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.
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)
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
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
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
Neurocognitive, Symptom, and Health- Related Quality of Life Outcomes of a Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma (NRG/RTOG 0825) Neuro-oncology
Wefel JS, Armstrong TS, Pugh SL, Gilbert MR, Wendland MM, Brachman DG, Roof KS, Brown PD, Crocker IR, Robins HI, Hunter G, Won M, Mehta MP
2021 Jan 30:noab011. doi: 10.1093/neuonc/noab011. Online ahead of print.
BACKGROUND: Results of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient reported outcomes (PRO) over time in bevacizumab treated patients. The present report provides additional results of patient centered outcomes over time and their prognostic association with survival endpoints.
METHODS: NCF tests, MD Anderson Symptom Inventory brain tumor module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire with brain-cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments was evaluated.
RESULTS: 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between arm differences in time to deterioration was found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (week 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms and interference.
CONCLUSION: The collection of patient centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.
PMID:33515019 | DOI:10.1093/neuonc/noab011
View details for PubMedID 33515019
Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a 3-arm sequential accrual clinical trial: NABTC 05-02 Neuro-oncology advances
Chen H, Kuhn J, Lamborn KR, Abrey LE, DeAngelis LM, Lieberman F, Robins HI, Chang SM, Yung KA, Drappatz J, Mehta MP, Levin VA, Aldape K, Dancey JE, Wright JJ, Prados MD, Cloughesy TF, Wen PY, Gilbert MR
2020 Sep 17;2(1):vdaa124. doi: 10.1093/noajnl/vdaa124. eCollection 2020 Jan-Dec.
BACKGROUND: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs.
METHODS: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6).
RESULTS: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated.
CONCLUSION: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.
PMID:33235994 | PMC:PMC7668489 | DOI:10.1093/noajnl/vdaa124
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A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma Neuro-oncology
Gilbert MR, Yuan Y, Wu J, Mendoza T, Vera E, Omuro A, Lieberman F, Robins HI, Gerstner ER, Wu J, Wen PY, Mikkelsen T, Aldape K, Armstrong TS
2021 Mar 25;23(3):468-477. doi: 10.1093/neuonc/noaa240.
BACKGROUND: No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas.
METHODS: Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI-Spine Tumor modules were collected.
RESULTS: The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients.
CONCLUSIONS: This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.
PMID:33085768 | PMC:PMC7992893 | DOI:10.1093/neuonc/noaa240
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Outcomes From Whole-Brain Reirradiation Using Pulsed Reduced Dose Rate Radiation Therapy Advances in radiation oncology
Burr AR, Robins HI, Bayliss RA, Baschnagel AM, Welsh JS, Tomé WA, Howard SP
2020 Jul 8;5(5):834-839. doi: 10.1016/j.adro.2020.06.021. eCollection 2020 Sep-Oct.
PURPOSE: Recurrent intracranial metastases after whole-brain irradiation pose a clinical challenge owing to the escalating morbidity associated with their treatment. Although stereotactic radiosurgery is increasingly being used, there are still situations in which whole-brain reirradiation (ReRT) continues to be appropriate. Here, we report our experience using whole-brain pulsed reduced dose rate radiation therapy (PRDR), a method that delivers radiation at a slower rate of 0.067 Gy/min to potentially increase sublethal damage repair and decrease toxicity.
METHODS AND MATERIALS: Patients undergoing whole-brain ReRT with PRDR from January 1, 2001 to March 2019 were analyzed. The median PRDR ReRT dose was 26 Gy in 2 Gy fractions, resulting in a median total whole-brain dose of 59.5 Gy. Cox regression analysis was used for multivariate analysis. The Kaplan-Meier method was used for overall survival, progression free survival, and to evaluate the ReRT score. Binary logistic regression was employed to evaluate variables associated with rapid death.
RESULTS: Seventy-five patients were treated with whole-brain PRDR radiation therapy. The median age was 54 (range, 26-72), the median Karnofsky performance status (KPS) was 80, and 86.7% had recursive partitioning analysis scores of 2. Thirty-two patients had over 10 metastases and 11 had leptomeningeal disease. The median overall survival was 4.1 months (range, 0.29-59.5 months) with a 1 year overall survival of 10.4%. Age, KPS, dexamethasone usage, and intracranial disease volume were significantly correlated with overall survival on multivariate analysis. A KPS ≤70 was associated with rapid death after radiation. The prognostic value of the ReRT score was validated. The most common acute toxicities were fatigue (23.1%) and headache (16.9%).
CONCLUSIONS: In this large cohort of patients with advanced intracranial metastases, PRDR achieves acceptable survival and may decrease toxicity associated with ReRT. PRDR is an easily implemented technique and is a viable treatment option for ReRT of brain metastases.
PMID:33083645 | PMC:PMC7557211 | DOI:10.1016/j.adro.2020.06.021
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A Phase II and Pharmacodynamic Trial of RO4929097 for Patients With Recurrent/Progressive Glioblastoma Neurosurgery
Peereboom DM, Ye X, Mikkelsen T, Lesser GJ, Lieberman FS, Robins HI, Ahluwalia MS, Sloan AE, Grossman SA
2021 Jan 13;88(2):246-251. doi: 10.1093/neuros/nyaa412.
BACKGROUND: Cancer stem-like cells are a major cause of resistance to therapy in patients with glioblastoma (GBM) as well as other cancers. Tumor cells are maintained in a stem-like proliferative state in large part through the Notch signaling pathway. The function of this pathway in turn depends on gamma secretase activity. Inhibition of this enzyme therefore inhibits the Notch pathway and tumor growth as measured by a reduction in the formation of brain tumor neurospheres in murine models. RO4929097 is an oral gamma secretase inhibitor.
OBJECTIVE: To estimate the 6-mo progression-free survival rate (PFS6) in patients with progressive GBM and to inhibit by 50% the generation of neurospheres in fresh tissue resected from patients treated with RO4929097.
METHODS: In this phase II and pharmacodynamic study, patients with recurrent GBM received RO4929097 in a study of 2 groups. Group A patients had unresectable disease and received drug in a standard phase II design. Group B patients had resectable disease and received drug before and after surgical resection. Endpoints included PFS6 and the inhibition of neurosphere formation in the resected tumor samples.
RESULTS: A total of 47 patients received treatment, 7 of whom had tumor resection. The PFS6 was 4%, and the inhibition of neurosphere formation occurred in 1 of 7 patient samples.
CONCLUSION: RO4929097 was inactive in recurrent GBM patients and demonstrated minimal inhibition of neurosphere formation in fresh tissue samples.
PMID:33027815 | PMC:PMC7919338 | DOI:10.1093/neuros/nyaa412
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NRG/RTOG 1122: A phase 2, double-blinded, placebo-controlled study of bevacizumab with and without trebananib in patients with recurrent glioblastoma or gliosarcoma Cancer
Lee EQ, Zhang P, Wen PY, Gerstner ER, Reardon DA, Aldape KD, deGroot JF, Pan E, Raizer JJ, Kim LJ, Chmura SJ, Robins HI, Connelly JM, Battiste JD, Villano JL, Wagle N, Merrell RT, Wendland MM, Mehta MP
2020 Jun 15;126(12):2821-2828. doi: 10.1002/cncr.32811. Epub 2020 Mar 10.
BACKGROUND: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM.
METHODS: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS).
RESULTS: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms.
CONCLUSION: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental.
PMID:32154928 | PMC:PMC7245544 | DOI:10.1002/cncr.32811
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The association between BMI and BSA-temozolomide-induced myelosuppression toxicities: a correlative analysis of NRG oncology RTOG 0525 Neuro-oncology practice
Robins HI, Eickhoff J, Gilbert MR, Armstrong TS, Shi W, Groot FD, Schultz CJ, Hunter GK, Valeinis E, Roach M, Youssef EF, Souhami L, Howard SP, Lieberman FS, Herman JG, Zhang P, Mehta MP
2019 Dec;6(6):473-478. doi: 10.1093/nop/npz006. Epub 2019 Apr 6.
BACKGROUND: Fearing increased myelotoxicity, many practitioners adjust the body surface area (BSA)-calculated doses in obese patients. Regarding temozolomide (TMZ), a prior study suggested men with a BSA >2 m2 may experience increased toxicity; however, surprisingly, the inverse observation was noted in women, ie, BSA <2 m2 was associated with higher toxicity. To further clarify this issue, data derived from a large clinical trial were analyzed.
METHODS: The incidence of grade 3 and 4 myelotoxicity in a newly diagnosed glioblastoma phase 3 trial (RTOG 0525) was statistically correlated with BMI and separately with BSA. All patients received radiation and TMZ followed by adjuvant standard dose TMZ vs dose-dense TMZ; dosing regimen-associated myelotoxicity and BMI/BSA were analyzed separately. Obesity was defined as a BMI ≥30.
RESULTS: There was no statistically significant correlation between gender and BSA and the occurrence of myotoxicities. For the standard arm, surprisingly the incidence of grade 3/4 myotoxicities in patients with a BMI <30 was significantly higher than in patients with a BMI ≥30 (12% vs 1%, odds ratio [OR] 12.5, P < .001). There was no significant difference between obese and nonobese patients (BMI "cut-point" of 30) in the dose-dense arm (OR = 0.9, 95% confidence interval: 0.4-1.6). The grade hematological 3/4 toxicity rate was significantly higher in women vs men (14% vs 8%) P = .009 in spite of the lack of association between gender and BSA or BMI.
CONCLUSION: TMZ dosing based on actual BSA is recommended with the caveat that woman are likely at higher toxicity risk.
PMID:31832217 | PMC:PMC6899045 | DOI:10.1093/nop/npz006
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Pulsed Reduced Dose Rate for Reirradiation of Recurrent Breast Cancer Practical radiation oncology
Burr AR, Robins HI, Bayliss RA, Howard SP
2020 Mar-Apr;10(2):e61-e70. doi: 10.1016/j.prro.2019.09.004. Epub 2019 Sep 14.
PURPOSE: Locoregionally recurrent breast cancer within a previously irradiated field requires weighing the benefits of reirradiation against the increased rates of toxicity. Here we evaluate the outcomes of patients treated with pulsed reduced dose rate (PRDR) radiation therapy with concurrent low-dose capecitabine as a method to increase the therapeutic ratio of re-treatment.
METHODS AND MATERIALS: Patients treated from November 2000 to June 1, 2018 with PRDR radiation therapy at University of Wisconsin were identified. Patients were re-treated to a median dose of 54 Gy (range, 37.5-66 Gy) using PRDR radiation therapy, delivering radiation at an apparent dose rate of 6.67 cGy/min to allow for increased sublethal damage repair of normal tissues. The median cumulative dose was 109.8 Gy. Twenty-two patients were treated with concurrent capecitabine, most frequently at 500 mg twice per day. The Kaplan-Meier method was used for survival analysis, and Cox regression analysis was used for univariate and multivariate analysis.
RESULTS: Forty-three patients were identified who underwent reirradiation for locoregionally recurrent invasive breast cancer, with a median follow-up of 20.5 months. Twenty-four patients had gross disease. Nineteen patients had simultaneous metastatic disease. The complete response rate was 83.3% in treated patients with gross disease. Locoregional recurrence-free survival was 81.3% and 73.8% for all patients at 1 and 2 years, respectively. Overall survival for patients with localized disease was 95.7% at 1 year and 91.1% at 2 years. The rate of acute grade 3 radiation dermatitis was 25.6% with no other acute grade 3 toxicities. Grade 3 late toxicity occurred in 18.6% of patients.
CONCLUSIONS: PRDR radiation therapy with capecitabine was a well-tolerated and effective method for treating patients with recurrent breast cancer. Prospective studies are necessary to compare side effects and efficacy with conventional dose rate reirradiation and to evaluate the potential role for capecitabine in the recurrent setting.
PMID:31526900 | DOI:10.1016/j.prro.2019.09.004
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[<sup>124</sup>I]CLR1404 PET/CT in High-Grade Primary and Metastatic Brain Tumors Molecular imaging and biology
Hall LT, Titz B, Baidya N, Kolk vd, Robins HI, Otto M, Perlman SB, Weichert JP, Kuo JS
2020 Apr;22(2):434-443. doi: 10.1007/s11307-019-01362-1.
PURPOSE: There is a continuous search for imaging techniques with high sensitivity and specificity for brain tumors. Positron emission tomography (PET) imaging has shown promise, though many PET agents either have a low tumor specificity or impractical physical half-lives. [124I]CLR1404 is a small molecule alkylphosphocholine analogue that is thought to bind to plasma membrane lipid rafts and has shown high tumor-to-background ratios (TBR) in a previous pilot study in brain tumor patients. This study attempts to define the clinical value of [124I]CLR1404 PET/CT (aka CLR124).
PROCEDURES: Adult patients with new or suspected recurrence of high-grade primary or metastatic brain tumors (N = 27) were injected with [124I]CLR1404 followed by PET/CT at 6, 24, and 48 h. Standard uptake values (SUV) and TBR values were calculated for all time points. Uptake of [124I]CLR1404 was qualitatively assessed, compared with magnetic resonance imaging (MRI), and correlated with clinical outcome. Final diagnosis (N = 25) was established based on surgically resected tissue or long-term follow-up.
RESULTS: Positive uptake with high TBR was detected in all but one patient with a final diagnosis of primary/recurrent brain tumor (12/13) and in less than half of patients with treatment-related changes (5/12). Concordance between [124I]CLR1404 uptake and contrast enhancement on MRI was seen in < 40 %, with no concordance between T2-hyperintensities and uptake. No significant difference in overall outcome was found between patients with and without [124I]CLR1404 uptake.
CONCLUSIONS: The uptake pattern in these patients suggests a very high sensitivity of [124I]CLR1404 PET/CT for diagnosing tumor tissue; however, tumor specificity needs to be further defined. Relative lack of concordance with standard MRI characteristics suggests that [124I]CLR1404 PET/CT provides additional information about brain tumors compared to MRI alone, potentially improving clinical decision-making.
PMID:31183841 | PMC:PMC7485611 | DOI:10.1007/s11307-019-01362-1
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Phase 2 Study of Radiation Therapy Plus Low-Dose Temozolomide Followed by Temozolomide and Irinotecan for Glioblastoma: NRG Oncology RTOG Trial 0420 International journal of radiation oncology, biology, physics
Lieberman FS, Wang M, Robins HI, Tsien CI, Curran WJ, Werner-Wasik M, Smith RP, Schultz C, Hartford AC, Zhang P, Mehta MP
2019 Mar 15;103(4):878-886. doi: 10.1016/j.ijrobp.2018.11.008. Epub 2018 Nov 27.
PURPOSE: To evaluate the toxicity and efficacy of adjuvant temozolomide (TMZ) and irinotecan (CPT-11) for 12 months after concurrent chemoradiation in patients with newly diagnosed glioblastoma (GBM).
METHODS AND MATERIALS: Trial RTOG 04-20, a single-arm, multi-institutional phase 2 trial, was designed to determine the efficacy and toxicity of concomitant TMZ and radiation therapy (RT) followed by adjuvant TMZ combined with CPT-11 given for 12 cycles compared with historical controls of adjuvant TMZ alone given for 6 cycles.
RESULTS: A total of 170 patients were enrolled, 152 of whom were eligible. Adjuvant CPT-11 combined with TMZ was more toxic than expected. A higher rate of hematologic and gastrointestinal toxicities was more frequently noted with the combination regimen compared with adjuvant TMZ alone. Grade 3/4 hematologic toxicity was 38% compared with 14% reported in the Stupp trial. After an early interim analysis, the adjuvant CPT-11 dose was reduced to 100 mg/m2 on days 1 and 5 for the first cycle. CPT-11 dose escalation proceeded over the first 3 cycles if tolerated. Median overall survival for all eligible patients was 16.9 months compared with 13.7 months of the historical control (P = .03). Post hoc subgroup analysis suggested an improvement in overall survival for patients with Radiation Therapy Oncology Group recursive partitioning analysis class 3, although improvement was limited to 22 patients (14% of eligible patients).
CONCLUSIONS: Although irinotecan and TMZ for 12 cycles given after chemoradiation for patients with newly diagnosed glioblastoma significantly improved median survival compared with 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 with the current standard.
PMID:30496882 | PMC:PMC7034757 | DOI:10.1016/j.ijrobp.2018.11.008
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Vision loss in glioblastoma: Disease mimicking presumed therapeutic toxicity Neuro-oncology practice
Nguyen HN, Vo BH, Howard S, Salamat MS, Rowely H, Robins HI
2018 Nov;5(4):223-226. doi: 10.1093/nop/npx037. Epub 2018 Feb 2.
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.
PMID:30402261 | PMC:PMC6213942 | DOI:10.1093/nop/npx037
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Molecular Evolution of a Glioblastoma Controlled With Tumor Treating Fields and Concomitant Temozolomide Frontiers in oncology
Robins HI, Nguyen HN, Field A, Howard S, Salamat S, Deming DA
2018 Oct 15;8:451. doi: 10.3389/fonc.2018.00451. eCollection 2018.
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.
PMID:30374424 | PMC:PMC6196276 | DOI:10.3389/fonc.2018.00451
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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 oncology
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 J, Kwok Y, Yu HM, Laack NN, Schultz CJ, Gray HJ, Robins HI, Mehta MP, Chakravarti A
2018 Oct 1;4(10):1405-1409. doi: 10.1001/jamaoncol.2018.1977.
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.
PMID:29955793 | PMC:PMC6117103 | DOI:10.1001/jamaoncol.2018.1977
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
2019 Jan 1;84(1):66-76. doi: 10.1093/neuros/nyy003.
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.
PMID:29618054 | PMC:PMC6500905 | DOI:10.1093/neuros/nyy003
View details for PubMedID 29618054
Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02 Journal of neuro-oncology
Nghiemphu PL, Ebiana VA, Wen P, Gilbert M, Abrey LE, Lieberman F, DeAngelis LM, Robins HI, Yung KA, Chang S, Drappatz J, Mehta MP, Levin VA, Aldape K, Dancey JE, Wright JJ, Prados M, Kuhn J, Cloughesy TF
2018 Jan;136(1):79-86. doi: 10.1007/s11060-017-2624-4. Epub 2017 Oct 7.
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.
PMID:28988377 | PMC:PMC5756101 | DOI:10.1007/s11060-017-2624-4
View details for PubMedID 28988377
PET/CT imaging of the diapeutic alkylphosphocholine analog <sup>124</sup>I-CLR1404 in high and low-grade brain tumors American journal of nuclear medicine and molecular imaging
Hall LT, Titz B, Robins HI, Bednarz BP, Perlman SB, Weichert JP, Kuo JS
2017 Sep 1;7(4):157-166. eCollection 2017.
CLR1404 is a cancer-selective alkyl phosphocholine (APC) analog that can be radiolabeled with 124I for PET imaging, 131I for targeted radiotherapy and/or SPECT imaging, or 125I 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 124I-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 124I-CLR1404 followed by PET/CT imaging at 6-, 24-, and 48-hour. 124I-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 124I-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. 124I-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. 124I-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 124I-CLR1404 PET findings.
PMID:28913154 | PMC:PMC5596318
View details for PubMedID 28913154
Impact of PET and MRI threshold-based tumor volume segmentation on patient-specific targeted radionuclide therapy dosimetry using CLR1404 Physics in medicine and biology
Besemer AE, Titz B, Grudzinski JJ, Weichert JP, Kuo JS, Robins HI, Hall LT, Bednarz BP
2017 Jul 6;62(15):6008-6025. doi: 10.1088/1361-6560/aa716d.
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.
PMID:28682793 | PMC:PMC6771923 | DOI:10.1088/1361-6560/aa716d
View details for PubMedID 28682793
The effect of Optune™ Tumor Treating Fields transducer arrays on skin radiation dose during radiotherapy Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
Bender E, Kozak K, Howard S, Hayes L, Bayouth J, Robins HI
2017 Aug;42:172-175. doi: 10.1016/j.jocn.2017.04.002. Epub 2017 Apr 17.
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.
PMID:28427800 | DOI:10.1016/j.jocn.2017.04.002
View details for PubMedID 28427800
Karenitecin (bnp1350) and flavopridol as radiosensitizers in malignant glioma Journal of neurology & neuromedicine
Rajesh D, Robins HI, Howard SP
2016;1(6):1-10. doi: 10.29245/2572.942x/2016/6.1061.
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.
PMID:28111642 | PMC:PMC5243123 | DOI:10.29245/2572.942x/2016/6.1061
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-oncology
Chang S, Zhang P, Cairncross JG, Gilbert MR, Bahary J, 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 Feb 1;19(2):252-258. doi: 10.1093/neuonc/now236.
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.
PMID:27994066 | PMC:PMC5463834 | DOI:10.1093/neuonc/now236
View details for PubMedID 27994066
The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
Clark PA, Gaal JT, Strebe JK, Pasch CA, Deming DA, Kuo JS, Robins HI
2017 Feb;36:120-124. doi: 10.1016/j.jocn.2016.10.042. Epub 2016 Nov 16.
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.
PMID:27865821 | PMC:PMC5215614 | DOI:10.1016/j.jocn.2016.10.042
View details for PubMedID 27865821
Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler KW, Jones TW, Luu B, Cavalli MG, Aldape K, Remke M, Mynarek M, Rutkowski S, Gururangan S, McLendon RE, Lipp ES, Dunham C, Hukin J, Eisenstat DD, Fulton D, van Landeghem H, Santi M, van Veelen C, Van Meir G, Osuka S, Fan X, Muraszko KM, Tirapelli PC, Oba-Shinjo SM, Marie KN, Carlotti CG, Lee JY, Rao AN, 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. doi: 10.1200/JCO.2015.65.7825. Epub 2016 Jun 6.
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.
PMID:27269943 | PMC:PMC4962737 | DOI:10.1200/JCO.2015.65.7825
View details for PubMedID 27269943
Erlotinib for the treatment of brain metastases in non-small cell lung cancer Expert opinion on pharmacotherapy
Brower JV, Robins HI
2016;17(7):1013-21. doi: 10.1517/14656566.2016.1165206. Epub 2016 Mar 30.
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.
PMID:26967582 | DOI:10.1517/14656566.2016.1165206
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 Journal of neuro-oncology
Robins HI, Zhang P, Gilbert MR, Chakravarti A, Groot Fd, Grimm SA, Wang F, Lieberman FS, Krauze A, Trotti AM, Mohile N, Kee YJ, Colman H, Cavaliere R, Kesari S, Chmura SJ, Mehta M
2016 Jan;126(2):309-16. doi: 10.1007/s11060-015-1966-z. Epub 2015 Oct 27.
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).
PMID:26508094 | PMC:PMC4720526 | DOI:10.1007/s11060-015-1966-z
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 1;121(23):4165-72. doi: 10.1002/cncr.29636. Epub 2015 Aug 26.
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.
PMID:26308485 | PMC:PMC5941922 | DOI:10.1002/cncr.29636
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 International journal of radiation oncology, biology, physics
Brachman DG, Pugh SL, Ashby LS, Thomas TA, Dunbar EM, Narayan S, Robins HI, Bovi JA, Rockhill JK, Won M, Curran WP
2015 Apr 1;91(5):961-7. doi: 10.1016/j.ijrobp.2014.12.050.
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.
PMID:25832688 | PMC:PMC4706375 | DOI:10.1016/j.ijrobp.2014.12.050
View details for PubMedID 25832688
Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study Journal of neuro-oncology
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. doi: 10.1007/s11060-015-1733-1. Epub 2015 Feb 15.
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.
PMID:25682091 | DOI:10.1007/s11060-015-1733-1
View details for PubMedID 25682091
Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients Neuro-oncology
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, Foundation C
2015 Mar;17(3):440-7. doi: 10.1093/neuonc/nou162. Epub 2014 Aug 13.
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.
PMID:25121770 | PMC:PMC4483095 | DOI:10.1093/neuonc/nou162
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 Clinical lung cancer
Boggs DH, Robins HI, Langer CJ, Traynor AM, Berkowitz MJ, Mehta MP
2014 Nov;15(6):433-40. doi: 10.1016/j.cllc.2014.06.008. Epub 2014 Jun 24.
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.
PMID:25069747 | DOI:10.1016/j.cllc.2014.06.008
View details for PubMedID 25069747
Recursive partitioning analysis of prognostic variables in newly diagnosed anaplastic oligodendroglial tumors Neuro-oncology
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 BR, 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. doi: 10.1093/neuonc/nou083. Epub 2014 Jul 4.
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.
PMID:24997140 | PMC:PMC4201067 | DOI:10.1093/neuonc/nou083
View details for PubMedID 24997140
ACR Appropriateness Criteria® pre-irradiation evaluation and management of brain metastases Journal of palliative medicine
Metastases RO, Lo SS, Gore EM, Bradley JD, Buatti JM, Germano I, Ghafoori AP, Henderson MA, Murad JA, Patchell RA, Patel SH, Robbins JR, Robins HI, Vassil AD, Wippold FJ, Yunes MJ, Videtic MM
2014 Aug;17(8):880-6. doi: 10.1089/jpm.2014.9417. Epub 2014 Jun 27.
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.
PMID:24971478 | PMC:PMC4275774 | DOI:10.1089/jpm.2014.9417
View details for PubMedID 24971478
Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02 Neuro-oncology
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 KA, Wright JJ, Dancey J, Aldape KD, Prados MD, Ligon KL
2014 Apr;16(4):567-78. doi: 10.1093/neuonc/not247. Epub 2014 Jan 26.
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.
PMID:24470557 | PMC:PMC3956354 | DOI:10.1093/neuonc/not247
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 International journal of radiation oncology, biology, physics
Robins HI, O'Neill A, Mehta M, Grossman S
2013 Aug 1;86(5):809-10. doi: 10.1016/j.ijrobp.2013.03.040.
Wide-field pulsed reduced dose rate radiotherapy (PRDR) for recurrent ependymoma in pediatric and young adult patients Anticancer research
Mohindra P, Robins HI, Tomé WA, Hayes L, Howard SP
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 review of neurotherapeutics
Kruser TJ, Mehta MP, Robins HI
2013 Apr;13(4):389-403. doi: 10.1586/ern.13.7.
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.
PMID:23545054 | DOI:10.1586/ern.13.7
View details for PubMedID 23545054
Histological predictors of outcome in ependymoma are dependent on anatomic site within the central nervous system Brain pathology (Zurich, Switzerland)
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 JT, Omuro A, Packer RJ, Partap S, Pollack IF, Prados MD, Robins HI, Soffietti R, Wu J, Miller CR, Gilbert MR, Aldape KD, Network ER
2013 Sep;23(5):584-94. doi: 10.1111/bpa.12050. Epub 2013 Mar 28.
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.
PMID:23452038 | DOI:10.1111/bpa.12050
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 International journal of radiation oncology, biology, physics
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 1;85(5):1312-8. doi: 10.1016/j.ijrobp.2012.11.042. Epub 2013 Feb 4.
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.
PMID:23391814 | PMC:PMC3740376 | DOI:10.1016/j.ijrobp.2012.11.042
View details for PubMedID 23391814
Cytokines associated with toxicity in the treatment of recurrent glioblastoma with aflibercept Targeted oncology
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, Groot Jd
2013 Jun;8(2):117-25. doi: 10.1007/s11523-013-0254-0. Epub 2013 Jan 24.
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.
PMID:23345034 | PMC:PMC4802008 | DOI:10.1007/s11523-013-0254-0
View details for PubMedID 23345034
Leptomeningeal Metastasis: Challenges in Diagnosis and Treatment Current cancer therapy reviews
Leal T, Chang JE, Mehta M, Robins HI
2011 Nov;7(4):319-327. doi: 10.2174/157339411797642597.
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.
PMID:23251128 | PMC:PMC3523178 | DOI:10.2174/157339411797642597
View details for PubMedID 23251128
RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients International journal of radiation oncology, biology, physics
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 1;85(5):1206-11. doi: 10.1016/j.ijrobp.2012.10.008. Epub 2012 Nov 22.
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.
PMID:23182702 | PMC:PMC4199329 | DOI:10.1016/j.ijrobp.2012.10.008
View details for PubMedID 23182702
Unexpected doxorubicin-mediated cardiotoxicity in sisters: possible role of polymorphisms in histamine n-methyl transferase Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners
Sachidanandam K, Gayle AA, Robins HI, Kolesar JM
2013 Sep;19(3):269-72. doi: 10.1177/1078155212461022. Epub 2012 Nov 15.
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.
PMID:23154571 | PMC:PMC3998823 | DOI:10.1177/1078155212461022
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-oncology
Lee EQ, Kuhn J, Lamborn KR, Abrey L, DeAngelis LM, Lieberman F, Robins HI, Chang SM, Yung KA, 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. doi: 10.1093/neuonc/nos264. Epub 2012 Oct 24.
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.
PMID:23099651 | PMC:PMC3499017 | DOI:10.1093/neuonc/nos264
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 Clinical cancer research : an official journal of the American Association for Cancer Research
Lee EQ, Puduvalli VK, Reid JM, Kuhn JG, Lamborn KR, Cloughesy TF, Chang SM, Drappatz J, Yung KA, 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 1;18(21):6032-9. doi: 10.1158/1078-0432.CCR-12-1841. Epub 2012 Aug 24.
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.
PMID:22923449 | PMC:PMC3947570 | DOI:10.1158/1078-0432.CCR-12-1841
View details for PubMedID 22923449
Initial treatment patterns over time for anaplastic oligodendroglial tumors Neuro-oncology
Panageas KS, Iwamoto FM, Cloughesy TF, Aldape KD, Rivera AL, Eichler AF, Louis DN, Paleologos NA, Fisher BJ, Ashby LS, Cairncross JG, Urgoiti BR, 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. doi: 10.1093/neuonc/nos065. Epub 2012 May 31.
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.
PMID:22661585 | PMC:PMC3367843 | DOI:10.1093/neuonc/nos065
View details for PubMedID 22661585
ACR Appropriateness Criteria® follow-up and retreatment of brain metastases American journal of clinical oncology
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, Metastases RO
2012 Jun;35(3):302-6. doi: 10.1097/COC.0b013e31824be246.
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.
PMID:22609733 | DOI:10.1097/COC.0b013e31824be246
View details for PubMedID 22609733
H. Ian Robins, MD, PhD600 Highland Avenue Madison,
Madison, WI 53792