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Desjardins, Annick

Positions:

Associate Professor of Neurology

Neurology, General & Community Neurology
School of Medicine

Associate Professor in Neurosurgery

Neurosurgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1998

M.D. — University of Sherbrooke

Resident, Neurology

University of Sherbrooke

Fellow In Neuro Oncology, Medicine

Duke University

News:

Grants:

Oncolytic Polovirus, Immunotoxin, and Checkpoint Inhibitor Therapy of Gliomas

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2015
End Date
July 31, 2022

Phase 3 randomized, open-label study to evaluate Eflornithine with Lomustine compared to Lomustine (STELLAR) alone in patients with Anaplastic Astrocytoma

Administered By
Duke Cancer Institute
AwardedBy
Orbus Therapeutics, Inc.
Role
Principal Investigator
Start Date
October 01, 2016
End Date
September 30, 2021

Phase 1b, Multicenter, Open-Label Study of Marizomib with Temozolomide and Radiotherapy in Patients with Newly Diagnosed WHO Grade IV Malignant Glioma

Administered By
Duke Cancer Institute
AwardedBy
Triphase Research and Development Corp
Role
Principal Investigator
Start Date
December 01, 2016
End Date
November 30, 2020

Phase 2 study of SYM004 for adult patients with recurrent glioblastoma

Administered By
Duke Cancer Institute
AwardedBy
Symphogen A/S
Role
Principal Investigator
Start Date
November 01, 2015
End Date
October 31, 2019

Ph1 Study of Marizomib and Bevacizumab-Naive Subjects with Grade IV Malignant Glioma

Administered By
Duke Cancer Institute
AwardedBy
Triphase Research and Development Corp
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2019

A Phase 1 Study of PTC in Patients with Advanced Solid Tumors

Administered By
Duke Cancer Institute
AwardedBy
PTC Therapeutics, Inc
Role
Principal Investigator
Start Date
January 01, 2016
End Date
March 03, 2017

CTO alone and in combination with Lomustine for Bev-niave patients

Administered By
Duke Cancer Institute
AwardedBy
Tactical Therapeutics, Inc.
Role
Principal Investigator
Start Date
October 01, 2013
End Date
November 03, 2016
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Publications:

A Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab.

Given that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan-bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2-5), overall CINV CR (days 1-5), and QoL, fatigue, and toxicity.A two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL-DEX. Validated surveys assessed fatigue and QoL.A total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL-DEX dose administrations 1-3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade ≥3 PAL-DEX treatment-related toxicities.Data suggest that PAL-DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma.

Authors
Affronti, ML; Woodring, S; Peters, KB; Herndon, JE; McSherry, F; Healy, PN; Desjardins, A; Vredenburgh, JJ; Friedman, HS
MLA Citation
Affronti, ML, Woodring, S, Peters, KB, Herndon, JE, McSherry, F, Healy, PN, Desjardins, A, Vredenburgh, JJ, and Friedman, HS. "A Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab." Therapeutics and clinical risk management 13 (January 2017): 33-40.
PMID
28096679
Source
epmc
Published In
Therapeutics and clinical risk management
Volume
13
Publish Date
2017
Start Page
33
End Page
40
DOI
10.2147/tcrm.s122480

Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier.

The proteasome plays a vital role in the physiology of glioblastoma (GBM), and proteasome inhibition can be used as a strategy for treating GBM. Marizomib is a second-generation, irreversible proteasome inhibitor with a more lipophilic structure that suggests the potential for penetrating the blood-brain barrier. While bortezomib and carfilzomib, the 2 proteasome inhibitors approved for treatment of multiple myeloma, have little activity against malignant gliomas in vivo, marizomib could be a novel therapeutic strategy for primary brain tumors.The in-vitro antitumor activity of marizomib was studied in glioma cell lines U-251 and D-54. The ability of marizomib to cross the blood-brain barrier and regulate proteasome activities was evaluated in cynomolgus monkeys and rats. The antitumor effect of marizomib in vivo was tested in an orthotopic xenograft model of human GBM.Marizomib inhibited the proteasome activity, proliferation, and invasion of glioma cells. Meanwhile, free radical production and apoptosis induced by marizomib could be blocked by antioxidant N-acetyl cysteine. In animal studies, marizomib distributed into the brain at 30% of blood levels in rats and significantly inhibited (>30%) baseline chymotrypsin-like proteasome activity in brain tissue of monkeys. Encouragingly, the immunocompromised mice, intracranially implanted with glioma xenografts, survived significantly longer than the control animals (P < .05) when treated with marizomib.These preclinical studies demonstrated that marizomib can cross the blood-brain barrier and inhibit proteasome activity in rodent and nonhuman primate brain and elicit a significant antitumor effect in a rodent intracranial model of malignant glioma.

Authors
Di, K; Lloyd, GK; Abraham, V; MacLaren, A; Burrows, FJ; Desjardins, A; Trikha, M; Bota, DA
MLA Citation
Di, K, Lloyd, GK, Abraham, V, MacLaren, A, Burrows, FJ, Desjardins, A, Trikha, M, and Bota, DA. "Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier." June 2016.
PMID
26681765
Source
epmc
Published In
Neuro-Oncology
Volume
18
Issue
6
Publish Date
2016
Start Page
840
End Page
848
DOI
10.1093/neuonc/nov299

Vaccine Therapy, Oncolytic Viruses, and Gliomas.

After years of active research and refinement, vaccine therapy and oncolytic viruses are becoming part of the arsenal in the treatment of gliomas. In contrast to standard treatment with radiation therapy and chemotherapy, vaccines are more specific to the patient and the tumor. The majority of ongoing vaccine trials are investigating peptide, heat shock protein, and dendritic cell vaccines. The immunosuppression triggered by the tumor itself and by its treatment is a major obstacle to vaccine and oncolytic virus therapy. Thus, combination therapy with different agents that affect the immune system will probably be necessary.

Authors
Desjardins, A; Vlahovic, G; Friedman, HS
MLA Citation
Desjardins, A, Vlahovic, G, and Friedman, HS. "Vaccine Therapy, Oncolytic Viruses, and Gliomas." Oncology (Williston Park, N.Y.) 30.3 (March 2016): 211-218.
PMID
26984213
Source
epmc
Published In
Oncology
Volume
30
Issue
3
Publish Date
2016
Start Page
211
End Page
218

Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas.

Cabozantinib inhibits mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) and has demonstrated activity in patients with recurrent glioblastoma, warranting evaluation of the addition of cabozantinib to radiotherapy (RT) and temozolomide (TMZ) for patients with newly diagnosed high-grade glioma.Cabozantinib doses of 40 mg and 60 mg were explored. Patients on the concurrent treatment arm received cabozantinib daily with standard TMZ and after RT continued cabozantinib daily with adjuvant TMZ. In the maintenance arm, patients who completed RT and ≥1 adjuvant cycle of TMZ continued adjuvant TMZ with added cabozantinib (3 schedules: days 1-28, days 1-14, or days 8-21).A total of 26 patients (25 with recurrent glioblastoma and 1 patient with anaplastic astrocytoma) aged 30 to 72 years were enrolled (10 to the concurrent arm and 16 to the maintenance arm). The median number of post-RT TMZ cycles was 4.5 (range, 0-14 cycles) in the concurrent arm and 5.5 (range, 1-12 cycles) in the maintenance arm. Cabozantinib at a dose of 60 mg daily was the maximum administered dose and a dose of 40 mg daily was determined to be the maximum tolerated dose for both treatment arms (schedule of days 1-28). The most frequent grade 3/4 adverse events were thrombocytopenia (31% of patients), leukopenia (27% of patients, including 5 patients with neutropenia), and deep vein thrombosis and/or pulmonary embolism (23% of patients) (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]).Cabozantinib at a dose of 40 mg daily with RT plus TMZ and post-RT TMZ for patients with newly diagnosed high-grade glioma was generally well tolerated, and demonstrated no pharmacokinetic interactions with concurrent TMZ. Given the strong theoretical rationale for combining anti-VEGF and anti-MET activity with standard therapy, cabozantinib at a dose of 40 mg daily warrants evaluation in combination with standard therapy for patients with newly diagnosed glioblastoma.

Authors
Schiff, D; Desjardins, A; Cloughesy, T; Mikkelsen, T; Glantz, M; Chamberlain, MC; Reardon, DA; Wen, PY
MLA Citation
Schiff, D, Desjardins, A, Cloughesy, T, Mikkelsen, T, Glantz, M, Chamberlain, MC, Reardon, DA, and Wen, PY. "Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas." Cancer 122.4 (February 2016): 582-587.
PMID
26588662
Source
epmc
Published In
Cancer
Volume
122
Issue
4
Publish Date
2016
Start Page
582
End Page
587
DOI
10.1002/cncr.29798

CCR 20th Anniversary Commentary: Bevacizumab in the Treatment of Glioblastoma--The Progress and the Limitations.

Vredenburgh and colleagues conducted the first phase II study of bevacizumab plus irinotecan in recurrent malignant glioma, confirming the safety and efficacy of bevacizumab. This study, which was published in the February 15, 2007, issue of Clinical Cancer Research, was a stepping stone for subsequent research, leading to regulatory approval of bevacizumab for recurrent glioblastoma.

Authors
Mar, N; Desjardins, A; Vredenburgh, JJ
MLA Citation
Mar, N, Desjardins, A, and Vredenburgh, JJ. "CCR 20th Anniversary Commentary: Bevacizumab in the Treatment of Glioblastoma--The Progress and the Limitations." Clinical cancer research : an official journal of the American Association for Cancer Research 21.19 (October 2015): 4248-4250.
PMID
26429979
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
19
Publish Date
2015
Start Page
4248
End Page
4250
DOI
10.1158/1078-0432.ccr-15-1381

Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032.

Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB).Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available.A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH-MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses.Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit.

Authors
Robinson, GW; Orr, BA; Wu, G; Gururangan, S; Lin, T; Qaddoumi, I; Packer, RJ; Goldman, S; Prados, MD; Desjardins, A; Chintagumpala, M; Takebe, N; Kaste, SC; Rusch, M; Allen, SJ; Onar-Thomas, A; Stewart, CF; Fouladi, M; Boyett, JM; Gilbertson, RJ; Curran, T; Ellison, DW; Gajjar, A
MLA Citation
Robinson, GW, Orr, BA, Wu, G, Gururangan, S, Lin, T, Qaddoumi, I, Packer, RJ, Goldman, S, Prados, MD, Desjardins, A, Chintagumpala, M, Takebe, N, Kaste, SC, Rusch, M, Allen, SJ, Onar-Thomas, A, Stewart, CF, Fouladi, M, Boyett, JM, Gilbertson, RJ, Curran, T, Ellison, DW, and Gajjar, A. "Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.24 (August 2015): 2646-2654.
PMID
26169613
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
24
Publish Date
2015
Start Page
2646
End Page
2654
DOI
10.1200/jco.2014.60.1591

Neuro-oncology: What is the optimal use of bevacizumab in glioblastoma?

Authors
Desjardins, A
MLA Citation
Desjardins, A. "Neuro-oncology: What is the optimal use of bevacizumab in glioblastoma?." Nature reviews. Neurology 11.8 (August 2015): 429-430.
PMID
26195258
Source
epmc
Published In
Nature Reviews Neurology
Volume
11
Issue
8
Publish Date
2015
Start Page
429
End Page
430
DOI
10.1038/nrneurol.2015.127

Phase II Trial of Upfront Bevacizumab, Irinotecan, and Temozolomide for Unresectable Glioblastoma.

Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy.Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted.Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM.Patients received up to 4 cycles of TMZ at 200 mg/m(2) per day on days 1-5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m(2) or 340 mg/m(2) depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater.Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial response, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2-13.5 months).Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.

Authors
Peters, KB; Lou, E; Desjardins, A; Reardon, DA; Lipp, ES; Miller, E; Herndon, JE; McSherry, F; Friedman, HS; Vredenburgh, JJ
MLA Citation
Peters, KB, Lou, E, Desjardins, A, Reardon, DA, Lipp, ES, Miller, E, Herndon, JE, McSherry, F, Friedman, HS, and Vredenburgh, JJ. "Phase II Trial of Upfront Bevacizumab, Irinotecan, and Temozolomide for Unresectable Glioblastoma." The oncologist 20.7 (July 2015): 727-728.
PMID
26025933
Source
epmc
Published In
The oncologist
Volume
20
Issue
7
Publish Date
2015
Start Page
727
End Page
728
DOI
10.1634/theoncologist.2015-0135

Severe adverse immunologic reaction in a patient with glioblastoma receiving autologous dendritic cell vaccines combined with GM-CSF and dose-intensified temozolomide.

Therapeutic vaccination of patients with cancer-targeting tumor-associated antigens is a promising strategy for the specific eradication of invasive malignancies with minimal toxicity to normal tissues. However, as increasingly potent modalities for stimulating immunologic responses are developed for clinical evaluation, the risk of inflammatory and autoimmune toxicities also may be exacerbated. In this report, we describe the induction of a severe (grade 3) immunologic reaction in a patient with newly diagnosed glioblastoma (GBM) receiving autologous RNA-pulsed dendritic cell (DC) vaccines admixed with GM-CSF and administered coordinately with cycles of dose-intensified temozolomide. Shortly after the eighth administration of the admixed intradermal vaccine, the patient experienced dizziness, flushing, conjunctivitis, headache, and the outbreak of a disseminated macular/papular rash and bilateral indurated injection sites. Immunologic workup of patient reactivity revealed sensitization to the GM-CSF component of the vaccine and the production of high levels of anti-GM-CSF autoantibodies during vaccination. Removal of GM-CSF from the DC vaccine allowed continued vaccination without incident. Despite the known lymphodepletive and immunosuppressive effects of temozolomide, these observations demonstrate the capacity for the generation of severe immunologic reactivity in patients with GBM receiving DC-based therapy during adjuvant dose-intensified temozolomide.

Authors
Mitchell, DA; Sayour, EJ; Reap, E; Schmittling, R; DeLeon, G; Norberg, P; Desjardins, A; Friedman, AH; Friedman, HS; Archer, G; Sampson, JH
MLA Citation
Mitchell, DA, Sayour, EJ, Reap, E, Schmittling, R, DeLeon, G, Norberg, P, Desjardins, A, Friedman, AH, Friedman, HS, Archer, G, and Sampson, JH. "Severe adverse immunologic reaction in a patient with glioblastoma receiving autologous dendritic cell vaccines combined with GM-CSF and dose-intensified temozolomide." Cancer immunology research 3.4 (April 2015): 320-325.
PMID
25387895
Source
epmc
Published In
Cancer Immunology Research
Volume
3
Issue
4
Publish Date
2015
Start Page
320
End Page
325
DOI
10.1158/2326-6066.cir-14-0100

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

Authors
Mitchell, DA; Batich, KA; Gunn, MD; Huang, M-N; Sanchez-Perez, L; Nair, SK; Congdon, KL; Reap, EA; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Batich, KA, Gunn, MD, Huang, M-N, Sanchez-Perez, L, Nair, SK, Congdon, KL, Reap, EA, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, Coan, A, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients." Nature 519.7543 (March 11, 2015): 366-369.
PMID
25762141
Source
epmc
Published In
Nature
Volume
519
Issue
7543
Publish Date
2015
Start Page
366
End Page
369
DOI
10.1038/nature14320

Impact of health-related quality of life and fatigue on survival of recurrent high-grade glioma patients.

Quality of life (QoL) impairment and fatigue are frequently experienced during treatment for recurrent high-grade glioma (HGG). Fatigue and QoL impairments can be due to primary neurological dysfunction, cytotoxic treatments, mood disturbances, and supportive medications. We now seek to understand how QoL and fatigue impacts survival in recurrent HGG. Using a prospective observational design, 237 patients with recurrent HGG and KPS ≥70 completed a self-administered questionnaire that evaluated QoL and fatigue. QoL was assessed with Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-Brain (FACT-Br) scales while fatigue was assessed using Functional Assessment of Chronic Illness Therapy (FACIT-F) scale. Cox proportional hazard models were utilized to evaluate the association between QoL and fatigue and survival. Seventy-three (31 %) subjects had recurrent WHO grade III gliomas and 164 (69 %) had recurrent WHO grade IV gliomas. Median follow-up analysis was 27.60 months. In univariate Cox analyses, the FACT-Br specific subscale (HR 0.88; CI 95 %, 0.77-1; p = 0.048) and FACIT-F (HR 0.82; CI 95 %, 0.68-0.99; p = 0.045) were both significant predictors of survival. Fatigue added prognostic information beyond that provided by KPS, age, sex, tumor grade, and number of prior progressions (HR 0.80; CI 95 %, 0.68-0.9; p = 0.031). A greater degree of fatigue was associated with poorer survival in recurrent HGG patients. In multivariable analyses, FACT-G and FACT-Br are not independent predictors of prognosis. Fatigue is a strong independent predictor of survival that provides incremental prognostic value to the traditional markers of prognosis in recurrent HGG. Pharmacological or non-pharmacological strategies to treat fatigue warrant investigation.

Authors
Peters, KB; West, MJ; Hornsby, WE; Waner, E; Coan, AD; McSherry, F; Herndon, JE; Friedman, HS; Desjardins, A; Jones, LW
MLA Citation
Peters, KB, West, MJ, Hornsby, WE, Waner, E, Coan, AD, McSherry, F, Herndon, JE, Friedman, HS, Desjardins, A, and Jones, LW. "Impact of health-related quality of life and fatigue on survival of recurrent high-grade glioma patients." Journal of neuro-oncology 120.3 (December 2014): 499-506.
PMID
25115739
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
120
Issue
3
Publish Date
2014
Start Page
499
End Page
506
DOI
10.1007/s11060-014-1574-3

AT-46 * VORINOSTAT AND BEVACIZUMAB FOR RECURRENT HIGH-GRADE GLIOMA: INTERIM ANALYSIS OF A PHASE II CLINICAL TRIAL

Authors
Peters, K; Reardon, D; Randazzo, D; Dutton, S; Edwards, A; Lipp, E; Herndon, J; McSherry, F; Desjardins, A; Ranjan, T; Vlahovic, G; Friedman, H
MLA Citation
Peters, K, Reardon, D, Randazzo, D, Dutton, S, Edwards, A, Lipp, E, Herndon, J, McSherry, F, Desjardins, A, Ranjan, T, Vlahovic, G, and Friedman, H. "AT-46 * VORINOSTAT AND BEVACIZUMAB FOR RECURRENT HIGH-GRADE GLIOMA: INTERIM ANALYSIS OF A PHASE II CLINICAL TRIAL." Neuro-Oncology 16.suppl 5 (November 1, 2014): v18-v18.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v18
End Page
v18
DOI
10.1093/neuonc/nou237.45

AT-20 * SINGLE INSTITUTION RETROSPECTIVE REVIEW OF PERFORMANCE STATUS AND CORTICOSTEROID USE IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS (PTS) TREATED ON BEVACIZUMAB (BEV)

Authors
Desjardins, A; Herndon, J; McSherry, F; Ravelo, A; Lipp, E; Healy, P; Peters, K; Vlahovic, G; Sampson, J; Friedman, A; Friedman, H
MLA Citation
Desjardins, A, Herndon, J, McSherry, F, Ravelo, A, Lipp, E, Healy, P, Peters, K, Vlahovic, G, Sampson, J, Friedman, A, and Friedman, H. "AT-20 * SINGLE INSTITUTION RETROSPECTIVE REVIEW OF PERFORMANCE STATUS AND CORTICOSTEROID USE IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS (PTS) TREATED ON BEVACIZUMAB (BEV)." Neuro-Oncology 16.suppl 5 (November 1, 2014): v12-v13.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v12
End Page
v13
DOI
10.1093/neuonc/nou237.20

IT-30 * ReACT: A PHASE II STUDY OF RINDOPEPIMUT VACCINE (CDX-110) PLUS BEVACIZUMAB IN RELAPSED GLIOBLASTOMA

Authors
Reardon, D; Schuster, J; Tran, D; Fink, K; Nabors, L; Li, G; Lukas, R; Desjardins, A; Ashby, L; Duic, JP; Aneiro, L; Hawthorne, T; Green, J; Yellin, M; Davis, T; Sampson, J
MLA Citation
Reardon, D, Schuster, J, Tran, D, Fink, K, Nabors, L, Li, G, Lukas, R, Desjardins, A, Ashby, L, Duic, JP, Aneiro, L, Hawthorne, T, Green, J, Yellin, M, Davis, T, and Sampson, J. "IT-30 * ReACT: A PHASE II STUDY OF RINDOPEPIMUT VACCINE (CDX-110) PLUS BEVACIZUMAB IN RELAPSED GLIOBLASTOMA." Neuro-Oncology 16.suppl 5 (November 1, 2014): v116-v116.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v116
End Page
v116
DOI
10.1093/neuonc/nou258.28

AT-21 * FINAL RESULTS OF A PHASE 1 TRIAL OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) AGAINST RECURRENT GLIOBLASTOMA (GBM)

Authors
Desjardins, A; Sampson, J; Peters, K; Vlahovic, G; Threatt, S; Herndon, J; Boulton, S; Lally-Goss, D; McSherry, F; Lipp, E; Friedman, A; Friedman, H; Bigner, D; Gromeier, M
MLA Citation
Desjardins, A, Sampson, J, Peters, K, Vlahovic, G, Threatt, S, Herndon, J, Boulton, S, Lally-Goss, D, McSherry, F, Lipp, E, Friedman, A, Friedman, H, Bigner, D, and Gromeier, M. "AT-21 * FINAL RESULTS OF A PHASE 1 TRIAL OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) AGAINST RECURRENT GLIOBLASTOMA (GBM)." Neuro-Oncology 16.suppl 5 (November 1, 2014): v13-v13.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v13
End Page
v13
DOI
10.1093/neuonc/nou237.21

MS-19 * LONG-TERM OUTCOMES FOR PATIENTS WITH INTRACRANIAL MENINGIOMAS: A SINGLE-INSTITUTION RETROSPECTIVE ANALYSIS

Authors
Mowery, Y; Wright, A; Desjardins, A; Peters, K; Ranjan, T; Vlahovic, G; Friedman, H; Zomorodi, A; Kaylie, D; Adogwa, O; Nimjee, S; Sperduto, W; Chagoya, G; Fatemi, P; McLendon, R; Cummings, T; Friedman, A; Sampson, J; Kirkpatrick, J
MLA Citation
Mowery, Y, Wright, A, Desjardins, A, Peters, K, Ranjan, T, Vlahovic, G, Friedman, H, Zomorodi, A, Kaylie, D, Adogwa, O, Nimjee, S, Sperduto, W, Chagoya, G, Fatemi, P, McLendon, R, Cummings, T, Friedman, A, Sampson, J, and Kirkpatrick, J. "MS-19 * LONG-TERM OUTCOMES FOR PATIENTS WITH INTRACRANIAL MENINGIOMAS: A SINGLE-INSTITUTION RETROSPECTIVE ANALYSIS." Neuro-Oncology 16.suppl 5 (November 1, 2014): v130-v131.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v130
End Page
v131
DOI
10.1093/neuonc/nou260.18

AT-22 * PHASE II TRIAL OF BEVACIZUMAB, RADIATION THERAPY (RT) AND TEMOZOLOMIDE FOLLOWED BY BEVACIZUMAB AND TEMOZOLOMIDE WITH CONTINUATION OF BEVACIZUMAB BEYOND PROGRESSION

Authors
Ghiaseddin, A; Dunn-Pirio, A; Peters, K; Vlahovic, G; Herndon, J; Threatt, S; Sampson, J; Friedman, A; Friedman, H; Desjardins, A
MLA Citation
Ghiaseddin, A, Dunn-Pirio, A, Peters, K, Vlahovic, G, Herndon, J, Threatt, S, Sampson, J, Friedman, A, Friedman, H, and Desjardins, A. "AT-22 * PHASE II TRIAL OF BEVACIZUMAB, RADIATION THERAPY (RT) AND TEMOZOLOMIDE FOLLOWED BY BEVACIZUMAB AND TEMOZOLOMIDE WITH CONTINUATION OF BEVACIZUMAB BEYOND PROGRESSION." Neuro-Oncology 16.suppl 5 (November 1, 2014): v13-v13.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v13
End Page
v13
DOI
10.1093/neuonc/nou237.22

IT-34 * PILOT STUDY OF COMBINATION OF ANTITUMOR IMMUNOTHERAPY TARGETED AGAINST CYTOMEGALOVIRUS (CMV) PLUS REGULATORY T-CELL INHIBITION IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM)

Authors
Vlahovic, G; Archer, G; Lally-Goss, D; Reap, E; Batich, K; Desjardins, A; Peters, K; Ranjan, T; Healy, P; Herndon, J; Friedman, A; Friedman, H; Bigner, D; Sampson, J
MLA Citation
Vlahovic, G, Archer, G, Lally-Goss, D, Reap, E, Batich, K, Desjardins, A, Peters, K, Ranjan, T, Healy, P, Herndon, J, Friedman, A, Friedman, H, Bigner, D, and Sampson, J. "IT-34 * PILOT STUDY OF COMBINATION OF ANTITUMOR IMMUNOTHERAPY TARGETED AGAINST CYTOMEGALOVIRUS (CMV) PLUS REGULATORY T-CELL INHIBITION IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM)." Neuro-Oncology 16.suppl 5 (November 1, 2014): v117-v117.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v117
End Page
v117
DOI
10.1093/neuonc/nou258.32

SM-02 * LEVETIRACETAM USAGE IN POST-OPERATIVE SEIZURE MANAGEMENT IN MALIGNANT GLIOMA

Authors
Kang, J; Desjardins, A; Healy, P; Herndon, J; Lipp, E; Peters, K; Vlahovic, G; Sampson, J; Friedman, H; Friedman, A; Adamson, C
MLA Citation
Kang, J, Desjardins, A, Healy, P, Herndon, J, Lipp, E, Peters, K, Vlahovic, G, Sampson, J, Friedman, H, Friedman, A, and Adamson, C. "SM-02 * LEVETIRACETAM USAGE IN POST-OPERATIVE SEIZURE MANAGEMENT IN MALIGNANT GLIOMA." Neuro-Oncology 16.suppl 5 (November 1, 2014): v206-v206.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v206
End Page
v206
DOI
10.1093/neuonc/nou277.2

AT-48 * A PHASE 1 TRIAL OF CARBOXYAMIDOTRIAZOLE OROTATE (CTO) IN COMBINATION WITH BEVACIZUMAB FOR ADULT PATIENTS WITH RECURRENT MALIGNANT GLIOMA POST-BEVACIZUMAB FAILURE

Authors
Ranjan, T; Peters, KB; Vlahovic, G; Watts, J; Dutton, S; Boulton, S; Lipp, E; Herndon, J; Healy, P; Miller, E; Friedman, H; Karmali, R; Desjardins, A
MLA Citation
Ranjan, T, Peters, KB, Vlahovic, G, Watts, J, Dutton, S, Boulton, S, Lipp, E, Herndon, J, Healy, P, Miller, E, Friedman, H, Karmali, R, and Desjardins, A. "AT-48 * A PHASE 1 TRIAL OF CARBOXYAMIDOTRIAZOLE OROTATE (CTO) IN COMBINATION WITH BEVACIZUMAB FOR ADULT PATIENTS WITH RECURRENT MALIGNANT GLIOMA POST-BEVACIZUMAB FAILURE." Neuro-Oncology 16.suppl 5 (November 1, 2014): v19-v19.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v19
End Page
v19
DOI
10.1093/neuonc/nou237.47

QL-21 * SPIRITUAL WELL-BEING AND ITS ASSOCIATION WITH HEALTH-RELATED QUALITY OF LIFE IN PRIMARY BRAIN TUMOR PATIENTS

Authors
Randazzo, D; Affronti, M; Lipp, E; McSherry, F; Herndon, J; Flahiff, C; Miller, E; Woodring, S; Freeman, M; Healy, P; Minchew, J; Boulton, S; Desjardins, A; Ranjan, T; Vlahovic, G; Friedman, H; Peters, K
MLA Citation
Randazzo, D, Affronti, M, Lipp, E, McSherry, F, Herndon, J, Flahiff, C, Miller, E, Woodring, S, Freeman, M, Healy, P, Minchew, J, Boulton, S, Desjardins, A, Ranjan, T, Vlahovic, G, Friedman, H, and Peters, K. "QL-21 * SPIRITUAL WELL-BEING AND ITS ASSOCIATION WITH HEALTH-RELATED QUALITY OF LIFE IN PRIMARY BRAIN TUMOR PATIENTS." Neuro-Oncology 16.suppl 5 (November 1, 2014): v182-v183.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v182
End Page
v183
DOI
10.1093/neuonc/nou269.20

AT-19 * SINGLE INSTITUTION RETROSPECTIVE COMPARISON OF GLIOBLASTOMA (GBM) PATIENTS (PTS) INITIATED ON BEVACIZUMAB (BEV) BEFORE VERSUS AFTER RECURRENCE IN CLINICAL PRACTICE

Authors
Desjardins, A; Herndon, J; McSherry, F; Ravelo, A; Lipp, E; Healy, P; Boulton, S; Peters, K; Vlahovic, G; Sampson, J; Friedman, A; Friedman, H
MLA Citation
Desjardins, A, Herndon, J, McSherry, F, Ravelo, A, Lipp, E, Healy, P, Boulton, S, Peters, K, Vlahovic, G, Sampson, J, Friedman, A, and Friedman, H. "AT-19 * SINGLE INSTITUTION RETROSPECTIVE COMPARISON OF GLIOBLASTOMA (GBM) PATIENTS (PTS) INITIATED ON BEVACIZUMAB (BEV) BEFORE VERSUS AFTER RECURRENCE IN CLINICAL PRACTICE." Neuro-Oncology 16.suppl 5 (November 1, 2014): v12-v12.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v12
End Page
v12
DOI
10.1093/neuonc/nou237.19

QL-20 * PROGNOSTIC IMPORTANCE OF HEALTH-RELATED QUALITY OF LIFE AND FATIGUE IN NEWLY DIAGNOSED GLIOBLASTOMA

Authors
Peters, K; Randazzo, D; Affronti, M; Lipp, E; McSherry, F; Herndon, J; Flahiff, C; Miller, E; Woodring, S; Freeman, M; Healy, P; Minchew, J; Boulton, S; Desjardins, A; Ranjan, T; Vlahovic, G; Jones, L; Friedman, H
MLA Citation
Peters, K, Randazzo, D, Affronti, M, Lipp, E, McSherry, F, Herndon, J, Flahiff, C, Miller, E, Woodring, S, Freeman, M, Healy, P, Minchew, J, Boulton, S, Desjardins, A, Ranjan, T, Vlahovic, G, Jones, L, and Friedman, H. "QL-20 * PROGNOSTIC IMPORTANCE OF HEALTH-RELATED QUALITY OF LIFE AND FATIGUE IN NEWLY DIAGNOSED GLIOBLASTOMA." Neuro-Oncology 16.suppl 5 (November 1, 2014): v182-v182.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v182
End Page
v182
DOI
10.1093/neuonc/nou269.19

Oncolytic polio virotherapy of cancer.

Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.

Authors
Brown, MC; Dobrikova, EY; Dobrikov, MI; Walton, RW; Gemberling, SL; Nair, SK; Desjardins, A; Sampson, JH; Friedman, HS; Friedman, AH; Tyler, DS; Bigner, DD; Gromeier, M
MLA Citation
Brown, MC, Dobrikova, EY, Dobrikov, MI, Walton, RW, Gemberling, SL, Nair, SK, Desjardins, A, Sampson, JH, Friedman, HS, Friedman, AH, Tyler, DS, Bigner, DD, and Gromeier, M. "Oncolytic polio virotherapy of cancer." Cancer 120.21 (November 2014): 3277-3286. (Review)
PMID
24939611
Source
epmc
Published In
Cancer
Volume
120
Issue
21
Publish Date
2014
Start Page
3277
End Page
3286
DOI
10.1002/cncr.28862

Oncolytic polio/rhinovirus recombinant (pvsripo) in recurrent glioblastoma (gbm): first phase I clinical trial evaluating the intratumoral administration.

PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. PVSRIPO recognizes nectin-like molecule-5, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. Within, we report on the ongoing phase I study evaluating the intratumoral convection-enhanced delivery (CED) of PVSRIPO.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Ranjan, T, Vlahovic, G, Threatt, S, Herndon, JE, Boulton, S, Lally-Goss, D, McSherry, F, Friedman, AH, Friedman, HS, Bigner, DD, and Gromeier, M. "Oncolytic polio/rhinovirus recombinant (pvsripo) in recurrent glioblastoma (gbm): first phase I clinical trial evaluating the intratumoral administration." Neuro Oncol 16 Suppl 3 (July 2014): iii43-.
PMID
25165331
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii43
DOI
10.1093/neuonc/nou209.5

Oncolytic poliovirus immunotherapy of glioblastoma.

With the exception of Burkitt lymphoma, almost all solid cancers are susceptible to infection with poliovirus, due to widespread ectopic expression of the poliovirus receptor, the onco-fetal cell adhesion molecule Necl5/CD155. We engineered a profoundly CNS-incompetent and genetically stable variant of polio through recombination of the cognate internal ribosomal entry site (IRES) with its counterpart from human rhinovirus type 2. The resulting PVSRIPO chimera is incapable of causing poliomyelitis or encephalitis in non-human primates or human subjects, even after high-dose intracerebral inoculation, but retains excellent cytotoxic properties in malignant cells. This is due to constitutively active signal transduction pathways via Raf-Erk MAPKs to the MAPK-interacting kinase, Mnk, and the translation apparatus.

Authors
Gromeier, M; Dobrikova, E; Dobrikov, M; Brown, M; Bryant, J; Threatt, S; Boulton, S; Carter, K; Herndon, J; Desjardins, A; Friedman, H; Sampson, J; Friedman, A; Bigner, D
MLA Citation
Gromeier, M, Dobrikova, E, Dobrikov, M, Brown, M, Bryant, J, Threatt, S, Boulton, S, Carter, K, Herndon, J, Desjardins, A, Friedman, H, Sampson, J, Friedman, A, and Bigner, D. "Oncolytic poliovirus immunotherapy of glioblastoma." Neuro Oncol 16 Suppl 3 (July 2014): iii41-.
PMID
25165326
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii41
DOI
10.1093/neuonc/nou208.69

Oncolytic polio virotherapy of cancer

© 2014 American Cancer Society.Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.

Authors
Brown, MC; Dobrikova, EY; Dobrikov, MI; Walton, RW; Gemberling, SL; Nair, SK; Desjardins, A; Sampson, JH; Friedman, HS; Friedman, AH; Tyler, DS; Bigner, DD; Gromeier, M
MLA Citation
Brown, MC, Dobrikova, EY, Dobrikov, MI, Walton, RW, Gemberling, SL, Nair, SK, Desjardins, A, Sampson, JH, Friedman, HS, Friedman, AH, Tyler, DS, Bigner, DD, and Gromeier, M. "Oncolytic polio virotherapy of cancer." Cancer 120.21 (January 1, 2014): 3277-3286. (Review)
Source
scopus
Published In
Cancer
Volume
120
Issue
21
Publish Date
2014
Start Page
3277
End Page
3286
DOI
10.1002/cncr.28862

Bevacizumab therapy for glioblastoma: a passionate discussion.

Authors
Desjardins, A; Friedman, HS
MLA Citation
Desjardins, A, and Friedman, HS. "Bevacizumab therapy for glioblastoma: a passionate discussion." CNS oncology 3.1 (January 2014): 1-3.
PMID
25054891
Source
epmc
Published In
CNS Oncology
Volume
3
Issue
1
Publish Date
2014
Start Page
1
End Page
3
DOI
10.2217/cns.13.53

Imaging descriptors improve the predictive power of survival models for glioblastoma patients.

BACKGROUND: Because effective prediction of survival time can be highly beneficial for the treatment of glioblastoma patients, the relationship between survival time and multiple patient characteristics has been investigated. In this paper, we investigate whether the predictive power of a survival model based on clinical patient features improves when MRI features are also included in the model. METHODS: The subjects in this study were 82 glioblastoma patients for whom clinical features as well as MR imaging exams were made available by The Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA). Twenty-six imaging features in the available MR scans were assessed by radiologists from the TCGA Glioma Phenotype Research Group. We used multivariate Cox proportional hazards regression to construct 2 survival models: one that used 3 clinical features (age, gender, and KPS) as the covariates and 1 that used both the imaging features and the clinical features as the covariates. Then, we used 2 measures to compare the predictive performance of these 2 models: area under the receiver operating characteristic curve for the 1-year survival threshold and overall concordance index. To eliminate any positive performance estimation bias, we used leave-one-out cross-validation. RESULTS: The performance of the model based on both clinical and imaging features was higher than the performance of the model based on only the clinical features, in terms of both area under the receiver operating characteristic curve (P < .01) and the overall concordance index (P < .01). CONCLUSIONS: Imaging features assessed using a controlled lexicon have additional predictive value compared with clinical features when predicting survival time in glioblastoma patients.

Authors
Mazurowski, MA; Desjardins, A; Malof, JM
MLA Citation
Mazurowski, MA, Desjardins, A, and Malof, JM. "Imaging descriptors improve the predictive power of survival models for glioblastoma patients." Neuro Oncol 15.10 (October 2013): 1389-1394.
PMID
23396489
Source
pubmed
Published In
Neuro-Oncology
Volume
15
Issue
10
Publish Date
2013
Start Page
1389
End Page
1394
DOI
10.1093/neuonc/nos335

Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial.

PURPOSE: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. METHODS AND MATERIALS: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. RESULTS: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. CONCLUSIONS: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.

Authors
Cabrera, AR; Cuneo, KC; Desjardins, A; Sampson, JH; McSherry, F; Herndon, JE; Peters, KB; Allen, K; Hoang, JK; Chang, Z; Craciunescu, O; Vredenburgh, JJ; Friedman, HS; Kirkpatrick, JP
MLA Citation
Cabrera, AR, Cuneo, KC, Desjardins, A, Sampson, JH, McSherry, F, Herndon, JE, Peters, KB, Allen, K, Hoang, JK, Chang, Z, Craciunescu, O, Vredenburgh, JJ, Friedman, HS, and Kirkpatrick, JP. "Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial." Int J Radiat Oncol Biol Phys 86.5 (August 1, 2013): 873-879.
PMID
23725997
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
86
Issue
5
Publish Date
2013
Start Page
873
End Page
879
DOI
10.1016/j.ijrobp.2013.04.029

O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma.

Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (≥30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated.

Authors
Jiang, X; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Quinn, JA; Austin, AD; Herndon, JE; McLendon, RE; Friedman, HS
MLA Citation
Jiang, X, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Quinn, JA, Austin, AD, Herndon, JE, McLendon, RE, and Friedman, HS. "O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma." United States. August 2013.
PMID
23686298
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
114
Issue
1
Publish Date
2013
Start Page
135
End Page
140
DOI
10.1007/s11060-013-1162-y

O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma.

Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (≥30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated.

Authors
Jiang, X; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Quinn, JA; Austin, AD; Herndon, JE; McLendon, RE; Friedman, HS
MLA Citation
Jiang, X, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Quinn, JA, Austin, AD, Herndon, JE, McLendon, RE, and Friedman, HS. "O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma." Journal of neuro-oncology 114.1 (August 2013): 135-140.
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
114
Issue
1
Publish Date
2013
Start Page
135
End Page
140
DOI
10.1007/s11060-013-1162-y

Phase II trial of upfront bevacizumab and temozolomide for unresectable or multifocal glioblastoma.

Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6-10 months. We conducted a phase II trial of upfront 5-day temozolomide (TMZ) and bevacizumab (BV) in patients with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m(2) on days 1-5, and BV at 10 mg/kg on days 1 and 15 of a 28-day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 nonhematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty-one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment-related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials.

Authors
Lou, E; Peters, KB; Sumrall, AL; Desjardins, A; Reardon, DA; Lipp, ES; Herndon, JE; Coan, A; Bailey, L; Turner, S; Friedman, HS; Vredenburgh, JJ
MLA Citation
Lou, E, Peters, KB, Sumrall, AL, Desjardins, A, Reardon, DA, Lipp, ES, Herndon, JE, Coan, A, Bailey, L, Turner, S, Friedman, HS, and Vredenburgh, JJ. "Phase II trial of upfront bevacizumab and temozolomide for unresectable or multifocal glioblastoma." Cancer Med 2.2 (April 2013): 185-195.
PMID
23634286
Source
pubmed
Published In
Cancer Med
Volume
2
Issue
2
Publish Date
2013
Start Page
185
End Page
195
DOI
10.1002/cam4.58

Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: A prospective trial

Purpose: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. Methods and Materials: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. Results: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. Conclusions: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach. © 2013 Elsevier Inc.

Authors
Cabrera, AR; Cuneo, KC; Desjardins, A; Sampson, JH; McSherry, F; II, JEH; Peters, KB; Allen, K; Hoang, JK; Chang, Z; Craciunescu, O; Vredenburgh, JJ; Friedman, HS; Kirkpatrick, JP
MLA Citation
Cabrera, AR, Cuneo, KC, Desjardins, A, Sampson, JH, McSherry, F, II, JEH, Peters, KB, Allen, K, Hoang, JK, Chang, Z, Craciunescu, O, Vredenburgh, JJ, Friedman, HS, and Kirkpatrick, JP. "Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: A prospective trial." International Journal of Radiation Oncology Biology Physics 86.5 (2013): 873-879.
Source
scival
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
86
Issue
5
Publish Date
2013
Start Page
873
End Page
879
DOI
10.1016/j.ijrobp.2013.04.029

Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients.

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.

Authors
Reardon, DA; Herndon, JE; Peters, KB; Desjardins, A; Coan, A; Lou, E; Sumrall, AL; Turner, S; Lipp, ES; Sathornsumetee, S; Rich, JN; Sampson, JH; Friedman, AH; Boulton, ST; Bigner, DD; Friedman, HS; Vredenburgh, JJ
MLA Citation
Reardon, DA, Herndon, JE, Peters, KB, Desjardins, A, Coan, A, Lou, E, Sumrall, AL, Turner, S, Lipp, ES, Sathornsumetee, S, Rich, JN, Sampson, JH, Friedman, AH, Boulton, ST, Bigner, DD, Friedman, HS, and Vredenburgh, JJ. "Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients." Br J Cancer 107.9 (October 23, 2012): 1481-1487.
PMID
23037712
Source
pubmed
Published In
British Journal of Cancer
Volume
107
Issue
9
Publish Date
2012
Start Page
1481
End Page
1487
DOI
10.1038/bjc.2012.415

Phase II study of Gleevec plus hydroxyurea in adults with progressive or recurrent low-grade glioma.

BACKGROUND: We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma. METHODS: A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on enzyme-inducing antiepileptic drugs (EIAEDs) and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival, and radiographic response rate. RESULTS: Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had before radiotherapy and 24 (38%) had received before chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%), and diarrhea (3%). CONCLUSIONS: Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible antitumor activity.

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Herndon, JE; Coan, A; Gururangan, S; Peters, KB; McLendon, R; Sathornsumetee, S; Rich, JN; Lipp, ES; Janney, D; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Herndon, JE, Coan, A, Gururangan, S, Peters, KB, McLendon, R, Sathornsumetee, S, Rich, JN, Lipp, ES, Janney, D, and Friedman, HS. "Phase II study of Gleevec plus hydroxyurea in adults with progressive or recurrent low-grade glioma." Cancer 118.19 (October 1, 2012): 4759-4767.
PMID
22371319
Source
pubmed
Published In
Cancer
Volume
118
Issue
19
Publish Date
2012
Start Page
4759
End Page
4767
DOI
10.1002/cncr.26541

PHASE II STUDY TO EVALUATE THE EFFICACY AND SAFETY OF INTRAVENOUS PALONOSETRON IN PRIMARY MALIGNANT GLIOMA PATIENTS RECEIVING STANDARD RADIOTHERAPY AND CONCOMITANT TEMOZOLOMIDE

Authors
Affronti, ML; Woodring, S; Allen, K; II, HJE; McSherry, F; Peters, KB; Friedman, HS; Desjardins, A; Freeman, W; Cheshire, S; Cone, C; Kalinowski, KH; Kim, J-Y; III, LHH; Poillucci, V; Southerland, C; Tetterton, J; Kirkpatrick, J; Vredenburgh, JJ
MLA Citation
Affronti, ML, Woodring, S, Allen, K, II, HJE, McSherry, F, Peters, KB, Friedman, HS, Desjardins, A, Freeman, W, Cheshire, S, Cone, C, Kalinowski, KH, Kim, J-Y, III, LHH, Poillucci, V, Southerland, C, Tetterton, J, Kirkpatrick, J, and Vredenburgh, JJ. "PHASE II STUDY TO EVALUATE THE EFFICACY AND SAFETY OF INTRAVENOUS PALONOSETRON IN PRIMARY MALIGNANT GLIOMA PATIENTS RECEIVING STANDARD RADIOTHERAPY AND CONCOMITANT TEMOZOLOMIDE." October 2012.
PMID
27271867
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
156
End Page
156

Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series.

Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted.

Authors
Lou, E; Sumrall, AL; Turner, S; Peters, KB; Desjardins, A; Vredenburgh, JJ; McLendon, RE; Herndon, JE; McSherry, F; Norfleet, J; Friedman, HS; Reardon, DA
MLA Citation
Lou, E, Sumrall, AL, Turner, S, Peters, KB, Desjardins, A, Vredenburgh, JJ, McLendon, RE, Herndon, JE, McSherry, F, Norfleet, J, Friedman, HS, and Reardon, DA. "Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series." J Neurooncol 109.1 (August 2012): 63-70.
PMID
22535433
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
109
Issue
1
Publish Date
2012
Start Page
63
End Page
70
DOI
10.1007/s11060-012-0861-0

Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma.

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, KB; Sathornsumetee, S; Threatt, S; Sampson, JH; Herndon, JE; Coan, A; McSherry, F; Rich, JN; McLendon, RE; Zhang, S; Friedman, HS
MLA Citation
Reardon, DA, Vredenburgh, JJ, Desjardins, A, Peters, KB, Sathornsumetee, S, Threatt, S, Sampson, JH, Herndon, JE, Coan, A, McSherry, F, Rich, JN, McLendon, RE, Zhang, S, and Friedman, HS. "Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma." J Neurooncol 108.3 (July 2012): 499-506.
PMID
22407177
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
108
Issue
3
Publish Date
2012
Start Page
499
End Page
506
DOI
10.1007/s11060-012-0848-x

Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas.

PURPOSE: Patients with recurrent malignant gliomas treated with stereotactic radiosurgery (SRS) and multiagent systemic therapies were reviewed to determine the effects of patient- and treatment-related factors on survival and toxicity. METHODS AND MATERIALS: A retrospective analysis was performed on patients with recurrent malignant gliomas treated with salvage SRS from September 2002 to March 2010. All patients had experienced progression after treatment with temozolomide and radiotherapy. Salvage SRS was typically administered only after multiple postchemoradiation salvage systemic therapies had failed. RESULTS: 63 patients were treated with SRS for recurrent high-grade glioma; 49 patients had World Health Organization (WHO) Grade 4 disease. Median follow-up was 31 months from primary diagnosis and 7 months from SRS. Median overall survival from primary diagnosis was 41 months for all patients. Median progression-free survival (PFS) and overall survival from SRS (OS-SRS) were 6 and 10 months for all patients, respectively. The 1-year OS-SRS for patients with Grade 4 glioma who received adjuvant (concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant bevacizumab (p = 0.005). Median PFS for patients with a WHO Grade 4 glioma who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for patients who did not receive adjuvant bevacizumab (p = 0.014). Karnofsky performance status (KPS) and age were not significantly different between treatment groups. Treatment-related Grade 3/4 toxicity for patients receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58).On multivariate analysis, the relative risk of death and progression with adjuvant bevacizumab was 0.37 (confidence interval [CI] 0.17-0.82) and 0.45 (CI 0.21-0.97). KPS >70 and age <50 years were significantly associated with improved survival. CONCLUSIONS: The combination of salvage radiosurgery and bevacizumab to treat recurrent malignant gliomas is well tolerated and seems to be associated with improved outcomes. Prospective multiinstitutional studies are required to determine efficacy and long-term toxicity with this approach.

Authors
Cuneo, KC; Vredenburgh, JJ; Sampson, JH; Reardon, DA; Desjardins, A; Peters, KB; Friedman, HS; Willett, CG; Kirkpatrick, JP
MLA Citation
Cuneo, KC, Vredenburgh, JJ, Sampson, JH, Reardon, DA, Desjardins, A, Peters, KB, Friedman, HS, Willett, CG, and Kirkpatrick, JP. "Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas." Int J Radiat Oncol Biol Phys 82.5 (April 1, 2012): 2018-2024.
PMID
21489708
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
5
Publish Date
2012
Start Page
2018
End Page
2024
DOI
10.1016/j.ijrobp.2010.12.074

A change in the apparent diffusion coefficient after treatment with bevacizumab is associated with decreased survival in patients with recurrent glioblastoma multiforme.

OBJECTIVES: The aim of this study was to determine the prognostic significance of changes in parameters derived from diffusion tensor imaging (DTI) that occur in response to treatment with bevacizumab and irinotecan in patients with recurrent glioblastoma multiforme. METHODS: 15 patients with recurrent glioblastoma multiforme underwent serial 1.5 T MRI. Axial single-shot echo planar DTI was obtained on scans performed 3 days and 1 day prior to and 6 weeks after initiation of therapy with bevacizumab and irinotecan. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were registered to whole brain contrast-enhanced three-dimensional (3D) spoiled gradient recalled and 3D fluid attenuation inversion recovery (FLAIR) image volumes. Anatomic image volumes were segmented to isolate regions of interest defined by tumour-related enhancement (TRE) and FLAIR signal abnormality (FSA). Mean ADC and mean FA were calculated for each region. A Bland-Altman repeatability coefficient was also calculated for each parameter based on the two pre-treatment studies. A patient was considered to have a change in FA or ADC after therapy if the difference between the pre- and post-treatment values was greater than the repeatability coefficient for that parameter. Survival was compared using a Cox proportional hazard model. RESULTS: DTI detected a change in ADC within FSA after therapy in nine patients (five in whom ADC was increased; four in whom it was decreased). Patients with a change in ADC within FSA had significantly shorter overall survival (p=0.032) and progression free survival (p=0.046) than those with no change. CONCLUSION: In patients with recurrent glioblastoma multiforme treated with bevacizumab and irinotecan, a change in ADC after therapy in FSA is associated with decreased survival.

Authors
Paldino, MJ; Desjardins, A; Friedman, HS; Vredenburgh, JJ; Barboriak, DP
MLA Citation
Paldino, MJ, Desjardins, A, Friedman, HS, Vredenburgh, JJ, and Barboriak, DP. "A change in the apparent diffusion coefficient after treatment with bevacizumab is associated with decreased survival in patients with recurrent glioblastoma multiforme." Br J Radiol 85.1012 (April 2012): 382-389.
PMID
21224297
Source
pubmed
Published In
British Journal of Radiology
Volume
85
Issue
1012
Publish Date
2012
Start Page
382
End Page
389
DOI
10.1259/bjr/24774491

Bevacizumab and daily temozolomide for recurrent glioblastoma.

BACKGROUND: The authors performed a phase 2 trial of combined protracted daily temozolomide and biweekly bevacizumab for patients with recurrent glioblastoma who had previously received radiation therapy and temozolomide. METHODS: There was no limit on the number of previous disease progressions or previous regimens allowed. Thirty-two adult patients were enrolled. Patients received temozolomide 50 mg/m(2) daily and bevacizumab 10 mg/kg intravenously every 14 days. Patients underwent physical examination and brain magnetic resonance imaging every 8 weeks. RESULTS: The authors observed a 6-month progression-free survival (PFS) rate of 18.8% (95% confidence interval [CI], 7.6%-33.7%) and a median PFS of 15.8 weeks. The median overall survival (OS) was 37 weeks, the 6-month OS rate was 62.5% (95% CI, 43.5%-76.7%), and the 12-month OS rate was 31.3% (95% CI, 16.4%-47.3%). Nine patients (28%) had a radiographic response, and 7 patients (22%) had disease progression within the first 8 weeks of treatment. Patterns of progression were available for 21 patients. The authors observed that 52% of patients (n = 11) progressed locally, 38% (n = 8) progressed with a diffuse pattern, and 10% (n = 2) progressed at a distant site. Two patients discontinued therapy secondary to toxicity (prolonged thrombocytopenia and grade 4 pancreatitis). One patient experienced grade 5 pneumonia. CONCLUSIONS: The current study demonstrated that a regimen of combined daily temozolomide and biweekly bevacizumab had some activity and was well tolerated. However, the results obtained in this study were inferior to those observed in studies of bevacizumab monotherapy and of combined irinotecan and bevacizumab therapy. The current patient population was more heterogeneous and was pretreated more heavily than patients in previous studies.

Authors
Desjardins, A; Reardon, DA; Coan, A; Marcello, J; Herndon, JE; Bailey, L; Peters, KB; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, A, Reardon, DA, Coan, A, Marcello, J, Herndon, JE, Bailey, L, Peters, KB, Friedman, HS, and Vredenburgh, JJ. "Bevacizumab and daily temozolomide for recurrent glioblastoma." Cancer 118.5 (March 1, 2012): 1302-1312.
PMID
21792866
Source
pubmed
Published In
Cancer
Volume
118
Issue
5
Publish Date
2012
Start Page
1302
End Page
1312
DOI
10.1002/cncr.26381

Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma.

We evaluated the efficacy of carboplatin, irinotecan, and bevacizumab among bevacizumab-naïve, recurrent glioblastoma (GBM) patients in a phase 2, open-label, single arm trial. Forty eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day one, while bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A-enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first two cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, non-compliance, or voluntary withdrawal. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints included safety and median overall survival (OS). All patients had progression after standard therapy. The median age was 51 years. Sixteen patients (40%) had a KPS of 90-100, while 27 (68%) were at first progression. The median time from original diagnosis was 11.4 months. The PFS-6 rate was 46.5% (95% CI: 30.4, 61.0%) and the median OS was 8.3 months [95% confidence interval (CI): 5.9, and 10.7 months]. Grade 4 events were primarily hematologic and included neutropenia and thrombocytopenia in 20 and 10%, respectively. The most common grade 3 events were neutropenia, thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively. Eleven patients (28%) discontinued study therapy due to toxicity and 17 patients (43%) required dose modification. One patient died due to treatment-related intestinal perforation. The addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naïve, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).

Authors
Reardon, DA; Desjardins, A; Peters, KB; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Bulusu, A; Threatt, S; Friedman, AH; Vredenburgh, JJ; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Peters, KB, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Bulusu, A, Threatt, S, Friedman, AH, Vredenburgh, JJ, and Friedman, HS. "Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma." J Neurooncol 107.1 (March 2012): 155-164.
PMID
21986722
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
107
Issue
1
Publish Date
2012
Start Page
155
End Page
164
DOI
10.1007/s11060-011-0722-2

Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme.

PURPOSE: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m(2) daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively. RESULTS: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study. CONCLUSIONS: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.

Authors
Vredenburgh, JJ; Desjardins, A; Kirkpatrick, JP; Reardon, DA; Peters, KB; Herndon, JE; Marcello, J; Bailey, L; Threatt, S; Sampson, J; Friedman, A; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Kirkpatrick, JP, Reardon, DA, Peters, KB, Herndon, JE, Marcello, J, Bailey, L, Threatt, S, Sampson, J, Friedman, A, and Friedman, HS. "Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme." Int J Radiat Oncol Biol Phys 82.1 (January 1, 2012): 58-66.
PMID
21036490
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
1
Publish Date
2012
Start Page
58
End Page
66
DOI
10.1016/j.ijrobp.2010.08.058

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma.

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.

Authors
Reardon, DA; Norden, AD; Desjardins, A; Vredenburgh, JJ; Herndon, JE; Coan, A; Sampson, JH; Gururangan, S; Peters, KB; McLendon, RE; Norfleet, JA; Lipp, ES; Drappatz, J; Wen, PY; Friedman, HS
MLA Citation
Reardon, DA, Norden, AD, Desjardins, A, Vredenburgh, JJ, Herndon, JE, Coan, A, Sampson, JH, Gururangan, S, Peters, KB, McLendon, RE, Norfleet, JA, Lipp, ES, Drappatz, J, Wen, PY, and Friedman, HS. "Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma." J Neurooncol 106.2 (January 2012): 409-415.
PMID
21938530
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
106
Issue
2
Publish Date
2012
Start Page
409
End Page
415
DOI
10.1007/s11060-011-0687-1

A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.

BACKGROUND: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells. OBJECTIVE: To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses. METHODOLOGY: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). RESULTS AND CONCLUSIONS: Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626015.

Authors
Sampson, JH; Schmittling, RJ; Archer, GE; Congdon, KL; Nair, SK; Reap, EA; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Mitchell, DA
MLA Citation
Sampson, JH, Schmittling, RJ, Archer, GE, Congdon, KL, Nair, SK, Reap, EA, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, Coan, A, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Mitchell, DA. "A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma." PLoS One 7.2 (2012): e31046-.
PMID
22383993
Source
pubmed
Published In
PloS one
Volume
7
Issue
2
Publish Date
2012
Start Page
e31046
DOI
10.1371/journal.pone.0031046

Adjuvant PCV chemo hikes oligodendroglioma survival: Commentary

Authors
Friedman, HS; Desjardins, A
MLA Citation
Friedman, HS, and Desjardins, A. "Adjuvant PCV chemo hikes oligodendroglioma survival: Commentary." Oncology Report JULY (2012): 6--.
Source
scival
Published In
Oncology Report
Issue
JULY
Publish Date
2012
Start Page
6-

Neuro-oncology: Glioblastoma-community adjusts to new standard of care

Recent analysis of treatment patterns and survival of newly diagnosed patients with glioblastoma in community settings in the USA has shown that the medical community rapidly adjusted to the new standard of treatment the so-called 'Stupp regimen'. The findings are encouraging, but further research is needed to improve patient survival. © 2012 Macmillan Publishers Limited. All rights reserved.

Authors
Desjardins, A; Friedman, HS
MLA Citation
Desjardins, A, and Friedman, HS. "Neuro-oncology: Glioblastoma-community adjusts to new standard of care." Nature Reviews Neurology 8.5 (2012): 244-246.
PMID
22430106
Source
scival
Published In
Nature Reviews Neurology
Volume
8
Issue
5
Publish Date
2012
Start Page
244
End Page
246
DOI
10.1038/nrneurol.2012.42

A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression

This phase II trial was undertaken to evaluate the efficacy of TLN-4601 in patients with glioblastoma (GBM) at first progression. TLN-4601 inhibits the RasMAPK signaling pathway, and in animal models crosses the blood-brain barrier and accumulates in implanted gliomas, possibly by binding specifically to the peripheral benzodiazepine receptor. A maximum of 40 patients with recurrent GBM were to be enrolled in this study. TLN4601 was administered at a dose of 480 mg/m2/day by continuous intravenous (CIV) administration. Each 21-day cycle consisted of a 14-day CIV administration and a 7-day recovery period. Samples were obtained from all patients for pharmacokinetic evaluations (PK) and for Raf1 and pERK biomarker assessment using immunohistochemistry and flow cytometry. Following enrollment of 20 patients, this study was terminated due to a lack of efficacy. Of 17 evaluable patients, 14 had MR scans performed after two cycles of TLN-4601. Of these 14 patients, three had stable disease and 11 had disease progression. Only three patients had MR scans performed after four cycles and all had evidence of radiographic progression. Serum PKs confirmed that patients were exposed to TLN-4601 at targeted drug levels. TLN-4601 was generally well tolerated although two patients discontinued treatment due to adverse events. Biomarker analysis did not show consistent changes. TLN-4601 infused via CIV at 480 mg/m2/day for 14 of 21 days is well tolerated by patients with progressive GBM. However, this agent is ineffective in progressive GBM when administered as monotherapy in this schedule. © Springer Science+Business Media, LLC. 2011.

Authors
Mason, WP; Belanger, K; Nicholas, G; Vallières, I; Mathieu, D; Kavan, P; Desjardins, A; Omuro, A; Reymond, D
MLA Citation
Mason, WP, Belanger, K, Nicholas, G, Vallières, I, Mathieu, D, Kavan, P, Desjardins, A, Omuro, A, and Reymond, D. "A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression." Journal of Neuro-Oncology 107.2 (2012): 343-349.
PMID
22048878
Source
scival
Published In
Journal of Neuro-Oncology
Volume
107
Issue
2
Publish Date
2012
Start Page
343
End Page
349
DOI
10.1007/s11060-011-0747-6

Outcome after bevacizumab clinical trial therapy among recurrent grade III malignant glioma patients

Although outcome following bevacizumab among recurrent grade IV malignant glioma patients is documented as poor by several analyses, outcome for recurrent grade III patients following bevacizumab therapy has not been specifically evaluated. We performed a pooled analysis of 96 recurrent grade III malignant glioma patients enrolled on three consecutive phase II bevacizumab salvage trials to evaluate overall outcome following bevacizumab trial discontinuation. Outcome on the three bevacizumab trials, which included similar eligibility, treatment and assessment criteria, was comparable. Fortynine patients who progressed on bevacizumab trial therapy and remained alive for at least 30 days elected to receive additional therapy. These patients achieved a median PFS- 6 and OS of 30.6% (95% CI: 18.4, 43.6) and 10.3 months (95% CI: 5.2, 11.7), respectively. Among patients who continued bevacizumab therapy (n = 23) after study progression, PFS-6 and median OS were 39.1% (95% CI: 19.9, 58.0) and 9.2 months (95% CI: 5.2, 13.6), respectively, compared to 23.1% (95% CI: 9.4, 40.3; P = 0.51) and 10.3 months (95% CI: 2.5, 14.4; P = 0.91) for patients who initiated non-bevacizumab containing therapy (n = 26). Outcome after discontinuation of bevacizumab therapy for recurrent grade III malignant glioma patients is associated with improved outcome compared to historical data for recurrent grade IV malignant glioma patients. Salvage therapies following bevacizumab failure have modest activity for grade III malignant glioma patients that is independent of further bevacizumab continuation. © Springer Science+Business Media, LLC. 2011.

Authors
Reardon, DA; Ii, JEH; Peters, K; Desjardins, A; Coan, A; Lou, E; Sumrall, A; Turner, S; Sathornsumetee, S; Rich, JN; Boulton, S; Lipp, ES; Friedman, HS; Vredenburgh, JJ
MLA Citation
Reardon, DA, Ii, JEH, Peters, K, Desjardins, A, Coan, A, Lou, E, Sumrall, A, Turner, S, Sathornsumetee, S, Rich, JN, Boulton, S, Lipp, ES, Friedman, HS, and Vredenburgh, JJ. "Outcome after bevacizumab clinical trial therapy among recurrent grade III malignant glioma patients." Journal of Neuro-Oncology 107.1 (2012): 213-221.
PMID
21997879
Source
scival
Published In
Journal of Neuro-Oncology
Volume
107
Issue
1
Publish Date
2012
Start Page
213
End Page
221
DOI
10.1007/s11060-011-0740-0

Avastin: More questions than answers...

Authors
Desjardins, A; Sampson, JH
MLA Citation
Desjardins, A, and Sampson, JH. "Avastin: More questions than answers.." Journal of Neurosurgery 116.2 (2012): 336-339.
PMID
22035270
Source
scival
Published In
Journal of neurosurgery
Volume
116
Issue
2
Publish Date
2012
Start Page
336
End Page
339
DOI
10.3171/2011.8.JNS111107

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy.

BACKGROUND: The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open-label, single-arm trial was evaluated. METHODS: Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression-free survival at 6 months (PFS-6), and secondary end points included safety and median overall survival (OS). RESULTS: All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0-7.0 months) and PFS-6 rate was 16% (95% CI, 5.0%-32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment-related deaths. CONCLUSIONS: Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously.

Authors
Reardon, DA; Desjardins, A; Peters, KB; Vredenburgh, JJ; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Coan, A; Threatt, S; Friedman, AH; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Peters, KB, Vredenburgh, JJ, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Coan, A, Threatt, S, Friedman, AH, and Friedman, HS. "Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy." Cancer 117.23 (December 1, 2011): 5351-5358.
PMID
21590689
Source
pubmed
Published In
Cancer
Volume
117
Issue
23
Publish Date
2011
Start Page
5351
End Page
5358
DOI
10.1002/cncr.26188

Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma.

We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, sunitinib, when administered with irinotecan among recurrent malignant glioma (MG) patients. For each 42-day cycle, sunitinib was administered once a day for four consecutive weeks followed by a 2 week rest. Irinotecan was administered intravenously every other week. Each agent was alternatively escalated among cohorts of 3-6 patients enrolled at each dose level. Patients on CYP3A-inducing anti-epileptic drugs were not eligible. Twenty-five patients with recurrent MG were enrolled, including 15 (60%) with glioblastoma (GBM) and 10 (40%) with grade 3 MG. Five patients progressed previously on bevacizumab and two had received prior VEGFR tyrosine kinase inhibitor therapy. The MTD was 50 mg of sunitinib combined with 75 mg/m(2) of irinotecan. DLT were primarily hematologic and included grade 4 neutropenia in 3 patients and one patient with grade 4 thrombocytopenia. Non-hematologic DLT included grade 3 mucositis (n = 1) and grade 3 dehydration (n = 1). Progression-free survival (PFS)-6 was 24% and only one patient achieved a radiographic response. The combination of sunitinib and irinotecan was associated with moderate toxicity and limited anti-tumor activity. Further studies with this regimen using the dosing schedules evaluated in this study are not warranted.

Authors
Reardon, DA; Vredenburgh, JJ; Coan, A; Desjardins, A; Peters, KB; Gururangan, S; Sathornsumetee, S; Rich, JN; Herndon, JE; Friedman, HS
MLA Citation
Reardon, DA, Vredenburgh, JJ, Coan, A, Desjardins, A, Peters, KB, Gururangan, S, Sathornsumetee, S, Rich, JN, Herndon, JE, and Friedman, HS. "Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma." J Neurooncol 105.3 (December 2011): 621-627.
PMID
21744079
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
105
Issue
3
Publish Date
2011
Start Page
621
End Page
627
DOI
10.1007/s11060-011-0631-4

A phase I trial of the farnesyl transferase inhibitor, SCH 66336, with temozolomide for patients with malignant glioma.

We conducted a phase I clinical trial of the combination of SCH 66336 with temozolomide administered on the standard 5-day dosing schedule. The primary objective was to determine the maximum tolerated dose and dose limiting toxicity (DLT) of twice daily SCH 66336 when administered with temozolomide to adults with malignant glioma previously treated with radiation therapy. Patients were enrolled to two strata: stratum A, patients not on enzyme-inducing antiepileptic drugs (EIAEDs); stratum B, patients receiving EIAEDs. Temozolomide was administered at a dose of 150 mg/m(2) daily for five days for the first 28-day cycle and escalated to 200 mg/m(2), during subsequent cycles. SCH 66336 was administered twice daily on a continuous daily dosing schedule. The starting dose of SCH 66336 was 75 mg twice daily for stratum A and 125 mg twice daily for stratum B. Cohorts of 3-6 patients were treated per dose level until DLT was observed. Thirty six patients were enrolled on study, including 21 patients on stratum A and 15 on stratum B. All DLTs were grade 3 events and included hepatic, gastrointestinal, renal, thrombotic and constitutional events. No grade 4 or 5 toxicities were observed. The phase II dose of SCH 66336 when combined with temozolomide is 150 mg twice daily for patients not on EIAEDs and 175 mg twice daily for patients on EIAEDs.

Authors
Desjardins, A; Reardon, DA; Peters, KB; Threatt, S; Coan, AD; Herndon, JE; Friedman, AH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, A, Reardon, DA, Peters, KB, Threatt, S, Coan, AD, Herndon, JE, Friedman, AH, Friedman, HS, and Vredenburgh, JJ. "A phase I trial of the farnesyl transferase inhibitor, SCH 66336, with temozolomide for patients with malignant glioma." J Neurooncol 105.3 (December 2011): 601-606.
PMID
21735117
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
105
Issue
3
Publish Date
2011
Start Page
601
End Page
606
DOI
10.1007/s11060-011-0627-0

Bevacizumab-induced reversible posterior leukoencephalopathy syndrome and successful retreatment in a patient with glioblastoma.

Authors
Lou, E; Turner, S; Sumrall, A; Reardon, DA; Desjardins, A; Peters, KB; Sampson, JH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Lou, E, Turner, S, Sumrall, A, Reardon, DA, Desjardins, A, Peters, KB, Sampson, JH, Friedman, HS, and Vredenburgh, JJ. "Bevacizumab-induced reversible posterior leukoencephalopathy syndrome and successful retreatment in a patient with glioblastoma." J Clin Oncol 29.28 (October 1, 2011): e739-e742.
PMID
21900098
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
28
Publish Date
2011
Start Page
e739
End Page
e742
DOI
10.1200/JCO.2011.36.1865

Everolimus tablets for patients with subependymal giant cell astrocytoma.

INTRODUCTION: Better understanding of aberrantly active molecular pathways in tumors offers potential to develop more specific and less toxic therapies. Abnormal mammalian target of rapamycin (mTOR) complex signaling and defects in TSC1 and TSC2 have been associated with the development of subependymal giant cell astrocytomas (SEGAs) in tuberous sclerosis complex (TSC) patients. Recently, mTOR inhibitors such as everolimus have shown encouraging benefit for patients with SEGAs. AREAS COVERED: The authors discuss a molecular genetic pathway linked with TSC, specifically the role of two proteins whose functional absence is responsible for most SEGA tumors that arise in TSC patients. The authors also examine the rationale for targeted agents against this pathway therapeutically and describe the clinical evidence underlying the FDA approval of everolimus for patients with inoperable SEGAs. EXPERT OPINION: Everolimus (Afinitor) selectively targets a molecular defect of SEGAs in TSC patients. Although surgery is effective, most SEGAs recur. An agent that inhibits an underlying molecular abnormality represents a particularly attractive therapeutic option for patients with inoperable or recurrent tumors. Studies are also underway to assess everolimus in treating other sequelae of TSC, and other gliomas. Finally, additional research aimed at better understanding aberrant cell signaling pathways may lead to the development of more effective therapeutics.

Authors
Turner, SG; Peters, KB; Vredenburgh, JJ; Desjardins, A; Friedman, HS; Reardon, DA
MLA Citation
Turner, SG, Peters, KB, Vredenburgh, JJ, Desjardins, A, Friedman, HS, and Reardon, DA. "Everolimus tablets for patients with subependymal giant cell astrocytoma." Expert Opin Pharmacother 12.14 (October 2011): 2265-2269. (Review)
PMID
21806479
Source
pubmed
Published In
Expert Opinion on Pharmacotherapy
Volume
12
Issue
14
Publish Date
2011
Start Page
2265
End Page
2269
DOI
10.1517/14656566.2011.601742

Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans.

Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (T(Regs); P = .0006). Monoclonal antibody (mAb)-mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted T(Regs) (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased T(Regs) (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti-IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced T(Reg) frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated T(Reg) depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti-IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.

Authors
Mitchell, DA; Cui, X; Schmittling, RJ; Sanchez-Perez, L; Snyder, DJ; Congdon, KL; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Cui, X, Schmittling, RJ, Sanchez-Perez, L, Snyder, DJ, Congdon, KL, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans." Blood 118.11 (September 2011): 3003-3012.
PMID
21768296
Source
epmc
Published In
Blood
Volume
118
Issue
11
Publish Date
2011
Start Page
3003
End Page
3012
DOI
10.1182/blood-2011-02-334565

Exercise behavior, functional capacity, and survival in adults with malignant recurrent glioma.

PURPOSE: Identifying strong markers of prognosis are critical to optimize treatment and survival outcomes in patients with malignant recurrent glioma. We investigated the prognostic significance of exercise behavior and functional capacity in this population. PATIENTS AND METHODS: Using a prospective design, 243 patients with WHO grades 3 to 4 recurrent malignant glioma and Karnofsky performance status (KPS) ≥ 70 completed a self-administered questionnaire that assessed exercise behavior and performed a 6-minute walk test (6MWT) to assess functional capacity. Cox proportional models were used to estimate the risk of all-cause mortality according to 6MWT distance (6MWD; < 390 meters, 390-489 meters, > 489 meters) and exercise behavior (metabolic equivalent [MET] -h/wk) adjusted for KPS and other important clinical factors. RESULTS: Median follow-up was 27.43 months. During this period, 149 deaths were recorded (61% of the total sample). Exercise behavior was an independent predictor of survival (P = .0081). Median survival was 13.03 months for patients reporting < 9 MET-h/wk relative to 21.84 months for those reporting ≥ 9 MET-h/wk. Exercise behavior added incremental prognostic value beyond that provided by KPS, age, sex, grade, and number of prior progressions (P < .001). Compared with patients reporting < 9 MET-h/wk, the adjusted hazard ratio for mortality was 0.64 (95% CI, 0.46 to 0.91) for patients reporting ≥ 9 MET-h/wk. Functional capacity was not an independent predictor of prognosis. CONCLUSION: Exercise behavior is a strong independent predictor of survival that provides incremental prognostic value to KPS as well as traditional markers of prognosis in malignant recurrent glioma.

Authors
Ruden, E; Reardon, DA; Coan, AD; Herndon, JE; Hornsby, WE; West, M; Fels, DR; Desjardins, A; Vredenburgh, JJ; Waner, E; Friedman, AH; Friedman, HS; Peters, KB; Jones, LW
MLA Citation
Ruden, E, Reardon, DA, Coan, AD, Herndon, JE, Hornsby, WE, West, M, Fels, DR, Desjardins, A, Vredenburgh, JJ, Waner, E, Friedman, AH, Friedman, HS, Peters, KB, and Jones, LW. "Exercise behavior, functional capacity, and survival in adults with malignant recurrent glioma." J Clin Oncol 29.21 (July 20, 2011): 2918-2923.
PMID
21690470
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
21
Publish Date
2011
Start Page
2918
End Page
2923
DOI
10.1200/JCO.2011.34.9852

The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma.

PURPOSE: To determine if the addition of bevacizumab to radiation therapy and temozolomide, followed by bevacizumab, temozolomide, and irinotecan, for newly diagnosed glioblastoma patients is safe and effective. EXPERIMENTAL DESIGN: A total of 75 patients with newly diagnosed glioblastoma were enrolled in the phase II trial that investigated the addition of bevacizumab to standard radiation therapy and daily temozolomide followed by the addition of bevacizumab and irinotecan to adjuvant temozolomide. The bevacizumab was given at 10 mg/kg every 14 days beginning a minimum of 4 weeks postcraniotomy. Two weeks after radiation therapy, the patients began 6 to 12 cycles of 5-day temozolomide with bevacizumab and irinotecan every 14 days. The primary endpoint was the proportion of patients alive 16 months after informed consent. RESULTS: The therapy had moderate toxicity. Three patients, one of whom had a grade 2 central nervous system hemorrhage, came off study during radiation therapy. Seventy patients started the postradiation therapy, and 16 (23%) terminated this adjuvant therapy early because of toxicity. The median overall survival was 21.2 months (95% CI: 17.2-25.4), and 65% of the patients were alive at 16 months (95% CI: 53.4-74.9). The median progression-free survival was 14.2 months (95% CI: 12-16). CONCLUSION: The addition of bevacizumab to standard radiation therapy and temozolomide, followed by bevacizumab, irinotecan, and temozolomide, for the treatment of newly diagnosed glioblastoma has moderate toxicity and may improve efficacy compared with historical controls. The results from phase III trials are required before the role of bevacizumab for newly diagnosed glioblastoma is established.

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, KB; Herndon, JE; Marcello, J; Kirkpatrick, JP; Sampson, JH; Bailey, L; Threatt, S; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Reardon, DA, Peters, KB, Herndon, JE, Marcello, J, Kirkpatrick, JP, Sampson, JH, Bailey, L, Threatt, S, Friedman, AH, Bigner, DD, and Friedman, HS. "The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma." Clin Cancer Res 17.12 (June 15, 2011): 4119-4124.
PMID
21531816
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
12
Publish Date
2011
Start Page
4119
End Page
4124
DOI
10.1158/1078-0432.CCR-11-0120

Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy.

We evaluated the efficacy of metronomic etoposide or temozolomide administered with bevacizumab among recurrent glioblastoma (GBM) patients who progressed on prior bevacizumab therapy in a phase 2, open-label, two-arm trial. Twenty-three patients received bevacizumab (10 mg/kg) every 2 weeks with either oral etoposide (50 mg/m2) daily for 21 consecutive days each month or daily temozolomide (50 mg/m2). The primary endpoint was 6-month progression-free survival (PFS-6) and secondary endpoints included safety and overall survival. Both the etoposide and temozolomide arms of the study closed at the interim analysis due to lack of adequate anti-tumor activity. No radiographic responses were observed. Although 12 patients (52%) achieved stable disease, PFS-6 was 4.4% and the median PFS was 7.3 weeks. The only grade 4 adverse event was reversible neutropenia. Grade 3 toxicities included fatigue (n = 2) and infection (n = 1). Metronomic etoposide or temozolomide is ineffective when administered with bevacizumab among recurrent GBM patients who have progressed on prior bevacizumab therapy. Alternative treatment strategies remain critically needed for this indication.

Authors
Reardon, DA; Desjardins, A; Peters, K; Gururangan, S; Sampson, J; Rich, JN; McLendon, R; Herndon, JE; Marcello, J; Threatt, S; Friedman, AH; Vredenburgh, JJ; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Peters, K, Gururangan, S, Sampson, J, Rich, JN, McLendon, R, Herndon, JE, Marcello, J, Threatt, S, Friedman, AH, Vredenburgh, JJ, and Friedman, HS. "Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy." J Neurooncol 103.2 (June 2011): 371-379.
PMID
20853132
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
103
Issue
2
Publish Date
2011
Start Page
371
End Page
379
DOI
10.1007/s11060-010-0403-6

A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma.

Glioblastoma, the most common primary malignant brain tumor among adults, is a highly angiogenic and deadly tumor. Angiogenesis in glioblastoma, driven by hypoxia-dependent and independent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encouraging rates of radiographic response and progression-free survival, and adequate safety, led the FDA to grant accelerated approval of bevacizumab, a humanized monoclonal antibody against VEGF, for the treatment of recurrent glioblastoma in May 2009. These results have triggered significant interest in additional antiangiogenic agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antipermeability effect of VEGF inhibitors, the Radiologic Assessment in Neuro-Oncology (RANO) criteria were recently implemented to better assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mechanisms to VEGF inhibitors and identification of effective therapy after bevacizumab progression are currently a critical need for patients with glioblastoma.

Authors
Reardon, DA; Turner, S; Peters, KB; Desjardins, A; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Jones, LW; Kirkpatrick, JP; Friedman, AH; Vredenburgh, JJ; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Turner, S, Peters, KB, Desjardins, A, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Jones, LW, Kirkpatrick, JP, Friedman, AH, Vredenburgh, JJ, Bigner, DD, and Friedman, HS. "A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma." J Natl Compr Canc Netw 9.4 (April 2011): 414-427. (Review)
PMID
21464146
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
4
Publish Date
2011
Start Page
414
End Page
427

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma.

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

Authors
Sampson, JH; Aldape, KD; Archer, GE; Coan, A; Desjardins, A; Friedman, AH; Friedman, HS; Gilbert, MR; Herndon, JE; McLendon, RE; Mitchell, DA; Reardon, DA; Sawaya, R; Schmittling, R; Shi, W; Vredenburgh, JJ; Bigner, DD; Heimberger, AB
MLA Citation
Sampson, JH, Aldape, KD, Archer, GE, Coan, A, Desjardins, A, Friedman, AH, Friedman, HS, Gilbert, MR, Herndon, JE, McLendon, RE, Mitchell, DA, Reardon, DA, Sawaya, R, Schmittling, R, Shi, W, Vredenburgh, JJ, Bigner, DD, and Heimberger, AB. "Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma." Neuro Oncol 13.3 (March 2011): 324-333.
PMID
21149254
Source
pubmed
Published In
Neuro-Oncology
Volume
13
Issue
3
Publish Date
2011
Start Page
324
End Page
333
DOI
10.1093/neuonc/noq157

Primary intracerebral Hodgkin lymphoma with recurrence.

OBJECTIVE: To report a case of primary intracerebral Hodgkin lymphoma with disease recurrence. METHODS: Case report and review of the literature. RESULTS: A 58-year-old immunocompetent male presented with aphasia. Neuroimaging revealed a left temporal lobe lesion. A craniotomy and resection were performed, and the diagnosis of classical Hodgkin lymphoma was made. Systemic work-up for lymphoma was negative. Postoperatively, the patient was treated with whole brain irradiation. 14 months later, the patient developed an enhancing lesion in his pons and received combination chemotherapy and radiation therapy. Repeat imaging demonstrated leptomeningeal enhancement and multiple lesions throughout the cerebral hemispheres, cerebellum and brainstem. COMMENT: We report what appears to be the first case of a patient with aggressive primary intracerebral Hodgkin lymphoma with disease recurrence.

Authors
Foo, W-C; Desjardins, A; Cummings, TJ
MLA Citation
Foo, W-C, Desjardins, A, and Cummings, TJ. "Primary intracerebral Hodgkin lymphoma with recurrence." Clin Neuropathol 30.2 (March 2011): 75-79.
PMID
21329616
Source
pubmed
Published In
Clinical neuropathology
Volume
30
Issue
2
Publish Date
2011
Start Page
75
End Page
79

A novel method for volumetric MRI response assessment of enhancing brain tumors.

Current radiographic response criteria for brain tumors have difficulty describing changes surrounding postoperative resection cavities. Volumetric techniques may offer improved assessment, however usually are time-consuming, subjective and require expert opinion and specialized magnetic resonance imaging (MRI) sequences. We describe the application of a novel volumetric software algorithm that is nearly fully automated and uses standard T1 pre- and post-contrast MRI sequences. T1-weighted pre- and post-contrast images are automatically fused and normalized. The tumor region of interest is grossly outlined by the user. An atlas of the nasal mucosa is automatically detected and used to normalize levels of enhancement. The volume of enhancing tumor is then automatically calculated. We tested the ability of our method to calculate enhancing tumor volume with resection cavity collapse and when the enhancing tumor is obscured by subacute blood in a resection cavity. To determine variability in results, we compared narrowly-defined tumor regions with tumor regions that include adjacent meningeal enhancement and also compared different contrast enhancement threshold levels used for the automatic calculation of enhancing tumor volume. Our method quantified enhancing tumor volume despite resection cavity collapse. It detected tumor volume increase in the midst of blood products that incorrectly caused decreased measurements by other techniques. Similar trends in volume changes across scans were seen with inclusion or exclusion of meningeal enhancement and despite different automated thresholds for tissue enhancement. Our approach appears to overcome many of the challenges with response assessment of enhancing brain tumors and warrants further examination and validation.

Authors
Kanaly, CW; Ding, D; Mehta, AI; Waller, AF; Crocker, I; Desjardins, A; Reardon, DA; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Kanaly, CW, Ding, D, Mehta, AI, Waller, AF, Crocker, I, Desjardins, A, Reardon, DA, Friedman, AH, Bigner, DD, and Sampson, JH. "A novel method for volumetric MRI response assessment of enhancing brain tumors. (Published online)" PLoS One 6.1 (January 26, 2011): e16031-.
PMID
21298088
Source
pubmed
Published In
PloS one
Volume
6
Issue
1
Publish Date
2011
Start Page
e16031
DOI
10.1371/journal.pone.0016031

Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma.

Sorafenib, an oral VEGFR-2, Raf, PDGFR, c-KIT and Flt-3 inhibitor, is active against renal cell and hepatocellular carcinomas, and has recently demonstrated promising activity for lung and breast cancers. In addition, various protracted temozolomide dosing schedules have been evaluated as a strategy to further enhance its anti-tumor activity. We reasoned that sorafenib and protracted, daily temozolomide may provide complementary therapeutic benefit, and therefore performed a phase 2 trial among recurrent glioblastoma patients. Adult glioblastoma patients at any recurrence after standard temozolomide chemoradiotherapy received sorafenib (400 mg twice daily) and continuous daily temozolomide (50 mg/m²/day). Assessments were performed every eight weeks. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary end points were radiographic response, overall survival (OS), safety and sorafenib pharmacokinetics. Of 32 enrolled patients, 12 (38%) were on CYP3-A inducing anti-epileptics (EIAEDs), 17 (53%) had 2 or more prior progressions, 15 had progressed while receiving 5-day temozolomide, and 12 (38%) had failed either prior bevacizumab or VEGFR inhibitor therapy. The most common grade ≥ 3 toxicities were palmer-planter erythrodysesthesia (19%) and elevated amylase/lipase (13%). Sorafenib pharmacokinetic exposures were comparable on day 1 regardless of EIAED status, but significantly lower on day 28 for patients on EIAEDs (P = 0.0431). With a median follow-up of 93 weeks, PFS-6 was 9.4%. Only one patient (3%) achieved a partial response. In conclusion, sorafenib can be safely administered with daily temozolomide, but this regimen has limited activity for recurrent GBM. Co-administration of EIAEDs can lower sorafenib exposures in this population.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, K; Gururangan, S; Sampson, JH; Marcello, J; Herndon, JE; McLendon, RE; Janney, D; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Vredenburgh, JJ, Desjardins, A, Peters, K, Gururangan, S, Sampson, JH, Marcello, J, Herndon, JE, McLendon, RE, Janney, D, Friedman, AH, Bigner, DD, and Friedman, HS. "Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma." J Neurooncol 101.1 (January 2011): 57-66.
PMID
20443129
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
101
Issue
1
Publish Date
2011
Start Page
57
End Page
66
DOI
10.1007/s11060-010-0217-6

Ulceration of Striae distensae in high-grade glioma patients on concurrent systemic corticosteroid and bevacizumab therapy.

Striae distensae (stretch marks) are a common complication seen in patients on chronic corticosteroid therapy. Under certain circumstances, primary brain tumor patients require chronic corticosteroid therapy and can suffer from striae distensae. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor-A (VEGF-A) is now more widely used for the treatment of primary brain tumors. In this paper, we present four cases of ulcerated striae distensae in primary brain tumor patients on concurrent corticosteroid and bevacizumab therapy. Because of bevacizumab's effects on wound healing and its recent accelerated approval for recurrent glioblastoma multiforme (GBM), the most common malignant primary brain tumor in adults, this novel skin complication should be considered in patients on concurrent corticosteroid and bevacizumab therapy.

Authors
Peters, KB; Coyle, TE; Vredenburgh, JJ; Desjardins, A; Friedman, HS; Reardon, DA
MLA Citation
Peters, KB, Coyle, TE, Vredenburgh, JJ, Desjardins, A, Friedman, HS, and Reardon, DA. "Ulceration of Striae distensae in high-grade glioma patients on concurrent systemic corticosteroid and bevacizumab therapy." J Neurooncol 101.1 (January 2011): 155-159.
PMID
20524043
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
101
Issue
1
Publish Date
2011
Start Page
155
End Page
159
DOI
10.1007/s11060-010-0239-0

Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma.

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens.

Authors
Sathornsumetee, S; Desjardins, A; Vredenburgh, JJ; McLendon, RE; Marcello, J; Herndon, JE; Mathe, A; Hamilton, M; Rich, JN; Norfleet, JA; Gururangan, S; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, S, Desjardins, A, Vredenburgh, JJ, McLendon, RE, Marcello, J, Herndon, JE, Mathe, A, Hamilton, M, Rich, JN, Norfleet, JA, Gururangan, S, Friedman, HS, and Reardon, DA. "Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma." Neuro Oncol 12.12 (December 2010): 1300-1310.
PMID
20716591
Source
pubmed
Published In
Neuro-Oncology
Volume
12
Issue
12
Publish Date
2010
Start Page
1300
End Page
1310
DOI
10.1093/neuonc/noq099

Bevacizumab fails to treat temporal paraganglioma: discussion and case illustration.

Temporal paragangliomas are highly vascular tumors treated primarily by surgical resection. However, surgery to remove these tumors is associated with significant morbidity, including cranial nerve dysfunction. Interestingly, these tumors have been shown to express vascular endothelial growth factor (VEGF). A variety of tumors expressing VEGF and the VEGF receptor have been shown to reduce in size and vascularity when treated with the VEGF-specific antibody, bevacizumab (Avastin). We hypothesized that paragangliomas may be treated noninvasively with bevacizumab, either as a primary treatment or as a useful adjuvant to surgical resection or radiation. Thus, our aim was to evaluate the effects of bevacizumab on this patient's paraganglioma. A 36-year-old female presented to us with a 3 month history of positional dizziness, light-headedness, and left ear pulsatile tinnitus and hearing loss. She was found to have a temporal paraganglioma (glomus jugulare tumor) on imaging. Histopathology confirmed significant staining for VEGF. This patient was treated with bevacizumab prior to surgical treatment; radiographic imaging at 3 months, however, showed no significant response. We discuss possible reasons for treatment failure.

Authors
Aliabadi, H; Vredenburgh, JJ; Everson, RG; Desjardins, A; Friedman, HS; McLendon, RE; Tucci, DL; Sampson, JH
MLA Citation
Aliabadi, H, Vredenburgh, JJ, Everson, RG, Desjardins, A, Friedman, HS, McLendon, RE, Tucci, DL, and Sampson, JH. "Bevacizumab fails to treat temporal paraganglioma: discussion and case illustration." J Neurooncol 98.3 (July 2010): 427-430.
PMID
20020179
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
98
Issue
3
Publish Date
2010
Start Page
427
End Page
430
DOI
10.1007/s11060-009-0091-2

Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma.

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Friedman, AH; Herndon, JE; Marcello, J; Norfleet, JA; McLendon, RE; Sampson, JH; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Friedman, AH, Herndon, JE, Marcello, J, Norfleet, JA, McLendon, RE, Sampson, JH, and Friedman, HS. "Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma." J Neurooncol 96.2 (January 2010): 219-230.
PMID
19562254
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
96
Issue
2
Publish Date
2010
Start Page
219
End Page
230
DOI
10.1007/s11060-009-9950-0

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study.

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; Sathornsumetee, S; McLendon, RE; Herndon, JE; Marcello, JE; Norfleet, J; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Sampson, JH, Sathornsumetee, S, McLendon, RE, Herndon, JE, Marcello, JE, Norfleet, J, Friedman, AH, Bigner, DD, and Friedman, HS. "Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study." Br J Cancer 101.12 (December 15, 2009): 1986-1994.
PMID
19920819
Source
pubmed
Published In
British Journal of Cancer
Volume
101
Issue
12
Publish Date
2009
Start Page
1986
End Page
1994
DOI
10.1038/sj.bjc.6605412

Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy.

This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients were treated with a maximum of three 6-week cycles of TMZ and CPT-11. Patients received TMZ at a dose of 200 mg/m(2)/day on days 1-5 and CPT-11 on days 1, 8, 22, and 29, with a dose adjustment for enzyme-inducing antiepileptic drug use. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Of the 42 patients treated, 8 (19%) patients achieved a partial response. Median PFS and median OS were 3.1 and 13.8 months, respectively. Grade 3 or 4 AEs were documented in 36% of patients, most of which were hematologic (29%). Twenty-four percent of patients had grade 3 or 4 non-hematologic AEs, with gastrointestinal AEs being the most common (12%) Two patients died, one of intracranial hemorrhage and one of treatment-related renal failure. Low MGMT expression, compared with high MGMT expression, showed no significant difference in ORR (25 vs. 8%), median PFS (14 vs. 5 months) or OS (21 vs. 15 months). Although TMZ plus CPT-11 is at least comparable in efficacy to TMZ alone, this combination appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs further evaluation in subsequent trials.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Friedman, AH; Sampson, JH; McLendon, RE; Herndon, JE; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Friedman, AH, Sampson, JH, McLendon, RE, Herndon, JE, and Friedman, HS. "Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy." Journal of neuro-oncology 95.3 (December 2009): 393-400.
PMID
19533023
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
95
Issue
3
Publish Date
2009
Start Page
393
End Page
400
DOI
10.1007/s11060-009-9937-x

Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients.

The purpose of this study was to determine the safety of tinzaparin for deep vein thrombosis prophylaxis in newly diagnosed grade III-IV malignant glioma patients. Patients were initiated on daily tinzaparin at a fixed dose of 4,500 IU subcutaneously between 48 h and 4 weeks post-operative for planned duration of 12 months. During chemotherapy cycles, blood counts were monitored weekly and tinzaparin was held if the platelet count decreased to <50,000 and was re-initiated at a platelet count >100,000. Forty patients were enrolled into the study, 35 with glioblastoma multiforme and 5 with anaplastic astrocytoma. Possible attributable toxicity was limited to two patients who developed CNS hemorrhages (one grade 1 and one grade 2) and one patient with an increase in liver enzymes (grade 3). There were no patients with a grade 4 or 5 CNS hemorrhages or systemic hemorrhages >or=grade 2. The median time on prophylactic tinzaparin was 161 days (range of 5 to 601 days). One patient developed a deep venous thrombosis while taking tinzaparin, and three patients developed thromboembolic complications while off tinzaparin. Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients.

Authors
Perry, SL; Bohlin, C; Reardon, DA; Desjardins, A; Friedman, AH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Perry, SL, Bohlin, C, Reardon, DA, Desjardins, A, Friedman, AH, Friedman, HS, and Vredenburgh, JJ. "Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients." J Neurooncol 95.1 (October 2009): 129-134.
PMID
19415455
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
95
Issue
1
Publish Date
2009
Start Page
129
End Page
134
DOI
10.1007/s11060-009-9911-7

Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma.

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O(6)-benzylguanine (O(6)-BG). Both TMZ and O(6)-BG were administered on days 1-5 of a 28-day treatment cycle. A bolus infusion of O(6)-BG was administered at 120 mg/m(2) over 1 h on days 1, 3, and 5, along with a continuous infusion of O(6)-BG at 30 mg/m(2)/day. TMZ was administered at the end of the first bolus infusion of O(6)-BG and then every 24 h for 5 days during the continuous infusion of O(6)-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m(2) on day 1 and 50 mg/m(2)/day on days 2-5; schedule 2, 50 mg/m(2)/day on days 1-5; and schedule 3, 50 mg/m(2)/day on days 1-5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O(6)-BG was schedule 1. This study provides the foundation for a phase II trial of O(6)-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Walker, A, and Friedman, HS. "Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma." Neuro Oncol 11.5 (October 2009): 556-561.
PMID
19289491
Source
pubmed
Published In
Neuro-Oncology
Volume
11
Issue
5
Publish Date
2009
Start Page
556
End Page
561
DOI
10.1215/15228517-2009-007

Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy.

BACKGROUND: Glioblastoma multiforme (GBM), the most lethal type of brain tumor, has a 1-year median survival. The effect of carmustine wafers on the survival of newly diagnosed GBM patients treated with radiotherapy (RT) and concurrent temozolomide (TMZ) plus RT plus rotational chemotherapy was investigated. METHODS: An institutional review board-approved retrospective study was conducted in 85 newly diagnosed GBM patients who received surgical resection with and without carmustine wafers followed by RT and concurrent TMZ plus rotational chemotherapy. Treatment group comparisons were conducted using the log-rank test. Survival experience of the Duke cohort was examined within specific patient subgroups defined by the original Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA) class and compared with the European Organization for Research and Treatment of Cancer (Stupp) and RTOG trial. RESULTS: Overall 1- and 2-year survival for the noncarmustine wafer cohort were 69% and 29%, respectively, with a median survival of 72.7 weeks. One- and 2-year survival for the carmustine wafer cohort were 81% and 47%, with median survival of 89.5 weeks. Carmustine wafer was not an independent predictor (P=.110) of survival after adjustment for RPA class. The proportion of patients in the carmustine wafer cohort who lived longer than predicted based upon Stupp regimen results was significantly greater than 0.5 (P<.006); similar results based upon the RTOG trial data were observed (P<.001). CONCLUSIONS: Carmustine wafer with concurrent TMZ and radiation followed by rotational chemotherapy is a well tolerated, effective therapy, and has a survival benefit compared with radiation alone. Prospective randomized trials are needed to rigorously compare the carmustine wafer regimen to the Stupp and postradiation multimodality regimens.

Authors
Affronti, ML; Heery, CR; Herndon, JE; Rich, JN; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Affronti, ML, Heery, CR, Herndon, JE, Rich, JN, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Friedman, AH, Bigner, DD, and Friedman, HS. "Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy." Cancer 115.15 (August 1, 2009): 3501-3511.
PMID
19514083
Source
pubmed
Published In
Cancer
Volume
115
Issue
15
Publish Date
2009
Start Page
3501
End Page
3511
DOI
10.1002/cncr.24398

Assessment of physical functioning in recurrent glioma: preliminary comparison of performance status to functional capacity testing.

BACKGROUND: Performance status (PS) scoring systems are tools of immense clinical importance in the management of patients with malignant disease but these tools are subjective and do not provide an objective evaluation of physical functioning. We conducted a pilot study to explore the feasibility and clinical utility of functional capacity testing to assess physical functioning in recurrent primary malignant glioma patients. PATIENTS AND METHODS: Using a cross-sectional design, consecutive patients with recurrent glioma performed a six minute walk (6MW) test to assess functional capacity. Performance status was assessed using Karnofsky Performance Status (KPS) scoring system. QOL was assessed by the Functional Assessment of Cancer Therapy-Brain scale. Self-reported exercise behavior was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ). RESULTS: A total of 171 patients were recruited and tested. Seventy percent were diagnosed with glioblastoma multiforme (WHO grade IV) and 85% were undergoing therapy. Median KPS was 90% (range, 70-100%). Median 6MW distance was 400 m (range, 102-630 m), equivalent to 56 +/- 13% (range, 14-87%) of that predicted for age and sex. KPS, self-reported exercise, and QOL increased across 6MW distance quartiles (P < 0.05) although there was considerable variation within each category. 6MW distance and KPS were significantly correlated with each other (r = 0.34, P < 0.01) and several QOL domains (range, r = -0.43 to 0.46, P < 0.05). CONCLUSIONS: 6MW distance is a clinically feasible tool that provides an objective measure of physical functioning in select patients with recurrent glioma. Further research is required to investigate the prognostic value of these tests in patients with advanced malignancy.

Authors
Jones, LW; Cohen, R-R; Mabe, SK; West, MJ; Desjardins, A; Vredenburgh, JJ; Friedman, AH; Reardon, DA; Waner, E; Friedman, HS
MLA Citation
Jones, LW, Cohen, R-R, Mabe, SK, West, MJ, Desjardins, A, Vredenburgh, JJ, Friedman, AH, Reardon, DA, Waner, E, and Friedman, HS. "Assessment of physical functioning in recurrent glioma: preliminary comparison of performance status to functional capacity testing." J Neurooncol 94.1 (August 2009): 79-85.
PMID
19212703
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
94
Issue
1
Publish Date
2009
Start Page
79
End Page
85
DOI
10.1007/s11060-009-9803-x

Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma.

The current study was a phase 1 clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT-11) when administered with temozolomide (TMZ) and O(6)-benzylguanine (O(6)-BG).All 3 drugs, CPT-11, TMZ, and O(6)-BG, were administered on Day 1 of a 21-day treatment. First, patients were treated with a 1-hour bolus infusion of O(6)-BG at a dose of 120 mg/m(2) followed immediately by a 48-hour continuous infusion of O(6)-BG at a dose of 30 mg/m(2)/d. Second, within 60 minutes of the end of the 1-hour bolus infusion of O(6)-BG, TMZ was administered orally at a dose of 355 mg/m(2). Third, 1 hour after administration of TMZ, CPT-11 was infused over 90 minutes. Patients were accrued to 1 of 2 strata based on CYP3A1- and CYP3A4-inducing antiepileptic drug (EIAED) use; dose escalation was conducted independently within these strata.Fifty-five patients were enrolled. In both strata, the dose-limiting toxicities were hematologic and included grade 4 neutropenia, febrile neutropenia, leukopenia, and/or thrombocytopenia. For Stratum 1 (EIAEDs), when TMZ was administered at a dose of 355 mg/m(2), the MTD of CPT-11 was determined to be 120 mg/m(2). In contrast, for Stratum 2 (no EIAEDs), when TMZ was administered at a dose of 200 mg/m(2), the MTD of CPT-11 was determined to be 80 mg/m(2).The authors believe that the results of the current study provide the foundation for a phase 2 trial of O(6)-BG in combination with CPT-11 and TMZ in patients with MG.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, and Friedman, HS. "Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma." Cancer 115.13 (July 2009): 2964-2970.
PMID
19402172
Source
epmc
Published In
Cancer
Volume
115
Issue
13
Publish Date
2009
Start Page
2964
End Page
2970
DOI
10.1002/cncr.24336

Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma.

BACKGROUND: This study determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients. METHODS: All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed. RESULTS: A total of 37 recurrent patients, 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal, and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures. CONCLUSIONS: Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea were well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and platelet-derived growth factor, respectively, were safe among recurrent malignant glioma patients and may enhance antiangiogenesis activity.

Authors
Reardon, DA; Egorin, MJ; Desjardins, A; Vredenburgh, JJ; Beumer, JH; Lagattuta, TF; Gururangan, S; Herndon, JE; Salvado, AJ; Friedman, HS
MLA Citation
Reardon, DA, Egorin, MJ, Desjardins, A, Vredenburgh, JJ, Beumer, JH, Lagattuta, TF, Gururangan, S, Herndon, JE, Salvado, AJ, and Friedman, HS. "Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma." Cancer 115.10 (May 15, 2009): 2188-2198.
PMID
19248046
Source
pubmed
Published In
Cancer
Volume
115
Issue
10
Publish Date
2009
Start Page
2188
End Page
2198
DOI
10.1002/cncr.24213

Repeatability of quantitative parameters derived from diffusion tensor imaging in patients with glioblastoma multiforme.

PURPOSE: To quantify the repeatability of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in patients with glioblastoma multiforme. MATERIALS AND METHODS: IRB approval and informed consent were obtained for this Health Insurance Portability and Accountability Act-compliant study. Sixteen patients with glioblastoma multiforme underwent MR imaging at two time points without interval intervention. ADC and FA maps were registered to the contrast-enhanced and fluid-attenuated inversion recovery (FLAIR) image volumes. Volumes of tumor-related enhancement (TRE) and FLAIR signal abnormality (FSA) were defined using a semiautomated segmentation technique. RESULTS: Repeated observations of mean ADC and mean FA were highly consistent within both TRE (ADC: r = 0.947,P < 0.0001; FA: r = 0.947, P < 0.0001) and FSA (ADC: r = 0.979, P < 0.0001; FA: r = 0.972, P < 0.0001). Within TRE, repeatability coefficients and 95% confidence intervals (CIs) for change measured 0.104 x 10(-3) mm(2)S(-1) and 7.4% (ADC) and 0.0196 and 13.9% (FA), respectively. Within FSA, repeatability coefficients and 95% CI for change measured 0.071 x 10(-3) mm(2)S(-1) and 5.2% (ADC) and 0.0159 and 8.7% (FA), respectively. To detect 10% changes in mean ADC, sample sizes of nine (TRE) and six (FSA) patients would be required. The same change in mean FA would require sample sizes of 21 (TRE) and 10 (FSA) patients, respectively. CONCLUSION: Changes after therapy greater than the repeatability coefficient or 95% CI for change are unlikely to be related to variability in the measurement of ADC and FA.

Authors
Paldino, MJ; Barboriak, D; Desjardins, A; Friedman, HS; Vredenburgh, JJ
MLA Citation
Paldino, MJ, Barboriak, D, Desjardins, A, Friedman, HS, and Vredenburgh, JJ. "Repeatability of quantitative parameters derived from diffusion tensor imaging in patients with glioblastoma multiforme." J Magn Reson Imaging 29.5 (May 2009): 1199-1205.
PMID
19388113
Source
pubmed
Published In
Journal of Magnetic Resonance Imaging
Volume
29
Issue
5
Publish Date
2009
Start Page
1199
End Page
1205
DOI
10.1002/jmri.21732

PHASE II STUDY OF BEVACIZUMAB AND ERLOTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME

Authors
Reardon, DA; Sathornsumetee, S; Vredenburgh, JJ; Rich, JN; Desjardins, A; Quinn, JA; Mathe, A; Gururangan, S; Friedman, AH; Friedman, HS
MLA Citation
Reardon, DA, Sathornsumetee, S, Vredenburgh, JJ, Rich, JN, Desjardins, A, Quinn, JA, Mathe, A, Gururangan, S, Friedman, AH, and Friedman, HS. "PHASE II STUDY OF BEVACIZUMAB AND ERLOTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME." NEURO-ONCOLOGY 11.2 (April 2009): 231-231.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
231
End Page
231

Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma.

This phase II trial was designed to define the role of O(6)-benzylguanine (O(6)-BG) in restoring temozolomide sensitivity in patients with recurrent or progressive, temozolomide-resistant malignant glioma and to evaluate the safety of administering O(6)-BG in combination with temozolomide.Patients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both temozolomide and O(6)-BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O(6)-BG infusion at a dose of 120 mg/m(2) followed immediately by a 48-hour infusion at a dose of 30 mg/m(2)/d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O(6)-BG infusion at a dose of 472 mg/m(2). The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety.Sixty-six of 67 patients who enrolled were treated with temozolomide and O(6)-BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients.O(6)-BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Walker, A, and Friedman, HS. "Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.8 (March 2009): 1262-1267.
PMID
19204199
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
8
Publish Date
2009
Start Page
1262
End Page
1267
DOI
10.1200/jco.2008.18.8417

Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme.

This phase II trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O6-benzylguanine (O6-BG) that suppresses tumor O6-alkylguanine-DNA alkyltransferase (AGT) levels in patients with recurrent glioblastoma multiforme for 5 days and to evaluate the safety of this combination therapy.This was a phase II, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O6-BG was administered at 120 mg/m2 over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m2/d. The primary end points were 6-month overall survival (OS) and safety, and the secondary end points were 1-year, 2-year, and median OS.Fifty-two patients were accrued. The 6-month OS was 82% [95% confidence interval (95% CI), 72-93%]. The 1- and 2-year OS rates were 47% (95% CI, 35-63%) and 10% (95% CI, 3-32%), respectively. The median OS was 50.3 weeks (95% CI, 36.1-69.4 weeks). Treatment-related toxicity with this drug combination included grade 3 hydrocephalus (9.6%), grade 3 cerebrospinal fluid (CSF) leak (19.2%), and grade 3 CSF/brain infection (13.4%).The efficacy of implanted Gliadel wafers may be improved with the addition of O6-BG. Although systemically administered O6-BG can be coadministered with Gliadel wafers safely, it may increase the risk of hydrocephalus, CSF leak, and CSF/brain infection. Future trials are required to verify that inhibition of tumor AGT levels by O6-BG results in increased efficacy of Gliadel wafers without added toxicity.

Authors
Quinn, JA; Jiang, SX; Carter, J; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Threatt, S; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Carter, J, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Threatt, S, and Friedman, HS. "Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme." Clinical cancer research : an official journal of the American Association for Cancer Research 15.3 (February 2009): 1064-1068.
PMID
19188181
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
3
Publish Date
2009
Start Page
1064
End Page
1068
DOI
10.1158/1078-0432.ccr-08-2130

Experience with irinotecan for the treatment of malignant glioma.

Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course. Chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival. Novel agents and new approaches to therapy are required to improve clinical outcomes. Irinotecan, a first-line treatment for metastatic colorectal cancer and an agent with high activity against solid tumors of the gastrointestinal tract, is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription. Irinotecan crosses the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts. Its antitumor activity has also been demonstrated against glioblastoma cells with multidrug resistance. Studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Studies of irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results. Irinotecan monotherapy has demonstrated efficacy; however, its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents. When administered concurrently with enzyme-inducing antiepileptic drugs, the dosage must be increased to compensate for enhanced cytochrome CY3A4/5 enzyme activity. Toxicities associated with irinotecan have been manageable; the most important dose-limiting toxicities are neutropenia and diarrhea. Irinotecan-based chemotherapy of malignant glioma merits further study.

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Reardon, DA, and Friedman, HS. "Experience with irinotecan for the treatment of malignant glioma." Neuro Oncol 11.1 (February 2009): 80-91. (Review)
PMID
18784279
Source
pubmed
Published In
Neuro-Oncology
Volume
11
Issue
1
Publish Date
2009
Start Page
80
End Page
91
DOI
10.1215/15228517-2008-075

Current available therapies and future directions in the treatment of malignant gliomas.

The prognosis of patients diagnosed with malignant glioma (MG) remains poor. However, recent advances in neuro-oncology allowing a better understanding of this particular disease have allowed the development of new therapeutics. Many molecular genetic and signal transduction pathway targets have been identified that are now being investigated. Novel locoregional treatments, as well as strategies to improve regional delivery, are being evaluated. Studies of combinations of these approaches are also underway. In this review, we will discuss the current and future therapies under evaluation for the treatment of malignant gliomas.

Authors
Desjardins, A; Reardon, DA; Vredenburgh, JJ
MLA Citation
Desjardins, A, Reardon, DA, and Vredenburgh, JJ. "Current available therapies and future directions in the treatment of malignant gliomas." Biologics 3 (2009): 15-25.
PMID
19707392
Source
pubmed
Published In
Biologics: Targets and Therapy
Volume
3
Publish Date
2009
Start Page
15
End Page
25

Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas.

PURPOSE: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma. EXPERIMENTAL DESIGN: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n=24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m(2) for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m(2) for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging. RESULTS: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura. CONCLUSION: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma.

Authors
Desjardins, A; Reardon, DA; Herndon, JE; Marcello, J; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Sampson, J; Bailey, L; Bigner, DD; Friedman, AH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, A, Reardon, DA, Herndon, JE, Marcello, J, Quinn, JA, Rich, JN, Sathornsumetee, S, Gururangan, S, Sampson, J, Bailey, L, Bigner, DD, Friedman, AH, Friedman, HS, and Vredenburgh, JJ. "Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas." Clin Cancer Res 14.21 (November 1, 2008): 7068-7073.
PMID
18981004
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
21
Publish Date
2008
Start Page
7068
End Page
7073
DOI
10.1158/1078-0432.CCR-08-0260

Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma.

The efficacy of high-dose chemotherapy (HDC) or standard salvage therapy was evaluated in patients with recurrent medulloblastoma (MBL) using retrospective chart review of all patients with recurrent MBL treated at Duke University Medical Center between 1995 and 2005 and who had undergone HDC with or without radiotherapy (RT) or standard salvage therapy after relapse. A total of 30 patients were diagnosed with recurrent MBL after standard RT alone or chemotherapy with RT. Nineteen patients (7 who received no RT before recurrence [group A] and 12 who received definitive RT before recurrence [group B]) underwent surgery and/or induction chemotherapy followed by HDC plus autologous stem-cell rescue. Eleven patients (group C) underwent standard salvage therapy. Six of seven group A patients also received standard RT just before or after recovery from HDC, and 5 of 12 group B patients received adjuvant palliative focal RT post-HDC. At a median follow-up of 28 months, three of seven patients in group A are alive and disease-free at >or=34, >or=110, and >or=116 months, respectively, post-HDC. All patients in groups B and C have died of tumor, at a median of 35 months and 26 months from HDC and standard salvage therapy, respectively. HDC or standard salvage therapy was ineffective in our patients with recurrent MBL who had received standard RT before recurrence. The favorable impact of HDC on disease control in the two long-term survivors cannot be clearly established due to the cofounding effect of definitive RT postrecurrence.

Authors
Gururangan, S; Krauser, J; Watral, MA; Driscoll, T; Larrier, N; Reardon, DA; Rich, JN; Quinn, JA; Vredenburgh, JJ; Desjardins, A; McLendon, RE; Fuchs, H; Kurtzberg, J; Friedman, HS
MLA Citation
Gururangan, S, Krauser, J, Watral, MA, Driscoll, T, Larrier, N, Reardon, DA, Rich, JN, Quinn, JA, Vredenburgh, JJ, Desjardins, A, McLendon, RE, Fuchs, H, Kurtzberg, J, and Friedman, HS. "Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma." Neuro Oncol 10.5 (October 2008): 745-751.
PMID
18755919
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
5
Publish Date
2008
Start Page
745
End Page
751
DOI
10.1215/15228517-2008-044

Bevacizumab/Irinotecan. An active treatment for recurrent high grade gliomas: Preliminary results of an ANOCEF Multicenter Study

Rationale: Second-line chemotherapy is disappointing in recurrent high-grade gliomas. Dramatic responses in recurrent high-grade gliomas have been reported in a recent monocentric trial with a novel association combining bevacizumab (anti-VEGF monoclonal antibody agent) and irinitecan. Objective: To report the experience of the ANOCEF group (French speaking neuro-oncology association) using the bevacizumab-irinotecan combination in recurrent high-grade gliomas. Methods: Eight centers were involved in this retrospective multicenter study. Bevacizumab-irinotecan was delivered as previously described in a compassional setting to non-selected patients suffering from a high-grade glioma (WHO grade III and IV). Response rate at two months of the onset of the treatment was analyzed using the Macdonald criteria. The toxicity profile of the treatment was also investigated. Results: From 2006 to 2007, 77 patients were treated (median age: 52 years; median Karnofsky score: 70) for a recurrent high-grade glioma (49 grade IV, 28 grade III). At two months, the response rates were objective response = 36% (54% in grade III and 27% in grade IV); stable disease = 39%; progressive disease = 13%; patients not evaluable because of a rapid fatal clinical deterioration = 12%. Improvement was noted in 49% of patients. Among the main toxicities, we noted; intratumoral hemorrage (n = 5 with spontaneous regression in three) and thromboembolic complications including venous thrombophlebitis (n = 4), pulmonary embolism (n = 2), myocardial infarction (n = 1), grade III-IV hematotoxicity (n = 2), reversible leukoencephalopathy (n = 1). Conclusion: This retrospective multicenter study adds further arguments in favor of the promising results of this new combination and its potential rapidity of action in recurrent high-grade gliomas. Antiangiogenic agents expose the patients to a well-known risk of thromboembolic and hemorragic complications, necessitating careful follow-up and patient selection in light of the cardiovascular contraindications. © 2008 Elsevier Masson SAS. All rights reserved.

Authors
Guiu, S; Taillibert, S; Chinot, O; Taillandier, L; Honnorat, J; Dietrich, PY; Maire, JP; Guillamo, JS; Guiu, B; Catry-Thomas, I; Capelle, F; Thiebaut, A; Cartalat-Carel, S; Deville, C; Fumoleau, P; Desjardins, A; Xuan, KH; Chauffert, B
MLA Citation
Guiu, S, Taillibert, S, Chinot, O, Taillandier, L, Honnorat, J, Dietrich, PY, Maire, JP, Guillamo, JS, Guiu, B, Catry-Thomas, I, Capelle, F, Thiebaut, A, Cartalat-Carel, S, Deville, C, Fumoleau, P, Desjardins, A, Xuan, KH, and Chauffert, B. "Bevacizumab/Irinotecan. An active treatment for recurrent high grade gliomas: Preliminary results of an ANOCEF Multicenter Study." Revue Neurologique 164.6-7 (June 1, 2008): 588-594.
Source
scopus
Published In
Revue Neurologique
Volume
164
Issue
6-7
Publish Date
2008
Start Page
588
End Page
594
DOI
10.1016/j.neurol.2008.04.003

Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma.

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150-200 mg/m(2) per day on days 4-8 plus imatinib mesylate administered orally on days 1-8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n=28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population.

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Sathornsumetee, S; Rich, JN; Quinn, JA; Lagattuta, TF; Egorin, MJ; Gururangan, S; McLendon, R; Herndon, JE; Friedman, AH; Salvado, AJ; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Sathornsumetee, S, Rich, JN, Quinn, JA, Lagattuta, TF, Egorin, MJ, Gururangan, S, McLendon, R, Herndon, JE, Friedman, AH, Salvado, AJ, and Friedman, HS. "Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma." Neuro Oncol 10.3 (June 2008): 330-340.
PMID
18359865
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
3
Publish Date
2008
Start Page
330
End Page
340
DOI
10.1215/15228517-2008-003

Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma.

Angiogenesis, the growth of new blood vessels from previously existing vasculature, is a requirement for tumor growth and metastasis. The first US FDA-approved drugs targeting angiogenesis have shown potential in the treatment of malignant gliomas. Immunotherapy as a treatment modality lends itself well to specifically targeting angiogenesis in tumors and may represent a powerful tool in the treatment of malignant gliomas. This review focuses on developments in immunotherapy targeting angiogenesis and tumor-vascular-specific endothelial cells using a variety of immunotherapeutic strategies including monoclonal antibodies and conjugated immunotoxins, as well as cellular, peptide, DNA and dendritic cell vaccines.

Authors
Everson, RG; Graner, MW; Gromeier, M; Vredenburgh, JJ; Desjardins, A; Reardon, DA; Friedman, HS; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Everson, RG, Graner, MW, Gromeier, M, Vredenburgh, JJ, Desjardins, A, Reardon, DA, Friedman, HS, Friedman, AH, Bigner, DD, and Sampson, JH. "Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma." Expert Rev Anticancer Ther 8.5 (May 2008): 717-732. (Review)
PMID
18471045
Source
pubmed
Published In
Expert Review of Anticancer Therapy
Volume
8
Issue
5
Publish Date
2008
Start Page
717
End Page
732
DOI
10.1586/14737140.8.5.717

A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost.

The purpose of this study was to determine the feasibility and assess the efficacy and toxicity, among newly diagnosed malignant glioma patients, of administering (131)I-labeled murine antitenascin monoclonal antibody 81C6 ((131)I-81C6) into a surgically created resection cavity (SCRC) to achieve a patient-specific, 44-Gy boost to the 2-cm SCRC margin. A radioactivity dose of (131)I-81C6 calculated to achieve a 44-Gy boost to the SCRC was administered, followed by conventional external beam radiotherapy (XRT) and chemotherapy. Twenty-one patients were enrolled in the study: 16 with glioblastoma multiforme (GBM) and 5 with anaplastic astrocytoma. Twenty patients received the targeted 44-Gy boost (+/-10%) to the SCRC. Attributable toxicity was mild and limited to reversible grade 3 neutropenia or thrombocytopenia (n = 3; 14%), CNS wound infections (n = 3; 14%), and headache (n = 2; 10%). With a median follow-up of 151 weeks, median overall survival times for all patients and those with GBM are 96.6 and 90.6 weeks, respectively; 87% of GBM patients are alive at 1 year. It is feasible to consistently achieve a 44-Gy boost dose to the SCRC margin with patient-specific dosing of (131)I-81C6. Our study regimen ((131)I-81C6 + XRT + temozolomide) was well tolerated and had encouraging survival. To determine if selection of good-prognosis patients affects outcome associated with this approach, the U.S. Food and Drug Administration has approved a trial randomizing newly diagnosed GBM patients to either our study regimen or standard XRT plus temozolomide.

Authors
Reardon, DA; Zalutsky, MR; Akabani, G; Coleman, RE; Friedman, AH; Herndon, JE; McLendon, RE; Pegram, CN; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Guruangan, S; Boulton, S; Raynor, RH; Dowell, JM; Wong, TZ; Zhao, X-G; Friedman, HS; Bigner, DD
MLA Citation
Reardon, DA, Zalutsky, MR, Akabani, G, Coleman, RE, Friedman, AH, Herndon, JE, McLendon, RE, Pegram, CN, Quinn, JA, Rich, JN, Vredenburgh, JJ, Desjardins, A, Guruangan, S, Boulton, S, Raynor, RH, Dowell, JM, Wong, TZ, Zhao, X-G, Friedman, HS, and Bigner, DD. "A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost." Neuro Oncol 10.2 (April 2008): 182-189.
PMID
18287339
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
2
Publish Date
2008
Start Page
182
End Page
189
DOI
10.1215/15228517-2007-053

Glioblastoma multiforme: an emerging paradigm of anti-VEGF therapy.

BACKGROUND: Adults with malignant glioma, especially the most common subtype, glioblastoma multiforme, have an unacceptably poor outcome with current therapies. Malignant gliomas are amongst the most angiogenic of cancers, and VEGF is the dominant angiogenic mediator in these tumors. OBJECTIVE: To summarize the clinical experience of VEGF-directed treatment for malignant glioma. METHODS: We reviewed the completed, ongoing and planned clinical trials evaluating anti-VEGF strategies for malignant glioma patients. RESULTS/CONCLUSIONS: Recent studies incorporating anti-VEGF agents plus cytotoxic therapy among recurrent malignant glioma patients have achieved unprecedented improvements in radiographic response, time to progression and survival. Furthermore, acceptable toxicity was observed. Hence, a major current focus in neuro-oncology is to further develop antiangiogenic strategies for this desperate patient population.

Authors
Reardon, DA; Wen, PY; Desjardins, A; Batchelor, TT; Vredenburgh, JJ
MLA Citation
Reardon, DA, Wen, PY, Desjardins, A, Batchelor, TT, and Vredenburgh, JJ. "Glioblastoma multiforme: an emerging paradigm of anti-VEGF therapy." Expert Opin Biol Ther 8.4 (April 2008): 541-553. (Review)
PMID
18352856
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
8
Issue
4
Publish Date
2008
Start Page
541
End Page
553
DOI
10.1517/14712598.8.4.541

The emerging role of anti-angiogenic therapy for malignant glioma.

OPINION STATEMENT: Adults with glioblastoma multiforme (GBM), the most common primary brain tumor, have an unacceptably poor outcome with conventional cytotoxic therapies. Malignant gliomas are remarkably angiogenic, and vascular endothelial growth factor (VEGF) is the dominant pro-angiogenic factor. Recent clinical trials targeting VEGF signaling have achieved unprecedented rates of durable radiographic and clinical response, while also confirming adequate safety among recurrent malignant glioma patients. An array of additional clinical trials evaluating anti-angiogenic strategies are underway for both recurrent and newly diagnosed malignant glioma patients. Promising results of these approaches suggest that the treatment of GBM may represent an emerging paradigm of anti-angiogenic therapy.

Authors
Reardon, DA; Desjardins, A; Rich, JN; Vredenburgh, JJ
MLA Citation
Reardon, DA, Desjardins, A, Rich, JN, and Vredenburgh, JJ. "The emerging role of anti-angiogenic therapy for malignant glioma." Curr Treat Options Oncol 9.1 (February 2008): 1-22. (Review)
PMID
18256938
Source
pubmed
Published In
Current Treatment Options in Oncology
Volume
9
Issue
1
Publish Date
2008
Start Page
1
End Page
22
DOI
10.1007/s11864-008-0052-6

Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan.

PURPOSE: The combination of a vascular endothelial growth factor (VEGF) -neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy. PATIENTS AND METHODS: In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2alpha were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers. RESULTS: Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016). CONCLUSION: In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.

Authors
Sathornsumetee, S; Cao, Y; Marcello, JE; Herndon, JE; McLendon, RE; Desjardins, A; Friedman, HS; Dewhirst, MW; Vredenburgh, JJ; Rich, JN
MLA Citation
Sathornsumetee, S, Cao, Y, Marcello, JE, Herndon, JE, McLendon, RE, Desjardins, A, Friedman, HS, Dewhirst, MW, Vredenburgh, JJ, and Rich, JN. "Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan." J Clin Oncol 26.2 (January 10, 2008): 271-278.
PMID
18182667
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
2
Publish Date
2008
Start Page
271
End Page
278
DOI
10.1200/JCO.2007.13.3652

In reply

Authors
Vredenburgh, JJ; Rich, JN; Reardon, DA; Desjardins, A; Friedman, HS
MLA Citation
Vredenburgh, JJ, Rich, JN, Reardon, DA, Desjardins, A, and Friedman, HS. "In reply." Journal of Clinical Oncology 26.32 (2008): 5305--.
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
32
Publish Date
2008
Start Page
5305-
DOI
10.1200/JCO.2008.18.0372

Bevacizumab/Irinotecan. An active treatment for recurrent high grade gliomas: Preliminary results of an ANOCEF Multicenter Study

Rationale: Second-line chemotherapy is disappointing in recurrent high-grade gliomas. Dramatic responses in recurrent high-grade gliomas have been reported in a recent monocentric trial with a novel association combining bevacizumab (anti-VEGF monoclonal antibody agent) and irinitecan. Objective: To report the experience of the ANOCEF group (French speaking neuro-oncology association) using the bevacizumab-irinotecan combination in recurrent high-grade gliomas. Methods: Eight centers were involved in this retrospective multicenter study. Bevacizumab-irinotecan was delivered as previously described in a compassional setting to non-selected patients suffering from a high-grade glioma (WHO grade III and IV). Response rate at two months of the onset of the treatment was analyzed using the Macdonald criteria. The toxicity profile of the treatment was also investigated. Results: From 2006 to 2007, 77 patients were treated (median age: 52 years; median Karnofsky score: 70) for a recurrent high-grade glioma (49 grade IV, 28 grade III). At two months, the response rates were objective response = 36% (54% in grade III and 27% in grade IV); stable disease = 39%; progressive disease = 13%; patients not evaluable because of a rapid fatal clinical deterioration = 12%. Improvement was noted in 49% of patients. Among the main toxicities, we noted; intratumoral hemorrage (n = 5 with spontaneous regression in three) and thromboembolic complications including venous thrombophlebitis (n = 4), pulmonary embolism (n = 2), myocardial infarction (n = 1), grade III-IV hematotoxicity (n = 2), reversible leukoencephalopathy (n = 1). Conclusion: This retrospective multicenter study adds further arguments in favor of the promising results of this new combination and its potential rapidity of action in recurrent high-grade gliomas. Antiangiogenic agents expose the patients to a well-known risk of thromboembolic and hemorragic complications, necessitating careful follow-up and patient selection in light of the cardiovascular contraindications. © 2008 Elsevier Masson SAS. All rights reserved.

Authors
Guiu, S; Taillibert, S; Chinot, O; Taillandier, L; Honnorat, J; Dietrich, PY; Maire, J-P; Guillamo, JS; Guiu, B; Catry-Thomas, I; Capelle, F; Thiebaut, A; Cartalat-Carel, S; Deville, C; Fumoleau, P; Desjardins, A; Xuan, KH; Chauffert, B
MLA Citation
Guiu, S, Taillibert, S, Chinot, O, Taillandier, L, Honnorat, J, Dietrich, PY, Maire, J-P, Guillamo, JS, Guiu, B, Catry-Thomas, I, Capelle, F, Thiebaut, A, Cartalat-Carel, S, Deville, C, Fumoleau, P, Desjardins, A, Xuan, KH, and Chauffert, B. "Bevacizumab/Irinotecan. An active treatment for recurrent high grade gliomas: Preliminary results of an ANOCEF Multicenter Study." Revue Neurologique 164.6-7 (2008): 588-594.
PMID
18565358
Source
scival
Published In
Revue Neurologique
Volume
164
Issue
6-7
Publish Date
2008
Start Page
588
End Page
594
DOI
10.1016/j.neurol.2008.04.003

Irinotecan and bevacizumab for the treatment of recurrent glioblastoma multiforme

Authors
Vredenburgh, J; Desjardins, A; Reardon, D
MLA Citation
Vredenburgh, J, Desjardins, A, and Reardon, D. "Irinotecan and bevacizumab for the treatment of recurrent glioblastoma multiforme." American Journal of Hematology/ Oncology 7.4 (2008).
Source
scival
Published In
American Journal of Oncology Review
Volume
7
Issue
4
Publish Date
2008

In reply

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Reardon, DA, and Friedman, HS. "In reply." Journal of Clinical Oncology 26.6 (2008): 1013--.
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
6
Publish Date
2008
Start Page
1013-
DOI
10.1200/JCO.2007.15.1746

Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.

PURPOSE: The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. PATIENTS AND METHODS: This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. RESULTS: The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). CONCLUSION: Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.

Authors
Vredenburgh, JJ; Desjardins, A; Herndon, JE; Marcello, J; Reardon, DA; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Sampson, J; Wagner, M; Bailey, L; Bigner, DD; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Herndon, JE, Marcello, J, Reardon, DA, Quinn, JA, Rich, JN, Sathornsumetee, S, Gururangan, S, Sampson, J, Wagner, M, Bailey, L, Bigner, DD, Friedman, AH, and Friedman, HS. "Bevacizumab plus irinotecan in recurrent glioblastoma multiforme." J Clin Oncol 25.30 (October 20, 2007): 4722-4729.
PMID
17947719
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
30
Publish Date
2007
Start Page
4722
End Page
4729
DOI
10.1200/JCO.2007.12.2440

Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of malignant gliomas.

Malignant gliomas represent the majority of primary brain tumors, and the prognosis of the patients afflicted with these tumors has been historically dismal, with almost uniform progressive neurologic impairment and rapid death. Even with multimodal treatment using surgery, focal radiation, and chemotherapy, no major strides were made until recently. The development of interstitial BCNU wafers (carmustine wafers, Gliadel((R))) has led to promising results in the treatment of a selected patients with malignant gliomas, as well as with other intracranial malignancies.BCNU is one of the first systemic chemotherapies which had obtained United States Food and Drug Administration (FDA) approval for the treatment of brain tumors. However, systemic use has been hampered by the modest prolongation of survival and by the prolonged myelosuppression and potentially fatal pulmonary toxicity. The development of interstitial therapies with BCNU represented a great step forward, allowing direct delivery to the tumor bed, with virtually no systemic toxicities. Clinical studies of BCNU wafers have showed good efficacy in both newly diagnosed and recurrent gliomas, as well as a possible therapeutic role in other primary or secondary intracranial malignancies. New studies are currently underway trying to improve the efficacy of the BCNU wafers (Gliadel((R))) by combining them with different systemic chemotherapies. An overview of the current knowledge ranging from the preclinical developments, to the efficacy and safety seen in the clinical trials and in clinical practice following the drug approval to the future avenues of research is therefore timely.

Authors
Bota, DA; Desjardins, A; Quinn, JA; Affronti, ML; Friedman, HS
MLA Citation
Bota, DA, Desjardins, A, Quinn, JA, Affronti, ML, and Friedman, HS. "Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of malignant gliomas." Ther Clin Risk Manag 3.5 (October 2007): 707-715.
PMID
18472995
Source
pubmed
Published In
Therapeutics and clinical risk management
Volume
3
Issue
5
Publish Date
2007
Start Page
707
End Page
715

Molecularly targeted therapy for malignant glioma.

Malignant gliomas are relatively uncommon but lethal cancers. Despite recent research efforts in cancer therapy, the prognosis of patients with malignant gliomas has remained dismal. Understanding the molecular pathogenesis of glioma may lead to a rational development of new therapies. Despite the genetic heterogeneity of malignant gliomas, common aberrations in the signaling elements of the growth and survival pathways are found. New treatments have emerged to target molecules in these signaling pathways with the goal to increase specific efficacy and minimize toxicity. Monoclonal antibodies and low molecular-weight kinase inhibitors are the most common classes of agents in targeted cancer treatment. Most clinical trials of these agents as monotherapies have failed to demonstrate survival benefit in unselected malignant glioma patient populations. Several mechanisms of treatment failure have been demonstrated. In response, multitargeted kinase inhibitors and combinations of single-targeted kinase inhibitors have been developed to overcome therapeutic resistance. In addition, multimodality combinations of targeted agents with radiation, chemotherapy, or immunotherapy/vaccines may enhance treatment efficacy. Future development of these agents will require advances in discovery and validation of new molecular targets, improvement of therapeutic delivery, and identification of correlative biomarkers. Novel clinical trial designs and endpoints may increase the efficiency of new drug evaluation. In this review, the authors discussed the current understanding of molecular pathogenesis and the development of molecularly targeted therapies in malignant glioma.

Authors
Sathornsumetee, S; Reardon, DA; Desjardins, A; Quinn, JA; Vredenburgh, JJ; Rich, JN
MLA Citation
Sathornsumetee, S, Reardon, DA, Desjardins, A, Quinn, JA, Vredenburgh, JJ, and Rich, JN. "Molecularly targeted therapy for malignant glioma." Cancer 110.1 (July 1, 2007): 13-24. (Review)
PMID
17520692
Source
pubmed
Published In
Cancer
Volume
110
Issue
1
Publish Date
2007
Start Page
13
End Page
24
DOI
10.1002/cncr.22741

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas.

PURPOSE: Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). PATIENTS AND METHOD: Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. RESULTS: Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1-7) and the median number of prior treatment regimens was 3 (range, 1-8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. CONCLUSION: Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

Authors
Desjardins, A; Quinn, JA; Vredenburgh, JJ; Sathornsumetee, S; Friedman, AH; Herndon, JE; McLendon, RE; Provenzale, JM; Rich, JN; Sampson, JH; Gururangan, S; Dowell, JM; Salvado, A; Friedman, HS; Reardon, DA
MLA Citation
Desjardins, A, Quinn, JA, Vredenburgh, JJ, Sathornsumetee, S, Friedman, AH, Herndon, JE, McLendon, RE, Provenzale, JM, Rich, JN, Sampson, JH, Gururangan, S, Dowell, JM, Salvado, A, Friedman, HS, and Reardon, DA. "Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas." J Neurooncol 83.1 (May 2007): 53-60.
PMID
17245623
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
83
Issue
1
Publish Date
2007
Start Page
53
End Page
60
DOI
10.1007/s11060-006-9302-2

Temozolomide in children with progressive low-grade glioma.

We conducted a phase II study to assess the efficacy of oral temozolomide (TMZ) in children with progressive low-grade glioma. Thirty eligible patients were enrolled on this study. Median age at enrollment was 10 years (range, 4-18 years). Eligible patients received TMZ (200 mg/m(2) per day) by mouth for five days every four weeks. Patients received a median of nine cycles (range, 2-12 cycles) of treatment. Best responses in the 26 patients (86%) with optic pathway glioma (OPG)/pilocytic astrocytoma (PA) included partial response in 3 patients (11%), minor response in 1 (4%), stable disease in 10 (38%), and progressive disease in 12 (46%). Only one of four patients with fibrillary astrocytoma had stable disease for 29 months after TMZ. The overall disease stabilization rate in patients with OPG/PA was 54%, and disease control was maintained for a median interval of 34 months. Seventeen of 26 patients had progressive disease either on or off therapy, and three have died of disease. The two-year progression-free and overall survivals in patients with OPG/PA were 49% (95% CI, 30%-67%) and 96% (95% CI, 89%-100%), respectively. Worst toxicity related to TMZ in all 30 patients included grade 2-4 thrombocytopenia in seven patients, grade 2-4 neutropenia in seven, grade 2 skin rash in one, and intratumor hemorrhage in one. TMZ given in this schedule was successful in stabilizing disease in a significant proportion of the patients with OPG/PA, with manageable toxicity.

Authors
Gururangan, S; Fisher, MJ; Allen, JC; Herndon, JE; Quinn, JA; Reardon, DA; Vredenburgh, JJ; Desjardins, A; Phillips, PC; Watral, MA; Krauser, JM; Friedman, AH; Friedman, HS
MLA Citation
Gururangan, S, Fisher, MJ, Allen, JC, Herndon, JE, Quinn, JA, Reardon, DA, Vredenburgh, JJ, Desjardins, A, Phillips, PC, Watral, MA, Krauser, JM, Friedman, AH, and Friedman, HS. "Temozolomide in children with progressive low-grade glioma." Neuro Oncol 9.2 (April 2007): 161-168.
PMID
17347491
Source
pubmed
Published In
Neuro-Oncology
Volume
9
Issue
2
Publish Date
2007
Start Page
161
End Page
168
DOI
10.1215/15228517-2006-030

Neurofibromatosis type 2.

Authors
Sathornsumetee, S; DesJardins, A; Reardon, DA; Rich, JN; Vredenburgh, JJ
MLA Citation
Sathornsumetee, S, DesJardins, A, Reardon, DA, Rich, JN, and Vredenburgh, JJ. "Neurofibromatosis type 2." Neurology 68.13 (March 27, 2007): E14-.
PMID
17389295
Source
pubmed
Published In
Neurology
Volume
68
Issue
13
Publish Date
2007
Start Page
E14
DOI
10.1212/01.wnl.0000257828.56178.9f

Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma.

PURPOSE: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma. EXPERIMENTAL DESIGN: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m(2), whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m(2). Toxicity and response were assessed. RESULTS: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was 72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli, and one patient had an arterial ischemic stroke. CONCLUSIONS: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.

Authors
Vredenburgh, JJ; Desjardins, A; Herndon, JE; Dowell, JM; Reardon, DA; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Wagner, M; Bigner, DD; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Herndon, JE, Dowell, JM, Reardon, DA, Quinn, JA, Rich, JN, Sathornsumetee, S, Gururangan, S, Wagner, M, Bigner, DD, Friedman, AH, and Friedman, HS. "Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma." Clin Cancer Res 13.4 (February 15, 2007): 1253-1259.
PMID
17317837
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
4
Publish Date
2007
Start Page
1253
End Page
1259
DOI
10.1158/1078-0432.CCR-06-2309

Phase II study of Cloretazine for the treatment of adults with recurrent glioblastoma multiforme.

Cloretazine (VNP40101M) is a newly synthesized alkylating agent belonging to a novel class of alkylating agents called 1,2-bis(sulfonyl)hydrazines. Agents that belong to this class do not produce vinylating and chloroethylating species, and hence this class of alkylating agents is thought to have minimal systemic toxicity. Cloretazine produces two short-lived active species: 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (a chloroethylating species) and a thiophilic carbamoylating methylisocyanate species. The chloroethylating species preferentially produces lesions at the O(6) position of guanine. The methylisocyanate species may inhibit O(6)-alkylguanine-DNA alkyltransferase, an important mechanism of resistance against alkylating agents. The purpose of this study was to determine the efficacy and tolerability of Cloretazine in patients with recurrent glioblastoma multiforme. The basis for the determination of efficacy was the proportion of patients alive without evidence of disease progression six months after initiation of treatment. Patients with recurrent glioblastoma multiforme received Cloretazine (300 mg/m(2)) intravenously every six weeks. Radiographic response, survival data, and toxicity were assessed. Thirty-two patients were enrolled. Median age was 56 years; 24 patients (75%) were men. At six months, two patients were alive and progression free, so the six-month progression-free survival (PFS) was 6%. The median PFS was 6.3 weeks. There were no objective radiographic responses. Twelve patients had stable disease for at least one cycle, but only two patients received more than three cycles. Nine patients experienced grade 4 thrombocytopenia and three patients experienced grade 4 neutropenia. Cloretazine administered every six weeks was relatively well tolerated, although this schedule has insignificant activity for patients with recurrent glioblastoma multiforme.

Authors
Badruddoja, MA; Penne, K; Desjardins, A; Reardon, DA; Rich, JN; Quinn, JA; Sathornsumetee, S; Friedman, AH; Bigner, DD; Herndon, JE; Cahill, A; Friedman, HS; Vredenburgh, JJ
MLA Citation
Badruddoja, MA, Penne, K, Desjardins, A, Reardon, DA, Rich, JN, Quinn, JA, Sathornsumetee, S, Friedman, AH, Bigner, DD, Herndon, JE, Cahill, A, Friedman, HS, and Vredenburgh, JJ. "Phase II study of Cloretazine for the treatment of adults with recurrent glioblastoma multiforme." Neuro Oncol 9.1 (January 2007): 70-74.
PMID
17108065
Source
pubmed
Published In
Neuro-Oncology
Volume
9
Issue
1
Publish Date
2007
Start Page
70
End Page
74
DOI
10.1215/15228517-2006-022

Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results.

UNLABELLED: Results from animal experiments have shown that human IgG2/mouse chimeric antitenascin 81C6 (ch81C6) monoclonal antibody exhibited higher tumor accumulation and enhanced stability compared with its murine parent. Our objective was to determine the effect of these differences on the maximum tolerated dose (MTD), pharmacokinetics, dosimetry, and antitumor activity of (131)I-ch81C6 administered into the surgically created resection cavity (SCRC) of malignant glioma patients. METHODS: In this phase I trial, eligible patients received a single injection of (131)I-ch81C6 administered through a Rickham catheter into the SCRC. Patients were stratified as newly diagnosed and untreated (stratum A), newly diagnosed after external beam radiotherapy (XRT) (stratum B), and recurrent (stratum C). (131)I-ch81C6 was administered either before (stratum A) or after (stratum B) conventional XRT for newly diagnosed patients. In addition, chemotherapy was prescribed for all patients after (131)I-ch81C6 administration. Dose escalation was performed independently for each stratum. Patients were observed for toxicity and response until death or progressive disease. RESULTS: We treated 47 patients with (131)I-ch81C6 doses up to 4.44 GBq (120 mCi), including 35 with newly diagnosed tumors (strata A and B) and 12 with recurrent disease (stratum C). Dose-limiting hematologic toxicity defined the MTD to be 2.96 GBq (80 mCi) for all patients, regardless of treatment strata. Neurologic dose-limiting toxicity developed in 3 patients; however, none required further surgery to debulk radiation necrosis. Median survival was 88.6 wk and 65.0 wk for newly diagnosed and recurrent patients, respectively. CONCLUSION: The MTD of (131)I-ch81C6 is 2.96 GBq (80 mCi) because of dose-limiting hematologic toxicity. Although encouraging survival was observed, (131)I-ch81C6 was associated with greater hematologic toxicity, probably due to the enhanced stability of the IgG2 construct, than previously observed with (131)I-murine 81C6.

Authors
Reardon, DA; Quinn, JA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Dowell, JM; Rich, JN; Vredenburgh, JJ; Desjardins, A; Sampson, JH; Gururangan, S; Wong, TZ; Badruddoja, MA; Zhao, X-G; Bigner, DD; Zalutsky, MR
MLA Citation
Reardon, DA, Quinn, JA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Pegram, CN, Provenzale, JM, Dowell, JM, Rich, JN, Vredenburgh, JJ, Desjardins, A, Sampson, JH, Gururangan, S, Wong, TZ, Badruddoja, MA, Zhao, X-G, Bigner, DD, and Zalutsky, MR. "Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results." J Nucl Med 47.6 (June 2006): 912-918.
PMID
16741299
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
47
Issue
6
Publish Date
2006
Start Page
912
End Page
918

Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma. PATIENTS AND METHODS: Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed. RESULTS: Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease. CONCLUSION: We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.

Authors
Reardon, DA; Quinn, JA; Vredenburgh, JJ; Gururangan, S; Friedman, AH; Desjardins, A; Sathornsumetee, S; Herndon, JE; Dowell, JM; McLendon, RE; Provenzale, JM; Sampson, JH; Smith, RP; Swaisland, AJ; Ochs, JS; Lyons, P; Tourt-Uhlig, S; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Reardon, DA, Quinn, JA, Vredenburgh, JJ, Gururangan, S, Friedman, AH, Desjardins, A, Sathornsumetee, S, Herndon, JE, Dowell, JM, McLendon, RE, Provenzale, JM, Sampson, JH, Smith, RP, Swaisland, AJ, Ochs, JS, Lyons, P, Tourt-Uhlig, S, Bigner, DD, Friedman, HS, and Rich, JN. "Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma." Clin Cancer Res 12.3 Pt 1 (February 1, 2006): 860-868.
PMID
16467100
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
3 Pt 1
Publish Date
2006
Start Page
860
End Page
868
DOI
10.1158/1078-0432.CCR-05-2215

Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results.

PURPOSE: To assess the efficacy and toxicity of intraresection cavity iodine-131-labeled murine antitenascin monoclonal antibody 81C6 (131I-m81C6) among recurrent malignant brain tumor patients. PATIENTS AND METHODS: In this phase II trial, 100 mCi of 131I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy. RESULTS: With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis. CONCLUSION: In this single-institution phase II study, administration of 100 mCi of 131I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific 131I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.

Authors
Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Badruddoja, M; Dowell, JM; Wong, TZ; Zhao, X-G; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Pegram, CN, Provenzale, JM, Quinn, JA, Rich, JN, Vredenburgh, JJ, Desjardins, A, Gururangan, S, Badruddoja, M, Dowell, JM, Wong, TZ, Zhao, X-G, Zalutsky, MR, and Bigner, DD. "Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results." J Clin Oncol 24.1 (January 1, 2006): 115-122.
PMID
16382120
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
1
Publish Date
2006
Start Page
115
End Page
122
DOI
10.1200/JCO.2005.03.4082

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

PURPOSE: We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS: Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION: Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Authors
Reardon, DA; Egorin, MJ; Quinn, JA; Rich, JN; Gururangan, S; Vredenburgh, JJ; Desjardins, A; Sathornsumetee, S; Provenzale, JM; Herndon, JE; Dowell, JM; Badruddoja, MA; McLendon, RE; Lagattuta, TF; Kicielinski, KP; Dresemann, G; Sampson, JH; Friedman, AH; Salvado, AJ; Friedman, HS
MLA Citation
Reardon, DA, Egorin, MJ, Quinn, JA, Rich, JN, Gururangan, S, Vredenburgh, JJ, Desjardins, A, Sathornsumetee, S, Provenzale, JM, Herndon, JE, Dowell, JM, Badruddoja, MA, McLendon, RE, Lagattuta, TF, Kicielinski, KP, Dresemann, G, Sampson, JH, Friedman, AH, Salvado, AJ, and Friedman, HS. "Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme." J Clin Oncol 23.36 (December 20, 2005): 9359-9368.
PMID
16361636
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
36
Publish Date
2005
Start Page
9359
End Page
9368
DOI
10.1200/JCO.2005.03.2185

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma.

BACKGROUND: The authors determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan (CPT-11), a topoisomerase I inhibitor, when administered with temozolomide among patients with recurrent malignant glioma (MG). METHODS: Patients with MG at any recurrence received temozolomide (TMZ) at a dose of 200 mg/m(2)/day on Days 1-5 plus CPT-11 administered as a 90-minute intravenous infusion during Weeks 1, 2, 4, and 5 of each 6-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing anticonvulsants (enzyme-inducing antiepileptic drugs [EIAEDs]). The CPT-11 dose was escalated in successive cohorts of patients independently for each stratum. RESULTS: CPT-11, at doses ranging from 40 mg/m(2) to 375 mg/m(2), was administered with TMZ to 107 patients. Ninety-one patients (85%) had recurrent glioblastoma multiforme (GBM) and 16 (15%) had recurrent anaplastic glioma. Sixty-eight patients (64%) were given EIAEDs. The MTD of CPT-11 for patients concurrently receiving and not receiving EIAEDs was 325 mg/m(2) and 125 mg/m(2), respectively. The DLTs were hematologic, gastrointestinal, and hepatic. Fifteen patients (14%) achieved either a radiographic complete (n = 5) or partial (n = 10) response across a wide range of CPT-11 dose levels. Patients with recurrent GBM who achieved radiographic response had a median time to disease progression of 54.9 weeks. CONCLUSIONS: The current study built on preclinical observations designed to increase the clinical activity of topoisomerase I inhibitors. CPT-11, administered at full dose levels, was well tolerated in combination with TMZ. Furthermore, durable responses were observed in this recurrent population. Ongoing Phase II studies will evaluate the efficacy of this regimen and its application to other malignancies.

Authors
Reardon, DA; Quinn, JA; Rich, JN; Desjardins, A; Vredenburgh, J; Gururangan, S; Sathornsumetee, S; Badruddoja, M; McLendon, R; Provenzale, J; Herndon, JE; Dowell, JM; Burkart, JL; Newton, HB; Friedman, AH; Friedman, HS
MLA Citation
Reardon, DA, Quinn, JA, Rich, JN, Desjardins, A, Vredenburgh, J, Gururangan, S, Sathornsumetee, S, Badruddoja, M, McLendon, R, Provenzale, J, Herndon, JE, Dowell, JM, Burkart, JL, Newton, HB, Friedman, AH, and Friedman, HS. "Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma." Cancer 104.7 (October 1, 2005): 1478-1486.
PMID
16088964
Source
pubmed
Published In
Cancer
Volume
104
Issue
7
Publish Date
2005
Start Page
1478
End Page
1486
DOI
10.1002/cncr.21316

Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.

Authors
Quinn, JA; Desjardins, A; Weingart, J; Brem, H; Dolan, ME; Delaney, SM; Vredenburgh, J; Rich, J; Friedman, AH; Reardon, DA; Sampson, JH; Pegg, AE; Moschel, RC; Birch, R; McLendon, RE; Provenzale, JM; Gururangan, S; Dancey, JE; Maxwell, J; Tourt-Uhlig, S; Herndon, JE; Bigner, DD; Friedman, HS
MLA Citation
Quinn, JA, Desjardins, A, Weingart, J, Brem, H, Dolan, ME, Delaney, SM, Vredenburgh, J, Rich, J, Friedman, AH, Reardon, DA, Sampson, JH, Pegg, AE, Moschel, RC, Birch, R, McLendon, RE, Provenzale, JM, Gururangan, S, Dancey, JE, Maxwell, J, Tourt-Uhlig, S, Herndon, JE, Bigner, DD, and Friedman, HS. "Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma." J Clin Oncol 23.28 (October 1, 2005): 7178-7187.
PMID
16192602
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
28
Publish Date
2005
Start Page
7178
End Page
7187
DOI
10.1200/JCO.2005.06.502

Chemotherapy and novel therapeutic approaches in malignant glioma.

Glial neoplasms represent 0.5-1% of all cancers in most Western countries. Malignant gliomas are among the most devastating cancers, leading to death in most cases. They present unique challenges due to their location, aggressive biological behavior and diffuse infiltrative growth. Notwithstanding the development of new surgical and radiation techniques in the last thirty years, a cure for malignant gliomas remains elusive. In this article, we will review the standard and new therapies used for malignant gliomas. As standard therapies, surgery, radiation therapy and systemic chemotherapy, are in a continuous process of evolution. Multiple chemotherapies have been used in malignant gliomas, as single agents, in combination, or with different modes of administration, including high-dose chemotherapy with stem cell rescue and intra-arterial chemotherapy. The last decade has been noticeable for the advent of a better understanding of the biology of malignant gliomas. This has stimulated active research in multiples areas and the advent of new treatment strategies. Techniques to circumvent the resistance mechanisms to chemotherapy have been evaluated, tyrosine kinase inhibitors have shown activity in malignant primary brain tumors and radioimmunotherapy remains an area of active research. In this article, we review the past, present and future treatments of malignant gliomas with a special interest on chemotherapy, resistance mechanisms and tyrosine kinase inhibitors.

Authors
Desjardins, A; Rich, JN; Quinn, JA; Vredenburgh, J; Gururangan, S; Sathornsumetee, S; Reardon, DA; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Desjardins, A, Rich, JN, Quinn, JA, Vredenburgh, J, Gururangan, S, Sathornsumetee, S, Reardon, DA, Friedman, AH, Bigner, DD, and Friedman, HS. "Chemotherapy and novel therapeutic approaches in malignant glioma. (Published online)" Front Biosci 10 (September 1, 2005): 2645-2668. (Review)
PMID
15970525
Source
pubmed
Published In
Frontiers in bioscience : a journal and virtual library
Volume
10
Publish Date
2005
Start Page
2645
End Page
2668

Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors: The Sherbrooke experience

BACKGROUND. The treatment of malignant brain tumors is hampered by the presence of the blood-brain barrier, which limits chemotherapy penetration to the central nervous system (CNS). In recent years, different strategies have been designed to circumvent this physiologic barrier. The osmotic blood-brain barrier disruption (BBBD) procedure is one such strategy, and has been studied extensively in preclinical and clinical studies. The authors detail their experience so far with the procedure in the context of an open Phase II study in the treatment of malignant brain tumors. METHODS. Patients with histologically proven malignant gliomas, primitive neuroectodermal tumors, primary CNS lymphomas, and metastatic disease to the brain were eligible. Patients enrolled were treated every 4 weeks (1 cycle) for ≤ 12 cycles. A methotrexate-based regimen was offered to patients with lymphomas, whereas a carboplatin-based regimen was offered to patients with all other histologies. Before intraarterial chemotherapy infusion, patients were submitted to an osmotic BBBD procedure. RESULTS. Seventy-two patients were included in the current report. The overall median survival times (MST) from treatment initiation for glioblastoma multiforme (GBM), anaplastic oligodendrogliomas, primary CNS lymphomas, and metastases were, respectively, 9.1, 13.9, not reached, and 9.9 months, whereas time to disease progression was 4.1, 9.2, 12.3, and 3.3 months. The MST from diagnosis was 32.2 months for GBM. CONCLUSIONS. These encouraging results prompted the authors to further refine their knowledge of the potential contribution of this procedure in the treatment of brain tumors. These authors designed a randomized Phase III study for patients with GBM that is now open.

Authors
Fortin, D; Desjardins, A; Benko, A; Niyonsega, T; Boudrias, M
MLA Citation
Fortin, D, Desjardins, A, Benko, A, Niyonsega, T, and Boudrias, M. "Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors: The Sherbrooke experience." Cancer 103.12 (2005): 2606-2615.
PMID
15880378
Source
scival
Published In
Cancer
Volume
103
Issue
12
Publish Date
2005
Start Page
2606
End Page
2615
DOI
10.1002/cncr.21112

Technical modification in the intracarotid chemotherapy and osmotic blood-brain barrier disruption procedure to prevent the relapse of carboplatin-induced orbital pseudotumor

The blood-brain barrier disruption (BBBD) procedure is an established strategy to enhance drug delivery to brain tumors. Complication rates associated with this procedure are usually low, but when complications do occur, they usually mandate discontinuation of treatment. Orbital pseudotumor is an inflammatory condition of one or more extraocular muscles that produces limitation of ocular motility. Patients usually experience sudden diplopia associated with orbital pain, conjunctival chemosis and injection, and proptosis. Imaging of the orbit shows diffuse enlargement of the extraocular muscles, exophthalmia, and, rarely, sinusal or intracranial infiltration. On pathologic examinations, the soft tissues of the orbit are infiltrated with a mixture of eosinophils, lymphocytes, and plasma cells. Many etiologies can induce this syndrome, including the intracarotid infusion of platinum molecules. As part of a phase II study, a total of 110 patients were treated for malignant brain tumors with intra-arterial carboplatin, enhanced by the BBBD procedure, at the Sherbrooke University Hospital. Here we report on three patients who developed orbital pseudotumor ipsilateral to the carotid infused a few hours to days after the procedure. After the occurrence of this syndrome in the first patient, we developed a technical modification to the procedure that enabled uninterrupted treatment in the other two patients. This modification was as follows: after the mannitol infusion, and before carboplatin, the catheter was changed for a 3.5 tracker and was repositioned just above the emergence of the ophthalmic artery.

Authors
Fortin, D; Salamé, JA; Desjardins, A; Benko, A
MLA Citation
Fortin, D, Salamé, JA, Desjardins, A, and Benko, A. "Technical modification in the intracarotid chemotherapy and osmotic blood-brain barrier disruption procedure to prevent the relapse of carboplatin-induced orbital pseudotumor." American Journal of Neuroradiology 25.5 (2004): 830-834.
PMID
15140730
Source
scival
Published In
American Journal of Neuroradiology
Volume
25
Issue
5
Publish Date
2004
Start Page
830
End Page
834
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