Chemotherapy for brain tumors with polymer drug delivery

Handbook of Clinical Neurology, Vol. 104 (3rd series) Neuro-oncology W. Grisold and R. Soffietti, Editors # 2012 Elsevier B.V. All rights reserved

Chapter 22

Chemotherapy for brain tumors with polymer drug delivery FRANK ATTENELLO, SHAAN M. RAZA, FRANCESCO DIMECO, AND ALESSANDRO OLIVI* Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA

INTRODUCTION Local delivery of chemical agents for brain tumors has offered improved prognosis for patients with brain tumors in recent years. Agents of local delivery are highly desired for their ability to concentrate local, targeted therapeutic agents, including cytotoxic, antiangiogenic, and immunomodulatory agents in the precise location of neoplastic growth. The introduction of polymer drug delivery has offered one such form of local delivery, offering the all the benefits of general local delivery agents, including (1) controlled and (2) sustained release of chemotherapeutic agents over long periods of time, as well as (3) avoidance of the high systemic doses often related to systemic toxicities. Unlike other methods of local delivery, including catheter administration and convection-enhanced delivery (CED), polymer drugs do not rely, respectively, on mechanical function or pressure gradients.

CENTRAL NERVOUS SYSTEM DRUG DELIVERY Pharmaceutical treatment of central nervous system (CNS) pathologies poses several problems for drug delivery. The first of these lies in the multiple biological barriers to drug diffusion, from blood vessel lumen to brain parenchyma. Such barriers include the blood– brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), the blood–tumor barrier (Lesniak and Brem, 2004), drug-metabolizing enzymes in cerebral microvessels (Ghersi-Egea et al., 1995), and the action of efflux transport proteins such as multidrug resistance-associated proteins, and P-glycoprotein (P-gp) (Kusuhara and Sugiyama, 2001a). The BBB, more than 5000 times the size of the BCSFB, is the primary filter for molecules isolated from the CNS (Kusuhara and Sugiyama, 2001b). Few

molecules can cross this barrier, as molecules must be small, electrically neutral, and lipid-soluble. Unfortunately, the majority of chemotherapeutics used are large, charged, and lipophilic (Greig, 1987; Abbott and Romero, 1996). The most relevant consequence of this barrier to treatment is an increase in the systemic concentration of chemotherapeutics needed to achieve therapeutic levels at target sites in the CNS. Attempts to confront these barriers have focused on three strategies: modification of chemotherapeutic properties, disruption of the BBB before administration of therapy, and local delivery. The first of these is modification of systemic chemotherapeutic agents to cross the BBB more easily. Permeability properties (lipid solubility, size, charge) of the BBB are guidelines for specific adaptations of chemotherapeutic agents. However, lipophilic variants of the common agent carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU) – lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, CCNU) and semustine (methyl-CCNU) – have not shown significant efficacy over BCNU in treating glial tumors (Kornblith and Walker, 1988). Other variants include attaching permeable carrier agents to the chemotherapeutic agent of interest, as is done with dihydropyridine carriers (Prokai et al., 2000), and transport vectors such as modified protein or receptor-specific monoclonal antibody (Pardridge, 1999), all of which have found initial success in delivering drugs to the CNS. A second strategy to traverse the BBB is that of disrupting this barrier with agents such as mannitol or bradykinin agonist. Unfortunately, mannitol has shown limited efficacy, likely due to lack of specificity in delivery to tumor site (Warnke et al., 1987). RMP-7 has shown promise, selectively increasing carboplatin uptake in brain tumors (Elliott et al., 1996). A final strategy is to circumvent the BBB entirely, with methods of delivering local doses of chemotherapeutic in a sustained and continual fashion with an

*Correspondence to: Alessandro Olivi, MD, The Johns Hopkins Hospital Department of Neurosurgery, Cancer Research Building II, 1550 Orleans Street, Room 247, Baltimore, MD 21231. USA. Tel: 410-955-0703, Fax: 410-614-9877, E-mail: [email protected]

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implanted substance. This system will avoid large, undesired systemic doses of chemotherapy while concentrating treatment on the specific area of interest. This method is particularly useful, as approximately 80% of glioma recurrences occur within 2 cm of the original resection cavity. Local delivery systems come in three categories: catheter administration, CED, and controlled-release polymers loaded with agents (Figure 22.1) Catheter administration is essentially use of an installed pump to infuse agent, with restrictions including potential mechanical failure, tissue debris, clot obstruction, and infection. CED is a newer system that facilitates diffusion to brain parenchyma using pressure gradients (Laske et al., 1997; Chen et al., 1999; Hamilton et al., 2001; Degen et al., 2003). Clinical studies using paclitaxel (Mardor et al., 2001; Lidar et al., 2004), immunotoxins (Sampson et al., 2003; Weber et al., 2003), and viral vectors for gene therapy (Ren et al., 2003; Voges et al., 2003) have shown the method to be safe. Catheter administration and CED are described in greater detail in other chapters of this volume.

Biocompatible polymers with sustained and controlled release of chemotherapeutics are the focus of this section. This delivery system is subdivided into two subtypes: (1) biodegradable – polymers that break down as they release their therapeutic, leaving nothing behind; and (2) nonbiodegradable – polymers that remain intact while releasing their associated agent.

POLYMER DEVELOPMENT Sustained and predictable release of macromolecules by polymer was first reported in 1976 by Langer and Folkman. Ethylene vinyl acetate (EVAc) copolymer, a nonbiodegradable polymer, was used for its ability to hold molecules within micropore spaces, much like a sponge, with agent diffusing from the polymer at a rate dependent on the agent being released. Factors influencing rate of diffusion include electrostatic charge, weight, and lipid solubility. This early nonbiodegradable polymer model has now found widespread use including in contraception, glaucoma, dental care, insulin therapy, asthma,

Targeted therapy across the blood-brain barrier

Catheter 2 Blood vessels in brain

Brain parenchyma

Astrocytes

Tumor

Endothelial cell

Polymer system (Gliadel TM)

1 4 Pericyte

Basement membrane

Microchip

Eosinophil monocyte

Tight junctions

H2O Lymphocyte

3

1

Use of polymers, microchips

2

Interstitial delivery of drugs via catheters

3

Temporary disruption of BBB

4

Enhancing drug permeability through BBB

H2O

Drug Direction of drug delivery/ osmosis of H2O

Fig. 22.1. View of varying methods of local delivery of chemotherapeutic agents in the central nervous system. BBB, blood– brain barrier. (Reproduced from Raza et al. (2005), with permission. # Informa Healthcare.)

CHEMOTHERAPY FOR BRAIN TUMORS WITH POLYMER DRUG DELIVERY and chemotherapy for CNS disorders. However, because EVAc is an inert polymer matrix requiring subsequent neurosurgical removal, it has never been cleared for use in the brain (Langer, 1984). In addition, over long periods, the release rate of EVAc copolymer decreases, changing the kinetic profile from zero to first order. Biodegradable polymers brought a newer generation of controlled-release polymer, offering diffusion of drug during concomitant degradation of the polymer, with desirable zero-order release kinetics. Among the first of these biodegradable polymers was poly-lactide-coglycolide acid (PLGA), a compound used in development of absorbable sutures (Frazza and Schmitt, 1971; Brady et al., 1973), with early studies showing biocompatibility in the rat brain (Lillehei et al., 1996; Kong et al., 1997). The polymer is composed of lactic acid and glycolic acid, with release rate of drug varying with concentrations of these two components (Lewis, 1990). This early polymer agent has been used extensively for delivery of steroids, anti-inflammatory agents, narcotic antagonists, antibiotics, anesthetics, and antineoplastic agents. Reduction of opsonization and elimination by the immune system has also been shown with this system. Nonuniform, bulk erosion of the polymer, however, can result in drug release in an irregular fashion, causing limited tissue exposure or toxicities (Brem and Langer, 1996), and limiting the clinical effectiveness of the compound. A second generation of biodegradable polymer, polyanhydride poly(1,3-bis(carboxyphenoxy)propane)co-sebacic-acid (PCPP:SA), was introduced in 1985 by Leong et al. (1985). The new compound provided the several features necessary for clinical implementation of controlled-release polymers: ● ● ●

●

●

●

hydrophobicity, shielding the drug from aqueous media which affects the short half-life zero-order steady kinetic drug release over prolonged periods an easy method of release rate management with alteration of components CPP:SA in a ratio: a 1-mm disk of pure PCPP degrades in approximately 3 years, but a PCPP:SA ratio of 20% CPP and 80% SA has a biological life of 3 weeks (Chasin et al., 1990) versatile shape: wafers, rods, sheets, and microspheres can be made (Leong et al., 1986; Bindschaedler et al., 1988; Howard et al., 1989) polymer degradation during drug release – as a result of polymer bonds hydrolyzed in aqueous environments, not requiring subsequent polymer removal biocompatibility, being not mutagenic, cytotoxic, or teratogenic, with no effects on cell growth (Brem et al., 1989; Tamargo et al., 1989).

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PCPP:SA safety was also measured against two common implanted neurosurgical compounds, Surgicel and Gelfoam, both agents commonly used for hemostasis in surgery. Results showed nontoxicity in rat brain with inflammation of 5 weeks, comparable to both Surgicel and Gelfoam. Importantly, functional outcomes following implantation of PCPP:SA into the frontal lobes of cynomalgus monkeys showed no changes in behavior or neurological deficits (Brem et al., 1994). PCPP:SA is now the polymer of choice for delivery of nitrosoureas in the only chemotherapeutic agent approved by the Food and Drug Administration (FDA) for local delivery in brain tumor treatment, GliadelW. Fatty acid dimer:sebacic acid (FAD:SA) copolymer is a newer polyanhydride polymer, improving on capabilities of PCPP:SA by delivering hydrophilic compounds more efficiently (Shieh et al., 1994). FAD:SA retains essential abilities to provide drug shielding, zero-order release kinetics, biodegradability, maleable shape, and adjustable release kinetics by ratio of comprising monomers (Shikani et al., 1994; Judy et al., 1995). Microspheres are another field of active research (Menei et al., 1994), offering delivery of microparticles, ranging from 2 to 50 mm in diameter. Delivery is typically in suspension by needle stereotaxy, with no significant damage to surrounding tissue. Ideally, this polymer formulation avoids the need for surgical implantation of large polymers, allowing for significant ease in polymer reimplantation if necessary. Placement of microspheres is possible in precise and, importantly, functional areas of brain with no damage on insertion. PLGA, discussed above, has been the primary component of tested microspheres, showing compatibility in this form of delivery with brain tissue (Menei et al., 1993). PLGA microspheres have been studied extensively in local delivery of 5-fluorouracil (5-FU) and mitoxantrone. Unfortunately, microsphere encapsulation of BCNU, the most commonly studied polymer-released chemotherapeutic drug, showed significant neurotoxicity in a rat model, discouraging the use of BCNU microspheres (Benoit et al., 2000). Other surgical materials have also been tested for ability to deliver local chemotherapeutic agents to brain tumors, including fibrin glue (Hirakawa et al., 1995), gelatin sponges (Ringkjob, 1968), Surgicel, polymethylmethacrylate (Rama et al., 1987), and Silastic tubing (Oda et al., 1979), all showing varying results.

GLIADELW Development W

Gliadel (3.8% BCNU; Guilford Pharmaceuticals, Baltimore, MD, USA) represents the first successful use of polymer-delivered chemotherapy in a clinical setting.

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Initial studies showed feasibility, safety, biodistribution, and efficacy. Clinical trials for safety, followed by efficacy, were also successful, leading to current use of GliadelW polymer, with 3.85% carmustine (BCNU) in PCPP:SA (20:80 formulation).

CHEMOTHERAPEUTIC

SELECTION/INFORMATION

Carmustine (BCNU) exerts cytotoxic effect by means of alkylation of the nitrogenous bases of DNA. It has a low molecular weight and low lipid solubility, compatible with little resistance to passage by the BBB (Walker et al., 1980). Because BCNU is lipophilic and, therefore, delivered by systemic routes with more ease than other chemotherapeutic agents, its use as the first selected agent for local delivery is often questioned. BCNU was chosen primarily because of the wealth of data from previous studies. The use of polymer for delivery, as well as large local CNS concentrations of drug, in contrast, were not well studied, with studies desiring minimization of unknowns (Brem et al., 1991). In addition, BCNU has doselimiting side-effects of bone marrow suppression and pulmonary fibrosis, as well as a relatively short half-life (< 15 min), limiting systemic delivery. Finally, systemic administration of BCNU was not associated with a significant prolongation of the survival of patients with brain tumors (Walker et al., 1980). Local delivery of BCNU thus offered the opportunity to decrease toxicity and increase the efficacy of a well-studied compound.

PRECLINICAL SAFETY

AND EFFICACY

Toxicity studies of BCNU polymer and radiation in primates showed no general or neurological clinical effects (Brem et al., 1994). Local edema was found on imaging, but resolved over time. Preclinical studies on efficacy in rabbit brain showed adequate distribution in cerebral parenchyma as well as prolongation of therapeutic levels of BCNU in the brain (Grossman et al., 1992). Primate studies with 20% PCPP:SA further showed tumoricidal concentrations of BCNU at 2.0 cm from the implantation site at 7 days, and 1.3 cm up to 30 days following administration (Grossman et al., 1992). Most importantly, studies of the intracranial 9L glioma in a rat model showed a 5.4–7.3-fold increase in the median survival of subjects over controls, compared with a 2.4-fold increased survival versus controls with systemic BCNU delivery (Tamargo et al., 1993). More impressively, there was a 30% long-term survival rate in polymer-treated rats, compared with no long-term survivors with systemic chemotherapy. At autopsy, no remaining tumor could be found in a third of animals treated with GliadelW.

CLINICAL

TRIALS OF

GLIADELW

The first clinical trials in 1987 for 20:80 PCPP:SA polymers loaded with BCNU addressed safety. Patients in the multi-institutional phase I–II trial were treated for very specific tumor pathologies (Brem et al., 1991). Eligible patients had unifocal, unilateral, malignant gliomas requiring debulking of recurrent tumor, after prior radiotherapy, and with or without prior chemotherapy. Patients also had a Karnofsky score of at least 60. Treatment consisted of debulking with implantation of up to eight wafers at the time of resection (Figure 22.2). Treatment of 21 patients was undertaken with 1.93%, 3.85%, and 6.35% BCNU loading. Patients showed no systemic effects or local adverse reactions to polymer on follow-up. Computed tomography (CT) showed thin, contrast-enhancing signal surrounding the area of wafer implantation in 13 of the 21 patients for up to 2 weeks postoperatively, although no correlation was seen between CT signal and neurological symptoms. Median survival was 46 weeks after polymer implantation and 87 weeks after initial diagnosis. A phase III trial was conducted comparing 3.8% BCNU-loaded polymer with empty polymer. Some 27 centers involving 222 patients were enrolled to determine the effects of loaded polymer on survival (Brem et al., 1995a). Selection criteria and polymer placement for patients were the same as those used for the phase I/II study, although no chemotherapy was permitted for 4 weeks preoperatively, and no nitrosoureas were allowed for 6 weeks prior to polymer implantation. Baseline characteristics showed no significant differences in histology, age, or other variables between treatment groups. Results showed a median survival of 31 versus 23 weeks

Fig. 22.2. Multiple GliadelW wafers secure in the resection cavity. Up to eight wafers can be placed at one time. (Reproduced from Raza et al. (2005), with permission. # Informa Healthcare.)

CHEMOTHERAPY FOR BRAIN TUMORS WITH POLYMER DRUG DELIVERY 1.0 0.9

Probability of survival

0.8 0.7 0.6 0.5 Carmustine polymer

0.4 0.3 0.2 0.1

Placebo polymer

0 0

20

40

60

80 100 120 140 160 180 200 Time (weeks)

Fig. 22.3. Kaplan–Meier survival curve for patients who received BCNU-loaded polymers versus controls during surgery for recurrent malignant glioma after adjustment for prognostic factors. (Reproduced from Brem et al. (1995b). # Elsevier.)

for BCNU and blank polymer respectively (Figure 22.3). Patients with glioblastoma (GBM) had a 50% increase in 6-month survival when treated with BCNU polymers (60% versus 47% survival rate at 6 months). Again, no adverse effects or systemic toxicity were seen with polymer use.

GLIADELW

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32 patients with primary malignant glioma divided equally between an active treatment group (BCNU polymer) and a placebo group, followed by RT. Results showed a median survival of 58.1 weeks for patients in treatment versus 39.9 weeks for patients receiving placebo ( p ¼ 0.012). In patients with GBM, survival was 53.3 versus 39.9 weeks for placebo ( p ¼ 0.008). At the conclusion of the study at 2 years, 6 patients were alive, of whom 5 were in the treatment group. A larger phase III trial was conducted in Europe with much of 240 patients along the same parameters (Westphal et al., 2003). Groups were again similar for KPS, age, sex, and tumor histology. Median survival was 13.9 months in the treatment group versus 11.6 months for placebo ( p ¼ 0.03). Adjusting for factors affecting survival, treatment showed a 27% reduction in risk of death ( p ¼ 0.03). Subsequent analysis at 2 and 3 years showed a significant survival advantage, with a 2-year survival rate of 15.8% with BCNU and 8.3% without BCNU, and 3-year survival of 9.2% and 1.7% respectively (Westphal et al., 2006). Two of surviving patients at 3 years had a diagnosis of GBM; both were in the BCNU treatment group.

CURRENT

USE

GliadelW was approved in 1996 by the FDA as an adjunct to surgery in the treatment of recurrent GBM. As initial therapy of patients with glioblastoma, GliadelW was approved in 2003 for unilateral/unifocal gliomas.

Efficacy and safety in early clinical use IN INITIAL TUMOR TREATMENT

A general rule of oncology if that treatments effective for recurrence are often more effective as initial therapy (Ettinger, 1990). Phase I/II trials were conducted using 3.8% BCNU-loaded polymers as initial treatment for malignant brain tumor in 22 patients. In addition, with previous primate studies showing no adverse effects of adjunctive radiation treatment with polymer placement, use of external-beam radiation therapy postoperatively with polymer placement was assessed and standardized in all patients (Brem et al., 1995b). Patient inclusion criteria included a unilateral tumor focus of at least 1 cm3, age over 18 years, Karnofsky Performance Status (KPS)
60, and intraoperative diagnosis of malignant glioma. Radiation therapy (RT) was provided postoperatively and chemotherapy was not given for the first 6 months. Results showed both efficacy and safety, with a median survival of 42 weeks, and no significant toxicity when compared to treatment with standard RT without polymer. Phase III trials were therefore initiated with placebocontrolled, randomized, double-blinded studies (Valtonen et al., 1997) in Finland and Norway. The study consisted of

Early retrospective studies analyzed patients treated from 1990 to 1999 at Johns Hopkins Hospital using GliadelW implantation prior to RT in newly diagnosed tumors (Kleinberg et al., 2004). The 45 patients in this group were evaluated for survival, postoperative infection, and pathology at reoperation, with toxicities measured 1 month after RT completion. Toxicities during and after 1 month of RT were evaluated among a 28-patient subset that received RT at Johns Hopkins. Median survival for patients with GBM was 12.8 months. Results showed that postoperative infection or need for reoperation within 30 days was uncommon following GliadelW placement. Neurological symptoms, including seizures, headache, lethargy, weakness, dysphasia, nausea, and vomiting, were seen in 19% of patients during RT, all of whom responded to increased steroids and/or anticonvulsants. A further 30% of patients showed neurological symptoms during steroid taper, all of whom responded to an increased steroid dosage. One-third of patients required reoperation or biopsy for new contrastenhancing lesions following the original GliadelW placement, with 33% of this subset having only necrosis

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with no evidence of active tumor on pathology. GliadelW was concluded to be both safe and effective in treatment of malignant glioma with adjuvant RT. The authors suggested careful monitoring of postoperative steroid taper, and identified the possibility that new contrastenhancing lesions postoperatively were tumor necrosis rather than new tumor.

CLINICAL LESSONS

LEARNED

Lawson et al. (2007) reviewed the clinical data and 18 years of GliadelW experience in the treatment of malignant gliomas. Variables of note included maximal tumor debulking before implantation of polymer, avoidance of GliadelW implantation in patients with large ventricular openings due to potential risk of polymer dislodgement and resulting obstructive hydrocephalus, and watertight closure of dura to reduce the risk of cerebrospinal fluid (CSF) leak or infection. In addition, prophylactic use of anticonvulsants in patients with a history of seizures was suggested by analysis of pertinent studies conducted by a practice parameters committee (Glantz et al., 2000). Further recommendations suggested the use of dexamethasone to prevent edema from the continuous release of chemotherapeutic from GliadelW. Dexamethasone, 4 mg intravenously or orally every 6 hours for 2–3 weeks, with close glucose monitoring, was suggested before tapering in patients with lack of neurological deficits. In patients with neurological deficits, an increase in steroid dosage up to 20 mg every 4 hours was suggested (Renaudin et al., 1973).

ADVANCES IN

DOSE ESCALATION

Studies by Sipos et al. (1997) examined increased levels of BCNU in polymer as well as altering the polymer makeup (CPP:SA ratio), theoretically prolonging the half-life of polymer in vivo. Twenty percent BCNU polymer had the safest and most effective profile, with a 75% long-term survival rate (> 120 days), 40-fold longer than that for controls. Primate studies initially showed few signs of toxicity from 20% BCNU polymers (Sipos et al., 1997). One of four animals showed hematoma and neurological changes, whereas the other three showed no toxicity. Brain magnetic resonance imaging at 150 days showed no difference from normal postoperative changes. A separate study (Fung et al., 1998) analyzed BCNU tissue concentration by thin layer chromatography within the implantation region. The surrounding region showed significant BCNU concentrations of 0.1–7.5 mmol/L within a range of 2 cm of implantation, a range within which 80% of treated gliomas recur. Local concentrations of BCNU when using polymer compared with systemic

administration exceeded a ratio of 4–1200:1 (depending on distance from implantation site). Human studies to determine the maximum tolerated dose of BCNU in polymers, when comparing loading doses of 6.5%, 10%, 14.5%, 20%, and 28% by weight loading doses, have supported the use of a 20% loading dose (Olivi et al., 2003). Toxicity consisting of severe brain edema and seizures, was seen in 3/4 in the 28% group, while 9 additional patients were added to the 20% dose showing safety. Phase III trials are now planned to evaluate the highest tolerated loading dose.

ADVANCES IN POLYMER-BASED CHEMOTHERAPY Metastases Current therapy for brain metastases consists of stereotactic radiosurgery for tumor removal with or without the addition of whole-brain radiation treatment (WBRT). Single brain metastases may respond to surgical excision and radiation (Patchell et al., 1990), but a significant number of patients show tumor recurrence at the original site of resection (Sawaya et al., 1996). Suboptimal treatment of metastatic brain tumors has inspired work investigating the use of local polymer-based chemotherapy. Ewend and colleagues (1996, 1998) have performed multiple studies on a rat model of metastatic brain lesions. Investigation focused on the five primary tumors that metastasize to brain most commonly: lung, renal cell, colon, melanoma, and colon carcinomas. Chemotherapeutic agents tested were BCNU, carboplatin, and campothecin. Treatments were evaluated in the following groups: chemotherapy, RT, and chemotherapy þ RT. Results showed varied responses of different tumor types to different chemotherapeutic agents, although the overall result showed prolonged survival consistently in two scenarios: (1) combination of RT and chemotherapy when compared to either modality alone; and (2) use of BCNU over other chemotherapeutic agents. A second significant finding showed an element of toxicity that must be accounted for when combining chemotherapy with RT. Although 20% BCNU polymers show no significant toxicity, the addition of RT requires a loading dose of 10% BCNU in polymers to ensure lack of toxicity. Early phase I and II trials in metastatic brain tumor treatment have shown promising results using GliadelW and surgery either with or without adjuvant RT (Brem et al., 2004; Golden et al., 2004; Ewend et al., 2007). In the three trials, 100% local control of newly diagnosed brain metastases was seen.

CHEMOTHERAPY FOR BRAIN TUMORS WITH POLYMER DRUG DELIVERY

Combination of local BCNU with systemic agents O6-BENZYLGUANINE-DNA ALKYL

TRANSFERASE

6

O -benzylguanine-DNA alkyl transferase (AGT) is a DNA repair enzyme that is often seen in brain tumors to provide resistance to chemotherapy, and BCNU in particular. O6-benzylguanine (O6-BG) irreversibly inactivates AGT (Pegg et al., 1993), thus allowing BCNU-mediated damage to occur to local tumor targets. Indeed, work showing the addition of O6-benzylguanine to BCNU with intraperitoneal injections show increased effectiveness in tumor size reduction in rat models (Friedman et al., 2002). Administration of polymer BCNU and systemic O6BG in the rat F98 glioma model has shown synergistic efficacy, with median survival in combined treatment of 34 days, compared with 25 days for treatment with BCNU alone ( p ¼ 0.0001) and 22 days for O6-BG treatment alone (Rhines et al., 2000). Phase I clinical trials have now shown the safety of systemic O6-BG in patients with malignant glioma, both with and without prior placement of BCNU wafers (Weingart et al., 2007). No increase in toxicity with addition of O6-BG to BCNU wafers was seen. Clinical trials of the efficacy of this combination are ongoing.

Platinum drugs Platinum drugs exert cytotoxic effects on tumors by creating DNA interstrand crosslinks, providing great therapeutic potential for CNS tumors including malignant gliomas, medulloblastomas, primitive neuroectodermal tumors, optic pathway gliomas, brainstem gliomas, and ependymomas (Gaynon et al., 1990). Among platinum drugs, carboplatin has the most evidence of efficacy (Doz et al., 1991) and reduced neurotoxicity (Olivi et al., 1993) in the treatment of CNS tumors. Intravenous carboplatin was administered 3–4 days after tumor resection and local delivery of GliadelW in a phase I clinical trial (Limentani et al., 2005). Results among 16 patients with high-grade glioma show no grade 3 or 4 toxicities.

Other antitumor agents for local delivery The safety and efficacy profile of BCNU-loaded polymers, providing local chemotherapy doses without systemic toxicity or side-effects, has sparked interest in the delivery of multiple different chemotherapeutic agents via polymer.

Taxol Paclitaxel (Taxol) is a naturally occurring microtubule stabilizer that has shown tumoricidal activity in vitro in glioblastoma cell cultures and human tumors (Cahan

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et al., 1994). It is an ideal candidate for local delivery, with poor BBB penetration and systemic toxicities at ideal CNS therapeutic doses, and little effect at maximum tolerated doses (Klecker et al., 1992). Early Taxol studies used concentrations of 20% and 40% PCPP:SA polymers, showing Taxol in tumoricidal concentrations at 5 cm from the implantation site for 30 days after implantation. Survival with 20% Taxol polymer in a 9L gliosarcoma rat model increased by up to 3-fold following implantation (median survival postimplant of 61.5 versus 19.5 days). Complications in release profile, with toxicity of a unexpected biphasic release, have limited its use. Microspheres consisting of biodegradable polilactofate (PaclimerW delivery system; Guilford Pharmaceuticals) have thus been tested for Taxol delivery. Safety and prolonged survival have shown with 10% PaclimerW in rat models with 9L gliosarcomas. More recent studies have shown safety in intracranial implantation in a dog model, with minimal to no Taxol levels in blood or CSF, and no signs of neurological toxicity (Pradilla et al., 2006). Although CED has also been shown to deliver local doses of Taxol with antitumor activity, significant treatment-associated complications were noted (Lidar et al., 2004). Complications included transient chemical meningitis, infection, and transient neurological deterioration. Docetaxel (Taxotere), a novel hemisynthetic cancer agent that is structurally related to paclitaxel, has also shown clinical efficacy against several tumors (Glantz et al., 1995), as well as functioning as a potent radiosensitizer against malignant gliomas (Pradier et al., 2001). Again, toxicities with systemic administration have inspired studies of interstitial treatment with docetaxel-loaded polymer CPP:SA in rat models with 9L gliosarcomas (Koukourakis et al., 1999). Results show a median survival of 39.1 days for docetaxel polymer versus 22.5 days in controls. BCNU-loaded CPP:SA combined with docetaxel-loaded CPP:SA was assessed in the same assay, with a median survival of 39.3 days with BCNU alone and 54.9 days with both BCNU and docetaxel.

Alkylating agents: 4-hydroxyperoxycyclophosphamide and temozolomide Hydroxyperoxycyclophosphamide (4-HC) is the active form of the alkylating agent, cyclophosphamide (CytoxanW; Bristol-Myers Squibb). Cyclophosphamide has shown success in the treatment of multiple myeloma (Reece et al., 1993), myeloid leukemia (Lemoli et al., 1991), and breast cancer. However, like other chemotherapeutic agents discussed, 4-HC shows poor BBB penetration. In addition, the hepatic P450 system is

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needed for conversion to the active form of 4-HC. Polymer delivery systems have circumvented these difficulties, loading the 4-HC molecule directly onto FAD:SA polymer . The FAD:SA polymer has shown favorable pharmacokinetic profiles and adequate distribution, both in vivo and in vitro (Pradier et al., 2001). Studies in a rat model showed maximum efficacy and minimum toxicity at a concentration of 20% 4-HC/FAD:SA, with a median survival of 77 days versus 14 days in controls, and a 40% survival rate beyond 80 days. The outlook for this agent is optimistic, with efficacy very favorable compared with other tumor chemotherapeutic agents (Recht et al., 1998). Temozolomide (TMZ, TemodarW) is an imidazotetrazine second-generation alkylating agent. As an alternative, or in some instances as an addition, to GliadelW wafer plus RT, Temodar is available orally for the treatment of patients with GBM. Due to myelosuppressive side-effects, however, oral dosage regimens are limited (Cohen et al., 2005). Direct administration by CPP:SA polymer in the 9L rat gliosarcoma model showed prolongation of survival, with oral TMZ showing a median survival of 22 days, with 28 days for single TMZ polymer, and 92 days for two TMZ polymer placement in the cavity (Brem et al., 2007).

5-Fluorouracil 5-FU is a thymidine analog metabolized to 5-fluoro20 deoxyuridine monophosphate and 5-fluorouridine triphosphate within both tumor and nontumor cells. Metabolites primarily interrupt thymidylate synthesis, blocking DNA synthesis. In addition, as a pyramidine analog, 5-FU is converted into a molecule capable of interrupting DNA and RNA synthesis by incorporation into replicating strands. Poor BBB penetration profile causes significant toxicities (myelosuppression and gastrointestinal mucosal injury) when administered systemically to therapeutic CNS doses. When incorporated into PLGA microspheres, 5-FU shows a reproducible, sustained, pharmacokinetic profile (Boisdron-Celle et al., 1995). Safety studies in the C6 and F98 rat glioma models showed no toxicity and significantly increased animal survival (Menei et al., 1996; Lemaire et al., 2001; Fournier et al., 2003a, b). Clinical studies in patients evaluated the implantation of 5-FU microspheres in 8 patients following neurosurgical debulking of newly diagnosed malignant gliomas and RT. Results show 5-FU concentrations in the CSF up to 1 month after surgery, with a median survival of 98 weeks (Menei et al., 1999). When treatment of newly diagnosed gliomas was undertaken stereotactically in 10 patients, median survival was 40 weeks with no systemic or local toxicity. Unfortunately, early phase

II trials of 5-FU-loaded PLGA microspheres showed no significant increase in the survival of patients with high-grade glioma (Menei et al., 2005).

Doxorubicin Doxorubicin (Adriamycin), a widely used anthracycline antibiotic for tumor treatment, exerts its action through inhibition of topoisomerase II and subsequent DNA synthesis. Common use is in treatment for Hodgkin’s disease, breast cancer, lung cancer, soft tissue sarcomas, and multiple myeloma. Studies attempting to improve the efficacy of doxorubicin by local polymer administration have tested PCPP:SA polymers containing 3% and 5% doxorubicin in mice with 9L gliosarcoma, showing a median survival of 21 days in the control group, 34 days ( p < 0.01) with 3% doxorubicin, and 45 days ( p < 0.0001) with 5% doxorubicin (Lesniak et al., 2005). Synergistic effects have also been seen when combining locally delivered immunotherapy (interleukin-2) with local doxorubicin in 9L gliosarcoma in rats, as discussed in detail below (Hsu et al., 2005). Mitoxantrone, another anthracycline antineoplastic agent, shows a similar mechanism and tumor treatment profile. This agent is also approved for use in hepatic and ovarian cancers. Early studies incorporating mitoxantrone into PCPP:SA polymers in the treatment of rat 9L gliosarcoma showed safety and efficacy, with 10% loaded polymers giving a median survival of 50 days, compared with 19 days in controls. Further study has supported the efficacy of mitoxantrone against 9L rat gliosarcoma when loaded onto EVAc polymer, with a mean survival of 33 days in treated animals and 13.8 days in controls (Saini et al., 2004). Rats given a direct intraperitoneal injection of mitoxantrone died 4 days after injection. Studies incorporating mitoxantrone into PLGA microspheres have further evaluated intracranial delivery, characterizing the drug effect on rat glioma (RG2) tumor size over time (Yemisci et al., 2006). Tumor in control rats reached a mean size of 76 and 107 mm on days 15 and 35, respectively. Use of mitoxantrone microspheres 7 days after implantation of tumor resulted in a mean tumor size of 17 and 23 mm on days 15 and 35. Concurrent implantation of tumor and microspheres showed no tumor growth.

Platinum drugs Although carboplatin has shown significant efficacy in the treatment of CNS tumors, predominant hematological toxicities under systemic administration with poor BBB penetration (Hannigan et al., 1993) have inspired studies delivering carboplatin via FAD:SA and PCPP: SA polymers with sustained release (Olivi et al., 1996).

CHEMOTHERAPY FOR BRAIN TUMORS WITH POLYMER DRUG DELIVERY PLG microspheres have also shown efficacy and safety, with significant prolongation of survival in RG2 rat gliomas (Emerich et al., 2002).

Camptothecin Camptothecin, a Chinese tree derivative, affects topoisomerase I, allowing DNA cleavage, but inhibiting subsequent ligation, and resulting in DNA strand breaks. The use of camptothecin systemically is also limited by significant toxicity (Slichenmyer et al., 1993). Camptothecin does show potent antiglioma activity in vitro, making it another popular candidate for polymer delivery. Sodium camptothecin loaded onto 50% EVAc polymers was tested in the 9L gliosarcoma rat model, and resulted in a significant increase in survival. Median survival was 19 days in control rats and more than 120 days with camptothecin polymers ( p < 0.001). Direct intratumoral injection of the camptothecin without polymer showed no increase in survival compared with controls. Studies incorporating camptothecin into 50% PCPP: SA polymers for the treatment of 9L gliosarcoma in rats showed safety and efficacy, with a median survival of 69 days in animals treated with camptothecin and 17 days in controls (Storm et al., 2002). Administration of intracranial camptothecin by polymer under similar conditions, with the addition of systemic BCNU, showed a significant increase in survival compared with camptothecin alone (Storm et al., 2004).

Proteasome inhibitors Lactacystin, a microbial product, shows antineoplastic activity based on inhibition of the ubiquitin proteasome proteolysis pathway (Fenteany et al., 1995), which controls cell turnover (An et al., 1998). To bypass systemic toxicity generated by concentrations necessary to penetrate the CNS, PCPP:SA polymers were loaded with lactacystin in the 9L gliosarcoma rat model; neither local nor systemic toxicity was observed below a drug concentration of 2% (Legnani et al., 2006). In addition, 1.0%, 1.3%, and 1.5% lactacystin all showed significant prolongation of survival when implanted simultaneously with tumor. Unfortunately, however, no significant increase in survival was seen when lactacystin was implanted 5 days after tumor implantation.

Immunomodulators With identification and cloning of genes encoding cytokines, another promising strategy has arisen for brain tumor therapy through immunomodulators (Gansbacher et al., 1990; Fine, 1995). The mechanism of action involves activation of host immune T-cell response and

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modulation to target tumor cells. Cytokines, including interleukins (ILs), interferons (IFNs), and colonystimulating factors, initiate the immune reaction. These are secreted by white blood cells or administered exogenously. In vivo activity has been shown by cytokines, such as IL-2, that do not exert direct cytotoxicity to neoplastic cells, instead exerting action by drawing a heavy local cytokine-specific immune response (Pardoll, 1995). However, much like considerations in BCNU, high systemic doses of IL-2 are necessary for adequate concentrations, resulting in considerable toxicity (Rosenberg et al., 1989). Local delivery of IL-2 is thus another highly active area of polymer-based delivery research. Initial work has shown successful delivery of genetically modified cells, releasing IL-2 in a paracrine fashion for the treatment of established brain tumors (Thompson et al., 1996; Ewend et al., 2000).

LOCAL POLYMER DELIVERY OF INTERLEUKIN-2 Sampath et al. (1999) reported on treatment effects during use of paracrine immunotherapy using nonreplicating, genetically engineered, tumor cells producing IL-2 in addition to standard implantation of local chemotherapy (10% BCNU-PCPP:SA polymer) in rat models with lethal aliquots of B16-F10 tumor cells. Results showed significant synergistic effects of cytokines with polymer therapy versus polymer or cytokine alone: animals receiving combined treatment showed chronic inflammation with rare degenerating tumor cells at day 14 and resolved inflammation and no tumor cells at day 72. More recent studies by Rhines et al. (2003) have shown synergistic tumor effects when using BCNU polymer combined with a microsphere system for delivery of IL-2 in the treatment of 9L gliosarcoma in rats. Median survival was 28 days following treatment with a combination of cytokine and 3.8% BCNU delivered locally, whereas survival was 45 days with combined cytokine and 10% BCNU. Use of cytokines, 3.8% BCNU and 10% BCNU alone resulted in median survival of 24, 24, and 32.5 days, respectively. Hsu et al. (2005) combined another chemotherapeutic, Adriamycin (ADR), delivered via biodegradable polymers, with IL-2 via polymer microspheres, in the treatment of 9L gliosarcomas in rats. Animals receiving the IL-2/5% ADR combination had a median survival of 53 days, showing significantly improved survival in comparison with ADR or IL-2 alone (median survival 30 and 39 days, respectively). Compared with control animals treated with empty microspheres and blank polymer, animals receiving empty microspheres and ADR polymer ( p < 0.0004),

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IL-2 MS and blank polymer ( p <0.0005), and IL-2 MS combined with ADR polymer ( p <0.0000002) all showed a statistically significant improvement in survival. In addition, animals receiving the IL-2/ADR combination had significantly extended survival compared with either ADR or IL-2 alone ( p < 0.000003 and p < 0.0004, respectively).

LOCAL DELIVERY OF ANGIOGENESIS INHIBITORS Angiogenesis is essential for both the survival and proliferation of tumors. Initial avascular tumor growth is a slow process dependent on simple diffusion for delivery of nutrients (Knighton et al., 1977). Release of diffusible angiogenic factors activates nearby endothelial cells to proliferate and migrate, leading to a vascularized tumor able to expand exponentially. GBM shows extensive angiogenesis activity, drawing interest in antiangiogenic activity for treatment. Early work with cartilage, an avascular tissue that loses its blood vessels early in embryonic development, inspired work by Brem and Folkman (1975), who demonstrated the existence of a diffusible molecule, now known to be troponin I (Moses et al. 1999), which inhibits angiogenesis in cartilage. The molecule was isolated and purified, after which it was incorporated into EVAc polymers and tested in a rabbit cornea angiogenesis assay (Langer et al., 1976), the first reported use of polymers for antiangiogenic molecule delivery. Subsequent work has shown successful incorporation of multiple antiangiogenesis molecules into polymer. Tetrahydrocortisol, a potent angiostatic steroid, exerts potent antitumor activity when coupled with heparin (Lee et al., 1990). Work has shown inhibition of carcinoma-induced angiogenesis in a rabbit cornea angiogenesis assay (Tamargo et al., 1990). Incorporation of heparin and tetrahydrocortisol into PCPP:SA polymers in the same study showed inhibition of 9L tumors in the flank of rats. Minocycline, a lipid-soluble tetracycline, shows anticollagenase activity and thus functioned as a potent antiangiogenic agent when studied in a VX2 carcinoma cornea assay (Tamargo et al., 1991). Local implantation of both minocycline and BCNU using controlled-release polymer has shown significantly increased survival in rats with 9L gliosarcoma (Weingart et al., 1995). Recent studies have also focused on endostatin, an antiangiogenic agent that exerts its action through inhibition of endothelial cell formation and inhibiting matrix metalloproteinase-2 activity. Synthetic endostatin fragment (EF) was loaded onto PCPP:SA polymers and implanted into the 9L gliosarcoma rat model (Pradilla et al., 2005). Although no significant prolongation of survival was seen with the EF polymer, combination with

systemic BCNU did show significant prolongation of survival with synergistic efficacy over control treatment. A significant decrease was seen in tumor angiogenesis, however, when the rat corneal angiogenesis assay was used in the same study.

FUTURE DIRECTIONS Nanospheres Circulating nanospheres, comprised of poly (hexadecylcyanoacrylate) (PEG-PHDCA), and as small as 100 nm in diameter, have become more popular in recent work for their ability not only to provide a carrier for sustained release of drug, but also to penetrate the discontinuities in tumor microvasculature, particularly in brain malignancies (Vajkoczy and Menger, 2000). Resulting drug concentrations have shown accumulation more focally within tumor interstitium (Brigger et al., 2002), possessing affinity for healthy BBB, and circumvention of the common drug-resistance transporter, P-glycoprotein efflux system. Unfortunately, however, doxorubicin-loaded nanospheres studied in a 9L tumor rat model showed no significant survival when compared to free doxorubicin (Brigger et al., 2004), as drug-loaded polymer was not able to accumulate in tumor as efficiently as free polymer.

CONCLUSION Polymer-based therapy provides a safe and effective method of tumor treatment, showing a modest, yet promising, increase in the survival of patients with current clinical GliadelW use. Great promise can be seen on the horizon, with multiple preclinical studies showing safety and efficacy of polymer use for delivery of a myriad of chemotherapeutic agents, either as single agents or in combination. In addition, early work has shown the feasibility of escalation in BCNU polymer levels greater than current levels of GliadelW, as well as the potential for combination with systemic resistance modifiers such as O6-BG for greater efficacy. Finally, early work with delivery systems has provided the hope of a future with smaller and more readily implantable forms of microspheres and nanospheres, not requiring open surgery for implantation. A significant amount of research is still required in the above areas, whether in the advancement of preclinical studies to clinical trials in patients, optimization of novel polymer composition, or simply acquiring more preclinical data. Polymer therapy has further experienced an expansion of drug classes aimed towards new targets, including angiogenesis inhibitors, immunotherapies, and proteasome inhibitors. Continuing improvement is seen in molecular biological agents focused on genomic targets, including p53 activators,

CHEMOTHERAPY FOR BRAIN TUMORS WITH POLYMER DRUG DELIVERY and both epidermal growth factor receptor and plateletderived growth factor inhibitors. With a reliable local polymer delivery system and continued development in molecular tumor targets, the possibilities for tumor treatment are innumerable. Current progress in polymer-based chemotherapeutic delivery, however, does suggest a future in which neurosurgical procedures will be a combination of both surgical manipulation and polymer delivery, for increased and prolonged efficacy in providing treatment for patients with brain tumors.

REFERENCES Abbott NJ, Romero IA (1996). Transporting therapeutics across the blood–brain barrier. Mol Med Today 2: 106–113. An B, Goldfarb RH, Siman R et al. (1998). Novel dipeptidyl proteasome inhibitors overcome bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ 5: 1062–1075. Benoit JP, Faisant N, Venier-Julienne MC et al. (2000). Development of microspheres for neurological disorders: from basics to clinical applications. J Control Release 65: 285–296. Bindschaedler C, Leong K, Mathiowitz E et al. (1988). Polyanhydride microsphere formulation by solvent extraction. J Pharm Sci 77: 696–698. Boisdron-Celle M, Menei P, Benoit JP (1995). Preparation and characterization of 5-fluorouracil-loaded microparticles as biodegradable anticancer drug carriers. J Pharm Pharmacol 47: 108–114. Brady JM, Cutright DE, Miller RA et al. (1973). Resorption rate, route, route of elimination, and ultrastructure of the implant site of polylactic acid in the abdominal wall of the rat. J Biomed Mater Res 7: 155–166. Brem H, Folkman J (1975). Inhibition of tumor angiogenesis mediated by cartilage. J Exp Med 141: 427–439. Brem H, Langer R (1996). Polymer-based drug delivery to the brain. Sci Med July/August: 52–61. Brem H, Kader A, Epstein JI et al. (1989). Biocompatibility of a biodegradable, controlled-release polymer in the rabbit brain. Sel Cancer Ther 5: 55–65. Brem H, Mahaley MS Jr, Vick NA et al. (1991). Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 74: 441–446. Brem H, Tamargo RJ, Olivi A et al. (1994). Biodegradable polymers for controlled delivery of chemotherapy with and without radiation therapy in the monkey brain. J Neurosurg 80: 283–290. Brem H, Ewend MG, Piantadosi S et al. (1995a). The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. J Neurooncol 26: 111–123. Brem H, Piantadosi S, Burger PC et al. (1995b). Placebocontrolled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of

349

chemotherapy for recurrent gliomas. The Polymer-Brain Tumor Treatment Group. Lancet 345: 1008–1012. Brem S, Staller A, Wotoczek-Obadia MEA (2004). Interstitial Chemotherapy for Local Control of CNS Metastases. Annual Meeting of the Society of Neuro-Oncology, Toronto, Ontario, Canada, November 18–21 (abstract). Brem S, Tyler B, Li K et al. (2007). Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model. Cancer Chemother Pharmacol 60: 643–650. Brigger I, Morizet J, Aubert G et al. (2002). Poly(ethylene glycol)-coated hexadecylcyanoacrylate nanospheres display a combined effect for brain tumor targeting. J Pharmacol Exp Ther 303: 928–936. Brigger I, Morizet J, Laudani L et al. (2004). Negative preclinical results with stealth nanospheres-encapsulated doxorubicin in an orthotopic murine brain tumor model. J Control Release 100: 29–40. Cahan MA, Walter KA, Colvin OM et al. (1994). Cytotoxicity of Taxol in vitro against human and rat malignant brain tumors. Cancer Chemother Pharmacol 33: 441–444. Chasin M, Domb A, Ron E et al. (1990). Polyanhydrides as drug delivery systems. In: M Chasin, R Langer (Eds.), Biodegradable Polymers as Drug Delivery Systems. Marcel Dekker, New York, pp. 43–70. Chen MY, Lonser RR, Morrison PF et al. (1999). Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue–cannula sealing time. J Neurosurg 90: 315–320. Cohen MH, Johnson JR, Pazdur R (2005). Food and drug administration drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme. Clin Cancer Res 11: 6767–6771. Degen JW, Walbridge S, Vortmeyer AO et al. (2003). Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats. J Neurosurg 99: 893–898. Doz F, Berens ME, Dougherty DV et al. (1991). Comparison of the cytotoxic activities of cisplatin and carboplatin against glioma cell lines at pharmacologically relevant drug exposures. J Neurooncol 11: 27–35. Elliott PJ, Hayward NJ, Dean RL et al. (1996). Intravenous RMP-7 selectively increases uptake of carboplatin into rat brain tumors. Cancer Res 56: 3998–4005. Emerich DF, Winn SR, Bartus RT (2002). Injection of chemotherapeutic microspheres and glioma. III: Parameters to optimize efficacy. Cell Transplant 11: 35–45. Ettinger DS (1990). Evaluation of new drugs in untreated patients with small-cell lung cancer: its time has come. J Clin Oncol 8: 374–377. Ewend MG, Williams JA, Tabassi K et al. (1996). Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. Cancer Res 56: 5217–5223. Ewend MG, Sampath P, Williams JA et al. (1998). Local delivery of chemotherapy prolongs survival in experimental brain metastases from breast carcinoma. Neurosurgery 43: 1185–1193.

350

F. ATTENELLO ET AL.

Ewend MG, Thompson RC, Anderson R et al. (2000). Intracranial paracrine interleukin-2 therapy stimulates prolonged antitumor immunity that extends outside the central nervous system. J Immunother 23: 438–448. Ewend MG, Brem S, Gilbert M et al. (2007). Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and provides excellent local control. Clin Cancer Res 13: 3637–3641. Fenteany G, Standaert RF, Lane WS et al. (1995). Inhibition of proteasome activities and subunit-specific aminoterminal threonine modification by lactacystin. Science 268: 726–731. Fine HA (1995). Novel biologic therapies for malignant gliomas. Antiangiogenesis, immunotherapy, and gene therapy. Neurol Clin 13: 827–846. Fournier E, Passirani C, Montero-Menei C et al. (2003a). Therapeutic effectiveness of novel 5-fluorouracil-loaded poly(methylidene malonate 2.1.2)-based microspheres on f98 glioma-bearing rats. Cancer 97: 2822–2829. Fournier E, Passirani C, Vonarbourg A et al. (2003b). Therapeutic efficacy study of novel 5-FU-loaded PMM 2.1.2based microspheres on C6 glioma. Int J Pharm 268: 31–35. Frazza EJ, Schmitt EE (1971). A new absorbable suture. J Biomed Mater Res 5: 43–58. Friedman HS, Keir S, Pegg AE et al. (2002). O6-benzylguaninemediated enhancement of chemotherapy. Mol Cancer Ther 1: 943–948. Fung LK, Ewend MG, Sills A et al. (1998). Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res 58: 672–684. Gansbacher B, Zier K, Daniels B et al. (1990). Interleukin 2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J Exp Med 172: 1217–1224. Gaynon PS, Ettinger LJ, Baum ES et al. (1990). Carboplatin in childhood brain tumors. A Children’s Cancer Study Group phase II trial. Cancer 66: 2465–2469. Ghersi-Egea JF, Leininger-Muller B, Cecchelli R et al. (1995). Blood–brain interfaces: relevance to cerebral drug metabolism. Toxicol Lett 82–83: 645–653. Glantz MJ, Choy H, Kearns CM et al. (1995). Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors. J Natl Cancer Inst 87: 1077–1081. Glantz MJ, Cole BF, Forsyth PA et al. (2000). Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54: 1886–1893. Golden GA, Meldorf MPROLONG Study Group (2004). Patients with metastatic brain cancer, undergoing resection and GliadelW implantation experienced low local recurrence rates in the PROLONG Registry. Annual meeting of the Society of Neuro-Oncology, Toronto, Ontario, Canada, November 18–21 (Abstract). Greig NH (1987). Optimizing drug delivery to brain tumors. Cancer Treat Rev 14: 1–28.

Grossman SA, Reinhard C, Colvin OM et al. (1992). The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers. J Neurosurg 76: 640–647. Hamilton JF, Morrison PF, Chen MY et al. (2001). Heparin coinfusion during convection-enhanced delivery (CED) increases the distribution of the glial-derived neurotrophic factor (GDNF) ligand family in rat striatum and enhances the pharmacological activity of neurturin. Exp Neurol 168: 155–161. Hannigan EV, Green S, Alberts DS et al. (1993). Results of a Southwest Oncology Group phase III trial of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide in advanced ovarian cancer. Oncology 50: 2–9. Hirakawa W, Kadota K, Asakura T et al. (1995). Local chemotherapy for malignant brain tumors using methotrexatecontaining fibrin glue. Gan To Kagaku Ryoho 22: 805–809. Howard MA 3rd, Gross A, Grady MS et al. (1989). Intracerebral drug delivery in rats with lesion-induced memory deficits. J Neurosurg 71: 105–112. Hsu W, Lesniak MS, Tyler B et al. (2005). Local delivery of interleukin-2 and Adriamycin is synergistic in the treatment of experimental malignant glioma. J Neurooncol 74: 135–140. Judy KD, Olivi A, Buahin KG et al. (1995). Effectiveness of controlled release of a cyclophosphamide derivative with polymers against rat gliomas. J Neurosurg 82: 481–486. Klecker T, Jamis-Dow C, Egorin M (1992). Distribution and metabolism of 3H-taxol in the rat. Proc Am Assoc Cancer Res 34: 380, (abstract). Kleinberg LR, Weingart J, Burger P et al. (2004). Clinical course and pathologic findings after GliadelW and radiotherapy for newly diagnosed malignant glioma: implications for patient management. Cancer Invest 22: 1–9. Knighton D, Ausprunk D, Tapper D et al. (1977). Avascular and vascular phases of tumour growth in the chick embryo. Br J Cancer 35: 347–356. Kong Q, Kleinschmidt-Demasters BK, Lillehei KO (1997). Intralesionally implanted cisplatin cures primary brain tumor in rats. J Surg Oncol 64: 268–273. Kornblith PL, Walker M (1988). Chemotherapy for malignant gliomas. J Neurosurg 68: 1–17. Koukourakis MI, Giatromanolaki A, Schiza S et al. (1999). Concurrent twice-a-week docetaxel and radiotherapy: a dose escalation trial with immunological toxicity evaluation. Int J Radiat Oncol Biol Phys 43: 107–114. Kusuhara H, Sugiyama Y (2001a). Efflux transport systems for drugs at the blood–brain barrier and blood–cerebrospinal fluid barrier (part 1). Drug Discov Today 6: 150–156. Kusuhara H, Sugiyama Y (2001b). Efflux transport systems for drugs at the blood–brain barrier and blood–cerebrospinal fluid barrier (part 2). Drug Discov Today 6: 206–212. Langer RS (1984). Medical Applications of Controlled Release. CRC Press, Boca Raton. Langer R, Folkman J (1976). Polymers for the sustained release of proteins and other macromolecules. Nature 263: 797–800.

CHEMOTHERAPY FOR BRAIN TUMORS WITH POLYMER DRUG DELIVERY Langer R, Brem H, Falterman K et al. (1976). Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193: 70–72. Laske DW, Morrison PF, Lieberman DM et al. (1997). Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with single-photon emission computerized tomography imaging. J Neurosurg 87: 586–594. Lawson HC, Sampath P, Bohan E et al. (2007). Interstitial chemotherapy for malignant gliomas: The Johns Hopkins experience. J Neurooncol 83: 61–70. Lee JK, Choi B, Sobel RA et al. (1990). Inhibition of growth and angiogenesis of human neurofibrosarcoma by heparin and hydrocortisone. J Neurosurg 73: 429–435. Legnani FG, Pradilla G, Thai QA et al. (2006). Lactacystin exhibits potent anti-tumor activity in an animal model of malignant glioma when administered via controlledrelease polymers. J Neurooncol 77: 225–232. Lemaire L, Roullin VG, Franconi F et al. (2001). Therapeutic efficacy of 5-fluorouracil-loaded microspheres on rat glioma: a magnetic resonance imaging study. NMR Biomed 14: 360–366. Lemoli RM, Gasparetto C, Scheinberg DA et al. (1991). Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid-specific monoclonal antibodies and drugs in combination. Blood 77: 1829–1836. Leong KW, Brott BC, Langer R (1985). Bioerodible polyanhydrides as drug-carrier matrices. I: Characterization, degradation, and release characteristics. J Biomed Mater Res 19: 941–955. Leong KW, Kost J, Mathiowitz E et al. (1986). Polyanhydrides for controlled release of bioactive agents. Biomaterials 7: 364–371. Lesniak MS, Brem H (2004). Targeted therapy for brain tumours. Nat Rev 3: 499–508. Lesniak MS, Upadhyay U, Goodwin R et al. (2005). Local delivery of doxorubicin for the treatment of malignant brain tumors in rats. Anticancer Res 25: 3825–3831. Lewis D (1990). Controlled release of bioactive agents from lactide/glycolide polymers. In: M Chasin, R Langer (Eds.), Biodegradable Polymers as Drug Delivery Systems. Marcel Dekker, New York, pp. 1–41. Lidar Z, Mardor Y, Jonas T et al. (2004). Convectionenhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg 100: 472–479. Lillehei KO, Kong Q, Withrow SJ et al. (1996). Efficacy of intralesionally administered cisplatin-impregnated biodegradable polymer for the treatment of 9L gliosarcoma in the rat. Neurosurgery 39: 1191–1197. Limentani S, Asher A, Heafner A et al. (2005). A phase I trial of surgery, GliadelW wafer implantation, and immediate postoperative carboplatin in combination with radiation therapy for primary anaplastic astrocytoma or glioblastoma multiforme. J Neurooncol 72: 241–244. Mardor Y, Roth Y, Lidar Z et al. (2001). Monitoring response to convection-enhanced taxol delivery in brain tumor

351

patients using diffusion-weighted magnetic resonance imaging. Cancer Res 61: 4971–4973. Menei P, Daniel V, Montero-Menei C et al. (1993). Biodegradation and brain tissue reaction to poly(d, l-lactide-coglycolide) microspheres. Biomaterials 14: 470–478. Menei P, Benoit JP, Boisdron-Celle M et al. (1994). Drug targeting into the central nervous system by stereotactic implantation of biodegradable microspheres. Neurosurgery 34: 1058–1064. Menei P, Boisdron-Celle M, Croue A et al. (1996). Effect of stereotactic implantation of biodegradable 5-fluorouracilloaded microspheres in healthy and C6 glioma-bearing rats. Neurosurgery 39: 117–123. Menei P, Venier MC, Gamelin E et al. (1999). Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma: a pilot study. Cancer 86: 325–330. Menei P, Capelle L, Guyotat J et al. (2005). Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of malignant glioma: a randomized phase II trial. Neurosurgery 56: 242–248. Moses MA, Wiederschain D, Wu I et al. (1999). Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci U S A 96: 2645–2650. Oda Y, Tokuriki Y, Tsuda E et al. (1979). Trial of anticancer pellet in malignant brain tumours; 5 FU and urokinase embedded in Silastic. Acta Neurochir Suppl (Wien) 28: 489–490. Olivi A, Gilbert M, Duncan KL et al. (1993). Direct delivery of platinum-based antineoplastics to the central nervous system: a toxicity and ultrastructural study. Cancer Chemother Pharmacol 31: 449–454. Olivi A, Ewend MG, Utsuki T et al. (1996). Interstitial delivery of carboplatin via biodegradable polymers is effective against experimental glioma in the rat. Cancer Chemother Pharmacol 39: 90–96. Olivi A, Grossman SA, Tatter S et al. (2003). Dose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: a New Approaches to Brain Tumor Therapy CNS Consortium trial. J Clin Oncol 21: 1845–1849. Pardoll DM (1995). Paracrine cytokine adjuvants in cancer immunotherapy. Annu Rev Immunol 13: 399–415. Pardridge WM (1999). Vector-mediated drug delivery to the brain. Adv Drug Deliv Rev 36: 299–321. Patchell RA, Tibbs PA, Walsh JW et al. (1990). A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322: 494–500. Pegg AE, Boosalis M, Samson L et al. (1993). Mechanism of inactivation of human O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine. Biochemistry 32: 11998–12006. Pradier O, Rave-Frank M, Lehmann J et al. (2001). Effects of docetaxel in combination with radiation on human head and neck cancer cells (ZMK-1) and cervical squamous cell carcinoma cells (CASKI). Int J Cancer 91: 840–845. Pradilla G, Legnani FG, Petrangolini G et al. (2005). Local delivery of a synthetic endostatin fragment for the treatment of experimental gliomas. Neurosurgery 57: 1032–1040.

352

F. ATTENELLO ET AL.

Pradilla G, Wang PP, Gabikian P et al. (2006). Local intracerebral administration of paclitaxel with the paclimer delivery system: toxicity study in a canine model. J Neurooncol 76: 131–138. Prokai L, Prokai-Tatrai K, Bodor N (2000). Targeting drugs to the brain by redox chemical delivery systems. Med Res Rev 20: 367–416. Rama B, Mandel T, Jansen J et al. (1987). The intraneoplastic chemotherapy in a rat brain tumour model utilizing methotrexate–polymethylmethacrylate-pellets. Acta Neurochir (Wien) 87: 70–75. Raza SM, Pradilla G, Legnani FG et al. (2005). Local delivery of antineoplastic agents by controlled-release polymers for the treatment of malignant brain tumours. Expert Opin Biol Ther 5: 477–494. Recht LD, Glantz MJ, Meitner P et al. (1998). Unexpected in vitro chemosensitivity of malignant gliomas to 4hydroxyperoxycyclophosphamide (4-HC). J Neurooncol 36: 201–208. Reece DE, Barnett MJ, Connors JM et al. (1993). Treatment of multiple myeloma with intensive chemotherapy followed by autologous BMT using marrow purged with 4-hydroperoxycyclophosphamide. Bone Marrow Transplant 11: 139–146. Renaudin J, Fewer D, Wilson CB et al. (1973). Dose dependency of decadron in patients with partially excised brain tumors. J Neurosurg 39: 302–305. Ren H, Boulikas T, Lundstrom K et al. (2003). Immunogene therapy of recurrent glioblastoma multiforme with a liposomally encapsulated replication-incompetent Semliki Forest virus vector carrying the human interleukin-12 gene – a phase I/II clinical protocol. J Neurooncol 64: 147–154. Rhines LD, Sampath P, Dolan ME et al. (2000). O6-benzylguanine potentiates the antitumor effect of locally delivered carmustine against an intracranial rat glioma. Cancer Res 60: 6307–6310. Rhines LD, Sampath P, DiMeco F et al. (2003). Local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma. Neurosurgery 52: 872–879. Ringkjob R (1968). Treatment of intracranial gliomas and metastatic carcinomas by local application of cytostatic agents. Acta Neurol Scand 44: 318–322. Rosenberg SA, Lotze MT, Yang JC et al. (1989). Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210: 474–484. Saini M, Roser F, Hussein S et al. (2004). Intralesional mitoxantrone biopolymer-mediated chemotherapy prolongs survival in rats with experimental brain tumors. J Neurooncol 68: 225–232. Sampath P, Hanes J, DiMeco F et al. (1999). Paracrine immunotherapy with interleukin-2 and local chemotherapy is synergistic in the treatment of experimental brain tumors. Cancer Res 59: 2107–2114. Sampson JH, Akabani G, Archer GE et al. (2003). Progress report of a phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of

the Pseudomonas exotoxin termed PR-38 (TP-38) for the treatment of malignant brain tumors. J Neurooncol 65: 27–35. Sawaya R, Ligon BL, Bindal AK et al. (1996). Surgical treatment of metastatic brain tumors. J Neurooncol 27: 269–277. Shieh L, Tamada J, Chen I et al. (1994). Erosion of a new family of biodegradable polyanhydrides. J Biomed Mater Res 28: 1465–1475. Shikani AH, Eisele DW, Domb AJ (1994). Polymer delivery of chemotherapy for squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 120: 1242–1247. Sipos EP, Tyler B, Piantadosi S et al. (1997). Optimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumors. Cancer Chemother Pharmacol 39: 383–389. Slichenmyer WJ, Rowinsky EK, Donehower RC et al. (1993). The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 85: 271–291. Storm PB, Moriarity JL, Tyler B et al. (2002). Polymer delivery of camptothecin against 9L gliosarcoma: release, distribution, and efficacy. J Neurooncol 56: 209–217. Storm PB, Renard VM, Moriarity JL et al. (2004). Systemic BCNU enhances the efficacy of local delivery of a topoisomerase I inhibitor against malignant glioma. Cancer Chemother Pharmacol 54: 361–367. Tamargo RJ, Epstein JI, Reinhard CS et al. (1989). Brain biocompatibility of a biodegradable, controlled-release polymer in rats. J Biomed Mater Res 23: 253–266. Tamargo RJ, Leong KW, Brem H (1990). Growth inhibition of the 9L glioma using polymers to release heparin and cortisone acetate. J Neurooncol 9: 131–138. Tamargo RJ, Bok RA, Brem H (1991). Angiogenesis inhibition by minocycline. Cancer Res 51: 672–675. Tamargo RJ, Myseros JS, Epstein JI et al. (1993). Interstitial chemotherapy of the 9L gliosarcoma: controlled release polymers for drug delivery in the brain. Cancer Res 53: 329–333. Thompson RC, Pardoll DM, Jaffee EM et al. (1996). Systemic and local paracrine cytokine therapies using transduced tumor cells are synergistic in treating intracranial tumors. J Immunother Emphasis Tumor Immunol 19: 405–413. Vajkoczy P, Menger MD (2000). Vascular microenvironment in gliomas. J Neurooncol 50: 99–108. Valtonen S, Timonen U, Toivanen P et al. (1997). Interstitial chemotherapy with carmustine-loaded polymers for highgrade gliomas: a randomized double-blind study. Neurosurgery 41: 44–48. Voges J, Reszka R, Gossmann A et al. (2003). Imagingguided convection-enhanced delivery and gene therapy of glioblastoma. Ann Neurol 54: 479–487. Walker MD, Green SB, Byar DP et al. (1980). Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303: 1323–1329. Warnke PC, Blasberg RG, Groothuis DR (1987). The effect of hyperosmotic blood–brain barrier disruption on bloodto-tissue transport in ENU-induced gliomas. Ann Neurol 22: 300–305.

CHEMOTHERAPY FOR BRAIN TUMORS WITH POLYMER DRUG DELIVERY Weber F, Asher A, Bucholz R et al. (2003). Safety, tolerability, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J Neurooncol 64: 125–137. Weingart JD, Sipos EP, Brem H (1995). The role of minocycline in the treatment of intracranial 9L glioma. J Neurosurg 82: 635–640. Weingart J, Grossman SA, Carson KA et al. (2007). Phase I trial of polifeprosan 20 with carmustine implant plus continuous infusion of intravenous O6-benzylguanine in adults with recurrent malignant glioma: new approaches to brain tumor therapy CNS consortium trial. J Clin Oncol 25: 399–404.

353

Westphal M, Hilt DC, Bortey E et al. (2003). A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (GliadelW wafers) in patients with primary malignant glioma. Neuro-oncol 5: 79–88. Westphal M, Ram Z, Riddle V et al. (2006). GliadelW wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 148: 269–275. Yemisci M, Bozdag S, Cetin M et al. (2006). Treatment of malignant gliomas with mitoxantrone-loaded poly (lactide-co-glycolide) microspheres. Neurosurgery 59: 1296–1302.