
reaction (rt-PCR) for the COVID-19 test, and getting an epidemiological history focusing
on COVID-19. The staff is guided to wear additional Personal Protective Equipment
(PPE), such as N95 and face shields[8]. Some centers also recommend acquiring a pulmonary computed tomography (CT) for
preliminary diagnosis of COVID-19 before hospitalization[9],[10]. For patients whose tests came out negative, hospital admission should be through
a particular lane to avoid cross-infection, and individual accommodation with rigorous
quarantine should be applied. Infected patients should have surgery postponed until
infection ceases. Patients with life-threatening conditions can bypass all these steps,
they should be kept in individual accommodations after surgery, and later analysis
would guide different paces. All postoperative patients should be regarded as suspected
cases, and quarantine for at least two weeks is recommended[9].
Awake craniotomy is a crucial procedure to achieve maximum safe resection in some
patients with high-grade gliomas, but this technique can be considered high-risk in
COVID-19 pandemic times. Patients require very close and direct contact between the
neurophysiologist during stimulation and a lot of technical personnel. Patients infected
with SARS-CoV-2 should not be referred to awake craniotomy, and the infection should
be treated first[11].
Regarding reoperations, probably other therapies should be preferred for the treatment
of recurrent glioblastoma (GBM).
Clinical follow-up and magnetic resonance imaging
Clinical visits are vital to patient guidance and for monitoring the adverse effects
of systemic therapy. Neuro-oncologists should rely on feasible telemedicine solutions
for follow-up, and patients should have their blood tested in local laboratories whenever
possible. In Brazil, most centers that treat neuro-oncological patients are inside
tertiary hospitals, private hospitals, and many other public hospitals, making cross-infection
an issue of concern in this fragile population. Therefore, clinical visits should
be reserved for those patients who cannot be followed remotely or with urgent symptoms[12].
Magnetic resonance imaging (MRI) is essential during treatment follow-up and is also
critical for decision making. Imaging units should employ safety strategies for receiving
patients during the pandemic, and adjustments in MRI surveillance protocols could
be discussed individually with the patient who has a stable condition and an excellent
molecular profile[12],[13].
Radiotherapy
Radiation therapy (RT) has an essential role in the treatment of high-grade gliomas.
It is performed through daily applications of ionizing radiation directed to a specific
brain area to control the primary tumor or avoid local recurrence after surgical resection.
During the coronavirus disease 2019 (COVID-19) pandemic, some strategies have been
used to restrict the exposure of patients and healthcare professionals to COVID-19.
Radiation Oncology services around the world have been considering three main strategies
to restrict this exposure:
-
postpone the start of RT whenever possible;
-
2- avoid RT when another treatment can replace it or when the indication of RT is
not proven to be beneficial;
-
employment of shorter RT duration through hypofractionated regimens.
To minimize exposure and reduce the risk of infection, older, frail, or patients with
poor performance status should receive hypofractionated schedules instead of a six-week
traditional radiotherapy course. Data supporting this recommendation come from earlier
trials concerning older patients, and non-inferiority results reinforce some of the
current suggestions[12]. Roa et al. reported results of a prospective study which randomized 100 patients
with GBM and aged 60 years old or older to receive standard RT fractionation (60 Gy
in 30 fractions) or a hypofractionated regimen (40 Gy in 15 fractions). They found
no difference in survival between patients receiving standard RT or short-course RT[14]. The International Atomic Energy Agency (IAEA) conducted an international prospective
and randomized trial to compare two RT regimens (40 Gy in 15 fractions and 25 Gy in
5 fractions) on the outcome of 98 patients with GBM and aged 50 years old or older.
They found no differences in OS time, progression-free survival time, and QOL between
patients receiving the two RT regimens. The authors concluded that a short 1-week
RT regimen might be recommended as a treatment option for aged or frail patients with
newly diagnosed GBM[15]. Perry et al., through a prospective and randomized study involving 562 patients
with GBM and aged 65 years old or older, showed median OS benefit when combining CT
with temozolomide (TMZ) to hypofractionated RT with 40 Gy in 15 fractions (9.3 vs. 7.6 months; p<0.001)[4].
For patients younger than 60–65 years of age and with good performance status and
MGMT methylated tumors, maintaining standard treatment with 60Gy in 30 fractions according
to Stupp Protocol is reasonable. However, patients should be offered the possibility
of reducing the number of visits, mainly because they are dealing with an incurable
type of cancer[12].
Chemotherapy
The leading cause of mortality from SARS-CoV-2 is the acute respiratory distress syndrome
(ARDS) and many events surrounding a hyperinflammatory syndrome leading to multiorgan
failure[16]. In a retrospective, multicenter cohort study in Wuhan, the presence of lymphopenia
in hospitalized patients with COVID-19 was a risk factor for death and usually seen
in severe cases[17]. Currently, temozolomide is the main chemotherapy used to treat glioblastoma patients,
employed in the concurrent and adjuvant phase, and can even be given after disease
recurrence[1],[2],[3]. Temozolomide added in the upfront treatment of glioblastoma resulted in OS benefit,
mainly for those harboring an MGMT promoter methylation status[3], but also determined about 14% of grade 3 or 4 hematologic toxicities in the studied
cohort of patients[1]. Therefore, the decision to keep or withhold chemotherapy should be carefully studied
after many considerations, like the presence of a good molecular profile, the local
situation despite COVID-19 pandemic, patients’ decision and patient adherence to treatment
and risk of hematologic toxicities.
The National Comprehensive Cancer Network (NCCN) guidelines claim that temozolomide's
omission during glioblastoma treatment is possible, mainly for those MGMT unmethylated
patients and the elderly with comorbidities, but could also be reasonable during this
pandemic[18]. In Brazil, temozolomide is still not widely available in most states[19], and patients with health insurance are those with the possibility of acquiring
treatment. Access to MGMT promoter status is also not widely available for most patients,
which could harden clinical decisions.
It is reasonable to prioritize temozolomide for patients with MGMT methylated status[3] and IDH mutated tumors[20], while keeping close attention to treatment toxicities and scheduling regular blood
exams. High-grade gliomas that harbor a mutation in IDH might benefit from the addition
of temozolomide to the treatment protocol; the EORTC phase III CATNON trial demonstrated
that IDH mutation was predictive of a significant benefit from adjuvant temozolomide,
with even the benefit of using it in concurrency[20],[21].
The CeTeG/NOA-09 trial recently investigated the effect of lomustine (CCNU) with temozolomide
vs. the standard regimen for newly diagnosed MGMT methylated glioblastomas undergoing
radiotherapy in a phase III trial[22]. This study suggested that this combination might improve OS compared to temozolomide
alone in MGMT-methylated patients, but the toxicities when both agents were combined
were significantly higher. The decision to employ this strategy during the COVID-19
pandemic should be critically reviewed, and is probably not recommended[12].
The use of corticosteroids
Glioblastoma frequently presents with symptomatic peritumoral vasogenic edema, and
dexamethasone alleviated neurological deficits and signs of increased intracranial
pressure. Low doses administered once or twice daily are sufficient in most cases[23]. Many studies suggest that caution should be used when employing steroids in neuro-oncology
due to a detrimental effect on survival outcomes. In an independent analysis of three
patients’ cohorts, Pitter et al. showed that the use of corticosteroids during radiotherapy
is an independent indicator of shorter survival in glioblastoma patients. Probably
dexamethasone-induced anti-proliferative effects can protect the tumor from radiation
or chemotherapy-induced genotoxic stress[24].
The RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial recently announced
that dexamethasone given once daily at the dose of 6mg once per day (either by mouth
or intravenous injection) for ten days reduced deaths by one-third in ventilated patients
and by one fifth in other patients receiving oxygen only[25]. Previous data suggested that patients with SARS-CoV-2 infection would not benefit
from corticosteroid treatment, and its usage should be cautioned considered[26].
Regardless of the current pandemic, the beneficial anti-inflammatory and anti-edematous
effects should be cautiously weighed against the potential adverse effects in glioblastoma
treatment and the lowest dose capable of controlling symptoms should be chosen.
Approaching glioblastoma patients during the COVID-19 pandemic will be challenging
in most centers that treat neuro-oncological patients. In Brazil, significant disparities
in healthcare among states will confront physicians to make proper treatment decisions.
Patients with good performance status and good molecular profile (mainly MGMT promoter
methylation and IDH mutation) should receive the standard protocol of treatment with
maximal safe resection followed by concurrent chemo-radiotherapy and adjuvant chemotherapy
with temozolomide whenever possible. Older patients and those with poor performance
status should be carefully treated, and probably a monotherapy regimen might best
fit during the COVID-19 pandemic, in case patients with good performance status and
no comorbidities could benefit from hypofractionated protocols with temozolomide ([Figure 2]). The current situation challenges us, and delivering the best healthcare and employing
new ways to communicate with our patients is essential. All efforts should focus on
safety and not compromise patient care and survival.
Figure 2 Proposed flowchart for the treatment of patients with glioblastoma during COVID-19
pandemic.
