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Tumor Discovery Understanding glioblastoma invasion and therapy

disruption, weakness, numbness, or pain. Tumors arising the pool of functional MGMT and are thus significantly
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in brain regions associated with more subtle symptoms, more sensitive to the effects of TMZ. In 2005, Stupp et al.
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such as memory disruption, executive dysfunction, published the results of a phase III randomized multicenter
mood disturbances, or fatigue, are more frequently larger clinical trial demonstrating that TMZ + radiation therapy
upon discovery. Approximately 24% of GBM patients (RT) (Stupp protocol) extends overall survival in GBM
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will present with seizures. Symptoms associated with by 2.5 months in comparison to RT alone. However,
5,43
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increased intracranial pressure (ICP), such as headache, stratifying the patients enrolled in the Stupp protocol trial
nausea, sleepiness, decreased alertness, atypical pupillary demonstrated that the median overall survival benefit for
response to light, and confusion, are common. 34 GBM patients with a hypermethylated MGMT promoter
Although GBM is frequently first detected with was 6.4 months. In contrast, the benefit for patients without
computed tomography scans in the emergent care a hypermethylated MGMT promoter was less than a
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setting, it is best visualized using magnetic resonance month. The Stupp protocol remains the standard-of-care
imaging (MRI). On MRI, GBM consistently appears as an for all GBM patients, regardless of MGMT methylation
irregularly shaped ring-enhancing mass associated with status, because more effective treatment alternatives do not
substantial peritumoral edema (Figure 2A). 36 currently exist.
Some patients additionally elect to treat their GBM
5.2. Standard-of-care treatment for GBM with tumor-treating field (TTF) technology. TTFs are anti-
Newly diagnosed GBMs are treated with maximally safe mitotic medical devices that use adhesive arrays of external
surgical resection, ionizing radiation, and temozolomide transducers to produce alternating electric fields of low-
(TMZ) chemotherapy. Among these three interventions, intensity and intermediate-frequency. These alternating
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5
surgery provides the greatest survival benefit to GBM electric fields disrupt cell polarization and microtubule
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patients and resection is usually performed as soon as dynamics. TTF clinical trials showed that the use of
clinically feasible. The extent of resection and residual TTFs in combination with Stupp protocol maintenance
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tumor volume are both directly correlated to overall TMZ significantly extended both the median progression-
survival time. The primary goal of neurosurgical GBM free survival and median overall survival by 2.7 and
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care is to balance aggressive tumor resection with the 4.9 months, respectively. However, these results required
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maintenance of patient function. Subtotal resection of that patients use the device at least 18 h/day. TTF uses
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GBM puts patients at considerable risk for potentially fatal currently requires patients to shave their heads to adhere
intratumoral hemorrhage and cerebral edema (wounded to transducer arrays accurately. However, adhesive-related
glioma syndrome). GBM resection should be pursued itching is a common complaint (approximately 42%). 46
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only when there is reasonable confidence that most of Standard clinical care beyond the Stupp protocol for
the mass can be removed. An estimated 17% of GBMs newly diagnosed GBM consists of palliative management
are unresectable due to their location, extent of spread, or of tumor-associated symptoms, including seizure control,
the existence of comorbid clinical features at the time of pain control, and depression treatment. Some patients
presentation (Karnosky performance score <70). 40,41 also pursue experimental therapy through enrollment in
Once surgical wounds are healed, GBM patients clinical trials. However, most clinical trials limit enrollment
complete the Stupp protocol chemoradiation. Targeted to cases of recurrent GBM.
external beam radiation is typically delivered in daily
2 Gy fractions, 5 days a week, for 6 weeks (total 60 Gy) 5.3. Patterns of recurrence
in combination with daily TMZ (75 mg/m ). Cycles of GBM is an aggressive malignancy that exhibits significant
2 5
2
maintenance TMZ (150 – 200 mg/m ) consisting of 5 resistance to therapeutic intervention and will recur
consecutive days of treatment per 28-day cycle are then in nearly all cases despite aggressive treatment efforts.
continued for approximately 6 – 12 cycles. TMZ is an oral The median progression-free survival time in GBM is
5
alkylating agent that creates DNA adducts at the O -guanine 6.9 months. Approximately 90% of GBMs recur within
6
5
to form O -methylguanine. O -methylguanine-DNA- 2 cm of the surgical resection bed margin, 47,48 and this
6
6
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methyltransferase (MGMT) is a DNA-damage repair is particularly interesting considering that this is the
response enzyme that repairs the TMZ-induced DNA area most heavily targeted by RT. There is no evidence
adduct by removing the methyl in a degenerative reaction indicating that tumor location, initial presentation, or
that depletes the MGMT enzyme pool. GBMs that other clinical factors influence the progression pattern or
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possess a hypermethylated MGMT promoter region are that progression pattern is linked to differences in overall
unable to upregulate MGMT transcription to regenerate survival time.
Volume 4 Issue 2 (2025) 25 doi: 10.36922/td.8578