New Directions in the Treatment of Glioblastoma

Zachary J. Reitman, MD, PhD; Frank Winkler, MD, PhD; Andrew E. H. Elia, MD, PhD


Semin Neurol. 2018;38(1):50-61. 

In This Article

Standard Therapy for Glioblastoma

The current standard of care for newly diagnosed GBM patients is resection followed by postoperative radiation therapy (RT) with concurrent and adjuvant temozolomide. Surgery serves to alleviate symptoms of mass effect, reduce tumor burden, and provide adequate tissue for diagnosis and molecular profiling. Although randomized evidence for the efficacy of maximal surgical resection is limited, numerous retrospective studies and a meta-analysis of 41,117 patients have found that gross total resection improves overall and progression-free survival relative to subtotal resection.[9] Furthermore, fluorescence-guided surgery using 5-aminolevulinic acid, which allows for more complete resection, was found to improve progression-free survival in a randomized trial.[10] Based on this and other evidence, maximal safe resection is considered the current standard for GBM treatment.

Postoperative radiation was established as the cornerstone of adjuvant therapy for GBM by the Brain Tumor Study Group (BTSG) 69–01 trial, which showed that whole brain radiation improved overall survival (median 35 versus 14 weeks).[11] Radiation dose was subsequently examined in a pooled analysis of BTSG trials showing longer survival for 60 Gy compared with 45 Gy,[12] which was confirmed in a subsequent randomized trial by the Medical Research Council,[13] making 60 Gy the standard of care. Further dose escalation to 70 Gy failed to improve survival,[14] as did stereotactic radiosurgery boost.[15] Modern guidelines typically call for the treatment of the postsurgical resection cavity, any gadolinium-enhancing residual tumor on magnetic resonance (MR) T1 imaging, and T2/FLAIR edema with a 2 to 3 cm anatomic expansion. This practice is based on studies showing that nearly 90% of recurrences occur within a 2 cm margin of the primary tumor site.[16]

Administration of the oral alkylating agent temozolomide during and following radiation was established as the standard of care by the EORTC 22981/26981 and NCIC CE.3 trial. In this trial, 573 GBM patients were randomized to 60 Gy radiation with or without concurrent and adjuvant temozolomide. Temozolomide was given at 75 mg/m2 daily during radiation and then at 150 to 200 mg/m2 during the first 5 days of a 4-week cycle for a total of six cycles. The addition of temozolomide improved median survival from 12.1 to 14.6 months and 5-year overall survival from 1.9% to 9.8%.[17] The relative benefit from concomitant versus adjuvant temozolomide remains unclear. Notably, intensifying postradiation temozolomide dose in another randomized trial, RTOG 0525, failed to improve survival further.[18] Contemporary randomized trials have utilized postoperative radiation with concurrent and adjuvant temozolomide as a backbone on which to add investigational therapies, and these trials are summarized in [Table 1].