115 results on '"Jaeckle KA"'
Search Results
2. GUIDELINES ON THE DETECTION OF PARANEOPLASTIC ANTI-NEURONAL-SPECIFIC ANTIBODIES - REPORT FROM THE WORKSHOP TO THE 4TH MEETING OF THE INTERNATIONAL-SOCIETY-OF-NEURO-IMMUNOLOGY ON PARANEOPLASTIC NEUROLOGICAL DISEASE, HELD OCTOBER 22-23, 1994, IN ROTTERDAM, THE NETHERLANDS
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Moll, Jwb, Antoine, Jc, Brashear, Hr, Delattre, J, Drlicek, M, Dropcho, Ej, Giometto, B, Graus, F, Greenlee, J, Honnorat, J, Jaeckle, Ka, Tanaka, K, Vecht, Cj, Moll, Jwb, Antoine, Jc, Brashear, Hr, Delattre, J, Drlicek, M, Dropcho, Ej, Giometto, B, Graus, F, Greenlee, J, Honnorat, J, Jaeckle, Ka, Tanaka, K, and Vecht, Cj
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- 1995
3. Correlation of enzyme-inducing anticonvulsant use with outcome of patients with glioblastoma.
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Jaeckle KA, Ballman K, Furth A, Buckner JC, Jaeckle, Kurt A, Ballman, Karla, Furth, Alfred, and Buckner, Jan C
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- 2009
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4. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study.
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Galanis E, Jaeckle KA, Maurer MJ, Reid JM, Ames MM, Hardwick JS, Reilly JF, Loboda A, Nebozhyn M, Fantin VR, Richon VM, Scheithauer B, Giannini C, Flynn PJ, Moore DF Jr, Zwiebel J, Buckner JC, Galanis, Evanthia, Jaeckle, Kurt A, and Maurer, Matthew J
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- 2009
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5. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177.
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Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle KA, Uhm JH, Geoffroy FJ, Arusell R, Kitange G, Jenkins RB, Kugler JW, Morton RF, Rowland KM Jr, Mischel P, Yong WH, Scheithauer BW, Schiff D, Giannini C, Buckner JC, and North Central Cancer Treatment Group Study N0177
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- 2008
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6. Is there an association between meningioma and hormone replacement therapy?
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Blitshteyn S, Crook JE, and Jaeckle KA
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- 2008
7. Nonconvulsive status epilepticus in metastatic CNS disease.
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Blitshteyn S and Jaeckle KA
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- 2006
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8. Clinical features and outcomes in primary nervous system histiocytic neoplasms.
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Nathoo N, Uhm JH, Porter AB, Hammack J, Jaeckle KA, Mrugala MM, Crum BA, Flanagan EP, Pittock SJ, Goyal G, Young JR, Koster MJ, Vassallo R, Ryu JH, Davidge-Pitts CJ, Bach C, Ravindran A, Sartori Valinotti JC, Bennani NN, Abeykoon JP, Shah MV, Hook CC, Rech KL, Go RS, and Tobin WO
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- Humans, Female, Male, Middle Aged, Adult, Aged, Adolescent, Young Adult, Child, Aged, 80 and over, Treatment Outcome, Child, Preschool, Nervous System Neoplasms therapy, Nervous System Neoplasms diagnosis, Nervous System Neoplasms pathology
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- 2024
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9. Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations.
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Brastianos PK, Twohy EL, Gerstner ER, Kaufmann TJ, Iafrate AJ, Lennerz J, Jeyapalan S, Piccioni DE, Monga V, Fadul CE, Schiff D, Taylor JW, Chowdhary SA, Bettegowda C, Ansstas G, De La Fuente M, Anderson MD, Shonka N, Damek D, Carrillo J, Kunschner-Ronan LJ, Chaudhary R, Jaeckle KA, Senecal FM, Kaley T, Morrison T, Thomas AA, Welch MR, Iwamoto F, Cachia D, Cohen AL, Vora S, Knopp M, Dunn IF, Kumthekar P, Sarkaria J, Geyer S, Carrero XW, Martinez-Lage M, Cahill DP, Brown PD, Giannini C, Santagata S, Barker FG 2nd, and Galanis E
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- Humans, Focal Adhesion Protein-Tyrosine Kinases genetics, Focal Adhesion Protein-Tyrosine Kinases therapeutic use, Mutation, Neoplasm Recurrence, Local drug therapy, Meningeal Neoplasms drug therapy, Meningeal Neoplasms genetics, Meningeal Neoplasms pathology, Meningioma drug therapy, Meningioma genetics
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Purpose: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas., Patients and Methods: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy., Results: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events., Conclusion: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2 -mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.
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- 2023
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10. Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.
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Le Rhun E, Devos P, Winklhofer S, Lmalem H, Brandsma D, Kumthekar P, Castellano A, Compter A, Dhermain F, Franceschi E, Forsyth P, Furtner J, Galldiks N, Gállego Pérez-Larraya J, Gempt J, Hattingen E, Hempel JM, Lukacova S, Minniti G, O'Brien B, Postma TJ, Roth P, Rudà R, Schaefer N, Schmidt NO, Snijders TJ, Thust S, van den Bent M, van der Hoorn A, Vogin G, Smits M, Tonn JC, Jaeckle KA, Preusser M, Glantz M, Wen PY, Bendszus M, and Weller M
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- Humans, Magnetic Resonance Imaging, Treatment Outcome, Brain Neoplasms pathology, Meningeal Carcinomatosis, Oncologists
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Background: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis., Methods: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement., Results: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions., Conclusion: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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11. Liquid biopsy in gliomas: A RANO review and proposals for clinical applications.
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Soffietti R, Bettegowda C, Mellinghoff IK, Warren KE, Ahluwalia MS, De Groot JF, Galanis E, Gilbert MR, Jaeckle KA, Le Rhun E, Rudà R, Seoane J, Thon N, Umemura Y, Weller M, van den Bent MJ, Vogelbaum MA, Chang SM, and Wen PY
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- Biomarkers, Tumor, DNA, Neoplasm, Humans, Liquid Biopsy methods, Circulating Tumor DNA genetics, Glioma diagnosis, Neoplastic Cells, Circulating metabolism
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Background: There is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring., Methods: The RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, that is circulating tumor DNA, circulating tumor cells, and extracellular vesicles in blood and CSF., Results: ctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA, and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict the outcome., Conclusions: There is a need for standardization of biofluid collection, choice of an analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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12. Phase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance).
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Galanis E, Anderson SK, Twohy E, Butowski NA, Hormigo A, Schiff D, Omuro A, Jaeckle KA, Kumar S, Kaufmann TJ, Geyer S, Kumthekar PU, Campian J, Giannini C, Buckner JC, and Wen PY
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Background: Patients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM., Methods: Phase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients received TRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated., Results: In total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade ≥3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75-1.78, P = .51). Quality of life scores were similar for both treatment arms., Conclusions: TRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
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- 2022
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13. Efficacy of Treatment With Armodafinil for Cancer-Related Fatigue in Patients With High-grade Glioma: A Phase 3 Randomized Clinical Trial.
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Porter AB, Liu H, Kohli S, Cerhan JL, Sloan J, McMurray RP, Le-Rademacher J, Loprinzi CL, Villano JL, Kizilbash SH, Mehta MP, Jaeckle KA, and Brown PD
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- Adult, Aged, Benzhydryl Compounds adverse effects, Double-Blind Method, Fatigue chemically induced, Fatigue etiology, Female, Humans, Male, Middle Aged, Modafinil adverse effects, Treatment Outcome, Glioma complications, Glioma drug therapy, Glioma radiotherapy, Quality of Life
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Importance: Nearly 96% of patients with high-grade glioma (HGG) report moderate-to-severe fatigue. Armodafinil is a psychostimulant that might help cancer-related fatigue in patients with HGG., Objective: To determine whether armodafinil reduces fatigue in patients with HGG and moderate-to-severe fatigue., Design, Setting, and Participants: In this randomized multicenter, phase 3, double-blinded, placebo-controlled clinical trial, adults with HGG and moderate-to-severe fatigue who were clinically stable at least 4 weeks after completing radiation therapy were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo over 8 weeks. A score of at least 6 out of 10 on severity scale for the brief fatigue inventory scale, with 10 being the worst, was required to suggest moderate-to-severe fatigue. Patients were allowed stable doses of corticosteroids but were excluded if they required increasing amounts of corticosteroids, were receiving some other treatment for fatigue, or had an uncontrolled seizure disorder. The study was conducted from June 2013 to December 15, 2019., Interventions: Patients were randomized to 150 mg of armodafinil, 250 mg of armodafinil, or placebo for a total of 8 weeks with assessments at weeks 4 and 8., Main Outcomes and Measures: The primary outcome was efficacy in treating cancer-related fatigue. Secondary outcomes included safety, neurocognitive function, and quality of life. Patients were evaluated at baseline and at weeks 4 and 8. Efficacy between the placebo and the 2 doses of study drug was determined by an improvement by 2 points on the 0 to 10 brief fatigue inventory scale. Kruskal-Wallis and χ2 tests were used and followed by confirmatory analyses., Results: A total of 328 patients were enrolled, of whom 297 had evaluable end point data. Of these, 103 received 150 mg of armodafinil (mean [SD] age, 58.5 [11.9] years; 42 women [40.8%]), 97 250 mg of armodafinil (mean [SD] age, 56.6 [12.5] years; 37 women [38.1%]), and 97 placebo (mean [SD] age, 57.1 [12.5] years; 39 women [40.2%]). There was no difference in the proportion of patients who achieved clinically meaningful fatigue reduction between arms (28% [95% CI 20%-30%] for 150 mg of armodafinil, 28% [95% CI 19%-38%] for 250 mg of armodafinil, and 30% [95% CI 21%-40%] for placebo). There was a statistically significant reduction in global fatigue for corticosteroid users compared with nonusers (-0.7 [95% CI, -1.5 to -0.3] vs -1.7 [95% CI, -2.1 to -1.3]; P < .001). More patients (2 vs 7) reported insomnia with treatment with 250 mg of armodafinil., Conclusions and Relevance: The results of this randomized clinical trial found no meaningful benefit of using treatment with armodafinil to reduce cancer-related fatigue in patients with HGG., Trial Registration: ClinicalTrials.gov Identifier: NCT01781468.
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- 2022
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14. Isocitrate Dehydrogenase Mutant Grade II and III Glial Neoplasms.
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Mellinghoff IK, Chang SM, Jaeckle KA, and van den Bent M
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- Adult, Humans, Isocitrate Dehydrogenase genetics, Mutation, Brain Neoplasms genetics, Brain Neoplasms therapy, Glioma drug therapy, Glioma genetics, Leukemia, Myeloid, Acute
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Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors., Competing Interests: Disclosure I.K. Mellinghoff reports serving as a consultant for Agios Pharmaceuticals, Inc, Black Diamond, DC Europa, Debiopharm, Puma Biotechnology, and Voyager, and research grants from Amgen, Eli Lilly, and General Electric. M. van den Bent reports serving as a consultant for Agios Pharmaceuticals, Karyopharm, Cellgene, Nerviano, Carthera, and Genenta. S.M. Chang reports institutional research support from Agios Pharmaceuticals., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2022
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15. CODEL: phase III study of RT, RT + TMZ, or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma. Analysis from the initial study design.
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Jaeckle KA, Ballman KV, van den Bent M, Giannini C, Galanis E, Brown PD, Jenkins RB, Cairncross JG, Wick W, Weller M, Aldape KD, Dixon JG, Anderson SK, Cerhan JH, Wefel JS, Klein M, Grossman SA, Schiff D, Raizer JJ, Dhermain F, Nordstrom DG, Flynn PJ, and Vogelbaum MA
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- Adult, Humans, Isocitrate Dehydrogenase genetics, Progression-Free Survival, Temozolomide therapeutic use, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Oligodendroglioma drug therapy, Oligodendroglioma genetics
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Background: We report the analysis involving patients treated on the initial CODEL design., Methods: Adults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm., Results: Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months., Conclusions: TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2021
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16. Intra-CSF topotecan in treatment of breast cancer patients with leptomeningeal metastases.
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Jaeckle KA, Dixon JG, Anderson SK, Moreno-Aspitia A, Colon-Otero G, Hebenstreit K, Patel TA, Reddy SL, and Perez EA
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- Adult, Aged, Aged, 80 and over, Breast Neoplasms cerebrospinal fluid, Breast Neoplasms diagnostic imaging, Breast Neoplasms pathology, Female, Humans, Infusions, Intraventricular, Magnetic Resonance Imaging, Meningeal Neoplasms cerebrospinal fluid, Meningeal Neoplasms diagnostic imaging, Meningeal Neoplasms secondary, Middle Aged, Progression-Free Survival, Radiotherapy, Adjuvant, Retrospective Studies, Time Factors, Topoisomerase I Inhibitors adverse effects, Topotecan adverse effects, Breast Neoplasms drug therapy, Meningeal Neoplasms drug therapy, Topoisomerase I Inhibitors administration & dosage, Topotecan administration & dosage
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Background: There are few treatment options for patients with leptomeningeal metastases (LM)., Methods: We report a case series of patients with breast cancer and LM treated with intra-CSF topotecan (TOPO). Outcome was assessed by clinical exam and MRI at baseline, at end of induction (4-5 weeks), then every 3 months; CSF cytology was determined at baseline and with each treatment., Results: Thirty-one women [median age, 58 (37-81); median KPS 60 (40-100)] received treatment. At baseline, 68% had positive CSF cytology, and 90%, leptomeningeal enhancement on MRI. 84% of patients also received focal RT (not during TOPO) and 77% received concomitant systemic hormonal or chemotherapy. Median number of TOPO treatments was 14.5 (range, 3-71); median duration of treatment, 11 weeks (1-176); and median OS, 6.9 months (range, 0.9-48.8). Patients remaining progression-free during 4-6 weeks of induction (81%) had a median OS of 11.5 months (range, 1.8-48.8). Overall neurologic PFS at 6, 12, and 24 months was 39%, 26%, and 6%, respectively. Clearing of CSF malignant cells for >3 consecutive samples occurred in 10/21 (48%) patients with positive CSF cytology at baseline, remaining clear for a median duration of 15.9 months (range, 1.4-34.5). Grade 3 adverse events included headache or vomiting (3pts), T2 hyperintensity surrounding the ventricular catheter (2 pts), and meningitis (2 pts)., Conclusions: Intra-CSF TOPO, with focal RT as needed for symptomatic areas of enhancement produced durable clearing of CSF malignant cells in 48% of patients positive at baseline, with promising median PFS and OS., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2020
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17. Correction to: Phase I-II trial of imatinib mesylate (Gleevec; STI571) in treatment of recurrent oligodendroglioma and mixed oligoastrocytoma. North central cancer treatment group study N0272 (ALLIANCE/NCCTG).
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Jaeckle KA, Anderson SK, Twohy EL, Dixon JG, Giannini C, Jenkins R, Egorin MJ, Sarkaria JN, Brown PD, Flynn PJ, Schwerkoske J, Buckner JC, and Galanis E
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The last author's first name was truncated in the initial online publication. The original article has been corrected.
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- 2019
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18. Phase I-II trial of imatinib mesylate (Gleevec; STI571) in treatment of recurrent oligodendroglioma and mixed oligoastrocytoma. North central cancer treatment group study N0272 (ALLIANCE/NCCTG).
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Jaeckle KA, Anderson SK, Twohy EL, Dixon JG, Giannini C, Jenkins R, Egorin MJ, Sarkaria JN, Brown PD, Flynn PJ, Schwerkoske J, Buckner JC, and Galanis E
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- Antineoplastic Agents pharmacokinetics, Astrocytoma pathology, Case-Control Studies, Cohort Studies, Female, Follow-Up Studies, Humans, Imatinib Mesylate pharmacokinetics, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local pathology, Oligodendroglioma pathology, Prognosis, Survival Rate, Tissue Distribution, Antineoplastic Agents therapeutic use, Astrocytoma drug therapy, Imatinib Mesylate therapeutic use, Neoplasm Recurrence, Local drug therapy, Oligodendroglioma drug therapy
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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 600 mg/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 1200 mg/D. For phase II patients, overall PFS6 was 33% and median PFS 4.0 months (95% CI 2.1, 5.7). Median overall survival (OS) was longer in imatinib-treated patients compared with controls (16.6 vs. 8.0 months; HR = 0.64, 95% CI 0.41,1.0, p = 0.049), and longer in patients with 1p/19q-codeleted tumors (19.2 vs. 6.2 months, 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 600 mg/D, mean steady-state imatinib plasma concentration was 2513 ng/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.
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- 2019
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19. Phase 1 study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma.
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Tun HW, Johnston PB, DeAngelis LM, Atherton PJ, Pederson LD, Koenig PA, Reeder CB, Omuro AMP, Schiff D, O'Neill B, Pulido J, Jaeckle KA, Grommes C, and Witzig TE
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- Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Central Nervous System Neoplasms pathology, Dexamethasone administration & dosage, Dexamethasone adverse effects, Female, Humans, Lymphoma pathology, Male, Middle Aged, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local pathology, Retinal Neoplasms pathology, Thalidomide administration & dosage, Thalidomide adverse effects, Thalidomide therapeutic use, Treatment Outcome, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Central Nervous System Neoplasms drug therapy, Dexamethasone therapeutic use, Lymphoma drug therapy, Retinal Neoplasms drug therapy, Thalidomide analogs & derivatives
- Abstract
The combination of pomalidomide (POM) and dexamethasone (DEX) was evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) to determine the maximal tolerated dose (MTD) of POM as the primary objective, and overall response rate (ORR), progression-free survival (PFS), and safety profile as secondary objectives. A cohorts-of-3 study design was used with a dose-escalation schedule consisting of POM (3, 5, 7, or 10 mg) orally daily for 21 days every 28 days and DEX 40 mg orally every week. After 2 cycles, POM was continued alone until disease progression, intolerance, or subject withdrawal. Following MTD determination, the MTD cohort was expanded. Twenty-five of 29 patients with the median of 3 prior treatments were eligible for assessment as per international PCNSL collaborative group criteria. The MTD of POM was 5 mg daily for 21 days every 28 days. Whole-study ORR was 48% (12 of 25; 95% confidence interval [CI], 27.8%, 68.7%) with 6 complete response (CR), 2 complete response, unconfirmed (CRu), and 4 partial response (PR). MTD cohort ORR was 50% (8 of 16; 95% CI, 24.7%, 75.4%) with 5 CR, 1 CRu, and 2 PR. Median PFS was 5.3 months (whole study) and 9 months (for responders). One patient had pseudoprogression. Grade 3/4 hematologic toxicities included neutropenia (21%), anemia (8%), and thrombocytopenia (8%). Grade 3/4 nonhematologic toxicities included lung infection (12%), sepsis (4%), fatigue (8%), syncope (4%), dyspnea (4%), hypoxia (4%), respiratory failure (8%), and rash (4%). POM/DEX treatment is feasible with significant therapeutic activity against relapsed/refractory PCNSL and PVRL. This trial was registered at www.clinicaltrials.gov as #NCT01722305., (© 2018 by The American Society of Hematology.)
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- 2018
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20. Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572.
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Schiff D, Jaeckle KA, Anderson SK, Galanis E, Giannini C, Buckner JC, Stella P, Flynn PJ, Erickson BJ, Schwerkoske JF, Kaluza V, Twohy E, Dancey J, Wright J, and Sarkaria JN
- Subjects
- Adult, Brain Neoplasms pathology, Female, Follow-Up Studies, Glioblastoma pathology, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local pathology, Prognosis, Sirolimus administration & dosage, Sirolimus analogs & derivatives, Sorafenib administration & dosage, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Neoplasm Recurrence, Local drug therapy
- Abstract
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., (© 2018 American Cancer Society.)
- Published
- 2018
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21. Treatment of a glioblastoma multiforme dural metastasis with stereotactic radiosurgery: A case report and select review of the literature.
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Hintenlang LL, Miller DH, Kaleem T, Patel N, May BC, Tzou KS, Vallow LA, Buskirk SJ, Miller RC, Ko SJ, Jaeckle KA, Trifiletti DM, and Peterson JL
- Subjects
- Antineoplastic Agents therapeutic use, Chemotherapy, Adjuvant, Combined Modality Therapy, Craniotomy, Fatal Outcome, Glioblastoma drug therapy, Humans, Lomustine therapeutic use, Magnetic Resonance Imaging, Male, Meningeal Neoplasms drug therapy, Middle Aged, Salvage Therapy, Dura Mater, Glioblastoma secondary, Glioblastoma surgery, Meningeal Neoplasms secondary, Meningeal Neoplasms surgery, Radiosurgery methods
- Abstract
Glioblastoma multiforme (GBM) is a primary brain neoplasm accounting for approximately 75% of all high grade gliomas. It is diffusely infiltrative and exhibits rapid proliferation with a poor overall prognosis. Maximum surgical resection and postoperative radiotherapy, accompanied by concurrent and adjuvant temozolomide chemotherapy, remain the standard of care without major therapeutic advances over the past 10 years. Herein, we present the case of a 64-year-old Caucasian male with a GBM who subsequently developed a left frontal dural metastasis, subsequently treated with stereotactic radiosurgery (20 Gy in 1 fraction). With six month follow-up, the patient showed near complete resolution of his dural metastases and no overall change in neurological symptoms or side effects following radiosurgery. Due to the paucity of clinical literature regarding dural metastases from GBM, its optimal treatment remains unknown. While the role of SRS has yet to be defined in this setting, here we provide evidence suggesting its overall efficacy in the treatment of select dural GBM metastases., (Copyright © 2017. Published by Elsevier Ltd.)
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- 2018
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22. Leptomeningeal metastases: a RANO proposal for response criteria.
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Chamberlain M, Junck L, Brandsma D, Soffietti R, Rudà R, Raizer J, Boogerd W, Taillibert S, Groves MD, Le Rhun E, Walker J, van den Bent M, Wen PY, and Jaeckle KA
- Subjects
- Clinical Trials as Topic standards, Disease Progression, Humans, Magnetic Resonance Imaging, Meningeal Neoplasms cerebrospinal fluid, Meningeal Neoplasms diagnostic imaging, Treatment Outcome, Meningeal Neoplasms diagnosis, Meningeal Neoplasms therapy
- Abstract
Leptomeningeal metastases (LM) currently lack standardization with respect to response assessment. A Response Assessment in Neuro-Oncology (RANO) working group with expertise in LM developed a consensus proposal for evaluating patients treated for this disease. Three basic elements in assessing response in LM are proposed: a standardized neurological examination, cerebral spinal fluid (CSF) cytology or flow cytometry, and radiographic evaluation. The group recommends that all patients enrolling in clinical trials undergo CSF analysis (cytology in all cancers; flow cytometry in hematologic cancers), complete contrast-enhanced neuraxis MRI, and in instances of planned intra-CSF therapy, radioisotope CSF flow studies. In conjunction with the RANO Neurological Assessment working group, a standardized instrument was created for assessing the neurological exam in patients with LM. Considering that most lesions in LM are nonmeasurable and that assessment of neuroimaging in LM is subjective, neuroimaging is graded as stable, progressive, or improved using a novel radiological LM response scorecard. Radiographic disease progression in isolation (ie, negative CSF cytology/flow cytometry and stable neurological assessment) would be defined as LM disease progression. The RANO LM working group has proposed a method of response evaluation for patients with LM that will require further testing, validation, and likely refinement with use., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2017
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23. Quantification of the impact of enzyme-inducing antiepileptic drugs on irinotecan pharmacokinetics and SN-38 exposure.
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Berg AK, Buckner JC, Galanis E, Jaeckle KA, Ames MM, and Reid JM
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- Adult, Aged, Antineoplastic Agents, Phytogenic blood, Brain Neoplasms metabolism, Camptothecin blood, Camptothecin pharmacokinetics, Carbamazepine pharmacology, Drug Interactions, Enzyme Induction, Female, Glioma metabolism, Humans, Irinotecan, Male, Middle Aged, Phenobarbital pharmacology, Phenytoin pharmacology, Anticonvulsants pharmacology, Antineoplastic Agents, Phytogenic pharmacokinetics, Camptothecin analogs & derivatives, Glucuronates blood
- Abstract
The population pharmacokinetic model reported here was developed using data from 2 phase 2 trials of irinotecan for treatment of malignant glioma to quantify the impact of concomitant therapy with enzyme-inducing antiepileptic drugs (EIAEDs) on irinotecan pharmacokinetics. Patients received weekly irinotecan doses of 100 to 400 mg/m(2) , and plasma samples were collected and analyzed for irinotecan and its APC, SN-38, and SN-38G metabolites. Nonlinear mixed-effects modeling was employed for population pharmacokinetic analysis. Concomitant therapy with phenytoin, phenobarbital, or carbamazepine increased the clearances of irinotecan, SN-38, and SN-38G but not APC. SN-38 clearance was 2-fold higher with concomitant EIAED use, resulting in 40% lower SN-38 exposure. Evaluation of additional covariates revealed no clinically relevant effects of sex or concomitant corticosteroid use. The population pharmacokinetic model suggests that a 1.7-fold increase in irinotecan dose may compensate for decreases in SN-38 exposure in the presence of concomitant EIAEDs. Although slightly more conservative, this dose adjustment is consistent with those recommended based on increases in the maximally tolerated dose for malignant glioma patients receiving EIAEDs and may be an appropriate starting point for further investigation when extrapolating to other cancer types or alternative regimens., (© 2015, The American College of Clinical Pharmacology.)
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- 2015
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24. A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K.
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Ma DJ, Galanis E, Anderson SK, Schiff D, Kaufmann TJ, Peller PJ, Giannini C, Brown PD, Uhm JH, McGraw S, Jaeckle KA, Flynn PJ, Ligon KL, Buckner JC, and Sarkaria JN
- Subjects
- Brain Neoplasms diagnostic imaging, Brain Neoplasms metabolism, Dacarbazine therapeutic use, Drug Therapy, Combination, Glioblastoma diagnostic imaging, Glioblastoma metabolism, Humans, Positron-Emission Tomography, Prognosis, Survival Analysis, TOR Serine-Threonine Kinases antagonists & inhibitors, Temozolomide, Treatment Outcome, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Brain Neoplasms radiotherapy, Dacarbazine analogs & derivatives, Everolimus therapeutic use, Glioblastoma drug therapy, Glioblastoma radiotherapy
- Abstract
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., Methods: Newly diagnosed patients with glioblastoma multiforme were eligible for this single arm, phase II study. Everolimus (70 mg/wk) was started 1 week prior to radiation and TMZ, followed by adjuvant TMZ, and continued until disease progression. The primary endpoint was overall survival at 12 months, and secondary endpoints were toxicity and time to progression. Eleven patients were imaged with 3'-deoxy-3'-(18)F-fluorothymidine ((18)FLT)-PET/CT before and after the initial 2 doses of everolimus before initiating radiation/TMZ. Imaged patients with sufficient tumor samples also underwent immunohistochemical and focused exon sequencing analysis., Results: This study accrued 100 evaluable patients. Fourteen percent of patients had grade 4 hematologic toxicities. Twelve percent had at least one grade 4 nonhematologic toxicity, and there was one treatment-related death. Overall survival at 12 months was 64% and median time to progression was 6.4 months. Of the patients who had (18)FLT-PET data, 4/9 had a partial response after 2 doses of everolimus. Focused exon sequencing demonstrated that (18)FLT-PET responders were less likely to have alterations within the PI3K/Akt/mTOR or tuberous sclerosis complex/neurofibromatosis type 1 pathway compared with nonresponders., Conclusion: Combining everolimus with conventional chemoradiation had moderate toxicity. (18)FLT-PET studies suggested an initial antiproliferative effect in a genetically distinct subset of tumors, but this did not translate into an appreciable survival benefit compared with historical controls treated with conventional therapy., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2015
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25. Leptomeningeal metastasis: a Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials.
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Chamberlain M, Soffietti R, Raizer J, Rudà R, Brandsma D, Boogerd W, Taillibert S, Groves MD, Le Rhun E, Junck L, van den Bent M, Wen PY, and Jaeckle KA
- Subjects
- Clinical Trials, Phase II as Topic standards, Endpoint Determination, Humans, Meningeal Neoplasms secondary, Treatment Outcome, Antineoplastic Agents therapeutic use, Meningeal Neoplasms drug therapy, Patient Outcome Assessment, Randomized Controlled Trials as Topic standards
- Abstract
Purpose: To date, response criteria and optimal methods for assessment of outcome have not been standardized in patients with leptomeningeal metastasis (LM)., Methods: A Response Assessment in Neuro-Oncology working group of experts in LM critically reviewed published literature regarding randomized clinical trials (RCTs) and trial design in patients with LM., Results: A literature review determined that 6 RCTs regarding the treatment of LM have been published, all of which assessed the response to intra-CSF based chemotherapy. Amongst these RCTs, only a single trial attempted to determine whether intra-CSF chemotherapy was of benefit compared with systemic therapy. Otherwise, this pragmatic question has not been formally addressed in patients with solid cancers and LM. The methodology of the 6 RCTs varied widely with respect to pretreatment evaluation, type of treatment, and response to treatment. Additionally there was little uniformity in reporting of treatment-related toxicity. One RCT suggests no advantage of combined versus single-agent intra-CSF chemotherapy in patients with LM. No specific intra-CSF regimen has shown superior efficacy in the treatment of LM, with the exception of liposomal cytarabine in patients with lymphomatous meningitis. Problematic with all RCTs is the lack of standardization with respect to response criteria. There was considerable variation in definitions of response by clinical examination, neuroimaging, and CSF analysis., Conclusion: Based upon a review of published RCTs in LM, there exists a significant unmet need for guidelines for evaluating patients with LM in clinical practice as well as for response assessment in clinical trials., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2014
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26. Oligodendroglial tumors.
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Jaeckle KA
- Subjects
- Antineoplastic Agents therapeutic use, Cognition, Genetic Association Studies, Humans, Molecular Diagnostic Techniques, Quality of Life, Radiotherapy, Adjuvant, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Brain Neoplasms therapy, Oligodendroglioma diagnosis, Oligodendroglioma genetics, Oligodendroglioma therapy
- Abstract
Oligodendroglial tumors are relatively rare, comprising approximately 5% of all glial neoplasms. Oligodendroglial tumor patients have a better prognosis than those with astrocytic neoplasms, and patients with tumors that contain 1p/19q co-deletions or IDH-1 mutations appear to be particularly sensitive to treatment. In the past decade, scientists have made significant progress in the unraveling the molecular events that relate to the pathogenesis of these neoplasms. There is considerable excitement resulting from the recent reports from two large phase III randomized trials (European Organization for Research and Treatment of Cancer [EORTC] 26951 and Radiation Therapy Oncology Group [RTOG] 9402), which disclosed that patients with newly diagnosed 1p/19q co-deleted anaplastic oligodendroglial tumors have a 7+year increase in median overall survival following chemoradiation, as compared to radiation alone. This has stimulated a renewed interest in the development of new therapeutic strategies for treatment and potential cure of oligodendroglial tumors, based on an improved scientific understanding of the molecular events involved in the pathogenesis of these neoplasms. The goal of this document is to summarize the key translational developments and recent clinical therapeutic trial data, with a correlative perspective on current and future directions., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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27. A randomized trial of bevacizumab for newly diagnosed glioblastoma.
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Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, and Mehta MP
- Subjects
- Adult, Angiogenesis Inhibitors adverse effects, Antibodies, Monoclonal, Humanized adverse effects, Bevacizumab, Brain Neoplasms mortality, Brain Neoplasms radiotherapy, Combined Modality Therapy, Dacarbazine adverse effects, Dacarbazine analogs & derivatives, Dacarbazine therapeutic use, Disease-Free Survival, Double-Blind Method, Glioblastoma mortality, Glioblastoma radiotherapy, Humans, Proportional Hazards Models, Survival Analysis, Temozolomide, Angiogenesis Inhibitors therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Brain Neoplasms drug therapy, Glioblastoma drug therapy
- Abstract
Background: Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known., Methods: In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary end points, with the addition of bevacizumab., Results: A total of 978 patients were registered, and 637 underwent randomization. There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group., Conclusions: First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00884741.).
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- 2014
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28. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial.
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Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, and Mehta MP
- Subjects
- Aged, Antineoplastic Agents, Alkylating adverse effects, Brain Neoplasms genetics, Brain Neoplasms radiotherapy, Chemoradiotherapy, DNA Methylation, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Dacarbazine administration & dosage, Dacarbazine adverse effects, Disease-Free Survival, Female, Glioblastoma genetics, Glioblastoma radiotherapy, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Temozolomide, Tumor Suppressor Proteins genetics, Antineoplastic Agents, Alkylating administration & dosage, Brain Neoplasms drug therapy, Dacarbazine analogs & derivatives, Glioblastoma drug therapy
- Abstract
Purpose: Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM., Patients and Methods: This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status., Results: A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue., Conclusion: This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.
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- 2013
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29. Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial.
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Galanis E, Anderson SK, Lafky JM, Uhm JH, Giannini C, Kumar SK, Kimlinger TK, Northfelt DW, Flynn PJ, Jaeckle KA, Kaufmann TJ, and Buckner JC
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Biomarkers, Tumor genetics, Brain Neoplasms pathology, Disease-Free Survival, Female, Glioblastoma pathology, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Neoplastic Cells, Circulating, Niacinamide administration & dosage, Polymorphism, Single Nucleotide, Proportional Hazards Models, Sorafenib, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor Receptor-2 genetics, Antibodies, Monoclonal, Humanized administration & dosage, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Neoplasm Recurrence, Local drug therapy, Niacinamide analogs & derivatives, Phenylurea Compounds administration & dosage
- Abstract
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., (©2013 AACR.)
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- 2013
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30. Primary central nervous system B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma.
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Jiang L, Li Z, Finn LE, Personnet DA, Edenfield B, Foran JM, Jaeckle KA, Reimer R, Menke DM, Ketterling RP, and Tun HW
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- Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Central Nervous System Neoplasms genetics, Fatal Outcome, Genes, bcl-2, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Lymphoma, B-Cell genetics, Male, Neoplasm Staging, Proto-Oncogene Proteins c-myc genetics, Radiotherapy, Central Nervous System Neoplasms pathology, Central Nervous System Neoplasms physiopathology, Lymphoma, B-Cell pathology, Lymphoma, B-Cell physiopathology
- Abstract
B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma (DLBCL/BL) is a new lymphoma entity which is recognized in the current World Health Organization (WHO) classification (2008). We report a case of a primary central nervous system lymphoma (PCNSL) with findings consistent with DLBCL/BL. It is characterized by a very aggressive clinical course, and a widespread multifocal involvement of the CNS. Our case shows that a DLBCL/BL can manifest in the CNS alone without any systemic involvement.
- Published
- 2012
31. North Central Cancer Treatment Group Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme.
- Author
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Sarkaria JN, Galanis E, Wu W, Peller PJ, Giannini C, Brown PD, Uhm JH, McGraw S, Jaeckle KA, and Buckner JC
- Subjects
- Administration, Oral, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Brain Neoplasms diagnostic imaging, Combined Modality Therapy adverse effects, Combined Modality Therapy methods, Dacarbazine administration & dosage, Dacarbazine adverse effects, Dacarbazine analogs & derivatives, Everolimus, Female, Fluorodeoxyglucose F18, Follow-Up Studies, Glioblastoma diagnostic imaging, Glioblastoma drug therapy, Glioblastoma radiotherapy, Humans, Male, Middle Aged, Positron-Emission Tomography methods, Radiopharmaceuticals, Sirolimus administration & dosage, Sirolimus adverse effects, Sirolimus analogs & derivatives, Temozolomide, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms drug therapy, Brain Neoplasms radiotherapy
- Abstract
Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. On the basis of promising preclinical data, the safety and tolerability of therapy with the mTOR inhibitor RAD001 in combination with radiation (RT) and temozolomide (TMZ) was evaluated in this Phase I study., Methods and Materials: All patients received weekly oral RAD001 in combination with standard chemoradiotherapy, followed by RAD001 in combination with standard adjuvant temozolomide. RAD001 was dose escalated in cohorts of 6 patients. Dose-limiting toxicities were defined during RAD001 combination therapy with TMZ/RT., Results: Eighteen patients were enrolled, with a median follow-up of 8.4 months. Combined therapy was well tolerated at all dose levels, with 1 patient on each dose level experiencing a dose-limiting toxicity: Grade 3 fatigue, Grade 4 hematologic toxicity, and Grade 4 liver dysfunction. Throughout therapy, there were no Grade 5 events, 3 patients experienced Grade 4 toxicities, and 6 patients had Grade 3 toxicities attributable to treatment. On the basis of these results, the recommended Phase II dosage currently being tested is RAD001 70 mg/week in combination with standard chemoradiotherapy. Fluorodeoxyglucose (FDG) positron emission tomography scans also were obtained at baseline and after the second RAD001 dose before the initiation of TMZ/RT; the change in FDG uptake between scans was calculated for each patient. Fourteen patients had stable metabolic disease, and 4 patients had a partial metabolic response., Conclusions: RAD001 in combination with RT/TMZ and adjuvant TMZ was reasonably well tolerated. Changes in tumor metabolism can be detected by FDG positron emission tomography in a subset of patients within days of initiating RAD001 therapy., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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32. Metastases involving spinal cord, roots, and plexus.
- Author
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Jaeckle KA
- Abstract
Neurogenic pain is common in patients with widespread metastatic cancer. Pain of this type is often severe and typically results from neoplastic invasion of the peripheral nerves, spinal roots, or spinal cord. Tumors may invade the cervical, brachial, or lumbosacral plexuses either by direct extension from contiguous structures or in association with metastases to regional soft tissues and lymph nodes. Most of these patients experience progressive pain, motor loss, and sensory dysfunction. Metastases directly to the peripheral nerves are rare in patients with solid tumors but are more frequently encountered in patients with hematologic malignancies. Metastases to the spinal roots and the spinal cord usually occur in patients who also have demonstrable evidence of leptomeningeal or intraparenchymal brain metastases. These conditions may overlap and must be distinguished from other causes of plexus, nerve, or spinal cord disorders in the patient with cancer. Early identification and appropriate treatment allow these patients to remain functional and interactive with family and friends.
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- 2011
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33. Transformation of low grade glioma and correlation with outcome: an NCCTG database analysis.
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Jaeckle KA, Decker PA, Ballman KV, Flynn PJ, Giannini C, Scheithauer BW, Jenkins RB, and Buckner JC
- Subjects
- Female, Glioblastoma mortality, Glioblastoma therapy, Glioma diagnosis, Glioma mortality, Humans, Male, Prospective Studies, Survival Analysis, Treatment Outcome, Clinical Trials as Topic statistics & numerical data, Databases as Topic, Glioblastoma pathology, Glioma secondary, Glioma therapy, Statistics as Topic
- Abstract
Glioblastomas (GBM) may originate de novo (primary), or following transformation from a lower grade glioma (secondary), and it has been postulated that these tumors may have different biological behaviors. We performed a correlative analysis involving 204 patients with glioma treated prospectively on NCCTG clinical trials. Central pathology review of tumor tissues taken at the time of initial diagnosis and at recurrence were performed in all patients. Tumors progressed from low (WHO grade 2) to high (grade 3-4) at recurrence in 45% low grade oligodendroglioma patients, in 70% with low grade oligoastrocytoma, and 74% with low grade astrocytoma (P = 0.031). Median overall survival (OS) from initial diagnosis varied by histology: oligodendroglioma, 8.8 years; (95% CI 5.7-10.2); oligoastrocytoma, 4.4 years (95% CI 3.5-5.6); astrocytoma grade 2 3.1 years (astrocytoma grade 2-4, 2.1 years) (95% CI 1.7-2.5, P < 0.001). Mean time to recurrence (TTR) also varied between patients with de novo GBM, those secondary GBM, and those that remained non-GBM at recurrence (1.1 ± 1.1 vs. 2.9 ± 1.8 vs. 4.0 ± 2.9 years, respectively, P < 0.001). Median OS from time of recurrence also varied between these three categories (0.7 years, 95% CI: 0.5-1.1 vs. 0.6 years, CI: 0.5-1.0 vs. 1.4 years, 95% CI: 1.1-2.0, respectively) (P < 0.001). At time of relapse, transformation to higher grade is frequent in low grade pure and mixed astrocytomas, but is observed in less than half of those with low grade oligodendroglioma. From time of recurrence, OS was not significantly different for those with primary versus secondary GBM, and it may thus be reasonable include patients with secondary GBM in clinical therapeutic trials for recurrent disease.
- Published
- 2011
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34. Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074.
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Uhm JH, Ballman KV, Wu W, Giannini C, Krauss JC, Buckner JC, James CD, Scheithauer BW, Behrens RJ, Flynn PJ, Schaefer PL, Dakhill SR, and Jaeckle KA
- Subjects
- Adult, Aged, Antineoplastic Agents adverse effects, Brain Neoplasms genetics, Brain Neoplasms mortality, Brain Neoplasms radiotherapy, Chemotherapy, Adjuvant methods, Dexamethasone administration & dosage, Diarrhea chemically induced, Disease-Free Survival, Drug Administration Schedule, Enzyme Activators administration & dosage, ErbB Receptors genetics, ErbB Receptors metabolism, Female, Gefitinib, Gene Amplification genetics, Genes, erbB-1 genetics, Glioblastoma genetics, Glioblastoma mortality, Glioblastoma radiotherapy, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Quinazolines adverse effects, Young Adult, Antineoplastic Agents administration & dosage, Brain Neoplasms drug therapy, ErbB Receptors antagonists & inhibitors, Glioblastoma drug therapy, Quinazolines administration & dosage
- Abstract
Purpose: Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM., Methods and Materials: Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals., Results: Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS., Conclusions: In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS., (Copyright © 2011 Elsevier Inc. All rights reserved.)
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- 2011
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35. Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks.
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Sarkaria JN, Galanis E, Wu W, Dietz AB, Kaufmann TJ, Gustafson MP, Brown PD, Uhm JH, Rao RD, Doyle L, Giannini C, Jaeckle KA, and Buckner JC
- Subjects
- Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Brain Neoplasms immunology, Combined Modality Therapy, Dose-Response Relationship, Drug, Female, Glioblastoma immunology, Humans, Male, Maximum Tolerated Dose, Middle Aged, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors therapeutic use, Risk Factors, Sirolimus adverse effects, Sirolimus therapeutic use, Treatment Outcome, Brain Neoplasms diagnosis, Brain Neoplasms therapy, Glioblastoma diagnosis, Glioblastoma therapy, Sirolimus analogs & derivatives
- Abstract
Purpose: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival., Methods: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy., Results: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells., Conclusions: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed., (©2010 AACR.)
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- 2010
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36. Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM.
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Jaeckle KA, Ballman KV, Giannini C, Schomberg PJ, Ames MM, Reid JM, McGovern RM, Safgren SL, Galanis E, Uhm JH, Brown PD, Hammack JE, Arusell R, Nikcevich DA, Morton RF, Wender DB, and Buckner JC
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Area Under Curve, Camptothecin therapeutic use, Cohort Studies, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Humans, Irinotecan, Male, Middle Aged, Statistics as Topic, Time Factors, Young Adult, Antineoplastic Agents therapeutic use, Brain Neoplasms therapy, Camptothecin analogs & derivatives, Carmustine therapeutic use, Glioblastoma therapy, Radiotherapy methods
- Abstract
Irinotecan has radiosensitizing effects and shows synergism with nitrosoureas. We performed a Phase II study of RT and irinotecan, followed by BCNU plus irinotecan in newly-diagnosed GBM. The MTD for patients receiving enzyme-inducing anticonvulsants (EIAC) was as follows: irinotecan 400 mg/m(2)/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m(2) Day 1, and irinotecan, 400 mg/m(2) on Days 1, 8, 22 and 29, every 6 weeks. The MTD for non-EIAC patients was as follows: irinotecan 125 mg/m(2)/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m(2) Day 1 and irinotecan 75 mg/m(2) Days 1, 8, 22 and 29, every 6 weeks. Median OS was 10.8 mos. (95% CI: 7.7-14.9); OS at 12 months was 44.6% (95% CI: 33.3-59.8) and PFS 6 was 28.6% (95% CI: 18.9-43.2). Patients went off treatment due to adverse events (7%), refusal (11%), progressive disease (48%), death (9%), and other (9%); 16% completed protocol treatment. Survival was similar in patients with variant (6/7 or 7/7) and wild-type (6/6) UGT1A1*28 genotypic alleles. Grade 3-4 toxicity was more common in non-EIAC patients with variant alleles. SN-38 C(max) and AUC in EIAC patients receiving 400 mg/m(2) irinotecan were 20.9 ng/ml and 212 ng/ml h, and in non-EIAC patients receiving 125 mg/m(2), 15.5 ng/ml and 207 ng/ml h. SN-38 AUC varied by UGT1A1*28 status in non-EIAC patients. This regimen was not significantly active and radiosensitization was not observed. Non-EIAC patients with UGT1A1*28 variant alleles appear particularly sensitive to toxicity from irinotecan.
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- 2010
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37. Neurologic manifestations of neoplastic and radiation-induced plexopathies.
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Jaeckle KA
- Subjects
- Diagnosis, Differential, Humans, Nervous System Diseases diagnosis, Nervous System Diseases therapy, Peripheral Nervous System Diseases diagnosis, Peripheral Nervous System Diseases therapy, Radiation Injuries diagnosis, Radiation Injuries therapy, Neoplasms complications, Nervous System Diseases etiology, Peripheral Nervous System Diseases etiology, Radiation Injuries complications
- Abstract
Metastatic plexopathy is often a disabling accompaniment of advanced systemic cancer, and may involve any of the peripheral nerve plexuses. Brachial plexopathy most commonly occurs in carcinoma of the breast and lung; lumbosacral plexopathy is most common with colorectal and gynecologic tumors, sarcomas, and lymphomas. Neoplastic plexopathy is often characterized initially by severe, unrelenting pain followed by development of weakness and focal sensory disturbances. In previously treated patients, the main differential diagnostic consideration is radiation-induced plexopathy, which can be difficult to distinguish from tumor plexopathy. Diagnosis is usually made following an analysis of the clinical, neuroimaging, and electrophysiologic features. Treatment of metastatic plexopathy has included surgical resection of tumor in selected cases, radiotherapy to the plexus, systemic chemotherapy, interventional pain management procedures, and symptomatic treatment. These measures often offer temporary (months) relief or improvement. Physicians treating these patients should focus on effective management of pain and prevention of complications of immobility produced by the neuromuscular dysfunction., (Thieme Medical Publishers.)
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- 2010
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38. Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent glioma.
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Wu W, Lamborn KR, Buckner JC, Novotny PJ, Chang SM, O'Fallon JR, Jaeckle KA, and Prados MD
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- Age Factors, Aged, Aged, 80 and over, Brain Neoplasms pathology, Brain Neoplasms therapy, Clinical Trials as Topic, Disease-Free Survival, Female, Glioma pathology, Glioma therapy, Humans, Male, Middle Aged, Prognosis, Proportional Hazards Models, Brain Neoplasms mortality, Glioma mortality
- Abstract
The purpose of this study is to determine prognostic factors in patients with high-grade recurrent glioma for 3 outcome variables (overall survival, progression-free survival [PFS], and PFS rate 6 months after study registration [PFS6]). Data from 15 North Central Cancer Treatment Group (NCCTG) trials (n = 469, 1980-2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n = 596, 1998-2002) were included. Eighteen prognostic variables were considered including type of treatment center (community/academic) and initial low-grade histology (yes/no). Recursive partitioning analysis (RPA), Cox proportional hazards, and logistic regression models with bootstrap resampling were used to identify prognostic variables. Longer survival was associated with last known grade (Grade) of III, younger age, ECOG performance score (PS) of 0, shorter time from initial diagnosis (DxTime), and no baseline steroid use. Factors associated with longer PFS were Grade III and shorter DxTime. For patients without temozolomide as part of the treatment regimen, the only factor associated with better PFS6 was Grade III, although DxTime was important in RPA and PS was important in logistic regression. Grade was the most important prognostic factor for all three endpoints regardless of the statistical method used. Other important variables for one or more endpoints included age, PS, and DxTime. Neither type of treatment center nor initial low-grade histology was identified as a major predictor for any endpoint.
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- 2010
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39. Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results.
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Santisteban M, Buckner JC, Reid JM, Wu W, Scheithauer BW, Ames MM, Felten SJ, Nikcevich DA, Wiesenfeld M, Jaeckle KA, and Galanis E
- Subjects
- Adult, Aged, Anticonvulsants therapeutic use, Antineoplastic Agents, Phytogenic pharmacokinetics, Area Under Curve, Camptothecin administration & dosage, Camptothecin adverse effects, Camptothecin blood, Camptothecin pharmacokinetics, Drug Interactions, Female, Glucuronides blood, Humans, Irinotecan, Kaplan-Meier Estimate, Male, Middle Aged, Antineoplastic Agents, Phytogenic administration & dosage, Brain Neoplasms drug therapy, Camptothecin analogs & derivatives, Glioma drug therapy, Neoplasm Recurrence, Local drug therapy
- Abstract
Purpose: The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment., Methods: Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m(2)/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m(2). A 20% dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal., Results: There was no difference in confirmed responses between the two groups (6.3%). PFS at 6 months was 6.25% (2/32 patients) on schedule A and 18.75% (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19%) was similar for both arms. The most common grade 3-4 toxicities on schedules A/B were: thrombocytopenia (15.6%/21.9%), diarrhea (6.3%/12.5%) and nausea and vomiting (0%/15.7%). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 clearance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule., Conclusions: Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.
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- 2009
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40. North Central Cancer Treatment Group--achievements and perspectives.
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Grothey A, Adjei AA, Alberts SR, Perez EA, Jaeckle KA, Loprinzi CL, Sargent DJ, Sloan JA, and Buckner JC
- Subjects
- Breast Neoplasms therapy, Cachexia therapy, Clinical Trials as Topic, Gastrointestinal Neoplasms therapy, Humans, Lung Neoplasms therapy, Neoplasms complications, Neoplasms psychology, Quality of Life, Medical Oncology organization & administration, Neoplasms therapy
- Abstract
The North Central Cancer Treatment Group (NCCTG) was founded in 1977 as a regional cooperative group to allow cancer patients in the upper Midwest of the United States to gain access to clinical trials in oncology by establishing a network of community oncology practices with one academic research base, the Mayo Clinic. Since then, the NCCTG has grown into an international cooperative group with 43 members in 33 US states and Canada. This article details 30 years of achievements of the NCCTG, including important scientific contributions from disease-specific and treatment modality committees, the cancer control program, patient-reported outcomes and quality-of-life research, and biostatisticians that support the NCCTG's specific aims: to improve the duration and quality of life of cancer patients, to enhance our understanding of the biological consequences of cancer and its treatment, and to improve methods for clinical trial conduct.
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- 2008
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41. Pathway analysis of primary central nervous system lymphoma.
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Tun HW, Personett D, Baskerville KA, Menke DM, Jaeckle KA, Kreinest P, Edenfield B, Zubair AC, O'Neill BP, Lai WR, Park PJ, and McKinney M
- Subjects
- Central Nervous System Neoplasms metabolism, Computational Biology, Genome, Human genetics, Humans, Immunohistochemistry, Lymphoma, Large B-Cell, Diffuse metabolism, Software, Central Nervous System Neoplasms genetics, Gene Expression Regulation, Neoplastic, Lymphoma, Large B-Cell, Diffuse genetics, Oligonucleotide Array Sequence Analysis
- Abstract
Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a "CNS signature." Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true "CNS signature" because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.
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- 2008
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42. Status epilepticus in patients with CNS metastases.
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Blitshteyn S and Jaeckle KA
- Subjects
- Central Nervous System Neoplasms mortality, Humans, Central Nervous System Neoplasms complications, Central Nervous System Neoplasms secondary, Status Epilepticus complications, Status Epilepticus mortality
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- 2007
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43. The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme.
- Author
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Ballman KV, Buckner JC, Brown PD, Giannini C, Flynn PJ, LaPlant BR, and Jaeckle KA
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms drug therapy, Brain Neoplasms radiotherapy, Combined Modality Therapy, Disease-Free Survival, Female, Glioblastoma drug therapy, Glioblastoma radiotherapy, Humans, Male, Middle Aged, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local radiotherapy, Survival Rate, Treatment Outcome, Brain Neoplasms mortality, Glioblastoma mortality, Neoplasm Recurrence, Local mortality
- Abstract
Common end points for phase II trials in patients with glioblastoma multiforme (GBM) are six-month progression-free survival (PFS6) and 12-month overall survival (OS12). OS12 can be accurately measured but may be confounded with subsequent therapies upon progression, whereas the converse is true for PFS6. Our goal was to assess the relationship between these end points separately for phase II trials in patients with newly diagnosed GBM and patients with recurrent GBM. Data were pooled from 11 North Central Cancer Treatment Group trials for patients with newly diagnosed GBM (n = 1348). All patients received radiotherapy and pharmaceutical therapy (before, during, or after radiotherapy). Data were pooled from 16 trials that used various pharmaceuticals in treating patients for recurrent GBM (n = 345). All trial regimens were declared nonefficacious by predefined criteria. Overall per-patient concordance was estimated with a kappa statistic. The relationship between OS12 and PFS6 across study arms was assessed by weighted linear regression and Pearson's correlation. Simulation was used to determine the agreement of study outcomes when using PFS6 versus OS12 end points. Cox models with progression status as a time-dependent variable and Kaplan-Meier estimators were used to ascertain the association between progression-free survival status and overall survival. At present, 97% of the patients with newly diagnosed GBM and 95% of those with recurrent GBM have died. The PFS6 and OS12 were 43% and 41%, respectively, for patients with newly diagnosed disease and 9% and 14% for patients with recurrent disease. There was only moderate concordance between the end points on both the patient level and the study level. For the simulation studies, we established phase II efficacy criteria for each end point by using the pooled estimates of OS12 (PFS6) as historical controls. The study decisions made using PFS6 and OS12 were in agreement 88% and 90% of the time for the trials of newly diagnosed and recurrent disease, respectively. Finally, there was a strong association between progression-free survival status and overall survival. PFS6 seems to be a reasonable end point for phase II trials in patients with recurrent glioblastoma.
- Published
- 2007
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44. Detrimental effects of tumor progression on cognitive function of patients with high-grade glioma.
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Brown PD, Jensen AW, Felten SJ, Ballman KV, Schaefer PL, Jaeckle KA, Cerhan JH, and Buckner JC
- Subjects
- Adult, Astrocytoma mortality, Astrocytoma pathology, Brain Neoplasms mortality, Brain Neoplasms pathology, Cognition Disorders classification, Disease Progression, Female, Glioma mortality, Glioma pathology, Gliosarcoma mortality, Gliosarcoma pathology, Humans, Male, Middle Aged, Survival Rate, Astrocytoma complications, Brain Neoplasms complications, Cognition Disorders etiology, Glioma complications, Gliosarcoma complications
- Abstract
Purpose: There is growing recognition that the primary cause of cognitive deficits in adult patients with primary brain tumors is the tumor itself and more significantly, tumor progression. To assess the cognitive performance of high-grade glioma patients, prospectively collected cognitive performance data were analyzed., Patients and Methods: We studied 1,244 high-grade brain tumor patients entered onto eight consecutive North Central Cancer Treatment Group treatment trials that used radiation and nitrosourea-based chemotherapy. Imaging studies and Folstein Mini-Mental State Examination (MMSE) scores recorded at baseline, 6, 12, 18, and 24 months were analyzed to assess tumor status and cognitive function over time., Results: The proportion of patients without tumor progression who experienced clinically significant cognitive deterioration compared with baseline was stable at 6, 12, 18, and 24 months (18%, 16%, 14%, and 13%, respectively). In patients without radiographic evidence of progression, clinically significant deterioration in MMSE scores was a strong predictor of a more rapid time to tumor progression and death. At evaluations preceding interval radiographic evidence of progression, there was significant deterioration in MMSE scores for patients who were to experience progression, whereas the scores remained stable for the patients who did not have tumor progression., Conclusion: The proportion of high-grade glioma patients with cognitive deterioration over time is stable, most consistent with the constant pressure of tumor progression over time. Although other factors may contribute to cognitive decline, the predominant cause of cognitive decline seems to be subclinical tumor progression that precedes radiographic changes.
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- 2006
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45. Phase I trial of erlotinib with radiation therapy in patients with glioblastoma multiforme: results of North Central Cancer Treatment Group protocol N0177.
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Krishnan S, Brown PD, Ballman KV, Fiveash JB, Uhm JH, Giannini C, Jaeckle KA, Geoffroy FJ, Nabors LB, and Buckner JC
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Neoplasms mortality, Combined Modality Therapy, Erlotinib Hydrochloride, Female, Glioblastoma mortality, Humans, Male, Maximum Tolerated Dose, Middle Aged, Quinazolines adverse effects, Radiotherapy Dosage, Brain Neoplasms drug therapy, Brain Neoplasms radiotherapy, ErbB Receptors antagonists & inhibitors, Glioblastoma drug therapy, Glioblastoma radiotherapy, Quinazolines therapeutic use
- Abstract
Purpose: To evaluate the toxicity and maximum tolerated dose (MTD) of erlotinib plus radiation therapy (RT) in patients with glioblastoma multiforme (GBM) in a multicenter phase I trial., Methods and Materials: Patients were stratified on the basis of the use of enzyme-inducing anticonvulsants (EIACs). After resection or biopsy, patients were treated with erlotinib for 1 week before concurrent erlotinib and 6 weeks (60 Gy) of RT and maintained on erlotinib until progression. The erlotinib dose was escalated in cohorts of 3 starting at 100 mg/day., Results: Twenty patients were enrolled and 19 were evaluable for the MTD and efficacy endpoints. Of these patients, 14 were males and 5 were females, with a median age of 54 years. Seven had undergone biopsy only, 5 had subtotal resections, and 7 had gross total resections. The highest dose level was 150 mg/day erlotinib for patients not on EIACs (Group 1) and 200 mg/day for patients on EIACs (Group 2). MTD was not reached in either group. In Group 1 at 100 mg (n=6) and at 150 mg (n=4), only 1 dose-limiting toxicity (DLT) occurred (stomatitis at 100 mg). No DLTs have occurred in Group 2 at 100 mg (n=3), 150 mg (n=3), and 200 mg (n=3). With a median follow-up of 52 weeks, progression was documented in 16 patients and 13 deaths occurred. Median time to progression was 26 weeks, and median survival was 55 weeks., Conclusion: Toxicity is acceptable at the current doses of erlotinib plus RT. The study was modified to include concurrent and adjuvant temozolomide, and accrual is in progress.
- Published
- 2006
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46. Neoplastic meningitis from systemic malignancies: diagnosis, prognosis and treatment.
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Jaeckle KA
- Subjects
- Antineoplastic Agents therapeutic use, Breast Neoplasms complications, Female, Humans, Lymphoma complications, Melanoma complications, Meningitis radiotherapy, Palliative Care, Paraneoplastic Syndromes radiotherapy, Prognosis, Survival Rate, Meningitis etiology, Paraneoplastic Syndromes etiology
- Abstract
Long-term survival is occasionally observed in patients with neoplastic meningitis (NM) accompanying breast cancer (13% one-year and 6% 2-year survival), melanoma, and lymphoma, but in general the survival of most patients is short and averages only 3 to 4 months. The incidence of NM appears to be increasing, in part due to earlier detection by magnetic resonance imaging (MRI), and in part due to development of more effective therapies for systemic cancer, which has resulted in a larger subset at risk for late-stage development of this complication. Survival of NM patients is negatively affected by concomitant progression of systemic disease despite multiple prior therapies. However, there are certain prognostic factors that have been identified as "favorable" in retrospective series, including age less than 60 years, long symptom duration, controlled systemic disease, Karnofsky performance status (KPS) > or =70, lack of encephalopathy or cranial nerve deficits, low initial cerebrospinal fluid (CSF) protein level, history of breast primary tumor, and lack of evidence of CSF compartmentalization or bulky meningeal disease as determined by CSF flow studies. Standard treatment has traditionally involved radiotherapy (RT) to sites of symptomatic or bulky disease, as detected by neuroimaging, and in selected patients, the administration of intrathecal, intraventricular, or systemic chemotherapy. However, treatment remains palliative and many patients and physicians choose supportive care only. Future hope is provided by studies that have improved our understanding of the disease pathogenesis, have identified prognostic variables associated with outcome, and have provided new therapeutic approaches, such as administration of high-dose systemic chemotherapy and investigations of novel therapeutic agents.
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- 2006
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47. Removal of an orbital metallic foreign body to facilitate magnetic resonance imaging: technical case report.
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Deen HG, Miller DA, Kostick DA, and Jaeckle KA
- Subjects
- Adult, Cerebellar Neoplasms diagnosis, Humans, Male, Medulloblastoma diagnosis, Meningeal Neoplasms diagnosis, Middle Aged, Orbit diagnostic imaging, Orbit surgery, Radiography, Eye Foreign Bodies diagnostic imaging, Eye Foreign Bodies surgery, Ferric Compounds, Magnetic Resonance Imaging methods
- Abstract
Objective and Importance: Magnetic resonance imaging (MRI) is the imaging modality of choice for brain tumors and other lesions of the central nervous system. However, this procedure is contraindicated in patients with orbital metallic foreign bodies. In such cases, the usual clinical strategy is to manage the patient without the benefit of MRI scans and, instead, to rely on less sensitive imaging modalities in particular computed tomographic scanning., Clinical Presentation: Two patients, one with a posterior fossa mass and one with suspected central nervous system lymphoma, were seen at our institution. MRI scanning was recommended, but had been precluded in both patients by the presence of metal fragments in the orbit., Intervention: In each case, the orbital foreign body was successfully localized and removed. Postprocedure computed tomographic scanning confirmed complete removal. MRI scanning was then performed without difficulty. The first patient underwent posterior fossa craniotomy and removal of the tumor, which proved to be a medulloblastoma. The second patient was found to have evidence of lymphoma in the cranial base and meninges and was treated with radiotherapy and systemic and intrathecal chemotherapy. MRI scanning provided superior diagnostic information and spared both patients the risks and discomfort of myelography and exposure to ionizing radiation from multiple computerized tomographic scans., Conclusion: Two patients with central nervous system tumors underwent removal of a metal fragment in the orbit for the specific purpose of facilitating MRI scans. This is a practical, straightforward concept, which should be considered when MRI scanning is needed for optimal patient management.
- Published
- 2006
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48. Ototoxicity of cisplatin plus standard radiation therapy vs. accelerated radiation therapy in glioblastoma patients.
- Author
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Marshall NE, Ballman KV, Michalak JC, Schomberg PJ, Burton GV, Sandler HM, Cascino TL, Jaeckle KA, and Buckner JC
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Brain Neoplasms complications, Brain Neoplasms radiotherapy, Carmustine therapeutic use, Chemotherapy, Adjuvant adverse effects, Cisplatin administration & dosage, Combined Modality Therapy adverse effects, Female, Glioblastoma complications, Glioblastoma radiotherapy, Hearing Tests, Humans, Male, Middle Aged, Otitis Media with Effusion chemically induced, Proportional Hazards Models, Radiation-Sensitizing Agents administration & dosage, Radiotherapy Dosage, Tinnitus chemically induced, Treatment Outcome, Brain Neoplasms drug therapy, Cisplatin adverse effects, Glioblastoma drug therapy, Hearing Loss chemically induced, Radiation-Sensitizing Agents adverse effects, Radiotherapy, Adjuvant adverse effects
- Abstract
Purpose: To assess the effect of cisplatin (CDDP) plus concurrent radiation therapy on hearing loss., Methods: 451 patients with glioblastoma multiforme (GBM) were randomly assigned after surgery to: Arm A: Carmustine (BCNU) + standard radiation therapy (SRT); Arm B: BCNU + accelerated radiation therapy (ART: 160 cGy twice daily for 15 days); Arm C: CDDP + BCNU + SRT; or Arm D: CDDP + BCNU + ART. Patients on arms C and D received audiograms at baseline, and prior to the start of RT, and prior to cycles 3 and 6. Otologic toxicities were recorded at each visit., Results: 56% of patients had hearing loss at baseline. 13% and 50% of patients experienced worsening ototoxicity after 1 year of treatment in arms A and B vs. C and D, respectively, with 13% of those on arms C and D experiencing significant ototoxicity (>or= grade 3) at 6 months. Increasing age was associated with an increased risk of ototoxicity., Conclusions: Increased exposure to CDDP increases the risk of ototoxicity over time. Older patients are more susceptible to hearing loss with CDDP. The low proportion of patients with clinically significant ototoxicity suggests that baseline screening is unnecessary in GBM patients.
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- 2006
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49. Current strategies in treatment of oligodendroglioma: evolution of molecular signatures of response.
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Jaeckle KA, Ballman KV, Rao RD, Jenkins RB, and Buckner JC
- Subjects
- Central Nervous System Neoplasms diagnosis, Central Nervous System Neoplasms genetics, Central Nervous System Neoplasms metabolism, Humans, Oligodendroglioma diagnosis, Oligodendroglioma genetics, Oligodendroglioma metabolism, Prognosis, Central Nervous System Neoplasms therapy, Oligodendroglioma therapy
- Abstract
Oligodendroglioma frequently (> or = 70%) responds to radiation and chemotherapy, and is the first CNS neoplasm in which a genetic signature (1p and 19q deletion) has been associated with outcome within the context of large clinical trials. Current translational investigations focus on deletions or mutations of potential tumor suppressor genes, epigenetic alterations, amplification or mutation of growth factor and regulatory genes, and characterization of signaling events and regulatory protein expression. The most compelling data has involved 1p and 19q loss, which is observed in over 50% of anaplastic oligodendrogliomas. In two randomized phase III trials (Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951), the addition of neoadjuvant or adjuvant procarbazine, lomustine, and vincristine (PCV; respectively) to radiotherapy did not produce superior survival as compared with radiotherapy alone. A modest increase in progression-free survival was observed with the addition of PCV, but at the cost of increased toxicity. Combined 1p and 19q loss identified a favorable prognostic group in both studies, which appeared to be independent of treatment arms. However, it is unclear whether these deletions represent surrogate markers of a favorable biologic tumor behavior, or are predictive of outcome after specific treatment. Currently, there is insufficient data to allow therapeutic decisions to be made solely on the basis of 1p and 19q gene deletion status. Future phase III trials are evaluating other chemotherapeutic and targeted agents, including temozolomide, and include correlative investigations of aberrant molecular events in these neoplasms, which may lead to future therapeutic strategies that are based on specific molecular signatures.
- Published
- 2006
- Full Text
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50. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study.
- Author
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Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, Peralba JM, Jenkins RB, Dakhil SR, Morton RF, Jaeckle KA, Scheithauer BW, Dancey J, Hidalgo M, and Walsh DJ
- Subjects
- Adult, Aged, Antineoplastic Agents, Alkylating adverse effects, Brain Neoplasms pathology, Disease-Free Survival, Female, Genes, erbB-1 physiology, Glioblastoma pathology, Humans, Male, Middle Aged, Neoplasm Recurrence, Local pathology, PTEN Phosphohydrolase, Phosphoric Monoester Hydrolases genetics, Prognosis, Protein Kinase Inhibitors adverse effects, Salvage Therapy, Sirolimus adverse effects, Sirolimus therapeutic use, TOR Serine-Threonine Kinases, Treatment Outcome, Tumor Suppressor Proteins genetics, Antineoplastic Agents, Alkylating therapeutic use, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Neoplasm Recurrence, Local drug therapy, Protein Kinase Inhibitors therapeutic use, Protein Kinases drug effects, Sirolimus analogs & derivatives
- Abstract
Background: Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM)., Methods: Recurrent GBM patients with < or = 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly., Results: Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme-inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04)., Conclusion: Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus-treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.
- Published
- 2005
- Full Text
- View/download PDF
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