The Black Laboratory, Glioma Research

Malignant Glioma Recurrence Model in Nude Mice

A phase I trial of a new recombinant human beta-interferon (BG9015) for the treatment of patients with recurrent gliomas
Primary brain tumors represent an important cause of cancer-related morbidity and mortality in the United States. Despite advances in neurosurgery and radiotherapy, the median survival of patients with malignant gliomas remains less than 1 year. A contributing factor to the poor prognoses of these patients is the diffuse, infiltrative nature of these tumors, which limits the effectiveness of focal therapies (i.e., surgery and radiation). Unfortunately, standard chemotherapy has been of limited benefit in the treatment of malignant gliomas, underlying the necessity for new drugs with novel mechanisms of action. On the basis of promising in vitro and clinical data demonstrating significant antiglioma activity of purified IFN-beta and a synthetic IFN-beta (Betaseron), we conducted a Phase I trial of a new, nonmutated, glycosylated recombinant human IFN-beta (BG9015) in patients with recurrent, high-grade astrocytomas. In this trial, we demonstrate that the maximally tolerated dose of BG9015 is 6 million units/m2 delivered by intramuscular injection three times per week. Dose-limiting neurotoxicity was seen in both patients treated at 8 million units/m2. Additionally, we demonstrate that high BG9015 serum levels are associated with a fall in natural killer cell number, radiographic response, and prolonged survival. We conclude that BG9015 has activity in patients with malignant gliomas, although the therapeutic index may be narrow. Future studies will be needed to confirm the observation that natural killer cell number and activity as well as BG9015 serum levels are important markers of antitumor activity.

Fine HA, Wen PY, Robertson M, O'Neill A, Kowal J, Loeffler JS, Black PM. A phase I trial of a new recombinant human beta-interferon (BG9015) for the treatment of patients with recurrent gliomas . Clin Cancer Res, 3(3): 381-387, 1997.

Assessment of alterations in gene expression in recurrent malignant glioma after radiotherapy using complementary deoxyribonucleic acid microarrays
We used complementary deoxyribonucleic acid expression microarrays to assess the effects of radiotherapy on gene expression in glioblastoma multiforme. We hypothesized that postradiation recurrent tumors may demonstrate alterations in gene expression from the primary tumor specimen. METHODS: Patients were diagnosed with glioblastoma multiforme at resection of the initial tumor, and they received 60 Gy of fractionated radiotherapy before recurrence. Ribonucleic acid samples from both the primary and the postradiation recurrent tumor in each patient were screened and compared using complementary deoxyribonucleic acid expression arrays and Northern blot analysis. RESULTS: Messenger ribonucleic acid levels of growth factors participating in paracrine loops, such as vascular endothelial growth factor and platelet-derived growth factor receptor beta, were decreased in postradiation recurrent tumors as compared with primary tumors in three of four patients. However, messenger ribonucleic acid levels of growth factors involved in autocrine loops, such as epidermal growth factor receptor, platelet-derived growth factor alpha, platelet-derived growth factor A, and basic fibroblast growth factor, were decreased in two of four, two of four, three of four, and three of four patients' recurrent tumors, respectively. Microvessel counts demonstrated that blood vessel growth was decreased significantly in postradiation recurrent tumor specimens. CONCLUSION: After radiotherapy of glioblastoma multiforme, levels of paracrine-acting growth factors are diminished in correspondence with the reduction in vascular density. In contrast, growth factors that participate in autocrine loops demonstrate elevated levels of gene expression. These results suggest that maintenance of autocrine loops may be important in tumor regrowth after radiotherapy.

Joki T, Carroll RS, Dunn IF, Zhang J, Abe T, Black PM. Assessment of Alterations in Gene Expression in Recurrent Malignant Gliomas After Radiotherapy Using Complementary Deoxyribonucleic Acid Microarrays . Neurosurgery, 48(1): 195-202, 2001.

Results of radiosurgery in the management of recurrent and residual medulloblastoma
Between June 1989 and January 1994, 14 patients with recurrent (n = 11) or posttreatment residual (n = 3) medulloblastoma were enrolled in a program to evaluate the efficacy and toxicity of stereotactic radiosurgery (SR). Initial treatment consisted of subtotal surgical resection in 12 patients and complete surgical resection in 2. Thirteen patients received systemic chemotherapy, and all had craniospinal irradiation prior to SR. SR was used as a technique for boosting sites of posttreatment residual disease in 3 patients (3 tumors) and as salvage therapy in 11 patients (14 tumors) with radiographically well-defined, discrete recurrent tumors. Patients underwent SR 1-97 (median 20) months after completing craniospinal irradiation. The median minimum peripheral tumor dose was 12 Gy. The median tumor volume at the time of SR was 6.9 cm3. With a median follow-up period from diagnosis of 27 (range 8-39) months, all patients treated with SR as a boost to sites of residual disease are alive without evidence of disease. In contrast, 6 of 11 patients who underwent SR for treatment of recurrent disease have died of progressive medulloblastoma. The median survival from the time of SR for patients treated for recurrent disease was 10 (range 5-59+) months. The predominant site of failure after SR was distant within the central nervous system, with 6 patients (43%) failing outside the posterior fossa. No patient failed locally within the radiosurgical target volume. Two patients (14%) developed marginal recurrences.(ABSTRACT TRUNCATED AT 250 WORDS)

Patrice SJ, Tarbell NJ, Goumnerova LC, Shrieve DC, Black PM, Loeffler JS. Results of Radiosurgery in the Management of Recurrent and Residual Medulloblastoma . Pediatr Neurosurg, 22(4): 197-203, 1995.

Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme
The purpose of this study was to compare the efficacy of stereotactic radiosurgery (SRS) and brachytherapy in the treatment of recurrent glioblastoma multiforme (GBM). The patients had either progressive GBM or pathologically proven GBM at recurrence after previous treatment for a lower grade astrocytoma. Thirty-two patients were treated with interstitial brachytherapy, and 86 received treatment with stereotactic radiosurgery (SRS). The patient characteristics were similar in the two groups. Those patients treated with SRS had a median tumor volume of 10.1 cm3 and received a median peripheral tumor dose of 13 Gy. Patients treated with brachytherapy had a median tumor volume of 29 cm3. Median dose to the periphery of the tumor volume was 50 Gy delivered at a median dose rate of 43 cGy/hour. Twenty-one patients (24%) treated with SRS were alive, with a median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with SRS was 10.2 months, with survivals of 12 and 24 months being 45 and 19%, respectively. A younger age and a smaller tumor volume were predictive of better outcome. The tumor dose, the interval from initial diagnosis, and the need for reoperation were not predictive of outcome after SRS. Five patients (16%) treated with brachytherapy were alive, with a median follow-up of 43.3 months. The median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals of 12 and 24 months were 44 and 17%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Shrieve DC , Alexander E, Wen PY, Fine HA, Kooy HM, Black PM, Loeffler JS. Comparison of Stereotactic Radiosurgery and Brachytherapy in the Treatment of Recurrent Glioblastoma Multiforme . Neurosurgery, 1995 Feb; 36(2): 275-284.