A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

Toxicity, efficacy, and pharmacology of suramin in adults with recurrent high-grade gliomas.

PURPOSE: To determine the toxicity, efficacy, and pharmacology of suramin in patients with recurrent or progressive recurrent high-grade gliomas. PATIENTS AND METHODS: Fifty adults were to receive suramin. However, if no responses were seen in the first ten patients, the study was to be terminated. A total of 12 patients were enrolled onto this trial. Ten patients had glioblastoma multiforme, and 11 had received prior nitrosoureas. RESULTS: Drug-related toxicities were modest and reversible. Three patients developed grade 3 to 4 neutropenia, constipation, diarrhea, or nausea. No CNS bleeding was observed. Median time to progression was 55 days (range, 17 to 242 days) and median survival was 191 days (range, 42 to 811 days). No partial or complete responses were seen at 12 weeks. However, the clinical outcome of three patients suggests that evidence of suramin activity may be delayed. One patient who "progressed" after 12 weeks of suramin had a subsequent marked reduction in tumor size and has maintained an excellent partial response for over 2 years without other therapy. Two others had disease stabilization and lived for 16 and 27 months. Pharmacokinetics from 11 patients revealed that all reached target suramin concentrations. CONCLUSION: This study demonstrates that suramin is well tolerated by patients with recurrent high-grade gliomas and may have efficacy in this disease. Its pharmacology seems unaffected by anticonvulsants. As a result of this data, suramin and radiation are now being administered concurrently to patients with newly diagnosed glioblastoma multiforme, with survival as the primary outcome.

Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors.

Standard treatment for neoplastic meningitis requires frequent intrathecal (IT) injections of chemotherapy and is only modestly effective. DepoCyt is a sustained-release formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg injection. We conducted a randomized, controlled trial of DepoCyt versus methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one patients with histologically proven cancer and positive CSF cytologies were randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients). Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses of methotrexate over 3 months. Treatment arms were well balanced with respect to demographic and disease-related characteristics. Responses occurred in 26% of DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log-rank P = 0.15). The DepoCyt group experienced a greater median time to neurological progression (58 versus 30 days; log-rank P = 0.007) and longer neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis-specific survival, 343 versus 98 days). Factors predictive of longer progression-free survival included absence of visible central nervous system disease on neuroimaging studies (P<0.001), longer pretreatment duration of CSF disease (P<0.001), history of intraparenchymal tumor (P<0.001), and treatment with DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable between treatment arms. In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.

Interferon-containing controlled-release polymers for localized cerebral immunotherapy.

Controlled-release ethylene-vinyl acetate copolymers (EVAc), which were used previously for the in vivo intracerebral delivery of chemotherapeutics, were evaluated as a possible route of localized intracerebral delivery of interferon (IFN). Natural mouse IFN-alpha/beta (Mu-IFN-alpha/beta) was incorporated into polymers at 5% or 10% by weight with 2 x 10(4) U or 4 x 10(4) U, respectively. In vitro and in vivo studies of the release of Mu-IFN-alpha/beta from EVAc polymers showed the released IFN to be biologically active, as determined by the inhibition assay of viral cytopathic effect (CPE). Evaluation of the in vitro kinetics of release showed that most of the IFN activity was released in the first 4 days, with the rest being released thereafter. The in vivo kinetic release of Mu-IFN-alpha/beta from intracerebrally implanted polymers showed that most of the IFN activity was released within 24 h after polymer implantation in the hemisphere ipsilateral to the polymer. This IFN activity gradually decreased over the next 72 h, with a significant linear trend (p < 0.0001). The hemisphere contralateral to the implanted polymer showed no significant levels of IFN activity throughout the 4 days of evaluation. By contrast, blood levels of IFN increased from day 1 to day 4, showing a significant linear trend (p = 0.0125), with IFN levels on day 4 being significantly higher (p < 0.05) than on day 1 after polymer implant. This study demonstrates the feasibility of intracranial controlled local delivery of IFN using a polymer delivery device.

Phase I study of intravenous bromodeoxyuridine used concomitantly with radiation therapy in patients with primary malignant brain tumors.

We report here the results of a Phase I study conducted to determine the toxicity and serum levels that could be tolerated by patients receiving i.v. bromodeoxyuridine (BUdR) concomitantly with radiation therapy. Because of severe thrombocytopenia and leukopenia that was produced in three patients treated by a 96 hour infusion of BUdR at a dose of 1.5 g/m2/24 hours, the dose was reduced to 0.8 g/m2/24 hours in these patients and the remaining 9 patients in the study group. Even at this dosage, myelotoxicity was observed. BUdR levels were measured by an isocratic high performance liquid chromatographic (HPLC) method developed for this study. Results of in vitro studies conducted by others suggest that serum levels produced in our patients by administration of doses of 0.6 to 0.8 g/m2/24 hours should be adequate to achieve a therapeutic effect.

Increasing Incidence of Primary Brain Tumors in the Elderly in Florida.

Based on data from the Florida Cancer Data System for the periods from 1981 through 1984 and 1986 through 1989, the incidence of primary malignant brain tumors in those aged 65 years or older rose steadily. The incidence of primary brain tumors in elderly Floridians has escalated independent of increased case ascertainment associated with the introduction of computed tomography scanning or magnetic resonance imaging and is observed in anaplastic astrocytoma, glioblastoma, and lymphoma, but not in low-grade astrocytoma.

Novel Methods of Evaluating the Growth Response Patterns of Treated Brain Tumors.

Unique methods for determining exact borders of intra-axial brain tumors using magnetic resonance imaging-based, computer-assisted, and automated systems are currently under development at the H. Lee Moffitt Cancer Center & Research Institute. Detection of tumor growth rate changes may be obtained more accurately and easily, leading to improved patient care through early institution of effective, new chemotherapy and radiotherapy regimens.

Supratentorial malignant gliomas of childhood. Results of treatment with radiation therapy and chemotherapy.

Twenty-seven patients aged 1 to 18 years harboring supratentorial (20 in the cerebrum and seven in the thalamus) malignant gliomas were treated between 1975 and 1982. There were four glioblastomas multiforme, 14 anaplastic astrocytomas, and nine malignant gliomas. All patients had a subtotal resection or biopsy as the initial procedure and received postoperative radiation therapy (RT). Fifteen of 27 patients were treated by RT alone; 14 had tumor progression with a median time to tumor progression (MTP) of 65 weeks. Twelve patients were treated with chemotherapy as an adjuvant to RT; only seven had tumor recurrence, with an MTP of 130 weeks. Of the 21 patients with recurrent tumors in both groups, 18 were treated with chemotherapy alone, or chemotherapy with a second surgical procedure or second course of RT. For all histological grades of tumor, the MTP for first recurrence was 75 weeks and the median survival time was 180 weeks. Age at initial diagnosis was found to be a statistically significant prognostic factor, with patients younger than 10 years of age surviving longer than patients aged over 10 years (p = 0.02).

Modulation of glioma cell growth and 5-lipoxygenase expression by interferon.

The effect of mouse interferon-alpha/beta (MuIFN-alpha/beta on growth/viability, cell cycle regulation, 5-lipoxygenase (5-LO) protein expression, leukotriene B4 (LTB4) biosynthesis and glial fibrillary acidic protein (GFAP) expression of mouse glioma (G-26) cells in vitro was studied. The G-26 cells were treated with 800 IU/ml of MuIFN-alpha/beta for 1, 2, 3 and 4 days. The growth and viability of glioma cells was evaluated by [3H]-thymidine incorporation and MTT (3(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazoliumbromi de) assay, resulted in a time dependent decrease in [3H]-thymidine incorporation into DNA and MTT formazan formation, respectively. The cell cycle regulation measured by flow cytometry with propidium iodide staining revealed that the cell multiplication cycle was slowed down due to accumulation of cell in S-phase of the cell cycle, leading to inhibition in G0/G1 phase of the cell cycle. The 5-LO protein expression (measured by Western immunoblot analysis) and LTB4 biosynthesis (measured by enzyme immunoassay) were found to be increased by 2 to 2.4 fold and several fold respectively on days 3 and 4 of MuIFN-alpha/beta treatment. The GFAP protein expression was also found to be increased at least by 3 fold on day 4 of the MuIFN-alpha/beta treatment. These results suggest that inhibition in growth and thereby slowing of the cell multiplication cycle of glioma cells has resulted in upregulation of GFAP expression and 5-LO pathway.

Response of recurrent brain metastases in malignant melanoma to 5-fluorouracil and interferon-alpha therapy.

A 36-year-old woman underwent removal of a stage II malignant melanoma from the left ankle in 1985. A single brain metastasis to the right frontal lobe was removed in July 1986. Postoperatively, she received 5-fluorouracil, cisplatin, and etoposide (VP-16) in conjunction with radiation therapy. She achieved remission until March 1988, when left hemiparesis occurred suddenly. Computed tomography and magnetic resonance scans revealed multiple brain metastases. She was treated with a combination of 5-fluorouracil, 1,000 mg/m2 in a 24-hour continuous IV infusion for 5 days; interferon-alpha, 10 million units in subcutaneous injection daily for 10 days; and oral cimetidine, 1,200 mg daily for 7 days. This regimen, repeated every 4 to 6 weeks for four cycles, was well tolerated, with complete remission of neurological deficits and resolution of the lesions seen on the brain scans until she died 11 months later of intracranial hemorrhage secondary to severe thrombocytopenia.

Automatic magnetic resonance tissue characterization for three-dimensional magnetic resonance imaging of the brain.

Computer-assisted diagnostic systems enhance the information available from magnetic resonance imaging. Segmentations are the basis on which three-dimensional volume renderings are made. The application of a raw data-based, operator-independent (automatic), magnetic resonance segmentation technique for tissue differentiation is demonstrated. Segmentation images of vasogenic edema with gross and histopathological correlation are presented for demonstration of the technique. A pixel was classified into a tissue class based on a feature vector using unsupervised fuzzy clustering techniques as the pattern recognition method. Correlation of fuzzy segmentations and gross and histopathology were successfully performed. Based on the results of neuropathological correlation, the application of fuzzy magnetic resonance image segmentation to a patient with a brain tumor and extensive edema represents a viable technique for automatically displaying clinically important tissue differentiation. With this pattern recognition technique, it is possible to generate automatic segmentation images that display diagnostically relevant neuroanatomical and neuropathological tissue contrast information from raw magnetic resonance data for use in three-dimensional volume reconstructions.

Magnetic resonance imaging of syrinx associated with intramedullary metastases and leptomeningeal disease.

Intramedullary spinal cord metastasis with an associated syrinx diagnosed by magnetic resonance imaging (MR) is described. The patient had documented simultaneous leptomeningeal spread of malignant cells and intramedullary spinal cord metastasis with hyalinized blood vessels, venous dilatation, and cavitation detected by autopsy. Metastasis to the spinal cord is unusual, but well described. Syrinx associated with intramedullary spinal cord metastasis has been detected rarely. MRI of syrinx and intramedullary spinal cord metastasis, and the possible pathogenesis of these lesions are discussed.

MRI: stability of three supervised segmentation techniques.

Supervised segmentation methods from three families of pattern recognition techniques were used to segment multispectral MRI data. Studied were the maximum likelihood method (MLM), k-nearest neighbors (k-NN), and a back-propagation artificial neural net (ANN). Performance was measured in terms of execution speed, and stability for the selection of training data, namely, region of interest (ROI) selection, and interslice and interpatient classifications. MLM proved to have the smallest execution times, but demonstrated the least stability. k-NN showed the best stability for training data selection. To evaluate the segmentation techniques, multispectral images were used of normal volunteers and patients with gliomas, the latter with and without MR contrast material. All measures applied indicated that k-NN provides the best results.

Comparison of supervised MRI segmentation methods for tumor volume determination during therapy.

Two different multispectral pattern recognition methods are used to segment magnetic resonance images (MRI) of the brain for quantitative estimation of tumor volume and volume changes with therapy. A supervised k-nearest neighbor (kNN) rule and a semi-supervised fuzzy c-means (SFCM) method are used to segment MRI slice data. Tumor volumes as determined by the kNN and SFCM segmentation methods are compared with two reference methods, based on image grey scale, as a basis for an estimation of ground truth, namely: (a) a commonly used seed growing method that is applied to the contrast enhanced T1-weighted image, and (b) a manual segmentation method using a custom-designed graphical user interface applied to the same raw image (T1-weighted) dataset. Emphasis is placed on measurement of intra and inter observer reproducibility using the proposed methods. Intra- and interobserver variation for the kNN method was 9% and 5%, respectively. The results for the SFCM method was a little better at 6% and 4%, respectively. For the seed growing method, the intra-observer variation was 6% and the interobserver variation was 17%, significantly larger when compared with the multispectral methods. The absolute tumor volume determined by the multispectral segmentation methods was consistently smaller than that observed for the reference methods. The results of this study are found to be very patient case-dependent. The results for SFCM suggest that it should be useful for relative measurements of tumor volume during therapy, but further studies are required. This work demonstrates the need for minimally supervised or unsupervised methods for tumor volume measurements.

Monitoring brain tumor response to therapy using MRI segmentation.

The performance evaluation of a semi-supervised fuzzy c-means (SFCM) clustering method for monitoring brain tumor volume changes during the course of routine clinical radiation-therapeutic and chemo-therapeutic regimens is presented. The tumor volume determined using the SFCM method was compared with the volume estimates obtained using three other methods: (a) a k nearest neighbor (kNN) classifier, b) a grey level thresholding and seed growing (ISG-SG) method and c) a manual pixel labeling (GT) method for ground truth estimation. The SFCM and kNN methods are applied to the multispectral, contrast enhanced T1, proton density, and T2 weighted, magnetic resonance images (MRI) whereas the ISG-SG and GT methods are applied only to the contrast enhanced T1 weighted image. Estimations of tumor volume were made on eight patient cases with follow-up MRI scans performed over a 32 week interval during treatment. The tumor cases studied include one meningioma, two brain metastases and five gliomas. Comparisons with manually labeled ground truth estimations showed that there is a limited agreement between the segmentation methods for absolute tumor volume measurements when using images of patients after treatment. The average intraobserver reproducibility for the SFCM, kNN and ISG-SG methods was found to be 5.8%, 6.6% and 8.9%, respectively. The average of the interobserver reproducibility of these methods was found to be 5.5%, 6.5% and 11.4%, respectively. For the measurement of relative change of tumor volume as required for the response assessment, the multi-spectral methods kNN and SFCM are therefore preferred over the seedgrowing method.

Application of fuzzy c-means segmentation technique for tissue differentiation in MR images of a hemorrhagic glioblastoma multiforme.

The application of a raw data-based, operator-independent MR segmentation technique to differentiate boundaries of tumor from edema or hemorrhage is demonstrated. A case of a glioblastoma multiforme with gross and histopathologic correlation is presented. The MR image data set was segmented into tissue classes based on three different MR weighted image parameters (T1-, proton density-, and T2-weighted) using unsupervised fuzzy c-means (FCM) clustering algorithm technique for pattern recognition. A radiological examination of the MR images and correlation with fuzzy clustering segmentations was performed. Results were confirmed by gross and histopathology which, to the best of our knowledge, reports the first application of this demanding approach. Based on the results of neuropathologic correlation, the application of FCM MR image segmentation to several MR images of a glioblastoma multiforme represents a viable technique for displaying diagnostically relevant tissue contrast information used in 3D volume reconstruction. With this technique, it is possible to generate segmentation images that display clinically important neuroanatomic and neuropathologic tissue contrast information from raw MR image data.

MRI measurement of brain tumor response: comparison of visual metric and automatic segmentation.

An automatic magnetic resonance imaging (MRI) multispectral segmentation method and a visual metric are compared for their effectiveness to measure tumor response to therapy. Automatic response measurements are important for multicenter clinical trials. A visual metric such as the product of the largest diameter and the largest perpendicular diameter of the tumor is a standard approach, and is currently used in the Radiation Treatment Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (EGOG) clinical trials. In the standard approach, the tumor response is based on the percentage change in the visual metric and is categorized into cure, partial response, stable disease, or progression. Both visual and automatic methods are applied to six brain tumor cases (gliomas) of varying levels of segmentation difficulty. The analyzed data were serial multispectral MR images, collected using MR contrast enhancement. A fully automatic knowledge guided method (KG) was applied to the MRI multispectral data, while the visual metric was taken from the MRI films using the T1 gadolinium enhanced image, with repeat measurements done by two radiologists and two residents. Tumor measurements from both visual and automatic methods are compared to "ground truth," (GT) i.e., manually segmented tumor. The KG method was found to slightly overestimate tumor volume, but in a consistent manner, and the estimated tumor response compared very well to hand-drawn ground truth with a correlation coefficient of 0.96. In contrast, the visually estimated metric had a large variation between observers, particularly for difficult cases, where the tumor margins are not well delineated. The inter-observer variation for the measurement of the visual metric was only 16%, i.e., observers generally agreed on the lengths of the diameters. However, in 30% of the studied cases no consensus was found for the categorical tumor response measurement, indicating that the categories are very sensitive to variations in the diameter measurements. Moreover, the method failed to correctly identify the response in half of the cases. The data demonstrate that automatic 3D methods are clearly necessary for objective and clinically meaningful assessment of tumor volume in single or multicenter clinical trials.

Case report: hypoglycemia secondary to a meningioma.

Hypoglycemia secondary to a meningioma that has not metastasized to the liver has not been reported previously. A 41-year-old woman with a spinal cord meningioma first diagnosed 5 years previously with 3 recurrences in the spinal cord resulting in 4 neurosurgical procedures was admitted with a serum glucose of 23 mg/dL. Six months before the current admission, the patient was noted to have an abdominal mass of 10 cm not present on previous computed tomography. Three months later, the mass was 15.2 cm, and on the current admission, had increased to 23 cm and encased both the aorta and inferior vena cava. A needle biopsy of this mass before referral to the authors' hospital with hypoglycemia revealed that it was a meningioma. Evaluation of the etiology of the hypoglycemia, which required continuous intravenous glucose therapy, revealed that circulating insulin, C-peptide (i.e., connecting peptide), insulin-like growth factor-I (i.e., somatomedin-C) and insulin-like growth factor-II were all normal or low. Serum cortisol also was not low. Based on her endocrine evaluation, the hypoglycemia was secondary to the large mass of tumor cells, requiring a large glucose uptake to sustain its growth. After radiation therapy of 3,770 CGy to the meningioma, the patient became euglycemic without glucose supplementation.

MRI of spinal cord radiation necrosis simulating recurrent cervical cord astrocytoma and syringomyelia.

BACKGROUND: Although primary intramedullary tumors of the spinal cord with syrinx formation are well documented, there have been no reports of extensive syrinx formation or cystic degeneration associated with radiation necrosis. METHODS: We report a case of radiation necrosis and syrinx formation in a 49-year-old woman with a 5-year history of astrocytoma grade II of the cervical cord, who progressed to quadriparesis following surgery and radiation therapy. Magnetic resonance imaging (MRI) of the cervical and thoracic spine demonstrated enlargement of upper cervical cord (C1-C6) with diffuse increased signal enhancing mass by gadolinium, as well as appearance of syrinx from T4-T10. RESULTS: Autopsy findings indeed revealed a small, residual, infiltrating glioma in the upper cervical areas, but the diffuse parenchymal abnormality seen on MRI as prolonged T2 characteristics on double-echo spin-echo sequence was revealed to be radiation necrosis. CONCLUSION: What appeared to be a cystic cavity or syrinx at the thoracic level was also diagnosed as radiation necrosis with cyst formation on histologic examination.