Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed a systematic approach for the discovery and evaluation of local treatment strategies for brain tumors using polymers. We demonstrated the feasibility of polymer-mediated drug delivery by using the standard chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and showed that local treatment of gliomas by this method is effective in animal models of intracranial tumors. This led to clinical trials for glioma patients, and subsequent approval of Gliadel [(3.8% BCNU): p(CPP:SA)] by the FDA and other worldwide regulatory agencies. Twenty-two additional clinical trials are currently underway evaluating other issues related to the BCNU polymer, such as dosage, combination with systemic treatments, and combination with various forms of radiation and resistance modifiers. These trials are a result of laboratory investigations using brain tumor models; based on these models, other research groups have initiated clinical trials with novel combinations of different drugs and new polymers for both intracranial tumors (5-fluorouracil delivered via poly(D-L lactide-co-glycolide) polymer) and for tumors outside the brain (paclitaxel in PPE microspheres for ovarian cancer). Since only 1/3 of patients with glioblastoma multiforme (GBM) are sensitive to BCNU, the need to search for additional drugs continues. Although we are attacking major resistance mechanisms, there still will be tumors that do not respond to BCNU therapy but are sensitive to agents with different mechanisms of action, such as taxanes, camptothecin, platinum drugs, and antiangiogenic agents. Thus, it is necessary to explore multiple single agents and ultimately to combine the most effective agents for the clinical treatment of GBM. Furthermore, multimodal approaches combining radiotherapy with microsphere delivery of cytokines and antiangiogenic agents have demonstrated encouraging results.
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PMID:Biodegradable polymer implants to treat brain tumors. 1148 83

Temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) has several characteristics that make it appealing for combination therapies: broad-spectrum antitumor activity, the ability to cross the blood-brain barrier, a good safety profile with nonoverlapping toxicities, an oral formulation, and the ability to overcome resistance to nitrosoureas. Preclinical and phase I trials have shown the additive or synergistic activity of temozolomide combined with carmustine against solid tumors, including malignant glioma, and the sequence-dependent effects of the combination. Toxicity is lower and the maximum tolerated dose is higher when carmustine is given before temozolomide. Studies also have examined the combination of temozolomide with the topoisomerase I inhibitor irinotecan (CPT-11), an alkaloid derivative of camptothecin that has shown activity against malignant glioma. Temozolomide followed by CPT-11 was more effective than either agent alone. A major issue facing investigators now is determining which of the several schedules of temozolomide and CPT-11 are optimal. Completed and ongoing studies of temozolomide in combination with carmustine, including polifeprosan carmustine implant (Gliadel wafers; Aventis Pharmaceuticals, Parsippany, NJ), and CPT-11 are described.
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PMID:Temozolomide in combination with other cytotoxic agents. 1155 Jan 36

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.
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PMID:Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas. 1158 94

A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers. Because of the small number of patients in that trial, a larger phase 3 trial was performed to confirm these results. Two hundred forty patients were randomized to receive either BCNU or placebo wafers at the time of primary surgical resection; both groups were treated with external beam radiation postoperatively. The two groups were similar for age, sex, Karnofsky performance status (KPS), and tumor histology. Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). Time to decline in KPS and in 10/11 neuroperformance measures was statistically significantly prolonged in the BCNU wafer-treated group ( P </= 0.05). Adverse events were comparable for the 2 groups, except for CSF leak (5% in the BCNU wafer-treated group vs. 0.8% in the placebo-treated group) and intracranial hypertension (9.1% in the BCNU wafer-treated group vs. 1.7% in the placebo group). This study confirms that local chemotherapy with BCNU wafers is well tolerated and offers a survival benefit to patients with newly diagnosed malignant glioma.
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PMID:A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. 1267 79

The results of a recently concluded phase III study have shown that Gliadel therapy (biodegradable polymer impregnated with 3.85% BCNU placed into the surgical cavity) significantly prolongs survival and time to relapse in patients having initial resective surgery for malignant glioma followed by radiotherapy. The indications and exclusion criteria for patients in this study were well defined. To determine the relative frequencies of Gliadel 'eligible' and 'ineligible' patients, and differences in prognostic variables between these two cohorts, we conducted a review of all Edinburgh patients with an initial diagnosis of malignant glioma managed throughout the period of patient accrual into the phase III Gliadel study (Edinburgh was one of 38 contributing centres). Independent predictors of outcome were taken from the MRC prognostic index. Analysis was done on an intention to treat basis. Only 25% of patients (14/56) with malignant glioma managed over this period were eligible for the Gliadel study and all were recruited. The patients in the study group were younger (median 51 v. 59 years, p = 0.085); in better clinical grade (median Karnofsky score 85 v. 80, p = 0.038); more likely to have resective surgery (86% v. 38%, p = 0.0001); more likely to have postoperative radiotherapy (93% v. 55%, p = 0.0001) and more likely to survive longer, even though one half of the Gliadel cohort received placebo, (66 v. 19 weeks, p = 0.06) than those not eligible. If the future use of Gliadel is limited to the eligibility criteria used in the phase III trial about 20% (95% confidence intervals 13-34%) of patients with newly diagnosed malignant glioma will receive this therapy.
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PMID:Gliadel therapy given for first resection of malignant glioma: a single centre study of the potential use of Gliadel. 1457 2

New approaches to malignant glioma are being actively investigated. Local drug delivery directly to the site of the tumor is one novel approach that has been approved by the US FDA and other regulatory agencies worldwide. This agent, Gliadel, delivers the chemotherapeutic drug carmustine (BCNU) from a biodegradable polymer placed in the resection cavity after brain tumor surgery. Gliadel represents the first clinical application of polymer delivery for brain tumors, but the potential for this new methodology is far greater. In this review, we will briefly summarize the development of Gliadel from a laboratory idea to its current role as an approved treatment for gliomas. Then we will present the most recent work being done to expand the potential benefits of polymeric delivery for brain tumors. This work includes trials for its use as the initial therapy for gliomas, as well as its use against metastasis. Further clinical trials exploring the maximum-tolerated dose and the combination of Gliadel with systemic chemotherapeutic treatments such as temozolamide and O(6)-benzylguanine will be reviewed. Finally, we will present preclinical work on the efficacy of polymeric methods for delivering other chemotherapeutic agents, and a variety of novel compounds that modify brain tumor biology. This latter work represents potential future clinical applications of local polymeric drug delivery to the brain and other sites where cancers can occur.
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PMID:Recent advances in brain tumor therapy: local intracerebral drug delivery by polymers. 1470 92

Randomized trials have demonstrated Gliadel improves survival for appropriately selected patients with newly diagnosed malignant glioma. As only limited information is available to guide the management of patients who have Gliadel controlled-release BCNU wafers implanted in the cranial resection cavity prior to radiotherapy (RT), this retrospective review was conducted to describe clinical course, toxicity, and pathologic findings after this therapy for newly diagnosed malignant glioma. Forty-six consecutive patients receiving Gliadel (3.8% BCNU impregnated wafers) followed by radiotherapy for newly diagnosed malignant glioma at Johns Hopkins Hospital from 1990 to August 1999 were identified, although one was lost to follow up and is excluded. Patients were evaluated for postoperative infection, pathology at reoperation, and survival. Twenty-eight patients received radiotherapy at Johns Hopkins and these patients are also evaluable for toxicity experienced during and one month after completion of RT. The median age of all patients is 57 years. Eighty-nine percent had glioblastoma, and median follow-up of surviving glioblastoma patients is 16.8 (12-20) months. Postoperative infection or need for reoperation within 30 days was uncommon after Gliadel placement. Full-dose radiotherapy was tolerable after Gliadel implantation. Five patients (19%) developed neurologic symptoms during radiotherapy responding to increased steroids and/or anticonvulsants, whereas an additional 8 of 27 (30%) developed neurologic symptoms during dexamethasone taper that responded to increases in dexamethasone dose. At one month after RT, 58% of patients were still on dexamethasone despite attempted taper. Fifteen of 45 patients, 33% underwent reoperation or biopsy for a new local contrast-enhancing lesion. In five of 15 (33%) the reoperation revealed necrosis or treatment effect without active tumor. Two of five patients with treatment/effect necrosis has a third surgery 2.9 and 3.2 months after the initial reoperation, and treatment effect/necrosis without tumor was demonstrated in both cases. The Kaplan-Meier median survival for all the glioblastoma patients is 12.8 (95% CI 9.6, 15.9) months. For glioblastoma patients under 55 years old, median survival is 15.9 (95% CI 13.5, too few events) months whereas for older patients it is 9.6 (7.7, 14.4) months. We conclude that Gliadel followed by full-dose standard radiotherapy is acutely well tolerated, although, close supervision should be emphasized during dexamethasone taper. Median survival in excess of one year suggests that there are not complications that result in overall premature death. The finding of necrosis/treatment effect was noted in five of 45 (11%) of all patients and five of 15 (33%) of those undergoing reoperation. Therefore, the possibility of necrosis/treatment effect should be considered for each patient with radiographic findings suspicious for local recurrence.
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PMID:Clinical course and pathologic findings after Gliadel and radiotherapy for newly diagnosed malignant glioma: implications for patient management. 1506 76

While the introduction of carmustine wafers (Gliadel wafers) into the tumor resection cavity has been shown to be a beneficial therapy for malignant glioma, it is recognized that clinically significant cerebral edema is a potential adverse effect. Following are two clinical case reports demonstrating profound cerebral edema associated with implantation of Gliadel wafers. As a result, one of these individuals had premature death. A brief literature review is provided to assist in explaining the mechanisms by which clinically significant cerebral edema may develop.
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PMID:Cerebral edema associated with Gliadel wafers: two case studies. 1570 Dec 85

Two types of chemotherapy used in the treatment of patients with malignant glioma are carboplatin and Gliadel wafer [(3.85% 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU)]. To date there have been no published data examining their concurrent use in this disease. The purpose of this study was to evaluate combination chemotherapy with Gliadel wafer and carboplatin in patients with high-grade, malignant glioma. In this prospective phase I study, 16 patients underwent surgery, Gliadel wafer implantation (up to 8 wafers), intravenous carboplatin given postoperatively (day 3 or 4) at a dose escalation range of area under the curve (AUC)=2-6, and external beam radiation. Median age was 55 years (range 27-66 years). Fourteen (88%) patients had glioblastoma multiforme and 2 (12%) had anaplastic astrocytoma. Performance status was as follows: Eastern Cooperative Oncology Group (ECOG)=0 (2 patients), ECOG=1 (13 patients), and ECOG=2 (2 patients). Three patients were treated at each dosing level (AUC=2-6), and 4 patients were treated at an AUC=5. Carboplatin was administered to all patients by postoperative day 4. Radiation was begun on day 14-36. No grade 3 or 4 toxicities were noted in this study. Median progression-free and overall survival was 266 and 679 days, respectively. We conclude that administering systemic carboplatin is safe and well tolerated in the postoperative period immediately following resection and implantation of Gliadel wafer for the treatment of malignant glioma. Further evaluation in a phase II setting, at maximal carboplatin dose to establish potential efficacy, with this combination is warranted.
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PMID:A phase I trial of surgery, Gliadel wafer implantation, and immediate postoperative carboplatin in combination with radiation therapy for primary anaplastic astrocytoma or glioblastoma multiforme. 1593 47

Targeting cell surface receptors with cytotoxins or immunotoxins provides a unique opportunity for brain tumor therapy. The authors have discovered that receptors for two cytokines, interleukin (IL)-4 and IL-13, are overexpressed on tumor biopsy samples and on cell lines derived from a variety of human tumors, including brain tumors. These investigators have demonstrated that the structure of these cytokine receptors on tumor cells is different from that found on normal immune cells. In human solid tumor cells, IL-4 binds to two chains (IL-4Ra and IL-13Ra1), whereas IL- 13 binds to three chains in many solid tumor cells, including glioma cells (to IL-4Ra, IL-13Ra1, and IL-13Ra2). To target IL-4Rs and IL-13Rs, the authors generated two recombinant fusion cytotoxins composed of IL-4 or IL-13 and a mutated form of pseudomonas exotoxin (PE), which for simplicity are called IL4-PE and IL13-PE in this paper. These chimeric cytotoxins are highly toxic in vitro to human tumor cell lines and primary cell cultures, including glioma cells, and in vivo to animal models of human tumors, including gliomas. In contrast, normal cells, including immune, endothelial, and brain cells, are spared from their cytotoxic effects. Based on numerous preclinical studies, IL13-PE (also known as IL13-PE38QQR or cintredekin besudotox) has been tested in four Phase I/II clinical trials. The agent IL13-PE was administered intracranially by using convection-enhanced delivery (CED). The drug was delivered through catheters placed either directly into the tumor bed or in the peritumoral region after resection of the lesion. The CED of IL13-PE was fairly well tolerated, with a reasonable benefit/risk profile for treatment of patients with glioma. Based on Phase I/II clinical trials, the Phase III Randomized Evaluation of CED of IL13-PE Compared to Gliadel Wafer with Survival Endpoint Trial (also known as the PRECISE Trial) in patients with initial recurrence of glioblastoma multiforme has recently been completed. Patients are being monitored for safety of the agents, duration of overall survival, and quality of life.
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PMID:The IL-4 and IL-13 pseudomonas exotoxins: new hope for brain tumor therapy. 1670 16


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