IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection

Background

IDH1 gene mutations identify gliomas with a distinct molecular evolutionary origin. We sought to determine the impact of surgical resection on survival after controlling for IDH1 status in malignant astrocytomas—World Health Organization grade III anaplastic astrocytomas and grade IV glioblastoma.

Methods

Clinical parameters including volumetric assessment of preoperative and postoperative MRI were recorded prospectively on 335 malignant astrocytoma patients: n = 128 anaplastic astrocytomas and n = 207 glioblastoma. IDH1 status was assessed by sequencing and immunohistochemistry.

Results

IDH1 mutation was independently associated with complete resection of enhancing disease (93% complete resections among mutants vs 67% among wild-type, P < .001), indicating IDH1 mutant gliomas were more amenable to resection. The impact of residual tumor on survival differed between IDH1 wild-type and mutant tumors. Complete resection of enhancing disease among IDH1 wild-type tumors was associated with a median survival of 19.6 months versus 10.7 months for incomplete resection; however, no survival benefit was observed in association with further resection of nonenhancing disease (minimization of total tumor volume). In contrast, IDH1 mutants displayed an additional survival benefit associated with maximal resection of total tumor volume (median survival 9.75 y for >5 cc residual vs not reached for <5 cc, P = .025).

Conclusions

The survival benefit associated with surgical resection differs based on IDH1 genotype in malignant astrocytic gliomas. Therapeutic benefit from maximal surgical resection, including both enhancing and nonenhancing tumor, may contribute to the better prognosis observed in the IDH1 mutant subgroup. Thus, individualized surgical strategies for malignant astrocytoma may be considered based on IDH1 status.     

Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201

Journal of Neuro-Oncology - Smoking is agreed to be a major health risk factor, but it is debated whether it has an influence on perioperative adverse events (AEs) in elective cranial tumor...     

Targeted Treatment of Brain Metastases

Purpose of Review

Brain metastases are the most common intracranial tumors in adults. Historically, the median survival after the diagnosis of brain metastases has been dismal and medical therapies had a limited role in the management of these patients.

Recent Findings

The advent of targeted therapy has ushered in an era of increased hope for patients with brain metastases. The most common malignancies that result in brain metastases—melanoma, lung cancer, and breast cancer, often have actionable mutations, which make them good candidates for targeted systemic therapy. These brain metastases have been shown to have relevant and sometimes divergent genetic alterations, and there has been a resurgence of interest in targeted drug delivery to the brain by using standard or pulsatile dosing to achieve adequate concentration in the brain.

Summary

An increased understanding of oncogenic alterations, a surge in targeted drug development with good blood barrier penetration, and inclusion of patients with active brain metastases on clinical trials have led to improved outcomes for patients with brain metastases.

     

Cerebellar glioblastoma: a retrospective review of 21 patients at a single institution

Primary cerebellar glioblastoma (CGB) comprises only 0.4–3.4% of all intracranial glioblastoma. The impact of surgical resection on survival and the efficacy of adjuvant therapies are uncertain as CGB is underrepresented in most studies. To elucidate prognostic factors we performed a single-institutional review of the largest series to date of CGB. The University of Texas MD Anderson Cancer Center database was reviewed from 1990 to 2010. Twenty-one consecutive patients met criteria for inclusion. The Kaplan–Meier product limit method was used to estimate overall survival (OS) and progression-free survival (PFS); groups were compared using the log-rank statistic. The multivariate Cox proportional hazards models were fitted to examine the association of resection with OS and PFS adjusted for other clinical variables. The median age was 39.9 years, and Karnofsky performance status (KPS) was ≥80 in 61.5% of patients. The mean extent of resection for contrast enhancement (EOR-CE) was 93.8% (SD = 10.4%; median = 100%), and the median follow-up was 18.4 months (range 1.5–116.1 months). There was no significant association of EOR with OS or PFS. On univariate analysis the presence of leptomeningeal disease (LMD) was associated with a worse OS (6.1 vs. 24.1 months; P = 0.0001) and PFS (3.3 vs. 9 months; P = 0.019). Patients who had adjuvant chemotherapy (CT) had extended PFS (10.1 vs. 2.8 months; P < 0.0001). Adjustment for the presence of leptomeningeal disease (LMD) tended toward an increased risk of progression (HR = 3.46; 95% confidence interval [CI], 0.83–14.5; P = 0.09) and was associated with a significantly increased risk of death (HR = 15.2; 95% CI, 1.3–180; P = 0.03). Having received adjuvant chemotherapy was associated with a decreased risk of progression (HR = 0.02; 95% CI, 0–0.26; P = 0.003). The presence of LMD is a critical factor in the clinical behavior of CGB resulting in markedly decreased OS and PFS. Adjuvant CT resulted in increased PFS but did not significantly affect OS. This was due to a lack of a sizable cohort who did not receive chemotherapy. Furthermore, three of the CT-naïve patients received CT at first progression. In the context of the high EOR in this study, an OS of 18.4 months was achieved.     

Cytokines associated with toxicity in the treatment of recurrent glioblastoma with aflibercept

Plasma profiling of patients treated with antiangiogenic agents may identify markers that correlate with toxicity. Objectives were to correlate changes in cytokine and angiogenic factors as potential markers of toxicity to aflibercept. Circulating cytokine and angiogenic factors were measured in 28 patients with recurrent glioblastoma in a single-arm phase II study of aflibercept. Plasma samples were analyzed at baseline, 24 h, and 28 days using multiplex assays or ELISA. We evaluated log-transformed baseline biomarker expressions with Cox proportional hazard regression models to assess the effect of markers on any grade II–IV (Gr II–IV) toxicity, on-target toxicity (hypertension, proteinuria, thromboembolism), and fatigue. All tests were two sided with a statistical significance level of p?=?0.05. Among 28 pts, there were 116 Gr II–IV events. Changes in IL-13 from baseline to 24 h predicted on-target toxicities. Increases in IL-1b, IL-6, and IL-10 at 24 h were significantly associated with fatigue. Progression-free survival was 14.9 months for patients in the all-toxicity group and 9.0 months for patients in the on-target toxicity group compared to 4.3 months for those who did not develop any Gr II–IV toxicity (p?=?0.002 and p?=?0.045, respectively). Toxicity from antiangiogenic therapy remains an important cause of antiangiogenic treatment discontinuation and patient morbidity. Changes in IL6, IL10, and IL13 were repeatedly correlated with toxicity. Profiling of IL-13 as a surrogate for endothelial dysfunction could individualize patients at risk during antiangiogenic therapy, as could identifying those at higher risk for fatigue using IL-6 and IL-10.