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Andrew D Norden,
Glenn J Lesser,
Jan Drappatz,
Keith L Ligon,
Samantha N Hammond,
Eudocia Q Lee,
David R Reardon,
Camilo E Fadul,
Scott R Plotkin, Tracy T Batchelor, [......],
Rameen Beroukhim,
Alona Muzikansky,
Lisa Doherty,
Debra Lafrankie,
Katrina Smith,
Vida Tafoya,
Rosina Lis,
Edward C Stack,
Myrna R Rosenfeld,
Patrick Y Wen
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ABSTRACT: Background
Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O(6)-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance.Methods
This was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m(2)/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6).ResultsFifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25-79 years) and a median Karnofsky performance score of 90 (range, 60-100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2).Conclusions
Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.
Neuro-Oncology 04/2013; · 5.72 Impact Factor
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Journal of Clinical Oncology 04/2013; · 18.37 Impact Factor
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ABSTRACT: Glioblastomas are heterogeneous neoplasms that are driven by complex signalling pathways, and are among the most aggressive and challenging cancers to treat. Despite standard treatment with resection, radiation and chemotherapy, the prognosis of patients with glioblastomas remains poor. An increasing understanding of the molecular pathogenesis of glioblastomas has stimulated the development of novel therapies, including the use of molecular-targeted agents. Identification and validation of diagnostic, prognostic and predictive biomarkers has led to the advancement of clinical trial design, and identification of glioblastoma subgroups with a more-favourable prognosis and response to therapy. In this Review, we discuss common molecular alterations relevant to the biology of glioblastomas, targeted, antiangiogenic and immunotherapies that have impacted on the treatment of this disease, and the challenges and pitfalls associated with these therapies. In addition, we emphasize current biomarkers relevant to the management of patients with glioblastoma.
Nature Reviews Clinical Oncology 11/2012; · 11.96 Impact Factor
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ABSTRACT: Primary central nervous system lymphoma (PCNSL) is an uncommon and aggressive variant of non-Hodgkin lymphoma that involves the brain, eyes, leptomeninges, or spinal cord. Therapeutic progress has been modest, and our understanding of the molecular mechanisms that drive this disease is limited. Clinicians treating PCNSL face a challenge to balance the need to administer aggressive regimens to achieve a cure with the risks of delayed neurotoxicity after treatment. The standard treatment is a methotrexate-containing chemotherapy regimen. The timing and dose of whole-brain radiation therapy is controversial, given the significant risks of late neurotoxic effects, particularly in elderly patients.
Hematology/oncology clinics of North America 08/2012; 26(4):897-916. · 2.05 Impact Factor
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Andrew S Chi, Tracy T Batchelor,
Dora Dias-Santagata,
Darrell Borger,
Charles D Stiles,
Daphne L Wang,
William T Curry,
Patrick Y Wen,
Keith L Ligon,
Leif Ellisen,
David N Louis,
A John Iafrate
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ABSTRACT: Gliomas consist of multiple histologic and molecular subtypes with different clinical phenotypes and responsiveness to treatment. However, enrollment criteria for clinical trials still largely do not take into account these underlying molecular differences. We have incorporated a high-throughput tumor genotyping program based on the ABI SNaPshot platform as well as other molecular diagnostic tests into the standard evaluation of glioma patients in order to assess whether prospective molecular profiling would allow rational patient selection onto clinical trials. From 218 gliomas we prospectively collected SNaPshot genotyping data on 68 mutated loci from 15 key cancer genes along with data from clinical assays for gene amplification (EGFR, PDGFRA, MET), 1p/19q co-deletion and MGMT promoter methylation. SNaPshot mutations and focal gene amplifications were detected in 38.5 and 47.1 % of glioblastomas, respectively. Genetic alterations in EGFR, IDH1 and PIK3CA closely matched frequencies reported in recent studies. In addition, we identified events that are rare in gliomas although are known driver mutations in other cancer types, such as mutations of AKT1, BRAF and KRAS. Patients with genetic alterations that activate signaling pathways were enrolled onto genetically selective clinical trials for malignant glioma as well as for other solid cancers. High-throughput molecular profiling incorporated into the routine clinical evaluation of glioma patients may enable the rational selection of patients for targeted therapy clinical trials and thereby improve the likelihood that such trials succeed.
Journal of Neuro-Oncology 07/2012; 110(1):89-98. · 3.21 Impact Factor
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New England Journal of Medicine 05/2012; 366(22):2112-20. · 53.30 Impact Factor
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Journal of Clinical Oncology 01/2012; 30(5):563-4. · 18.37 Impact Factor
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ABSTRACT: Glioblastoma (GBM) is a highly vascular tumor dependent on angiogenesis through the vascular endothelial growth factor (VEGF) signaling cascade. Inhibition of VEGF signaling is an important therapeutic strategy. We report our experience with bevacizumab (BEV), a VEGF targeting antibody, following failure of a VEGF receptor targeting tyrosine kinase inhibitor (TKI). We retrospectively identified patients treated on clinical trials with VEGFR-TKIs for recurrent GBM followed by BEV at next recurrence. Survival was estimated by the Kaplan-Meier method. Fourteen patients were identified (six women; median age 57). All received VEGFR-TKIs (sunitinib 11, cediranib 2, sorafenib 1) then BEV at next recurrence. There were no radiographic responses to VEGFR-TKIs; best response was stable disease in 50% (7/14). Patients received BEV alone (21%, 3/14) or in combination with chemotherapy (79%, 11/14). On BEV, 29% (4/14) had a partial response, and 36% (5/14) stabilized. Of evaluable patients, 42% (5/12) had neurological improvement and 56% (5/9) reduced corticosteroid requirement. Median survival on BEV was 7.8 months (95% CI 4.0-15.8), median progression-free survival (PFS) was 4.0 months (95% CI 1.6-10.5), and the 6-month PFS rate was 29% (95% CI 9-52). Our radiographic and survival outcomes with BEV following progression after VEGFR-TKIs are similar to data from studies of BEV as initial salvage therapy, although our sample size was small. Prior exposure to VEGFR-TKIs may not preclude response to BEV, but sensitivity to BEV may be lower following more robust VEGFR inhibition.
Journal of Neuro-Oncology 12/2011; 107(2):407-11. · 3.21 Impact Factor
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Journal of Clinical Oncology 12/2011; 30(3):e30-3. · 18.37 Impact Factor
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A Gregory Sorensen,
Kyrre E Emblem,
Pavlina Polaskova,
Dominique Jennings,
Heisoog Kim,
Marek Ancukiewicz,
Meiyun Wang,
Patrick Y Wen,
Percy Ivy, Tracy T Batchelor,
Rakesh K Jain
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ABSTRACT: The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of antiangiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, direct clinical evidence is lacking for improvements in blood perfusion after antiangiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than 1 month in 7 of 30 patients, in whom it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival.
Cancer Research 11/2011; 72(2):402-7. · 7.86 Impact Factor
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Chi-Chao Chan,
James L Rubenstein,
Sarah E Coupland,
Janet L Davis,
J William Harbour,
Patrick B Johnston,
Nathalie Cassoux,
Valerie Touitou,
Justine R Smith, Tracy T Batchelor,
Jose S Pulido
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ABSTRACT: Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%-90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of Ig(H) or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.
The Oncologist 11/2011; 16(11):1589-99. · 3.91 Impact Factor
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Patrick Y Wen,
David Schiff,
Timothy F Cloughesy,
David A Reardon, Tracy T Batchelor,
Bruce A Chabner,
Keith Flaherty,
John F de Groot,
Mark R Gilbert,
Evanthia Galanis,
Susan M Chang,
Gary K Schwartz,
David Peereboom,
Minesh P Mehta,
W K Alfred Yung,
Stuart A Grossman,
Michael D Prados,
Lisa M DeAngelis
Journal of Clinical Oncology 08/2011; 29(24):3211-3. · 18.37 Impact Factor
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Gregory M Cote,
Ephraim P Hochberg,
Alona Muzikansky,
Fred H Hochberg,
Jan Drappatz,
Steven L McAfee, Tracy T Batchelor,
Ann S LaCasce,
David C Fisher,
Jeremy S Abramson,
Philippe Armand,
Yi-Bin Chen
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ABSTRACT: Primary central nervous system non-Hodgkin lymphoma (PCNSL) carries a poor prognosis and, although it responds to chemotherapy, fewer than 20% of patients are long-term disease-free survivors. Secondary CNS non-Hodgkin lymphoma (SCNSL) has an even worse prognosis with a median survival of only months and very few reported long-term survivors. For both of these groups of patients, there has been interest in using high-dose chemotherapy with autologous stem cell transplantation (ASCT) following conditioning with thiotepa, busulfan, and cyclophosphamide (TBC). We performed a retrospective review (from 2006-2010) of 32 patients from the Dana-Farber Cancer Institute and Massachusetts General Hospital with PCNSL or SCNSL who underwent ASCT with TBC conditioning. Of the 32 patients, 56% received TBC/ASCT after achieving brain magnetic resonance imaging (MRI) and/or cerebrospinal fluid complete response in brain, and 44% of patients were treated with TBC/ASCT in the setting of measurable CNS disease. The 100-day transplant-related mortality rate was only 3%. The most common nonhematologic grade 3 or 4 toxicity was mucositis, which occurred in 73% of patients. Notably, there was only 1 patient with prolonged significant neurologic toxicity that manifested as ataxia and dysphagia. The 1-year OS estimate is 93% (95% confidence interval [CI]: 75%-98%), and the 1-year progression-free survival (PFS) estimate is 90% (95% CI: 72%-96%) from the date of transplantation. Although these outcomes are encouraging, longer follow-up is required and comparison with other traditional ASCT regimens used for patients with non-Hodgkin lymphoma (NHL) is warranted.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2011; 18(1):76-83. · 3.15 Impact Factor
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ABSTRACT: Proton magnetic resonance spectroscopy is increasingly used in clinical studies of brain tumor to provide information about tissue metabolic profiles. In this study, we evaluated changes in the levels of metabolites predominant in recurrent glioblastoma multiforme (rGBM) to characterize the response of rGBM to antiangiogenic therapy. We examined 31 rGBM patients treated with daily doses of cediranib, acquiring serial chemical shift imaging data at specific time points during the treatment regimen. We defined spectra from three regions of interest (ROI)--enhancing tumor (ET), peritumoral tissue, and normal tissue on the contralateral side (cNT)--in post-contrast T1-weighted images, and normalized the concentrations of N-acetylaspartate (NAA) and choline (Cho) in each ROI to the concentration of creatine in cNT (norCre). We analyzed the ratios of these normalized metabolites (i.e., NAA/Cho, NAA/norCre, and Cho/norCre) by averaging all patients and categorizing two different survival groups. Relative to pretreatment values, NAA/Cho in ET was unchanged through day 28. However, after day 28, NAA/Cho significantly increased in relation to a significant increase in NAA/norCre and a decrease in Cho/norCre; interestingly, the observed trend was reversed after day 56, consistent with the clinical course of GBM recurrence. Notably, receiver operating characteristic analysis indicated that NAA/Cho in tumor shows a high prediction to 6-month overall survival. These metabolic changes in these rGBM patients strongly suggest a direct metabolic effect of cediranib and might also reflect an antitumor response to antiangiogenic treatment during the first 2 months of treatment. Further study is needed to confirm these findings.
Cancer Research 06/2011; 71(11):3745-52. · 7.86 Impact Factor
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ABSTRACT: Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small molecule inhibitors of the VEGF pathway will likely have a positive impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to determine the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiographic response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small molecule inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.
Journal of Neuro-Oncology 06/2011; 103(2):325-32. · 3.21 Impact Factor
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ABSTRACT: A 'vascular normalization index' (VNI) based on the changes in the magnetic resonance imaging (MRI) parameters K(trans) and cerebral blood volume (CBV), combined with blood sampling, has been shown to correlate with patient outcome in recurrent glioblastoma after a single dose of antiangiogenic therapy. Here, by applying a novel contrast agent extravasation correction method insensitive to variations in tissue mean transit time, we show that a similar VNI parameter can be derived from a single dynamic susceptibility contrast MR acquisition rather than the three parameters shown previously. Our results show that this new VNI parameter, which combines changes in tumoral CBV and an apparent transfer constant from our leakage correction method, may provide prognostic information in an even simpler manner than prior efforts.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2011; 31(10):2054-64. · 5.46 Impact Factor
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Katrin Patrij,
Marcel Reiser,
Luise Wätzel,
Hendrik Pels,
Annika Kowoll,
Ulrich Herrlinger,
Andreas Engert,
Michael Linnebank,
Gabriele Schackert,
Marlies Vogt-Schaden,
Gerlinde Egerer,
Monika Lamprecht, Tracy T Batchelor,
Uwe Schlegel,
Ingo G H Schmidt-Wolf
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ABSTRACT: We analyzed clinical outcome of patients with an isolated central nervous system lymphoma (CNSL) relapse after systemic non-Hodgkin's lymphoma (NHL). All 23 patients with an isolated secondary CNSL (SCNSL) treated at two institutions from 04/2003-12/2007 were included into this analysis. At cerebral relapse, 15/23 patients were treated with a regimen consisting of high-dose methotrexate (Bonn protocol). After a median follow-up of 6.5 months (range 1-68), 15/23 (65%) patients with SCNSL had relapsed or progressed. HD (high-dose)- methotrexate (MTX) chemotherapy according to the Bonn protocol is effective concerning response rates; however, overall survival of patients with SCNSL seems to be impaired in comparison to relapses in primary CNSL (PCNSL).
German medical science : GMS e-journal 01/2011; 9:Doc11.
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Dora Dias-Santagata,
Quynh Lam,
Kathy Vernovsky,
Natalie Vena,
Jochen K Lennerz,
Darrell R Borger, Tracy T Batchelor,
Keith L Ligon,
A John Iafrate,
Azra H Ligon,
David N Louis,
Sandro Santagata
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ABSTRACT: Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs.
PLoS ONE 01/2011; 6(3):e17948. · 4.09 Impact Factor
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Emmanuelle di Tomaso,
Matija Snuderl,
Walid S Kamoun,
Dan G Duda,
Pavan K Auluck,
Ladan Fazlollahi,
Ovidiu C Andronesi,
Matthew P Frosch,
Patrick Y Wen,
Scott R Plotkin,
E Tessa Hedley-Whyte,
A Gregory Sorensen, Tracy T Batchelor,
Rakesh K Jain
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ABSTRACT: Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are 2 prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular, and vascular parameters in autopsy tissues from 5 rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus 7 patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood-brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM, cellular density in the central area of the tumor was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemoradiation. Finally, cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy--characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology--without a second wave of angiogenesis.
Cancer Research 01/2011; 71(1):19-28. · 7.86 Impact Factor
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ABSTRACT: Non-Hodgkin lymphoma rarely presents as an extranodal lymphoma that is restricted to the CNS known as primary CNS lymphoma
(PCNSL). PCNSL can affect multiple parts of the neuraxis including the eyes, brain, leptomeninges, or spinal cord and accounts
for approximately 3% of all the primary CNS tumors diagnosed each year in the United States. Between 1970 and 2000, the incidence
of PCNSL increased largely due to the HIV pandemic. However, the incidence has stabilized or decreased over the last decade
to about 0.47 cases per 100,000 persons [1,2]. Congenital or acquired immunodeficiency is the only established risk factor
for PCNSL and HIV-infected individuals are at greater risk of developing this tumor. Approximately 2–13% of patients with
a previous diagnosis of AIDS develop PCNSL.
KeywordsPrimary central nervous system lymphoma-Diffuse large B-cell lymphoma-High-dose methotrexate
12/2010: pages 333-353;
