Introduction
Grade IV astrocytoma (glioblastoma) is the most common
primary malignant brain tumor in adults.[]
Moreover, the incidence increases with age, which is
most common in patients older than 70.[,] Maximal
safe resection and adjuvant chemoradiotherapy in 60
Gy with concomitant and adjuvant temozolomide are
standard treatments; however, despite the aggressive
treatment approach, the median survival is almost 15
months in glioblastoma.[] While improved survival
has been reported with the standard approach, there
are still open questions about managing aggressive
high-grade tumors in older adults. Some physicians
may prefer more conservative approaches when treating
patients in elderly patients.[] However, this paradigm
has recently been faced with increasing evidence
to suggest that elderly patients also benefit from maximally
safe resection and chemoradiotherapy.[]
Another question is the optimal treatment and treatment
sequences in terms of the progression of glioblastoma.
Unlike de novo disease, there is no standard
of care in treating recurrent disease, and the preferred
treatments are not superior. Options include resection,
reirradiation, chemotherapy, and systemic therapies (i.e.,
bevacizumab).[] However, more evidence-based, highquality
knowledge is required in recurrent situations.
There is a need for more data about managing various
scenarios and for more consensus on managing patients
with glioblastoma. Hence, through a nationwide
survey, we aimed to determine the prevailing clinical
practice patterns in radiotherapy for glioblastoma
management.
Methods
This study was performed in accordance with the principles
of the Declaration of Helsinki and ethical approval
was obtained from our Marmara University Faculty
of Medicine ethics committee (the reference number:
02.07.2021 and 09.2021.921). A cross-sectional survey
of radiation oncology practitioners in Türkiye was
undertaken between January 2021 and March 2021.
The web-based online questionnaires were prepared
on the Google.doc site, and the invitation was sent to
registered members of the Turkish Society of Radiation
Oncology via e-mail. The questionnaire contained
13 items, including different scenarios and situations.
The questions were determined to identify the current
practice of treating patients with glioblastoma, surgery, reirradiation, or systemic treatments in routine care,
commonly used dose fractionation in older patients,
and those with worse performance status. The responses
were collected using custom-built software.
Results
The Participants" Profiles and Their Facilities
A total of 195 radiation oncologists responded to the
survey. The characteristics of study participants are
summarized in Table 1. All participants utilized intensity-
modulated radiotherapy; some had access to
(30%) stereotactic radiosurgery and linear acceleratorbased
stereotactic body radiotherapy (67%) facilities. A
multidisciplinary tumor board is held in all academic
centers, and patients are treated both within this center
and in other centers based on the board"s decisions.
One-third of these centers are reference hospitals with
a high patient load; physicians saw more than five new
patients diagnosed with glioblastoma, and 31% followed
more than ten patients per month.
Table 1: Participants" professional features, treatment time, planning, and fractionation preferences
Radiotherapy Time and Planning Details
Approximately 60% of the participants initiated postoperative
radiotherapy for glioblastoma patients either
three weeks after surgery or immediately following suture
removal. Most participants favored the two-phase approach
for defining target volumes in radiotherapy planning
(61%). Phase I was described as tumor and/or the
cavity and edema, and phase II was defined as the same
but without edema. The rest of the physicians defined the
target volume in a single phase as tumor and/or cavity ±
edema (21%) or tumor and/ or cavity ± edema with a simultaneous
integrated boost technique (Table 1).
The Scenarios and Situations
Table 2 provides all scenarios and situations, and Figure1 sketches the results. Among the physicians, the
Karnofsky Performance Status Scale (KPS) (96.9%),
the patient"s age (53.6%), and tumor characteristics
(45.9%) were factors in deciding the radiotherapy fraction
scheme.
Table 2: Survey scenarios and situations
Fig. 1: Results from all the scenarios and situations provided from Table 2.
KPS: Karnofsky Performance Status Scale; RT: Radiotherapy; TMZ: Temozolomide.
The Patient Younger Than 70 Years and KPS
More Than 60 After Resection or Biopsy
All participants agreed on the standard adjuvant treatment,
which included 60 Gy radiotherapy and concurrent
temozolomide. However, following the concurrent
therapy, the number of adjuvant chemotherapy courses
administered varied: 44% of physicians prescribed six
courses, 34% opted for 12 courses, and 19% continued
treatment until disease progression.
The Patients Older Than 70 Years After Resection
or Biopsy
The physicians preferred the standard approach (80%)
rather than the short fraction scheme (20%) in elderly
patients who have good performance status (KPS≥60).
However, the standard approach (8.8%), short fraction
radiotherapy (24.7%), temozolomide (28.4%), or short
fraction and chemotherapy (37.1%) were administered
to patients with KPS<60.
Treatment Decisions in Progress
Considering re-irradiation in recurrence after standard
treatments in patients younger than 70 years and KPS
more than 60, stereotactic radiosurgery (73%) was the most common treatment preference, and the systemic
treatment recommendation was bevacizumab (87%)
in the patients who progressed. Surgical consultation
was requested for patients who had good performance
(95%), had limited tumors (84%), and were younger
(64%). In these patients, re-irradiation was applied to
the cavity following surgery (43.5%).
Treatment Decisions for Radionecrosis
In symptomatic radionecrosis, steroids (86%), bevacizumab
(60%), and surgery (64%), respectively, were
recommended. The decision not to administer radiotherapy
was based on performance (96%), age (54%), tumor
characteristics (46.6%), and methylation status (21.5%).
Discussion
Current management of newly diagnosed glioblastoma
includes postoperative chemoradiotherapy, although survival
is worse for older patients. In all patients, including
elderly patients, standard approaches are preferred for the
first diagnosis in line with the guidelines. The first point
that radiation oncologists pay attention to when choosing a fractionation schema is the patient"s performance, even
for elderly patients. In those patients, evaluating clinical
criteria or evaluation tools other than performance at the
beginning of radiotherapy may be beneficial. Temozolomide
alone is not associated with survival advantages in
elderly patients with unmethylated tumors. Hypofractionated
radiotherapy may be considered for patients unsuitable
for combined chemoradiotherapy.
The optimal time from surgery to the beginning of
radiotherapy is uncertain, and guidelines vary widely.
In our study, participants also suggested varying waiting
times before initiating radiotherapy following surgery.
According to the Dutch Cancer Society Glioma
Guideline, radiotherapy should begin up to 6 weeks after
surgery.[] Laureiro et al.,[] in a meta-analysis of 19
retrospective studies published between 1974 and 2014,
examined the effect of prolonging the time from surgery
to radiotherapy. No significant correlation was observed
between the prolongation of the time from surgery to
radiotherapy and overall survival (OS). (HR=0.98; 95%
CI 0.90-1.08; p=0.70). However, this meta-analysis included
studies published before the Stupp regime era. A
more recent study showed that delayed postop chemoradiotherapy
may result in worse survival.[,] Seidlitz
et al.[] published their retrospective cohort study; 369
patients treated between 2001 and 2014 were included,
and the effect of waiting time was investigated. In this
large series of patients, the time between surgery and adjuvant radiotherapy (median 27 days, range 11-112
days), duration of radiation therapy (median 45, range
40-71 days), and total time from surgery to the end of
radiotherapy (median 54, range 71-154 days) did not
show any effect on OS or progression-free survival
(PFS). Buszek et al.[] analyzed 45,942 glioblastoma
patients archived in the National Cancer Database.
They revealed that delays of more than eight weeks in
patients with a gross total resection and delays of less
than four weeks in patients with a subtotal resection or
biopsy resulted in worse survival. They concluded that
the impact of time delay from surgery to radiotherapy,
in conjunction with the extent of resection, should be
considered in the clinical management of patients and
future designs of clinical trials.
Several studies compare the efficacy and safety of
standard and extended adjuvant temozolomide following
concurrent chemoradiotherapy in patients with newly
diagnosed glioblastoma multiforme. Attia et al.,[] in
a retrospective study evaluating a total of 121 patients,
showed that extended temozolomide therapy was safe
and tolerable but did not significantly improve PFS or
OS compared to the standard cycle course. Feldheim et
al.[] showed that temozolomide causes loss of methylation
status of the O6-methylguanine-DNA methyltransferase
(MGMT) promoter hypermethylation and
triggers migratory behavior. After temozolomide administration,
cells with the unmethylated MGMT promoter showed more aggressive behavior.[] GEINO-14-01,
a randomized trial comparing prolonged adjuvant temozolomide
(n=80) and six courses of temozolomide
(n=79) treatment according to MGMT status and the
presence or absence of residual disease in 159 patients,
found no difference in OS or PFS.[] In our study, we
observed that the participants had different approaches
regarding adjuvant treatment duration. No patients were
without adjuvant treatment, but the application times
differed. Extensive, randomized studies in which patients
are categorized according to MGMT and other molecular
markers are needed to elucidate the current issue.
There is no clear standard of care or salvage treatment
when recurrence occurs in glioblastoma patients.
Treatment guidelines make recommendations
for these patients, such as surgery, re-administration
of temozolomide, nitrosoureas, bevacizumab, and reirradiation.[] Neither of these methods is superior to
the other. In our study, the participants stated that they
recommend bevacizumab-based systemic treatment at
a rate of 86% in cases of recurrence.
In our study, 84% of the participants recommended
resection if the patient was suitable for surgery in case of
progression. Here, the determining factors were performance,
a small tumor, a location far from risky areas, and
patients younger than 70. A prospective, randomized,
multicenter study, DIRECTOR, compared a 2-dose intensified
temozolomide regimen in relapsed glioblastoma
patients.[] In this study, a total of 61 patients were
examined, and a difference in post-recurrence survival
was found between surgery with total resection (12.9
mo [95% CI: 11.5-18.2] vs. 6.5 mo [95% CI: 3.6-9.9],
p<0.001). In a study examining current models of care
in the Australian population for recurrent glioblastoma,
76% of patients received re-resection, and 24% received
medical therapy.[] Surgery may contribute to symptomatic
and large lesions, but this patient group should
be carefully selected. There are also publications trying
to develop algorithms for choosing between re-irradiation
and second surgery for relapsed glioblastoma.[]
In our study, the determining factor in the radiotherapy
recommendations of the radiation oncologists
was primarily the patients" performance. In addition,
the patient"s MGMT status and age were also influential.
In elderly patients with poor performance, hypofractionated
treatments were chosen in addition to the
standard fraction. Similarly, the patient"s performance
status was the definitive factor for hypofractionated regimes.
In the study of 488 patients with a diagnosis of
glioblastoma, Malakhov et al.[] showed better outcomes
for patients receiving chemoradiotherapy rather than radiation alone, regardless of the performance
status. In another study, among the 70 glioblastoma patients
who were 60 years old or older, gross total resection
provided significantly longer overall survival, and
patients who received postoperative adjuvant therapy
had more prolonged overall survival than those with
no postoperative adjuvant therapy.[]
For patients with symptomatic radionecrosis, corticosteroids
were the first choice (76%), followed by
surgery (64%) and bevacizumab (60%) in our survey.
Corticosteroids reduce inflammatory signals and cytokines
from necrotic tissue and reduce blood-brain barrier
leakage.[] Bevacizumab, the vascular endothelial
growth factor inhibitor, is also widespread and is an essential
mediator in radionecrosis.[] In a study evaluating
71 patients diagnosed with radionecrosis, bevacizumab
administration showed a 97% radiographic
response rate, 79% clinical improvement, and a mean 6
mg reduction in dexamethasone.[,] Previous publications
have demonstrated that surgical application in
treating radionecrosis carries the risk of morbidity.[]
The approach to treating radiation necrosis, a complication
of radiation therapy, varies depending on the severity
of the necrosis and the individual patient"s symptoms
and may involve a combination of the treatments.
Limitations
Our survey has some limitations. Although almost
1000 radiation oncologists work in our country, 195
participants responded to our survey. Given this number,
the actual clinical practice may not be fully reflected
in these results, and physicians with a particular interest
and neurooncological experience may have been
overrepresented in our survey. Beyond the limitations,
our survey provides essential insights into how care is
delivered nationally for glioblastoma. More research to
examine the effects of preferred treatments on patients"
quality of life will be of great importance in the future.
Conclusion
Substantial parallelism was observed between the
questionnaire responses and the guideline recommendations,
especially in treating younger glioblastoma patients
at diagnosis. However, further research and standardization
are necessary for adjuvant chemotherapy
cycles, radiotherapy fractionation schemes in elderly
patients, and treatment options for glioblastoma progression.
Consequently, guidelines should encompass
diverse clinical scenarios supported by more robust evidence
for the enhanced management of glioblastoma.
Ethics Committee Approval: The study was approved by
the Marmara University Faculty of Medicine Ethics Committee
(no: 09.2021.921, date: 02/07/2021).
Conflict of Interest: All authors declared no conflict of interest.
Financial Support: None declared.
Use of AI for Writing Assistance: No AI technologies utilized.
Authorship Contributions: Concept - B.M.A., Z.A.,
U.A., K.O.; Design - B.M.A., Z.A., U.A., K.O.; Supervision
- B.M.A., Z.A., U.A., K.O.; Materials - B.M.A., Z.A., U.A.,
K.O.; Data collection and/or processing - B.M.A., Z.A., U.A.,
K.O.; Data analysis and/or interpretation - B.M.A., Z.A.,
U.A., K.O.; Literature search - B.M.A., Z.A., U.A., K.O.; Writing
- B.M.A., Z.A.; Critical review - B.M.A., Z.A., U.A., K.O.
Peer-review: Externally peer-reviewed.
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