|
The
epidemiological study of the brain tumors world wide
is limited, more so in India, due to various factors. It has been
reported that the incidence range is about is 1-10/100,000 depending on
the population studied. It is reported to be lowest in Mexico, and
highest in Israel. The incidence of Gliomas (primary brain parenchymal
tumors), the commonest brain tumor is about 5/100,000. The incidence of
Meningioma, the commonest benign brain tumor, is about 1.23/100,000. Metastases
constitute 30% to 50% of them.The Pediatric brain
tumors form 20-30% of childhood malignancy.
Pathology:
The etiology of brain tumors
remain largely unknown, except for the hereditary form of
retinoblastomas, genetically determined neurocutaneous
syndromes and rare examples of tumors resulting from radiation or trauma.
However, the following factors appear to
have a role:
Racial factors: Though brain
tumors are found throughout the world, certain
varieties appear to be less frequently seen in certain races. Germinomas are more common in Japan than elsewhere in
the world. Acoustic schwannomas have been reported to be rare in African
Blacks.
Familial and genetic factors: An inborn,
hereditary or inherited factor plays a role in the origin of gliomas.
Oncogenes, a class of structural genes, play a decisive role in the
development of neoplasms. Studies on malignant and low grade gliomas and
on glioma cell lines have led to some speculative hypotheses about
genetic pathways that may determine the transformation of normal glial
cells to glioblastoma cells. < 5% of glioma patients have a family
history of brain tumor. Several inherited diseases, such as tuberous
sclerosis, neurofibromatosis type I, Turcot’s
syndrome, and Li-Fraumeni syndrome, predispose
to the development of gliomas. However, these tumors tend to occur in
children or young adults and do not account for the majority of gliomas,
which appear in later years. Neurogenetic aspects
are discussed elsewhere.
Transformation of ectopic tissue
and vestigeal rests: Neoplasms, most
often benign in nature, are seen to arise from vestigeal
tissues. These include the teratomas and teratoid neoplasms, dermoid and epidermoid cysts, craniopharyngiomas and chordomas.
These are clearly of malformative origin.
Age and Sex: While medulloblastomas and cerebellar astrocytomas
are tumors almost entirely restricted to childhood, glioblastomas are
generally seen in the adult. Primary parenchymal tumors are twice as
common in males as in females, thus implicating obvious hormonal factors
in the etiopathogenesis. Meningiomas
are commoner in females, though some Indian and African neurosurgeons
found a slight male preponderance.
Trauma: While head
injury has been invoked in the pathogenesis of meningiomas,
there is no evidence that such an injury plays any significant role in
the development of a subsequent glioma. There are rare case reports of a
glioblastoma occurring in the tract of a leucotomy or at the site of a
gunshot wound.
Environmental factors: Prior cranial
irradiation clearly increases the risk of subsequent intracranial
neoplasms. Certain environmental factors have been tentatively linked to
the development of gliomas, but they apply to few patients. Severe head
trauma, chronic exposure to petrochemicals, or employment in the
aerospace industry may be predisposing factors. Some reports suggest that
with long term use of cell phones, there appears to be an increased risk
for cases with tumors in the temporal, temporoparietal,
or occipital lobe. No increased risk for brain tumors was found for
medical diagnostic x-ray investigations. Brain tumors are not associated
with lifestyle characteristics, such as cigarette smoking or alcohol use.
Irradiation: While gliomas
do not appear to have resulted from previous therapeutic radiation to the
head, this procedure might be an inciting factor in the production of an
intracranial sarcoma. The hazard appears particularly associated with
radiotherapy for pituitary adenomas and the resultant tumor is more
frequently a fibrosarcoma of the dura,
developing anywhere from 20 years later.
Chemical factors: Carcinogenic
chemicals have long been employed to induce intracranial tumors in
experimental animals. The most important of those are the
nitrosamines-both methyl and ethyl nitrosourea.
The exact mechanism of action is not clear, but may involve the binding
of polycyclic hydrocarbon metabolites to guanine in DNA. It must be noted
that to date no chemical carcinogen has been implicated in the production
of a human cerebral neoplasm. There is no specific evidence linking human
CNS tumors to chemical carcinogens.
Infective agents: Experimentally
a large number of viruses have been used for this purpose in animals. In
man the only known virologic disorder of the
brain associated with the production of bizarre astrocytes consistent
with cytologic features of malignant cells, is
the rare condition of progressive multifocal leucoencephalopathy.
Here virions belonging to the papova group of viruses have been detected. Some
patients with JC virus induced demyelination have developed multifocal astrocytomas
There is a wide histopathological
variability (click for WHO classification) in brain tumors. Most
brain tumors are named after the cells from which they develop. They may
be intrinsic and arise from both the glial cells (mature and immature neuroepithelial
cells), or extrinisic from the meninges, schwann
cells of the nerve sheaths, and the pituitary.
Local extension from tumors of the skull
or paranasal sinuses, metastasis from a distant organ, and occasionally,
primary CNS lymphoma,
form most of the rest. Hematological disorders, such as, leukemia, and
rarely, myeloma are the other possibilities.
Hamartomas from the vestigeal
remnants, and cysts
are also traditionally included in brain tumor category. Other rare tumors have also been
reported.
In fetal life
and the first two years, supratentorial tumors
are more common. Between 3 and 15 years infratentorial
growth is much more frequent. In adults, supratentorial
compartment is more commonly involved.
Intrinsic tumors produce regional
parenchymal effects include, compression, invasion and destruction
of surrounding brain leading to hypoxia, competition for nutrients and
spread of necrosis. Diffuse Intracranial effects include elevated
intracranial pressure due to tumor induced increases in the volumes
of brain, blood and CSF, vasogenic
edema, infarction due to venous or arterial occlusion, and alteration in
the balance of CSF production and absorption.
Extrinsic lesions, such as meningiomas,
displace the brain, thereby compromising the brain function. In late
stages, there may be degeneration,
hemorrhage or necrosis. Peritumoral cysts
arise from adhesions and accumulation of protein containing CSF, reactive
gliosis, fibroblastic proliferation in the final stage of peritumoral edema or rarely as an exudate from the
tumor surface, and behave like an intrinisic tumor.
There may be associated hydrocephalus
which may be due to obstruction to CSF pathways, or change in CSF
dynamics. It is more frequent in infratentorial
lesions.
While
the brain is a favorite site for metastases from tumors from the rest of
the body, it is well known that central nervous system tumors do not
metastasize outside the nervous system, except on rare occasions, when
surgery has resulted in contact of the tumor with extracranial tissues.
Malignant
cells have been found in the veins in the neighborhood of a malignant
glioma. Similarly such cells are also released into the
CSF. There may be an immunological defence
of the body tissue to the circulating malignant glial cells. On the
contrary, the brain itself seems to be incapable of any significant
degree of defence response. Though there
are no lymphatic channels in the brain, mononuclear cells expressing T
lymphocytes and macrophage cell surface markers have been identified in
the perivascular spaces of the brain. It has also been observed that
a third of all human gliomas show lymphocytic and mononuclear
infiltration mostly around the blood vessels. Gliomas containing such
infiltrates had a longer survival.
There are a few reports of the presence
of sensitized lymphocytes as well as humoral antibodies in patients with
gliomas. Considerable evidence indicates that tumors in man and
animals can provoke an immune response in the host, thus providing the
basis for employing immunotherapy in the treatment of human tumors.
In the perivascular lymphocytic collections, cytotoxic and suppressor T
lymphocytes are predominant. Monocytes, macrophages with cell surface
expression of major histocompatability
antigens, are also present. Abnormalities in cell mediated and
humoral immunity occur in patients with gliomas. Abnormalities in
cell mediated immunity are more severe in patients with higher grade
gliomas.
Clinical
features:
The
evolution of illness is usually insidious and progressive. Occasionally,
as in intratumoral bleed, the symptoms may be
acute. Shorter duration usually suggests malignancy. In most cases, the
general clinical manifestations are due to elevated intracranial
pressure, whereas focal signs and symptoms reflect tumor action on
adjacent structures.
A
patient with a 'brain tumor' may present with one or more of the
following:
Symptoms
and signs of raised intracranial pressure: Early morning
throbbing headache which gets worse progressively suggest increased
intracranial pressure, especially when associated with projectile
vomiting. There may no nausea. Vomiting is more common in children. Site
of headache has some importance occasionally. Pain at the back of head
may indicate tonsilar herniation.
Papilledema
and visual failure suggest long standing increased intracranial pressure.
Disturbed
concentration, judgment, and memory, may result from increased
intracranial pressure. On the contrary, most children with raised ICP,
are well behaved and mature in their actions.
Focal
or generalized epilepsy: Seizures occur in about 30% of all brain
tumors, and about 50% of all supratentorial
tumors. 1% of all with epilepsy have brain tumors. A tumor must be ruled
out in any late on set epilepsy. It is the first symptom in 50% of
temporal tumors, 78% of frontal tumors, and 93% of central tumors.
Generally, seizure as the only symptom suggest a benign or low grade
lesion. It may be focal or generalized. Focal seizure may suggest the
site of lesion. In late stages of increased intracranial pressure
seizures may occur irrespective of tumor location.
Symptoms
related to location: Patients with left sided dominant hemispheric
lesions may have language deficits, difficulty with verbal learning and
memory, problems with verbal reasoning and impaired right sided motor
dexterity. A higher incidence of depressive disorders along with dementia
and psychotic symptoms is also seen. On the other hand, right hemispheric
tumors may produce visual perceptual difficulties, difficulty in facial
recognition and defects of left sided motor dexterity.
Frontal
lobe
lesions often results in profound changes in personality and behavior.
Convexity involvement tumors may manifest with depression and motor programming deficits and impaired speech
initiative. Orbitofrontal involvement is associated with some degree of
impulsivity, lack of inhibition, tendency to make puerile jokes with
silly laughter, and a lack of concern. Medial frontal involvement is more
likely to manifest as an inflexible attitude, apathy, and impaired
motivation.
Temporal
lobe
lesions, most commonly, produce seizures, with olfactory and gustatory
hallucinations. Impaired visual and auditory functions can occur.
Inferior temporal or temporo limbic involvement
leads to psychiatric symptoms, more commonly with dominant sided lesions.
Involvement of insula, claustrum, and para hippocampal gyrus may produce
panic attacks and anxiety.
Parietal
lobe
involvement is suggested by cortical sensory disturbances, such as
tactile localization, joint position sense; sensory inattention, loss of
awareness of the affected half of the body, may be an early feature.
Progressive weakness may be seen in motor strip involvement.
In
occipital lobe tumors, visual field defect is common. Cortical
blindness can occur.
Features
of associated hydrocephalus may be predominant in midline lesions.
Sella and parasellar lesions present with
visual, hypothalamic-pituitary dysfunction and neighborhood cranial nerve
dysfunction may be there. Lesions near the falx
may cause bilateral signs. Irritation of the supplementary motor area
may result in focal seizures.
Basal
ganglia
lesions result in abnormal movements, rigidity or tremors.
Tumors
involving the hypothalaums usually
present with hypothalamic-pituitary dysfunction.
Intraventricular tumors usually
present with features of hydrocephalus.
Brainstem
lesions
are associated with lower cranial neuropathies with hiccups and
swallowing difficulties. Pupillary abnormalities can occur.Bilateral
limb weakness with hypertonia and sensory disturbances may occur.
Features of associated hydrocephalus may be present.
Cerebellar lesions present
with incoordination and ataxia. Cognitive dysfunction may manifest in
children. Cerebellopontine angle tumors , in
addition to cerebellar signs, may exhibit lower cranial dysfunction.
False
signs:
A disturbance of blood supply to distant areas or by shifts and changes
in the position of various structures may lead distant effects which may
present as the primary symptoms. Abducent nerve
paresis is the most common, due to its long intracranial route. However,
such false signs occur only in late stages, which should be rare these
days.
Deformity
of head: Macrocrania is common in
infants. Localized skull swelling due to long standing lesions may occur
in adolescents. Malignant tumors may erode the skull and present as skull
deformity.
Investigations:
Skull X-rays, angiograms, ventriculograms, pneumoencephalograms
have become history and been replaced with CT and MRI these days.
Magnetic resonance imaging (MRI) , introduced by Moorey
and Hinshaw in 1979, has made
enormous strides and is the imaging of choice these days. MRI imaging,
particularly, contrast enhanced is much more sensitive than CT due to
inherent high contrast and spatial resolution, multiplanner
capability. Soft tissue changes, mass effect, and the distorted anatomy
are better demonstrated by T1 images. T2 images demonstrate the extent of
tumor edema complex. Contrast enhanced MRI is important to assess the
vascularity and the blood brain barrier(BBB) break down.
Computerized tomography (CT)
scan, introduced
by Hounfield in 1967 has equally
improved in leaps and bounds. It may be an alternative when MRI is not
available, and is particularly useful to study the associated bone
involvement. 3D images are as informative as a MRI. Contrast enhancement,
as in MRI, indicates the vascularity and
BBB breakdown.
CT
anigiogram and MR angiogram have
replaced the conventional 4 vessel angiography. The tumor vascularity, incasement,and displacement
of major vessels, and involvement of venous sinuses may be studied
adequately, before surgery.
Limitations of structural MR/CT imaging, include, limited prognostic value, poor indicator of
true extent of tumor, especially in high grade
lesions,
post-treatment changes (surgical, radiation) which limit capability to detect tumor
recurrence,
overlap in imaging appearance among tumor
types and between tumors and non-neoplastic
lesions, with potential implications for treatment approach.
Magnetic resonance
spectroscopy (MRS) is
a non-invasive analytical technique that has been used to study metabolic
changes in brain tumors, strokes, seizure disorders, Alzheimer's disease,
depression and other diseases affecting the brain.
MRS can be done as part of a routine MRI
on commercially available MRI instruments. MRS and MRI use different
software to acquire and mathematically manipulate the signal; the
difference is the use of a state of the art technology that analyze the
chemical composition of proton (hydrogen)-based molecules, some of which
are very specific to nerve cells. This technology evaluates the chemical
composition and integrity of functioning upper motor neurons in the
brain, particularly motor neurons.
It has also been used to study the
metabolism of other organs.
Unlike magnetic resonance imaging (MRI),
which gives us a picture of anatomical and physiological conditions, MRS
generates a frequency domain spectrum that provides information about
biochemical and metabolic processes occurring within tissues. It is very useful in distinguishing destructive
lesions from neoplastic processes. In addition, it provides a definition of
tumor grade, aggressiveness, and relevant biochemistry. It also helps in
monitoring of a successful tumor response before its regression during
non-surgical treatments, and conversely the early definition of tumor
recurrence. Increased choline, decreased NAA, increased lactate,
increased Lipid, and decreased total creatinine, are the biochemical
defects in varying degrees , common to the majority of brain tumors as
measured by MRS. However, it is not reliable in irregularly shaped and cystic lesions.
Recently, multi Voxel chemical shift imaging has shown promising results.
Positron emission
tomography (PET) scan uses a small dosage of a chemical called
radionuclide combined with a sugar. This combination is injected into
patient. The radionuclide emits positrons. A PET scanner will rotate
around a patient's head to detect the positron emissions given off by the
radionuclide. Because malignant tumors are growing at such a fast rate
compared to healthy tissue, the tumor cells will use up more of the sugar
which has the radionuclide attached to it. The computer then uses the
measurements of glucose used to produce a picture which is color coded.
It is ideal for measurement of blood
flow, glucose metabolism, receptor binding, DNA and protein synthetic
processes
and helps in distinguishing recurrent high
grade tumors from radiation necrosis, and lymphoma from infectious lesions in AIDS. It is of
limited value in small lesions(< 1cm).
Single photon
emission tomography (SPECT) is more widely
available and less expensive. It utilizes isotopes to study cerebral
blood flow and tissue metabolism of glucose and amino acids, and helps in
distinguishing recurrent high grade tumors from radiation necrosis, and lymphoma from infectious lesions in AIDS, similar to PET
scan. However, it has poorer
resolution and decreased sensitivity as compared to PETscan.
Functional
MRI (fMRI) is
a convenient technique for providing complimentary information to other
imaging studies. fMRI offers possibility of
performing these cortical localization routinely and in existing rather
than new instrumentation. It is an indirect way of assessing the neuronal
integrity. Neuronal activity results in a disproportionately increased
cerebral blood flow in the region causing an overcompensation of the fall
in oxyhemoglobin. Reduced deoxyhemoglobin and increased oxyhemoglobin
levels contribute to the fMRI signal which is subsequently processed and
activation maps created. fMRI has been used to
map the sensorimotor cortex, visual cortex, primary auditory cortex,
association areas and language regions. This preoperative mapping allows
evaluation of surgical feasibility and approach. It can also provide
information post surgical recovery. It can also
be used to visualize epileptic focus. It is likely to replace wada test.
CSF
Cytology,
whenever possible, may give a clue to the nature of the tumor,
especially in high grade lesions. In addition to neoplastic cells, tumor markers, such
as alpha fetoprotein (AFP) and human chorionic gonadotropin (HCG) are
useful for diagnosis and monitoring therapeutic responses.
Histopathology gives the final
diagnosis so that optimal treatment
and prognosis can now be determined.
Tumor
pathology may be studied at operation (by frozen section or by
cytological preparation), or in the postoperative period.
A
comprehensive range of histochemical, and molecular biological tests can
be performed on sections of frozen or formalin-fixed, paraffin embedded
tumor tissue using light and electron microscope techniques. When a tumor
is morphologically undifferentiated or anaplastic, its nature may be
revealed by immunohistochemistry
which demonstrates the expression of proteins that characterize
particular cells. One example would be the presence of glial fibrillary
acidic protein (GFAP) in astrocytic tumors and other gliomas. An
alternative approach is to examine the tumor at the ultrastructral
level for diagnostic cytological features, such as core vesicles in
tumors of neuronal origin.
Management:
Symptomatic
medical therapy
is discussed elswhere.
Surgery in some tumor
types, such as meningiomas, and
schwannomas, surgery may be curative. Surgery has a
central role in interdisciplinary glioma management, currently
representing its basic therapy (discussed elsewhere).
Total excision is the goal, with
resultant improvement in neurology and quality of life.
The
proximity of vital brain structures may limit the ideal goal of complete
tumor removal with preservation of function.
Surgery
may not be offered to patients who might benefit from it on the
assumption that their tumor is too close to so-called 'eloquent' brain,
such as the areas responsible for controlling movement or speech.
Nowadays,
a variety of tools are available to help the neurosurgeon counter this
problem.
Recent advances
have
made removal of a strategically located tumor possible.
Stereotactic
craniotomy (with or without a frame) involves
preoperative localization the lesion stereotactically.
A small superficial cortical or subcortical
lesions or deep lesions that can be easily missed by conventional means;
and also when accurate
localization is crucial to excise tumors in highly eloquent areas.
Brain mapping, also termed
cortical mapping, with awake craniotomy, uses electrical stimulation
of the cortical surface to define areas of functional cortex, such as
primary motor, sensory, or speech cortex. By pinpointing the exact
location of these areas prior to tumor resection, the surgeon can perform
a more aggressive resection and still safely avoid these structures,
thereby preserving neurologic function. Recent advances in imaging
techniques allow for nonivasive brain
"mapping", by which the precise relationship of areas
controlling brain function to a nearby tumor can be determined. One such
method is functional MRI, or fMRI.
Neuronavigation
using, a
sophisticated computer, which is capable of taking information from
the CT and MRI scans is used intraoperatively in advanced centers. It
creates a display on a computer screen in the operating room which the
surgeon can use during surgery. It is able to use a special pointer in
the area where surgery is being performed, and that location will be
displayed on the screen in reference to the abnormalities on the imaging
studies. During the procedure continuous exhibition of the distance as
well as the orientation towards the target point minimizes unnecessary
destruction of brain tissue.
MRI and CT images are superimposed on
volume in the stereotactic space which allows a volumetrical
tumor resection as well as staying oriented within the lesion during
resection.
Robotic
surgery
has been developed in various surgical specialties including brain and
spine surgery. The evolution of robotic neurosurgery
has been very rapid since the first robot assisted surgery by James M
Drake in 1991. It can perform brain
surgery that was not possible till now. It is supposed to perform so accurately
in areas where human hand till now was not considered absolutely safe.
The
robot is guided by extremely high resolution brain scans, allowing it to
work to an accuracy of a millimeter, marking it possible to operate close
to vital parts of the brain. In contrast, neurosurgeons operating by hand
have an accuracy of only a couple of millimeters and have to avoid
various operations in case they cause permanent and possibly fatal
damage. There are large areas in the brain that the surgeons are unable to
operate upon.
A computer controlled robotic system that positions and
inserts an 'Endoscopic Surgical Laser' through a hole in the skull 3 mm
across. The robot head needs a path through the brain only 1 mm wide.
Tests suggest that the robot will be able to remove a tumor in about half
an hour but more complex operations may take several hours, but unlike human surgeon
the robot doesn't get tired. With little damage to the skull and the
brain the patients should be able to leave the hospital in 24 hours.It may be just a beginning. The uses of such a
robot may be numerous.
Endovascular
procedures have contributed in successful excision of highly vascular
tumors.
Modern anesthesia have greatly helped the surgeons towards
his goal.
Various multidisciplinary approaches, involving the ENT and
plastic surgeons have been refined and complex skull base tumors can now
be excised with satisfying outcome.
In 1957, Yasergil introduced Intraoperative microscope
in Neurosurgery. A quality microscope in mandatory.
CUSA (cavitron
ultrasonic aspirator) by Epstwein, and
laser by Tew in 1983, facilitates tumor
resection.
Intraraoperative endoscopy was
introduced by Oppel in 1987.Neuroendoscopic
techniques, even though in its infancy, have greatly reduced the
morbidity in selected procedures. Use of endoscopy,
during microsurgery greatly facilitates in visualization of vital
neighborhood structures, such as brainstem in acoustic surgery, with
minimal brain retraction.
'A fool with a tool is still a fool'.
All the recent advances are not a substitute for meticulous microsurgical
techniques.
Various approaches and
modifications are discussed in individual tumor discussions.
Radiotherapy plays a central role
in the treatment of most brain tumors, whether benign or malignant.
It is discussed elsewhere.
In
selected, strategically located benign tumors, such as, acoustic
schwannoma, radiosurgery
is increasingly being used with success, especially in residual lesions.
Very occasionally, pre operative radiotherapy is employed to reduce the
tumor vascularity.
Chemotherapy forms an
essential adjuvant therapy in gliomas. It is discussed elsewhere.
There are occasional reports on
use of Tamoxifen, and Bromocriptine in meningiomas.
Use of bromocreptine
is well established in pituitary prolactinomas.
Genetherapy is discussed
elsewhere. Perhaps the most appealing means
of curing brain tumors is to correct the underlying defects in the genes
that lead to tumor control. Genes that promote growth could be turned
off, those that suppress growth could be turned on, defective monitoring
mechanisms could be turned on, genes that
produce a beacon for the immune system could be delivered, and so on.
Gene therapy has been used successfully in mice to rid them
of primary and secondary tumors. The principal problem with gene therapy
as the primary treatment of brain tumors is that, in theory, every tumor
cell must be treated with gene therapy. If even one cell escapes, it
could regrow into a large tumor. It is in the experimental stage,
with encouraging reports as an adjuvant treatment for gliomas. However, there
appears to be a role in meningiomas and other
benign tumors as well.
For
patients with brain tumors, gene therapy offers the hope of replacing the
defective genes, amplifying the immune response to cancer. The malignant
phenotype of a brain tumor results from a series of mutations, including
genetic deletions. Therefore, the simple paradigm of replacing a
defective protein does not typically apply to children with brain tumors.
While it is possible to inject enough reparative genes into
a tumor in a mouse to eradicate the tumor, it is quite a different thing
to inject enough gene therapy into a human brain tumor, which is likely
to be much larger. To date gene therapy has been shown to kill human
tumor cells, unfortunately, current delivery mechanisms are inefficient
and unable to deliver enough to cure the whole tumor. Nonetheless, gene
therapy may well become an important future treatment of human brain
tumors, alone or in combination with the above therapies. Further study
is required.
Immunotherapy represents a
promising new class of treatments that, in theory, could confer lifelong
immunity to a variety of tumors affecting the brain and is still in
experimental stage as a treatment for gliomas.
In theory, the body's immune system should recognize tumor
cells as abnormal and then attack and destroy them. This immune
surveillance probably occurs daily and destroys many early tumor cells. A
tumor cell may develop, however, that can fool the immune system by
making substances that block the signals that tell the immune system to
seek and destroy the abnormal cells. Or, the body's immune system may be
weakened by HIV infection, drugs, or alcoholism and allow tumor cells to
escape control. Animal studies have shown that a healthy immune
system that is being fooled by the tumor can be taught to recognize the
tumor and resume its control duties.
This
is a form of therapy aimed at activating the patient's own immune system
in order to kill tumor cells. This group of substances includes the
interferons, interleukins, growth factors and others.
Radioimmunotherapy with Monoclonal
Antibodies.
Radioimmunotherapy is showing special promise
as a treatment approach to brain tumors. It typically employs monoclonal
antibodies (MAbs), which are genetically
engineered antibodies designed to work against a specific target. MAbs are bound with radioactive substances and
delivered directly into the brain and sometimes into the tumor. The MAbs are specifically designed to lock with the
surface of certain cells in the tumor. Once they do so, the radioactive
substances destroy the cell.
The approach is essentially
mini-radiation therapy without the damage or severe side effects of
standard radiation treatments.
A number of different radioimmunotherapies are being investigated, and
trials of some are reporting improved survival rates in high-grade
gliomas. Some experts believe this approach could prove to be the most
effective therapy against these cancers.
Interleukins. Interleukins
are natural proteins created by the immune system. Certain tumor cells
carry receptors for specific interleukins, which are being investigated
for a possible therapeutic role. For example, some drugs combine an
interleukin with an agent that is toxic to cancer cells. The interleukin
locks onto the receptor on the cancer cell and the toxic chemical enters
the tumor with the intent to kill it. Some interleukins are also being
investigated alone for their own tumor-cell killing properties.
Tumor
Vaccines.
Tumor cells removed from the patient are inactivated to form a vaccine;
when they are transferred back to the patient, they are harmless but can
elicit a powerful immunologic response against the tumor. For example, a
vaccine that combines tumor proteins with the patient’s nerve cells is
being tested in astrocytomas.
Efforts to
augment patients’ immune responses to tumors by means of enhancing
agents, passive immunity, and adoptive immunity have been
ineffective. Active immunotherapy by administration of interferon,
interleukin-2 and/or lymphokine-activated
killer cells (LAKC) however, yielded encouraging results in some trials.
Since the tumors are extremely heterogeneous with respect to cell cycle,
antigen-expression and growth-factor/cytokine susceptibility,
immunotherapy has to be improved before it becomes apart
of standard therapy protocols.
Angiostatic Therapy is a promising new technique. Many tumors
produce substances that promote the growth of new blood vessels to help
provide oxygen and nutrients for their nearly insatiable needs.
Eventually these tumor cells become dependent on these new vessels.
Substances (antiangiogenesis factors) that
inhibit these blood vessels, thereby starving the tumor cells. These
factors can obliterate certain malignant tumors in mice, although they
have not been used in humans.
Angiogenesis
inhibitors are drugs that interfere with the growth of blood vessels in
the tumor, effectively starving tumors of vital nutrients and oxygen.They include the following:
Thalidomide was one of the
first drugs tested. In one 2001 study of recurrent glioblastoma the
one-year survival rate was 35%. Researchers are investigating different
doses to improve results.
Suramin,
another angiostatic agent, produced a delayed
response in some patients with high-grade gliomas and was well tolerated.
Antiseizure medication did not affect it. It is
now being studied in combination with radiation therapy.
A number of similar agents
are under investigation. Recent reports have suggested that these drugs
may lead to a cure of cancer within two years. Although this predication
may prove to be true for some tumor types, primary brain tumors are,
unfortunately, composed of cells that are metabolically voracious and
cells that have much more modest requirements.
Antiangiogenesis
treatment, if it works, may only turn high-grade tumors into lower-grade
ones. Furthermore, there are situations in which production of new blood
vessels is important for health. The role of antiangiogenesis
factors in humans is promising but remains to be defined.
|
