New Directions in the Treatment of Glioblastoma

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

Disclosures

Semin Neurol. 2018;38(1):50-61. 

In This Article

Elderly Patients

Nearly half of patients with GBM are diagnosed over the age of 65.[1] Due to upper age limits or poor accrual of such patients in clinical trials, randomized evidence for the elderly population was relatively lacking until recently. To determine whether elderly patients should be treated with the same intensity as younger patients, several studies initially examined whether surgery or radiation provides a survival benefit in the elderly. A Finnish study confirmed that surgical debulking was associated with improved overall survival compared with biopsy alone in patients > 65 years old.[26] Subsequently, a French trial demonstrated that 50 Gy adjuvant radiation improved overall survival relative to supportive care alone in GBM patients > 70 years old with good performance status.[27] Together, these studies support intervention with surgery and radiation rather than supportive care alone in the elderly.

With randomized evidence supporting radiation in the elderly, subsequent trials have focused on abbreviating radiation regimens and examining the role of chemotherapy (Table 2). In one trial, GBM patients ≥ 60 years old were randomized to conventional 60 Gy in 30 fractions versus hypofractionated 40 Gy in 15 fractions, and no difference in overall survival between the two regimens was observed (44.7% versus 41.7% at 6 months).[28] In a subsequent randomized trial, an extremely hypofractionated regimen of 25 Gy in 5 fractions was explored in a population of elderly (>65) and/or frail (age >50 and KPS 50–70) GBM patients.[29] While this regimen had survival equivalent to that of 40 Gy in 15 fractions, it is likely to have adverse effects on neurocognitive function, which may preclude its adoption. In the German NOA-08 trial, patients > 65 years were randomized to either temozolomide alone or radiation alone (60 Gy in 30 fractions).[30] Median survival was 8.6 months in the temozolomide group compared with 9.6 months in the radiation group, meeting the noninferiority margin for temozolomide (p = 0.033 for noninferiority) and validating the use of temozolomide alone in the elderly. Similarly, in the Nordic Clinical Brain Tumor Study Group trial, GBM patients ≥ 60 years old were randomized to temozolomide alone, hypofractionated radiation (34 Gy in 10 fractions), or standard radiation (60 Gy in 30 fractions).[31] Median survival was longer for patients receiving temozolomide compared with standard radiation but was not significantly different among patients receiving temozolomide versus hypofractionated radiation. While the German NOA-08 and Nordic trials compared temozolomide alone to radiation alone, the most recent EORTC 26062/NCIC CE.6 trial examined the addition of temozolomide to radiation. Importantly, it showed a survival benefit for the addition of concurrent and adjuvant temozolomide to hypofractionated radiation (40 Gy in 15 fractions) in patients ≥ 65 years.[32] These trials, summarized in [Table 2], establish a spectrum of treatment options for elderly patients that can be considered based on age, performance status, and tumor molecular features (Figure 1).

Figure 1.

Selection of adjuvant therapy for elderly patients with glioblastoma (GBM). Evaluation of a patient's age, performance status, and MGMT promoter methylation status can guide selection of therapy for elderly GBM patients. Options include standard radiation (60 Gy/30 fractions) with concurrent and adjuvant temozolomide (TMZ), hypofractionated radiation (HoFx radiation, 34–40 Gy/10–15 fractions) with concurrent and adjuvant TMZ, HoFx radiation alone, TMZ alone, or supportive care alone.100

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