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BACKGROUND Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is common in patients with low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. METHODS Fifty-eight patients with pathologic evidence of recurrence after they had initially been diagnosed with World Health Organization (WHO) grade II gliomas were enrolled into a prospective phase 2 clinical trial and received daily everolimus (RAD001) for 1 year or until progression. Tissue at the time of enrollment was analyzed for markers of PI3K/mTOR pathway activation. Thirty-eight patients underwent serial multiparametric magnetic resonance imaging, with the tumor volume and the perfusion metrics (the fractional blood volume [fBV] for capillary density and the transfer coefficient [Kps ] for vascular permeability) measured during treatment. The primary endpoint was progression-free survival at 6 months (PFS-6) in patients with WHO II disease at enrollment. RESULTS For patients with WHO II gliomas at enrollment, the PFS-6 rate was 84%, and this met the primary endpoint (P

Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is common in patients with low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population.Fifty-eight patients with pathologic evidence of recurrence after they had initially been diagnosed with World Health Organization (WHO) grade II gliomas were enrolled into a prospective phase 2 clinical trial and received daily everolimus (RAD001) for 1 year or until progression. Tissue at the time of enrollment was analyzed for markers of PI3K/mTOR pathway activation. Thirty-eight patients underwent serial multiparametric magnetic resonance imaging, with the tumor volume and the perfusion metrics (the fractional blood volume [fBV] for capillary density and the transfer coefficient [KFor patients with WHO II gliomas at enrollment, the PFS-6 rate was 84%, and this met the primary endpoint (P .001 for an improvement from the historical rate of 17%). Evidence of PI3K/mTOR activation by immunohistochemistry for phosphorylated ribosomal S6Patients with recurrent LGGs demonstrated a high degree of disease stability during treatment with everolimus. PI3K/mTOR activation, as measured by immunohistochemistry for p-S6, was associated with a worse prognosis. Tumor vascular changes were observed that were consistent with the antiangiogenic effects of mTOR inhibitors. These results support further study of everolimus for LGGs. Cancer 2017;123:4631-4639. © 2017 American Cancer Society.

BACKGROUND Options for chemotherapy at the time of recurrence in patients with malignant glioma are limited. The authors describe the efficacy and safety results of their institution's open-label, compassionate-use protocol of temozolomide for patients with recurrent malignant glioma. METHODS Patients with recurrent malignant glioma at any time during recurrence were treated with oral temozolomide at a dose pf 150 mg/m2 per day on a 5-day schedule every 28 days. If this dose was tolerated, then escalation to 200 mg/m2 was allowed. Clinical evaluations and assessments of tumor response were performed every 2 months. All patients or their surrogates signed approved Institutional Review Board consent forms. RESULTS Among 213 patients who were treated, 33% had Grade 3 tumors, and 67% had Grade 4 tumors. The overall objective response rate was 16% in both of these patient groups; and an additional 51% and 30% of patients with Grade 3 and Grade 4 tumors, respectively, had stable disease as their best response. The 6-month progression-free survival rates were 41% and 18% for patients with Grade 3 and Grade 4 tumors, respectively. The median survival was 49 weeks for patients with Grade 3 tumors and 32 weeks for patients with Grade 4 tumors. The major toxicity was hematologic toxicity. In multivariate analysis, the Karnofsky performance score was a significant predictor of survival for patients with Grade 4 tumors. CONCLUSIONS Temozolomide was well tolerated in patients with recurrent malignant glioma and had modest efficacy, even at the time of multiple recurrences. Cancer 2004. © 2003 American Cancer Society.

BACKGROUND The primary objective of the current study was to determine the response rate of paclitaxel in patients with recurrent malignant glioma by using different doses dependent on the concomitant use of anticonvulsants. Secondary objectives were to determine the time period to treatment failure, to evaluate toxicities, and to obtain pharmacokinetic data. METHODS Adult patients who had recurrent malignant glioma were treated with paclitaxel. Patients were treated at different doses depending on the concomitant use of anticonvulsants known to induce the p450 hepatic enzyme system. Patients on such agents were treated at a dose of 330mg/m2, whereas those not on these anticonvulsants were treated at a dose of 210 mg/m2. Tumor response was assessed at 6-week intervals. Treatment was continued until documented tumor progression or unacceptable toxicity occurred, or a total of 12 paclitaxel infusions was completed. RESULTS From January 1997 to June 1997, 23 patients were treated with paclitaxel. Four patients were ineligible for the current study. Of the 19 eligible patients, there were no responses seen. Four (21%) had stabilization of disease. Median time to treatment failure was 1 month (95% confidence interval [CI], 1–2 mos) and median survival was 7 months (95% CI, 6–10mos). Three patients were removed from the current study because they had toxicity. Pharmacokinetic studies demonstrated that drug levels and clearance values were consistent with previously reported findings. CONCLUSION Even though higher doses were administered to patients who had recurrent malignant glioma and who were on concomitant anticonvulsants, there were no objective responses to paclitaxel. Time to tumor progression was 1 month. Further testing of paclitaxel at this dose schedule does not appear to be warranted in this patient population. Cancer 2001;91:417–22. © 2001 American Cancer Society.

BACKGROUND It is often assumed that a cerebral lesion that is nonenhancing on a magnetic resonance imaging study with gadolinium contrast is a low grade tumor. Some physicians recommend observation rather than biopsy for such lesions. METHODS The authors prospectively evaluated the incidence of anaplastic tumor histology in a consecutive series of patients who presented to a neuro-oncology service with a nonenhancing mass of the cerebral hemisphere. RESULTS During a 5-month period, the authors evaluated 31 patients who had a nonenhancing lesion in the cerebral hemisphere on initial magnetic resonance images. Thirty patients underwent stereotactic biopsy (27%) or open resection (73%). The median patient age was 36 years (range, 6-63 years). There was no mortality or permanent neurologic morbidity from surgery. Twenty-eight patients had pathologic confirmation of diagnosis while their lesions were still nonenhancing. Of these patients, 9 (32%) had Grade 3 lesions (anaplastic astrocytoma or oligoastrocytoma), 13 (43%) had Grade 2 lesions (astrocytoma, oligodendroglioma, or oligoastrocytoma), and 2 (7%) had Grade 1 lesions (dysembryoplastic neuroepithelial tumors). Two additional patients (ages 33 and 59 years) who developed enhancement within their lesions during preoperative periods of observation had glioblastomas at surgery. Logistic regression was used to relate patient age to the risk of anaplasia in a nonenhancing cerebral mass lesion. Older age predicted a significantly higher risk of anaplasia (P = 0.025). The model predicted that nonenhancing cerebral masses in patients older than 44 years were more likely to be anaplastic tumors than low grade tumors. There was no "safe" age below which low grade histology could be confidently assumed. CONCLUSIONS Magnetic resonance-nonenhancing cerebral lesions may be histologically anaplastic, even in young patients. The risk of anaplasia in magnetic resonance-nonenhancing lesions increases significantly with patient age. Cancer 1997; 80:936-41. © 1997 American Cancer Society.

BACKGROUND After intensive initial radiation therapy for malignant glioma, magnetic resonance imaging (MRI) and computerized tomography (CT) cannot distinguish tumor progression from radiation injury. METHODS The authors studied the prognostic value of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in 55 patients with malignant glioma for whom MRI obtained after initial surgery and radiation therapy demonstrated enlarging, enhancing lesions consistent with either tumor progression or radiation necrosis. Forty patients (73%) had an initial diagnosis of Grade 4 malignant glioma and 15 (27%) had Grade 3 malignant glioma. The FDG-PET scans were graded visually on a four-level scale at the time of acquisition. RESULTS In univariate analysis, the FDG-PET score was a significant predictor of survival time after FDG-PET scanning (P = 0.005). Median survival was 10 months for patients with FDG-PET scores of 2 or 3 (glucose uptake ≥ adjacent cortex) and 20 months for those with scores of 0 or 1 (glucose uptake < adjacent cortex). In multivariate proportional hazards analysis, the FDG-PET score was a significant predictor of survival (P = 0.019) in a model that included patient age, recurrence number, and FDG-PET score. There was no significant difference in the FDG-PET score hazard ratio for patients with Grade 3 or 4 tumors at initial diagnosis, first or later suspected recurrence, initial photon irradiation given with standard fractions or hyperfractionation, or stereotactic irradiation prior to FDG-PET scanning. CONCLUSIONS This analysis demonstrates that FDG-PET scanning has prognostic value in a cohort limited to patients with suspected recurrent high grade glioma. Cancer 1997; 79:115-26. © 1997 American Cancer Society.

BACKGROUND Many pathologists require the presence of tumor necrosis within an astrocytic neoplasm to establish the diagnosis of glioblastoma multiforme (GM). Two new grading systems for astrocytic neoplasms allow a tumor to be diagnosed at the highest level of anaplasia without requiring the presence of tumor necrosis. METHODS To determine whether GMs without necrosis had biologic behavior most compatible with a diagnosis of GM or of anaplastic astrocytoma (AA), we examined the survival of 299 patients whose tumors were diagnosed as GM because they contained endothelial proliferation and who were treated according to prospective clinical protocols. Multivariate proportional-hazards survival analysis was used to assess the importance of tumor necrosis after adjustment for other prognostic factors. RESULTS Of 275 patients with GMs containing endothelial proliferation, 88% had tumor necrosis. Absence of necrosis was associated with younger age and with less extensive surgical resection. The absence of necrosis predicted longer survival in univariate analysis (P = 0.02) and after adjustment for age, Karnofsky performance score, and extent of resection in a multivariate analysis (P = 0.04). However, the magnitude of the survival difference was not clinically important: patients without tumor necrosis had a median survival of 12.5 months, and those with tumor necrosis had a median survival of 10.9 months. Kaplan-Meier survival rates two years after diagnosis were 13.0% for patients with necrosis and 27.1% for patients without necrosis; the difference in 2-year survival was not statistically significant (difference in survival rates = 14.1%, 95% confidence interval −2.2% to 30.4%). CONCLUSIONS The survival of patients with astrocytic neoplasms containing endothelial proliferation and no necrosis conforms best to the pattern expected for patients with GM rather than AA. This supports the classification of these tumors as GM in the revised World Health Organization grading system and as grade 4 astrocytomas in the St. Anne-Mayo grading system. Cancer 1996;77:1161-6.

Background. Carboplatin, which is used in the treatment of several childhood tumors, increasingly has been reported to cause hypersensitivity reactions, the majority reported in adults. Five cases of children with primary brain tumors who were treated with carboplatin and developed acute allergic reactions are presented. Methods. The clinical history of each patient is described, as is the schedule, cumulative dose, and number of infusions of carboplatin, type of reaction, and retreatment. Results. Four of the five patients had histologically proven low grade astrocytic tumors; three had juvenile pilocytic astrocytomas, and one had a mixed oligoastrocytoma. One patient with neurofibromatosis type I had radiographically-defined bilateral optic nerve gliomas. Three patients had prior chemotherapy, one with cisplatin. All five patients developed hypersensitivity reactions such as urticaria, facial erythema, and facial swelling after multiple infusions of carboplatin. Two were retreated with carboplatin after receiving antihistamines, but still developed a reaction. Carboplatin therapy was discontinued in all patients. Conclusion. The purpose of this report is to heighten awareness of this potentially serious complication of carboplatin in children so that potentially dangerous retreatment is avoided. As use of a weekly schedule of carboplatin in children with low grade gliomas increases, with planned therapy extending for more than 50 weeks, more hypersensitivity reactions are anticipated. Cancer 1995;75:1171–5.

BACKGROUND Social factors influence cancer treatment choices, potentially affecting patient survival. In the current study, the authors studied the interrelations between marital status, treatment received, and survival in patients with glioblastoma multiforme (GM), using population-based data. METHODS The data source was the Surveillance, Epidemiology, and End Results (SEER) Public Use Database, 1988–2001, 2004 release, all registries. Multivariate logistic, ordinal, and Cox regression analyses adjusted for demographic and clinical variables were used. RESULTS Of 10,987 patients with GM, 67% were married, 31% were unmarried, and 2% were of unknown marital status. Tumors were slightly larger at the time of diagnosis in unmarried patients (49% of unmarried patients had tumors larger than 45 mm vs. 45% of married patients; P = 0.004, multivariate analysis). Unmarried patients were less likely to undergo surgical resection (vs. biopsy; 75% of unmarried patients vs. 78% of married patients) and were less likely to receive postoperative radiation therapy (RT) (70% of unmarried patients vs. 79% of married patients). On multivariate analysis, the odds ratio (OR) for resection (vs. biopsy) in unmarried patients was 0.88 (95% confidence interval [95% CI], 0.79–0.98; P = 0.02), and the OR for RT in unmarried patients was 0.69 (95% CI, 0.62–0.77; P < 0.001). Unmarried patients more often refused both surgical resection and RT. Unmarried patients who underwent surgical resection and RT were found to have a shorter survival than similarly treated married patients (hazard ratio for unmarried patients, 1.10; P = 0.003). CONCLUSIONS Unmarried patients with GM presented with larger tumors, were less likely to undergo both surgical resection and postoperative RT, and had a shorter survival after diagnosis when compared with married patients, even after adjustment for treatment and other prognostic factors. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND Temozolomide (TMZ) and 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU) are reported to be active agents in anaplastic glioma (AG). TMZ has also been shown to deplete alkyltransferase, a DNA repair enzyme that contributes to nitrosourea resistance. The objective of the current study was to determine the efficacy and toxicity profile of a combination of these agents before radiotherapy in newly diagnosed AG. METHODS Eligibility criteria included histologically confirmed newly diagnosed AG with measurable enhancing disease, a Karnofsky performance score (KPS) ≥ 60, normal pulmonary function, and normal laboratory parameters. In addition, informed consent was obtained from all patients. BCNU given at a dose of 150 mg/m2 intravenously was followed after 2 hours by TMZ given at a dose of 550 mg/m2 orally on Day 1 of a 42-day cycle to a maximum of 4 cycles, unless there was tumor progression or unacceptable toxicity. RESULTS Forty-one eligible patients were accrued. Their median age was 40 years. Seventy-six percent of patients had a KPS of 90–100. The histology was 81% anaplastic astrocytoma, 12% anaplastic oligodendroglioma, and 7% mixed tumors. Twenty-two percent of patients did not complete 4 cycles because of toxicity, mainly hematologic. Forty-six percent of patients experienced Grade 3 or 4 (according to National Cancer Institute Common Toxicity Criteria) thrombocytopenia. Twenty percent had Grade 4 granulocytopenia. Two patients died while receiving therapy, 1 of progressive disease and the other of Pneumocystis carinii pneumonia. The complete and partial response rates were 2% and 27% respectively. An additional 54% of patients had stable disease. Seventeen percent developed progressive disease (10% after the first cycle and 7% after the second cycle). CONCLUSIONS This neoadjuvant strategy was associated with significant myelosuppression and a modest response rate in patients with newly diagnosed AG. Cancer 2004. © 2004 American Cancer Society.

BACKGROUND Patient participation in well-designed and conducted clinical trials enables researchers to test new therapies. An understanding of the variables that possibly influence patient enrollment may help in patient recruitment for future trials. The authors evaluated factors that influenced patient enrollment in clinical trials using a prospective, large, multi-institutional registry of patients with malignant glioma. METHODS Data were examined from 708 patients who underwent first or second surgery for a malignant glioma who were enrolled in the Glioma Outcomes Project, which is a prospective observational data base that captures clinical practice patterns. The frequency of clinical trial participation and the variables that may have been associated with trial participation were evaluated. These variables included age, gender, race, household income, educational level, first versus second craniotomy, histology, and whether the patient was treated at an academic institution. RESULTS One hundred fifty-one of 708 patients (21.3%) participated in a clinical trial, which was higher than the participation reported typically for patients with other types of primary malignancies. In univariate analysis, race, histology, and first craniotomy were significant between the two groups, with Caucasian patients and patients with glioblastoma histology showing higher participation rates. In a multivariate logistic regression model, significant predictors included young age and glioblastoma multiforme histology. CONCLUSIONS The authors present information on factors that may influence clinical trial participation among patients with malignant glioma and compare their data with information described previously on patients with other types of malignant disease. The percent of participation among the patients in the current study was greater than among patients with other primary tumor sites. Strategies should be implemented to improve recruitment to neuro-oncology trials, especially in elderly and minority populations. Cancer 2002;94:2681–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10536