A Review and Update: Gliomas
by Leonard
J. Cerullo, M.D.
Brain tumors account for nearly 1.4 % of all adult
tumors, with gliomas being the most prevalent and accounting
for 60% of brain tumors.(8) While neoplasms can arise
from either the neuronal or glial components of the
central nervous system, the glial tumors (gliomas) are
by far more important both in terms of frequency and
clinical aggressiveness. The most common gliomas are
those derived from astrocytes and oligodendrocytes.
These tumors vary in pathology, invasiveness, recurrence,
and resistance to treatment. Even their treatments differ.
More importantly, therapeutic options and outcomes vary
among the types and grades of tumor. In this CINN Foundation
Report, we will briefly discuss the key features of
each tumor class, as well as current views on treatment
options and new directions for future management, including
advancements in molecular research.
Tumor Classification
The World Health Organization (WHO) has developed a
classification scheme that rates (grades) gliomas from
the least malignant to the most aggressive tumor type.
The grading scale encompasses the various histopathological
delineations and ranks them from Grades I thru IV (sometimes
referred to as low vs. high grade). The most aggressive
tumors have been assigned Grade IV or glioblastoma multiforme.
The epidemiology of these tumors is extremely variable.
While it is extremely rare for primary brain tumors
to metastasize, metastases to the brain are a common
complication of other types of cancer occurring five
to ten times more frequently than primary glial tumors.
Clinical Presentation
The clinical manifestation of various tumors can be
appreciated in terms of tumor location, growth rate
and size. There are three issues to consider in terms
of symptomatology. First, tumor location plays a significant
role in the focal neurological deficits exhibited by
patients. For example, if the tumor is located in the
frontal lobe, there may be motor, mood or personality
changes. Similarly, tumors located in the dominant temporal
region may be associated with speech or memory disturbances.
Fast growing gliomas often produce increased intracranial
pressure (ICP). Elevated ICP can be the result of obstructive
hydrocephalus or edema, in addition to tumor burden
and failure of cerebral compensatory mechanisms to accommodate
the volume. In any event, the increased pressure will
most likely result in complaints of headache, visual
changes, vomiting, and nausea. Lastly, patients often
present with seizures, especially in the case of oligodendroglioma.
Again, the anatomical location of the mass would determine
the type of seizure (e.g., motor with frontotemporal
tumors and visual with occipital). In many instances,
tumors are discovered incidentally by cranial imaging
studies when a patient is seeking treatment for an unrelated
health issue or following a head injury. This more likely
occurs in benign, slow growing tumors.
Diagnostic and Treatment Options
Stereotactic Biopsy(9)
After imaging studies confirm the presence of an abnormality,
the first step in the treatment of any glioma is the
determination of the tumor’s cell type and grade
of malignancy. It is not generally accepted practice
to use results from imaging alone to diagnose a glioma,
unless the location is such that a stereotactic biopsy
or open biopsy would run an unacceptable risk of neurological
complication. A biopsy should be obtained at the time
of surgical intervention. If resection is not possible,
a stereotactic biopsy should be performed in most cases.
The stereotactic biopsy utilizes imaging and computer
technology to access the lesion through “silent”
areas of the brain through a burr hole. The obvious
advantage is that the procedure is minimally invasive,
thus reducing surgically related complications as well
as recovery time. The procedure can be performed under
local or general anesthesia. Following placement of
the stereotactic headframe, the patient’s brain
is imaged by Computed Tomography (CT), or Magnetic Resonance
Imaging (MRI) scan, or a combination of the two. The
entry point and target coordinates are then defined.
A small burr hole is used to access the surface of the
brain. The stereotactic probe is inserted using the
coordinates determined by computer analysis beforehand.
Obviously, the tissue sample is limited. As with any
surgical procedure, there are limitations and risks
to stereotactic biopsy. If the tumor is particularly
solid, the probe may displace it. The surrounding tissue,
rather than the tumor, will be sampled. There also is
the possibility of a sampling error. Since this is a
blind procedure, there is potential for damage to minor
or major blood vessels depending on the location. Intracranial
hemorrhage occurs in 1 – 3% of cases and may require
open surgical treatment or result in significant neurological
deficits. Furthermore, some targets may not be accessible
with this technique.
Surgical Resection
Surgical resection is typically the first line of therapy
in the treatment of gliomas. Resection is generally
followed by adjuvant therapies described below. The
goal of surgery is to maximally debulk the lesion and
establish a tissue diagnosis. “Gross total resection”
may be possible in lower grade lesions. True “gross
total resection” is rarely possible with higher
grade gliomas. There is debate on the value of extent
of surgical resection of high grade gliomas. Some studies
have indicated that if greater than 95% of the tumor
can be surgically removed, there may be enhanced survival
in high grade lesions. This, of course, selects fairly
well demarcated lesions in non-eloquent areas of the
brain. Therefore, this methodology does produce a selection
bias. New technology, including Image Guidance and Neurophysiologic
Monitoring, is allowing surgeons to more safely optimize
resection. Awake craniotomy is occasionally indicated
when resecting tumor in or near “eloquent”
brain. Awake craniotomies have been utilized in the
surgical treatment of epilepsy for decades. More recently,
this technique has been selectively utilized in conjunction
with cortical stimulation to allow for better outcome
and better quality of life. Intraoperative diagnostic
ultrasound can help compensate for brain shift when
using image guidance. Intraoperative MR is being investigated
in terms of cost/benefit in allowing a more complete
intraoperatively verified resection.
Radiation Options
Following surgery, radiation therapy is recommended
for higher grade lesions. This may either be conventional
fractionated radiation therapy with a significant margin
around the resected tumor bed (perhaps determined by
FLAIR sequence MR), or intensity modulated radiation
therapy (IMRT).iv IMRT allows for a more homogeneous
field coverage of a complex geometric shape. Both are
performed over several daily sessions. Hyperfractionated
irradiation is the use of two or more treatments per
day with fraction doses lower than conventional dosages.
In theory, this enables the radiation oncologist to
deliver a higher dose in the same overall treatment
time. Following the completion of conventional or IMRT
treatment, a boost to the tumor bed may be given using
focused ionizing radiation.ii Stereotactic radiosurgery
is the highly precise delivery of ionizing radiation
in a single session. The two major types of radiosurgery
delivery systems are the “fixed source” (Leksell
Gamma Knife®) and the movable source linear accelerator
(LINAC) devices. LINAC systems are either modified from
standard equipment or specifically designed for radiosurgery
(CyberKnife®, Novalis®). Stereotactic radiosurgery
may also be used in selective cases as an alternative
to reoperation at a later date.i There are volume limitations
to avoid excessive dosing of the previously treated
brain. Similarly, the presence of significant brain
edema may be a contraindication to the therapy.7
Brachytherapy is another focal radiation technique
that involves the implantation of radiation seeds (typically
radioactive iodine) at the tumor site at some time after
conventional radiation therapy. A major disadvantage
is that the procedure requires the re-opening of the
craniotomy. In addition, the radiation dose is less
conformal than stereotactic radiosurgery and may produce
significant necrosis. With the advent of stereotactic
radiosurgery, most surgeons have opted to use brachytherapy
less frequently or abandoned it completely.
Despite aggressive therapies and in even the face of
improved surgical resection techniques, the statistical
success in the treatment of high grade gliomas remains
dismal. Clearly, new approaches to genetic modeling
may offer more specific therapies designed for an individual
neoplasm. Good prognostic indices include younger age
of patient, higher Karnofsky scores, lower grade of
tumor and extent of surgical resection. Patients with
focal tumors do better than those with diffuse or multi-focal
lesions. At the time of recurrence (which is usually
at the site of the initial resection) a decision regarding
salvage treatment may be made. Treatments include re-resection,
stereotactic radiosurgery, and the use of implantable
gene modifiers.
Chemotherapy
Systemic chemotherapy is often used to complement surgical
resection and radiation for higher grade tumor. The
most frequently used drugs are Temodor®, CCNU, and
BCNU. The most promising drug today seems to be Temodar®.
A chemotherapy wafer impregnated with BCNU (Gliadel®)
is being utilized in specific cases as a local chemotherapy
treatment. The wafers are small dime-sized biopolymer
wafers that deliver BCNU directly into the tumor cavity.
At present, the wafers are being used at first resection
(if appropriate) and at recurrence. The principal advantage
of this technique is delivery of a higher concentration
of BCNU. It is likely that other agents will be used
via the same vehicle, which dissolves over two or three
weeks releasing the agent at a constant rate into the
tumor cavity and its immediate surrounding tissue.
Shortly, CINN will initiate a clinical research trial
designed to investigate a technology to enhance the
delivery of chemotherapy or targeted tumor therapy into
recurrent glial tumors. Positive-pressure Convection-Enhanced
Delivery (CED) infuses powerful anti-tumor agents (e.g.,
chemotherapy, gene therapy, immunotherapy) into the
tumor cavity and extends them deeper into the peri-tumoral
tissue. Early results are promising. CINN’s initial
drug will be a highly specific tumoral targeting agent
(Recombinant hIL13-PE38QQR cytotoxin). Selection criteria
for the study include patients who:
 |
have had previous cytoreductive
surgery establishing the diagnosis of glioblastoma
or biopsy surgery for GBM; |
|
have had previous cytoreductive
surgery establishing the diagnosis of glioblastoma
or biopsy surgery for GBM; |
|
have received external beam
radiotherapy with š 48 Gy tumor dose, completed
š 4 weeks prior to study entry; |
|
have clinical or radiographic
evidence of recurrent or progressive supratentorial
tumor less than 5cm in maximum diameter measured
less than two weeks prior to study entry; |
|
Gross total resection (i.e.,
š 95% resection of the solid, contrast-enhancing
tumor component) must be planned. |
The treatment time will extend from three to five days.
Genetic Research
Results from several studies indicate that tumors within
the same histological class are quite heterogeneous
from a molecular genetic perspective.(10) By identifying
key molecular markers, it may be possible to provide
targets for tumor treatment. Several researchers have
demonstrated that the mutation of the tumor suppressor
gene, p53, is indicative of tumor formation in astrocytic
tumors. Loss of p53 wild-type activity in cancer cells
has been considered to be a major predictive factor
in the failure to respond to chemotherapy11.
Given that some tumors express molecular mutations
that are predictive of their sensitivity to various
treatment strategies, these studies highlight the importance
of developing therapeutic approaches that will be applicable
to tumors with a range of genetic alterations. Ultimately,
these data may provide the foundation upon which to
develop new and more tumor specific drug therapies.
We have ongoing research investigating the use of chemo-immuno-gene
therapy combined with novel molecular genetic therapy
in hopes of creating another mechanism of treatment
for this otherwise fatal disease.
Alternative Therapeutic Options
Complementary and alternative medicine (CAM), as defined
by National Center for Complementary and Alternative
Medicine (NCCAM), a component of the National Institutes
of Health, is a group of diverse medical and health
care systems, practices, and products that are not presently
considered to be part of conventional medicine. While
some scientific evidence exists regarding some CAM therapies,
for most there are key questions that are yet to be
answered through well-designed scientific studies—questions
such as whether they are safe and whether they work
for the diseases or medical conditions for which they
are used.
By definition, complementary medicine is used together
with conventional medicine. An example of a complementary
therapy is using aromatherapy to help lessen a patient’s
discomfort following surgery. Conversely, alternative
medicine is used in place of conventional medicine.
An example of an alternative therapy is using a special
diet to treat cancer in lieu of undergoing surgery,
radiation, or chemotherapy that would normally be the
prescribed course of treatment. Examples of alternative
medical systems that have developed in Western cultures
include homeopathic medicine and naturopathic medicine.
Examples of systems that have developed in non-Western
cultures include traditional Chinese medicine and Ayurveda,
which has been practiced primarily in the Indian subcontinent
for 5,000 years.
Mind-body medicine uses a variety of techniques designed
to enhance the mind’s capacity to affect bodily
function and symptoms. Some techniques that were considered
CAM in the past have become mainstream (for example,
patient support groups and cognitive-behavioral therapy).
Other mind-body techniques are still considered CAM,
including meditation, prayer, mental healing, and therapies
that use creative outlets such as art, music, or dance.
Conclusions
Malignant gliomas continue to be among the most lethal
of human cancers. In some instances there are still
more questions than answers. However, technological
progress continues to provide insight and hope for increased
therapeutic outcomes. Moreover, there are therapies
(namely chemo-immuno-gene therapy) with tremendous potential
as a protective therapy against recurrence. Perhaps
another future direction is to begin by stratifying
patients according to their genetic diagnosis, and design
therapeutic modalities aimed at preventing malignant
progression. Although at the present time, no molecular
system for the classification of brain tumors has been
generally accepted, there are many unfolding technologies
that offer the exciting prospect of practical molecular
classification in the future.
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