Essential Evidence for Glioblastoma: A Must-Know for Neurosurgery Exams

The Stupp protocol was published in 2005 as a landmark paper combining radiotherapy and chemotherapy with maximal surgical resection as the gold standard.

The Stupp protocol radiotherapy consists of 60 Gy over 6 weeks, with 2 Gy daily Monday to Friday (30 fractions total).

Concomitant temozolomide in the Stupp protocol is 75 mg daily for six weeks during radiotherapy.

Adjuvant temozolomide is 150-200 mg per meter squared for the first 5 days of each 28-day cycle for a total of 6 cycles.

RANO (Response Assessment in Neuro-Oncology) criteria classify resections based on residual contrast-enhancing tumor on T1 and non-contrast-enhancing hyperintense tissue on FLAIR, believed to represent glioblastoma infiltrative tissue.

RANO Class 1 (supramaximal contrast-enhancing resection) is defined as 0 cubic centimeters of contrast-enhancing and less than 5 cubic centimeters of non-contrast-enhancing tissue postoperatively, with median overall survival of 24 months.

Maximal surgical resection (leaving less than 1 cubic centimeter of contrast-enhancing tissue) leads to 19 months median overall survival.

Submaximal contrast-enhancing resection (leaving less than 5 or more than 5 cubic centimeters of contrast-enhancing tissue) leads to 15 months overall survival, which is the gold standard quoted to patients.

Biopsy only (Class 4, no tumor volume reduction) gives 10 months overall survival if the patient receives chemoradiotherapy.

5-ALA crosses the blood-brain barrier and is converted in mitochondria to protoporphyrin IX, which accumulates in glioblastoma cells because ferrochelatase enzyme is less effective in these tumors.

Protoporphyrin IX emits bright pink fluorescence when exposed to blue light microscope with wavelength 405 to 633 nanometers, allowing tumor visualization during surgery.

5-ALA is administered as 1.5 g powder reconstituted in 50 mL drinking water (30 mg/mL oral solution) at a dosage of 20 mg per kg, given 2 to 4 hours before surgery.

A randomized controlled trial of fluorescence-guided surgery with 5-ALA showed complete contrast-enhancing resection in 65% of patients using 5-ALA compared to 36% using white light.

5-ALA fluorescence-guided surgery allows higher 6-month progression-free survival compared to white light surgery.

Awake craniotomy offers significant advantages over general anesthesia for glioblastomas near eloquent brain by allowing real-time patient interaction to map and preserve critical functions like speech and movement.

Awake craniotomy helps maximize tumor resection while minimizing postoperative neurological deficits, ultimately improving outcomes.

Drawbacks of awake craniotomy include careful patient selection requirements, potential discomfort and anxiety during surgery, and longer operative times in some cases.

Intraoperative MRI allows real-time imaging during surgery, enhancing the surgeon's ability to achieve maximal resections and increasing the rate of complete resections.

Intraoperative MRI is not available in all hospitals and requires strong infrastructure and investment to install in neurosurgical theaters.

Senft 2011 study on intraoperative MRI showed more patients had complete tumor resection than the control group, and postoperative neurological deficits did not differ between groups.

VEGF (vascular endothelial growth factor) is responsible for stimulating endothelial cell proliferation and migration in the glioblastoma microenvironment.

Bevacizumab reduces regression of existing microvessels and inhibits growth of new blood vessels, acting like dexamethasone but with more potent effect.

Overall survival is increased by only a few months using bevacizumab alone.

Bevacizumab is FDA approved in the United States but has not been proven cost-effective by the European Medicines Agency or UK NICE guidance.

Tumor treating fields is a non-invasive modality applying mild electric fields that disturb cancer cell division.

Tumor treating fields combined with temozolomide shows significant improvement in progression-free survival.

There is currently a trial running in the UK to evaluate tumor treating fields effectiveness for inclusion in NICE guidelines.

Tumor treating fields plus temozolomide versus temozolomide alone increased progression-free survival by 2.7 months and overall survival by 4.9 months.