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figure 2.4

of the blood-brain barrier. Cisplatin and carboplatin can be administered intravenously or intra-arterially. They have both demonstrated efficacy for the treatment of adult and pediatric PBT [71-73].

Cisplatin has variable activity against a wide range of tumors including anaplastic astrocytoma, glioblastoma multiforme, medulloblastoma, central nervous system lymphoma, germ-cell tumors, recurrent gliomas, and primitive neuroectodermal tumors [8,21,71-73]. It can be administered as a single agent or in combination with other drugs, such as BCNU, etoposide, cyclophosphamide, or vincristine. In the pediatric population, cisplatin as a single agent (60-120 mg/m2 per cycle IV) has proved beneficial for patients with recurrent medulloblastoma, ependy-moma, and primitive neuroectodermal tumors [106,107]. In combination with CCNU or cyclopho-sphamide plus vincristine, cisplatin has efficacy against high risk and recurrent medulloblastoma (see Nitrosourea section) [88,108,109]. In adult patients with malignant gliomas after nitrosourea failure, single-agent intravenous cisplatin showed modest activity, although the duration of responses was brief [110]. When used in combination with etoposide or BCNU, intravenous cisplatin has efficacy against a variety of recurrent malignant PBT [71-73].

Numerous investigators have attempted to administer cisplatin intra-arterially to patients with newly diagnosed and recurrent gliomas [8,21,71-73, 111-114]. Early reports suggested significant activity of the drug (60-100 mg/m2 per cycle) when used by this route [111,112]. Response rates of 40-60 per cent (i.e., partial responses plus stable disease) were noted, with overall time to progression ranging from 13 to 22 weeks [111-113]. However, reports by other authors suggest minimal efficacy of IA cisplatin against these tumors, as well as unacceptable toxicity [114]. In general, IA cisplatin is associated with increased risk for encephalopathy, cerebral edema, seizure activity, stroke, and retinal damage.

The major acute toxicity of cisplatin is severe nausea and emesis, which can be acute or delayed (24-120 h after treatment) in onset. Patients will require a potent prophylactic antiemetic regimen, such as a 5-HT3-receptor antagonist, plus or minus dexamethasone, for acute emesis and prochlorpera-zine for delayed emesis [14,15]. Nephrotoxicity is another common side effect that involves several mechanisms, including coagulative necrosis, drug-protein interactions, and inactivation of specific renal brush border enzymes [8]. The areas of the kidney most severely affected on histological examination include the loops of Henle, distal tubules, and collecting ducts. To reduce the risk of renal damage, aggressive hydration (often in conjunction with mannitol) is necessary. Other potential side effects include ototoxicity, myelosuppression, and peripheral neuropathy.

Carboplatin is an analog of cisplatin that has a similar profile of activity against low-grade and malignant PBT [8,21,71-73]. In vitro drug testing of cisplatin and carboplatin has shown comparable cytotoxicity against glioma cell lines at clinically relevant concentrations [115]. Although it is more myelosuppressive than cisplatin (i.e., thrombocytopenia), carboplatin causes less ototoxicity, nephrotoxi-city, nausea and emesis, and peripheral neuropathy. Single-agent intravenous carboplatin (175 mg/m2 weekly or 560 mg/m2 monthly) has demonstrated efficacy in pediatric patients for the treatment of low-grade gliomas and recurrent malignant PBT [116,117]. In adult patients, single-agent carboplatin (400-450 mg/m2 IV every 4 weeks) was moderately effective for the treatment of recurrent malignant gliomas [118]. The overall response rate was 48 per cent, with a median time to progression of 26 weeks in respon-ders. In multi-agent regimens, carboplatin has been combined with etoposide and teniposide, with results similar to that achieved by cisplatin or BCNU [119,120]. Carboplatin has also been administered intra-arterially, either alone or in combination with etoposide and BBB disruption, with a similar level of activity to IA cisplatin [121,122]. However, significantly less neurological and retinal toxicity is noted with IA carboplatin.

Temozolomide. Temozolomide is an imidazote-trazine derivative of the alkylating agent dacarbazine with activity against systemic and CNS malignancies [123-125]. The drug undergoes chemical conversion at physiological pH to the active species 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) (see Fig. 2.5). Temozolomide exhibits schedule-dependent

temozolomide figure 2.5

antineoplastic activity by interfering with DNA replication through the process of methylation. The methylation of DNA is dependent upon the formation of a reactive methyldiazonium cation, which interacts with DNA at the following sites: N7-guanine (70 per cent), N3-adenine (9.2 per cent), and O6-guanine (5 per cent). The cytotoxicity of temozolomide can be modulated by the degree of activity of three DNA-repair enzyme systems: DNA-mismatch repair, O6-alkylguanine-DNA alkyltrans-ferase (AGT), and poly (ADP-ribose) polymerase [124,126-128]. The DNA-mismatch repair pathways must be at a normal functional capacity to confer temozolomide cytotoxicity. The mechanism remains unclear, but may involve initiation of apoptosis in those cells that cannot repair the methylated sites. Tumor cells with mutations in, or phenotypically low expression of, DNA-mismatch repair genes are more resistant to temozolomide and other methylating agents. Conversely, high expression of AGT confers resistance to temozolomide by removing methyl groups from DNA before cell injury and death can occur. This relationship has been noted in vitro and is also clinically relevant, as shown by Friedman and colleagues in a series of 33 newly diagnosed patients with malignant gliomas [128]. Patients with tumors that stained strongly for AGT did not respond well to temozolomide. Depletion of AGT levels with O6-benzylguanine can restore sensitivity to temozolo-mide and other alkylating agents [129].

The antitumor activity of temozolomide is schedule dependent as shown by in vitro and in vivo experiments [124,125]. A five-day administration schedule is superior to single-day dosing for numerous malignancies, including lymphoma, leukemia, and CNS tumor xenografts. As this drug is stable at acid pH, it can be taken orally in capsules. Oral bioavailability is approximately 100 per cent, with rapid absorption of the drug. Mean peak plasma concentrations (Cmax) are reached 60 min after oral dosing. Temozolomide pharmacokinetics appear to be linear, so that Cmax and the area under the concentration-time curve (AUC) increase proportionally with single oral doses over a range of 200-1200 mg/m2. Administration of temozolomide with food results in a 33 per cent decrease in Cmax and a 9 per cent decrease in AUC. Therefore, it is recommended that the drug be given without food. The drug is eliminated by pH-dependent degradation to MTIC, followed by further degradation to 4-amino-5-imidazole-carboxamide. Temozolomide has excellent penetration of the blood-brain barrier and brain tumor tissue. In glioma patients, tumor uptake and concentration of 11C-temozolomide, as measured by positron emission tomography, correlated with response duration (p<0.01) [130].

Pre-clinical testing of temozolomide using glioma cell lines and animal models has consistently demonstrated significant activity [124,125]. Temozolomide was found effective against U251 and SF-295 human xenografts implanted subcutaneously or intracere-brally into athymic mice [131]. A synergistic response was noted when temozolomide was used in conjunction with BCNU. Similarly, temozolomide was effective against subcutaneously or intracerebrally implanted tumor xenografts derived from adult glioma, pediatric glioma, and ependymoma cell lines [132]. The cytotoxicity of temozolomide was increased after pre-treatment with O6-benzylguanine.

Temozolomide has shown significant activity and excellent tolerability in clinical trials against both adult and pediatric malignant gliomas [124,125, 128,133-141]. Initial clinical reports from Europe by Newlands and colleagues suggested that temozolo-mide was very active against newly diagnosed, as well as recurrent and progressive, high-grade gliomas [124,133,134]. Over 100 patients with glioblastama multiforme (GBM) and AA were treated with temo-zolomide (150-200 mg/m2 per day x 5 days, every 28 days); some newly diagnosed patients received the drug prior to irradiation, while others were treated after recurrence or progression. The objective response rate was 30 per cent for newly diagnosed patients and 11-25 per cent for patients with progressive disease. The response rates were similar between AA and GBM patients, with a median duration of response of 4.6 months in patients with progressive disease. Toxicity was mainly hematologi-cal, but also included nausea and emesis, headache, fatigue, and constipation. Several phase I studies using temozolomide in pediatric patients with advanced solid tumors have demonstrated objective responses in PNET, medulloblastoma, high-grade astrocytoma, and brainstem glioma [135,136]. The drug was generally well tolerated, although nausea and emesis occurred frequently. A phase II study of AA and anaplastic mixed glioma at first relapse also found temozolomide (150-200 mg/m2 per day x 5 days) to have significant activity [137]. The objective response rate was 25 per cent (8 per cent CR, 27 per cent PR), with an additional 26 per cent having stable disease. The median progression-free survival was 5.4 months, with a median overall survival of 13.6 months. In 225 patients with GBM at first relapse, a randomized phase II trial by Yung and coworkers compared temozolomide to PCB (125-150 mg/m2 per day x 28 days, every 56 days) [138]. Progression-free survival at 6 months was significantly better for temozolomide than for PCB (21 versus 8 per cent; p < 0.008). Median progressionfree survival showed a similar advantage for temo-zolomide over PCB (2.89 versus 1.88 months; p <0.0063). The six-month overall survival was also significantly different between the two drugs: 60 per cent for temozolomide and 44 per cent for PCB (p <0.019). In a further comparison of temozolo-mide and PCB, Osoba and colleagues reviewed health-related quality of life in a cohort of patients with recurrent GBM [140]. Treatment with temozolo-mide was well tolerated and associated with overall improvement in quality of life scores. PCB therapy was more toxic, and patients generally had deterioration in quality of life scores, independent of disease progression. Temozolomide is now FDA (Food and Drug Adminstration) approved for adult patients with recurrent anaplastic astrocytoma and is undergoing extensive clinical testing in other clinical trials (see Chapter 24).

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