Brain Cancer Treatment Controlled Release Implants

The first pharmaceutical product available on the market being based on the principle of intracranial controlled drug delivery was Gliadel® (41,50-57). It is a disc-shaped wafer (flat cylinder), containing 3.85% of the anticancer drug BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea; carmustine]. BCNU alkylates the nitrogen bases of DNA. Although it is a low molecular weight, lipophilic drug (and can, thus, cross the BBB to a certain extent), a systemic treatment is not efficient due to the severe, dose-limiting side effects (in particular bone marrow suppression and pulmonary fibrosis) and relatively short half-life (<15 min) (58,59). In Gliadel, BCNU is embedded within a biodegradable matrix based on poly[bis(p-carboxyphenoxy) propane-sebacic acid] [p(CPP:SA)], a polyanhydride that is hydrolytically cleaved into shorter chain acids upon contact with water. This advanced drug delivery system has been developed by the group of Brem, presenting a major breakthrough in the field of controlled local brain delivery. It got approved by the Food and Drug Administration (FDA) in 1996 for the treatment of recurrent glioblastoma multiforme. The basic principle of this treatment method is illustrated in Figure 7: Schematic cross-sections of a human brain are shown. The tumor is represented by the black circle (Fig. 7A), the surrounding tissue is infiltrated by tumor cells. If operable, the surgeon removes the tumor (Fig. 7B). Unfortunately, large quantities of surrounding tissue cannot be removed at the same time, because the risk to affect vital brain functions is considerable. Thus, the probability that tumor cells remain within the brain is important (infiltrated neighboring tissue). Consequently, many patients die due to local tumor recurrence in the direct vicinity of the primary tumor. To reduce this risk one or more (maximal 8) disc-shaped, BCNU-loaded wafers are placed into the resection cavity of the tumor (during the same operation, not requiring an extra opening of the crane) (Figs. 7C and 8). The anticancer drug is then released in a time-controlled manner into the resection cavity and penetrates into the surrounding tissue.

In the early nineties, a phases I-II clinical trial demonstrated the safety of using this type of p(CPP:SA)-based wafers loaded with BCNU for intracranial tumor treatment (50): Twenty one patients with recurrent malignant glioma (that had previously undergone a craniotomy for debulking and in whom standard therapy had failed) were treated with p (CPP:SA)-based discs containing 1.93%, 3.85%, and 6.35% (w/w) BCNU. Each wafer had a mass of 200 mg and in most patients the maximal number of discs (eight) was implanted. Importantly, there was no evidence for systemic toxicity (including bone marrow suppression). Based on this phases I-II clinical trial, the efficiency of the 3.85% BNCU-loaded, polyanhydride-based wafers were studied in a phase III clinical trial (51). The latter was multicentered, randomized, double-blinded and placebo-controlled.

Tumor

(B) Surgical resection

(C) Wafer implantation

Tumor

(B) Surgical resection

(C) Wafer implantation

Figure 7 Principle of the treatment of operable brain tumors with BCNU-loaded, p(CPP:SA)-based wafers (Gliadel). Schematic cross-sections through a human brain: (A) The tumor is illustrated as a black circle; the surrounding tissue is infiltrated by tumor cells. (B) The tumor has been removed surgically. (C) To minimize the risk of local tumor recurrence, drug-loaded wafers (up to 8) are placed into the resection cavity of the tumor (see Fig. 8).

Figure 8 Principle of the treatment of recurrent glioblastoma multiforme with Gliadel®. Upon tumor resection, up to 8 anticancer drug-loaded, polymeric wafers are placed into the resection cavity. The drug is then released in a time-controlled manner from the wafers into the cavity. Source: From Ref. 57.

Figure 8 Principle of the treatment of recurrent glioblastoma multiforme with Gliadel®. Upon tumor resection, up to 8 anticancer drug-loaded, polymeric wafers are placed into the resection cavity. The drug is then released in a time-controlled manner from the wafers into the cavity. Source: From Ref. 57.

Two hundred and twenty two patients with recurrent malignant brain tumors requiring re-operation were randomly assigned to receive intra-cranially implanted p(CPP:SA)-based discs containing or not BCNU. Randomization balanced the treatment groups for all examined prognostic factors. Importantly, the median survival time of the 110 patients who were treated with drug-loaded wafers was 31 weeks compared to only 23 weeks in the case of the 112 patients who received placebo discs. The 6-month survival rate was 60% in the treatment population vs. 47% in the placebo group. Figure 9A illustrates the overall survival of the patients (after adjustment for the examined prognostic factors). Furthermore, there were no clinically important side effects caused by the drug-loaded, biodegradable wafers: neither locally within the brain, nor systemically. Based on these results the FDA approved this treatment method for recurrent glioblastoma multiforme. It was the first time in 23 years that the FDA approved a novel treatment method for malignant gliomas.

Afterwards, Gliadel was also used for the initial treatment of malignant gliomas (52). Generally, it can be expected that an anticancer treatment that has proven to be effective against recurrent tumors is likely to be more effective when used as initial therapy. A phases I-II clinical trial with 21 patients receiving postoperative external beam radiation therapy (5000 rad) showed a median survival of 44 weeks from the time of implantation, with 4 patients surviving >18 months. Thus, this trial demonstrated the safety of Gliadel in combination with radiation therapy also for patients with newly diagnosed malignant gliomas. Based on these results, a phase III clinical trial (multicentered, randomized, double-blinded and placebo-controlled) was planned and started for 100 patients (56). Unfortunately, this study had to be prematurely terminated because of a temporary unavailability of the anticancer drug BCNU. At the end, only 32 patients could be included in the trial. The obtained results were nevertheless encouraging: The median

Figure 9 Clinical efficiency of Gliadel® for the treatment of recurrent and newly diagnosed malignant gliomas. Overall survival of the (A) 222 patients with recurrent brain tumors participating in a phase III clinical trial after adjustment for prognostic factors; (B) 240 patients with newly diagnosed brain tumors participating in a phase III clinical trial, including results from the long-term follow-up. Source: From Refs. 51 and 60.

Figure 9 Clinical efficiency of Gliadel® for the treatment of recurrent and newly diagnosed malignant gliomas. Overall survival of the (A) 222 patients with recurrent brain tumors participating in a phase III clinical trial after adjustment for prognostic factors; (B) 240 patients with newly diagnosed brain tumors participating in a phase III clinical trial, including results from the long-term follow-up. Source: From Refs. 51 and 60.

survival time was 58 versus 40 weeks in the treatment versus placebo group. Due to the limited number of patients a further, larger (also randomized and placebo-controlled) phase III study was performed, including 240 patients with primary malignant gliomas (60). Upon surgical tumor resection the patients received either BCNU-loaded or drug-free wafers. Both groups were postoperatively treated with external beam radiation. The median survival time in the intent-to-treat group was 13.9 months for the Gliadel treated patients and 11.6 months for the placebo group. The 1-year survival rates were 59.2% and 49.6%, respectively. Recently, a long-term follow-up of this phase III clinical trial was reported (61). Of the 59 patients available for this follow-up, 11 were alive at 56 months: 9 of them had been treated with Gliadel, and only 2 with placebo wafers. The extended Kaplan-Meier curves for all 240 patients are shown in Figure 9B. As it can be seen, the survival advantage of the Gliadel treated group was clearly maintained at 1, 2, and 3 years.

The effects of the BCNU loading and composition of the biodegradable matrix former p(CPP:SA) on the efficiency of this type of disc-shaped implants to treat intracranial 9L-gliosarcomas bearing rats were studied by Sipos et al. (55). The anticancer drug loading was varied from 4% to 32% and the monomer ratio CPP:SA of the co-polymer was either 20:80 or 50:50. In the latter case, the degradation rate of the matrix is reduced, resulting in decreased drug release rates and prolonged release periods. Figure 10 (A and B) shows the observed survival curves in the respective animal groups. Clearly, the BCNU loading had a significant effect on the efficiency of the treatment: A drug content of 20 and 32% led to the longest survival rates in the case of p (CPP:SA) 20:80 and 50:50-based discs, respectively. In contrast, the pharmacodynamic effects of the wafers were similar for the two types of co-polymers differing in the monomer ratio (at equal drug contents) (Fig. 10A vs. 10B).

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