implantation. The patients were randomly divided into two groups, equally distributed for prognostic factors such as median age, histological grade, and neurological performance, and administered either BCNU (n = 110) or placebo (n = 112) polymers. The overall post-operative median survival was 31 weeks for the BCNU treatment arm and 23 weeks for the placebo group (hazard ratio = 0.67, p = 0.0006) (Fig. 19.5). Furthermore, the 6-month survival rate was 60 per cent in the treatment group versus 47 per cent in the placebo group. More significantly, in the GBM group, there was 50 per cent greater survival at six months in patients treated with BCNU polymer than placebo alone (p = 0.02). Consistent with the Phase I-II trials, there was no evidence of systemic toxicity. With the successful completion of the safety and efficacy clinical trials, the Food and Drug Administration (FDA) approved 3.85 per cent BCNU-loaded PCPP:SA wafer for the treatment of recurrent glioblastoma in 1996.
With the establishment of BCNU-PCPP:SA polymers as a safe and effective treatment for recurrent gliomas, attention naturally turned to its use in the treatment of primary gliomas. First, a Phase I trial with 22 patients newly diagnosed with malignant glioma was performed to test the safety of BCNU-PCPP:SA polymers and also the safety of concurrent standard external beam radiation therapy. Enrollment criteria consisted of: unilateral tumor focus greater than or equal to 1 cm3, age > 18 years, KPS greater than or equal to 60, and intraoperative diagnosis of malignant gliomas. In addition, all of the patients received adjuvant standard radiation therapy after their surgical resection. There was no evidence of systemic or neurological toxicity. The median survival was 42 weeks, with four patients surviving greater than 18 months. Thus, BCNU-PCPP:SA polymers with conventional radiotherapy in the treatment of primary gliomas was established as safe.
Next, two Phase III trials were performed to establish the effectiveness of a 3.8 per cent BCNU-loaded polymer in the management of primary gliomas. In the first trial,  32 patients with a histopathological diagnosis of grade III astrocytoma or GBM on intraoperative frozen sections were randomly assigned to receive BCNU-loaded polymer or placebo. The median survival was 58.1 weeks in the treatment group, compared to 39.3 weeks for the placebo group (p = 0.012) (Fig. 19.6A). The survival rates were significantly better for BCNU versus placebo at one (63 vs 19 per cent), two (31 vs 6 per cent), and three (25 vs 6 per cent) years postimplantation. Again, no signs of local or systemic toxicities were observed.
In the larger scale Phase III study by Westphal et al.,  240 patients with newly diagnosed malignant glioma were randomized to receive either BCNU or placebo wafers during their surgical resection. Radiation therapy was instituted 14-21 days post-operatively. The primary endpoint for this study was survival. The median survival in the
treatment group was 13.9 months with a 29 per cent risk reduction in death, while the placebo group had a median survival of 11.6 months (p = 0.03). Moreover, at three years post-implantaion, 11 of the patients who received Gliadel® were alive compared to 2 patients in the placebo group. This study demonstrated that BCNU-PCPP:SA polymer treatment reduced the overall risk of death during the 3-4 years post-treatment, as determined by a hazard ratio of 0.73 (95 per cent confidence interval: 0.56; p < 0.05). Time to decline in functional status was also significantly prolonged in the treatment group. Together with the Valtonen study, this large scale Phase III study of BCNU-PCPP:SA polymer as a treatment for primary malignant gliomas proved to be successful (Fig. 19.6B). As such, the FDA approved its use in initial resections of malignant gliomas in February of 2003.
New Clinical Trials Involving Gliadel® (Tables 19.3-19.6)
Since the approval of BCNU-PCPP:SA polymers for treatment of malignant gliomas, there have been multiple investigations to improve its therapeutic benefit. Twenty-eight additional clinical trials are underway evaluating other issues related to the BCNU-PCPP:SA polymer, including dosage, combination with systemic treatments, and combination with various forms of radiation and resistant modifiers, use in specialized populations, and use in those with cerebral metastases (Tables 19.3 and 19.4). Here we describe just a few of the many clinical trials involving BCNU-PCPP:SA.
Once the safety and efficacy of the 3.8 per cent BCNU-PCPP:SA was well established, a logical next step was to study the effect of increasing the BCNU-loading dose. Initial laboratory investigations indicated improved efficacy with higher doses of BCNU loaded polymers implanted into 9L gliosarcoma models . In a recently completed Phase I-II dose escalation study, funded by the National Institutes of Health and involving 11 medical centers in the United States, Olivi et al., found that doses ranging from 6.5 per cent to 20 per cent loaded into PCPP:SA polymers were well tolerated without significant adverse effects . This Phase I-II escalation study established that the maximal non-toxic loading dose is 20 per cent . A phase III efficacy trial is currently underway with PCPP:SA wafers loaded with this highest-tolerated dose.
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