What Next for Newly Diagnosed Glioblastoma?

Abstract

Glioblastoma is the most common primary brain tumor in adults. Despite current multimodality treatment including surgical resection and temozolomide-based chemoradiotherapy, median survival is only 14-16 months. Characterization of molecular alterations in glioblastoma has identified prognostic subgroups and therapeutic opportunities for clinical trials across glioblastoma subsets. Following a number of negative Phase III trials testing temozolomide dose intensification and angiogenesis inhibition, recent interim analysis data indicate survival prolongation with use of a device (Optune™) delivering alternating electrical field therapy in newly diagnosed glioblastoma patients. In this review, we present an overview of the data supporting the current standard of care and discuss novel experimental therapies in early and late phase clinical testing including devices, small molecule drugs, angiogenesis inhibitors, oncolytic virotherapy and immunotherapy. KEYWORDSGlioblastoma (grade IV astrocytoma) is the most common primary brain tumor in adults. Median survival is 14-16 months after diagnosis, and survival following progression is on average only 6-8 months [1]. The WHO classification of grade IV astrocytomas also includes gliosarcoma, which shares clinical and genetic similarities with glioblastoma, and giant cell glioblastoma, which represents a distinct subset with comparatively better prognosis [2][3][4]. A new version of WHO c lassification incorporating molecular markers is expected to be released in spring 2016.In the past decade, there have been important gains in our understanding of genetic alterations associated with gliomagenesis, although this knowledge to date has not been translated into significant survival improvements. Better understanding of key pathways driving tumor growth and development and the role of the tumor microenvironment extends the promise of further improvements in therapy. Surgery, radiation and chemotherapy have established roles with some room for refinement, but new devices, small molecule cell cycle inhibitors, biologic and immune-based therapies have started yielding promising results in Phase II and early readings of Phase III trials and create optimism for future changes in the treatment landscape and standard of care. Standard-of-care therapyThe standard backbone in the treatment of newly diagnosed glioblastoma is surgical resection, when feasible, followed by radiation therapy (RT) administered concurrently with oral temozolomide (TMZ), followed by six cycles of adjuvant TMZ therapy. RT for glioblastoma has formed the basis of postoperative therapy for decades [5]; developments in radiation delivery techniques have led to the current standard of involved field RT at a dose of 60 Gy delivered in 30 fractions. Increasing RT dose up to 90 Gy has been studied, and it provides no additional benefit regardless of the For reprint orders, please contact: reprints@futuremedicine.com

PAXX Participates in Base Excision Repair via Interacting with Pol β and Contributes to TMZ Resistance in Glioma Cells

“…So, DNA repair is believed to be one of the major fields for discovering new drugs that may overcome resistance of DNA damaging agents. TMZ was originally approved by US Food and Drug Administration in 1999 for treatment of refractory adult anaplastic astrocytoma (Middleton et al 2000 ) and newly diagnosed glioblastoma since in adult in 2005 (Domingo-Musibay and Galanis 2015 ). Unfortunately, major portion of glioma patients developed TMZ resistance and left with very limited options for alternative chemotherapeutic drugs.…”

Stability of Programmable Shunt Valve Settings with Simultaneous Use of the Optune Transducer Array: A Case Report

“…However, the relatively localized magnetic field introduced by the Optune differs importantly from that of the magnetic field of an MRI. Patients undergoing therapy with an Optune transducer array experience electric fields that are at highest intensity at the tumor site, thereby decreasing field interference with the magnetic shunt valves [ 6 ]. Indeed, we demonstrate that the Optune transducer array does not alter the stability of the Strata NSC shunt setting, likely due to the ability of NovoTTF to generate its manageable alternating electric fields.…”

The Personalisation of Glioblastoma Treatment Using Whole Exome Sequencing: A Pilot Study

“…The current standard treatment regime for GBM patients involves surgery, radiotherapy and treatment with the chemotherapy drug temozolomide (TMZ) [11,17,18]. This regime remains largely ineffective, with recurrence common and survival rates poor.…”

“…With MGMT promotor methylation being identified as an important factor influencing response to TMZ it has consequently been used to stratify patients in clinical trials [14,15,18]. While this is an important step in associating molecular factors to drug response, more biomarkers for response to different therapies need to be identified.…”