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Locoregional Therapies for Glioma

Locoregional Therapies for Glioma

ABSTRACT: Glioma is the most common form of primary brain tumor, as well as the most lethal. Primary treatment strategies for glioma, including cytoreductive surgery, external-beam irradiation, and systemic chemotherapy have had generally disappointing results for these tumors. Limitations of these approaches include tumor invasion into functional brain tissue, lack of chemosensitivity, and shortcomings of systemic delivery. Recent attention has focused on locoregional strategies for treatment, as well as new methods for delivering therapy. Identification of tumorspecific surface targets, biologic agents, and more sophisticated means to deliver macromolecules to the brain is offering new promise in the treatment of these tumors. This paper will review the current state of the art of available locoregional therapies for glioma, with a particular focus on convection-enhanced delivery, targeted toxin, and other biologic strategies.

In the United States, an estimated
40,900 new cases of primary brain
tumors were diagnosed in 2004.[1]
The American Cancer Society estimates
that approximately 18,400 malignant
tumors of the brain or spinal cord were
diagnosed during 2004. The incidence
of primary brain tumors appears to be
on the rise, although it is unclear if this
is attributable to better reporting, environmental,
or genetic factors.[2]

Glioma, including glioblastoma
multiforme, anaplastic astrocytoma,
astrocytoma, and oligodendroglioma,
are the most lethal forms of primary
brain tumors.[2] Approximately
13,000 brain cancer deaths related to
glioma occur annually in the United
States. The median survival for glioblastoma
multiforme is approximately
12 months. For anaplastic astrocytoma,
the survival is approximately
3 years, and for low-grade (World
Health Organization grade 2) astrocytomas,
5 to 7 years.[2] These grim
statistics make gliomas among the
most severe and deadly forms of
cancer. Despite over 3 decades of intensive
research and a variety of chemotherapy,
radiotherapy, and surgical
approaches, the prognosis for these
tumors has not changed significantly.

Standard of Care-2005

The current standard-of-care treatment
for gliomas includes cytoreductive
surgery (when feasible),external-beam radiation therapy, and
adjuvant chemotherapy during and after
radiation. Unfortunately, all of
these treatment methods have severe
limitations.

Surgery
Open surgical removal of brain tumors
has been a mainstay of glioma
management for decades.[3-6] The
goals of surgery are threefold: (1) to
alleviate mass effect and compression
of brain structures, (2) to restore normal
cerebrospinal fluid pathways, and
(3) to reduce the tumor burden for
other therapies. Unfortunately, total
excision of glioma is rarely possible.
Glioma cells are highly invasive, and
have been demonstrated 4 cm or more
away from the primary tumor mass.[7]
Most of these cells are interdigitated
with normal functioning brain parenchyma,
and resection of these regions
can result in unacceptable neurologic
deficits. Further, while gliomas rarely
metastasize outside the central nervous
system, they can disseminate
widely in both hemispheres of the
brain.

Tools to aid surgeons in differentiating
normal tissue from glial cells at
the periphery of tumors can improve
the extent of microscopic removal.
These methods include the use of tumor
fluorescence,[8,9] infrared imaging,[
10] and diffusion-weighted
tensor imaging of white matter pathways.[
11] The utility of intraoperative
magnetic resonance imaging in
this setting has not been validated.

Gross total removal of all enhancing
components of glioma has never
been clearly correlated with a higher
cure rate. However, cytoreductive
surgery to remove all of the enhancing
volume of high-grade glioma has
been correlated with improved length
of survival and improved quality of life
compared with biopsy alone.[3,6,12,13]
Despite its limitations, surgical resection
remains the most effective single
therapy for gliomas, especially when
tumors recur or progress.[12]

Radiation Therapy
Gliomas are not particularly radiosensitive
tumors. Radiation doses of
approximately 60 Gy and greater are
effective in retarding glioma progression
but have not been demonstrated
to provide long-term control.[14] To
some degree, increasing doses of radiation
have increasing efficacy on
higher-grade tumors, although most
dose-escalation studies have failed to
demonstrate improved survival.

Unfortunately, normal brain parenchyma
is also sensitive to radiation effects.
The tolerance against brain injury
decreases quite rapidly above 70 Gy,
effectively limiting total radiation doses
to the 60-70 Gy range. The use of
radiosensitizers has not proven to significantly
improve the effects of radiation
or long-term outcome.[15]

Chemotherapy
Systemic chemotherapy has proven
to be quite disappointing in the
treatment of gliomas. This is partially
attributable to the poor distribution of
drug in the brain due to the bloodbrain
barrier. Many agents, including
carmustine (BCNU [BiCNU]), lomustine
(CCNU [CeeNU]), procarbazine
(Matulane), and temozolomide (Temodar)
have demonstrated response
against high-grade gliomas. However,
these agents tend to produce fairly
limited or partial responses in both
upfront and recurrent settings. Most
recently, the combination of temozolomide
with radiation therapy in
patients with newly diagnosed glioblastoma
multiforme, followed by a
course of temozolomide, has been
found to increase median survival by
2 months compared to radiation alone,
with approximately 35% of patients
surviving beyond 18 months.[16,17]

Locoregional Methods

The limitations of these traditional
locoregional treatment methods, coupled
with the disappointing results of
systemic chemotherapy have led to
the development of alternative locoregional
treatment approaches. These
methods are outlined below.

Locoregional Radiotherapy
Improved delivery of high doses
of radiation to the main tumor volume
and immediate surrounding tissue
where infiltrating cells are most
numerous has been widely tested.
Brachytherapy with implantable I-125
seeds was frequently employed in the
1980s and 1990s, with good results in
younger patients but a high rate of
symptomatic brain necrosis.[18,19] In
more recent years, brachytherapy has
been largely supplanted by stereotactic
radiosurgery, with very similar
results.[20,21] These methods are generally
limited to small tumor volumes
of 3 cm or less. The addition of hyperthermia
has not proven beneficial
in this setting.[22]

Most recently, an I-125-filled balloon
(Gliasite) has been approved by
the US Food and Drug Administration
(FDA) for delivery of brachytherapy
in resected tumor cavities.
Early results with this method appear
similar to those seen with more traditional
brachytherapy seeds.[23] The
high rate of brain necrosis and general
failure of these methods to affect
the overall survival of patients with
glioma has limited enthusiasm for
these approaches.[20]

Targeted Radioimmunotherapy
and Radiopeptide Therapy

Nonviral targeted cancer therapies
principally depend on receptor-mediated
selective binding of drugs to tumor
cells. The success of this approach
requires high specificity or selectivity
of binding to tumor cells. This can be
accomplished by either overexpression
of receptors by tumor cells or
preferential expression of receptors
not found on normal brain tissues.
Because the blood-brain barrier effectively
limits the size of molecules
entering the brain, direct delivery of
these targeted therapies via a locoregional
delivery system is imperative
for most agents.

One approach for receptor-based
targeted therapy of glioma is the
utilization of tumor-specific antibodies
to selectively bind gliomas and
deliver various cytotoxic agents to the
tumor. Examples of this approach in
glioma therapy include targeting the
epidermal growth factor receptor
(EGFR),[24] fibronectin,[25] and the
extracellular matrix molecule tenascin-
81C6 with I-131-radiolabeled
ligands. A phase II trial of I-131-
antitenacin antibodies injected into a
postresection surgical cavity (doses
of up to 100 mCi) followed by radiotherapy
and chemotherapy was completed
in 33 patients with glioblastoma
multiforme. A median survival of 79.4
weeks was reported.[26] However,
imaging studies demonstrate that the
antibodies were too large to penetrate
beyond a few millimeters into the surrounding
brain parenchyma, essentially
neutralizing any potential targeting
advantage.[27] Furthermore, tenascin
is widely expressed throughout the
nervous system, and epidermal growth
factor receptor, while upregulated in
some gliomas, is also widely expressed
by normal brain cells, limiting
the specificity of these approaches.
Both of these compounds are now in
phase II clinical trials.

Targeted therapy of glioma with
smaller molecules has also gained attention
in recent years. Chlorotoxin, a
36-amino acid peptide identified as a
neurotoxin in a scorpion venom, has
been found to bind to a variety of
malignancies with minimal to no binding
on normal cells.[28,29] Although
the exact binding site for chlorotoxin
has not been clearly identified, a synthetic
analog of this compound has
been conjugated to I-131 and has undergone
phase I testing for recurrent
glioma.[30] The compound, I-131-
TM-601, was injected into the
resection cavity of 18 patients with
recurrent high-grade gliomas via an
Ommaya reservoir. Exquisite and
long-term binding of the radioligand
to the tumor was observed for up to 8
days postinjection. Median survival
in the trial was 5.7 months, with three
long-term survivors and two complete
responses. The main advantages of
this approach appear to be that (1) the
small size of the protein permits larger
scale diffusion in the brain and the
potential to cross the blood-brain
barrier,[31] (2) no toxicities have been
observed, and (3) it offers ease of
delivery. A phase II trial of this agent
is currently under way. Utilization
of the targeting strategy conjugated
to biologic toxins is also under
consideration.

Locoregional Chemotherapy
Methods of delivering higher concentrations
of chemotherapeutic
agents directly to the brain tumor have
been of great interest for many years,
and the strategies employed parallel
trends in methods of delivering a variety
of agents such as targeted toxins
and viral gene therapy. These delivery
methods will be reviewed in conjunction
with this discussion of
locoregional chemotherapy but apply
just as well to later topics.

The most obvious method for locoregional
delivery of drugs to a brain
tumor is direct injection of drug into
the tumor or tumor resection cavity
via an implanted Ommaya reservoir
or syringe at the time of surgical resection
or biopsy. This approach is
simple, can be performed by almost
any physician, and has been tested
with several drugs, including BCNU,
methotrexate, cisplatin, and cyclophosphamide.[
32] While toxicities
have been tolerable, tumor responses
have been very disappointing, resulting
in an abandonment of this strategy.
Lack of diffusion of these compounds
into the surrounding parenchyma is a
major limiting factor, and methods to
increase the tissue penetration of drugs
are being tested. A current trial of
intratumoral injection of BCNU dissolved
in ethanol (DTI-105) to increase
tissue penetration is the most
prominent example of this modified
approach.[33]

Intracarotid injection of chemotherapy
supplemented by methods to
transiently open the blood-brain barrier,[
34] has been studied for many
years. Again, the main goal of this
approach is to increase concentrations
of drug in the brain utilizing a "firstpass"
effect. Cisplatin and etopiside
have been most frequently employed,[
35,36] although many agents
have been tested.[37,38] Success with
this strategy has been variable, and
most studies have failed to demonstrate
a clear benefit in survival or
time to progression. There have been
no randomized prospective trials utilizing
this method. Further, it is highly
invasive, requiring a cerebral angiogram,
and complications such as blindness
due to infusion of the ophthalmic
artery have been reported.[35,39]
Improvements in angiographic technique
have reduced complications, but
these methods have failed to gain
acceptance as a standard method of
treatment.

Delivery of chemotherapy via timereleased
polymer wafers is currently
the only FDA-approved form of locoregional
chemotherapy.[40] Polifeprosan
20 with carmustine (Gliadel)
is a synthetic biodegradable polymer
wafer containing a 3.8% concentration
of BCNU.[41] Typically, six to
eight wafers are implanted directly
along the walls of a resected tumor at
the time of surgery. Several animal
and human studies indicate the effect
mimics a 4- to 6-week infusion of
BCNU. A phase III trial comparing
Gliadel to placebo wafers demonstrated
a slight improvement in median
survival of about 8 weeks.[40]

A main advantage of this form of
administration is that it avoids many
of the untoward side effects of systemic
BCNU such as thrombocytopenia.
The cost of the wafers roughly
approximates the cost of six courses
of systemic BCNU. Efforts to increase
the concentration of BCNU in the
wafers have led to increased adverse
events, although concentrations of up
to 20% have been achieved and felt to
be tolerable.[42] No agent other than
BCNU is commercially available or
FDA-approved in this formulation.
Various shapes of the polymer are also
being tested to ease insertion.[41,42]
Several other polymer-based methods
of cancer treatment are also being tested.[
43] In addition, several phase I
trials investigated the effects of combining
intracavitary chemotherapy
with systemic chemotherapy.[44]
FDA-approved in this formulation.
Various shapes of the polymer are also
being tested to ease insertion.[41,42]
Several other polymer-based methods
of cancer treatment are also being tested.[
43] In addition, several phase I
trials investigated the effects of combining
intracavitary chemotherapy
with systemic chemotherapy.[44]

Most recently, significant interest
has developed around the use of convection-
enhanced delivery (CED) of
chemotherapies to brain tumors. CED
refers to the process of applying uniform
positive pressure to overcome
the natural resistance of the surrounding
tissues and essentially "push" the
drug into the parenchyma. Using very
slow infusion rates (0.5-4 μL/min)
over long time periods (3-5 days),
one can deliver relatively uniform concentrations
of drug up to 4 cm away
from the tip of the infusion catheter,
with well-tolerated side effects and a
reasonable risk profile.[45] CED is a
rapidly advancing field, with improvements
in catheter placement, drug
delivery techniques, and drug preparation
all having an impact on the
potential efficacy of this method.

One phase I/II study of CEDdelivered
paclitaxel has been reported.[
13] This study of 15 patients with
recurrent high-grade glioma demonstrated
a 73% response rate (five complete
responses, six partial responses)
but also a high rate of complications.
Other drugs such as docetaxel (Taxotere)
have been tested, with more preliminary
results available.[46] Animal
models have suggested that this technique
may also be very promising for
brain stem gliomas.[47] Several other
studies are either under way or being
planned. CED seems particularly
promising for unresectable tumors and
as an adjunctive therapy before or after
radiotherapy.

Biologic TherapiesViral Gene Therapy
The promise of viral-based gene
therapy for glioma has prompted extensive
investigation. The basic concept
employed is that a virus acts as a
genetic "carrier" to deliver a transgene
to tumor cells. The transgene
either integrates into the host DNA or
uses the host cell replication mechanism
to produce a gene product, which
then effects tumor-killing. The exact
mechanism of tumor cell death depends
on the transgene product. The viruses
are usually packaged into murine cells
as a delivery vehicle and injected directly
into the tumor cavity.

The most widely utilized trangene
construct is the herpes simplex virus-
thymidine kinase (HSV-TK)/ganciclovir
system.[48-50] Transduction of
tumor cells with HSV-TK makes these
cells over 5,000-fold more sensitive
to the antiviral drug ganciclovir. When
cells infected with HSV-TK are
exposed to orally administered ganciclovir,
they are terminally phosphorylated
and die. In addition, a
prominent bystander effect occurs in
cells not infected with HSV-TK-presumably
due to cell-cell interactions-
that also kills noninfected cells.

Alternative prodrug strategies such
as the cytosine deaminase/fluorocytosine
(5-FC) system have been tested,[
51] although not clinically. In this
system, viral particles containing the
cytosine deaminase transgene infect
tumor cells, leading to the production
of the enzyme cytosine deaminase.
When cells containing the enzyme are
exposed to 5-FC, they convert the
5-FC to fluorouracil (5-FU), a potent
antitumor drug. Other strategies include
production of cytokines such
as interleukin (IL)-2 for immune
modification.

  • Retroviruses-The choice of a viral
    vector is of critical importance for
    gene therapy. Retroviruses have been
    most commonly used for brain tumor
    therapy. Retroviruses are RNA viruses
    that can integrate viral DNA into
    the host cell genome. Because most
    retroviruses preferentially infect dividing
    cells, they are ideally suited
    for use in tumors, especially brain tumors,
    where the majority of neurons
    are postmitotic and normal glia have
    a low mitotic index (< 0.5%).

    Adenoviruses-particularly replication-
    selective "oncolytic" viruses-
    have also been utilized for glioma
    therapy. The main advantage of this
    approach is that the virus can reproduce
    and spread to other cells, thereby
    increasing cellular killing. A
    replication-specific ("oncolytic") variant
    of the DNA virus HSV-1 has also
    been developed and tested in glioma.
    The main advantages of the HSV-1
    vector are its large transgene capacity,
    high titer level, sensitivity to
    ganciclovir, and lack of insertional
    mutagenesis in the host genome. A
    detailed discussion of viral and gene
    therapy strategies that have been tested
    for brain tumor therapy is beyond
    the scope of this article, but excellent
    review articles are available.[52]

  • Clinical Trials-Several clinical
    trials have been carried out utilizing
    viral gene therapy in recurrent highgrade
    gliomas. In the majority of these
    trials, murine virus-producing cells
    (VPCs) carrying a retrovirus producing
    the HSV-TK transgene were used.
    A phase I/II study in France with 12
    patients that received VPCs injected
    into the walls of the tumor cavity followed
    by 14 days of ganciclovir reported
    no treatment-related adverse
    events, a median survival of 206 days,
    and one long-term survivor.[49] A
    multicenter international phase II trial
    of 48 patients demonstrated a median
    survival of 8.6 months, with a
    12-month survival rate of 27%.[53]

    A phase III randomized trial of
    VPCs containing the HSV-TK was
    performed in 248 patients with newly
    diagnosed glioblastoma.[54] A total
    of 128 patients received the
    HSV-TK VPCs injected into the tumor
    cavity wall, followed by 14 to 27
    days of ganciclovir, and then radiation
    therapy, while the control group
    received surgery and radiation alone.
    Although the trial demonstrated the
    method to be feasible and safe, there
    was no change in median survival or
    progression-free survival in the group
    receiving the gene therapy, indicating
    a lack of efficacy. Several phase I
    or I/II trials have been carried out
    with an adenoviral HSV-TK. Results
    have been similar to those seen in the
    retroviral studies, although one study
    suggested that the adenoviral approach
    may have a higher rate of
    infectivity.[55] Finally, two phase I
    trials of oncolytic mutant HSV-1 have
    been performed, with a total of 30
    patients.[56,57]

    In all, these studies suggest that
    the viral transgene approach is appealing
    but currently very limited due
    to inability to infect a sufficient number
    of cells to have an impact on disease
    control. Of note, all of these
    studies have been performed utilizing
    direct injection of VPCs into the tumor
    cavity. Increased distribution of
    VPCs utilizing CED may also improve
    results in future studies.

Targeted Toxins
Mechanisms of cell-specific killing
other than radiation or chemotherapy
have been developed and
tested. Utilization of toxins produced
by bacteria is of current interest. These
toxins are usually taken up by cells
via active transport, resulting in inhibition
of protein synthesis and subsequent
cell death. Tumor-selective
targeting is accomplished by joining
these toxins with cell-specific antibodies
or ligands.

One example of this approach is a
chimeric fusion molecule made from
modified diphtheria toxin (DT) conjugated
to human transferring receptor
(Tf-CRM107).[58] Transferrin is
ubiquitously expressed on many cells
but is highly upregulated in rapidly
dividing cells, especially glioma. Conjugation
of DT to the transferrin receptor
mediates a dramatic increase
in sensitivity to cellular death. Tf-
CRM107 has been tested as an antiglioma
agent in several phase I and
phase II trials.[58,59] In these trials,
the agent was given via direct convection
due to its large size (128 kD)
and poor diffusability. In a phase I
trial involving 32 patients, Tf-
CRM107 was given intratumorally via
CED for a period of 3 to 45 days, at
rates of 0.5 to 4 μL/min. The drug
produced 2 complete responses and 8
partial responses, with 19 nonresponders
and many adverse events,
mostly neurologic. A phase II trial of
this same agent in 44 patients produced
an 11% complete response rate
and 16% partial response rate. Median
survival was 37 weeks. The most
severe drug-related adverse event was
brain edema, which occurred in six
patients. A phase III trial of this agent
compared with the best standard of
care is currently under way.

Another approach targets IL-13
receptors shown to be preferentially
expressed on gliomas.[7-9] Specifically,
a mutant form of IL-13, termed
IL-13?, has very high specificity for
overexpression in high-grade glioma.
Recombinant forms of IL-13 receptor
antibody coupled to Pseudomonas
exotoxin (PE) and delivered by CED
via a catheter, have completed earlystage
clinical development.[9,10]
Several phase I trials demonstrated
very promising tumor responses when
the CED catheters were placed at
least 2 cm from any sulcal or ependymal
surface, but minimal responses
otherwise.[60]

These studies emphasize the importance
of accurate delivery of the
compound to the tumor parenchyma
if targeted therapy of large-molecule
toxins is to be effective. A phase III
trial comparing IL-13-PE to BCNU
wafers after resection of recurrent
glioma is currently under way. Prominent
enhancement of the tumor periphery
that may mimic progressive
tumor is commonly seen following
administration of toxins but will often
resolve within a few months if corticosteroid
therapy is initiated. The delivery
of targeted toxins to the brain
via CED is a very promising and rapidly
advancing treatment option for
locoregional therapy.

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