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Background The optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma. Methods Between 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Results For all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2–10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3–6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter 27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. Conclusions Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.

Following the identification of key molecular alterations that provided superior prognostication and led to the updated 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification, the understanding of glioma behavior has rapidly evolved. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are present in the majority of adult grade 2 and 3 gliomas, and when used in conjunction with 1p/19q codeletion for classification, the prognostic distinction between grade 2 versus grade 3 is diminished. As such, the previously often used term of “low-grade glioma,” which referred to grade 2 gliomas, has now been replaced by the phrase “lower-grade glioma” to encompass both grade 2 and 3 tumors. Additional molecular characterization is ongoing to even further classify this heterogeneous group of tumors. With such a colossal shift in the understanding of lower-grade gliomas, management of disease is being redefined in the setting of emerging molecular-genetic biomarkers. In this article, we review recent progress and future directions regarding the surgical, radiotherapeutic, chemotherapeutic, and long-term management of adult lower-grade gliomas.

The treatment of newly diagnosed oligodendroglioma has been revolutionized in the past decade by multiple studies demonstrating that the addition of chemotherapy to radiation therapy results in a significant survival benefit. While the most direct evidence comes from clinical trials that utilized PCV, a chemotherapy regimen consisting of procarbazine, CCNU (lomustine), and vincristine, there is circumstantial evidence suggesting that the oral agent temozolomide (TMZ), which is both better tolerated and logistically simpler than PCV, may also be effective. The lack of currently available direct comparative data for PCV vs TMZ results in a diversity of practice. In this article, Ruff and Buckner argue for PCV as part of the standard-of-care regimen for newly diagnosed anaplastic oligodendroglioma, while Geurts and van den Bent defend the use of TMZ.

PURPOSE NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375 ) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

Purpose Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. Methods and Materials NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher’s exact tests. Results Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P = .01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P = .66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P = .14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P = .09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P = .18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade ≥3 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P = .03). Conclusions This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care.

Aims Rhabdomyosarcomas of bone are extremely rare, with fewer than 10 reported cases. A very rare subtype of spindle cell/sclerosing rhabdomyosarcoma harbouring a FUS-TFCP2 fusion and involving both soft tissue and bone locations has been reported very recently. We report only the fourth case of this unusual, clinically aggressive rhabdomyosarcoma. Material and results A previously well 72-year-old male presented with a destructive lesion of the mandible. Morphological and immunohistochemical study of a needle biopsy and the subsequent resection showed a spindle cell rhabdomyosarcoma. RNA-seq, RT-PCR and FISH confirmed the presence of the FUS-TFCP2 fusion. Conclusions Spindle cell rhabdomyosarcomas carrying the FUS-TFCP2 fusion are very rare rhabdomyosarcoma variants with osseous predilection. The classification and differential diagnosis of this unusual molecular variant of spindle cell/sclerosing rhabdomyosarcoma are discussed.

Background Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. Methods Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. Results The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. Conclusions The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

To determine whether whole-brain radiation therapy (WBRT) is associated with improved overall survival among non-small cell lung cancer (NSCLC) patients with favorable prognoses at diagnosis.In the N0574 trial, patients with 1 to 3 brain metastases were randomized to receive stereotactic radiosurgery (SRS) or SRS plus WBRT (SRS + WBRT), with a primary endpoint of cognitive deterioration. We calculated diagnosis-specific graded prognostic assessment (DS-GPA) scores for NSCLC patients and evaluated overall survival according to receipt of WBRT and DS-GPA score using 2 separate cut-points (≥2.0 vs2.0 and ≥2.5 vs2.5).A total of 126 NSCLC patients were included for analysis, with median follow-up of 14.2 months. Data for DS-GPA calculation were available for 86.3% of all enrolled NSCLC patients. Overall, 50.0% of patients had DS-GPA score ≥2.0, and 23.0% of patients had DS-GPA scores ≥2.5. The SRS and SRS + WBRT groups were well balanced with regard to prognostic factors. The median survival according to receipt of WBRT was 11.3 months (+WBRT) and 17.9 months (-WBRT) for patients with DS-GPA ≥2.0 (favorable prognoses, P=.63; hazard ratio 0.86; 95% confidence interval 0.47-1.59). Median survival was 3.7 months (+WBRT) and 6.6 months (-WBRT) for patients with DS-GPA2.0 patients (unfavorable prognoses, P=.85; hazard ratio 0.95; 95% confidence interval 0.56-1.62). Outcomes according to the receipt of WBRT and DS-GPA remained similar utilizing DS-GPA ≥2.5 as a cutoff for favorable prognoses. There was no interaction between the continuum of the DS-GPA groups and WBRT on overall survival (P=.53).We observed no significant differences in survival according to receipt of WBRT in favorable-prognosis NSCLC patients. This study further supports the approach of SRS alone in the majority of patients with limited brain metastases.

BACKGROUND PCV+RT substantially prolongs survival in AO patients, but long-term CF and QOL implications are unclear. We compared CF and QOL by treatment arm in RTOG 9402 participants and evaluated the impact that baseline characteristics had on CF, QOL, and survival. METHODS CF and QOL were evaluated using the Mini Mental State Exam (MMSE) and Brain-Quality of Life (B-QOL) scale at baseline and annually. Scores were analyzed between treatment arms at each time point for patients with ≥ 10 years of follow-up data. Shared parameter models evaluated MMSE and B-QOL scores and survival for all patients. RESULTS 42/148 (28.4%) participants in PCV+RT and 20/143 (14%) in RT alone arms survived ≥ 10 years. 35/42 and 39/42 (PCV+RT) and 18/20 and 17/20 (RT) participants completed baseline B-QOL and MMSE assessments, respectively. B-QOL scores did not differ between treatment groups at any time-point. Among 16 patients (10 PCV+RT, 6 RT) who completed year 10 MMSE evaluations, mean MMSE score at 10 years was higher in the RT arm (29.83 [95% CI 22.1, 30.0] vs. 26.50 [95% CI 29.4, 30.0], P= 0.04). Change in MMSE and B-QOL scores from baseline did not differ significantly between treatment groups at any time. In shared parameter models including all patients with baseline assessments, MMSE and B-QOL scores decreased over time (MMSE P= 0.0189, B-QOL P= 0.0005), but this did not differ by treatment group (MMSE P= 0.5727, B-QOL P= 0.3592). Younger age and higher KPS predicted better scores (MMSE P < 0.0001, P = 0.0002; B-QOL P = 0.0043, P = 0.0007). PCV+RT predicted better survival in both models. CONCLUSIONS PCV+RT improves survival in AO. Shared parameter models show decrease in MMSE and B-QOL over time. However, relative to RT alone, the addition of PCV did not impact change in CF and QOL over time.

The blood–brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.

BACKGROUND: Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. METHODS: Patients received oral vorinostat (300 or 400 mg/day) on days 1–5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1–7 and 15–21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. RESULTS: Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m(2)/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. CONCLUSIONS: Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.

PURPOSE To provide a final update on oncologic and cognitive outcomes of high dose versus low dose radiation for low-grade glioma. METHODS Between 1986 and 1994, 203 patients with supratentorial low grade glioma were randomized to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Histologic subtype was oligodendroglioma (71%) or astrocytoma (29%). Primary outcome was overall survival (OS). Cognitive status was followed using Folstein Mini-Mental State Examination (MMSE). RESULTS For the entire cohort of 203 patients, median OS was 8.4 years (95% CI: 7.2 – 10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3 – 6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve OS (15-yr OS: 22.4% vs. 24.9%, log rank p=0.978) or PFS (15-yr PFS: 15.2% vs. 9.5%, p=0.7142). OS was significantly better for patients with pre-operative tumor diameter < 5 cm (15-yr OS: 39.4% vs. 15.2%, p< 0.001), baseline MMSE > 27 (15-yr OS: 27.3% vs. 9.8%, p=0.001), and for patients who underwent gross total resection (GTR) (15-yr OS: 39.3% GTR vs. 16.4% subtotal resection vs. 24.5% biopsy only, p=0.0119). PFS was improved for patients with oligodendroglioma versus astrocytoma (15-yr PFS: 13.8% vs. 8.6%, p=0.0221). PFS was also improved for patients with pre-operative tumor diameter < 5 cm, patients who had GTR, and patients with baseline MMSE > 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. CONCLUSIONS Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Minimal late decline in cognitive function after radiation was seen by MMSE. SUPPORT: U10CA180821,U10CA180882. https://acknowledgments.alliancefound.org

In the context of the new WHO classification system, all low-grade gliomas must have an IDH mutation, with or without 1p/19q codeletion. Upon discovery of the tumor, maximal safe surgical resection is the most appropriate first step due to the current inability to differentiate between IDH mutant and IDH wild–type tumors by imaging alone. In the postoperative setting, based on the synthesis and interpretation of the available data, we recommend utilizing conventional radiation therapy and PCV in all high-risk–low-grade gliomas. For patients felt to be in a low risk category, we recommend maintaining a low threshold to initiate treatment. In the setting of tumor recurrence, consideration of all treatment options is reasonable, but treatment with alkylator therapy has the strongest supporting data.

Oligodendrogliomas are now defined by the presence of whole-arm co-deletion in chromosomal arms 1p and 19q. The treatment paradigm for oligodendroglioma has shifted, owing to new diagnostic criteria and phase III clinical trial evidence. The treatment with radiation therapy plus chemotherapy with procarbazine, lomustine, and vincristine (PCV) results in prolongation of both progression-free and OS compared to treatment with radiation alone. Clinical trials, including RTOG 9402, EORTC 26951, and RTOG 9802, in contrast to NOA-04 and EORTC 22033, have conclusively demonstrated that chemoradiation is superior to either radiation therapy alone or chemotherapy alone for patients with oligodendroglioma. Regardless of grade, PCV chemotherapy, in addition to radiation, has a clear benefit in patients with oligodendroglioma and IDH mutated astrocytoma. Temozolomide may be less effective in the treatment of oligodendroglioma, but clearly has a benefit in astrocytoma.

Background: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM. Methods: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6). Results: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P=.22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3months and 7.7months, respectively; P=.93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P=.52), but with a significantly longer duration in patients treated on arm A (16.3months vs 2months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome. Conclusions: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.

Purpose: To evaluate the pharmacokinetics and efficacy of imatinib in patients with recurrent oligodendroglial tumors. Methods: Patients with progressive WHO grade II-III recurrent tumors after prior RT and chemotherapy were eligible. A phase I dose-escalation study was conducted for patients on enzyme-inducing anticonvulsants (EIAC). A phase II study for non-EIAC patients utilized a fixed dose of 600mg/D. Primary efficacy endpoint was 6-month progression-free survival (PFS6). A 2-stage design was utilized, with 90% power to detect PFS6 increase from 25 to 45%. Results: In the Phase I, maximum tolerated dose was not reached at 1200mg/D. For phase II patients, overall PFS6 was 33% and median PFS 4.0months (95% CI 2.1, 5.7). Median overall survival (OS) was longer in imatinib-treated patients compared with controls (16.6 vs. 8.0months; HR = 0.64, 95% CI 0.41,1.0, p = 0.049), and longer in patients with 1p/19q-codeleted tumors (19.2 vs. 6.2months, HR = 0.43, 95% CI 0.21,0.89, p = 0.019). Confirmed response rate was 3.9% (PR = 1; REGR = 1), with stable disease observed in 52.9%. At 600mg/D, mean steady-state imatinib plasma concentration was 2513ng/ml (95% CI 1831,3195). Grade 3–4 adverse events (hematologic, fatigue, GI, hypophosphatemia, or hemorrhage) occurred in 61%. Conclusions: Although adequate plasma levels were achieved, the observed PFS6 of 33% did not reach our pre-defined threshold for success. Although OS was longer in imatinib-treated patients than controls, this finding would require forward validation in a larger cohort. Imatinib might show greater activity in a population enriched for PDGF-dependent pathway activation in tumor tissue.

Accurate pathologic diagnoses and molecularly informed treatment decisions for a wide variety of cancers depend on robust clinical molecular testing that uses genomic, epigenomic, and transcriptomic-based tools. Nowhere is this more essential than in the workup of brain tumors, as emphasized by the incorporation of molecular criteria into the 2016 World Health Organization classification of central nervous system tumors and the updated official guidelines of the National Comprehensive Cancer Network. Despite the medical necessity of molecular testing in brain tumors, access to and utilization of molecular diagnostics is still highly variable across institutions, and a lack of reimbursement for such testing remains a significant obstacle. The objectives of this review are (i) to identify barriers to adoption of molecular testing in brain tumors, (ii) to describe the current molecular tools recommended for the clinical evaluation of brain tumors, and (iii) to summarize how molecular data are interpreted to guide clinical care, so as to improve understanding and justification for their coverage in the routine workup of adult and pediatric brain tumor cases.

Background Optimum management of low-grade gliomas remains controversial, and widespread practice variation exists. This evidence-based meta-analysis evaluates the association of extent of resection, radiation, and chemotherapy with mortality and progression-free survival at 2, 5, and 10 years in patients with low-grade glioma. Methods A quantitative systematic review was performed. Inclusion criteria included controlled trials of newly diagnosed low-grade (World Health Organization Grades I and II) gliomas in adults. Eligible studies were identified, assigned a level of evidence for every endpoint considered, and analyzed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relative risk of mortality and of progression at 2, 5, and 10 years was calculated for patients undergoing resection (gross total, subtotal, or biopsy), radiation, or chemotherapy. Results Gross total resection was significantly associated with decreased mortality and likelihood of progression at all time points compared to subtotal resection. Early radiation was not associated with decreased mortality; however, progression-free survival was better at 5 years compared to patients receiving delayed or no radiation. Chemotherapy was associated with decreased mortality at 5 and 10 years in the high-quality literature. Progression-free survival was better at 5 and 10 years compared to patients who did not receive chemotherapy. In patients with isocitrate dehydrogenase 1 gene (IDH1) R132H mutations receiving chemotherapy, progression-free survival was better at 2 and 5 years than in patients with IDH1 wild-type gliomas. Conclusions Results from this review, the first to quantify differences in outcome associated with surgery, radiation, and chemotherapy in patients with low-grade gliomas, can be used to inform evidence-based management and future clinical trials.

e13603 Background: Over half of Americans report favoring access to experimental treatments even if they have yet to be proven either safe or effective, yet only 3-5% are enrolled in clinical trials and a fraction of a percent in expanded access. The Expanded Access (EA) program (aka “compassionate use”) and Right-to-Try (RTT) are parallel federal mechanisms that offer qualifying patients access to off-trial experimental treatments. Our study aimed to capture the views and experiences of oncologists on obtaining eligible medicine using the FDA’s EA and is the first to report findings on physician attitudes toward RTT. Methods: We conducted 21 semi-structured interviews and qualitative analysis of oncologists at a major cancer center with 3 main sites across the U.S. Participants were purposely selected to have experience with EA. Results: Oncologists’ considerations for offering EA options to patients were based on a sound scientific rationale, reasonable risk-benefit ratio, functional status of the patient, and patient motivation. Although oncologists’ experience positively correlated with level of ease in navigating EA, most remained largely unfamiliar with RTT. Only 4 oncologists had experience discussing RTT with patients and none had obtained an experimental therapeutic under this pathway. When informed about RTT, oncologists articulated 3 sets of concerns including limited safety and oversight, unclear structure and lack of requirements to collect and report data, and the potential for inflating patient expectations. Published work by others have shown that patients desire experimental options to be offered and report that physicians do not always offer experimental medicine taking into account factors, such as, reimbursement. Given that oncologists may factor in variables such as patient motivation, and potentially affordability or health literacy, when considering whether experimental medicine is appropriate to offer their patient, there may be a need to develop a conversation aid so that clinically relevant options are presented to patients equitably and patient choice is enhanced. Conclusions: Further research to better understand patient perspectives and potential discordant views between patients and oncologists is needed in order to design shared decision-making tools to inform oncologists about off-trial preapproval pathways and help both oncologists and patients navigate the thorny issues of experimental oncology.

Purpose: Imaging biomarker research focuses on discovering relationships between radiological features and histological findings. In glioblastoma patients, methylation of the O6-methylguanine methyltransferase (MGMT) gene promoter is positively correlated with an increased effectiveness of current standard of care. In this paper, the authors investigate texture features as potential imaging biomarkers for capturing the MGMT methylation status of glioblastoma multiforme (GBM) tumors when combined with supervised classification schemes. Methods: A retrospective study of 155 GBM patients with known MGMT methylation status was conducted. Co-occurrence and run length texture features were calculated, and both support vector machines (SVMs) and random forest classifiers were used to predict MGMT methylation status. Results: The best classification system (an SVM-based classifier) had a maximum area under the receiver-operating characteristic (ROC) curve of 0.85 (95% CI: 0.78–0.91) using four texture features (correlation, energy, entropy, and local intensity) originating from the T2-weighted images, yielding at the optimal threshold of the ROC curve, a sensitivity of 0.803 and a specificity of 0.813. Conclusions: Results show that supervised machine learning of MRI texture features can predict MGMT methylation status in preoperative GBM tumors, thus providing a new noninvasive imaging biomarker.

BackgroundGrade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results. MethodsWe included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy...

Seizures occur in most patients with primary malignant tumors and are associated with poor quality of life. To our knowledge, no previous studies have sought descriptions of quality of life in patients' own words. Patients with a history of a malignant primary brain tumor and seizures participated in semi-structured interviews, which were analyzed with qualitative methodology. Twenty-seven patients participated, most with high grade brain tumors. Most were receiving anti-seizure medication. Three distinct themes emerged: (1) the first seizure as a sentinel event, as manifested in part by how patients described their first seizure in remarkable detail ("I clearly remember the date…"); (2) seizures as inextricably tied to the brain tumor itself; for example, one patient explained how he "always wondered what was happening with my brain tumor" with each seizure; and (3) adaptation and acceptance-or lack therefore-to seizures. With respect to this third theme, patients conveyed frustration from an inability to work, to drive, and to take care of their children ("It's like you are 15 all over again.") Others described frustration with taking antiseizure medications ("I felt like an 80 year old, now taking her pills every day"). However, some patients had adapted or resigned themselves ("…so much of life is out of control-you just gotta take what you get."). These findings have future research implications but should also serve to make healthcare providers more aware of the heavy emotional burden that seizures thrust upon brain tumor patients.

e24176 Background: Decision aids for prostate cancer treatment can improve knowledge, but the relative effect of pre-consultation and within-consultation DAs is not known. Methods: We conducted a parallel design, 2-by-2 factorial, 4-arm, cluster-RCT in urology practices affiliated with the NCI’s Alliance research base. We compared patient knowledge immediately after consultation (%12-item% correct) intervention arms compared to usual care. We used mixed effects regression modeling to assess effect of interventions on knowledge adjusting for site-clustering, race/ethnicity (non-Hispanic White; Other), age (years), clinical stage (T1-3), PSA, and Gleason score. Results: 15 of 21 randomized centers accrued 158 pts from Nov 2017 to June 2019. The arm delivering both DAs (n = 3 sites) recruited 25 pts. The pre-consultation DA arm (n = 4 sites) recruited 39 pts. The within-consultation DA arm (n = 4 sites) recruited 44 pts. The no DA arm (n = 4 sites) accrued 50 pts. Overall, mean age was 64; 54% were AA; 73% had T1 stage; median Gleason = 7; and median PSA = 7. The combined DAs group, followed by pre-consultation reported higher median knowledge (75% and 67%, respectively). The within-consultation and no DA arms both reported median knowledge scores (58%). Within arm, inter-site standard deviations in mean knowledge scores ranged from 0.164 in in the pre-consultation arm to 0.232 in the usual care arm. Neither pre-consultation nor within-consultation DAs had statistically significant effects (p = .15 and p = .99, respectively). Pre-specified adjusted difference [97.5% CIs], comparing the pre-consultation DA and the within-consultation DA with the control was 9.4% [-7.3%, 26.2%] and -0.4% [-16.9%, 16.1%], respectively. Intra-cluster correlation (ICC) coefficient was high (.24). No interaction effects were identified (p = .98). A post-hoc analysis comparing any DA vs usual care found a mean adjusted difference [95% CI] of 5.6% [-8.5%, 19.8%] (p = 0.40), 63.9% for any DA and 58.3% for usual care. Conclusions: Possible knowledge gains associated with some DAs for early prostate cancer were obscured by larger-than-expected intra-cluster correlation effects associated with the primary outcome. How interventions were used was not measured. Support:UG1CA189823; https://acknowledgments.alliancefound.org ; R01 MD008934-06. Clinical trial information: NCT03103321 .

BACKGROUND: 18F-DOPA-PET thresholds reliably delineate areas of high-grade astrocytoma not otherwise recognized with standard MRI and may more accurately identify regions of aggressive, high-density disease. Herein we report the preliminary safety and feasibility data from an ongoing phase II study (MC1374; R01CA178200) evaluating 18F-DOPA-PET guided-dose-escalated radiotherapy for glioblastoma. METHODS: Newly diagnosed glioblastoma patients without contra-indications to 18F-DOPA-PET are eligible for study enrollment. Target volumes include: CTV51Gy=T1-gadolinium contrast-enhancing (T1-CE) disease, T2 FLAIR signal abnormality, and low-grade 18F-DOPA-PET uptake, +1cm; CTV60Gy=T1-CE and high-grade 18F-DOPA-PET uptake, +1cm; and CTV76Gy=T1-CE and high-grade 18F-DOPA-PET disease without expansion all given in 30 fractions simultaneously. Patients are followed with 18F-DOPA-PET in addition to standard clinical follow-up. Safety stopping rule specifies that after 10 or more patients have been enrolled, if more than 10% experience any of the following adverse events considered to be at least possibly related to treatment, enrollment will be suspended: Grade 3 or 4 irreversible CNS toxicity, Grade 4 non-hematologic, non-CNS toxicity, any Grade 5 toxicity. Futility analysis (and primary study aim) is powered to consider a success to be an MGMT-unmethylated patient who is without progression within 6 months from the time of craniotomy. If 16 or more successes are observed in the first 25 evaluable patients study will continue. RESULTS: 77 patients have been accrued since December 2013 with 68 evaluable for toxicity. Grade 3 CNS necrosis was noted in 3 (4.4%) patients; 2 additional patients developed symptoms that resolved in the subsequent cycle so did not count towards stopping rule. Other grade 3+ toxicities include: 1 patient with pre-existing vision dysfunction had Grade 4 optic nerve dysfunction; 2 Grade 4 hematologic events and 1 Grade 5 event(sepsis) due to temozolamide-induced cytopenias. CONCLUSION: 18F-DOPA-PET -guided dose escalation appears reasonably safe and tolerable in patients with high-grade glioma.

Background The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy.

Predicting methylation of the O6-methylguanine methyltransferase (MGMT) gene status utilizing MRI imaging is of high importance since it is a predictor of response and prognosis in brain tumors. In this study, we compare three different residual deep neural network (ResNet) architectures to evaluate their ability in predicting MGMT methylation status without the need for a distinct tumor segmentation step. We found that the ResNet50 (50 layers) architecture was the best performing model, achieving an accuracy of 94.90% (+/− 3.92%) for the test set (classification of a slice as no tumor, methylated MGMT, or non-methylated). ResNet34 (34 layers) achieved 80.72% (+/− 13.61%) while ResNet18 (18 layers) accuracy was 76.75% (+/− 20.67%). ResNet50 performance was statistically significantly better than both ResNet18 and ResNet34 architectures (p

Despite recent randomized, prospective evidence supporting use of RT and chemotherapy (CRT) for high-risk low-grade gliomas (LGG), many patients have historically received RT alone, chemotherapy alone or observation postoperatively. The purpose of this study is to evaluate outcomes for historical treatments in comparison to CRT for high-risk diffuse WHO grade II glioma patients. Records from 309 adults with WHO grade II glioma (1997-2008) eligible for RTOG 9802 (incomplete resection/biopsy or age ≥40 years) were retrospectively reviewed. Kaplan-Meier estimates were used for progression-free survival (PFS) and overall survival (OS). The Cox proportional hazards model was used for estimates of risk ratios for univariate and multivariate analyses. Median follow-up was 10.6 years. Adjuvant treatments included radiotherapy (RT) alone (45%), observation (31%), CRT (21%) and chemotherapy alone (3%). Non-astrocytic histology, TERT promoter mutation, 1p/19q codeletion and extensive resections were associated with improved PFS and OS on univariate analysis (all p

2025 Background: Low-grade gliomas (LGG) account for 17-22% of all primary brain tumors. Optimal surgical management consists of optimum safe resection with the goal of complete resection. We performed a systematic review and meta-analysis to quantify the association of extent of resection with likelihood of survival, expressing our results in numbers needed to treat (NNT). Methods: A systematic review and study-level meta-analysis to determine the association of resection with overall survival and progression-free survival in newly diagnosed, supratentorial LGG in adults was performed by querying PubMed. Data were extracted to compare gross total resection (GTR) to subtotal resection (STR) and STR to biopsy (Bx) to determine relative risks (RR) of death and progression at 2, 5, and 10 years. Data were analyzed using a random effects model. NNT were calculated from significant comparisons and rounded up to the nearest whole number. Quality of evidence was determined by American Academy of Neurology criteria. Results: The systematic review resulted in 283 potential studies. Ultimately 29 studies were included in at least one comparison. There were no high quality (class I and II) or prospective studies discovered in the review. Comparing GTR to STR, RR with 95% confidence intervals (CI) of death at 2, 5, and 10 years, and NNT to avoid one death at 2, 5, and 10 years (GTR vs. STR) were 0.29 [0.17-0.52, p < 0.0001, NNT 17], 0.39 [0.29-0.51, p < 0.00001, NNT 6], and 0.50 [0.35-0.70, p < 0.0001 NNT 4]. RR and NNT for progression (GTR vs. STR) at 2, 5, and 10 years were 0.37 [0.24-0.57, p < 0.0001 NNT 7], 0.50 [0.39-0.64, p < 0.0001 NNT 4], and 0.67 [0.53-0.84, p = 0.0005 NNT 4]. Comparing STR to Bx, RR of death at 2, 5, and 10 years were 0.55 [0.34-0.88, p = 0.01 NNT 10], 0.9 [0.61-1.34], and 0.95 [0.73-1.23]. Conclusions: Increasing resection thresholds appear to be associated with improved overall and progression free survival, but the body of literature consists of low quality studies. Prospective studies are required to explore whether extent of resection matters or whether resectable tumors share a favorable biology associated with better outcome.

2057 Background: The optimal role of chemotherapy and radiation (RT) in adult low-grade glioma (LGG, WHO grade 1 & 2) is unclear. We conducted a systematic review and study-level meta-analysis of the literature on overall survival (OS) and progression free survival (PFS) in patients with LGG. Methods: Pubmed was queried with MeSH terms. All comparative studies of adults with newly diagnosed, supratentorial LGG were included. Comparisons of interest were OS and PFS at 2, 5, and 10 years in chemotherapy versus no chemotherapy and early RT versus delayed or no RT. Data were extracted from studies and synthesized with a random effects model. Quality of evidence was determined by American Academy of Neurology criteria and further analysis was performed, separating high quality (class I and II) from low quality (class III and IV) evidence. Numbers needed to treat (NNT) were determined from the risk difference. Results: 1531 articles were screened; 18 studies were included. Chemotherapy was not associated with a significant survival advantage compared to control. However, an analysis of high quality data revealed a survival advantage at 10 years associated with chemotherapy compared to control with NNT 5 (relative risk death chemo vs control 0.69 [0.56-0.86] p = 0.0006). Furthermore, NNT to prevent one progression with chemotherapy at 5 and 10 years was 6 and 3, respectively. Early RT was not associated with an OS advantage compared to control. However, early RT had progression benefit at all time points, with NNT of 10, 6, and 5 at 2, 5, and 10 years. Conclusions: Further study will be needed to confirm the optimal role of chemotherapy and RT. Caution must be used in interpretation as much of the literature consists of low-quality studies. [Table: see text]

Introduction: Low-grade gliomas (LGG, WHO grade I-II) account for 16.9-22% of all primary brain tumors. Management of these tumors consists of surgery, sometimes followed by radiation and/or chemotherapy. Arigorous, quantitative evaluation of the literature investigating the management of LGG has never been published. Methods: We conducted an exhaustive, PRISMA-compliant systematic review of the literature from January 1966 to September 2016 comparing the association of chemotherapy, radiation, or extent of resection with survival and progression-free survival at 2, 5, and 10years in LGG. Included studies were graded for quality using AAN criteria. Pre-specified data were extracted and summary statistics were calculated using the inverse variance method and random effects model. Results: Five studies (n=567) report on LGG patients treated with chemotherapy. The relative risk (RR) and 95% confidence intervals [95% CI] for death (chemotherapy vs. no chemotherapy) at 2, 5, and 10years was 1.34 [0.85-2.12], 0.83 [0.64-1.09], and 0.77 [0.58-1.03]. RR for progression at 2, 5, and 10years was 0.92 [0.64-1.33], 0.69 [0.55-0.87, p=0.001], and 0.58 [0.39-0.87, p=0.008]. Asensitivity analysis of OS including only classIand II studies showed a RR of death (chemotherapy vs. no chemotherapy) at 2, 5, and 10years of 1.23 [0.72-2.08], 0.78 [0.58-1.05, p=0.1], and 0.69 [0.56-0.86, p=0.0006]. Among only IDH1-mutated patients, the RR of progression with chemotherapy compared to control at 2, 5, and 10years was 0.48 [0.06-4.1], 0.27 [0.08-0.84, p=0.02], and 0.21 [0.03-1.59]. Ten studies (n=1918) provide data regarding the effect of post-operative radiation vs. delayed or no radiation. RR and 95% CI for death at 2, 5, and 10years was 0.92 [0.53-1.58], 0.93 [0.60-1.43], and 0.99 [0.69-1.41]. RR for progression at 2, 5, and 10years was 0.66 [0.51-0.86, p=0.002], 0.73 [0.61-0.88, p=0.0008], and 0.74 [0.60-0.91, p=0.005]. Twenty-three studies (n=3891) compare gross total resection (GTR) vs. subtotal resection (STR) in LGG. RR and 95% CI of death at 2, 5, and 10years (GTR vs. STR) was 0.29 [0.17-0.52, p

We provide historical and scientific guidance on imaging response assessment for incorporation into clinical trials to stimulate effective and expedited drug development for recurrent glioblastoma by addressing 3 fundamental questions: (i) What is the current validation status of imaging response assessment, and when are we confident assessing response using today's technology? (ii) What imaging technology and/or response assessment paradigms can be validated and implemented soon, and how will these technologies provide benefit? (iii) Which imaging technologies need extensive testing, and how can they be prospectively validated? Assessment of T1 +/- contrast, T2/FLAIR, diffusion, and perfusion-imaging sequences are routine and provide important insight into underlying tumor activity. Nonetheless, utility of these data within and across patients, as well as across institutions, are limited by challenges in quantifying measurements accurately and lack of consistent and standardized image acquisition parameters. Currently, there exists a critical need to generate guidelines optimizing and standardizing MRI sequences for neuro-oncology patients. Additionally, more accurate differentiation of confounding factors (pseudoprogression or pseudoresponse) may be valuable. Although promising, diffusion MRI, perfusion MRI, MR spectroscopy, and amino acid PET require extensive standardization and validation. Finally, additional techniques to enhance response assessment, such as digital T1 subtraction maps, warrant further investigation.

On January 30, 2014, a workshop was held on neuroimaging endpoints in high-grade glioma. This workshop was sponsored by the Jumpstarting Brain Tumor Drug Development Coalition, consisting of the National Brain Tumor Society, the Society for Neuro-Oncology, Accelerate Brain Cancer Cure, and the Musella Foundation for Research and Information, and conducted in collaboration with the Food and Drug Administration. The workshop included neuro-oncologists, neuroradiologists, radiation oncologists, neurosurgeons, biostatisticians, patient advocates, and representatives from industry, clinical research organizations, and the National Cancer Institute. This report summarizes the presentations and discussions of that workshop and the proposals that emerged to improve the Response Assessment in Neuro-Oncology (RANO) criteria and standardize neuroimaging parameters.

Central nervous system primitive neuroectodermal tumors (CNS PNETs) predominantly occur in children and rarely in adults. Because of the rarity of this tumor, its outcomes and prognostic variables are not well characterized. The purpose of this study was to evaluate clinical outcomes and prognostic factors for children and adults with CNS PNET. The records of 26 patients (11 children and 15 adults) with CNS PNET from 1991 to 2011 were reviewed retrospectively. Disease-free survival (DFS) and overall survival (OS) were estimated with the Kaplan-Meier method, and relevant prognostic factors were analyzed. For the cohort, both the 5-year DFS and the OS were 46 %. For pediatric patients, the 5-year DFS was 78 %; for adult patients, it was 22 % (P = 0.004). Five-year OS for the pediatric and adult patients was 67 and 33 %, respectively (P = 0.07). With bivariate analysis including chemotherapy regimen (high dose vs. standard vs. nonstandard) or risk stratification (standard vs. high) and age, the increased risk of disease recurrence in adults persisted. A nonsignificant tendency toward poorer OS in adult patients relative to pediatric patients also persisted. High-dose chemotherapy with stem cell rescue was associated with a statistically significant improvement in OS and a tendency toward improved DFS, although the findings were mitigated when the effect of age was considered. Local recurrence was the primary pattern of treatment failure in both adults and children. Our results suggest that adult patients with CNS PNETs have inferior outcomes relative to the pediatric cohort. Further research is needed to improve outcomes for CNS PNET in populations of all ages.

Purpose Patients with 1p/19q codeleted anaplastic oligodendroglial tumors who participated in RTOG (Radiation Therapy Oncology Group) 9402 lived much longer after chemoradiotherapy (CRT) than radiation therapy (RT) alone. However, some patients with noncodeleted tumors also benefited from CRT; survival curves separated after the median had been reached, and significantly more patients lived ≥ 10 years after CRT than RT. Thus, 1p/19q status may not identify all responders to CRT. Patients and Methods Using trial data, we inquired whether an IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas identified the patients in RTOG 9402 who benefited from CRT. Results IDH status was evaluable in 210 of 291 patients; 156 (74%) had mutations. rs55705857 was evaluable in 245 patients; 76 (31%) carried the G risk allele. Both were associated with longer progression-free survival after CRT, and mutant IDH was associated with longer overall survival (9.4 v 5.7 years; hazard ratio [HR], 0.59; 95% CI, 0.40 to 0.86; P = .006). For those with wild-type tumors, CRT did not prolong median survival (1.3 v 1.8 years; HR, 1.14; 95% CI, 0.63 to 2.04; P = .67) or 10-year survival rate (CRT, 6% v RT, 4%). Patients with codeleted mutated tumors (14.7 v 6.8 years; HR, 0.49; 95% CI, 0.28 to 0.85; P = .01) and noncodeleted mutated tumors (5.5 v 3.3 years; HR, 0.56; 95% CI, 0.32 to 0.99; P < .05) lived longer after CRT than RT. Conclusion IDH mutational status identified patients with oligodendroglial tumors who did (and did not) benefit from alkylating-agent chemotherapy with RT. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after CRT.

Background Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The core of standard of care for newly diagnosed GBM was established in 2005 and includes maximum feasible surgical resection followed by radiation and temozolomide, with subsequent temozolomide with or without tumor-treating fields. Unfortunately, nearly all patients experience a recurrence. Bevacizumab (BV) is a commonly used second-line agent for such recurrences, but it has not been shown to impact overall survival, and short-term response is variable. Methods We collected MRI perfusion and diffusion images from 54 subjects with recurrent GBM treated only with radiation and temozolomide. They were subsequently treated with BV. Using machine learning, we created a model to predict short term response (6 months) and overall survival. We set time thresholds to maximize the separation of responders/survivors versus non-responders/short survivors. Results We were able to segregate 21 (68%) of 31 subjects into unlikely to respond categories based on Progression Free Survival at 6 months (PFS6) criteria. Twenty-two (69%) of 32 subjects could similarly be identified as unlikely to survive long using the machine learning algorithm. Conclusion With the use of machine learning techniques to evaluate imaging features derived from pre- and post-treatment multimodal MRI, it is possible to identify an important fraction of patients who are either highly unlikely to respond, or highly likely to respond. This can be helpful is selecting patients that either should or should not be treated with BV.

Neuroendocrine neoplasms (NENs) are malignancies with rare reports of central nervous system development. A 34-year-old woman was found to have a primary NEN of the brain, and she had recurrence with identical histology 10 years later. Extracranial NENs were excluded. She had routine surveillance for the first 5 years with MRIs and positron emission tomography/CTs after the initial presentation which was treated with radiation followed by cisplatin and etoposide. This case highlights the difference in primary NENs versus NEN metastases to the brain, and that longer periods of surveillance are likely required for primary NENs. This is important because the prognosis between primary NENs and metastatic NENs to the brain are vastly different and should not be treated as equal diseases. The patient eventually died of her recurrence secondary to complications of a ventriculoperitoneal shunt placed for treatment of hydrocephalus from the disease.

Low-grade glioma (LGG) is a heterogeneous group of primary, diffuse, and slowly growing glial brain tumors. These tumors often remain clinically stable for many years, and patients are commonly only followed clinically without specific antitumor therapy. Based on retrospective studies suggesting an improved survival with early, extensive, and maximal tumor resections, radical surgery is often advocated. Prospective controlled studies evaluating the role of surgery are lacking, and a large part of the benefit presumed from extensive resection may be due to patient selection. If tumor location makes the surgery difficult or even impossible, a biopsy is performed to ascertain the nature of the tumor and establish a pathological diagnosis. Immediate (postoperative) radiotherapy has not been shown to offer an advantage in overall survival (OS) over deferred radiotherapy; although progression-free survival (PFS) is lengthened, the optimal timing remains debatable. There is no apparent effect of dose; 2 randomized studies by the European Organisation for Research and Treatment of Cancer (EORTC) and of the North Central Cancer Treatment Group (NCCTG)/Radiation Therapy Oncology Group (RTOG)/Eastern Cooperative Oncology Group (ECOG) Intergroup showed no significant difference in survival when researchers compared lower and higher irradiation doses (45 vs 59.4 Gy and 50.4 vs 64.8 Gy, respectively).1,2,8 The role of postoperative chemotherapy alone or in combination with radiation therapy remains investigational.3 Individual prognosis of patients is highly variable. In order to choose the best strategy for a patient among the various treatment options, prognostic models and scores can be useful. A major limitation in addressing prognostic models for LGG is the considerable interobserver variability in both the grading and the typing of these tumors.4,5 The widely used EORTC prognostic scoring model for LGG was based on 2 prospective randomized clinical trials. However, patient inclusion into these trials relied upon a diagnosis made by the local pathologist, which was often not confirmed by central pathology review.6 The external validity of the EORTC scoring system was recently evaluated in a dataset of LGG patients treated in a North American Intergroup trial (NCCTG 86-72-51).7 In that dataset, the distinction between the low-risk and the high-risk group was predominantly determined by the prognostic impact of histology and tumor size; other factors, like age and extent of surgery, did not contribute significantly. A major difference between the US and European trials was the mandatory central pathology review prior to inclusion in the American trials. Thus, we reanalyzed the pooled data from the 2 EORTC studies, restricting the analysis to patients with LGG whose histology had been confirmed upon central pathology review. Patients with histologies other than grade II glioma and patients from whom no tumor tissue was available for central review were excluded. We subsequently assessed the external validity of the EORTC studies with the individual patient data from large studies conducted by 2 US cooperative groups (RTOG and NCCTG).8,9 Based on this analysis, we developed prognostic calculators for PFS and OS that provide estimates for both median and fixed time probabilities of survival.

Purpose: We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity. Experimental Design: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1–5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B). Results: Fifty-four patients were enrolled: 19 patients in group A and 35 in group B. Objective response rate was 18.5% with median duration of 6.7 months (range 0.5–24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7–8.2]; outcome was similar between the two dose groups. We identified SNPs in the VEGF and VEGFR2 promoter regions, which were associated with PFS6 (P < 0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell–derived factor-1 was associated with PFS6 success (P = 0.04). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P = 0.022). Imaging analysis showed a trend associating ADC-L with poor outcome. Conclusions: The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation. Clin Cancer Res; 19(17); 4816–23. ©2013 AACR.

Background. To identify changes in patient presentation, treatment, and outcomes of low-grade gliomas (LGGs) over the past 50 years. Methods. Records of 852 adults who received a diagnosis at Mayo Clinic from 1960 through 2011 with World Health Organization grade II LGGs were reviewed and grouped by those who received a diagnosis before (group I: 1960–1989) and after (group II: 1990–2011) the routine use of postoperative MRI. Results. Median follow-up was 23.3 and 8.7 years for groups I and II, respectively. Patients in group I more often presented with seizures, headaches, sensory/ motor impairment, and astrocytoma histology. Over time, more gross total resections (GTRs) were achieved, fewer patients received postoperative radiotherapy (PORT), and more received chemotherapy. Median progression-free survival (PFS) and overall survival (OS) were 4.4 and 8.0 years, respectively. Although PFS was similar, 10-year OS was better in group II (47%) than in group I (33%; P , .0001). Improved PFS in multivariate analysis was associated with group I patients, nonastrocytoma histology, small tumor size, successful GTR, or radical subtotal resection (rSTR), PORT, and postoperative chemotherapy. Factors associated with improved OS in multivariate analysis were younger age, nonastrocytoma histology, small tumor size, and GTR/ rSTR. Conclusions. OS for LGG has improved over the past 50 years, despite similar rates of progression. In the modern cohort, more patients are receiving a diagnosis of oligodendroglioma and are undergoing extensive resections, both of which are associated with improvements in OS. Because of risk factor stratification by clinicians, the use of PORT has decreased and is primarily being used to treat high-risk tumors in modern patients.

Gliomatosis cerebri is a rare diffusely infiltrating primary neoplastic glial process of the brain. Our objective is to review clinical presentation, management, and outcome in a large single institution series of gliomatosis cerebri patients. 54 consecutive gliomatosis cerebri cases presenting to Mayo Clinic Rochester between 1991 and 2008 were retrospectively reviewed. Inclusion criteria included involvement of at least three cerebral lobes, lack of a single discrete mass and pathological confirmation of diffuse glioma. Median overall survival (OS) was 18.5 months. Age, gender, presenting symptoms, and contrast enhancement did not correlate significantly with survival, though there was a trend toward decreased overall survival in patients above the median age of 46 years. Karnofsky performance score

Purpose Anaplastic oligodendrogliomas, pure (AO) and mixed (anaplastic oligoastrocytoma [AOA]), are chemosensitive, especially if codeleted for 1p/19q, but whether patients live longer after chemoradiotherapy is unknown. Patients and Methods Eligible patients with AO/AOA were randomly assigned to procarbazine, lomustine, and vincristine (PCV) plus radiotherapy (RT) versus RT alone. The primary end point was overall survival (OS). Results Two hundred ninety-one eligible patients were randomly assigned: 148 to PCV plus RT and 143 to RT. For the entire cohort, there was no difference in median survival by treatment (4.6 years for PCV plus RT v 4.7 years for RT; hazard ratio [HR] = 0.79; 95% CI, 0.60 to 1.04; P = .1). Patients with codeleted tumors lived longer than those with noncodeleted tumors (PCV plus RT: 14.7 v 2.6 years, HR = 0.36, 95% CI, 0.23 to 0.57, P < .001; RT: 7.3 v 2.7 years, HR = 0.40, 95% CI, 0.27 to 0.60, P < .001), and the median survival of those with codeleted tumors treated with PCV plus RT was twice that of patients receiving RT (14.7 v 7.3 years; HR = 0.59; 95% CI, 0.37 to 0.95; P = .03). For those with noncodeleted tumors, there was no difference in median survival by treatment arm (2.6 v 2.7 years; HR = 0.85; 95% CI, 0.58 to 1.23; P = .39). In Cox models that included codeletion status, the adjusted OS for all patients was prolonged by PCV plus RT (HR = 0.67; 95% CI, 0.50 to 0.91; P = .01). Conclusion For the subset of patients with 1p/19q codeleted AO/AOA, PCV plus RT may be an especially effective treatment, although this observation was derived from an unplanned analysis.

Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial.To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT.At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013.The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone.The primary end point was cognitive deterioration (decline1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3-month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival.There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT, n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when combined with WBRT (44/48 patients [91.7%]; difference, -28.2%; 90% CI, -41.9% to -14.4%; P .001). Quality of life was higher at 3 months with SRS alone, including overall quality of life (mean change from baseline, -0.1 vs -12.0 points; mean difference, 11.9; 95% CI, 4.8-19.0 points; P = .001). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P .001). There was no significant difference in functional independence at 3 months between the treatment groups (mean change from baseline, -1.5 points for SRS alone vs -4.2 points for SRS plus WBRT; mean difference, 2.7 points; 95% CI, -2.0 to 7.4 points; P = .26). Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI, 0.75-1.38; P = .92). For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; difference, -48.7%; 95% CI, -87.6% to -9.7%; P = .007) and at 12 months (6/10 [60%] vs 17/18 [94.4%]; difference, -34.4%; 95% CI, -74.4% to 5.5%; P = .04).Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months. In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy.clinicaltrials.gov Identifier: NCT00377156.

Anaplastic oligodendrogliomas have long attracted interest because of their sensitivity to chemotherapy, in particular in the subset of 1p/19q co-deleted tumors. Recent molecular studies have shown that all 1p/19q co-deleted tumors have IDH mutations and most of them also have TERT mutations. Because of the presence of similar typical genetic alterations in astrocytoma and glioblastoma, the current trend is to diagnose these tumors on the basis of their molecular profile. Further long-term follow-up analysis of both EORTC and RTOG randomized studies on (neo)adjuvant procarbazine, lomustine, vincristine (PCV) chemotherapy have shown that adjuvant chemotherapy indeed improves outcome, and this is now standard of care. It is also equally clear that benefit to PCV chemotherapy is not limited to the 1p/19q co-deleted cases; potential other predictive factors are IDH mutations and MGMT promoter methylation. Moreover, a recent RTOG study on low-grade glioma also noted an improved outcome after adjuvant PCV chemotherapy, thus making (PCV) chemotherapy now standard of care for all 1p/19q co-deleted tumors regardless of grade. It remains unclear whether temozolomide provides the same survival benefit, as no data from well-designed clinical trials on adjuvant temozolomide in this tumor type are available. Another question that remains is whether one can safely leave out radiotherapy as part of initial treatment to avoid cognitive side-effects of radiotherapy. The current data suggest that delaying radiotherapy and treatment with chemotherapy only may be detrimental for overall survival.

Purpose A prior Radiation Therapy Oncology Group (RTOG) clinical trial in anaplastic oligodendroglioma suggested a progression-free survival benefit for procarbazine, lomustine, and vincristine (PCV) chemotherapy in addition to radiation therapy (RT), as have smaller trials in low-grade glioma (LGG). Patients and Methods Eligibility criteria included supratentorial WHO grade 2 LGG, age 18 to 39 years with subtotal resection/biopsy, or age ≥ 40 years with any extent resection. Patients were randomly assigned to RT alone or RT followed by six cycles of PCV. Survival was compared by using the modified Wilcoxon and log-rank tests. Results In all, 251 patients were accrued from 1998 to 2002. Median overall survival (OS) time and 5-year OS rates for RT versus RT + PCV were 7.5 years versus not reached and 63% versus 72%, respectively (hazard ratio [HR]; 0.72; 95% CI, 0.47 to 1.10; P = .33; log-rank P = .13). Median progression-free survival (PFS) time and 5-year PFS rates for RT versus RT + PCV were 4.4 years versus not reached and 46% versus 63%, respectively (HR, 0.6; 95% CI, 0.41 to 0.86; P = .06; log-rank P = .005). OS and PFS were similar for all patients between years 0 and 2. After 2 years, OS and PFS curves separated significantly, favoring RT + PCV. For 2-year survivors (n = 211), the probability of OS for an additional 5 years was 74% with RT + PCV versus 59% with RT alone (HR, 0.52; 95% CI, 0.30 to 0.90; log-rank P = .02). Conclusion PFS but not OS was improved for adult patients with LGG receiving RT + PCV versus RT alone. On post hoc analysis, for 2-year survivors, the addition of PCV to RT conferred a survival advantage, suggesting a delayed benefit for chemotherapy.