*3.2.2. Preclinical evidence*

**3. Polymeric drug delivery**

320 Neurooncology - Newer Developments

**3.2. Carmustine implants**

*3.2.1. Background information*

In order to overcome the drawbacks mentioned above and to achieve the local controlled release of chemotherapeutics, efforts have been made to develop delivery system with synthetic polymers. Early in 1970s, an ethylene vinylacetate copolymer (EVAc) was em‐ ployed to generate a poriferous matrix and incorporate macromolecules such as chemothera‐ peutics (14). The impregnated agents are released from the matrix in a predictable and sustained style by diffusion. The rate of release depends on the physicochemical property of the agents, such as solubility, charge, and molecular weight. However, EVAc was restricted

Various biodegradable polymers, such as the 1,3‐bis(p‐carboxyphenoxy) propane and sebacic acid (PCPP‐SA), the fatty acid dimer sebacic acid (FAD‐SA), and poly(lactide‐co‐glycolide) (PLGA) polymers, have been investigated in the last 3 decades. But until now, PCPP‐SA is the most successful and widely used polymer for brain tumors. This compound has several advantages as matrix (15). Firstly, PCPP‐SA is hydrophobic and can therefore protect the impregnated drug from inactivation by the surrounding aqueous environment. Secondly, the two‐stage degradation of PCPP‐SA matrix results in the gradual release of the content. At the first stage, the bonds between sebacic acid and sebacic acid or those between sebacic acid and CPP rapidly hydrolyzed, whereas the bonds between CPP and CPP take a longer time to degrade. This initial degradation is followed by a process of inward erosion which starts at the surface of the matrix and goes interiorly into the core. By modulating the ratio of sebacic acid and CPP in the matrix, the speed of degradation can be adjusted from hours to days as required. In addition, the breakdown of the PCPP‐SA does not leave foreign body behind. Currently, the only US Food and Drug Administration (FDA) approved local chemothera‐ peutical agent for brain tumors, that is, Gliadel wafer, is composed by PCPP‐SA as matrix

BCNU is one of the most effective chemotherapeutics against malignant brain tumors at the time when the first local polymeric drug delivery system was being developed. BCNU is a classic alkylating and exerts its anti‐tumor effect by forming inter‐strand crosslink in DNA and subsequently inhibiting the replication and transcription of DNA in tumor cells (16). The highly lipid‐soluble and nonpolar nature of BCNU makes it ideal for cancers in CNS be‐ cause the agent has a good penetration of BBB. The concentration of BCNU in cerebral spinal fluid (CSF) is as high as 30% of that in plasma after intravenous injection. Clinical studies have demonstrated that systemic administration of BCNU is capable of prolonging the survival of patients with malignant gliomas (17). As a result, BCNU alone or combined with other agents has once been the most frequently used chemotherapy regimens for malignant gliomas. Although effective, intravenously administered BCNU is limited by its toxicities (18).

by the non‐degradable nature and was therefore seldom used in neuro‐oncology.

and 1,3‐bis(2‐chloroethyl)‐1‐nitrosurea (carmustine or BCNU) as content.

**3.1. History**

Preclinical exploration established the safety of the wafers in the CNS. Brem and colleagues (19) implanted the PCCP‐SA polymers in the frontal lobe of rabbits and evaluated the biocompatibility. No neurological deficits or behavioral abnormalities suggestive of toxicity were observed. All the tested animals survived to the date of sacrifice. The histological analysis revealed that the inflammatory reaction from PCCP‐SA was not significantly different from that in the controlled group implanted with Gelform, a widely used hemostatic material in neurosurgical operations. In primate models, the interstitial chemotherapy with BCNU polymers alone or combined with external beam radiation was found to be safe. The local‐ ized inflammatory response induced by BCNU wafers was well tolerated and manageable (20).

The *in vivo* experiments were also performed to evaluate the pharmacokinetics of BCNU wafers. In a rat model, the concentration of radiolabelled BCNU on the coronal sections of the brains was measured (21). BCNU delivered by polymers was at a concentration of 1 mM around the implanted site for the entire 30‐day experiment. On day one, after implantation, BCNU penetrated the brain at a radius of 5 mm at a significant concentration, which was defined as 10% of the maximum concentration at the brain/polymer interface. Grossman and colleagues (22) investigated the intra‐cerebral drug distribution in rabbits after the implanta‐ tion of BCNU wafers. Radiolabeled BCNU was detected in 50% the area of the brain sections 3 days after BCNU‐polymer implantation. On day seven, the concentration of BCNU was as high as 6 mM at the distance of 10 mm from the implantation site, which is far more than the active concentration of 14–16 μM against glioma cells *in vitro*. Because BCNU impregnated in polymers is released in a controlled manner, Fung and colleagues (23) calculated and compared the area under curve (AUC, concentration over time) of BCNU delivered by polymers to monkey brain and that administered by intravenous injection. In that study, polymeric BCNU delivery was estimated to achieve a 4-fold larger AUC in distant sites of brain and as high as 1200‐fold more at the brain/polymer interface, in comparison with the conven‐ tional intravenous administration.

The efficacy of interstitial chemotherapy with BCNU was then tested in animal models. Tamargo and colleagues (24) demonstrated that local delivery of BCNU via polymers significantly prolonged the survival of rats intracranially implanted with 9 L gliosarcoma cells, compared with intraperitonal injection of the agent. The median survival of animals treated with BCNU polymers was 62 days, which was more than double that for rats treated with systemic administration. In another study with the rat orthotopic glioma model, BCNU‐ impregnated polymers were found to be superior to extend the lifespan of tumor‐bearing rats, compared with the direct injection of BCNU into the tumor tissues (25).

## *3.2.3. Clinical trials*

The preclinical evidence of the safety and the effectiveness of polymeric BCNU delivery rationalized the investigation of the clinical benefit of this therapy. Brem and colleagues reported a multicenter Phase I–II trial with BCNU polymers in recurrent glioma patients. In that study, twenty‐one patients with recurrent malignant glioma were enrolled (26). Up to 8  BCNU polymer wafers with three escalating concentrations, that is, 1.93, 3.85, and 6.35%, were implanted in the tumor beds. The authors demonstrated that the local treatment with BCNU was well tolerated, and no systemic adverse effects related to the therapy were observed in all patients. The study also recorded the survival outcome. The average survival time was 65, 64, and 32 weeks for patients treated with the low, medium, and high concentration of BCNU, respectively. Based on the result of this study, the further efficacy evaluation employed polymeric wafers with the 3.85% dose of BCNU. However, it is worth noting that patients treated with the highest dose of BCNU in the study had the shortest survival, which was not due to the adverse effects. In fact, the small sample size and the difference in the grade of gliomas among three groups account for the paradox. The group treated with the highest dose composed a higher proportion of GBM than the other two groups. In another multicenter single‐arm Phase I trial, Brem and colleagues (27) demonstrated that the placement of polymeric BCNU wafers followed by the external radiation was safe for newly diagnosed malignant gliomas.

The role of interstitial chemotherapy with BCNU in recurrent malignant glioma was ex‐ plored in a multicenter, double‐blinded, placebo‐controlled trial of 222 patients from 27 centers (28). Biodegradable polymers with 3.85% BCNU or empty polymer wafers were randomly implanted in the tumor site after resection. One hundred and ten patients re‐ ceived BCNU polymers and 112 had placebo‐wafers. The median survival of patients with BCNU wafers was 31 weeks, which is superior to 23 weeks for patients with empty poly‐ mers (HR = 0.67, *p* = 0.006, after accounting for the effects of prognostic factors). Among 212 patients, 145 (65.3%) had pathologically confirmed GBM. Significantly reduced mortality at 6 months was observed in GBM patients treated with BCNU wafers (44%, 32 of 72 cases) than those treated with placebo implants (64%, 47 of 73 patients, *p* = 0.02). As a result, FDA approved the use of 3.85% BCNU wafers (Gliadel®) for recurrent malignant gliomas. However, a recent meta‐analysis from the Cochrane library doubted the benefit of BCNU wafers in the treat‐ ment of recurrent malignant gliomas (29). No statistical difference in survival was found between patients treated with Gliadel® and those with placebo (HR = 0.83, 95% CI 0.62–1.10, *p* = 0.2). The acquired chemoresistant by the point of the implantation of BCNU wafers and the treatment‐associated changes, such as the radiation‐induced gliosis, which may restrict the diffusion of BCNU around the resection cavity, was suggested to be responsible for the ineffectiveness.

compared with intraperitonal injection of the agent. The median survival of animals treated with BCNU polymers was 62 days, which was more than double that for rats treated with systemic administration. In another study with the rat orthotopic glioma model, BCNU‐ impregnated polymers were found to be superior to extend the lifespan of tumor‐bearing rats,

The preclinical evidence of the safety and the effectiveness of polymeric BCNU delivery rationalized the investigation of the clinical benefit of this therapy. Brem and colleagues reported a multicenter Phase I–II trial with BCNU polymers in recurrent glioma patients. In that study, twenty‐one patients with recurrent malignant glioma were enrolled (26). Up to 8  BCNU polymer wafers with three escalating concentrations, that is, 1.93, 3.85, and 6.35%, were implanted in the tumor beds. The authors demonstrated that the local treatment with BCNU was well tolerated, and no systemic adverse effects related to the therapy were observed in all patients. The study also recorded the survival outcome. The average survival time was 65, 64, and 32 weeks for patients treated with the low, medium, and high concentration of BCNU, respectively. Based on the result of this study, the further efficacy evaluation employed polymeric wafers with the 3.85% dose of BCNU. However, it is worth noting that patients treated with the highest dose of BCNU in the study had the shortest survival, which was not due to the adverse effects. In fact, the small sample size and the difference in the grade of gliomas among three groups account for the paradox. The group treated with the highest dose composed a higher proportion of GBM than the other two groups. In another multicenter single‐arm Phase I trial, Brem and colleagues (27) demonstrated that the placement of polymeric BCNU wafers followed by the external radiation was safe for newly diagnosed

The role of interstitial chemotherapy with BCNU in recurrent malignant glioma was ex‐ plored in a multicenter, double‐blinded, placebo‐controlled trial of 222 patients from 27 centers (28). Biodegradable polymers with 3.85% BCNU or empty polymer wafers were randomly implanted in the tumor site after resection. One hundred and ten patients re‐ ceived BCNU polymers and 112 had placebo‐wafers. The median survival of patients with BCNU wafers was 31 weeks, which is superior to 23 weeks for patients with empty poly‐ mers (HR = 0.67, *p* = 0.006, after accounting for the effects of prognostic factors). Among 212 patients, 145 (65.3%) had pathologically confirmed GBM. Significantly reduced mortality at 6 months was observed in GBM patients treated with BCNU wafers (44%, 32 of 72 cases) than those treated with placebo implants (64%, 47 of 73 patients, *p* = 0.02). As a result, FDA approved the use of 3.85% BCNU wafers (Gliadel®) for recurrent malignant gliomas. However, a recent meta‐analysis from the Cochrane library doubted the benefit of BCNU wafers in the treat‐ ment of recurrent malignant gliomas (29). No statistical difference in survival was found between patients treated with Gliadel® and those with placebo (HR = 0.83, 95% CI 0.62–1.10, *p* = 0.2). The acquired chemoresistant by the point of the implantation of BCNU wafers and the treatment‐associated changes, such as the radiation‐induced gliosis, which may restrict the

compared with the direct injection of BCNU into the tumor tissues (25).

*3.2.3. Clinical trials*

322 Neurooncology - Newer Developments

malignant gliomas.

Efforts have also been put to investigate the efficacy of BCNU wafers as the initial treatment for newly diagnosed malignant gliomas. Two phase III multicenter, double‐blinded, placebo‐ controlled trials drew the similar conclusions. In 1997, Valtonen and colleagues (30) publish‐ ed the study that was prematurely terminated due to the unavailability of the wafers. Thirty‐ two patients (16 in each group) with newly diagnosed malignant gliomas were randomly assigned to the active treatment group with BCNU wafers or the placebo group at the time of the primary surgery. An improved survival was observed in active treatment group (58.1 weeks), compared with the placebo group (39.9 weeks) (*p* = 0.012). For the subset of patients with GBM, BCNU wafers also offered survival benefit compared with placebo (53.3 vs. 39.9  weeks, *p* = 0.008). To confirm this positive result, a Phase III clinical trial with a larger sam‐ ple size of 240 patients with newly diagnosed malignant glioma was subsequently per‐ formed (31). Patients randomly received the placement of either BCNU or empty polymers in the tumor bed, followed by the postoperative external radiation therapy. Prognostic factors, such as age, sex, Karnofsky performance status (KPS), and tumor grading, were balanced. The BCNU‐treatment group had a significantly longer median survival (13.9 months) than placebo group (11.6 months) (*p* = 0.03). The risk of death was reduced by 29% in the treatment group. More adverse events including symptomatic intracranial hypertension (9.1 vs. 1.7%) and CSF leaking (5 vs. 0.8%) were observed in patients treated with BCNU wafers. In 2003, FDA granted the approval of Gliadel® wafers to treat newly diagnosed malignant gliomas. Until now, Gliadel® wafers are commercially available in the United States, Canada, Europe, and Japan for the adjuvant treatment of newly diagnosed malignant gliomas.

A preclinical works have revealed that the anti‐glioma effect positively related to the load‐ ing dose of BCNU in biodegradable polymers in primate models (32). The question of whether a higher concentration of BCNU for interstitial chemotherapy is safe and capable of prolong‐ ing the overall survival of glioma patients was raised. The New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium therefore investigated the safety of polymer wafers with higher concentrations of BCNU in a dose escalation trial (33). Forty‐four patients with malignant gliomas were treated with polymer wafers containing BCNU at escalating doses of 6.5, 10, 14.5, 20, and 28%, respectively. The authors demonstrated that BCNU‐impregnat‐ ed wafers with a higher concentration of up to 20%, which was more than five times the dose of commercially available Gliadel®, were safe. The median OS of the patients after the placement of BCNU wafers was 251 days. Although further large‐scale trials were suggested to explore the efficacy of high‐dose BCNU wafers, the group has not initiated any of the studies. Recently, we evaluated the safety of high‐dose BCNU‐loaded biodegradable wafers in Chinese patients with recurrent malignant glioma (34). The wafers we used are comprised of poly (lactide‐co‐glycolide) (PLGA) containing 10% BCNU. PLGA is also a FDA approved materi‐ al for drug delivery, which has more tunable mechanical properties and can be stored at 2– 10°C in comparison with PCCP used in Gliadel®. In addition, PLGA degrades directly into water and carbon dioxide and does not need clearance in liver or kidney. The dosage of 10% BCNU is 2.5 times that of Gliadel®. Our study demonstrated that 12 implants with 240 mg BCNU was well tolerated in tested patients. No dose‐limiting toxicity was found. The median survival of this cohort of patients was 322 days. The 6‐months, 1‐year, and 2‐year survival rates were 66.7, 40, and 13.3%, respectively. A registered double‐blinded randomized Phase III trial is on‐going to investigate the efficacy of the high‐dose BCNU‐impregnated PLGA wafers for recurrent malignant gliomas.

In 2005, Stupp and colleagues (35) published the milestone Phase III trial on the efficacy of adjuvant chemotherapy with temozolomide (TMZ) for GBMs. TMZ is a second generation alkylating agent, which can be administered orally. The Stupp regimen, that is, the concur‐ rent chemoradiation with TMZ followed by six cycles of adjuvant TMZ, offered a modest but statistically significant extension of the survival of patients with GBM. As a result, TMZ is currently the standard‐of‐care for GBMs. The preclinical data presented by Plowman and colleagues (36) revealed that sequential administration of BCNU and TMZ resulted in a dramatic synergism and significantly inhibited the growth of glioma xenograft in mice. At the time when TMZ emerges, the safety profile and treatment outcome of TMZ with additional Gliadel® wafers was unclear. Gururangan and colleagues (37) investigated the safety of TMZ combined with BCNU wafers in a dose‐escalation trial. Ten patients with recurrent malig‐ nant glioma were treated with BCNU implants followed by oral administration of TMZ at daily dose of 100, 150, and 200 mg/m<sup>2</sup> , respectively. The combined treatment was well tolerated. Only one patient treated with TMZ at the highest daily dose of 200 mg/m<sup>2</sup> suf‐ fered from grade III thrombocytopenia. Until now, no randomized Phase III trial has been conducted to explore the efficacy of combined therapies in comparison with either TMZ or Gliadel® alone. Several prospective and retrospective studies with small number of patients indicated that sequential treatment with Gliadel® and TMZ resulted in an incremental gain of 2–3 months in median survival (38). Although the level of clinical evidence is not high enough, the combined treatment with Gliadel® and TMZ is currently recommended as an active option for newly diagnosed and recurrent malignant gliomas by the National Comprehensive Cancer Network (NCCN) guidelines (39).

#### *3.2.4. Prevention for complications*

The implantation of BCNU wafers is generally safe, but clinical lessons have been learned from the employment of Gliadel® for the management of malignant gliomas. The common ad‐ verse effects include healing abnormalities, seizures, and intracranial hypertension (40). Several strategies have been suggested to decrease the risks associated with BCNU implants (41). After the resection of the tumor, BCNU wafers should line up the surface of the tumor bed. Stack of the implants should be avoided because the stacking may result in an irregular release of BCNU due to the altered degradation kinetics of polymers. A large communica‐ tion between resection cavity and ventricle is the contraindication for wafer implantation. The unexpected translocation of BCNU wafers into ventricle may lead to the life‐threatening hydrocephalus. In addition, a watertight closure of the dura is critical to avoid CSF leak and decreases the risk of healing abnormalities and infection. Perioperative anti‐convulsants are necessary to prevent seizures. Since the implantation of BCNU wafers is associated with increased risk of cerebral edema and intracranial hypertension, steroid is suggested to continue for at least 2 weeks after surgery.

#### *3.2.5. Economic consideration*

BCNU was well tolerated in tested patients. No dose‐limiting toxicity was found. The median survival of this cohort of patients was 322 days. The 6‐months, 1‐year, and 2‐year survival rates were 66.7, 40, and 13.3%, respectively. A registered double‐blinded randomized Phase III trial is on‐going to investigate the efficacy of the high‐dose BCNU‐impregnated PLGA wafers for

In 2005, Stupp and colleagues (35) published the milestone Phase III trial on the efficacy of adjuvant chemotherapy with temozolomide (TMZ) for GBMs. TMZ is a second generation alkylating agent, which can be administered orally. The Stupp regimen, that is, the concur‐ rent chemoradiation with TMZ followed by six cycles of adjuvant TMZ, offered a modest but statistically significant extension of the survival of patients with GBM. As a result, TMZ is currently the standard‐of‐care for GBMs. The preclinical data presented by Plowman and colleagues (36) revealed that sequential administration of BCNU and TMZ resulted in a dramatic synergism and significantly inhibited the growth of glioma xenograft in mice. At the time when TMZ emerges, the safety profile and treatment outcome of TMZ with additional Gliadel® wafers was unclear. Gururangan and colleagues (37) investigated the safety of TMZ combined with BCNU wafers in a dose‐escalation trial. Ten patients with recurrent malig‐ nant glioma were treated with BCNU implants followed by oral administration of TMZ at

tolerated. Only one patient treated with TMZ at the highest daily dose of 200 mg/m<sup>2</sup> suf‐ fered from grade III thrombocytopenia. Until now, no randomized Phase III trial has been conducted to explore the efficacy of combined therapies in comparison with either TMZ or Gliadel® alone. Several prospective and retrospective studies with small number of patients indicated that sequential treatment with Gliadel® and TMZ resulted in an incremental gain of 2–3 months in median survival (38). Although the level of clinical evidence is not high enough, the combined treatment with Gliadel® and TMZ is currently recommended as an active option for newly diagnosed and recurrent malignant gliomas by the National

The implantation of BCNU wafers is generally safe, but clinical lessons have been learned from the employment of Gliadel® for the management of malignant gliomas. The common ad‐ verse effects include healing abnormalities, seizures, and intracranial hypertension (40). Several strategies have been suggested to decrease the risks associated with BCNU implants (41). After the resection of the tumor, BCNU wafers should line up the surface of the tumor bed. Stack of the implants should be avoided because the stacking may result in an irregular release of BCNU due to the altered degradation kinetics of polymers. A large communica‐ tion between resection cavity and ventricle is the contraindication for wafer implantation. The unexpected translocation of BCNU wafers into ventricle may lead to the life‐threatening hydrocephalus. In addition, a watertight closure of the dura is critical to avoid CSF leak and decreases the risk of healing abnormalities and infection. Perioperative anti‐convulsants are necessary to prevent seizures. Since the implantation of BCNU wafers is associated with

, respectively. The combined treatment was well

recurrent malignant gliomas.

324 Neurooncology - Newer Developments

daily dose of 100, 150, and 200 mg/m<sup>2</sup>

*3.2.4. Prevention for complications*

Comprehensive Cancer Network (NCCN) guidelines (39).

Although effective, BCNU wafers are expensive for the treatment of malignant gliomas. Much attention should be paid to the financial implication of the use of BCNU wafers. Rogers and colleagues (42) conducted a cost‐utility analysis. The authors demonstrated that neurosur‐ gery with Gliadel® implantation followed by radiation therapy costs 54,500 English pounds per additional quality‐adjusted life‐year (QALY) gained in comparison with surgery com‐ bined with radiotherapy alone. Probabilistic sensitivity model revealed a <10% probability that Gliadel® would be considered as cost‐effective at a willingness‐to‐pay threshold of 30,000 English pounds per QALY. The authors concluded that Gliadel® is not cost‐effective for healthcare resources but can be considered as an alternative adoption for the dreadful disease with a shortage of effective treatments.

#### *3.2.6. Future prospects*

Gliadel® represents the first success of the interstitial chemotherapy with biodegradable polymers. With the increased understanding of glioma biology and the advances in pharma‐ ceutical technology, exploration of how to improve the efficacy of polymeric drug delivery is on the way. For example, O6 ‐alkylguanine‐DNA alkyltransferase (AGT) is a well‐known DNA repair protein, which protects tumor cells from damage through removing O6 ‐alkylguanine lesions introduced by alkylating agents such as BCNU and TMZ (43). Brain tumors, especial‐ ly malignant gliomas, are rich in AGT. The level of AGT is negatively associated with the prognosis of patients with malignant glioma, who receive BCNU therapy (44). Therefore, the inhibition of AGT is a promising strategy to reverse the resistance of glioma cells to BCNU. Quinn and colleagues (45) reported the results of a Phase II trial to test the efficacy of the combination of O6 ‐benzylguanine (O<sup>6</sup> ‐BG), an AGT inhibitor, with BCNU implantation. Fifty‐ two patients with recurrent malignant glioma were treated with infusion of O6 ‐BG and implantation of Gliadel® wafers. The median OS was 50.3 weeks, and the 1‐ and 2‐year OS was 47 and 10% respectively, which suggested the potential clinical benefit. In addition, various chemotherapeutic agents other than BCNU have been exploited to deliver through polymeric system. Preclinical studies demonstrated that many drugs such as temozolomide, paclitaxel, taxotere, and camptothecin were efficacious against gliomas through polymeric delivery (46–49). Further clinical investigation of the safety and efficacy is therefore warranted.
