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ABSTRACT: PURPOSE: Diffuse intrinsic pontine gliomas (DIPGs) are rapidly progressive and aggressive tumors that usually arise in children. Their anatomic location makes gross total surgical resection impossible, and fewer than 10 % of patients survive more than 2 years after diagnosis. Often, these lesions are treated based on imaging characteristics alone. However, despite aggressive chemotherapy and radiation treatments available, prognosis remains poor. There is therefore a need for new therapies directed by biologic profiling. This necessitates a tissue diagnosis and, therefore, surgical biopsy. We have reviewed the results of biopsy for DIPGs in children at a single institution and compared our results to those available in the literature to elucidate the utility of biopsy for DIPGs. METHODS: A historical cohort study was performed using medical records of patients under the age of 18 who underwent surgical biopsy of a DIPG at a single institution. RESULTS: Nine patients were included, four males and five females. Age at presentation ranged from 8 months to 10 years (average 5.7 years). Pathologic diagnoses included five high grade (WHO grade III or IV) gliomas and four low grade (WHO grade II) astrocytomas. There were no intraoperative complications, and only one patient developed a new postoperative neurologic deficit. CONCLUSIONS: Stereotactic biopsy of DIPGs is essential to obtain a pathologic diagnosis and is associated with low morbidity. This technique is important to elucidate biological characteristics of these tumors in order to direct multidisciplinary treatment plans possibly involving chemotherapy, radiation therapy, or other future clinical trial interventions for children with DIPGs.
Child s Nervous System 05/2013; · 1.54 Impact Factor
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ABSTRACT: Recurrent glioblastoma (GBM) can occur locally or at distant sites within the brain. Though MRI is the standard imaging modality for primary and recurrent GBM, the full extent of diffuse lesions may not be appreciated on MRI alone. Glioblastomas with ependymal and/or subependymal spread are examples of diffuse infiltrative tumors that are incompletely seen on MRI. Some other adjuvant visualization technique such as intraoperative fluorescence-assisted 5-aminolevulinic acid (5-ALA) could be used to assist the surgeon in localizing the infiltrating tumor. The authors report on a 56-year-old man who presented 7 years after initial resection of an occipital lobe GBM with imaging consistent with distant discrete foci of tumor recurrence. Because these foci were distant from the original resection cavity, there was concern for diffuse, infiltrative tumor elsewhere throughout the brain versus a distant multicentric recurrence. Therefore, the patient was given 5-ALA prior to surgery to aid in tumor detection intraoperatively. Using fluorescent visualization of the resection cavity, it was confirmed that there was subependymal and ependymal spread of the recurrent tumor along the lateral ventricle connecting the recurrence to the previous tumor site. Magnetic resonance imaging may not completely detect the presence of diffuse tumor infiltrating the ependymal or subependymal spaces. Therefore, adjunct intraoperative use of fluorescence-assisted visualization with 5-ALA may be helpful in highlighting and detecting infiltrative tumor to accurately detect tumor burden and distinguish it from a separate multicentric recurrence.
Journal of Neurosurgery 02/2013; · 2.96 Impact Factor
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Nicole Shonka,
Yuji Piao,
Mark Gilbert,
Alfred Yung,
Susan Chang,
Lisa M Deangelis,
Andrew B Lassman,
Jun Liu,
Timothy Cloughesy,
H Ian Robins,
Rita Lloyd,
Alice Chen, Michael Prados,
Patrick Y Wen,
John Heymach,
John de Groot
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ABSTRACT: 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.
Targeted Oncology 01/2013; · 3.61 Impact Factor
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Rintaro Hashizume,
Ivan Smirnov,
Sharon Liu,
Joanna J Phillips,
Jeanette Hyer,
Tracy R McKnight,
Michael Wendland, Michael Prados,
Anu Banerjee,
Theodore Nicolaides,
Sabine Mueller,
Charles D James,
Nalin Gupta
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ABSTRACT: Diffuse intrinsic pontine gliomas arise almost exclusively in children, and despite advances in treatment, the majority of patients die within 2 years after initial diagnosis. Because of their infiltrative nature and anatomic location in an eloquent area of the brain, most pontine gliomas are treated without a surgical biopsy. The corresponding lack of tissue samples has resulted in a limited understanding of the underlying genetic and molecular biologic abnormalities associated with pontine gliomas, and is a substantial obstacle for the preclinical testing of targeted therapeutic agents for these tumors. We have established a human glioma cell line that originated from surgical biopsy performed on a patient with a pontine glioma. To insure sustainable in vitro propagation, tumor cells were modified with hTERT (human telomerase ribonucleoprotein reverse transcriptase), and with a luciferase reporter to enable non-invasive bioluminescence imaging. The hTERT modified cells are tumorigenic in athymic rodents, and produce brainstem tumors that recapitulate the infiltrative growth of brainstem gliomas in patients.
Journal of Neuro-Oncology 09/2012; · 3.21 Impact Factor
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Joann L Ater,
Tianni Zhou,
Emiko Holmes,
Claire M Mazewski,
Timothy N Booth,
David R Freyer,
Ken H Lazarus,
Roger J Packer, Michael Prados,
Richard Sposto,
Gilbert Vezina,
Jeffrey H Wisoff,
Ian F Pollack
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ABSTRACT: PURPOSE Surgery is curative therapy for pediatric low-grade gliomas (LGGs) in areas of the brain amenable to complete resection. However, LGGs located in areas where complete resection is not possible can threaten both function and life. The purpose of this study was to compare two chemotherapy regimens for LGGs in children younger than age 10 years for whom radiotherapy was felt by the practitioner to pose a high risk of neurodevelopmental injury. PATIENTS AND METHODS Previously untreated children younger than age 10 years with progressive or residual LGGs were eligible. Children were randomly assigned to receive carboplatin and vincristine (CV) or thioguanine, procarbazine, lomustine, and vincristine (TPCV). Children with neurofibromatosis are reported separately. Results Of 274 randomly assigned patients who met eligibility requirements, 137 received CV and 137 received TPCV. The 5-year event-free survival (EFS) and overall survival (OS) rates for all eligible patients were 45% ± 3.2% and 86% ± 2.2%, respectively. The 5-year EFS rates were 39% ± 4% for CV and 52% ± 5% for TPCV (stratified log-rank test P = .10; cure model analysis P = .007). On multivariate analysis, factors independently predictive of worse EFS and OS were younger age and tumor size greater than 3 cm(2). Tumor location in the thalamus was also associated with poor OS. CONCLUSION The difference in EFS between the regimens did not reach significance on the basis of the stratified log-rank test. The 5-year EFS was higher for TPCV on the basis of the cure model analysis. Differences in toxicity may influence physician choice of regimens.
Journal of Clinical Oncology 06/2012; 30(21):2641-7. · 18.37 Impact Factor
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ABSTRACT: We initiated a prospective multicenter phase II trial using rituximab and temozolomide in immunocompetent patients with progressive or recurrent primary central nervous system lymphoma (PCNSL) based on activity observed in retrospective studies. Treatment consisted of an induction phase with rituximab (750 mg/m(2)) on days 1, 8, 15 and 22 and temozolomide (150 mg/m(2)) days 1-7 and 15-21, followed by six cycles of consolidation temozolomide (150-200 mg/m(2) × 5/28 days), followed by maintenance with methylprednisolone (1 g IV every 28 days) until progression. Sixteen patients were enrolled, and a complete response was seen in 2/14 (14%) evaluable patients. The median progression-free survival was 7 weeks and median overall survival was not reached (median follow-up: 37 months). Treatment was well tolerated, but due to slow accrual and preliminary analysis suggesting futility, the trial was closed early. Given the overall modest activity, this regimen should be reserved for patients who are not candidates for other, more aggressive salvage treatments.
Leukemia & lymphoma 06/2012; · 2.40 Impact Factor
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Whitney B Pope,
Xin Joe Qiao,
Hyun J Kim,
Albert Lai,
Phioanh Nghiemphu,
Xi Xue,
Benjamin M Ellingson,
David Schiff,
Dawit Aregawi,
Soonmee Cha, [......],
Dan Barboriak,
Lauren E Abrey,
Tom Mikkelsen,
Rajan Jain,
Nina A Paleologos,
Patricia Lada Rn, Michael Prados,
Jonathan Goldin,
Patrick Y Wen,
Timothy Cloughesy
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ABSTRACT: We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI's from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. Mean ADC-L was 1,209 × 10(-6)mm(2)/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L <1,209 and LCP >0.71 versus ADC-L >1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.
Journal of Neuro-Oncology 03/2012; 108(3):491-8. · 3.21 Impact Factor
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ABSTRACT: The prognosis for diffuse infiltrating pontine gliomas (DIPG) remains extremely poor, with the majority of patients surviving less than 2 years. Here, we have adapted standard xenograft techniques to study glioma growth in the mouse brainstem, and have utilized the mouse model for studying a relevant therapeutic for treating DIPGs. bioluminescence imaging monitoring revealed a progressive increase in signal following the injection of either of two tumor cell types into the brainstem. Mice with orthotopic GS2 tumors, and receiving a single 100 mg/kg dose of temozolomide showed a lengthy period of decreased tumor luminescence, with substantially increased survival relative to untreated mice (P < 0.001). A small molecule inhibitor that targets cdk4/6 was used to test AM-38 brainstem xenograft response to treatment. Drug treatment resulted in delayed tumor growth, and significantly extended survival. Our results demonstrate the feasibility of using an orthotopic brainstem tumor model in athymic mice, and for application to testing therapeutic agents in treating DIPG.
Journal of Neuro-Oncology 01/2012; 108(1):29-35. · 3.21 Impact Factor
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ABSTRACT: The disease outcome for patients with cancer is typically described in terms of estimated survival from diagnosis. Conditional probability offers more relevant information regarding survival for patients once they have survived for some time. We report conditional survival probabilities on the basis of 498 patients with glioblastoma multiforme receiving radiation and chemotherapy. For 1-year survivors, we evaluated variables that may inform subsequent survival. Motivated by the trend in data, we also evaluated the assumption of constant hazard.
Patients enrolled onto seven phase II protocols between 1975 and 2007 were included. Conditional survival probabilities and 95% CIs were calculated. The Cox proportional hazards model was used to evaluate prognostic values of age, Karnofsky performance score (KPS), and prior progression 1-year post diagnosis. To assess the constant hazard assumption, we used a likelihood-ratio test to compare the Weibull and exponential distributions.
The probabilities of surviving an additional year given survival to 1, 2, 3, and 4 years were 35%, 49%, 69%, and 93%, respectively. For patients who survived for 1 year, lower KPS and progression were significantly predictive of shorter survival (both P < .001), but age was not (hazard ratio, 1.22 for a 10-year increase; P = .25). The Weibull distribution fits the data significantly better than exponential (P = .02), suggesting nonconstant hazard.
Conditional probabilities provide encouraging information regarding life expectancy to survivors of glioblastoma multiforme. Our data also showed that the constant hazard assumption may be violated in modern brain tumor trials. For single-arm trials, we advise using individual patient data from historical data sets for efficacy comparisons.
Journal of Clinical Oncology 11/2011; 29(31):4175-80. · 18.37 Impact Factor
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Mark R Gilbert,
John Kuhn,
Kathleen R Lamborn,
Frank Lieberman,
Patrick Y Wen,
Minesh Mehta,
Timothy Cloughesy,
Andrew B Lassman,
Lisa M Deangelis,
Susan Chang, Michael Prados
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ABSTRACT: Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvβ3 and αvβ5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.
Journal of Neuro-Oncology 07/2011; 106(1):147-53. · 3.21 Impact Factor
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Jeffrey S Wefel,
Timothy Cloughesy,
James L Zazzali,
Maoxia Zheng, Michael Prados,
Patrick Y Wen,
Tom Mikkelsen,
David Schiff,
Lauren E Abrey,
W K Alfred Yung,
Nina Paleologos,
Martin K Nicholas,
Randy Jensen,
James Vredenburgh,
Asha Das,
Henry S Friedman
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ABSTRACT: Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial. All patients underwent MRI and neurocognitive testing at baseline and every 6 weeks thereafter. Memory, visuomotor scanning speed, and executive function were evaluated using the Hopkins Verbal Learning Test-Revised, the Trail Making Test, and the Controlled Oral Word Association test, respectively. NCF relative to baseline for patients with an OR, PFS >6 months, or disease progression was evaluated at time of OR, 24 weeks, and time of progression, respectively. For patients with an OR or PFS >6 months, median standardized test scores were examined from baseline to week 24. Most patients with an OR or PFS >6 months had poorer NCF performance compared to the general population at baseline and had improved or stable NCF at the time of response or at the 24-week assessment, respectively; most patients with progressive disease had neurocognitive decline at the time of progression. For patients with an OR or PFS >6 months, median standardized test scores were largely stable across the first 24 weeks on study. Neurocognitive testing was an objective, valid, and feasible method of monitoring NCF in patients with recurrent glioblastoma.
Neuro-Oncology 06/2011; 13(6):660-8. · 5.72 Impact Factor
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Rupa Parvataneni,
Mei-Yin Polley,
Teresa Freeman,
Kathleen Lamborn, Michael Prados,
Nicholas Butowski,
Raymond Liu,
Jennifer Clarke,
Margaretta Page,
Jane Rabbitt,
Anne Fedoroff,
Emelia Clow,
Emily Hsieh,
Valerie Kivett,
Rebecca Deboer,
Susan Chang
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ABSTRACT: The purpose of this study is to identify the needs of brain tumor patients and their caregivers to provide improved health services to these populations. Two different questionnaires were designed for patients and caregivers. Both questionnaires contained questions pertaining to three realms: disease symptoms/treatment, health care provider, daily living/finances. The caregivers' questionnaires contained an additional domain on emotional needs. Each question was evaluated for the degree of importance and satisfaction. Exploratory analyses determined whether baseline characteristics affect responder importance or satisfaction. Also, areas of high agreement/disagreement in satisfaction between the participating patient-caregiver pairs were identified. Questions for which >50% of the patients and caregivers thought were "very important" but >30% were dissatisfied include: understanding the cause of brain tumors, dealing with patients' lower energy, identifying healthful foods and activities for patients, telephone access to health care providers, information on medical insurance coverage, and support from their employer. In the emotional realm, caregivers identified 9 out of 10 items as important but need further improvement. Areas of high disagreement in satisfaction between participating patient-caregiver pairs include: getting help with household chores (P value = 0.006) and finding time for personal needs (P value < 0.001). This study provides insights into areas to improve services for brain tumor patients and their caregivers. The caregivers' highest amount of burden is placed on their emotional needs, emphasizing the importance of providing appropriate medical and psychosocial support for caregivers to cope with emotional difficulties they face during the patients' treatment process.
Journal of Neuro-Oncology 02/2011; 104(3):737-44. · 3.21 Impact Factor
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Michael Prados,
Timothy Cloughesy,
Meghna Samant,
Liang Fang,
Patrick Y Wen,
Tom Mikkelsen,
David Schiff,
Lauren E Abrey,
W K Alfred Yung,
Nina Paleologos,
Martin K Nicholas,
Randy Jensen,
James Vredenburgh,
Asha Das,
Henry S Friedman
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ABSTRACT: Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.
Neuro-Oncology 11/2010; 13(1):143-51. · 5.72 Impact Factor
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Judith A Schwartzbaum,
Yuanyuan Xiao,
Yanhong Liu,
Spyros Tsavachidis,
Mitchel S Berger,
Melissa L Bondy,
Jeffrey S Chang,
Susan M Chang,
Paul A Decker,
Bo Ding, [......], Michael Prados,
Terri Rice,
Lindsay B Robertson,
Minouk J Schoemaker,
Sanjay Shete,
Anthony J Swerdlow,
Joe L Wiemels,
John K Wiencke,
Ping Yang,
Margaret R Wrensch
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ABSTRACT: To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk.
Carcinogenesis 10/2010; 31(10):1770-7. · 5.70 Impact Factor
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Sandeep Kunwar,
Susan Chang,
Manfred Westphal,
Michael Vogelbaum,
John Sampson,
Gene Barnett,
Mark Shaffrey,
Zvi Ram,
Joseph Piepmeier, Michael Prados,
David Croteau,
Christoph Pedain,
Pamela Leland,
Syed R Husain,
Bharat H Joshi,
Raj K Puri
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ABSTRACT: Convection-enhanced delivery (CED) of cintredekin besudotox (CB) was compared with Gliadel wafers (GW) in adult patients with glioblastoma multiforme (GBM) at first recurrence. Patients were randomized 2:1 to receive CB or GW. CB (0.5 microg/mL; total flow rate 0.75 mL/h) was administered over 96 hours via 2-4 intraparenchymal catheters placed after tumor resection. GW (3.85%/7.7 mg carmustine per wafer; maximum 8 wafers) were placed immediately after tumor resection. The primary endpoint was overall survival from the time of randomization. Prestated interim analyses were built into the study design. Secondary and tertiary endpoints were safety and health-related quality-of-life assessments. From March 2004 to December 2005, 296 patients were enrolled at 52 centers. Demographic and baseline characteristics were balanced between the 2 treatment arms. Median survival was 36.4 weeks (9.1 months) for CB and 35.3 weeks (8.8 months) for GW (P = .476). For the efficacy evaluable population, the median survival was 45.3 weeks (11.3 months) for CB and 39.8 weeks (10 months) for GW (P = .310). The adverse-events profile was similar in both arms, except that pulmonary embolism was higher in the CB arm (8% vs 1%, P = .014). This is the first randomized phase III evaluation of an agent administered via CED and the first with an active comparator in GBM patients. There was no survival difference between CB administered via CED and GW. Drug distribution was not assessed and may be crucial for evaluating future CED-based therapeutics.
Neuro-Oncology 08/2010; 12(8):871-81. · 5.72 Impact Factor
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ABSTRACT: The transition from childhood to adulthood through adolescence has been clearly identified as a time of great physical, psychological, emotional, social, and sexual change. Clinical care is currently divided into adult or pediatric care; adolescent patients require specific expertise that most clinical practices do not have. When illness coincides with the adolescent transition, the health system is severely challenged. Health systems historically have varied widely in the age they choose for allocating an individual to the adult model of health care. Tumors of the CNS complicate the difficult adjustments required in adolescents and young adults by virtue of their morbidity, complex treatment, and prognosis. Some brain tumors are unique to children, some occur predominantly in adults, and others peak in adolescence. Delays in the diagnosis of brain tumors can occur at any age but are particularly common in adolescence because of difficulties of accessing health systems, the difficulties of discriminating pathologic from typical adolescent behavioral characteristics, and changing endocrine function. Coming to terms with the cancer diagnosis; coping personally, socially, and financially with cancer treatments; accepting the risk of a shortened life span; confronting acquired disability; and coping with complex rehabilitation and adjusted plans for life are challenges for which there are no established specialist health models. This article will discuss the changing brain tumor profile of children, adolescents, and adults, with a focus on our limited understanding of the adolescent/young adult transition period.
Journal of Clinical Oncology 05/2010; 28(32):4783-9. · 18.37 Impact Factor
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ABSTRACT: We assessed six-month progression-free survival (PFS) as an alternative primary efficacy endpoint to overall survival in newly diagnosed glioblastoma multiforme (GBM) patients receiving temozolomide (TMZ). A total of 183 patients with newly diagnosed GBM enrolled in 3 phase II protocols at the University of California-San Francisco were included. Patients were treated with interventions based on the Stupp regimen, each with the added component of a second oral agent given concurrently with radiotherapy and TMZ, followed by its coadministration with adjuvant TMZ. We examined whether progression status at 2, 4, and 6 months predicted subsequent survival using the landmark analysis. The hazard ratios of death as a function of progression status were estimated based on the Cox proportional hazards model after adjustment for putative prognostic factors. Progression status at 2, 4, and 6 months were all consistently found to be strong predictors of subsequent survival in all studies. The study-specific hazard ratios associated with progression status at 6 months ranged from 2.03 to 3.39. The hazard ratios associated with the earlier time points (2- and 4-month progression) all exceeded 2 in magnitude, ranging from 2.29 to 4.73. P-values were statistically significant for all time points. In this report, we demonstrated a strong association between the endpoints of PFS at 2, 4, and 6 months and survival. Patients who showed the signs of early progression were at significantly higher risk of earlier death. Our analysis suggests that 6-month PFS may be an appropriate primary endpoint in the context of phase II upfront GBM trials in the TMZ era.
Neuro-Oncology 03/2010; 12(3):274-82. · 5.72 Impact Factor
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James J Vredenburgh,
Timothy Cloughesy,
Meghna Samant, Michael Prados,
Patrick Y Wen,
Tom Mikkelsen,
David Schiff,
Lauren E Abrey,
W K Alfred Yung,
Nina Paleologos,
Martin K Nicholas,
Randy Jensen,
Asha Das,
Henry S Friedman
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ABSTRACT: Vascular endothelial growth factor inhibitors have corticosteroid-sparing effects in patients with high-grade gliomas. We assessed corticosteroid use in patients with recurrent glioblastoma treated with bevacizumab (BEV) in the BRAIN study (J Clin Oncol 2009;27:4733-4740).
BRAIN was a phase II, multicenter, randomized, noncomparative trial of BEV alone (n = 85) or in combination with irinotecan (CPT-11) (n = 82) in adults with recurrent glioblastoma. Median corticosteroid dose for patients who used corticosteroids at baseline was summarized by treatment arm; the percentage of patients who had sustained (≥50% corticosteroid dose reduction for ≥50% of time on study drug) or complete (discontinuation of corticosteroid for ≥25% of time on study drug) reduction in corticosteroid dose overall and by objective response and progression-free survival was calculated. The incidence of corticosteroid-related adverse events was summarized.
In each treatment group, 50% of patients were using systemic corticosteroids at baseline. The majority of those experienced a reduction in dose while receiving BEV-based therapy. Thirteen (30.2%) BEV and 20 (46.5%) BEV + CPT-11 patients had a sustained reduction of corticosteroid dose; 7 (16.3%) BEV and 9 (20.9%) BEV + CPT-11 patients had a complete reduction of corticosteroid dose. The majority of patients who had an objective response or progression-free survival >6 months experienced corticosteroid dose reduction. Approximately 64% of patients who used corticosteroids while receiving BEV-based therapy experienced infection.
BEV may have corticosteroid-sparing effects in patients with recurrent glioblastoma. Corticosteroid reduction may positively affect patient health-related quality of life. Given the exploratory nature of the analyses in a noncomparative study, these results should be interpreted cautiously.
The Oncologist 01/2010; 15(12):1329-34. · 3.91 Impact Factor
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ABSTRACT: Atypical Teratoid/Rhabdoid tumors (AT/RT) of the central nervous system are rare but aggressive tumors of childhood. Median survival with surgery and standard chemotherapy is less than 12 months. In an attempt to improve outcome, patients were treated with aggressive surgical resection and multi-agent chemotherapy, followed by high dose chemotherapy with autologous stem cell rescue. Nine consecutive children (median age 21 months) were diagnosed with AT/RT at the University of California San Francisco Childrens Hospital from 1997 to 2007 and treated with this aggressive approach. Diagnosis was confirmed using molecular markers. There are two long-term survivors (78 and 98 months from diagnosis). One additional patient is alive with disease. Three patients died of disease during therapy. Three patients died of disease after therapy was complete. There were no toxic deaths. Two of nine patients treated for AT/RT at our institution with high dose chemotherapy and autologous bone marrow transplant are long-term survivors, suggesting that a subset of patients can be cured with this approach.
Journal of Neuro-Oncology 11/2009; 98(1):117-23. · 3.21 Impact Factor
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Sean M McBride,
Daniel A Perez,
Mei-Yin Polley,
Scott R Vandenberg,
Justin S Smith,
Shichun Zheng,
Kathleen R Lamborn,
John K Wiencke,
Susan M Chang, Michael D Prados,
Mitchel S Berger,
David Stokoe,
Daphne A Haas-Kogan
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ABSTRACT: Recent evidence suggests the Akt-mTOR pathway may play a role in development of low-grade gliomas (LGG). We sought to evaluate whether activation of this pathway correlates with survival in LGG by examining expression patterns of proteins within this pathway. Forty-five LGG tumor specimens from newly diagnosed patients were analyzed for methylation of the putative 5'-promoter region of PTEN using methylation-specific PCR as well as phosphorylation of S6 and PRAS40 and expression of PTEN protein using immunohistochemistry. Relationships between molecular markers and overall survival (OS) were assessed using Kaplan-Meier methods and exact log-rank test. Correlation between molecular markers was determined using the Mann-Whitney U and Spearman Rank Correlation tests. Eight of the 26 patients with methylated PTEN died, as compared to 1 of 19 without methylation. There was a trend towards statistical significance, with PTEN methylated patients having decreased survival (P = 0.128). Eight of 29 patients that expressed phospho-S6 died, whereas all 9 patients lacking p-S6 expression were alive at last follow-up. There was an inverse relationship between expression of phospho-S6 and survival (P = 0.029). There was a trend towards decreased survival in patients expressing phospho-PRAS40 (P = 0.077). Analyses of relationships between molecular markers demonstrated a statistically significant positive correlation between expression of p-S6(235) and p-PRAS40 (P = 0.04); expression of p-S6(240) correlated positively with PTEN methylation (P = 0.04) and negatively with PTEN expression (P = 0.03). Survival of LGG patients correlates with phosphorylation of S6 protein. This relationship supports the use of selective mTOR inhibitors in the treatment of low grade glioma.
Journal of Neuro-Oncology 09/2009; 97(1):33-40. · 3.21 Impact Factor
