Diffuse gliomas consist of both low- and high-grade varieties, each with distinct morphological and biological features. The often extended periods of relative indolence exhibited by low-grade ...gliomas (LGG; WHO grade II) differ sharply from the aggressive, rapidly fatal clinical course of primary glioblastoma (GBM; WHO grade IV). Nevertheless, until recently, the molecular foundations underlying this stark biological contrast between glioma variants remained largely unknown. The discoveries of distinctive and highly recurrent genomic and epigenomic abnormalities in LGG have both informed a more accurate classification scheme and pointed to viable avenues for therapeutic development. As such, the field of neuro-oncology now seems poised to capitalize on these gains to achieve significant benefit for LGG patients. This report will briefly recount the proceedings of a workshop held in January 2013 and hosted by Accelerate Brain Cancer Cure (ABC(2)) on the subject of LGG. While much of the meeting covered recent insights into LGG biology, its focus remained on how best to advance the clinical management, whether by improved preclinical modeling, more effective targeted therapeutics and clinical trial design, or innovative imaging technology.
The prognosis for glioblastoma is poor despite optimal therapy with surgery, radiation, and chemotherapy. New therapies that improve survival and quality of life are needed. Research has increased ...our understanding of the molecular pathways important for gliomagenesis and disease progression. Novel agents have been developed against these targets, including receptor tyrosine kinases, intracellular signaling molecules, epigenetic abnormalities, and tumor vasculature and microenvironment. This article reviews novel therapies for glioblastoma, with an emphasis on targeted agents.
Recently, there has been increasing interest in the use of targeted molecular agents for the treatment of malignant gliomas. These agents are generally well tolerated but have demonstrated only ...modest activity. In this article, the current status of targeted molecular agents for malignant gliomas will be reviewed and strategies to improve their effectiveness will be discussed.
Precise assessment of treatment response in glioblastoma during combined anti-angiogenic and chemoradiation remains a challenge. In particular, early detection of treatment response by standard ...anatomical imaging is confounded by pseudo-response or pseudo-progression. Metabolic changes may be more specific for tumor physiology and less confounded by changes in blood-brain barrier permeability. We hypothesize that metabolic changes probed by magnetic resonance spectroscopic imaging can stratify patient response early during combination therapy. We performed a prospective longitudinal imaging study in newly diagnosed glioblastoma patients enrolled in a phase II clinical trial of the pan-vascular endothelial growth factor receptor inhibitor cediranib in combination with standard fractionated radiation and temozolomide (chemoradiation). Forty patients were imaged weekly during therapy with an imaging protocol that included magnetic resonance spectroscopic imaging, perfusion magnetic resonance imaging, and anatomical magnetic resonance imaging. Data were analyzed using receiver operator characteristics, Cox proportional hazards model, and Kaplan-Meier survival plots. We observed that the ratio of total choline to healthy creatine after 1 month of treatment was significantly associated with overall survival, and provided as single parameter: (1) the largest area under curve (0.859) in receiver operator characteristics, (2) the highest hazard ratio (HR = 85.85,
= 0.006) in Cox proportional hazards model, (3) the largest separation (
= 0.004) in Kaplan-Meier survival plots. An inverse correlation was observed between total choline/healthy creatine and cerebral blood flow, but no significant relation to tumor volumetrics was identified. Our results suggest that in vivo metabolic biomarkers obtained by magnetic resonance spectroscopic imaging may be an early indicator of response to anti-angiogenic therapy combined with standard chemoradiation in newly diagnosed glioblastoma.
Targeted drug therapy for meningiomas Norden, Andrew D; Drappatz, Jan; Wen, Patrick Y
Neurosurgical focus,
2007, Letnik:
23, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Although advances in surgery, radiation therapy, and stereotactic radiosurgery have significantly improved the treatment of meningiomas, there remains an important subset of patients whose tumors are ...refractory to conventional therapy. Treatment with traditional chemotherapeutic agents has provided minimal benefit. In this review, the role of targeted molecular therapies for recurrent or progressive meningiomas is discussed.
Abstract
Background
Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) ...pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs.
Methods
Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6).
Results
Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated.
Conclusion
This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.
Molecular profiling has uncovered genetic subtypes of glioblastoma (GBM), including tumors with IDH1 mutations that confer increase survival and improved response to standard-of-care therapies. By ...mapping the genetic landscape of brain tumors in routine clinical practice, we enable rapid identification of targetable genetic alterations.
A 29-year-old male presented with new onset seizures prompting neuroimaging studies, which revealed an enhancing 5 cm intra-axial lesion involving the right parietal lobe. He underwent a subtotal resection and pathologic examination revealed glioblastoma with mitoses, microvascular proliferation and necrosis. Immunohistochemical (IHC) analysis showed diffuse expression of GFAP, OLIG2 and SOX2 consistent with a tumor of glial lineage. Tumor cells were positive for IDH1(R132H) and negative for ATRX. Clinical targeted-exome sequencing (DFBWCC Oncopanel) identified multiple functional variants including IDH1 (p.R132H), TP53 (p.Y126_splice), ATRX (p.R1302fs*), HNF1A (p.R263H) and NF1 (p.H2592del) variants and a NAB2-STAT6 gene fusion event involving NAB2 exon 3 and STAT6 exon 18. Array comparative genomic hybridization (aCGH) further revealed a focal amplification of NAB2 and STAT6. IHC analysis demonstrated strong heterogenous STAT6 nuclear localization (in 20 % of tumor cells).
While NAB2:STAT6 fusions are common in solitary fibrous tumors (SFT), we report this event for the first time in a newly diagnosed, secondary-type GBM or any other non-SFT. Our study further highlights the value of comprehensive genomic analyses in identifying patient-specific targetable mutations and rearrangements.
Reply to B. Freidlin et al Trippa, Lorenzo; Lee, Eudocia Q; Wen, Patrick Y ...
Journal of clinical oncology,
2013-Mar-01, Letnik:
31, Številka:
7
Journal Article
The spread of systemic cancer to the brain is a common complication for cancer patients. Conventional radiotherapy offers modest palliation, and surgery is helpful only for the patient with a single ...metastasis in an accessible location. Stereotactic radiosurgery, a technique that permits the precise delivery of a high dose of radiation to a small intracranial target while sparing the surrounding normal brain, has been used as an alternative treatment for brain metastases.
Our medical center's 7-year experience with radiosurgery for metastases was reviewed to establish the effectiveness of the treatment and to understand the prognoses in patients so treated.
Retrospective analysis of hospital records, from 248 consecutive patients (421 lesions) that were treated with radiosurgery between May 1986 and May 1993, was performed. Patients were only excluded for a Karnofsky performance score of less than 70, evidence of acute neurologic deterioration, or tumor diameter more than 4 cm. Median follow-up was 26.2 months. Seventy-six percent of patients had recurrent disease, 69% had evidence of systemic disease, 69% had a single metastasis. Treatment was performed using a 6-MeV linear accelerator. The median tumor volume was 3 cm3. The median treatment dose was 1500 cGy. Whole brain radiotherapy was given to all newly diagnosed patients. Patients were followed by neurological examination and neuroimaging at regular intervals. Local control of disease was defined as a lack of progression of solid-contrast enhancement on computed tomography scan or magnetic resonance imaging.
Median overall survival from radiosurgery was 9.4 months. The absence of active systemic disease, younger than 60 years of age, two or fewer lesions, and female sex were significantly associated with increased survival (two-sided P < .05). Actuarial local control rates were approximately 85% at 1 year and 65% at 2 years. Factors associated with a significantly decreased local control rate were location below the tentorium, recurrent tumor, and larger tumor volume (two-sided P < .05). Radioresponsive and radioresistant tumor types had similar control rates. The median drop in Karnofsky performance score at 1 year was 10%.
The results of this retrospective analysis show that radiosurgery is an effective, minimally invasive outpatient treatment option for small intracranial metastases. Results of this study also indicate that radiosurgery not only provides local control rates equivalent to those from surgical series but is also effective in treating patients with surgically inaccessible lesions, with multiple lesions, or with tumor types that are resistant to conventional treatment.
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