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FIGURE 18.1 The two-compartment model. Carboplatin (carbo) is administered intra-arterially immediately after osmotic disruption of the BBB with hypertonic mannitol. (A) shows delivery of carboplatin across the BBB. Sodium thiosulfate (STS) is administered intravenously 4 (or 4 and 8) h after osmotic disruption, after BBB permeability has returned to baseline levels. (B) shows exclusion of STS from the brain.

FIGURE 18.1 The two-compartment model. Carboplatin (carbo) is administered intra-arterially immediately after osmotic disruption of the BBB with hypertonic mannitol. (A) shows delivery of carboplatin across the BBB. Sodium thiosulfate (STS) is administered intravenously 4 (or 4 and 8) h after osmotic disruption, after BBB permeability has returned to baseline levels. (B) shows exclusion of STS from the brain.

various sequences of radiation therapy and BBBD chemotherapy in rodents. Drug delivery, acute toxicity and long-term (one year) neuropathological effects of methotrexate, or carboplatin plus etoposide, were evaluated. External beam radiation of 2000 cGy as a single fraction using parallel opposed portals, either 30 days before or concurrent with BBBD, resulted in a statistically significant decrease in drug delivery compared to animals not receiving cranial irradiation. Seizures were observed in 26 per cent of the animals that received irradiation before or concurrent with BBBD and methotrexate, but not carboplatin. The mortality rate for animals receiving radiotherapy 30 days prior to chemotherapy was significantly higher than the mortality rate for animals receiving only BBBD chemotherapy without irradiation [9,11].

Additional rodent studies evaluated whether prior irradiation influenced the efficacy of antibody targeted chemotherapy given with BBBD. Results showed that BR96-DOX, an antitumor mAb-doxorubicin immunoconjugate, administered prior to irradiation significantly increased survival compared to rodents receiving irradiation prior to chemotherapy, or compared to those receiving chemotherapy concurrently [10]. These findings were later supported in the clinic when subjects with PCNSL who received cranial irradiation before beginning BBBD chemotherapy, had significantly decreased median survival time compared to subjects who received initial BBBD chemotherapy [12].

The BBB pre-clinical and clinical teams carefully conduct toxicity studies, in animals and humans respectively, to determine which chemotherapy agents can be administered with BBBD with an acceptable safety and toxicity profile. However, extensive pre-clinical toxicity studies are always conducted prior to phase 1 clinical studies. For example, important knowledge was gained when laboratory studies showed severe neurotoxicity when adriamy-cin (intra-arterial) [13], cisplatinum (intra-arterial), or 5-FU (intra-arterial) [14] were administered as single agents after BBBD. Fortin [15] reported unexpected neurotoxicity when etoposide phosphate (intra-arterial) was administered in combination with melphalan (intra-arterial), methotrexate (intra-arterial), or carboplatin (intra-arterial) after BBBD, when propofol anesthesia was used.

Chemotherapy agents used most frequently in conjunction with BBBD in the clinical setting are methotrexate (intra-arterial, 2500 mg/day x two consecutive days), carboplatin (intra-arterial, 200 mg/m2 per day x two consecutive days), melphalan (intra-arterial, a dose of 8 mg/m per day x two consecutive days is currently under study), cyclophosphamide (intravenous, 500 mg/m2 per day x two consecutive days when given with methotrexate; 330 mg/m2 per day x two consecutive days when given with carboplatin), etoposide and etoposide phosphate (intravenous, 150 mg/m2 per day x two consecutive days when given with methotrexate; 200 mg/m2 per day x two consecutive days when given with carboplatin). Depending on brain tumor histology and according to the specific IRB-approved protocol, a combination of the above drugs are given with BBBD. These agents infused by the respective routes and doses have been routinely used in the clinical setting and have shown acceptable toxicity [12,16-19].

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