University of Wisconsin–Madison
Ian Robins, MD

H. Ian Robins, MD, PhD

Professor

Department of Medicine

Department of Human Oncology

Department of Neurology

I am a professor in the Departments of Medicine, Human Oncology and Neurology. My board certification includes internal medicine and medical oncology. I am a fellow of the American College of Physicians and a nationally and internationally recognized investigator in the area of neuro-oncology. I have served as a principal investigator on various National Institutes of Health/National Cancer Institute cooperative group protocols and continue to have NIH support. I am currently listed among Best Doctors® in America and America’s Top Doctors for Cancer. I participate in the Radiation Therapy Oncology Group, the Eastern Cooperative Oncology Group and Alliance Oncology and am on the executive neuro-oncology committees of these groups. I have published more than 200 peer-reviewed papers, 40 books and chapters and 200 abstracts. Much of my clinical activity relates to an interdisciplinary neuro-oncology clinic located in the Radiation Oncology Department.

Education

Fellow, Wisconsin Clinical Cancer Center, Research Oncology (1982)

Fellow, Wisconsin Clinical Cancer Center, Clinical Oncology (1981)

Resident, University of Wisconsin–Madison, Internal Medicine (1979)

Intern, University of Wisconsin–Madison, Internal Medicine (1977)

MD, Boston University School of Medicine, Medicine (1976)

PhD, Boston University, Molecular Biology and Radiation Biology (1971)

AM, Boston University, Biochemistry (1968)

AB, Boston University, Biology (1966)

Academic Appointments

Professor, Neurology (1993)

Professor, Human Oncology, Medicine (1992)

Director, University of Wisconsin Clinical Cancer Center Clinical Trials Unit (1991–1992)

Chief, Medical Oncology, Department of Medicine (1990–1993)

Associate Director, University of Wisconsin Clinical Cancer Center Clinical Trials Unit (1990–1991)

Associate Professor, Neurology (1988)

Associate Director, University of Wisconsin General Clinical Research Center (1986)

Associate Professor, Human Oncology, Medicine (1986)

Assistant Professor, Human Oncology, Medicine (1983)

Instructor, Human Oncology, Medicine (1982)

Selected Honors and Awards

UW Physican Excellence Award (2014)

America’s Top Doctors for Cancer (Castle Connolly) (2014–2017)

Best Doctors® in America (2011-2016)

American College of Radiology Appropriateness Criteria Committee: Brain Metastases (2008–2015)

American College of Radiology, CNS Quality & Safety (2009)

European Whole Body Hyperthermia Award (2000)

International Society of Police Surgeons

Fellow, American Board of Forensic Examiners

F.M. Kirby Clinical Research Award (1994)

Fellow, American College of Physicians

Fellow, American College of Physicians

American Cancer Society, Junior Faculty Clinical Fellowship (1983–1986)

American Cancer Society Fellow

Sigma Xi

N.I.H. Postdoctoral Fellowship

Shields Warren Radiation Biology Fellow

Boston University Teaching Fellow

Boards, Advisory Committees and Professional Organizations

New York Academy of Sciences

American Association for the Advancement of Science

American College of Physicians

International Clinical Hyperthermia Society Board of Directors (1983–1985)

Radiation Research Society

North American Hyperthermia Group

World Medical Association

Consultant, Wisconsin Cancer Information Service

Wisconsin Oncology Group

American Federation for Clinical Research

Eastern Cooperative Oncology Group

European Society for Hyperthermic Oncology

Veterinary Cancer Society

Transplantation Society

Collaborative Ocular Melanoma Study Group

Systemic Hyperthermia Oncological Working Group (SHOWG)

American Society of Forensic Medicine

American Society of Forensic Examiners

American Society of Clinical Hypnosis

Wisconsin Society of Clinical Hypnosis

Minnesota Society of Clinical Hypnosis

Society of Neuro-Oncology

Radiation Therapy Oncology Group

Wisconsin Medical Society

American Society for Therapeutic Radiology and Oncology (ASTRO)

North American Brain Tumor Consortium

Research Focus

Neuro-oncology

  • Phase 2 Study of Radiation Therapy Plus Low Dose Temozolomide Followed by Temozolomide and Irinotecan for Glioblastoma: NRG Oncology RTOG Trial 0420. Int J Radiat Oncol Biol Phys
    Lieberman FS, Wang M, Robins HI, Tsien CI, Curran WJ, Werner-Wasik M, Smith RP, Schultz C, Hartford AC, Zhang P, Mehta MP
    2018 Nov 26; :
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      PURPOSE: Evaluate the toxicity and efficacy of adjuvant temozolomide (TMZ) and irinotecan (CPT-11) for 12 months following concurrent chemo-radiation in newly diagnosed glioblastoma (GBM).

      METHODS: Trial XXXX, a single arm, multi-institutional phase 2 trial was designed to determine the efficacy and toxicity of concomitant TMZ and radiation (RT) followed by adjuvant TMZ combined with CPT-11 given for 12 cycles compared to historical controls of adjuvant TMZ alone given for 6 cycles.

      RESULTS: A total of 170 patients were enrolled, of which 152 were eligible. Adjuvant CPT-11 combined with TMZ was more toxic than expected. A higher rate of hematologic and gastrointestinal toxicities was most frequently noted with the combination regimen compared to adjuvant TMZ alone. Grade 3/4 hematologic toxicity was 38% compared to 14% reported in the Stupp trial. Following an early interim analysis, adjuvant CPT-11 dose was reduced to100 mg/m2 D1 and D15 for the first cycle. CPT-11 dose escalation proceeded over first 3 cycles if tolerated. Median overall survival (OS) for all eligible patients was 16.9 months compared to 13.7 months of the historical control (p=0.03). Post-hoc subgroup analysis suggested an improvement in OS for patients with RTOG recursive partitioning analysis (RPA) Class III although limited to 22 patients (14% of eligible patients).

      CONCLUSIONS: Although Irinotecan and TMZ for 12 cycles given after chemoradiation for patients with newly diagnosed GBM significantly improved median survival compared to historical control data at the time the study was conducted, the historical control median survival time of 13.7 months does not represent the current benchmark for this patient population. Treatment intensification does prolong overall survival compared to the current standard.

      View details for PubMedID 30496882
  • Vision loss in glioblastoma: Disease mimicking presumed therapeutic toxicity. Neurooncol Pract
    Nguyen HN, Vo KBH, Howard S, Salamat MS, Rowely H, Robins HI
    2018 Nov; 5 (4): 223-226
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      Glioblastoma is the most common and lethal form of primary brain cancer. In the recurrent setting, bevacizumab is a common choice for salvage therapy. Loss of vision in patients initially treated with radiation at the time of diagnosis and later treated with bevacizumab at time of recurrence has been reported, and presumed to be a treatment-related optic neuropathy. Strikingly, only 1 case report described a postmortem biopsy to rule out tumor involvement of the optic tracts. We report the first case of recurrent glioblastoma infiltrating the prechiasmatic and chiasmatic optic nerve, which at the time of vision loss was presumed to be secondary to bevacizumab. It is noteworthy that the MRI findings in the previously reported bevacizumab/radiation-induced optic neuropathy cases (without pathology follow-up) are comparable to our patient.

      View details for PubMedID 30402261
  • Molecular Evolution of a Glioblastoma Controlled With Tumor Treating Fields and Concomitant Temozolomide. Front Oncol
    Robins HI, Nguyen HN, Field A, Howard S, Salamat S, Deming DA
    2018; 8: 451
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      Tumor Treating Field (TTFields) therapy has demonstrated efficacy in a Phase 3 study of newly diagnosed glioblastoma (GB) following radiation (RT) and temozolomide (TMZ). We report the appearance of an isolated satellite anterior temporal lobe lesion, 2 months post primary RT/TMZ directed at the primary GB (MGMT methylated) parietal lobe lesion and one adjuvant cycle of TMZ and TTFields. The mean RT dose delivered to the temporal lobe lesion was negligible, i.e., 4.53 ± 0.95 Gy. Mapping of the generated TTFields demonstrated that both lesions were encompassed by a field intensity in a therapeutic range. The temporal lobe lesion remained under the control of TTFields up to 12 months, at which point progression on a T1 contrast MRI resulted in surgery and a definitive diagnosis of GB without MGMT methylation. The primary parietal lobe at this time was in remission. Molecular sequencing on the GB tissue from multiple time points demonstrates clonal evolution of the cancer over time and in response to treatment.

      View details for PubMedID 30374424
  • Association of MGMT Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide: An Analysis From the NRG Oncology/RTOG 0424 Trial. JAMA Oncol
    Bell EH, Zhang P, Fisher BJ, Macdonald DR, McElroy JP, Lesser GJ, Fleming J, Chakraborty AR, Liu Z, Becker AP, Fabian D, Aldape KD, Ashby LS, Werner-Wasik M, Walker EM, Bahary JP, Kwok Y, Yu HM, Laack NN, Schultz CJ, Gray HJ, Robins HI, Mehta MP, Chakravarti A
    2018 Jun 28; :
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      Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial-evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes-was not previously reported.

      Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes.

      Design, Setting, and Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses.

      Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS).

      Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P < .001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P < .001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P = .045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P = .02).

      Conclusions and Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status.

      Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.

      View details for PubMedID 29955793
  • Influence of Residual Disease Following Surgical Resection in Newly Diagnosed Glioblastoma on Clinical, Neurocognitive, and Patient Reported Outcomes. Neurosurgery
    Hall WA, Pugh SL, Wefel JS, Armstrong TS, Gilbert MR, Brachman DG, Werner-Wasik M, Wendland MM, Brown PD, Chao ST, Roof KS, Robins HI, Mehta MP, Curran WJ, Movsas B
    2018 Mar 30; :
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      BACKGROUND: The influence of subtotal resection (STR) on neurocognitive function (NCF), quality of life, and symptom burden in glioblastoma is unknown. If bevacizumab preferentially benefits patients with STR is unknown.

      OBJECTIVE: To examine these uncertainties.

      METHODS: NCF and patient reported outcomes (PRO) were prospectively collected in NRG Oncology RTOG 0525 and 0825. Changes in NCF and PRO measures from baseline to prespecified times were examined by Wilcoxon test, and mixed effects longitudinal modeling, to assess differences between patients who received STR vs gross-total resection. Changes were also compared among STR patients on 0825 receiving placebo vs bevacizumab to assess for a preferential therapeutic effect. Overall survival between STR and gross-total resection patients was compared using the Kaplan-Meier method.

      RESULTS: A total of 427 patients were eligible with STR present in 37%. At baseline, patients with STR had worse NCF, worse MD Anderson Symptom Inventory Brain Tumor Neurological Factor ratings (P = .004), and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (P = .002). Longitudinal multivariate analysis associated STR with worse NCF (Hopkins Verbal Learning Test-Revised Delayed Recognition [P = .048], Trail Making Test Part A [P = .035], and Controlled Oral Word Association [P = .049]). One hundred eighty-three STR patients from 0825 were analyzed (89 bevacizumab, 94 placebo); bevacizumab failed to demonstrate improvement in select NCF or PRO measures.

      CONCLUSION: STR patients had worse NCF and PROs before therapy. During adjuvant therapy, STR patients had worse objective NCF, despite accounting for tumor location. STR did not result in a detriment to OS. The addition of bevacizumab did not preferentially improve PRO or NCF outcomes in STR patients.

      View details for PubMedID 29618054
  • Survival of patients with prior anti-angiogenic therapy. Neuro Oncol
    Eickhoff J, Robins HI
    2018 Mar 27; :
  • Go, no-go decision making for phase 3 clinical trials: ACT IV revisited. Lancet Oncol
    Nguyen HTN, Grogan P, Robins HI
    2017 12; 18 (12): e708
  • Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02. J Neurooncol
    Nghiemphu PL, Ebiana VA, Wen P, Gilbert M, Abrey LE, Lieberman F, DeAngelis LM, Robins HI, Yung WKA, Chang S, Drappatz J, Mehta MP, Levin VA, Aldape K, Dancey JE, Wright JJ, Prados M, Kuhn J, Cloughesy TF
    2017 Oct 07; :
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      Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

      View details for PubMedID 28988377
  • PET/CT imaging of the diapeutic alkylphosphocholine analog (124)I-CLR1404 in high and low-grade brain tumors. Am J Nucl Med Mol Imaging
    Hall LT, Titz B, Robins HI, Bednarz BP, Perlman SB, Weichert JP, Kuo JS
    2017; 7 (4): 157-166
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      CLR1404 is a cancer-selective alkyl phosphocholine (APC) analog that can be radiolabeled with (124)I for PET imaging, (131)I for targeted radiotherapy and/or SPECT imaging, or (125)I for targeted radiotherapy. Studies have demonstrated avid CLR1404 uptake and prolonged retention in a broad spectrum of preclinical tumor models. The purpose of this pilot trial was to demonstrate avidity of (124)I-CLR1404 in human brain tumors and develop a framework to evaluate this uptake for use in larger studies. 12 patients (8 men and 4 women; mean age of 43.9 ± 15.1 y; range 23-66 y) with 13 tumors were enrolled. Eleven patients had suspected tumor recurrence and 1 patient had a new diagnosis of high grade tumor. Patients were injected with 185 MBq ± 10% of (124)I-CLR1404 followed by PET/CT imaging at 6-, 24-, and 48-hour. (124)I-CLR1404 PET uptake was assessed qualitatively and compared with MRI. After PET image segmentation SUV values and tumor to background ratios were calculated. There was no significant uptake of (124)I-CLR1404 in normal brain. In tumors, uptake tended to increase to 48 hours. Positive uptake was detected in 9 of 13 lesions: 5/5 high grade tumors, 1/2 low grade tumors, 1/1 meningioma, and 2/4 patients with treatment related changes. (124)I-CLR1404 uptake was not detected in 1/2 low grade tumors, 2/4 lesions from treatment related changes, and 1/1 indeterminate lesion. For 6 malignant tumors, the average tumor to background ratios (TBR) were 9.32 ± 4.33 (range 3.46 to 15.42) at 24 hours and 10.04 ± 3.15 (range 5.17 to 13.17) at 48 hours. For 2 lesions from treatment related change, the average TBR were 5.05 ± 0.4 (range 4.76 to 5.33) at 24 hours and 4.88 ± 1.19 (range 4.04 to 5.72) at 48 hours. PET uptake had areas of both concordance and discordance compared with MRI. (124)I-CLR1404 PET demonstrated avid tumor uptake in a variety of brain tumors with high tumor-to-background ratios. There were regions of concordance and discordance compared with MRI, which has potential clinical relevance. Expansion of these studies is required to determine the clinical significance of the (124)I-CLR1404 PET findings.

      View details for PubMedID 28913154
  • Impact of PET and MRI threshold-based tumor volume segmentation on patient-specific targeted radionuclide therapy dosimetry using CLR1404. Phys Med Biol
    Besemer AE, Titz B, Grudzinski JJ, Weichert JP, Kuo JS, Robins HI, Hall LT, Bednarz BP
    2017 Jul 06; 62 (15): 6008-6025
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      Variations in tumor volume segmentation methods in targeted radionuclide therapy (TRT) may lead to dosimetric uncertainties. This work investigates the impact of PET and MRI threshold-based tumor segmentation on TRT dosimetry in patients with primary and metastatic brain tumors. In this study, PET/CT images of five brain cancer patients were acquired at 6, 24, and 48 h post-injection of 124I-CLR1404. The tumor volume was segmented using two standardized uptake value (SUV) threshold levels, two tumor-to-background ratio (TBR) threshold levels, and a T1 Gadolinium-enhanced MRI threshold. The dice similarity coefficient (DSC), jaccard similarity coefficient (JSC), and overlap volume (OV) metrics were calculated to compare differences in the MRI and PET contours. The therapeutic 131I-CLR1404 voxel-level dose distribution was calculated from the 124I-CLR1404 activity distribution using RAPID, a Geant4 Monte Carlo internal dosimetry platform. The TBR, SUV, and MRI tumor volumes ranged from 2.3-63.9 cc, 0.1-34.7 cc, and 0.4-11.8 cc, respectively. The average  ±  standard deviation (range) was 0.19  ±  0.13 (0.01-0.51), 0.30  ±  0.17 (0.03-0.67), and 0.75  ±  0.29 (0.05-1.00) for the JSC, DSC, and OV, respectively. The DSC and JSC values were small and the OV values were large for both the MRI-SUV and MRI-TBR combinations because the regions of PET uptake were generally larger than the MRI enhancement. Notable differences in the tumor dose volume histograms were observed for each patient. The mean (standard deviation) 131I-CLR1404 tumor doses ranged from 0.28-1.75 Gy GBq-1 (0.07-0.37 Gy GBq-1). The ratio of maximum-to-minimum mean doses for each patient ranged from 1.4-2.0. The tumor volume and the interpretation of the tumor dose is highly sensitive to the imaging modality, PET enhancement metric, and threshold level used for tumor volume segmentation. The large variations in tumor doses clearly demonstrate the need for standard protocols for multimodality tumor segmentation in TRT dosimetry.

      View details for PubMedID 28682793
  • The effect of Optune™ Tumor Treating Fields transducer arrays on skin radiation dose during radiotherapy. J Clin Neurosci
    Bender E, Kozak K, Howard S, Hayes L, Bayouth J, Robins HI
    2017 Aug; 42: 172-175
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      A Phase 3 clinical study demonstrated that the addition of 200kHz Tumor Treating Fields (TTF) to temozolomide in the post-radiation (RT) phase of therapy in newly diagnosed glioblastoma increases progression free and overall survival (resulting in FDA and European Union approval). Preclinical studies have demonstrated the ability of TTF to act as a radiosensitizer, suggesting concurrent TTF and RT may have clinical utility. The removal and replacement of TTF transducer arrays from the scalps of patients on a daily basis, i.e., just before and after RT treatments, would be extremely cumbersome. Based on these considerations, phantom studies of the effect of Optune (TM) transducer arrays on radiation dose distribution were performed to evaluate the feasibility of leaving arrays in place during RT. Film measurements were performed using Gafchromic EBT3 film and an Epson 11000XL scanner. Film calibration was done based on the ratio of the red to blue color channel data. A Siemens Oncor linear accelerator operating at 6MV, 10cm×10cm field size, and 100cm source-to-film distance was used for all measurements. For each exposure, two films were stacked, providing planes of measurement that were ∼0.1 and 0.4mm in depth. Data accrued demonstrated that radiation attenuation should not be a clinically significant issue. However, TTF transducer arrays were found to cause both a radiation bolus effect, as well as an increased exit dose effect. These studies predict increased skin toxicity, which merits significant caution for further clinical development of this combination.

      View details for PubMedID 28427800
  • Cancer-related cognitive impairment and its relation to PTSD. Breast
    Robins HI, Johnson L, LoConte N, Brandt K
    2017 08; 34: 134
  • Karenitecin (bnp1350) and flavopridol as radiosensitizers in malignant glioma. J Neurol Neuromedicine
    Rajesh D, Robins HI, Howard SP
    2016; 1 (6): 1-10
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      The poor prognosis of malignant glioma patients highlights the need to develop low toxicity, tumor specific agents with the ability to synergize with proven efficacious treatment modalities, e.g., ionizing irradiation. This paper investigates the potential of BNP1350 (karenitecin), a topoisomerase I-targeting anticancer agent, and flavopridol a cyclin-dependent kinase inhibitor as radiosensitizers at clinically relevant doses in glioblastoma cell lines. A clonogenic survival and apoptosis assays were performed to test the effect of karenitecin (0.1 nM to 10 nM), flavopridol, (50 nM to 500 nM), radiation (1 Gy to 5.5 Gy) and a combination of radiation and karenitecin or radiation and flavopridol on the glioma cell lines T986 and M059K. Cells were stained for cyclins B and D using antibodies followed by flow cytometry. Propidium Iodide staining was used to reveal the various phases of the cell cycle; cyclin staining in the G0/G1 and G2/M phase of the cell cycle was estimated as the Mean Fluorescence Intensity (MFI) after subtracting the MFI recorded by the isotype controls. Results demonstrated that in irradiated cells, pretreatment with karenitecin induced apoptosis, a transient arrest in the G2/M phase of the cell cycle and increased the expression of cyclin B1. Flavopridol treatment also induced apoptosis and a transient block in the G2/M phase of the cell cycle. The combined effects of karenitecin and flavopridol displayed synergistic effects. The unique radiosensitizing activity of orally administrable karenitecin and flavopridol is consistent with continued investigation of these compounds preclinically, as well as in the clinical setting.

      View details for PubMedID 28111642
  • Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813. Neuro Oncol
    Chang S, Zhang P, Cairncross JG, Gilbert MR, Bahary JP, Dolinskas CA, Chakravarti A, Aldape KD, Bell EH, Schiff D, Jaeckle K, Brown PD, Barger GR, Werner-Wasik M, Shih H, Brachman D, Penas-Prado M, Robins HI, Belanger K, Schultz C, Hunter G, Mehta M
    2017 02 01; 19 (2): 252-258
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      Background: The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome.

      Methods: Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99). The study closed early because the target accrual rate was not met.

      Results: Median follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P = .36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+NU arm experienced more grade ≥3 toxicity (75.8% vs 47.9%, P < .001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1-R132H status (60 RT+TMZ and 51 RT+NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P = .004, HR = 0.50; 95% CI, 0.31-0.81).

      Conclusions: RT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival.

      View details for PubMedID 27994066
  • The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells. J Clin Neurosci
    Clark PA, Gaal JT, Strebe JK, Pasch CA, Deming DA, Kuo JS, Robins HI
    2017 Feb; 36: 120-124
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      A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a ⩾10-fold increase in TMZ resistance of MGMT-expressing (12.1GSCs: IC50=160μM; 22GSCs: IC50=44μM) compared to MGMT non-expressing (33GSCs: IC50=1.5μM; 114GSCs: IC50=5.2μM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500kHz) with an optimal frequency of 200kHz. At 200kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1GSC: 74±2.9% and 38±3.2%, respectively; 22GSC: 61±11% and 38±2.6%, respectively; 33GSC: 56±9.5% and 60±7.1%, respectively; 114 GSC: 79±3.5% and 41±4.3%, respectively). In combination, TTFields (200kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., ± MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications.

      View details for PubMedID 27865821
  • Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol
    Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler KW, Jones DT, Luu B, Cavalli FM, Aldape K, Remke M, Mynarek M, Rutkowski S, Gururangan S, McLendon RE, Lipp ES, Dunham C, Hukin J, Eisenstat DD, Fulton D, van Landeghem FK, Santi M, van Veelen ML, Van Meir EG, Osuka S, Fan X, Muraszko KM, Tirapelli DP, Oba-Shinjo SM, Marie SK, Carlotti CG, Lee JY, Rao AA, Giannini C, Faria CC, Nunes S, Mora J, Hamilton RL, Hauser P, Jabado N, Petrecca K, Jung S, Massimi L, Zollo M, Cinalli G, Bognár L, Klekner A, Hortobágyi T, Leary S, Ermoian RP, Olson JM, Leonard JR, Gardner C, Grajkowska WA, Chambless LB, Cain J, Eberhart CG, Ahsan S, Massimino M, Giangaspero F, Buttarelli FR, Packer RJ, Emery L, Yong WH, Soto H, Liau LM, Everson R, Grossbach A, Shalaby T, Grotzer M, Karajannis MA, Zagzag D, Wheeler H, von Hoff K, Alonso MM, Tuñon T, Schüller U, Zitterbart K, Sterba J, Chan JA, Guzman M, Elbabaa SK, Colman H, Dhall G, Fisher PG, Fouladi M, Gajjar A, Goldman S, Hwang E, Kool M, Ladha H, Vera-Bolanos E, Wani K, Lieberman F, Mikkelsen T, Omuro AM, Pollack IF, Prados M, Robins HI, Soffietti R, Wu J, Metellus P, Tabori U, Bartels U, Bouffet E, Hawkins CE, Rutka JT, Dirks P, Pfister SM, Merchant TE, Gilbert MR, Armstrong TS, Korshunov A, Ellison DW, Taylor MD
    2016 Jul 20; 34 (21): 2468-77
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      PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.

      METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.

      RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.

      CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.

      View details for PubMedID 27269943
  • Erlotinib for the treatment of brain metastases in non-small cell lung cancer. Expert Opin Pharmacother
    Brower JV, Robins HI
    2016; 17 (7): 1013-21
    • More

      INTRODUCTION: Brain metastases (BM) are a common and lethal complication of non-small cell lung cancer (NSCLC) with up to 40% experiencing this complication. The use of erlotinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, holds promise in this somewhat refractory cohort of patients, and has become the subject of active clinical investigation.

      AREAS COVERED: This review covers the preclinical and clinical studies of erlotonib as it relates to its use in the treatment of NSCLC patients with BM. A literature search in part utilized the PubMed database up through Dec 2015.

      EXPERT OPINION: Preclinical and retrospective data for erlotinib provide evidence of CNS penetration, and objective responses in the setting of BM from EGFR mutated NSCLC. Phase I and II data have demonstrated the feasibility of concomitant delivery of erlotinib and WBRT in the treatment of BM from NSCLC. Phase II/III data however, from non-EGFR mutation enriched populations, have demonstrated no benefit in progression free or overall survival with the addition of erlotinib to metastasis directed radiotherapy. Currently the utilization of erlotinib with WBRT or SRS is therefore investigational and may be a reasonable option in erlotinib naïve, EGFR mutated patients with refractory BM.

      View details for PubMedID 26967582
  • A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study. J Neurooncol
    Robins HI, Zhang P, Gilbert MR, Chakravarti A, de Groot JF, Grimm SA, Wang F, Lieberman FS, Krauze A, Trotti AM, Mohile N, Kee AY, Colman H, Cavaliere R, Kesari S, Chmura SJ, Mehta M
    2016 Jan; 126 (2): 309-16
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      This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT-888) was tested using two randomized schedules (5 vs. 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m(2) (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150-200 mg/m(2)) schedule was known from prior trials (arm2). Two cohorts were studied: bevacizumab (BEV) naïve (n = 151), and BEV refractory (n = 74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0 %. For the BEV refractory cohort, the PFS 6 was 4.4 %; for the BEV naïve cohort, PFS6 was 17 %. Overall survival was similar for both arms in both the BEV naïve [median survival time (MST) 10.3 M; 95 % CI 8.4-12] and BEV refractory cohort (MST 4.7 M; 95 %CI 3.5-5.6). The median PFS was essentially the same for both arms and both cohorts at ~2.0 M (95 % CI 1.9-2.1).

      View details for PubMedID 26508094
  • Multicenter phase 2 study of patupilone for recurrent or progressive brain metastases from non-small cell lung cancer. Cancer
    Nayak L, DeAngelis LM, Robins HI, Govindan R, Gadgeel S, Kelly K, Rigas JR, Peereboom DM, Rosenfeld SS, Muzikansky A, Zheng M, Urban P, Abrey LE, Omuro A, Wen PY
    2015 Dec 01; 121 (23): 4165-72
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      BACKGROUND: Treatment options for patients with non-small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood-brain barrier-penetrating, microtubule-targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases.

      METHODS: Adult patients with NSCLC and confirmed progressive brain metastases received patupilone intravenously at 10 mg/m(2) every 3 weeks. The primary endpoint of this multinomial 2-stage study combined early progression (EP; death or progression within 3 weeks) and progression-free survival at 9 weeks (PFS9w) to determine drug activity.

      RESULTS: Fifty patients with a median age of 60 years (range, 33-74 years) were enrolled; the majority were men (58%), and most had received prior therapy for brain metastases (98%). The PFS9w rate was 36%, and the EP rate was 26%. Patupilone blood pharmacokinetic analyses showed mean areas under the concentration-time curve from time zero to 504 hours for cycles 1 and 3 of 1544 and 1978 ng h/mL, respectively, and a mean steady state distribution volume of 755 L/m(2) . Grade 3/4 adverse events (AEs), regardless of their relation with the study drug, included diarrhea (24%), pulmonary embolisms (8%), convulsions (4%), and peripheral neuropathy (4%). All patients discontinued the study drug: 31 (62%) for disease progression and 13 (26%) for AEs. Twenty-five of 32 deaths were due to brain metastases. The median time to progression and the overall survival were 3.2 and 8.8 months, respectively.

      CONCLUSIONS: This is the first prospective study of chemotherapy for recurrent brain metastases from NSCLC. In this population, patupilone demonstrated activity in heavily treated patients.

      View details for PubMedID 26308485
  • Phase 1/2 trials of Temozolomide, Motexafin Gadolinium, and 60-Gy fractionated radiation for newly diagnosed supratentorial glioblastoma multiforme: final results of RTOG 0513. Int J Radiat Oncol Biol Phys
    Brachman DG, Pugh SL, Ashby LS, Thomas TA, Dunbar EM, Narayan S, Robins HI, Bovi JA, Rockhill JK, Won M, Curran WP
    2015 Apr 01; 91 (5): 961-7
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      PURPOSE: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls.

      METHODS AND MATERIALS: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method.

      RESULTS: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy.

      CONCLUSIONS: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

      View details for PubMedID 25832688
  • Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study. J Neurooncol
    Mehta MP, Wang D, Wang F, Kleinberg L, Brade A, Robins HI, Turaka A, Leahy T, Medina D, Xiong H, Mostafa NM, Dunbar M, Zhu M, Qian J, Holen K, Giranda V, Curran WJ
    2015 Apr; 122 (2): 409-17
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      Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood-brain barrier. This was a phase 1 dose-escalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10-300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were non-small cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, ≥15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only Grade 3/4 AEs deemed possibly related to veliparib observed in ≥2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9-13.5) and for the breast cancer subgroup was 7.7 mo (2.8-15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3-3.8) and 4.9 mo (4.2-5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing.

      View details for PubMedID 25682091
  • Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients. Neuro Oncol
    Vera-Bolanos E, Aldape K, Yuan Y, Wu J, Wani K, Necesito-Reyes MJ, Colman H, Dhall G, Lieberman FS, Metellus P, Mikkelsen T, Omuro A, Partap S, Prados M, Robins HI, Soffietti R, Wu J, Gilbert MR, Armstrong TS, CERN Foundation
    2015 Mar; 17 (3): 440-7
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      BACKGROUND: Ependymomas are rare CNS tumors. Previous studies describing the clinical course of ependymoma patients were restricted to small sample sizes, often with patients at a specific institution.

      METHODS: Clinically annotated ependymoma tissue samples from 19 institutions were centrally reviewed. Patients were all adults aged 18 years or older at the time of diagnosis. Potential prognostic clinical factors identified on univariate analysis were included in a multivariate Cox proportional hazards model with backwards selection to model progression-free survival.

      RESULTS: The 282 adult ependymoma patients were equally male and female with a mean age of 43 years (range, 18-80y) at diagnosis. The majority were grade II (78%) with the tumor grade for 20 cases being reclassified on central review (half to higher grade). Tumor locations were spine (46%), infratentorial (35%), and supratentorial (19%). Tumor recurrence occurred in 26% (n = 74) of patients with a median time to progression of 14 years. A multivariate Cox proportional hazards model identified supratentorial location (P < .01), grade III (anaplastic; P < .01), and subtotal resection, followed or not by radiation (P < .01), as significantly increasing risk of early progression.

      CONCLUSIONS: We report findings from an ongoing, multicenter collaboration from a collection of clinically annotated adult ependymoma tumor samples demonstrating distinct predictors of progression-free survival. This unique resource provides the opportunity to better define the clinical course of ependymoma for clinical and translational studies.

      View details for PubMedID 25121770
  • Strategies to prevent brain metastasis in high-risk non-small-cell lung cancer: lessons learned from a randomized study of maintenance temozolomide versus observation. Clin Lung Cancer
    Boggs DH, Robins HI, Langer CJ, Traynor AM, Berkowitz MJ, Mehta MP
    2014 Nov; 15 (6): 433-40
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      BACKGROUND: This study investigated whether maintenance temozolomide (TMZ) after definitive therapy for locally advanced non-small-cell lung cancer (NSCLC) could decrease the incidence of brain metastasis (BM).

      PATIENTS AND METHODS: Eligible patients included those with stage IIIA, IIIB, or IV (for stage IV, only with malignant pleural/pericardial effusion) NSCLC with no BM at diagnosis and stable disease, partial response, or complete response after first-line chemotherapy using at least 2 agents. Patients were randomized to observation or TMZ (75 mg/m(2) for 21 consecutive days followed by a 7-day rest for up to 6 cycles or progression). The primary end point was incidence of radiographically diagnosed BM within 12 months from day 1 of first-line chemotherapy. Secondary end points included overall survival (OS), time to progression, incidence of BM at first progression, and toxicity.

      RESULTS: The study was closed early on the basis of a futility analysis; 45 of 53 enrolled patients were evaluable from an original target of 100. No difference was noted in the incidence of BM at 1 year in the TMZ and observation groups (18% and 13%, respectively), in median time to progression (11.7 and 10.7 months, respectively), or in median OS (27.1 and 22.5 months, respectively). Common Terminology Criteria for Adverse Events grade 3 or 4 adverse events were 46% in the TMZ group and 19% in the observation group.

      CONCLUSIONS: TMZ monotherapy does not appear to decrease the incidence of BM in patients with locally advanced NSCLC. These results considered in the context of the existing literature have implications for future clinical trial design.

      View details for PubMedID 25069747
  • Recursive partitioning analysis of prognostic variables in newly diagnosed anaplastic oligodendroglial tumors. Neuro Oncol
    Panageas KS, Reiner AS, Iwamoto FM, Cloughesy TF, Aldape KD, Rivera AL, Eichler AF, Louis DN, Paleologos NA, Fisher BJ, Ashby LS, Cairncross JG, Urgoiti GB, Wen PY, Ligon KL, Schiff D, Robins HI, Rocque BG, Chamberlain MC, Mason WP, Weaver SA, Green RM, Kamar FG, Abrey LE, DeAngelis LM, Jhanwar SC, Rosenblum MK, Lassman AB
    2014 Nov; 16 (11): 1541-6
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      BACKGROUND: Anaplastic oligodendroglial tumors are rare, and median survival varies widely. Analysis of 1p19q deletion is performed commonly and is an important prognostic factor. However, age and other clinical variables also carry prognostic value, and it is unclear how to incorporate them into clinical decision making or to combine them for prognostication.

      METHODS: We compiled a retrospective database of 1013 patients with newly diagnosed anaplastic oligodendrogliomas or oligoastrocytomas and performed a recursive partitioning analysis to generate independent prognostic classes among 587 patients with informative 1p19q status. Variables included for survival classification were age (continuous), history of prior low-grade glioma, 1p19q deletion status, histology (presence or absence of an astrocytic component), tumor lobe, tumor hemisphere, gender, extent of resection, postresection treatment, and performance status at diagnosis.

      RESULTS: Recursive partitioning analysis identified 5 prognostic groups based on hazard similarity: class I (age <60 y, 1p19q codeleted), class II (age <43 y, not codeleted), class III (age 43-59 y, not codeleted, frontal lobe tumor or age ≥60 y, codeleted), class IV (age 43-59 y, not codeleted, not frontal lobe tumor or age 60-69 y, not codeleted), and class V (age ≥70 y, not codeleted). Survival differences were highly significant (P < .0001), with medians ranging from 9.3 years (95% CI: 8.4-16.0) for class I to 0.6 years (95% CI: 0.5-0.9) for class V.

      CONCLUSIONS: These 5 distinct classification groups were defined using prognostic factors typically obtained during routine management of patients with anaplastic oligodendroglial tumors. Validation in a prospective clinical trial may better differentiate patients with respect to treatment outcome.

      View details for PubMedID 24997140
  • ACR Appropriateness Criteria® pre-irradiation evaluation and management of brain metastases. J Palliat Med
    Expert Panel on Radiation Oncology-Brain Metastases, Lo SS, Gore EM, Bradley JD, Buatti JM, Germano I, Ghafoori AP, Henderson MA, Murad GJ, Patchell RA, Patel SH, Robbins JR, Robins HI, Vassil AD, Wippold FJ, Yunes MJ, Videtic GM
    2014 Aug; 17 (8): 880-6
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      Pretreatment evaluation is performed to determine the number, location, and size of the brain metastases and magnetic resonance imaging (MRI) is the recommended imaging technique, particularly in patients being considered for surgery or stereotactic radiosurgery. A contiguous thin-cut volumetric MRI with gadolinium with newer gadolinium-based agents can improve detection of small brain metastases. A systemic workup and medical evaluation are important, given that subsequent treatment for the brain metastases will also depend on the extent of the extracranial disease and on the age and performance status of the patient. Patients with hydrocephalus or impending brain herniation should be started on high doses of corticosteroids and evaluated for possible neurosurgical intervention. Patients with moderate symptoms should receive approximately 4-8 mg/d of dexamethasone in divided doses. The routine use of corticosteroids in patients without neurologic symptoms is not necessary. There is no proven benefit of anticonvulsants in patient without seizures. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

      View details for PubMedID 24971478
  • "TRIMing" the patient population to increase the benefit of mTOR inhibition. J Natl Cancer Inst
    Robins HI, Burkard ME, Halberg RB
    2014 Apr 28; 106 (5):
  • Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02. Neuro Oncol
    Wen PY, Chang SM, Lamborn KR, Kuhn JG, Norden AD, Cloughesy TF, Robins HI, Lieberman FS, Gilbert MR, Mehta MP, Drappatz J, Groves MD, Santagata S, Ligon AH, Yung WK, Wright JJ, Dancey J, Aldape KD, Prados MD, Ligon KL
    2014 Apr; 16 (4): 567-78
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      BACKGROUND: Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.

      METHODS: We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.

      RESULTS: Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.

      CONCLUSION: Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.

      View details for PubMedID 24470557
  • A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT & SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320: in regard to Sperduto et al. Int J Radiat Oncol Biol Phys
    Robins HI, O'Neill A, Mehta M, Grossman S
    2013 Aug 01; 86 (5): 809-10
  • Wide-field pulsed reduced dose rate radiotherapy (PRDR) for recurrent ependymoma in pediatric and young adult patients. Anticancer Res
    Mohindra P, Robins HI, Tomé WA, Hayes L, Howard SP
    2013 Jun; 33 (6): 2611-8
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      AIM: This retrospective analysis evaluates feasibility of wide-field re-irradiation using pulsed reduced dose rate (PRDR) technique in patients with recurrent ependymoma. PRDR employs a dose rate of 6 cGy/min, as opposed to 400-600 cGy/min for conventional radiation, allowing for enhanced normal tissue repair.

      PATIENTS AND METHODS: Five patients with recurrent ependymoma having eight lesions (two brain, six spinal cord) were treated with PRDR. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan Meier method.

      RESULTS: The median interval between two radiation courses was 58 months (range: 32-212 months). The median PRDR dose was 40 Gy (range: 30.6-54 Gy) with a median cumulative lifetime dose of 105.2 Gy (range: 90-162.4 Gy). At a median post-PRDR follow-up of 64 months, estimated 4-year OS and PFS from PRDR was 60% and 35.7%, respectively. None of the patients developed necrosis on serial magnetic resonance imaging scans, and only one patient had progressive mild radiculopathy.

      CONCLUSION: In patients with large-volume recurrent ependymoma, re-irradiation with wide-field PRDR is a feasible option.

      View details for PubMedID 23749916
  • Pseudoprogression after glioma therapy: a comprehensive review. Expert Rev Neurother
    Kruser TJ, Mehta MP, Robins HI
    2013 Apr; 13 (4): 389-403
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      Over the last decade, pseudoprogression as a clinically significant entity affecting both glioma patient management and the conduct of clinical trials has been recognized as a significant issue. The authors have summarized the literature relative to the incidence, chronological sequence, therapy-relatedness, impact of O-6-methylguanine-DNA methyltransferase methylation status and clinical features of pseudoprogression. Evidence regarding numerous neuroradiologic techniques to differentiate pseudoprogression from tumor recurrence is summarized. The implications of pseudoprogression on prognosis and clinical trial design are substantial, and are reviewed. Relative to this, the overlapping terms pseudoprogression and radiation necrosis are clarified to produce an appropriate basis for future consideration and research regarding this important biological phenomenon.

      View details for PubMedID 23545054
  • Histological predictors of outcome in ependymoma are dependent on anatomic site within the central nervous system. Brain Pathol
    Raghunathan A, Wani K, Armstrong TS, Vera-Bolanos E, Fouladi M, Gilbertson R, Gajjar A, Goldman S, Lehman NL, Metellus P, Mikkelsen T, Necesito-Reyes MJ, Omuro A, Packer RJ, Partap S, Pollack IF, Prados MD, Robins HI, Soffietti R, Wu J, Miller CR, Gilbert MR, Aldape KD, Collaborative Ependymoma Research Network
    2013 Sep; 23 (5): 584-94
    • More

      Ependymomas originate in posterior fossa (PF), supratentorial (ST) or spinal cord (SC) compartments. At present, grading schemes are applied independent of anatomic site. We performed detailed histological examination on 238 World Health Organization grade II and III ependymomas. Among PF ependymomas, the presence of hypercellular areas, necrosis, microvascular proliferation and elevated mitotic rate (all P < 0.01) were significantly associated with worse progression-free survival (PFS), while extensive ependymal canal formation was not (P = 0.89). Similar to the PF tumors, microvascular proliferation (P = 0.01) and elevated mitotic rate (P = 0.03) were significantly associated with worse PFS in the ST tumors. However, in contrast to PF tumors, extensive ependymal canals (P = 0.03) were associated with worse clinical outcome in ST ependymomas, but hypercellularity (P = 0.57) and necrosis (P = 0.47) were not. On multivariate Cox regression, after adjusting for relevant clinical variables, individual histological factors and a composite histological score remained significant among ST and PF ependymoma. In contrast to both PF and ST ependymoma, histological features were not found to be associated with PFS in SC tumors. Taken together, the clinical relevance of specific histological features in ependymoma appears to be related to the anatomic site of origin and suggests that site-specific grading criteria be considered in future classification systems.

      View details for PubMedID 23452038
  • A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys
    Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, Souhami L, Buyyounouski MK, Khuntia D, Demas W, Shah SA, Nedzi LA, Perry G, Suh JH, Mehta MP
    2013 Apr 01; 85 (5): 1312-8
    • More

      BACKGROUND: A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the blood-brain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS.

      METHODS AND MATERIALS: NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy × 15 to 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m(2)/day × 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150-200 mg/m(2)/day × 5 days/month) could be continued for as long as 6 months after WBRT + SRS. The primary endpoint was OS.

      RESULTS: After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT + SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001).

      CONCLUSION: The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms.

      View details for PubMedID 23391814
  • Cytokines associated with toxicity in the treatment of recurrent glioblastoma with aflibercept. Target Oncol
    Shonka N, Piao Y, Gilbert M, Yung A, Chang S, DeAngelis LM, Lassman AB, Liu J, Cloughesy T, Robins HI, Lloyd R, Chen A, Prados M, Wen PY, Heymach J, de Groot J
    2013 Jun; 8 (2): 117-25
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      Plasma profiling of patients treated with antiangiogenic agents may identify markers that correlate with toxicity. Objectives were to correlate changes in cytokine and angiogenic factors as potential markers of toxicity to aflibercept. Circulating cytokine and angiogenic factors were measured in 28 patients with recurrent glioblastoma in a single-arm phase II study of aflibercept. Plasma samples were analyzed at baseline, 24 h, and 28 days using multiplex assays or ELISA. We evaluated log-transformed baseline biomarker expressions with Cox proportional hazard regression models to assess the effect of markers on any grade II-IV (Gr II-IV) toxicity, on-target toxicity (hypertension, proteinuria, thromboembolism), and fatigue. All tests were two sided with a statistical significance level of p = 0.05. Among 28 pts, there were 116 Gr II-IV events. Changes in IL-13 from baseline to 24 h predicted on-target toxicities. Increases in IL-1b, IL-6, and IL-10 at 24 h were significantly associated with fatigue. Progression-free survival was 14.9 months for patients in the all-toxicity group and 9.0 months for patients in the on-target toxicity group compared to 4.3 months for those who did not develop any Gr II-IV toxicity (p = 0.002 and p = 0.045, respectively). Toxicity from antiangiogenic therapy remains an important cause of antiangiogenic treatment discontinuation and patient morbidity. Changes in IL6, IL10, and IL13 were repeatedly correlated with toxicity. Profiling of IL-13 as a surrogate for endothelial dysfunction could individualize patients at risk during antiangiogenic therapy, as could identifying those at higher risk for fatigue using IL-6 and IL-10.

      View details for PubMedID 23345034
  • Leptomeningeal Metastasis: Challenges in Diagnosis and Treatment. Curr Cancer Ther Rev
    Leal T, Chang JE, Mehta M, Robins HI
    2011 Nov; 7 (4): 319-327
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      As therapeutic options and supportive care for the treatment of neoplastic disease have improved, there has been an associated increase in the incidence of leptomeningeal disease. In this review, the clinical presentation, natural history, diagnostic evaluation, and treatment options for this often devastating sequela of solid tumors, lymphoma, and leukemia will be summarized. The therapeutic efficacy of ionizing radiation, systemic agents, and intrathecal drugs will be examined from the existing literature. Additionally the pathophysiology, which in part defines the therapeutic limitations in approaching this patient population, will be discussed in order to assist in individualized clinical decision making.

      View details for PubMedID 23251128
  • RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients. Int J Radiat Oncol Biol Phys
    Chakravarti A, Wang M, Robins HI, Lautenschlaeger T, Curran WJ, Brachman DG, Schultz CJ, Choucair A, Dolled-Filhart M, Christiansen J, Gustavson M, Molinaro A, Mischel P, Dicker AP, Bredel M, Mehta M
    2013 Apr 01; 85 (5): 1206-11
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      PURPOSE: To determine the safety and efficacy of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with radiation for newly diagnosed glioblastoma (GBM) patients.

      METHODS AND MATERIALS: Between March 21, 2002, and May 3, 2004, Radiation Therapy Oncology Group (RTOG) 0211 enrolled 31 and 147 GBM patients in the phase 1 and 2 arms, respectively. Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy (RT) and continued post RT for 18 months or until progression. Tissue microarrays from 68 cases were analyzed for EGFR expression.

      RESULTS: The maximum tolerated dose (MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs (non-EIAEDs). All patients in the phase 2 component were treated at a gefitinib dose of 500 mg; patients receiving EIADSs could be escalated to 750 mg. The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal. Median survival was 11.5 months for patients treated per protocol. There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone, matched by RTOG recursive partitioning analysis (RPA) class distribution. Younger age was significantly associated with better outcome. Per protocol stratification, EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients.

      CONCLUSIONS: The addition of gefitinib to RT is well tolerated. Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone.

      View details for PubMedID 23182702
  • Unexpected doxorubicin-mediated cardiotoxicity in sisters: possible role of polymorphisms in histamine n-methyl transferase. J Oncol Pharm Pract
    Sachidanandam K, Gayle AA, Robins HI, Kolesar JM
    2013 Sep; 19 (3): 269-72
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      The anthracycline anticancer agent doxorubicin has long been recognized to induce a dose-limiting cardiotoxicity and may be associated with genes relevant to doxorubicin disposition. Recent reports suggest a role for a number of single nucleotide polymorphisms in anthracycline cardiotoxicity in children. We describe two adult sisters with anthracycline cardiotoxicity that developed after a relatively low dose of doxorubicin. One sister carried the variant genotype for histamine N-ethyl transferase (HNMT, rs17583889) while the other was heterozygous, suggesting a similar role for these genotypes in adults with anthracycline cardiotoxicity. Although this requires further study, these genotypes may be important in the clinical dosing, or use of the liposomal formulation of doxorubicin.

      View details for PubMedID 23154571
  • Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02. Neuro Oncol
    Lee EQ, Kuhn J, Lamborn KR, Abrey L, DeAngelis LM, Lieberman F, Robins HI, Chang SM, Yung WK, Drappatz J, Mehta MP, Levin VA, Aldape K, Dancey JE, Wright JJ, Prados MD, Cloughesy TF, Gilbert MR, Wen PY
    2012 Dec; 14 (12): 1511-8
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      The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.

      View details for PubMedID 23099651
  • Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03. Clin Cancer Res
    Lee EQ, Puduvalli VK, Reid JM, Kuhn JG, Lamborn KR, Cloughesy TF, Chang SM, Drappatz J, Yung WK, Gilbert MR, Robins HI, Lieberman FS, Lassman AB, McGovern RM, Xu J, Desideri S, Ye X, Ames MM, Espinoza-Delgado I, Prados MD, Wen PY
    2012 Nov 01; 18 (21): 6032-9
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      PURPOSE: A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG).

      EXPERIMENTAL DESIGN: This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days of the first cycle and 200 mg/m(2)/day for 5 days of the subsequent 28-day cycles.

      RESULTS: In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells.

      CONCLUSION: Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway.

      View details for PubMedID 22923449
  • Initial treatment patterns over time for anaplastic oligodendroglial tumors. Neuro Oncol
    Panageas KS, Iwamoto FM, Cloughesy TF, Aldape KD, Rivera AL, Eichler AF, Louis DN, Paleologos NA, Fisher BJ, Ashby LS, Cairncross JG, Roldán Urgoiti GB, Wen PY, Ligon KL, Schiff D, Robins HI, Rocque BG, Chamberlain MC, Mason WP, Weaver SA, Green RM, Kamar FG, Abrey LE, Deangelis LM, Jhanwar SC, Rosenblum MK, Lassman AB
    2012 Jun; 14 (6): 761-7
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      Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 1981-2007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50% of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67% in 1980-1984 vs 5% in 2005-2007, P < .0001). CT alone was more frequently administered in later years (0% in 1980-1984 vs 38% in 2005-2007; P < .0001), especially in patients with 1p19q codeleted tumors (57% of codeleted vs 4% with no deletion in 2005-2007; P < .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87% vs 2% in 2005-2007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P < .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P < .0001), 1p19q codeletion (P < .0001), pure anaplastic oligodendroglioma histology (P < .01), and frontal lobe predominance (P < .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy.

      View details for PubMedID 22661585
  • ACR Appropriateness Criteria® follow-up and retreatment of brain metastases. Am J Clin Oncol
    Patel SH, Robbins JR, Gore EM, Bradley JD, Gaspar LE, Germano I, Ghafoori P, Henderson MA, Lutz ST, McDermott MW, Patchell RA, Robins HI, Vassil AD, Wippold FJ, Videtic GM, Expert Panel on Radiation Oncology–Brain Metastases
    2012 Jun; 35 (3): 302-6
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      Multiple options for retreatment are available, which include whole-brain radiation therapy, stereotactic radiosurgery, surgery, chemotherapy, and supportive care. Size, number, timing, location, histology, performance status, and extracranial disease status all need to be carefully considered when choosing a treatment modality. There are no randomized trials examining the retreatment of brain metastases. Repeat whole-brain radiation has been examined in a single-institution experience, showing the potential for clinical responses in selected patients. Local control rates as high as 91% using stereotactic radiosurgery for relapses after whole-brain radiation are reported. Surgery can be indicated in progressive and/or hemorrhagic lesions causing mass effect. The role of chemotherapy in the recurrent setting is limited but some agents may have activity on the basis of experiences on a smaller scale. Supportive care continues to be an important option, especially in those with a poor prognosis. Follow-up for brain metastases patients is discussed, examining the modality, frequency of imaging, and imaging options in differentiating treatment effect from recurrence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of the current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

      View details for PubMedID 22609733
  • Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov
    Vivanco I, Robins HI, Rohle D, Campos C, Grommes C, Nghiemphu PL, Kubek S, Oldrini B, Chheda MG, Yannuzzi N, Tao H, Zhu S, Iwanami A, Kuga D, Dang J, Pedraza A, Brennan CW, Heguy A, Liau LM, Lieberman F, Yung WK, Gilbert MR, Reardon DA, Drappatz J, Wen PY, Lamborn KR, Chang SM, Prados MD, Fine HA, Horvath S, Wu N, Lassman AB, DeAngelis LM, Yong WH, Kuhn JG, Mischel PS, Mehta MP, Cloughesy TF, Mellinghoff IK
    2012 May; 2 (5): 458-71
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      UNLABELLED: Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types.

      SIGNIFICANCE: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.

      View details for PubMedID 22588883
  • Clinical use of the low-molecular-weight heparins in cancer patients: focus on the improved patient outcomes. Thrombosis
    Chao BH, Lepeak L, Leal T, Robins HI
    2011; 2011: 530183
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      Patients with malignant neoplastic diseases represent a high-risk population relative to thromboembolic disease. With the advent of improved and accessible diagnostic technology, for example, ultrasound and/or spiral CT scans, timely diagnosis of venous thromboembolic events (VTE) is readily accomplished. The introduction of low-molecular-weight heparin (LMWH) approximately two decades ago (in contrast to unfractionated heparin and vitamin K antagonists) has provided a class of agents with a favorable therapeutic index. In the review to follow, the literature regarding the use of LMWH in oncologic patient populations is summarized. Topics addressed include prophylaxis, and treatment as well as consideration of the potential anti-neoplastic properties of this class of drugs.

      View details for PubMedID 22084664
  • An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov
    Guo D, Reinitz F, Youssef M, Hong C, Nathanson D, Akhavan D, Kuga D, Amzajerdi AN, Soto H, Zhu S, Babic I, Tanaka K, Dang J, Iwanami A, Gini B, Dejesus J, Lisiero DD, Huang TT, Prins RM, Wen PY, Robins HI, Prados MD, Deangelis LM, Mellinghoff IK, Mehta MP, James CD, Chakravarti A, Cloughesy TF, Tontonoz P, Mischel PS
    2011 Oct; 1 (5): 442-56
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      Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)-dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1-dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)-mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1-dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients.

      View details for PubMedID 22059152
  • Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma? Neuro Oncol
    Clarke JL, Ennis MM, Yung WK, Chang SM, Wen PY, Cloughesy TF, Deangelis LM, Robins HI, Lieberman FS, Fine HA, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Lamborn KR, Prados MD, North American Brain Tumor Consortium
    2011 Oct; 13 (10): 1118-24
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      Historically, the North American Brain Tumor Consortium used 6-month progression-free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes. Two data sets were analyzed. The first included 511 patients enrolled during the period 1998-2005, 105 of whom had surgery (excluding biopsies) during the study or ≤ 30 days prior to registration. Analysis was stratified on the basis of whether temozolomide was part of the protocol treatment regimen. The second data set included 247 patients enrolled during 2005-2008, 103 of whom underwent surgery during the clinical trial or immediately prior to study registration. A combined data set consisting of all patients who did not receive temozolomide was also compiled. No statistically significant difference in PFS6 or OS was found between the surgery and nonsurgery groups in either data set alone or in the combined data set (P > .45). We conclude that PFS6 and OS results for patients with and without surgical intervention at the time of progression are similar, allowing data from these patients to be combined in assessing the benefit of new treatments without the need for stratification or other statistical adjustment.

      View details for PubMedID 21813511
  • International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol
    Lassman AB, Iwamoto FM, Cloughesy TF, Aldape KD, Rivera AL, Eichler AF, Louis DN, Paleologos NA, Fisher BJ, Ashby LS, Cairncross JG, Roldán GB, Wen PY, Ligon KL, Schiff D, Robins HI, Rocque BG, Chamberlain MC, Mason WP, Weaver SA, Green RM, Kamar FG, Abrey LE, DeAngelis LM, Jhanwar SC, Rosenblum MK, Panageas KS
    2011 Jun; 13 (6): 649-59
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      Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.

      View details for PubMedID 21636710
  • Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept. Clin Cancer Res
    de Groot JF, Piao Y, Tran H, Gilbert M, Wu HK, Liu J, Bekele BN, Cloughesy T, Mehta M, Robins HI, Lassman A, DeAngelis L, Camphausen K, Chen A, Yung WK, Prados M, Wen PY, Heymach JV
    2011 Jul 15; 17 (14): 4872-81
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      PURPOSE: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma.

      EXPERIMENTAL DESIGN: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients.

      RESULTS: Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1(+) monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9.

      CONCLUSIONS: These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis.

      View details for PubMedID 21632852
  • Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol
    de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K, Yao J, Jackson EF, Lieberman F, Robins HI, Mehta MP, Lassman AB, Deangelis LM, Yung WK, Chen A, Prados MD, Wen PY
    2011 Jul 01; 29 (19): 2689-95
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      PURPOSE: Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma.

      PATIENTS AND METHODS: Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle.

      RESULTS: The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance.

      CONCLUSION: Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.

      View details for PubMedID 21606416
  • A phase I trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys
    Nghiemphu PL, Wen PY, Lamborn KR, Drappatz J, Robins HI, Fink K, Malkin MG, Lieberman FS, DeAngelis LM, Torres-Trejo A, Chang SM, Abrey L, Fine HA, Demopoulos A, Lassman AB, Kesari S, Mehta MP, Prados MD, Cloughesy TF, North American Brain Tumor Consortium
    2011 Dec 01; 81 (5): 1422-7
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      PURPOSE: To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ.

      PATIENTS AND METHODS: After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts.

      RESULTS: Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year.

      CONCLUSION: Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED.

      View details for PubMedID 20934264
  • ACR Appropriateness Criteria: single brain metastasis. Curr Probl Cancer
    Suh JH, Videtic GM, Aref AM, Germano I, Goldsmith BJ, Imperato JP, Marcus KJ, McDermott MW, McDonald MW, Patchell RA, Robins HI, Rogers CL, Wolfson AH, Wippold FJ, Gaspar LE
    2010 May-Jun; 34 (3): 162-74
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      Single brain metastasis represents a common neurologic complication of cancer. Given the number of treatment options that are available for patients with brain metastasis and the strong opinions that are associated with each option, appropriate treatment for these patients has become controversial. Prognostic factors such as recursive partitioning analysis and graded prognostic assessment can help guide treatment decisions. Surgery, whole brain radiation therapy (WBRT), stereotactic radiosurgery or combination of these treatments can be considered based on a number of factors. Despite Class I evidence suggestive of best therapy, the treatment recommendation is quite varied among physicians as demonstrated by the American College of Radiology's Appropriateness Panel on single brain metastasis. Given the potential concerns of the neurocognitive effects of WBRT, the use of SRS alone or SRS to a resection cavity has gained support. Since aggressive local therapy is beneficial for survival, local control and quality of life, the use of these various treatment modalities needs to be carefully investigated given the growing number of long-term survivors. Enrollment of patients onto clinical trials is important to advance our understanding of brain metastasis.

      View details for PubMedID 20541055
  • Reirradiation of large-volume recurrent glioma with pulsed reduced-dose-rate radiotherapy. Int J Radiat Oncol Biol Phys
    Adkison JB, Tomé W, Seo S, Richards GM, Robins HI, Rassmussen K, Welsh JS, Mahler PA, Howard SP
    2011 Mar 01; 79 (3): 835-41
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      PURPOSE: Pulsed reduced-dose-rate radiotherapy (PRDR) is a reirradiation technique that reduces the effective dose rate and increases the treatment time, allowing sublethal damage repair during irradiation.

      PATIENTS AND METHODS: A total of 103 patients with recurrent glioma underwent reirradiation using PRDR (86 considered to have Grade 4 at PRDR). PRDR was delivered using a series of 0.2-Gy pulses at 3-min intervals, creating an apparent dose rate of 0.0667 Gy/min to a median dose of 50 Gy (range, 20-60) delivered in 1.8-2.0-Gy fractions. The mean treatment volume was 403.5±189.4 cm3 according to T2-weighted magnetic resonance imaging and a 2-cm margin.

      RESULTS: For the initial or upgraded Grade 4 cohort (n=86), the median interval from the first irradiation to PRDR was 14 months. Patients undergoing PRDR within 14 months of the first irradiation (n=43) had a median survival of 21 weeks. Those treated ≥14 months after radiotherapy had a median survival of 28 weeks (n=43; p=0.004 and HR=1.82 with a 95% CI ranging from 1.25 to 3.10). These data compared favorably to historical data sets, because only 16% of the patients were treated at first relapse (with 46% treated at the second relapse, 32% at the third or fourth relapse, and 4% at the fourth or fifth relapse). The median survival since diagnosis and retreatment was 6.3 years and 11.4 months for low-grade, 4.1 years and 5.6 months for Grade 3, and 1.6 years and 5.1 months for Grade 4 tumors, respectively, according to the initial histologic findings. Multivariate analysis revealed age at the initial diagnosis, initial low-grade disease, and Karnofsky performance score of ≥80 to be significant predictors of survival after initiation of PRDR.

      CONCLUSION: PRDR allowed for safe retreatment of larger volumes to high doses with palliative benefit.

      View details for PubMedID 20472350
  • Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro Oncol
    Iwamoto FM, Lamborn KR, Robins HI, Mehta MP, Chang SM, Butowski NA, Deangelis LM, Abrey LE, Zhang WT, Prados MD, Fine HA
    2010 Aug; 12 (8): 855-61
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      The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib, a multi-targeted tyrosine kinase inhibitor, against vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor-alpha and -beta, and c-Kit, in recurrent glioblastoma. Patients with < or =2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-week cycles without planned interruptions. Brain magnetic resonance imaging and clinical reassessment were made every 8 weeks. The primary endpoint was efficacy as measured by 6-month progression-free survival (PFS6). Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued. Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose reduction. Two patients had a partial radiographic response by standard bidimensional measurements, whereas 9 patients (6 at the 8-week point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% reduction in tumor. The median PFS was 12 weeks (95% confidence interval [CI]: 8-14 weeks) and only 1 patient had a PFS time > or =6 months (PFS6 = 3%). Thirty patients (86%) had died and median survival was 35 weeks (95% CI: 24-47 weeks). Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents. Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses. ClinicalTrials.gov identifier: NCT00459381.

      View details for PubMedID 20200024
  • A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol
    Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG, Yung WK, Gilbert MR, Aldape KA, Wen PY, Fine HA, Mehta M, Deangelis LM, Lieberman F, Cloughesy TF, Robins HI, Dancey J, Prados MD, North American Brain Tumor Consortium
    2010 Jan; 12 (1): 95-103
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      Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was not allowed. Patients received 150 mg/day erlotinib. Patients requiring surgery were treated 7 days prior to tumor removal for PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) and intracellular signaling pathways. Ninety-six patients were evaluable (53 recurrent MG and 43 NP GBM); 5 patients were not evaluable for response. PFS-6 in recurrent GBM was 3% with a median PFS of 2 months; PFS-6 in recurrent AG was 27% with a median PFS of 2 months. Twelve-month survival was 57% in NP GBMs post-RT. Primary toxicity was dermatologic. The tissue-to-plasma ratio normalized to nanograms per gram dry weight for erlotinib and OSI-420 ranged from 25% to 44% and 30% to 59%, respectively, for pretreated surgical patients. No effect on EGFR or intratumoral signaling was seen. Patients with NP GBM post-RT who developed rash in cycle 1 had improved survival (P < .001). Single-agent activity of erlotinib is minimal for recurrent MGs and marginally beneficial following RT for NP GBM patients. Development of rash in cycle 1 correlates with survival in patients with NP GBM after RT.

      View details for PubMedID 20150372
  • A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas. Neuro Oncol
    Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG, Yung WK, Gilbert MR, Aldape KD, Wen PY, Fine HA, Mehta M, Deangelis LM, Lieberman F, Cloughesy TF, Robins HI, Dancey J, Prados MD, North American Brain Tumor Consortium
    2010 Jan; 12 (1): 87-94
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      The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 x 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where < or = 1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs.

      View details for PubMedID 20150371
  • EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci Signal
    Guo D, Prins RM, Dang J, Kuga D, Iwanami A, Soto H, Lin KY, Huang TT, Akhavan D, Hock MB, Zhu S, Kofman AA, Bensinger SJ, Yong WH, Vinters HV, Horvath S, Watson AD, Kuhn JG, Robins HI, Mehta MP, Wen PY, DeAngelis LM, Prados MD, Mellinghoff IK, Cloughesy TF, Mischel PS
    2009 Dec 15; 2 (101): ra82
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      Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This response was mediated by Akt; however, clinical data from rapamycin-treated patients showed that SREBP-1 activation was independent of the mammalian target of rapamycin complex 1, possibly explaining rapamycin's poor efficacy in the treatment of such tumors. Glioblastomas without constitutively active EGFR signaling were resistant to inhibition of fatty acid synthesis, whereas introduction of a constitutively active mutant form of EGFR, EGFRvIII, sensitized tumor xenografts in mice to cell death, which was augmented by the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin. These results identify a previously undescribed EGFR-mediated prosurvival metabolic pathway and suggest new therapeutic approaches to treating EGFR-activated glioblastomas.

      View details for PubMedID 20009104
  • Therapeutic advances in malignant glioma: current status and future prospects. Neuroimaging Clin N Am
    Robins HI, Lassman AB, Khuntia D
    2009 Nov; 19 (4): 647-56
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      This article reviews the current status and trends in the treatment of primary gliomas, focusing predominantly on glioblastoma. It also discusses the current standard of care and new targeted agents currently under investigation. Furthermore, the concepts of pseudoprogression and pseudoresponse are introduced, which are new imaging correlates that have significant impact on understanding of the disease.

      View details for PubMedID 19959010
  • American College of Radiology appropriateness criteria on multiple brain metastases. Int J Radiat Oncol Biol Phys
    Expert Panel on Radiation Oncology-Brain Metastases, Videtic GM, Gaspar LE, Aref AM, Germano IM, Goldsmith BJ, Imperato JP, Marcus KJ, McDermott MW, McDonald MW, Patchell RA, Robins HI, Rogers CL, Suh JH, Wolfson AH, Wippold FJ
    2009 Nov 15; 75 (4): 961-5
  • Bevacizumab induced reversible thrombocytopenia in a patient with recurrent high-grade glioma: a case report. Cancer Chemother Pharmacol
    Leal T, Robins HI
    2010 Jan; 65 (2): 399-401
    • More

      We report a case of bevacizumab (BEV)-induced thrombocytopenia in a 36-year-old woman treated with BEV as a single-agent for a recurrent high-grade glioma. The thrombocytopenia was both reversible and reproducible on multiple treatment cycles. The patient has improved clinically and by brain MR imaging with single-agent BEV for approximately 7 months to date. She did not have bleeding or thromboembolic complications. Treatment delays have been 1-2 weeks relative to a conventional plan of treatment, i.e., 10 mg/kg every 2 weeks. This is a rare complication that has not been previously reported.

      View details for PubMedID 19756604
  • Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma. J Neurooncol
    Norden AD, Raizer JJ, Abrey LE, Lamborn KR, Lassman AB, Chang SM, Yung WK, Gilbert MR, Fine HA, Mehta M, Deangelis LM, Cloughesy TF, Robins HI, Aldape K, Dancey J, Prados MD, Lieberman F, Wen PY
    2010 Jan; 96 (2): 211-7
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      There are no established treatments for recurrent meningioma when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00-01) and erlotinib (NABTC 01-03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Patients with recurrent histologically confirmed meningiomas with no more than 2 previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Twenty-five eligible patients were enrolled with median age 57 years (range 29-81) and median Karnofsky performance status (KPS) score 90 (range 60-100). Sixteen patients (64%) received gefitinib and 9 (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and 8 (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 25%, 12-month PFS (PFS12) 13%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical and malignant tumors, PFS6 was 29%, PFS12 18%, OS6 71%, and OS12 65%. The PFS and OS were not significantly different by histology. There were no objective imaging responses, but 8 patients (32%) maintained stable disease. Although treatment was well-tolerated, neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear. Evaluation of multi-targeted inhibitors and EGFR inhibitors in combination with other targeted molecular agents may be warranted.

      View details for PubMedID 19562255
  • More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med
    Robins HI, Holen KD
    2009 Apr 23; 360 (17): 1790; author reply 1791-2
  • Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08). Neuro Oncol
    Wen PY, Yung WK, Lamborn KR, Norden AD, Cloughesy TF, Abrey LE, Fine HA, Chang SM, Robins HI, Fink K, Deangelis LM, Mehta M, Di Tomaso E, Drappatz J, Kesari S, Ligon KL, Aldape K, Jain RK, Stiles CD, Egorin MJ, Prados MD
    2009 Dec; 11 (6): 853-60
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      Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently coexpressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary end point was 6-month progression-free survival (6M-PFS). Patients requiring enzyme-inducing antiepileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptable toxicities. Plasma concentrations of imatinib and its active metabolite, CGP74588, were assessed. Twenty-three heavily pretreated patients were enrolled into the study (13 benign, 5 atypical, and 5 malignant meningiomas), of whom 22 were eligible. The study was closed prematurely due to slow accrual. Tissue was available only from a minority of patients, but in these specimens there was uniform distribution of PDGFR, the drug target. Imatinib was generally well tolerated. Of 19 patients evaluable for response, 10 progressed at the first scan, and 9 were stable. There were no complete or partial responses. Overall median PFS was 2 months (range, 0.7-34 months); 6M-PFS was 29.4%. For benign meningiomas, median PFS was 3 months (range, 1.1-34 months); 6M-PFS was 45%. For atypical and malignant meningiomas, median PFS was 2 months (range, 0.7-3.7 months); 6M-PFS was 0%. Cycle 1 trough concentrations of imatinib and CGP74588 were 2,129 +/- 1,600 ng/ml and 517 +/- 326 ng/ml, respectively. Single-agent imatinib was well tolerated but had no significant activity in recurrent meningiomas. Trough plasma concentrations of imatinib exceeded those associated with imatinib activity in chronic myelogenous leukemia.

      View details for PubMedID 19293394
  • Neurooncology clinical trial design for targeted therapies: lessons learned from the North American Brain Tumor Consortium. Neuro Oncol
    Chang SM, Lamborn KR, Kuhn JG, Yung WK, Gilbert MR, Wen PY, Fine HA, Mehta MP, DeAngelis LM, Lieberman FS, Cloughesy TF, Robins HI, Abrey LE, Prados MD, North American Brain Tumor Consortium
    2008 Aug; 10 (4): 631-42
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      The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study.

      View details for PubMedID 18559968
  • Pulsed reduced dose-rate radiotherapy: a novel locoregional retreatment strategy for breast cancer recurrence in the previously irradiated chest wall, axilla, or supraclavicular region. Breast Cancer Res Treat
    Richards GM, Tomé WA, Robins HI, Stewart JA, Welsh JS, Mahler PA, Howard SP
    2009 Mar; 114 (2): 307-13
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      PURPOSE: Reirradiation of breast cancer locoregional recurrence (LRR) in the setting of prior post-mastectomy radiation poses a significant clinical challenge due to the high risk for severe toxicity. In an attempt to reduce these toxicities, we have developed pulsed reduced dose-rate radiotherapy (PRDR), a reirradiation technique in which a series of 0.2 Gy pulses separated by 3-min time intervals is delivered, creating an apparent dose rate of 0.0667 Gy/min. Here we describe our early experience with PRDR.

      PATIENTS AND METHODS: We reirradiated 17 patients with LRR breast cancer to the chest wall, axilla, or supraclavicular region using PRDR. The median prior radiation dose was 60 Gy. We delivered a median PRDR dose of 54 Gy (range 40-66 Gy) in 1.8-2.0 Gy per fraction. Eight patients received concomitant low dose capecitabine for radiosensitization. The median treatment volume was 2,084 cm(3) (range 843-7,881 cm(3)).

      RESULTS: At a median follow-up of 18 months (range 4-75 months) only 2 patients have had tumor failure in the treatment region. Estimated 2-year local control rate is 92%. Treatment was well tolerated with 4 patients experiencing grade 3 acute skin toxicity. Despite a median cumulative dose of 110 Gy (range 80-236 Gy), there has been only one grade 3 and one grade 4 late toxicity.

      CONCLUSIONS: With a median follow-up of 18 months, PRDR appears to be an effective method to reirradiate large volumes of previously irradiated tissue in selected patients with locoregional chest wall, axilla, and supraclavicular recurrences.

      View details for PubMedID 18389365
  • Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol
    Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD, North American Brain Tumor Consortium
    2008 Apr; 10 (2): 162-70
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      The North American Brain Tumor Consortium (NABTC) uses 6-month progression-free survival (6moPFS) as the efficacy end point of therapy trials for adult patients with recurrent high-grade gliomas. In this study, we investigated whether progression status at 6 months predicts survival from that time, implying the potential for prolonged survival if progression could be delayed. We also evaluated earlier time points to determine whether the time of progression assessment alters the strength of the prediction. Data were from 596 patient enrollments (159 with grade III gliomas and 437 with grade IV tumors) in NABTC phase II protocols between February 1998 and December 2002. Outcome was assessed statistically using Kaplan-Meier curves and Cox proportional hazards models. Median survivals were 39 and 30 weeks for patients with grade III and grade IV tumors, respectively. Twenty-eight percent of patients with grade III and 16% of patients with grade IV tumors had progression-free survival of >26 weeks. Progression status at 9, 18, and 26 weeks predicted survival from those times for patients with grade III or grade IV tumors (p < 0.001 and hazard ratios < 0.5 in all cases). Including KPS, age, number of prior chemotherapies, and response in a multivariate model did not substantively change the results. Progression status at 6 months is a strong predictor of survival, and 6moPFS is a valid end point for trials of therapy for recurrent malignant glioma. Earlier assessments of progression status also predicted survival and may be incorporated in the design of future clinical trials.

      View details for PubMedID 18356283
  • A phase I study of gemcitabine plus palliative radiation therapy for advanced lung cancer. Cancer Chemother Pharmacol
    Choi B, Robins HI, Schiller J, Mehta M
    2008 Dec; 63 (1): 175-9
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      PURPOSE: To determine the maximum-tolerated dose (MTD) and antitumor activity of twice-weekly gemcitabine when combined with palliative-dose thoracic radiation therapy (RT) in patients with recurrent or progressive lung cancer.

      METHODS: Patients were enrolled in a dose-escalating study of gemcitabine with a starting dose level of 40 mg/m(2) given as 30-minute infusions twice weekly concurrent with RT. The RT dose was 30 Gy in 10 fractions, 5 fractions per week.

      RESULTS: A total of 18 patients were enrolled on three dose levels: 40, 50, and 65 mg/m(2). Four patients came off study early due to rapid progression of disease and therefore were not evaluated. The MTD of gemcitabine was found to be 50 mg/m(2). Dose-limiting toxicities were grade-4 esophagitis in one patient and grade-4 neutropenia in another patient. Overall response included 1 partial response (PR). Local response included six PR, four minor response (MR), three stable disease (SD), and one progressive disease (PD).

      CONCLUSION: The MTD of gemcitabine with concominant palliative thoracic radiation therapy is 50 mg/m(2) twice weekly. The DLTs observed were grade-4 esophagitis and grade-4 myelotoxicity at 65 mg/m(2).

      View details for PubMedID 18305938
  • Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme. Clin Adv Hematol Oncol
    Chang JE, Khuntia D, Robins HI, Mehta MP
    2007 Nov; 5 (11): 894-902, 907-15
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      Effective treatment of glioblastoma multiforme (GBM) is complicated by multiple factors, including the diffusely infiltrative nature of the disease, which limits complete surgical resection; the difficulty in overcoming the blood-brain barrier with systemic therapies; and the challenge of identifying novel means of treating the residual hypoxic tumor cells that are relatively resistant to radiotherapy (RT) and chemotherapy. Clear survival advantages have been demonstrated with postresection RT to doses of 5,000-6,000 cGy, but further attempts at dose escalation over 6,000 cGy have resulted in increased toxicity without a survival benefit. In an effort to improve local control of tumor and limit toxicity to normal brain tissue, novel imaging techniques (eg, chemical shift imaging) are being explored in order to better define RT fields. Brachytherapy and stereotactic radiosurgery are effective therapies for relapsed GBM but have undefined roles outside of clinical trials in treating newly diagnosed GBM. Stereotactic RT may have a survival advantage in subgroups that have undergone a gross total resection and have favorable (recursive partitioning analysis class IV) disease. In contrast, experience with hyperfractionated RT in GBM has shown that survival outcomes may actually be unfavorable in certain patient subgroups. Novel means of delivering RT, including radioimmunotherapy, have demonstrated efficacy with acceptable toxicity. Systemic agents are being explored as potential radiosensitizers, with the recent emergence of temozolomide as a model radiosensitizing agent having a positive impact on survival. Ongoing investigations are evaluating temozolomide in combination with other systemic agents, and additional agents (eg, motexafin gadolinium, mammalian target of rapamycin inhibitors, farnesyltransferase inhibitors) have shown promising activity in combination with RT.

      View details for PubMedID 18185489
  • A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118). Int J Radiat Oncol Biol Phys
    Knisely JP, Berkey B, Chakravarti A, Yung AW, Curran WJ, Robins HI, Movsas B, Brachman DG, Henderson RH, Mehta MP
    2008 May 01; 71 (1): 79-86
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      PURPOSE: To compare whole-brain radiation therapy (WBRT) with WBRT combined with thalidomide for patients with brain metastases not amenable to resection or radiosurgery.

      PATIENTS AND METHODS: Patients with Zubrod performance status 0-1, MRI-documented multiple (>3), large (>4 cm), or midbrain brain metastases arising from a histopathologically confirmed extracranial primary tumor, and an anticipated survival of >8 weeks were randomized to receive WBRT to a dose of 37.5 Gy in 15 fractions with or without thalidomide during and after WBRT. Prerandomization stratification used Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) Class and whether post-WBRT chemotherapy was planned. Endpoints included overall survival, progression-free survival, time to neurocognitive progression, the cause of death, toxicities, and quality of life. A protocol-planned interim analysis documented that the trial had an extremely low probability of ever showing a significant difference favoring the thalidomide arm given the results at the time of the analysis, and it was therefore closed on the basis of predefined statistical guidelines.

      RESULTS: Enrolled in the study were 332 patients. Of 183 accrued patients, 93 were randomized to receive WBRT alone and 90 to WBRT and thalidomide. Median survival was 3.9 months for both arms. No novel toxicities were seen, but thalidomide was not well tolerated in this population. Forty-eight percent of patients discontinued thalidomide because of side effects.

      CONCLUSION: Thalidomide provided no survival benefit for patients with multiple, large, or midbrain metastases when combined with WBRT; nearly half the patients discontinued thalidomide due to side effects.

      View details for PubMedID 18164847
  • Prospective evaluation of quality of life and neurocognitive effects in patients with multiple brain metastases receiving whole-brain radiotherapy with or without thalidomide on Radiation Therapy Oncology Group (RTOG) trial 0118. Int J Radiat Oncol Biol Phys
    Corn BW, Moughan J, Knisely JP, Fox SW, Chakravarti A, Yung WK, Curran WJ, Robins HI, Brachman DG, Henderson RH, Mehta MP, Movsas B
    2008 May 01; 71 (1): 71-8
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      PURPOSE: Radiation Therapy Oncology Group (RTOG) 0118 randomized patients with multiple brain metastases to whole-brain radiotherapy (WBRT) +/- thalidomide. This secondary analysis of 156 patients examined neurocognitive and quality of life (QOL) outcomes.

      METHODS AND MATERIALS: Quality of life was determined with the Spitzer Quality of Life Index (SQLI). The Folstein Mini-Mental Status Exam (MMSE) assessed neurocognitive function. SQLI and MMSE were administered at baseline and at 2-month intervals. MMSE was scored with a threshold value associated with neurocognitive functioning (absolute cutoff level of 23) and with the use of corrections for age and educational level.

      RESULTS: Baseline SQLI predicted survival. Patients with SQLI of 7-10 vs. <7 had median survival time (MST) of 4.8 vs. 3.1 months, p = 0.05. Both arms showed steady neurocognitive declines, but SQLI scores remained stable. Higher levels of neurocognitive decline were observed with age and education-level corrections. Of patients considered baseline age/educational level neurocognitive failures, 32% died of intracranial progression.

      CONCLUSIONS: Quality of life and neuropsychological testing can be prospectively administered on a Phase III cooperative group trial. The MMSE should be evaluated with adjustments for age and educational level. Baseline SQLI is predictive of survival. Despite neurocognitive declines, QOL remained stable during treatment and follow-up. Poor neurocognitive function may predict clinical deterioration. Lack of an untreated control arm makes it difficult to determine the contribution of the respective interventions (i.e., WBRT, thalidomide) to neurocognitive decline. The RTOG has developed a trial to study the role of preventative strategies aimed at forestalling neurocognitive decline in this population.

      View details for PubMedID 18164829
  • Pharmacokinetic and tumor distribution characteristics of temsirolimus in patients with recurrent malignant glioma. Clin Cancer Res
    Kuhn JG, Chang SM, Wen PY, Cloughesy TF, Greenberg H, Schiff D, Conrad C, Fink KL, Robins HI, Mehta M, DeAngelis L, Raizer J, Hess K, Lamborn KR, Dancey J, Prados MD, North American Brain Tumor Consortium and the National Cancer Institute
    2007 Dec 15; 13 (24): 7401-6
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      PURPOSE: To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue.

      EXPERIMENTAL DESIGN: Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis.

      RESULTS: Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus.

      CONCLUSIONS: Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.

      View details for PubMedID 18094423
  • Reversible paclitaxel-induced vocal cord paralysis with later recall with vinorelbine. Cancer Chemother Pharmacol
    Choi BS, Robins HI
    2008 Feb; 61 (2): 345-6
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      Described is the first reported case of paclitaxel-induced recurrent laryngeal nerve paralysis in a patient receiving adjuvant therapy for breast cancer. This rare form of neuropathy was reversible at 3 months, but it was re-induced 11 months later when the patient received vinorelbine.

      View details for PubMedID 18026678
  • Effect of dalteparin and radiation on survival and thromboembolic events in glioblastoma multiforme: a phase II ECOG trial. Cancer Chemother Pharmacol
    Robins HI, O'Neill A, Gilbert M, Olsen M, Sapiente R, Berkey B, Mehta M
    2008 Jul; 62 (2): 227-33
    • More

      Laboratory and clinical studies support the concept that heparins, particularly the low molecular component, may serve as an inhibitor of angiogenesis, providing anti-neoplastic effects. Further, treatment with low molecular weight heparin (LMWH) may provide prophylaxis for thromboembolic events (TEE), in glioblastoma (GBM) patients. Dalteparin (5,000 U sub-Q daily) was given with and after conventional radiotherapy to newly diagnosed GBM patients. Forty-five patients were accrued between 5/02 and 9/04; 3 were ineligible. At time of progression, patients could continue dalteparin in addition to standard regimens. Pretreatment characteristics included: median age 61 (range 26-78); ECOG Performance status: 0 = 38%, 1 = 57%, 2 = 5%; gross total resection 45%. There were no grade 3/4 bleeding or thrombocytopenic events, and no TEE occurred while on dalteparin. Median time on dalteparin was 6.3 months, median time to progression was 3.9 months; median survival was 11.9 months. There was no significant improvement in survival when compared to the RTOG GBM database (with various radiation/drug doublets including BCNU) using recursive partitioning analysis. Historically the incidence of TEE in GBM patients is approximately 30%. As this study suggests dalteparin reduces the incidence of TEE, and does not have significant overlapping toxicities with most other drugs; its testing in a combined modality approach with other medications may be warranted in future trials.

      View details for PubMedID 17882417
  • Phase-1 trial of gefitinib and temozolomide in patients with malignant glioma: a North American brain tumor consortium study. Cancer Chemother Pharmacol
    Prados MD, Yung WK, Wen PY, Junck L, Cloughesy T, Fink K, Chang S, Robins HI, Dancey J, Kuhn J
    2008 May; 61 (6): 1059-67
    • More

      PURPOSE: This is a phase-I study of gefitinib in combination with temozolomide in patients with gliomas. The goal of the study was to define the maximum tolerated dose (MTD) and to characterize the pharmacokinetics of gefitinib when combined with temozolomide.

      PATIENTS AND METHODS: Patients were stratified according to co-administration of enzyme-inducing anti-epileptic drugs (EIAEDs). There were 26 evaluable patients enrolled (16 on EIAEDs, 10 not on EIAEDs). All but seven patients had Glioblastoma Multiforme (GBM), and only six cases had a Karnosfsky Performance Status (KPS) of less than 80; median age was 51 years. All had received prior radiotherapy and 14 patients had no prior chemotherapy. The starting dose of temozolomide was 150 mg/m(2)/day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m(2)/day in subsequent cycles. The starting dose of gefitinib was 500 mg/day given by mouth on a continuous basis. Dose-limiting toxicity was assessed in cycle one only.

      RESULTS: For patients on EIAEDs, the MTD of gefitinib was 1,000 mg/day in combination with temozolomide. Dose-limiting toxicity (DLT) was due to diarrhea, nausea and vomiting. For patients not on EIAEDs, the MTD was 250 mg/day in combination with temozolomide. The DLT was due to increases in liver transaminases. Rash was not a significant toxicity at these dose levels. The peak concentration and AUC(0-24hr) at the 500 mg dose level was 1.8 and 2.5-fold lower, respectively, in the EIAED group compared to the non-EIAED group; trough levels of gefitinib increased in both groups consistent with the reported terminal half-life ranging from 27 to 51 h.

      CONCLUSION: The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs.

      View details for PubMedID 17694310
  • Temozolomide as prophylaxis for brain metastasis in non-small cell lung cancer. J Thorac Oncol
    Robins HI, Traynor AM, Mehta M
    2006 Sep; 1 (7): 732-3; author reply 733
  • Therapeutic advances in the treatment of brain metastases. Clin Adv Hematol Oncol
    Chang JE, Robins HI, Mehta MP
    2007 Jan; 5 (1): 54-64
    • More

      Brain metastases are a frequent sequelae of many solid tumors. Whole-brain radiotherapy (WBRT) has been the standard treatment for decades, with modest long-term complications observed using doses no greater than 3 Gy/fraction. Surgical resection may be beneficial in select populations of patients with single brain metastases, controlled systemic disease, and good performance status. Radiosurgery has demonstrated consistent improvement in local control, with some reports showing a survival benefit when combined with WBRT. However, the role of radiosurgery as a single modality is unclear, particularly given concerns that higher rates of distant brain relapse result in increased risk of neurologic compromise and death from neurologic causes. Increasingly, the importance of neurocognitive assessment with brain metastases is being recognized, and recent data have strongly correlated neurocognitive dysfunction with tumor progression. Systemic agents showing activity in brain metastases including temozolomide, RSR13, motexafin gadolinium, and lapatinib are being explored.

      View details for PubMedID 17339829
  • Primary disease resection in metastatic breast cancer improves survival. J Clin Oncol
    Choi BS, Robins HI
    2007 Feb 10; 25 (5): 603-4; author reply 604
  • Pulsed reduced dose-rate radiotherapy: case report : a novel re-treatment strategy in the management of recurrent glioblastoma multiforme. J Neurooncol
    Cannon GM, Tomé WA, Robins HI, Howard SP
    2007 Jul; 83 (3): 307-11
    • More

      The initial management of malignant gliomas is multimodality in nature, consisting of surgery, radiation therapy and chemotherapy. However, once progression has occurred, treatment options are limited both in terms of selection and efficacy. We report a case of a 37 year-old male diagnosed with a Grade II astrocytoma initially treated with surgery and external beam radiation therapy consisting of 54 Gy delivered in 1.8 Gy fractions that subsequently progressed to a Grade IV astrocytoma. This was managed with temozolomide chemotherapy until the patient exhibited further progression. Although the patient had received prior full dose radiotherapy, he was re-treated with external beam radiotherapy delivered at a substantially reduced dose-rate. This reduction in dose-rate is obtained by delivering treatment in a series of 0.2 Gy pulses separated by 3 min time intervals, creating an apparent dose rate of 0.0667 Gy/min. The region of recurrence was treated to a dose of 50 Gy delivered using 25 daily fractions of 2.0 Gy. The patient had both a radiographic response and clinical improvement following re-irradiation using pulsed reduced dose-rate radiotherapy with no apparent acute or late neurologic toxicities at a time when other treatment options were not available. Despite delivering 104 Gy to the tumor bed and the surrounding brain parenchyma, at no time was there radiographic evidence of radiation-induced normal tissue necrosis. The radiobiologic basis for the use of pulsed reduced dose-rate external beam radiotherapy in the management of recurrent glioma patients is discussed.

      View details for PubMedID 17252184
  • Therapeutic advances for glioblastoma multiforme: current status and future prospects. Curr Oncol Rep
    Robins HI, Chang S, Butowski N, Mehta M
    2007 Jan; 9 (1): 66-70
    • More

      Glioblastoma multiforme (GBM) is the most common central nervous system malignancy. It is rapidly progressive with rare opportunity for cure. After three decades of laboratory and clinical research, a newly evolved chemoradiotherapy approach using the alkylating agent temozolomide during and after radiotherapy has resulted in the first significant impact on this disease. Here we discuss the basis for this positive interaction as well as potential mechanisms of resistance to it. Additionally, in the context of current and planned research, we explore approaches to take advantage of this combination and the use of targeted therapies to exploit cell signaling alterations found in GBM. We anticipate that a multimodality approach directed at tumor-specific biology will result in more meaningful advancements in the treatment of this fatal disease.

      View details for PubMedID 17164050
  • Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res
    Wen PY, Yung WK, Lamborn KR, Dahia PL, Wang Y, Peng B, Abrey LE, Raizer J, Cloughesy TF, Fink K, Gilbert M, Chang S, Junck L, Schiff D, Lieberman F, Fine HA, Mehta M, Robins HI, DeAngelis LM, Groves MD, Puduvalli VK, Levin V, Conrad C, Maher EA, Aldape K, Hayes M, Letvak L, Egorin MJ, Capdeville R, Kaplan R, Murgo AJ, Stiles C, Prados MD
    2006 Aug 15; 12 (16): 4899-907
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      PURPOSE: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib.

      EXPERIMENTAL DESIGN: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response.

      RESULTS: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by approximately 68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages.

      CONCLUSIONS: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

      View details for PubMedID 16914578
  • Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol
    Cloughesy TF, Wen PY, Robins HI, Chang SM, Groves MD, Fink KL, Junck L, Schiff D, Abrey L, Gilbert MR, Lieberman F, Kuhn J, DeAngelis LM, Mehta M, Raizer JJ, Yung WK, Aldape K, Wright J, Lamborn KR, Prados MD
    2006 Aug 01; 24 (22): 3651-6
    • More

      PURPOSE: A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs). Because tipifarnib undergoes extensive hepatic metabolism, MTD is doubled in patients on EIAEDs. The population included 67 patients with glioblastoma multiforme (GBM) and an exploratory group of 22 patients with anaplastic glioma (AG).

      PATIENTS AND METHODS: Patients received tipifarnib (300 and 600 mg bid for 21 days every 4 weeks in non-EIAED and EIAED patients, respectively). All patients were assessable for efficacy and safety.

      RESULTS: Two AG patients (9.1%) and eight GBM patients (11.9%) had progression-free survival (PFS) more than 6 months. Among the latter eight GBM patients, six of 36 patients (16.7%; 95% CI, 7% to 32%) were not receiving EIAEDs and two of 31 patients (6.5%; 95% CI, 1% to 20%) were receiving EIAEDs. Four patients had partial responses in group A GBM and one patient had a partial response group B GBM. An exploratory comparison of PFS between GBM groups A and B was statistically significant (P = .01). Patients not receiving EIAEDs had a higher incidence and increased severity of hematologic events. However, the incidence and severity of rash (the previously determined dose-limiting toxicity in patients receiving EIAEDs) seemed similar in EIAED and non-EIAED subgroups.

      CONCLUSION: Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.

      View details for PubMedID 16877733
  • Pathophysiology and management of fever revisited. J Support Oncol
    Robins HI, Brandt K, Longo WL
    2006 Jun; 4 (6): 265-6; author reply 266
  • A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. Neuro Oncol
    Prados MD, Lamborn K, Yung WK, Jaeckle K, Robins HI, Mehta M, Fine HA, Wen PY, Cloughesy T, Chang S, Nicholas MK, Schiff D, Greenberg H, Junck L, Fink K, Hess K, Kuhn J, North American Brain Tumor Consortium
    2006 Apr; 8 (2): 189-93
    • More

      The purpose of this study was to determine the response to CPT-11 administered every three weeks to adults with progressive malignant glioma, treated with or without enzyme-inducing antiepileptic drug (EIAED) therapy, at the recommended phase 2 dose determined from a previous phase 1 study. Adult patients age 18 or older with a KPS of 60 or higher who had measurable recurrent grade III anaplastic glioma (AG) or grade IV glioblastoma multiforme (GBM) were eligible. No more than one prior chemotherapy was allowed, either as adjuvant therapy or for recurrent disease. The CPT-11 dose was 350 mg/m(2) i.v. every three weeks in patients not on EIAED and 750 mg/m(2) in patients on EIAED therapy. Patients with stable or responding disease could be treated until tumor progression or a total of 12 months of therapy. The primary end point of the study was to determine whether CPT-11 could significantly delay tumor progression, using the rate of six-month progression-free survival (PFS-6). The trial was sized to be able to discriminate between a 15% and 35% rate for the GBM group alone and between a 20% and 40% rate for the entire cohort. There were 51 eligible patients, including 38 GBM and 13 AG patients, enrolled. The median age was 52 and 42 years, respectively. PFS-6 for the entire cohort was 17.6%. PFS-6 was 15.7% (95% confidence interval [CI], 0.07-0.31) for the GBM patients and 23% (95% CI, 0.07-0.52) for AG patients. Toxicity for the group included diarrhea and myelosuppression. We conclude that the recommended phase 2 dose of CPT-11 for patients with or without EIAED was ineffective on this schedule, in this patient population.

      View details for PubMedID 16533878
  • Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR-0021. Neuro Oncol
    Robins HI, Won M, Seiferheld WF, Schultz CJ, Choucair AK, Brachman DG, Demas WF, Mehta MP
    2006 Jan; 8 (1): 47-52
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      Preclinical studies support the concept that inhibition of protein kinase C (PKC) by tamoxifen (TAM) should provide both antineoplastic effects and radiosensitization. High-dose TAM (80 mg/m2 p.o. daily in divided doses) was given with and after conventional radiotherapy (XRT) to inhibit PKC-mediated signaling, which is known to be enhanced in glioblastoma (GBM). Seventy-seven patients were accrued between December 2000 and December 2001; two were ineligible and not included in the efficacy results. Pretreatment characteristics of the patients included the following: 52% were less than 60 years of age, 39% had a Zubrod score of 0, 70% had minor or no neurological symptoms, and 65% were Radiation Therapy Oncology Group-recursive partition analysis (RPA) class III and IV. Eighty-six percent of patients achieved acceptable dosing of TAM. Notable toxicity included late radiation grade 3 in two patients and thromboembolic events in 16 patients (two grade 2, 10 grade 3, three grade 4, and one grade 5), for an incidence of 20.8% (which is lower than expected, based on the literature for deep vein thrombophlebitis in GBM patients not receiving TAM). Median survival time (MST) was 9.7 months as compared (by three different statistical methodologies) to the historical GBM control database of 1457 RPA class III, IV, and V drug/XRT-treated patients. After controlling for RPA class IV, the MST was 11.3 months, which compares to the historical RPA control of 11.3 months (P = 0.37). The results obtained do not exhibit a substantial advance over those of previous studies with various XRT/drug doublets, including BCNU. However, as TAM does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be justified in future clinical trials. Historically, the incidence of thromboembolic events in GBM patients is approximately 30%. The lower-than-expected incidence seen here has also been observed in other high-dose TAM GBM studies. We speculate that TAM inhibited the PKC-mediated phosphorylation of coagulation factors.

      View details for PubMedID 16443947
  • Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol
    Cloughesy TF, Kuhn J, Robins HI, Abrey L, Wen P, Fink K, Lieberman FS, Mehta M, Chang S, Yung A, DeAngelis L, Schiff D, Junck L, Groves M, Paquette S, Wright J, Lamborn K, Sebti SM, Prados M
    2005 Sep 20; 23 (27): 6647-56
    • More

      PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs.

      PATIENTS AND METHODS: Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed.

      RESULTS: Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC).

      CONCLUSION: Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.

      View details for PubMedID 16170172
  • Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs
    Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, De Angelis L, Raizer J, Hess K, Aldape K, Lamborn KR, Kuhn J, Dancey J, Prados MD, North American Brain Tumor Consortium and the National Cancer Institute
    2005 Aug; 23 (4): 357-61
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      PURPOSE: Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug.

      EXPERIMENTAL DESIGN: CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival.

      RESULTS: Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks.

      CONCLUSIONS: CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.

      View details for PubMedID 16012795
  • Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs. Invest New Drugs
    Chang SM, Kuhn J, Wen P, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, Cloughesy T, De Angelis L, Razier J, Hess K, Dancey J, Prados MD, North American Brain Tumor Consortium And The National Cancer Institute
    2004 Nov; 22 (4): 427-35
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      OBJECTIVES: CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs.

      STUDY DESIGN: The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria.

      RESULTS: Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs.

      CONCLUSIONS: The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.

      View details for PubMedID 15292713
  • Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study. Int J Radiat Oncol Biol Phys
    Schulz CA, Mehta MP, Badie B, McGinn CJ, Robins HI, Hayes L, Chappell R, Volkman J, Binger K, Arzoomanian R, Simon K, Alberti D, Feierabend C, Tutsch KD, Kunugi KA, Wilding G, Kinsella TJ
    2004 Jul 15; 59 (4): 1107-15
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      PURPOSE: To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma.

      METHODS AND MATERIALS: Patients were required to have biopsy-proven malignant glioma. Patients received 100 (n = 4), 200 (n = 3), 300 (n = 3), 400 (n = 6), 500 (n = 4), 625 (n = 5), or 781 (n = 6) mg/m(2)/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost [2.0 Gy for 5 Saturdays]). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used.

      RESULTS: Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (n = 3), thrombocytopenia (n = 3), and elevated liver function studies (n = 3). The maximal tolerated dose was 625 mg/m(2)/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 microM).

      CONCLUSION: In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m(2)/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.

      View details for PubMedID 15234045
  • Phase II study of neoadjuvant 1, 3-bis (2-chloroethyl)-1-nitrosourea and temozolomide for newly diagnosed anaplastic glioma: a North American Brain Tumor Consortium Trial. Cancer
    Chang SM, Prados MD, Yung WK, Fine H, Junck L, Greenberg H, Robins HI, Mehta M, Fink KL, Jaeckle KA, Kuhn J, Hess K, Schold C
    2004 Apr 15; 100 (8): 1712-6
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      BACKGROUND: Temozolomide (TMZ) and 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU) are reported to be active agents in anaplastic glioma (AG). TMZ has also been shown to deplete alkyltransferase, a DNA repair enzyme that contributes to nitrosourea resistance. The objective of the current study was to determine the efficacy and toxicity profile of a combination of these agents before radiotherapy in newly diagnosed AG.

      METHODS: Eligibility criteria included histologically confirmed newly diagnosed AG with measurable enhancing disease, a Karnofsky performance score (KPS) > or = 60, normal pulmonary function, and normal laboratory parameters. In addition, informed consent was obtained from all patients. BCNU given at a dose of 150 mg/m(2) intravenously was followed after 2 hours by TMZ given at a dose of 550 mg/m(2) orally on Day 1 of a 42-day cycle to a maximum of 4 cycles, unless there was tumor progression or unacceptable toxicity.

      RESULTS: Forty-one eligible patients were accrued. Their median age was 40 years. Seventy-six percent of patients had a KPS of 90-100. The histology was 81% anaplastic astrocytoma, 12% anaplastic oligodendroglioma, and 7% mixed tumors. Twenty-two percent of patients did not complete 4 cycles because of toxicity, mainly hematologic. Forty-six percent of patients experienced Grade 3 or 4 (according to National Cancer Institute Common Toxicity Criteria) thrombocytopenia. Twenty percent had Grade 4 granulocytopenia. Two patients died while receiving therapy, 1 of progressive disease and the other of Pneumocystis carinii pneumonia. The complete and partial response rates were 2% and 27% respectively. An additional 54% of patients had stable disease. Seventeen percent developed progressive disease (10% after the first cycle and 7% after the second cycle).

      CONCLUSIONS: This neoadjuvant strategy was associated with significant myelosuppression and a modest response rate in patients with newly diagnosed AG.

      View details for PubMedID 15073861
  • Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. Neuro Oncol
    Prados MD, Yung WK, Jaeckle KA, Robins HI, Mehta MP, Fine HA, Wen PY, Cloughesy TF, Chang SM, Nicholas MK, Schiff D, Greenberg HS, Junck L, Fink KL, Hess KR, Kuhn J, North American Brain Tumor Consortium study
    2004 Jan; 6 (1): 44-54
    • More

      This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m(2) i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m(2) increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m(2) of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the 2, but no relationship dosage range of 350 to 800 mg/m between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m(2) dose, the AUC for CPT-11 (21.6 microg x h/ml) matched the AUC (21.6 microg x h/ml) in the non-EIAED group treated with 350 mg/m(2) of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m(2) when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.

      View details for PubMedID 14769140
  • Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme: North American Brain Tumor Consortium study. Neuro Oncol
    Prados MD, Yung WK, Fine HA, Greenberg HS, Junck L, Chang SM, Nicholas MK, Robins HI, Mehta MP, Fink KL, Jaeckle KA, Kuhn J, Hess KR, Schold SC, North American Brain Tumor Consortium study
    2004 Jan; 6 (1): 33-7
    • More

      The purpose of this study was to evaluate the activity, measured in terms of progression-free survival (PFS) and response rates, of 1,3-bis(chloro-ethyl)-1-nitrosourea (BCNU) plus temozolomide in adult patients with recurrent glioblastoma multiforme. The phase 2 dose and schedule for this trial was BCNU 150 mg/m(2) i.v. followed in 2 h by temozolomide 550 mg/m(2) as a single oral dose. Treatment was repeated every 6 weeks for up to 8 cycles unless tumor progression was documented. The primary end point was PFS at 6 months (PFS-6). Response was a secondary end point, measured by MR imaging, neurological status, and steroid requirements prior to each 6-week cycle. The median age of eligible patients was 53, and 89.5% had no prior chemotherapy. All patients were evaluable for toxicity and time to progression. The PFS-6 was 21%. Overall survival was 68% at 6 months and 26% at 1 year. The MRI response for 36 patients was 2 partial responses, 2 minor responses, 19 cases of stable disease, and 13 immediate progressions. Median survival was 34 weeks, and median PFS was 11 weeks. Toxicity was primarily myelosuppression; no toxic deaths occurred. Historical phase 2 study data in this patient population show a PFS-6 of 15%. Recent data for use of temozolomide alone have shown a PFS-6 of 21%. We conclude that BCNU plus temozolomide when used in these doses and schedule has only modest activity, with significant toxicity, and appears to be no more effective than single-agent temozolomide.

      View details for PubMedID 14769138
  • O6-benzylguanine suppression of O6-alkylguanine-DNA alkyltransferase in anaplastic gliomas. Neuro Oncol
    Schold SC, Kokkinakis DM, Chang SM, Berger MS, Hess KR, Schiff D, Robins HI, Mehta MP, Fink KL, Davis RL, Prados MD
    2004 Jan; 6 (1): 28-32
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      The purpose of the study was to determine the dose of O(6)-benzylguanine (BG) that would suppress O(6)-alkylguanine-DNA alkyltransferase (AGT) activity to undetectable levels in > 90% of anaplastic gliomas, as measured 6 h after a 1-h BG infusion. Subjects who were scheduled for surgical resection of a known or presumed anaplastic glioma received a 1-h infusion of BG. Tumor tissue was surgically removed approximately 6 h after the end of the infusion and was analyzed for AGT activity. The BG dose was escalated until at least 11 of 14 subjects had no detectable AGT activity. An additional cohort of patients received the identified effective dose of BG approximately 18 h before tumor resection in order to compare our results with an earlier study using the longer time interval. In the 79 subjects who were enrolled, there was no significant toxicity that was attributed to the BG. A dose-response relationship was determined between the BG dose and the percentage of subjects with undetectable AGT. A dose of 120 mg/m(2) suppressed AGT to less than detectable levels in 17 of 18 patients when the drug-resection interval was 6 h. With an 18-h interval, only 5 of 11 subjects had undetectable AGT at the 120-mg/m(2) dose. We conclude that a BG dose of 120 mg/m(2) given 6 h before an alkylating drug would be effective in suppressing AGT and possibly potentiating the cytotoxic effects of the drug.

      View details for PubMedID 14769137
  • Combined modality treatment for central nervous system malignancies. Semin Oncol
    Robins HI, Peterson CG, Mehta MP
    2003 Aug; 30 (4 Suppl 9): 11-22
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      This review summarizes the current status and future prospects for combined modality treatment of primary and metastatic central nervous system malignancies. The laboratory and clinical basis for multimodality therapy, including surgery, ionizing radiation, and drug therapy, are outlined and critically reviewed. The central nervous system diseases discussed include: glioma (low and high grade), brain metastases, and primary central nervous system lymphoma. Collectively, these data suggest a shift favoring combined modality approaches in several of these diseases; however, the incremental gains are indeed modest. The individual practitioner must weigh these with the additional toxicities before making a therapeutic decision for a particular patient. The future direction of combined modality therapy in these diseases will likely revolve around the increased use of molecular diagnostics resulting in the application of targeted therapy. Clearly, such promising innovations must be delineated in the context of continued preclinical studies and controlled clinical trials.

      View details for PubMedID 12908133
  • A Systemic Hyperthermia Oncologic Working Group trial. Ifosfamide, carboplatin, and etoposide combined with 41.8 degrees C whole-body hyperthermia for metastatic soft tissue sarcoma. Oncology
    Westermann AM, Wiedemann GJ, Jager E, Jager D, Katschinski DM, Knuth A, Vörde Sive Vörding PZ, Van Dijk JD, Finet J, Neumann A, Longo W, Bakhshandeh A, Tiggelaar CL, Gillis W, Bailey H, Peters SO, Robins HI, Systemic Hyperthermia Oncologic Working Group
    2003; 64 (4): 312-21
    • More

      BACKGROUND: Based on earlier clinical and preclinical studies, we conducted a phase II trial in metastatic sarcoma patients of the combination of 41.8 degrees C (x60 min) radiant heat (Aquatherm) whole-body hyperthermia (WBH) with 'ICE' chemotherapy. The ICE regimen consists of ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (100 mg/m(2)), concurrent with WBH, with etoposide also on days 2 and 3 post-WBH.

      METHODS: Therapy was delivered every 4 weeks for a maximum of 4 cycles. All patients received filgrastim or lenograstim.

      RESULTS: Of 108 patients enrolled as of September 2001, 95 are evaluable for response. Of the evaluable patients (mean ECOG performance status approximately 1; mean age 42.3; 58% male) 33 had no prior therapy for metastatic disease, and 62 were pretreated (mean: 1.5 prior regimens). The overall response rate was 28.4% (4 complete remissions and 23 partial remissions) with stable disease (SD) in 31 patients. For no prior therapy, the response rate was 36%; in pretreated patients it was 24%. The median overall survival by Kaplan-Meier estimates was 393 days (95% CI 327, 496); the median time to treatment failure was 123 days (95% CI 77, 164). The major toxicity (287 cycles) was grade 3 or 4 neutropenia and thrombocytopenia seen in 79.7 and 60.6% of treatments respectively; there were 7 episodes of infection (grade 3/4) with 2 treatment-related deaths, bot involving disease progression and ureteral obstruction.

      CONCLUSION: These results are consistent with continued clinical investigation of this combined modality approach.

      View details for PubMedID 12759526
  • Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma. Lung Cancer
    Bakhshandeh A, Bruns I, Traynor A, Robins HI, Eberhardt K, Demedts A, Kaukel E, Koschel G, Gatzemeier U, Kohlmann T, Dalhoff K, Ehlers EM, Gruber Y, Zumschlinge R, Hegewisch-Becker S, Peters SO, Wiedemann GJ
    2003 Mar; 39 (3): 339-45
    • More

      We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated.

      View details for PubMedID 12609573
  • A phase II trial of thymidine and carboplatin for recurrent malignant glioma: a North American Brain Tumor Consortium Study. Neuro Oncol
    Robins HI, Chang SM, Prados MD, Yung WK, Hess K, Schiff D, Greenberg H, Fink K, Nicolas K, Kuhn JG, Cloughesy T, Junck L, Mehta M
    2002 Apr; 4 (2): 109-14
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      This phase II study in recurrent high-grade glioma evaluated the response rate, toxicities, and time to treatment failure of high-dose carboplatin modulated by a 24-h infusion of thymidine (75 g/m(2)). The trial was based on preclinical data and a prior phase I study ( J. Clin. Oncol. 17, 2922-2931, 1999); a phase II recurrent high-grade glioma study was initiated in July of 1998. Thymidine was given over 24 h; carboplatin was given over 20 min at hour 20 of the thymidine infusion. The starting dose of carboplatin had a value of 7 for the area under the curve (AUC), with allowance for dose escalation of 1 AUC unit per cycle if grade 2 toxicity was observed. Treatment cycles were repeated every 4 weeks. Accrual as of September 1999 was 45 patients [4 were unevaluable]: 76% with glioblastoma multiforme (GBM), 20% with anaplastic oligodendroglioma, 2% with mixed type, and 2% with anaplastic astrocytoma. Most patients had prior chemotherapy (78%). As observed in the earlier phase I study (in which carboplatin pharmacokinetics were unaltered by thymidine or antiseizure medications), thymidine was myeloprotective, resulting in a minimal need for dose reduction for patients having a >2 grade toxicity (in only 4% of the courses of treatment). Of 101 total courses, the number of courses (at the AUCs) was 3 (5), 4 (6), 58 (7), 20 (8), 11 (9), and 5 (10). Grade 3 nonhematologic toxicities included headache (4%), altered consciousness (3%), fatigue (1%), and nausea (3%). Responses included 2 partial (1 oligodendroglioma, 1 GBM; 5%); 3 minor (1 anaplastic astrocytoma, 2 GBM; 7.3%); 6 stable disease (14.6%); and 30 progressive disease (73.2%). For GBM patients, median survival was 23 weeks (with a 95% confidence interval of 20 to 50 weeks), and progression-free survival was 8 weeks (with a 95% confidence interval of 7-16 weeks). These results in GBM were comparable to other phase II GBM trials and thus do not represent a therapeutic advance in the treatment of GBM. Taken collectively, however, results are consistent with continued investigation of thymidine in combination with chemotherapeutic agents for high-grade glioma and other malignant diseases. The significant myeloprotection afforded by thymidine may have particular relevance to polychemotherapeutic regimens.

      View details for PubMedID 11916502
  • Trastuzumab for breast cancer-related carcinomatous meningitis. Clin Breast Cancer
    Robins HI, Liu G, Hayes L, Mehta M
    2002 Jan; 2 (4): 316
  • Pineal sarcoma. Acta Neurochir (Wien)
    Liu Z, Salamat MS, Hafez GR, Mehta MP, Robins HI, Amoli RS, Tomic S
    2002 Jan; 144 (1): 89-92
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      We report a case of fibrosarcoma arising in the pineal of a 36-year-old female patient. She died at the age 43 following biopsy, radiation therapy, tumor resection, chemotherapy, and stereotactic radiosurgery. Light microscopic study of all tissues obtained, including immunohistochemistry and electron microscopy of surgically resected tumor and autopsied tissue revealed a slowly progressing primary fibrosarcoma.

      View details for PubMedID 11807650
  • Late recurrence of a primitive neuro-ectodermal tumor. Oncology
    Rao RD, Robins HI, Mehta MP
    2001; 61 (3): 189-91
    • More

      Late recurrences after therapy are rare in primitive neuro-ectodermal tumor (PNET). Most recurrences occur within the first 2 years after therapy, although a small number of recurrences may occur up to 5 years after therapy. We present a rare case of a recurrence of PNET in a 31-year-old woman 17 years after her initial presentation. The potential biological implications of this late recurrence as well as responses to subsequent therapy, including temozolomide, are discussed.

      View details for PubMedID 11574773
  • Modulation of VP-16 cytotoxicity by carboplatin and 41.8 degrees C hyperthermia. J Cancer Res Clin Oncol
    Katschinski DM, Jacobson EL, Wiedemann GJ, Robins HI
    2001 Jul; 127 (7): 425-32
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      PURPOSE: To study in vitro the effect of carboplatin and/or hyperthermia in relation to etoposide (VP-16) cytotoxicity in L929 cells.

      METHODOLOGY/RESULTS: Cell survival assays demonstrated that the addition of 41.8 degrees C (x60 min) hyperthermia and carboplatin to VP-16 produced an antagonistic effect relative to VP-16 cytotoxicity in L929 cells; administering carboplatin and hyperthermia 24 h before VP-16 reduced this drug resistance; administering carboplatin and hyperthermia 48 h before VP-16, however, produced a supra-additive cytotoxicity. In order to gain insight into the molecular basis for these observations, we investigated the effect of hyperthermia and/or carboplatin on the stress protein GRP78, which is known to affect VP-16 cytotoxicity. Results obtained were consistent with the hypothesis that carboplatin and hyperthermia perturbation of NAD + pools results in down-regulation of GRP78 with subsequent modulation of VP-16 cytotoxicity. To further explicate these results we studied G-361 as a control cell line that had significantly higher pretreatment NAD+ levels, which were not affected by carboplatin and/or hyperthermia. This cell line did not exhibit a down-regulation of GRP78 or modulation of VP-16 cytotoxicity as a function of carboplatin and hyperthermia.

      CONCLUSIONS: These data taken collectively, demonstrate a sequence effect (regarding the aforementioned antineoplastic agents), and provide a framework for future studies directed at the therapeutic optimization of the sequential application of carboplatin, hyperthermia, and VP-16.

      View details for PubMedID 11469679
  • A pilot study of whole body hyperthermia and carboplatin in platinum-resistant ovarian cancer. Eur J Cancer
    Westermann AM, Grosen EA, Katschinski DM, Jäger D, Rietbroek R, Schink JC, Tiggelaar CL, Jäger E, Zum Vörde sive Vörding P, Neuman A, Knuth A, Van Dijk JD, Wiedemann GJ, Robins HI
    2001 Jun; 37 (9): 1111-7
    • More

      The aim of this study was to determine whether the addition of whole body hyperthermia (WBH) to carboplatin (CBDCA) can induce responses in patients with platinum-resistant ovarian cancer. 16 pretreated patients with platinum-resistant ovarian cancer were entered on a Systemic Hyperthermia Oncological Working Group (SHOWG) study; (14 patients were eligible with 14 evaluable for toxicity and 12 for response). The patients were treated with WBH (Aquatherm) 41.8 degrees C x 60 min in combination with carboplatin (CBDCA) (area under the curve (AUC) of 8) every 4 weeks. Disease status was evaluated every two cycles. Patients were treated for a maximum of six cycles. One patient had a complete response (CR) and 4 had a partial response (PR). 4 patients had stable disease (SD). 3 patients had progressive disease (PD). 2 patients were unevaluable: 1 had a bowel obstruction shortly after her first treatment; the second patient achieved a CR, but only had one treatment secondary to an idiosyncratic reaction to sedative drugs. 2 patients entered on study were ineligible, as they did not meet criteria for platinum resistance; 1 entered a CR and 1 had SD. Dose-limiting toxicity, which required CBDCA dose reductions, was grade 4 thrombocytopenia. Other toxicities included neutropenia (grade 3/4), and nausea and/or vomiting. Consistent with preclinical modelling, these results suggests that 41.8 degrees C WBH can overcome platinum resistance in ovarian cancer. These observations suggest further investigation of the therapeutic potential of WBH in a group of patients who historically fail to respond to salvage therapies is warranted.

      View details for PubMedID 11378341
  • A phase I trial of 1,3-bis(2-chloroethyl)-1-nitrosourea plus temozolomide: a North American Brain Tumor Consortium study. Neuro Oncol
    Schold SC, Kuhn JG, Chang SM, Bosik ME, Robins HI, Mehta MP, Spence AM, Fulton D, Fink KL, Prados MD
    2000 Jan; 2 (1): 34-9
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      The North American Brain Tumor Consortium conducted a phase I trial of the combination 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide. Eligibility included a patient with a cancer type that was considered refractory to standard therapy. Prior nitrosourea treatments were not permitted. There were parallel dose escalations in two treatment schedules. Forty-five patients were enrolled during an 18-month period. The maximum tolerated doses (MTDs) when temozolomide followed BCNU (Arm A) were temozolomide at 550 mg/m2/p.o. and BCNU at 150 mg/m2/i.v.), whereas the MTD when temozolomide preceded BCNU (Arm B) was temozolomide at 400 mg/m2/p.o. and BCNU at 100 mg/m2/i.v. Toxicity was predominantly hematologic, although there were three instances of pulmonary toxicity, which in one case could have represented potentiation of nitrosourea-induced pulmonary fibrosis. The half-life of temozolomide was 1.86 (+/-0.31) h. There was a moderate relationship between dose and peak concentration and a strong relationship between dose and plasma concentration time curve. Pharmacokinetic parameters of temozolomide were unaffected by the treatment schedule, so the difference in MTD between the schedules is likely due to a biologic rather than a pharmacokinetic sequence interaction. There were 9 partial responses among 43 patients evaluable for response, including 5 of 25 with a histologic diagnosis of glioblastoma. The recommended dose and schedule for phase II trials of this regimen are BCNU 150 mg/m2/i.v. followed in 2 h by temozolomide 550 mg/m2/p.o. repeated every 6 weeks. We are also recommending screening and periodic pulmonary function testing during treatment to assess the possible potentiation of nitrosourea-induced pulmonary fibrosis.

      View details for PubMedID 11302252
  • A Phase II study of paclitaxel in patients with recurrent malignant glioma using different doses depending upon the concomitant use of anticonvulsants: a North American Brain Tumor Consortium report. Cancer
    Chang SM, Kuhn JG, Robins HI, Schold SC, Spence AM, Berger MS, Mehta M, Pollack IF, Rankin C, Prados MD
    2001 Jan 15; 91 (2): 417-22
    • More

      BACKGROUND: The primary objective of the current study was to determine the response rate of paclitaxel in patients with recurrent malignant glioma by using different doses dependent on the concomitant use of anticonvulsants. Secondary objectives were to determine the time period to treatment failure, to evaluate toxicities, and to obtain pharmacokinetic data.

      METHODS: Adult patients who had recurrent malignant glioma were treated with paclitaxel. Patients were treated at different doses depending on the concomitant use of anticonvulsants known to induce the p450 hepatic enzyme system. Patients on such agents were treated at a dose of 330 mg/m2, whereas those not on these anticonvulsants were treated at a dose of 210 mg/m2. Tumor response was assessed at 6-week intervals. Treatment was continued until documented tumor progression or unacceptable toxicity occurred, or a total of 12 paclitaxel infusions was completed.

      RESULTS: From January 1997 to June 1997, 23 patients were treated with paclitaxel. Four patients were ineligible for the current study. Of the 19 eligible patients, there were no responses seen. Four (21%) had stabilization of disease. Median time to treatment failure was 1 month (95% confidence interval [CI], 1-2 mos) and median survival was 7 months (95% CI, 6-10 mos). Three patients were removed from the current study because they had toxicity. Pharmacokinetic studies demonstrated that drug levels and clearance values were consistent with previously reported findings.

      CONCLUSION: Even though higher doses were administered to patients who had recurrent malignant glioma and who were on concomitant anticonvulsants, there were no objective responses to paclitaxel. Time to tumor progression was 1 month. Further testing of paclitaxel at this dose schedule does not appear to be warranted in this patient population.

      View details for PubMedID 11180089
  • Non-Hodgkin's tumor and Pancoast's syndrome. Oncol Rep
    Rao RD, Robins HI
    2001 Jan-Feb; 8 (1): 165-6
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      A 60-year old man presented with Horner's syndrome, and acute right hand and lower extremity weakness. Chest X-ray and MRI revealed a right apical lung tumor (presumed to be a primary lung cancer), with brachial plexus infiltration and spinal cord compression. Emergent radiotherapy was initiated for spinal cord compression and a biopsy was obtained 24 h later. A careful review of pathology demonstrated a non-Hodgkin's lymphoma. The patient subsequently received chemotherapy, and is now in remission. This case illustrates the importance of a tissue diagnosis before initiating therapy for a Pancoast's tumor.

      View details for PubMedID 11115591
  • Whole body hyperthermia cytokine induction: a review, and unifying hypothesis for myeloprotection in the setting of cytotoxic therapy. Cytokine Growth Factor Rev
    Katschinski DM, Wiedemann GJ, Longo W, d'Oleire FR, Spriggs D, Robins HI
    1999 Jun; 10 (2): 93-7
    • More

      Whole Body Hyperthermia (WBH) enhancement of chemotherapy and/or radiation without a concomitant increase in myelosuppression has been documented in clinical trials. We propose that the biological basis for this phenomena relates in part to the previously reported induction of peripheral cytokines by WBH, that is, granulocyte colony stimulating factor (G-CSF), interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), and the regulatory cytokine IL-10. To further explain this myeloprotection and the additional clinical observation that WBH promotes early engraftment of bone marrow (when used as part of an allogenic bone marrow transplant preconditioning regimen) we developed a hypothesis: WBH increases peripheral IL-1 beta, IL-6, and TNF-alpha resulting in a secondary induction of IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF) in the bone marrow, for which supportive data also exists. Taken collectively, these data provide an increased understanding of the biological sequelae of fever, as well as a testable unifying hypothesis, for future antineoplastic treatment strategies.

      View details for PubMedID 10743501
  • Nephrotoxicity of ifosfamide, carboplatin and etoposide (ICE) alone or combined with extracorporeal or radiant-heat-induced whole-body hyperthermia. J Cancer Res Clin Oncol
    Gerke P, Filejski W, Robins HI, Wiedemann GJ, Steinhoff J
    2000 Mar; 126 (3): 173-7
    • More

      Although whole-body hyperthermia combined with specific genotoxic chemotherapy can be shown to enhance neoplastic cell killing without a concomitant rise in bone marrow toxicity, nephrotoxicity can become treatment-limiting. This study compares the kidney toxicity to the kidney of ifosfamide, carboplatin and etoposide (ICE) chemotherapy alone, and ICE chemotherapy combined with either extracorporeal (e-WBH) or radiant-heat-induced hyperthermia (r-WBH) in 43 patients with refractory sarcoma. Within 3 days of ICE chemotherapy treatment there was a significant increase in urinary protein excretion and a reduction of the glomerular filtration rate. These effects were more pronounced if WBH was added. The use of immunoluminometric assays revealed a predominance of low-molecular-mass proteins. This increase in protein excretion persisted in the e-WBH-treated group, whereas it vanished within 3 weeks in both the group treated with ICE alone and that treated with r-WBH. Our findings suggest that ICE chemotherapy causes transient tubular and glomerular damage, which is enhanced by WBH. In terms of long-term nephrotoxicity e-WBH was more nephrotoxic than r-WBH. This finding is consistent with our clinical observations.

      View details for PubMedID 10741912
  • Whole body hyperthermia induction of soluble tumor necrosis factor receptors: implications for rheumatoid diseases. J Rheumatol
    Robins HI, Grosen E, Katschinski DM, Longo W, Tiggelaar CL, Kutz M, Winawer J, Graziano F
    1999 Dec; 26 (12): 2513-6
    • More

      OBJECTIVE: To test the hypothesis that 41.8 degrees C x 60 min whole body hyperthermia (WBH) induces increased serum levels of soluble necrosis factor receptors (sTNF-R).

      METHODS: We tested the serum of cancer patients for changes in sTNF-RI and RII levels, as a function of time, pre and post: (1) WBH alone, (2) WBH and chemotherapy, i.e., melphalan (L-PAM), and (3) L-PAM alone.

      RESULTS: For sTNF-RI there was a marked increase (over pre-treatment values, i.e., 86%) in serum levels after WBH alone (n = 3), which peaked 2.5 h post-WBH; L-PAM (iv) only resulted in a dip in sTNF-RI seen 40 min postadministration; the combination (WBH + L-PAM), resulted in both the dip at 40 min and the increase at 2.5 h post-treatment. For sTNF-RII both WBH alone (n = 3) and WBH + L-PAM (n = 2), there was an increase in receptor serum levels of 25% and 30%, respectively, which peaked 5.5 h post-treatment, and remained elevated at 24 h. L-PAM alone resulted in a dip in levels only at 40 min post-treatment. sTNF-RI and RII levels returned to baseline values within 7 days post-treatment.

      CONCLUSION: 41.8 degrees C WBH results in transient increases in TNF-RI and RII. These results may have therapeutic implications for the application of WBH to TNF mediated disease processes.

      View details for PubMedID 10606355
  • Phase I trial of intravenous thymidine and carboplatin in patients with advanced cancer. J Clin Oncol
    Robins HI, Tutsch K, Katschinski DM, Jacobson E, Mehta M, Olsen M, Cohen JD, Tiggelaar CL, Arzoomanian RZ, Alberti D, Feierabend C, Wilding G
    1999 Sep; 17 (9): 2922-31
    • More

      PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m(2) in a phase I trial.

      PATIENTS AND METHODS: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m(2) (n = 3); 300 mg/m(2) (n = 7); 350 mg/m(2) (n = 4); 400 mg/m(2) (n = 3); 480 mg/m(2) (n = 10); and 576 mg/m(2) (n = 5). At the maximum-tolerated dose (480 mg/m(2)), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy.

      RESULTS: Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m(2)-dose level, and disease stabilization (7 months) at the 400-mg/m(2-dose) level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m(2)-dose level.

      CONCLUSION: The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.

      View details for PubMedID 10561372
  • Phase I clinical and pharmacokinetic study of an one-hour infusion of ormaplatin (NSC 363812). Invest New Drugs
    Tutsch KD, Arzoomanian RZ, Alberti D, Tombes MB, Feierabend C, Robins HI, Spriggs DR, Wilding G
    1999; 17 (1): 63-72
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      Ormaplatin (NSC 363812, tetraplatin) is a stable platinum (IV) analog which has exhibited activity against cisplatin-resistant cell lines. A phase I trial of ormaplatin administered as a 1-h infusion every 4 weeks was performed. Forty-one patients received 101 cycles of drug over the dose range 4-128 mg/m2. The dose-limiting toxicity was reversible thrombocytopenia and granulocytopenia. Minimal myelosuppression was observed at dose levels < or = 78 mg/m2, while grade 3 or 4 myelosuppression (thrombocytopenia and/or granulocytopenia) was seen in 4/8 patients at 98 mg/m2 and 4/5 patients at 123 mg/m2. Nausea and vomiting was observed at all dose levels but was controlled with antiemetic premedication. Neurotoxicity was observed in 5/41 patients and the incidence appeared related to cumulative dose rather than to dose level or drug clearance. Platinum was measured by furnace atomic absorption spectrophotometry. Ormaplatin-derived plasma ultrafilterable platinum (UF-Pt) exhibited linear pharmacokinetics over the dose range studied. The mean total body clearance of UF-Pt was 135 ml/min/m2 and the mean elimination half-life (t1/2beta) was 13.6 h. Ormaplatin exhibited a high degree of protein binding, with more than 70% of platinum protein bound by the end of the infusion. Urinary excretion of platinum accounted for 37% of the total dose of ormaplatin in 24 hours. A phase II dose of 98 mg/m2 is recommended for testing in a patient population with cisplatin-refractory disease.

      View details for PubMedID 10555124
  • Whole body hyperthermia: simple complexities. Intensive Care Med
    Robins HI, Longo W
    1999 Sep; 25 (9): 898-900

Contact Information

H. Ian Robins, MD, PhD

600 Highland Avenue Madison,
Box 5664
Madison, WI 53792