Advances in Treatment Options for High-grade Glioma Figure 1: Aberrant Pathways in High-grade Glioma and Selected Targeted Agents VEGF: afibercept
EGF: cetuximab, nimotuzumab SF/HGF: AMG 102 VEGF: bevacizumab
GF RTK PIP3 XL 765 Akt
Sirolimus, deferolimus, everolimus, temsirolimus
PI3K PTEN
Perifosine, MK2206
PKC mTOR
ABT 888, BSI 201
PARP Vorinostat HDAC DNA repair PIP2 RAS (inactive)
Lonafarnib, tipifarnib
Enzastaurin ERK
Client protein
Proteosome Gene transcription Nucleus Bortezomib
EGFR = epidermal growth factor receptor; ERK = extracellular signal-regulated kinase; HDAC = histone deacetylase; HGF = hepatocyte growth factor; HSP90 = heat shock protein 90; MEK = methyl ethyl ketone; mTOR = mammalian target of rapamycin; PARP = poly (ADP-ribose) polymerase; PDGFR = platelet-derived growth factor receptor; PI3K = phosphatidylinositol 3-kinase; PKC = protein kinase C; PTEN = phosphatase and tensin homologue; RTK = receptor tyrosine kinases; SF = scatter factor; VEGFR = vascular endothelial growth factor receptor. Source: Quant EC, Wen PY, Neuroimaging Clin N Am, 2010;20(3): in press.
regimens have marginal efficacy.41 Table 1 summarises the standard therapeutic options for GBM.
Chemotherapy for Anaplastic Glioma
Due to the paucity of randomised clinical trials, there is no consensus in terms of treatment of newly diagnosed anaplastic gliomas (AGs). The recent Randomized Phase III Study of Sequential Radio- chemotherapy of Anaplastic Glioma With PCV or Temozolomide (NOA-04) that randomised patients with AG to initial radiation followed by chemotherapy (temozolomide or PCV) at progression or initial chemotherapy followed by radiation at progression showed no difference in PFS between the two groups, regardless of histology.42 Commonly used adjuvant regimens for anaplastic astrocytoma (AA) following biopsy or surgery include RT with temozolomide (using a similar regimen to GBM) or RT with adjuvant temozolomide only. An ongoing randomised phase III trial of radiation versus radiation plus temozolomide in non-1p/19q co-deleted AG patients may provide further guidance on management of AA.
Tumours with oligodendroglial components, including anaplastic oligodendrogliomas (AO) and anaplastic oligoastrocytomas (AOAs), are less common than AA. However, they have a better prognosis than pure astrocytic tumours and may have increased sensitivity to treatment.43
of chromosomes 1p and 19q43 19p to 1q.44
to PCV chemotherapy4,45
The majority of AOs and 14–20% of AOAs have deletions due to an unbalanced translocation of
with an increase in response rate from 34 to 59% in one study.26
Tumours with 1p/19q co-deletion are particularly sensitive and likely have sensitivity to temozolomide, The
value of PCV chemotherapy in combination with RT for newly diagnosed AO/AOA has been evaluated in two large phase III trials.46,47 Although neither study showed an overall survival benefit, patients treated with both RT and PCV chemotherapy had 10–12 months of additional PFS compared with RT alone. As previously mentioned, the
EUROPEAN NEUROLOGICAL REVIEW
NOA-04 trial that randomised AG patients to initial radiation or to initial chemotherapy (PCV or temozolomide) did not demonstrate a difference in PFS, regardless of treatment.42
In all of these studies,
1p/19q co-deletion and MGMT status were associated with marked survival prolongation.
As most published studies in AO/AOA were initiated prior to 2005, the majority of available data involve PCV chemotherapy. Although the NOA-04 study was not powered to directly compare PCV and temozolomide, no PFS difference was observed between patients randomised to initial PCV versus initial temozolomide,42
although
temozolomide may be associated with less toxicity than PCV.43 Several large intergroup trials are under way evaluating the optimal combination of RT and temozolomide in patients with newly diagnosed AO/AOA.
Experimental Therapies Targeted Molecular Therapies
With improved understanding of the pathways that drive gliomagenesis, targeted molecular therapy has emerged as an important treatment paradigm in HGG in the upfront and recurrent setting. Many investigational drugs target signal transduction pathways involved in cell proliferation, growth, survival, adhesion, motility and differentiation.48
Targets of particular importance include
receptor tyrosine kinases (RTK) such as vascular endothelial growth factor receptor (VEGFR), integrins, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and cMet. RTKs may be inhibited extracellularly by monoclonal antibodies (mAb) and intracellularly by tyrosine kinase inhibitors (TKIs). Inhibitors of intracellular signalling molecules are also being developed against downstream signalling targets such as phosphatidylinositol 3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), Raf and methyl ethyl ketone (MEK). Figure 1 is a schematic of these pathways.
51 RAF MEK STAT3 17-AAG Dasatinib HSP90 Sorafenib
Client protein
HSP90
RAS (active)
Src JAK
EGFR: erlotinib, gefitinib, lapatinib, vandetanib, BIBW 2992 PDGFR: imatinib, cediranib, dasatinib, pazopanib, sorafenib, sunitinib, tandutinib, vatalanib VEGFR: cediranib, dasatinib, pazopanib, sorafenib, suntinib, vandetinib, vatalanib
Integrins
Cilengitide
GF
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