Residency · Residency · Radiation Oncology

Glioblastoma: Standard Chemoradiation and Emerging Approaches

Overview

Glioblastoma (GBM), classified as WHO grade 4, represents the most common and aggressive primary brain malignancy in adults. Despite advances in treatment, median survival with the current standard therapy remains approximately 14 to 16 months, with a 5-year survival rate of less than 10%. Since 2005, the Stupp protocol, which combines concurrent temozolomide chemotherapy with radiation followed by adjuvant temozolomide, has been the cornerstone of GBM management. Among biomarkers, MGMT promoter methylation status stands out as the strongest prognostic and predictive factor, influencing both survival outcomes and treatment responsiveness. However, despite extensive research efforts, significant improvements in survival beyond what the Stupp protocol offers have been limited.

Epidemiology and Pathology

The incidence of glioblastoma is about 3 cases per 100,000 people annually, with peak occurrence between 65 and 75 years of age and a slight predominance in males. According to the WHO 2021 classification, a diagnosis of GBM requires IDH-wildtype status; tumors harboring IDH mutations are classified separately as astrocytoma, IDH-mutant, grade 4. Histologically, GBM is characterized by microvascular proliferation and necrosis, which may be palisading or geographic in pattern. Molecularly, common alterations include TERT promoter mutations, chromosome 7 gain and chromosome 10 loss (+7/-10), and EGFR amplification.

Standard Treatment: The Stupp Protocol

EORTC 26981/NCIC CE.3 Trial (2005)

The landmark phase III EORTC 26981/NCIC CE.3 trial established the current standard of care by comparing radiation therapy alone to radiation combined with concurrent and adjuvant temozolomide. Radiation was delivered as 60 Gy in 30 fractions over six weeks, while temozolomide was administered at 75 mg/m² daily during radiation, followed by 150-200 mg/m² on days 1 to 5 of 28-day cycles for six cycles. This combined approach improved median survival to 14.6 months compared to 12.1 months with radiation alone. Two-year survival rates increased from 10.4% to 26.5%, and five-year survival improved from 1.9% to 9.8%. These results firmly established concurrent chemoradiation as the standard treatment for newly diagnosed GBM.

MGMT Methylation

The enzyme O6-methylguanine-DNA methyltransferase (MGMT) repairs DNA damage caused by alkylating agents like temozolomide. When the MGMT promoter is methylated, the gene is silenced, rendering tumor cells more sensitive to temozolomide-induced DNA damage. Approximately 35-45% of GBM tumors exhibit MGMT promoter methylation. This biomarker is strongly prognostic, indicating better survival regardless of treatment, and predictive, signifying greater benefit from temozolomide therapy. Patients with methylated MGMT have a median survival of about 21 to 23 months when treated with the Stupp protocol, whereas those with unmethylated MGMT have a median survival closer to 12 to 14 months. Although the benefit of temozolomide is less clear in unmethylated tumors, it remains part of the standard treatment regimen.

Radiation Therapy Technique

Target Volume Delineation

Two major approaches exist for defining the clinical target volume (CTV) in radiation planning for GBM.

The RTOG approach employs a two-phase strategy. In phase one, the CTV1 includes the T2/FLAIR abnormality plus a 2 cm margin, adjusted to respect anatomic barriers, and is treated to 46 Gy. Phase two targets the T1 contrast-enhancing tumor, the resection cavity, and a 2 cm margin (CTV2) with a boost to 60 Gy, delivering an additional 14 Gy. This approach uses more generous margins based on autopsy data indicating microscopic tumor infiltration within the FLAIR abnormality.

In contrast, the EORTC approach uses a single-phase treatment targeting the T1 contrast-enhancing tumor plus the resection cavity with a 2 to 3 cm margin, excluding the entire T2/FLAIR abnormality. This single-phase plan delivers 60 Gy in 30 fractions and generally results in smaller treatment volumes.

PTV Margins

Planning target volume (PTV) margins typically involve a uniform expansion of 3 to 5 mm from the CTV. With daily cone-beam CT (CBCT) image guidance, these margins may be reduced to 2 to 3 mm. It is essential that the CTV respects anatomic barriers such as the falx cerebri, tentorium, skull base, and uninvolved ventricles to avoid unnecessary irradiation of normal brain structures.

Technical Considerations

Intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) are preferred techniques due to their ability to conform dose distributions tightly around the target while sparing organs at risk (OARs). Critical OARs include the optic chiasm and nerves, which should receive less than 54 Gy; the brainstem, with surface dose limits of less than 54 Gy and small volume doses under 60 Gy; the cochlea, with a mean dose below 45 Gy; the hippocampi, which should be spared when feasible; and the lenses, which should receive less than 7 Gy. Accurate target delineation requires mandatory fusion of MRI sequences, including T1 post-contrast and T2/FLAIR images. Postoperative MRI should be obtained within 24 to 72 hours after surgery to differentiate residual tumor from postoperative changes, as delayed imaging beyond 72 hours can confound treatment planning.

Elderly and Poor Performance Status Patients

Hypofractionated Radiation

In elderly patients over 65 years, hypofractionated radiation regimens have been studied to balance efficacy and tolerability. Perry et al. (2017) demonstrated that 40 Gy in 15 fractions combined with concurrent and adjuvant temozolomide improved median survival to 9.3 months compared to 7.6 months with radiation alone. The survival benefit from temozolomide was primarily observed in patients with MGMT-methylated tumors. The Nordic trial compared standard fractionation (60 Gy in 30 fractions) to hypofractionated radiation (34 Gy in 10 fractions) and temozolomide alone in elderly patients. The hypofractionated regimen was non-inferior to standard radiation, and temozolomide alone was superior to radiation in patients older than 70 years, particularly those with MGMT methylation. For very elderly or poor performance status patients, a regimen of 25 Gy in 5 fractions over one week is sometimes used, offering reasonable palliation despite limited data.

Treatment Selection by MGMT Status in Elderly

Treatment decisions in elderly patients are guided by MGMT methylation status. For those with methylated MGMT, either temozolomide alone or hypofractionated radiation combined with temozolomide are reasonable options. In contrast, patients with unmethylated MGMT derive questionable benefit from temozolomide; hypofractionated radiation alone is preferred, as temozolomide monotherapy is inferior to radiation in this group. Patients who are unfit for any active treatment should receive best supportive care.

Tumor Treating Fields (TTFields)

EF-14 Trial

Tumor Treating Fields (TTFields) utilize alternating electric fields at 200 kHz delivered via transducer arrays placed on the shaved scalp. The EF-14 phase III trial compared TTFields combined with adjuvant temozolomide to temozolomide alone following completion of concurrent chemoradiation. The addition of TTFields improved median survival to 20.9 months versus 16.0 months with temozolomide alone. Maximum benefit requires wearing the device for at least 18 hours per day. TTFields have received FDA approval for newly diagnosed GBM. However, the therapy poses a significant compliance burden and is associated with cosmetic and skin toxicities such as contact dermatitis. The monthly cost is approximately $21,000, and adoption varies widely across institutions and regions. Some controversy exists regarding the trial design, which was unblinded and lacked a sham control.

Emerging and Investigational Approaches

Dose Escalation

Attempts to improve outcomes by escalating radiation dose beyond the standard 60 Gy have not demonstrated survival benefits. Trials increasing doses to 70-80 Gy have failed to show improvement. For example, RTOG 9305 investigated a stereotactic radiosurgery boost prior to external beam radiation but found no survival advantage. Current dose escalation strategies focus on MRI-guided dose painting targeting biologically active tumor subvolumes.

Immunotherapy

Checkpoint inhibitors such as nivolumab have not improved survival in newly diagnosed or recurrent GBM, as demonstrated in the CheckMate 143, 498, and 548 trials. GBM is considered immunologically "cold," characterized by a low mutational burden, an immunosuppressive microenvironment, and T-cell exhaustion. Vaccine approaches, including rindopepimut targeting EGFRvIII and dendritic cell vaccines, showed early promise but failed to demonstrate benefit in phase III trials.

Targeted Therapy

Bevacizumab, an anti-VEGF agent, is approved for recurrent GBM based on response rates but does not improve overall survival, as shown in the RTOG 0825 and AVAglio trials. EGFR-targeted therapies have largely been unsuccessful despite frequent EGFR amplification in GBM. IDH inhibitors are under investigation for IDH-mutant grade 4 astrocytomas, which have distinct biology from IDH-wildtype GBM.

Recurrence Management

There is no established standard of care for recurrent GBM, with median survival after recurrence ranging from 6 to 9 months. Treatment options include re-resection, re-irradiation (often hypofractionated or stereotactic radiosurgery), bevacizumab, temozolomide rechallenge, lomustine, and enrollment in clinical trials. Re-irradiation typically involves doses of 30-35 Gy in 10-15 fractions or stereotactic radiosurgery delivering 12-18 Gy to the recurrent tumor, with careful attention to cumulative dose constraints for the spinal cord and brainstem.

<image>An axial T1-weighted post-contrast MRI of a glioblastoma showing a ring-enhancing mass in the right temporal lobe with central necrosis and surrounding T2/FLAIR edema. Overlaid contours show the GTV (red, enhancing rim and resection cavity), CTV per RTOG approach (blue, including FLAIR abnormality + 2 cm, respecting midline falx and tentorium), and CTV per EORTC approach (green, enhancing tumor + 2 cm only). The difference in CTV volumes between approaches is clearly visible.</image>

<image>A Kaplan-Meier survival curve from the Stupp trial showing overall survival for RT alone versus RT + temozolomide, with the curves separating after 6 months and the 5-year survival benefit clearly annotated. A second panel shows the same survival data stratified by MGMT methylation status, demonstrating the dramatic survival advantage in methylated patients receiving temozolomide versus the modest benefit in unmethylated patients.</image>

<image>A decision algorithm flowchart for newly diagnosed GBM treatment by age and MGMT status. For patients younger than 70 with good performance status: standard Stupp protocol (60 Gy/30 fx + TMZ) regardless of MGMT. For elderly patients (>70) or poor KPS: MGMT methylated leads to hypofractionated RT + TMZ or TMZ alone; MGMT unmethylated leads to hypofractionated RT alone; very poor KPS leads to best supportive care. TTFields are shown as an add-on option after concurrent chemoradiation for eligible patients.</image>

Key Clinical Pearls

It is essential to obtain MGMT methylation status at diagnosis, as it is the most important biomarker guiding treatment decisions, particularly in elderly patients where treatment intensity must be carefully calibrated. Postoperative MRI performed within 24 to 72 hours after surgery is critical to distinguish residual enhancing tumor from postoperative blood products and enhancement; imaging delayed beyond 72 hours complicates accurate target delineation. The debate between the RTOG and EORTC contouring approaches remains unresolved, with institutional practices varying; however, both methods are acceptable as long as the enhancing tumor and resection cavity are included with an adequate margin while respecting anatomic barriers. Radiation therapy should not be delayed in GBM; treatment initiation within 3 to 6 weeks post-surgery is recommended, as delays beyond 6 weeks may worsen outcomes. Pseudoprogression, a treatment-related imaging phenomenon mimicking tumor progression, occurs in 20 to 30% of patients within the first 3 to 6 months after chemoradiation, especially in those with MGMT-methylated tumors. Therefore, premature discontinuation of temozolomide based solely on imaging should be avoided.

References

• Stupp R et al. "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma." N Engl J Med. 2005;352(10):987-996.
• Stupp R et al. "Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial." Lancet Oncol. 2009;10(5):459-466.
• Perry JR et al. "Short-course radiation plus temozolomide in elderly patients with glioblastoma." N Engl J Med. 2017;376(11):1027-1037.
• Stupp R et al. "Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial." JAMA. 2017;318(23):2306-2316.
• Hegi ME et al. "MGMT gene silencing and benefit from temozolomide in glioblastoma." N Engl J Med. 2005;352(10):997-1003.

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