C

figure 2.2

treatment of malignant PBT, and have also been applied to MBT [3,8,21,71-73]. Included in this class are CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), PCNU, fotemustine, streptozotocin, and MeCCNU (see Figs. 2.2A-2.2C). As a group, nitrosoureas are highly lipid soluble, non-ionized, cell-cycle-nonspecific agents that readily cross the blood-brain barrier [8,21]. They spontaneously decompose into two active intermediates, a chlor-oethyldiazohydroxide and an isocyanate group. DNA alkylation leads to the formation of DNA-DNA and DNA-protein cross-links; mediated by the chlor-oethyl-diazohydroxide intermediate. The isocyanate intermediate produces carbamoylation of amino groups, which depletes glutathione, inhibits DNA repair, and interferes with RNA synthesis. After systemic administration, BCNU concentrations within brain reach 15-70 per cent of plasma concentrations, while CCNU concentrations are equivalent to that of plasma. The nitrosoureas have been used either as single agents (BCNU - most effective) or in combination with other cytotoxic drugs (e.g., PCV: procarbazine, CCNU, and vincristine). In addition, several of the nitrosoureas (BCNU, ACNU) have been applied to PBT and MBT by IA delivery techniques (see Chapters 17 and 35).

Seminal studies by the Brain Tumor Study Group demonstrated that the addition of nitrosoureas could improve survival in patients with malignant PBT [84-86]. Walker and colleagues analyzed 358 patients with malignant glioma and demonstrated that survival at 18 months was superior for patients receiving irradiation plus BCNU in comparison to those treated with irradiation alone [84]. Green and associates studied 527 patients with malignant glioma after surgery and irradiation, randomizing them into four groups (BCNU, methylprednisolone, procarbazine, or BCNU plus methylprednisolone) [85]. Median survival for patients treated with single-agent BCNU (50 weeks) and procarbazine (47 weeks) were superior to survival in the groups receiving other regimens or irradiation alone (36 weeks).

CCNU (110 mg/m2 every 6-8 weeks) is an integral component of the PCV regimen that is commonly used for anaplastic oligodendroglioma, recurrent oligodendroglioma, anaplastic astrocytoma, and mixed gliomas [8,21,71-73]. In addition, CCNU has proved beneficial in multi-agent regimens for treatment of high-risk medulloblastoma patients [87,88]. In a Children's Cancer Study Group prospective, randomized trial of radiation therapy versus radiation plus chemotherapy in 233 patients with medullo-blastoma, the addition of CCNU, vincristine, and prednisone extended event-free and overall survival in the high-risk group [87].

The major acute toxicity of the nitrosoureas is gastrointestinal (i.e., nausea and emesis). The dose-limiting side effect is myelosuppression, which develops at 3-5 weeks after the treatment. In up to 20 per cent of the patients receiving nitrosoureas (mainly BCNU), pulmonary fibrosis can occur. Risk factors for the development of pulmonary fibrosis include the total cumulative dose (>1100 mg/m2) and number of cycles of drug (> 5 cycles), co-morbid lung disease, age, smoking history, and platelet count nadir after the first course of treatment [89].

Procarbazine. Procarbazine is a drug that requires hepatic activation to intermediate forms before developing potent activity as an alkylating agent (see Fig. 2.3) [90,91]. PCB is taken orally and is rapidly absorbed by the gastrointestinal tract. Following absorption, it is first metabolized into an azo-PCB derivative, which has similar potency to PCB. Further metabolism by the cytochrome P-450 system converts

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