Advances in the treatment of newly diagnosed glioblastoma

Abstract

Glioblastoma is a refractory malignancy with limited treatment options at tumor recurrence. Only a small proportion of patients survive 2 years or longer with the current standard of care. Gene expression profiling can segregate newly diagnosed patients into groups with different prognoses, and these biomarkers are being incorporated into a new generation of personalized clinical trials. Using the experience from recently completed large scale, multi-faceted, randomized glioblastoma clinical trials, a new clinical trial paradigm is being established to move promising therapies forward into the newly diagnosed treatment setting. Upcoming trials using the immune check-point inhibitors are an example of this changing paradigm and these and other immunotherapies have potential as promising new treatment modalities for newly diagnosed GB patients.

Fig. 1

Frequency, overlap, and relative survival of glioblastomas (GBs) (includes GB and all GB variants including gliosarcoma) based on molecular profile. Relative frequency of G-CIMP status, gene expression profiles, IDH1 mutation, and MGMT promoter methylation in GBs. IDH1 mutation and G-CIMP are depicted as discrete categories, while gene expression and MGMT methylation status are depicted as a continuum. GBs with a proneural gene expression profile and IDH1 mutations cluster almost exclusively within G-CIMP GBs, and have improved clinical outcomes (left side). Mesenchymal GBs are exclusively non-G-CIMP and IDH1 wild-type, and have inferior clinical outcomes. G-CIMP, CpG island methylator phenotype; IDH1 mut, isocitrate dehydrogenase 1 gene mutation; IDH1 wt, isocitrate dehydrogenase 1 wild-type gene. Adapted from Theeler BJ et al. [33], with permission from Wolters Kluwer Health, Inc.

Fig. 2

Example of a next generation phase II/III clinical trial for newly diagnosed GB. Patients are randomized after stratification by presence or absence of MGMT promoter methylation (MGMT), clinical factors (recursive partitioning analysis or RPA), and molecular features (gene expression profile or MCP). All patients receive standard temozolomide (TMZ) chemotherapy on days 1 to 42 during radiotherapy and on days 1 to 5 of 28-day cycles during adjuvant treatment. Patients will also receive a combination of placebo, ipilimumab (Ipi), or nivolumab (Nivo) in four treatment arms. A “pick the winner” trial design will be used during phase II to move the most efficacious treatment arm forward into a larger phase III clinical trial. A combination of OS, treatment-related toxicity, neurocognitive function (NCF), and symptom burden will be used to pick the best treatment (arms). Figure was created for this manuscript by the authors

Fig. 3

Example of imaging and pathologic features of pseudoprogression in a glioblastoma patient 4 months after completing chemoradiation. a Medial, right frontal lobe enhancing mass which was completely resected due to concern for tumor recurrence. Pathology revealed treatment-related necrosis, hyalinized blood vessels, and b gliosis (hematoxylin and eosin stain), and a small amount of residual tumor which was not mitotically active (not shown). Figure was created for this manuscript by the authors