INTRALESIONALLY IMPLANTED CISPLATIN PLUS SYSTEMIC CARMUSTINE FOR THE TREATMENT OF BRAIN-TUMOR IN RATS

Background and Objectives: The benefit of conventional chemotherapy fo r the treatment of malignant brain tumors, although limited, is real. A major obstacle in the treatment of these lesions is the ability to d eliver drug across the blood-brain barrier (BBB). Local drug implantat ion, circumventing the BBB, has been a useful strategy for treatment o f intracranial lesions, and may work synergistically with systemic che motherapy. To test this hypothesis, either intraperitoneal tip) carmus tine or cisplatin was combined with the intracranial (ic) administrati on of polymer-delivered cisplatin in rats with intracranial tumors. Me thods and Results: 9L gliosarcoma tumor cells (5 x 10(3)) were adminis tered through a right frontal lobe cannula in rats 7 days prior to tre atments. Cisplatin-loaded biodegradable polymer was then administered via the cannula, with free cisplatin or carmustine injected ip. Animal s were monitored for 60 days post-treatment. In experiment 1, ic cispl atin at a dose of 0.5, 1.0, 2.0, and 4.0 mg/m(2) resulted in a mean su rvival time of 34 +/- 3, 39 +/- 14, 47 +/- 11, and 31 +/- 20 days (MST +/- SD), respectively, compared to 26 +/- 4 days in the control group and 30 +/- 7 days in the group treated with 50 mg/m(2) ip free cispla tin. In experiment 2, ip free cisplatin at 25, 40, 50, and 100 mg/m(2) resulted in a MST of 28 +/- 3, 30 +/- 4, 32 +/- 3, and 14 +/- 8 days, respectively, compared to 26 +/- 1 days in the control group. In expe riment 3, the MST in the groups treated with 0.5 mg/m(2) of ic cisplat in, 25 mg/m(2) of ip cisplatin, 10 mg/kg of ip carmustine, ic cisplati n (0.5 mg/m(2)) plus ip cisplatin (25 mg/m(2)), and ic cisplatin (0.5 mg/m(2)) plus ip carmustine (10 mg/kg) was 30 +/- 4 days (P > 0.05), 2 8 +/- 2 (P > 0.05), 36 +/- 4 (P < 0.01), 32 +/- 3 (P < 0.01), and 50 /- 11 days (P < 0.01), respectively, compared to the tumor control gro up (26 +/- 1 days). Long-term survivors (29%) were seen only in the ic cisplatin plus ip carmustine group. Additive toxicity was not observe d.Conclusions: Intralesional polymer-delivered (ic) cisplatin plus sys temic (ip) carmustine is highly effective for the treatment of intracr anial 9L gliosarcoma in tumors. (C) 1998 Wiley-Liss, Inc.