Implantable Slow-Release Chemotherapeutic Polymers for the Treatment of
Malignant Brain Tumors
Prakash Sampath, MD, and Henry Brem, MD
The polymeric delivery of chemotherapeutic implants shows promise
in the treatment of patients with malignant gliomas.
Due to copyright restrictions, this article differs
from its printed counterpart; some tables and figures have been removed from the online
article that follows. Please refer to the printed version found in Cancer Control
Journal Volume 3, Number 5 Supplemental, to view this article in its entirety
Background: Despite significant advances in neurosurgery, radiation
therapy, and chemotherapy, the prognosis for patients with malignant brain tumors remains
dismal. In an effort to improve control of local disease, we have developed a
biodegradable, controlled-release polymer that is implanted directly at the tumor site.
Methods: The preclinical and clinical development of the polymeric
delivery of chemotherapeutic agents for treatment of patients with malignant gliomas is
reviewed.
Results: Carmustine (BCNU)-impregnated biodegradable polymer is the first
new therapy approved by the FDA for patients with gliomas in 23 years. This delivery
system provides high local concentration of drug with minimal systemic toxicity and
obviates the need for drug to cross the blood-brain barrier. Randomized,
multi-institutional, double-blinded, placebo-controlled studies have shown improved
survival in patients treated for gliomas both at initial presentation and at
recurrence. Several clinical principles have emerged from the use of this polymer
system, and further applications are currently being investigated.
Conclusions: Local delivery of therapeutic agents via biodegradable
polymers may play an increasing role in patients with brain tumors.
Introduction
Approximately 13,000 new cases of primary malignant brain tumors are
diagnosed each year in the United States.1 Despite significant advances in
imaging, neurosurgery, radiation therapy, and oncology, the prognosis for most patients
remains dismal. For patients with glioblastoma, median survival is still less than one
year even after surgical resection, conventional external-beam radiotherapy, and systemic
chemotherapy.2-4 In recent years, our efforts to improve survival for patients
harboring malignant gliomas have centered on controlling local disease. This is based on
clinical and experimental observations that most malignant brain tumors recur locally,
within 2 cm of the original resection field,5 and that extracranial spread is
exceedingly rare.
Improving treatment for malignant brain tumors has been hindered by
the unique environment of the central nervous system (CNS). New chemotherapeutic agents,
angiogenesis inhibitors, cytokines, and other anticancer therapies are often unable to
cross the blood-brain barrier. Furthermore, significant systemic toxicity can result from
administration of these agents in doses large enough to achieve efficacious concentrations
in the brain. To overcome some of these limitations, strategies at improving delivery of
therapeutic agents have become a major focus of brain tumor research.
The development of implantable polymers that release
chemotherapeutic agents directly into the CNS has had an impact on glioma therapy.6-8
This technology makes it possible to achieve very high local concentrations of anticancer
agents while minimizing systemic toxicity and circumventing the need for a drug to cross
the blood-brain barrier. Clinical trials with systemic nitrosoureas have shown only modest
improvement in patient survival2-4,9,10 and were associated with significant
systemic toxicity. In this paper, we review the development of biodegradable, slow-release
polymers and the basis for their use in the treatment of patients with malignant brain
tumors. We then discuss the clinical use of the first FDA-approved, controlled-delivery
polymer, Gliadel (Guilford Pharmaceutical Corp, Baltimore, Md), and comment on ongoing and
planned clinical protocols with this delivery system. Finally, we briefly discuss other
therapeutic agents that are currently in development for use in biodegradable polymers to
treat brain tumors.
Polymer Technology
Implantable polymer matrices loaded with chemotherapeutic agents
provide a novel approach to treating patients with intratumoral therapy.11,12 A
number of biocompatible polymer systems have been developed that are capable of delivering
chemotherapeutic agents when implanted in tissue. For brain tumors, the polymer is
surgically implanted in the tumor resection cavity (Fig 1) and allows the drug to be
delivered over an extended period of time in the peritumoral region where microscopic
neoplastic cells may persist.
The first polymers developed for controlled drug delivery utilized a
nonbiodegradable polymer matrix with incorporated micropores.13 The drug
diffuses out of these polymers at a rate determined by the permeability of the release
matrix and the diffusion properties of the drug itself. The prototypical polymers that
work in this fashion are the hydrogels and ethylene-vinyl acetate (EVAc), first described
by Langer and Folkman.14 Although these systems have found clinical application
in glaucoma, asthma, and contraceptive therapy, they have had limited use as drug delivery
vehicles in the brain.15,16 One drawback is that they remain as a
space-occupying foreign body in the brain once the drug is dispersed.
The polyanhydride, poly[1,3-bis(carboxyphenoxy)propane-co-sebacic-acid]
(PCPP-SA) matrix is an example of a biodegradable polymer that is useful in treating brain
tumors (Fig 2).7,17,18 Polyanhydride biodegradable polymers offer several
advantages over diffusion-controlled matrices.7,18 First, since the matrix
degrades at a steady rate, the drug can be released over an extended period of time with a
relatively steady concentration. Second, biodegradable polyanhydrides prevent hydrolytic
breakdown of the chemotherapeutic agent, thus maintaining its desired cytotoxic effects.
Third, the rate of degradation can be controlled depending on the relative ratios of
monomers in the copolymer matrix.13,17 Consequently, the drug can be delivered
over weeks, months, or years as needed. Finally, the polymers themselves degrade as they
release the drug, minimizing the need for surgical removal after the drug has been
released.
There are currently a number of polymeric systems designed to
optimize local delivery. A second polyanhydride, the fatty acid dimer-sebacic acid
(FAD-SA) copolymer, has been developed to deliver hydrophilic agents such as platinum
drugs.19 The introduction of poly(lactide-co-glycolide) polymer allows
chemotherapeutic agents as well as larger molecules to be incorporated into microspheres
that can be stereotactically injected into the brain.20
Polyethyleneglycol-coated liposomes that encapsulate anthracyclines show promise as
delivery agents that both decrease systemic side effects and improve the therapeutic
indices of these drugs.21,22 Also, poly (lactide-co-glycolide)
nanospheres can be covalently linked to a polyethylene glycol coating that reduces
opsonization and elimination by the immune system before drug release.23
Finally, gelatin microspheres have recently been shown to release cytokines in vivo.24
Gliadel
Nitrosoureas, including carmustine (BCNU), have been widely used for
the treatment of malignant gliomas.2-4 Because of their relative lipid
solubility and low molecular weight, these agents can penetrate the blood-brain barrier
moderately well and can achieve tumoricidal concentrations in the brain with generally
tolerable systemic doses. Nevertheless, marginal efficacy combined with severe toxicity
such as myelosuppression and pulmonary fibrosis have precluded the widespread use of
systemic BCNU as an effective antiglioma agent.3,4,9,10 Furthermore, BCNU
administered intravenously is rapidly cleared from tissue (t1/2 <20
minutes), limiting its bioavailability for brain tumors.25
In an effort to improve the effectiveness of nitrosoureas against
malignant gliomas, BCNU has been incorporated into polymers and delivered intracranially
directly at the tumor site. In the laboratory, BCNU polymer preparations have been shown
to release active drug in rat26 and rabbit27 brain for up to three
weeks after implantation. Moreover, BCNU has been shown to diffuse widely from the
polymer.27 Further pharmacokinetic studies in nonhuman primates (cynomolgus
monkeys) with 20%-loaded BCNU polyanhydride polymer showed that BCNU concentrations in the
brain achieved by polymeric delivery were four to 1,200 times higher than that produced by
intravenous administration of drug.28 By using quantitative autoradiography and
thin-layer chromatography, tumoricidal drug concentrations were detected 4 cm from the
polymer implantation site one day after surgery, 2 cm on day 7 after surgery, and 1.3 cm
30 days later.
In preclinical in vivo studies, BCNU-loaded polymer
significantly prolongs survival in rats challenged either intracranially or subcutaneously
with 9L glioma when compared to intraperitoneal injection of drug.29 In animals
in which BCNU was delivered from the EVAc polymer, flank tumor growth was delayed by 44%
(16.3 days; P<0.05) when compared with control animals with empty polymer
implants. In an established intracranial 9L glioma, local polymer implants loaded with 20%
BCNU (using both EVAc and PCPP:SA) not only prolonged the median survival of the treated
animals significantly when compared to empty polymer or intraperitoneal administration of
BCNU, but also produced long-term survivors in the treated groups (range of 20% to 50% in
different polymer formulations). Toxicity experiments in nonhuman primates (cynomolgus
monkeys) with BCNU delivered from PCPP:SA polymers implants showed no evidence of
significant systemic or neurologic toxicity even in conjunction with radiation therapy.30
Autopsies of these same animals revealed transient, mild, localized inflammation
surrounding the polymer implants.
As a result of encouraging preclinical data, clinical trials were
initiated using a BCNU polymer formulation. In a phase I trial of 21 patients who had
failed standard therapy for gliomas and were undergoing reoperation, escalating doses of
BCNU loaded in PCPP:SA polymer showed no evidence of systemic toxicity and no deleterious
effect on neurologic performance (eg, Karnofsky performance).31 The mean
survival after reoperation and implantation of BCNU-impregnated polymer for the five
patients receiving 1.9% (by weight) BCNU loading was 65 weeks; the mean survival for the
five patients receiving 3.8% BCNU was 64 weeks; and the mean survival for the 11 patients
receiving 6.35% BCNU was 32 weeks. On the basis of these results, 3.8% loading was
selected for phase III studies.
To evaluate the efficacy of Gliadel (3.8% BCNU in polyanhydride
polymer), a randomized, placebo-controlled, double-blinded, prospective phase III clinical
trial32 was carried out in patients with recurrent gliomas who had failed
standard therapy. A total of 222 patients from 27 medical centers in the United States and
Canada were entered. Enrolled patients received either Gliadel or "empty"
placebo polymers implanted on the surface of the resected tumor cavity. The patients were
equally distributed between the two groups for all known prognostic factors (eg, median
age, neurologic function, prior treatment, median interval from first operation, number of
previous operations, and tumor grade). The majority of patients (65.5% for the Gliadel
group and 65.2% for the placebo group) had the highest grade tumor -- glioblastoma
multiforme. Before enrollment, 52.7% of the BCNU group and 48.2% of the control group had
undergone previous systemic chemotherapy and all patients had received conventional
external-beam whole-brain radiation therapy. A few patients had received experimental
immunotherapy or brachytherapy. Postoperatively, approximately 25% of patients underwent
additional systemic chemotherapy (equally distributed in both groups).
For these patients, all of whom had failed prior therapy, those who
received Gliadel had an additional median survival of 31 weeks compared with 23 weeks for
the control group. Use of a Cox proportional hazards model that adjusts for patient age,
prior treatment, and tumor grade gave a hazard ratio of 0.67 (P=.007). When
patients with glioblastoma multiforme were analyzed separately, their six-month survival
improved by 50% (Fig 3). Of importance, no significant local or systemic adverse reactions
were attributable to Gliadel. This study established that BCNU delivered via polyanhydride
polymers is a safe, effective treatment for patients with recurrent malignant gliomas.
This "pivotal" study32 provided the basis of the Food and Drug
Administration’s approval of Gliadel as a treatment for patients with recurrent
glioblastoma.
The encouraging results with controlled-release polymers for
patients with recurrent gliomas has led to the development of more effective treatments
for patients initially presenting with gliomas. A phase I study33 with
22 patients newly diagnosed with malignant glioma was conducted to evaluate the overall
safety of Gliadel and also the safety of receiving both Gliadel and concurrent standard
external beam radiation therapy. Of the 22 patients, 21 had glioblastoma multiforme. No
neurotoxicity or systemic toxicity was attributable to the locally released BCNU in
conjunction with radiation therapy. Therefore, it was concluded that Gliadel with
subsequent radiation therapy appeared to be safe and well tolerated for the initial
treatment of patients presenting with malignant gliomas.
To evaluate further the effectiveness of Gliadel in the initial
therapy of malignant gliomas, Valtonen et al34 conducted a prospective,
randomized, double-blinded clinical trial in Europe. Thirty-two patients were enrolled at
the time of initial surgical resection, with half of the patients randomized to receive
Gliadel and the other half to receive empty polymer. All patients had subsequent radiation
therapy. Median survival was 58 weeks for the BCNU treatment group vs 40 weeks for the
placebo group (P=0.001) (Fig 4 - Please refer to the printed version of the
journal.) When patients with glioblastoma, the largest subgroup, were evaluated
separately, median survival was 53 weeks with Gliadel (11 patients) and 40 weeks with
placebo implants (15 patients) (P=0.0083). At one year, 63% of the Gliadel patients
were alive vs 19% for the control group; at two years, 31% of the Gliadel patients were
alive vs only 6% of the control group; and at three years, 25% of the Gliadel group were
alive (three glioblastoma multiforme, one anaplastic astrocytoma) compared with 6% (one
glioblastoma multiforme) of the control group. This study establishes that polymer
technology is a safe, effective treatment for patients presenting with malignant gliomas.
Clinical Principles Associated With Gliadel Use
As clinical experience with Gliadel has increased, certain lessons
for its usage have emerged. First, it is important to achieve maximal tumor debulking
before insertion of the Gliadel wafers into the tumor resection cavity. Released
chemotherapeutic agent, which kills residual tumor cells, can result in localized
increased intracranial pressure from cerebral edema. Therefore, it is important to create
as much space as possible at the time of surgical debulking and to exercise caution when
using Gliadel in minimally debulked tumors.
Secondly, because the effective release of chemotherapy into the
brain can cause edema in the surrounding brain, high doses of corticosteroids are
recommended in all patients receiving Gliadel. Moreover, corticosteroids should be
maintained in patients for at least three weeks after surgery, since it is in this period
that the maximal amount of chemotherapy is being released from the polymer. In patients
where edema is of particular concern or where there is postoperative neurologic deficit,
we use supra-physiologic corticosteroid doses (as high as 120 mg of dexamethasone per day)
and slowly taper the dose as clinically indicated. We have found minimal deleterious
effects of extremely high corticosteroid doses administered for short periods of time.
Blood sugar should be carefully monitored during such administration.
In assessing the adverse effects of Gliadel in clinical trials, it
was found that intracranial or wound infections occurred more commonly in patients who
received BCNU (4 of 110 patients who received Gliadel vs 1 of 112 patients receiving
placebo).32 Although this difference was not found to be statistically
significant, high doses of local BCNU can adversely affect wound healing. All patients who
had a serious infection were found to have a prior CSF leak. Therefore, it is recommended
that a watertight closure of the dura be achieved either primarily or with a dural graft.
Furthermore, if a CSF leak does develop, vigorous rapid treatment should be initiated. By
utilizing these meas-ures, the rate of infection has fallen in subsequent clinical trials.
In addition, we use preoperative and postoperative antibiotics for 24 hours in all
patients who undergo craniotomy and Gliadel placement.
We have found that small openings into the ventricle do not preclude
the use of Gliadel. Preclinical studies in rabbits did not demonstrate a risk of direct
exposure of the ventricle to Gliadel. If there is a large opening of the ventricle,
however, the wafer itself could enter the ventricle system and cause mechanical
obstruction of CSF pathways, possibly leading to acute hydrocephalus. In this
circumstance, Gliadel is not indicated, and other adjuvant therapies should be considered.
Patients receiving Gliadel should have anticonvulsants before
surgery and should remain on therapeutic levels of these medications postoperatively.
Clinical studies have shown postoperative seizures overall are not more common in patients
receiving Gliadel, but they occur with greater frequency in the immediate postoperative
period.32 This underscores the need to initiate anticonvulsive therapy in all
patients preoperatively and to pay particular attention to serum drug levels, especially
since corticosteroids can affect the anticonvulsant dose.
Ongoing and Planned Clinical Trials
Several clinical trials are now underway to evaluate the safety and
efficacy of Gliadel in a variety of different clinical situations.
Recent studies in rats have demonstrated that increasing
concentrations of up to 20% BCNU are more effective in prolonging survival than are lower
doses and that 20% BCNU is not associated with increased toxicity.35 Further
studies in monkeys have shown that 20%-BCNU-loaded polymer is well tolerated and yields
effective prolonged distribution of intracranial BCNU.28 Therefore, even though
the 3.8%-BCNU-loaded polymer is effective and has received Food and Drug Administration
approval, a new clinical study has been initiated to determine the feasibility of using
even higher doses intracranially (a New Approaches in Brain Tumor Therapy [NABTT-NIH]
study). An open-label, multicenter, dose-escalation study is currently underway to
evaluate the safety of Gliadel wafers containing between 6.5% and 20% BCNU in patients
with recurrent glioma and to define at which level dose-limiting toxicity occurs.
Gliadel is also being evaluated for both safety and efficacy as a
therapy for radioresistant metastatic brain tumors. Preclinical studies in murine models
of intracranial metastatic melanoma, colon cancer, lung cancer, breast, and renal cell
carcinoma demonstrate efficacy of BCNU-loaded polyanhydride polymers.36,37 In
patients, current therapies have limited ability to control CNS disease, and many die of
intracranial metastases despite aggressive multimodality treatment and good systemic
control of disease.38 Furthermore, as improved systemic therapies become
available, intracranial relapse may become more common.39 Therefore, it is
hoped that Gliadel will be a useful addition to the armamentarium available for the
treatment of CNS metastases. Two multi-institutional trials are currently underway.
The application of Gliadel for pediatric patients is promising in
that most pediatric patients already receive adjuvant systemic chemotherapy for brain
tumors. Currently, a phase I-II study is underway for pediatric patients with
supratentorial malignant CNS tumors. A clinical study of the use of Gliadel in the
posterior fossa is also planned.
In recent years, much work has been focused on chemotherapeutic
resistance mechanisms expressed by various tumors. Tumor cells are known to exhibit
differing susceptibility to BCNU based on their ability to repair drug-induced alkylation.
The major repair pathway utilizes the enzyme alkylguanine-DNA alkyltransferase (AGAT).
O6-benzylguanine (O6-BG) is an excellent substrate for AGAT and irreversibly binds to
AGAT, thus diminishing the cells’ ability to repair alkylation.40 Studies
both in vitro and in vivo have shown that O6-BG potentiates the cytotoxicity
of BCNU in cells expressing AGAT.40-43 Since many human gliomas have AGAT
activity, 43,44 we have hypothesized that O6-BG will enhance the therapeutic
effectiveness of locally delivered BCNU. To test this hypothesis, a phase I multicenter
trial of Gliadel with prior intravenous administration of O6-BG in patients with recurrent
malignant gliomas is being initiated (through the NIH).
Other Chemotherapeutic Agents
Several other chemotherapeutic agents delivered via
controlled-release biodegradable polymer technology have been investigated in the
laboratory, in preparation for clinical trials.
The camptothecin (CPT) class of drugs is composed of potent
antitumor agents that exert their pharmacologic effect by inhibiting topoisomerase I
during the S and G1 phases of the cell cycle.45 The sodium analog of
camptothecin has been shown to have limited systemic efficacy and to penetrate the
blood-brain barrier poorly,46 but it can be incorporated into polymers, thus
markedly improving its bioavailability. Although potent in vitro against gliomas,
sodium camptothecin was found to be ineffective when administered systemically or by
direct injection to treat the rat 9L glioma. By contrast, when incorporated into polymers,
sodium camptothecin showed significant prolongation of survival in a 9L intracranial rat
glioma model.47 Fifty-nine percent of implant-treated animals survived beyond
120 days, whereas median survival for the control animals ranged from 20 to 32 days. The
CPTs represent the most potent drugs to date in preclinical studies using local delivery.
The recent development of more cytotoxic and stable CPT analogs will allow for the
development of these drugs as effective cytotoxic agents that can be incorporated into
polymers.48,49
The taxoid group of anticancer agents, including paclitaxel (Taxol)
and docetaxel (Taxotere), has been linked to microtubule stabilization, cell cycle block
in the G2 phase, and cell death by apoptosis.50 Since taxoids do not
readily cross the blood-brain barrier, they may be an ideal class of drugs to use with
biodegradable polymers. In preclinical studies, Taxol51 and Taxotere52
exhibited marked cytotoxicity in brain tumor xenografts in vitro and in a rat
intracranial 9L glioma model, delivery by biodegradable polymers prolonged survival 3.1
times over that in control animals.53
A hydrophilic derivative of cyclophosphamide (Cytoxan),
4-hydroperoxy-cyclophosphamide (4-HC), spontaneously converts to the active metabolite of
cyclophosphamide, 4-hydroxy-cyclophosphamide, and does not effectively cross the
blood-brain barrier. This makes 4-HC an excellent candidate for local delivery.
Preclinical studies demonstrate that 4-HC incorporated into an FAD-SA polyanhydride
polymer matrix significantly prolongs survival in rats challenged with intracranial F98
gliomas.54,55 When compared to control rats receiving empty polymers, the
median survival was extended from 14 days to 77 days.
Platinum-based drugs such as carboplatin and cisplatin represent
another class of antitumor agents that have been incorporated into biodegradable
polyanhydride matrices and have shown efficacy against intracranial rat gliomas in vivo.19,54,56,57
Adriamycin,58 an anthracycline antitumor antibiotic, and angiogenesis
inhibitors such as heparin-cortisone59 and minocycline60,61 also
have been incorporated into polymers and have shown great promise in preclinical studies.
Since many of these agents exert their anticancer effect through a variety of mechanisms,
it is hoped they can be used in combination with Gliadel.
Conclusions
Interstitial drug delivery via biodegradable polymers has
significant clinical implications for the treatment of malignant brain tumors. It provides
an effective means for bypassing the blood-brain barrier, it produces a high concentration
of desired drug directly in the region of the tumor for an extended period of time, it
protects the drugs from potential degradation, and it minimizes systemic adverse effects
and toxicity of the drug.
To date, large-scale clinical trials on patients with malignant
brain tumors have demonstrated that improved survival can be achieved in patients
receiving biodegradable implants with BCNU when compared to control "empty"
implants. As newer drugs become available for local delivery either alone or in
combination, the challenge will be to improve on these initial results and develop
treatment strategies that further enhance patient survival and quality of life. With the
development of experimental therapies such as novel chemotherapeutic agents, immunotherapy
or virus-mediated gene therapy, local delivery with biodegradable polymers will play an
increasing role in the management of patients with malignant brain tumors.
The laboratory research reviewed in this paper was partially
funded by the National Cooperative Drug Discovery Group (UO1-CA52857) of the National
Cancer Institutes of Health, Bethesda, Md., and by Guilford Pharmaceutical Corp.,
Baltimore, Md.
The clinical trials described in this manuscript were funded in
part by Scios-Nova Corp, Mountain View, Calif; Guilford Pharmaceuticals, Inc, Baltimore,
Md; and the New Approaches to Brain Tumor Therapy (NABTT) Group of the National Institutes
of Health, Bethesda, Md.
Dr Sampath is the recipient of the NIH National Research Service
Award CA-09574.
Dr Brem is a consultant to Guilford Pharmaceuticals, Inc, and to
Rhone-Poulenc Rorer. Guilford Pharmaceuticals has provided a gift for research in
Dr Brem’s laboratory. The Johns Hopkins University and Dr Brem own Guilford stock,
the sale of which is subject to certain restrictions under University policy.
The terms of this arrangement are being managed by the University in accordance
with its conflict of interest policies.
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From the departments of Neurological Surgery (P.S., H.B.), and Oncology (H.B.) at The
Johns Hopkins School of Medicine, Baltimore, Md.
Address reprint requests to Henry Brem, MD, at the Department of
Neurological Surgery, Hunterian 817, The Johns Hopkins School of Medicine, 725 North Wolfe
St, Baltimore, MD 21205.
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