Showing papers by "Michael D. Prados published in 2005"
TL;DR: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors, and effects of the molecular abnormalities in vitro are identified.
Abstract: Background The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. Methods We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. Results Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rap...
1,433 citations
TL;DR: Among glioma patients, those with glioblastoma multiforme tumors who have high levels of EGFR expression and low levels of phosphorylated PKB/Akt had better response to erlotinib treatment than those with low levels.
Abstract: Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (also known as Tarceva or OSI-774) has shown promising response rates in malignant gliomas. We investigated the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylating agent temozolomide. Methods: Expression of EGFR and ligand-independent EGFRvIII mutant proteins and of phosphorylated protein kinase B (PKB)/Akt in specimens from glioma patients were assessed by immunohistochemistry. EGFR gene amplifi cation was evaluated by fl uorescence in situ hybridization. Mutations in PTEN and EGFR were assessed by polymerase chain reaction amplifi cation and sequencing. Response was evaluated by sequential magnetic resonance imaging every 2 months. The Cochran – Mantel – Haenzel test was used to assess associations between biomarker status and response. All statistical tests were two-sided. Results: Of 41 glioma patients, eight responded to treatment. Response to erlotinib was associated with EGFR expression ( P = .07) and EGFR amplifi cation ( P = .08). These associations were stronger and statistically signifi cant among the 29 patients initially diagnosed with glioblastoma multiforme ( P = .03 and P = .02, respectively). Among six responders with suffi cient tumor tissue, none had EGFRvIII mutations. None of the 22 tumors with high levels of phosphorylated PKB/Akt responded to erlotinib treatment, whereas eight of the 18 tumors with low levels of phosphorylated PKB/Akt responded to erlotinib treatment ( P <.001). The level of phosphorylated PKB/Akt was also associated with time to progression ( P <.001). Conclusions: Among glioma patients, those with glioblastoma multiforme tumors who have high levels of EGFR expression and low levels of phosphorylated PKB/Akt had better response to erlotinib treatment than those with low levels of EGFR expression and high levels of phosphorylated PKB/Akt. [J Natl Cancer Inst 2005;97:880 – 7]
466 citations
University of California, San Francisco1, Harvard University2, University of California, Los Angeles3, University of Michigan4, University of Virginia5, University of Texas MD Anderson Cancer Center6, University of Texas at Austin7, Memorial Sloan Kettering Cancer Center8, University of Texas at San Antonio9, National Institutes of Health10
TL;DR: CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM, and the low toxicity profile may merit exploration in combination with other modalities.
Abstract: Purpose: Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug. Experimental Design: CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival. Results: Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks. Conclusions: CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.
386 citations
University of South Florida1, University of Nebraska Medical Center2, Dana Corporation3, University of Utah4, Johns Hopkins University5, Ohio State University6, Memorial Sloan Kettering Cancer Center7, Roswell Park Cancer Institute8, University of Texas MD Anderson Cancer Center9, Duke University10, Fox Chase Cancer Center11, University of Michigan12, City of Hope National Medical Center13, University of California, San Francisco14, Northwestern University15, University of Alabama16, University Of Tennessee System17, Seattle Cancer Care Alliance18
TL;DR: These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus and include expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastoma, supratentorial primitive neuroectodermal tumors, and brain metastases.
Abstract: Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN.org, contains recommendations on additional subtypes.
292 citations
Memorial Sloan Kettering Cancer Center1, Roswell Park Cancer Institute2, Northwestern University3, University of Pittsburgh4, University of California, San Francisco5, University of Texas Health Science Center at San Antonio6, Washington University in St. Louis7, Harvard University8, University of Texas MD Anderson Cancer Center9
TL;DR: As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects.
Abstract: Purpose: We investigated the molecular effect of the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib in vivo on all available tumors from patients treated on North American Brain Tumor Consortium trials 01-03 and 00-01 for recurrent or progressive malignant glioma. Experimental Design: EGFR expression and signaling during treatment with erlotinib or gefitinib were analyzed by Western blot and compared with pre–erlotinib/gefitinib–exposed tissue or unexposed controls. Tumors were also analyzed for EGFR mutations and for other genomic abnormalities by array-based comparative genomic hybridization. Clinical data were used to associate molecular features with tumor sensitivity to erlotinib or gefitinib. Results: Erlotinib and gefitinib did not markedly affect EGFR activity in vivo. No lung signature mutations of EGFR exons 18 to 21 were observed. There was no clear association between erlotinib/gefitinib sensitivity and deletion or amplification events on array-based comparative genomic hybridization analysis, although novel genomic changes were identified. Conclusions: As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects. Additionally, the mechanism of erlotinib/gefitinib sensitivity likely differs between brain and lung tumors. Finally, novel genomic changes, including deletions of chromosomes 6, 21, and 22, represent new targets for further research.
241 citations
Journal Article•
TL;DR: Investigation of dynamic susceptibility contrast-enhanced DSC MR imaging characteristics of the two most common subtypes of low-grade infiltrating glioma suggested that tumor rCBV(max) derived from D SC MR imaging can be used to distinguish between the two low- grade gliomas.
Abstract: BACKGROUND AND PURPOSE: Histopathologic evaluation remains the reference standard for diagnosis of glioma and classification of histologic subtypes, but is challenged by subjective criteria, tissue sampling error, and lack of specific tumor markers. Anatomic imaging is essential for surgical planning of gliomas but is limited by its nonspecificity and its inability to depict beyond morphologic aberrations. The purpose of our study was to investigate dynamic susceptibility contrast-enhanced (DSC) MR imaging characteristics of the two most common subtypes of low-grade infiltrating glioma: astrocytoma and oligodendroglioma. We hypothesized that tumor blood-volume measurements, derived from DSC MR imaging, would help differentiate the two on the basis of differences in tumor vascularity. METHODS: We studied 25 consecutive patients with treatment-naive, histopathologically confirmed World Health Organization grade II astrocytoma (n = 11) or oligodendroglioma (n = 14). All patients underwent anatomic and DSC MR imaging immediately before surgical resection. Histologic confirmation was obtained in all patients. Anatomic MR images were analyzed for morphologic features, and DSC MR data were processed to yield quantitative cerebral blood volume (CBV) measurements. RESULTS: The maximum relative CBV (rCBVmax) in tumor ranged from 0.48 to 1.34 (0.92 ± 0.27, median ± SD) in astrocytomas and from 1.29 to 9.24 (3.68 ± 2.39) in oligodendrogliomas. The difference in median rCBVmax between the two tumor types was significant (P CONCLUSION: The tumor rCBVmax measurements derived from DSC MR imaging were significantly higher in low-grade oligodendrogliomas than in astrocytomas. Our findings suggest that tumor rCBVmax derived from DSC MR imaging can be used to distinguish between the two low-grade gliomas.
212 citations
TL;DR: A single focus of GBM that later demonstrates Type I dissemination on progression does not have a worse prognosis than a lesion that exhibits only local recurrence, and appears to preclude aggressive treatment if a patient is otherwise well.
Abstract: Object. The clinical outcome and treatment of adult patients with disseminated intracranial glioblastoma multiforme (GBM) is unclear. The objective in the present study was to assess the prognostic significance of disseminated intracranial GBM in adults at presentation and at the time of tumor progression. Methods. Clinical data from 1491 patients older than 17 years and harboring a GBM that had been diagnosed between 1988 and 1998 at the University of California at San Francisco neurooncology clinic were retrospectively reviewed. Dissemination of the GBM (126 patients) was determined based on Gd-enhanced magnetic resonance images. Classification of dissemination was as follows: Type I, single lesion with subependymal or subarachnoid spread; Type II, multifocal lesions without subependymal or subarachnoid spread; and Type III, multifocal lesions with subependymal or subarachnoid spread. Subgroups of patients were compared using Kaplan—Meier curves that depicted survival probability. The median postprogres...
117 citations
TL;DR: The authors demonstrate the challenges in determining efficacy when surrogate end points such as time to tumor progression as defined by new or progressive contrast enhancement on MR imaging are used with this treatment modality.
Abstract: Object. Convection-enhanced delivery (CED) is a novel method for delivering therapeutic agents to infiltrative brain tumor cells. For agents administered by CED, changes on magnetic resonance (MR) imaging directly resulting from catheter placement, infusion, and the therapeutic compound may confound any interpretation of tumor progression. As part of an ongoing multiinstitutional Phase I study, 14 patients with recurrent malignant glioma underwent CED of interleukin (IL) 13—PE38QQR, a recombinant cytotoxin consisting of human IL-13 conjugated with a truncated Pseudomonas exotoxin. Serial neuroradiographic changes were assessed in this cohort of patients. Methods. Patients were treated in two groups: Group 1 patients received IL13—PE38QQR before and after tumor resection; Group 2 patients received infusion only after tumor resection. Preoperative and postinfusion MR images were obtained prospectively at specified regular intervals. Changes were noted along catheter tracks on postresection MR images obtaine...
87 citations
TL;DR: Large patient numbers and long follow-up demonstrate that local relapse rates for spinal ependymomas are higher than previously cited, with a large proportion of failures occurring more than 5 years after diagnosis, and it is recommended to recommend excision aimed at maximal resection while avoiding surgical morbidity.
Abstract: Data on spinal ependymomas are sparse, and prognostic factors remain controversial. The primary aim of this study is to review a historical cohort, with large patient numbers and long follow-up, and provide estimates of time to progression (TTP) and survival after progression. As a secondary aim, we assess the effects of potential prognostic variables. Thirty-seven patients with spinal cord ependymomas received postoperative radiation therapy from 1955 to 2001. The influences of radiation dose, extent of resection, Karnofsky performance score, tumor location, and multifocality were assessed in univariate analyses by using the Cox proportional hazards model. The median follow-up for patients who did not fail was 121 months (range, 8-312 months). Kaplan-Meier estimates of 5-, 10-, and 15-year percentage progression free are 75%+/-7.4%, 50%+/-9.1%, and 46%+/-9.3%, respectively. Median TTP, for those who recurred, is 68 months (range, 2-324 months), with 12 of 21 failures occurring after five years. Of the prognostic factors examined, only greater extent of resection significantly correlated with longer TTP (P=0.02). Local relapse rates for spinal ependymomas are higher than previously cited, with a large proportion of failures occurring more than five years after diagnosis. Extensive surgical resection correlates with longer time to recurrence, and we thus recommend maximal excision while avoiding surgical morbidity. The overall high rate of recurrence leads us to recommend radiation to doses of 45 to 54 Gy for all patients who do not have gross total resections, and long, close follow-up.
70 citations
TL;DR: It was shown that patients whose tumors exhibited overexpression and amplification of EGFR responded better than patients who had normal levels of this gene and protein, and it was demonstrated that the phosphorylation state of PKB/Akt was an important determinant for response.
Abstract: Epidermal growth factor receptors (EGFRs) are amplified and overexpressed in many different human cancers, a phenomenon generally associated with poor prognosis. Inhibitors of the tyrosine kinase activity associated with this receptor have been approved for the treatment of chemotherapy-refractory nonsmall cell lung cancer, and are in clinical trials for additional tumor types. While these inhibitors, gefitinib and erlotinib, display limited response rates when assessed in cohorts that include all patients, there are subgroups, defined by patient and tumor characteristics, that preferentially respond to these agents. We recently performed an analysis of tumors obtained from a Phase I trial of erlotinib in patients with glioblastoma multiforme (GBM), the most common malignant brain tumor in adults. We showed that patients whose tumors exhibited overexpression and amplification of EGFR responded better than patients who had normal levels of this gene and protein. We also demonstrated that the phosphorylation state of PKB/Akt was an important determinant for response, with low phospho-PKB/Akt levels predicting good response to erlotinib. We discuss these findings in the context of recent molecular analyses of the placebo-controlled Phase III trials that led to approval of EGFR inhibitors. These data underscore the importance of placebo-controlled trials to distinguish between prognostic indicators of disease progression more generally and predictive markers of response to therapy. Ultimately the goal of these studies is to allow selection of patients who will preferentially respond to EGFR inhibitors.
66 citations
TL;DR: Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs, and even in the presence of EIAeds, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs.
Abstract: Purpose To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs. Patients and Methods Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed. Results Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration‐time curve (AUC)0-12 hours was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC). Conclusion Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC0-12 hours, and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.
TL;DR: Based on this study, cRA does not seem to add a significant synergistic effect to TMZ and XRT, but there was no survival advantage compared with historical studies using XRT either with adjuvant nitrosourea chemotherapy, with TMZ alone, or with the combination of TMZ and thalidomide.
Abstract: Purpose: This Phase II study was designed to determine the median survival time of adults with supratentorial glioblastoma treated with a combination of temozolomide (TMZ) and 13-cis-retinoic acid (cRA) given daily with conventional radiation therapy (XRT). Methods and Materials: This was a single arm, open-labeled, Phase II study. Patients were treated with XRT in conjunction with cRA and TMZ. Both drugs were administered starting on Day 1 of XRT, and chemotherapy cycles continued after the completion of XRT to a maximum of 1 year. Results: Sixty-one patients were enrolled in the study. Time to progression was known for 55 patients and 6 were censored. The estimated 6-month progression-free survival was 38% and the estimated 1-year progression-free survival was 15%. Median time to progression was estimated as 21 weeks. The estimated 1-year survival was 57%. The median survival was 57 weeks. Conclusions: The combined therapy was relatively well tolerated, but there was no survival advantage compared with historical studies using XRT either with adjuvant nitrosourea chemotherapy, with TMZ alone, or with the combination of TMZ and thalidomide. Based on this study, cRA does not seem to add a significant synergistic effect to TMZ and XRT.
TL;DR: Different clinical outcomes measures are addressed separately and the value of multiple outcome measures are illustrated using the results of a recent clinical trial comparing temozolomide with procarbazine in the treatment of Glioblastoma Multiforme.
Abstract: Since high-grade malignant gliomas can seldom be treated curatively, the main aim of first line therapy is to improve progression free survival (PFS), to reduce morbidity, and to preserve, if not restore neurological functions and the capacity to perform daily activities. Focusing on a single clinical efficacy parameter in clinical trials may provide a potentially biased result, as for patients the overall result of treatment entails a more complex picture of weighing and balancing gains and losses on different outcome measures. In this paper we address different clinical outcomes measures separately and we illustrate the value of multiple outcome measures using the results of a recent clinical trial comparing temozolomide with procarbazine in the treatment of Glioblastoma Multiforme. Compared with procarbazine, temozolomide not only prolonged PFS, but also maintained neurological functioning and performance status for a longer period of time, and also improved health-related quality of life (HRQL). All these statistically significant outcomes demonstrate a remarkable consistency. In addition, temozolomide showed a trend of extending overall survival over procarbazine.
TL;DR: The maximum tolerated dose and recommended phase II dose of IT mafosfamide in patients younger than 3 years with newly diagnosed embryonal CNS tumors is 14 mg.
Abstract: Purpose A phase I trial of intrathecal (IT) mafosfamide was performed to determine the optimal dose, dose-limiting toxicities, and incidence and severity of other toxicities when administered in association with concomitant multiagent systemic chemotherapy to children younger than 3 years with newly diagnosed embryonal tumors. Patients and Methods Twenty-five assessable patients received IT mafosfamide at one of six dose levels ranging from 5 mg to 17 mg. Patients were premedicated with dexamethasone (0.15 mg/kg) and morphine (0.1 mg/kg) before receiving IT mafosfamide. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs. Results Irritability, presumably secondary to pain or headache during mafosfamide administration, was dose limiting in two of three patients at the 17-mg dose level. The maximum-tolerated dose of IT mafosfamide following premedication with dexamethasone and morphine was 14 mg. Conclusion The maximum tolerated dose and recommended...
TL;DR: Safety and tolerability of IL13PE, different dosing regimens, catheter positioning, and efficacy as measured by overall survival (OS) were evaluated.
Abstract: 1506 Background: IL13-PE38QQR (IL13PE) is a recombinant cytotoxin which binds selectively to the IL13 receptor that is over-expressed on malignant glioma cells. CED utilizes positive pressure infus...
TL;DR: Stereotactic radiosurgery is playing an increasing role in the primary treatment of brain metastases, as well as for salvage after whole-brain radiation.
Abstract: Brain metastases of breast cancer remain a difficult problem for clinical management. Their incidence appears to be increasing, which is likely due to longer survival times for advanced breast cancer patients as well as additional and improved tools for detection. Molecular features of tumors associated with this syndrome are not yet understood. In general, survival may be improving for brain metastases due to better local control in the CNS, as well as improvements in systemic disease management. Selected patients with brain metastases are able to undergo surgical resection, which has been associated with extended disease control in some patients. However, whole-brain radiation has been the mainstay for treatment for most patients. Stereotactic radiosurgery is playing an increasing role in the primary treatment of brain metastases, as well as for salvage after whole-brain radiation. Recent series have reported median survivals of 13 months or longer with stereotactic radiosurgery. Further improvements in radiation-based approaches may come from ongoing studies of radiosensitizing agents. The ability of systemic treatments to impact brain metastases has been debated, and specific treatment regimens have yet to be defined. New approaches include chemotherapy combinations, biologic therapies and novel drug-delivery strategies.