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The primary goal of management of
gliomas is not only to prolong the survival, but also to protect/improve
the neurological function. Treatment strategies should be such that it
should achieve total ablation of the tumor without morbidity, and prevent
or delay the recurrence.
Emotional
support for the patients
and their families is a critical component of treatment and management,
because of the low-curability rates of most malignant brain tumors.
Experts have made a number of recommendations to help both patients and
caregivers:
Any physical impairment that could
benefit from home equipment or physical therapy should be identified and
treated.
Patients should discuss emotional as
well as physical issues with their physicians. Depression, for instance,
can be medically treated.
Relaxation techniques, meditation, and
spiritual resources can be extremely helpful. Support groups are
beneficial, but experts recommend separate groups for patients and their
families.
The
children with cancer have no more emotional or social problems than their
healthy peers. In fact, teachers and students reported that, on average,
such children tended to be less aggressive and more likable than their
peers. It is more likely that the parents and caregivers suffer more
emotionally. Caregivers themselves must seek help for the inevitable
stress, depression, and tension arising from their difficult role.
Medical therapy is symptomatic and usually
involves the use of steroids, and anticonvulsant medication in
addition to analgesics, and antiemetics. Side effects of steroids can be
significant, and all patients should be treated with an H2-receptor
blocker. The dose of steroids should be tailored for each patient and
assessed on a regular basis. It is better to avoid late-night dosing if
possible, as it can lead to sleep disturbances and behavioral problems.
The
typical dexamethasone dose employed by most physicians
preoperatively is 4 mg (po/IV) every 6 hours, and the dose is tapered postoperatively.
Patients need to be followed closely during the tapering period.
Antiepileptic drug
practice has historically been dependent on the neurosurgeon's
preference, and most patients are started on prophylactic
anticonvulsants. It is recommended that prophylactic anticonvulsants is
not required in newly diagnosed brain tumor patients who have never had a
seizure. he patients who have had seizure need to continue the
anticonvulsants post operatively.
Surgery continues to be
its basic therapy and plays a central role in interdisciplinary glioma
management.
Rickman Godlee performed the
first surgery for a glioma in 1884.
Cushing, Dandy, and Krause
redefined the neurosurgical principles in the early 90s.
Today's surgeon has a battery of tools
in imaging and surgery.
The principles and techniques of surgery
and adjuvant therapy are the same for all intrinsic brain tumors.
The sites and types of tumor may
necessitate minor modifications, and are discussed elsewhere.
Various
surgical options are available, and the surgical approach should be
carefully chosen to maximize tumor resection while preserving vital brain
structures and minimizing the risk of postoperative neurologic deficits.
The
choice of operative approach depends on the location, size, gross
characteristics (extent of demarcation, consistency, and vascularity),
probable histology, and radio sensitivity of the tumor, as well as on the
neurological status and general condition of the patient, and, of course,
the surgeon's technical ability, and available tools.
Open Surgery:
A
meticulous preoperative planning is mandatory. The planning starts
at bedside.
Intrinsic
tumors, generally, is confined to sulcal boundaries, and do not cross
pial barriers.
A
proper history and clinical examination, obtained at the bedside, may
give a 'clue' about the exact site where the tumor started, and help in
tumor excision. A tumor, which appears to be a fronto-parietal on
CT/MRI, may be actually a frontal tumor starting in the frontal lobe and
growing backwards pushing the central sulcus backwards, and will have
significant motor deficit with no sensory deficit at examination. Hence a
generous excision may be planned, and will not damage the motor strip.
A
thorough pre operative study of all radiological imaging must be
reviewed, with special attention to tumor location and neighborhood
'eloquent areas', vascular channels, central sulcus, sylvian fissure
,widened sulci overlying the tumor, and other safe corridors; special
reference to be made to the preferred position of the patient at surgery,
and aim of the surgery.
"The
brain floats in a sea of CSF, with rivers of CSF which allows access to
its interior", says Yasergil.
Recent advances in neuroimaging with
MRI, MR/CT angiogram, MR spectroscopy, and functional MRI have greatly
helped the surgeon decide on the so called 'safe corridors'.
Preoperative corticosteroids
provide rapid, often dramatic, symptomatic improvement. Therapeutic
effect of steroids is limited to 6-8 weeks. The daily standard dose
is 16 to 24 mg for dexamethasone and 80 to 120 mg for
methylprednisolone. Dose-related symptomatic improvement with
minimal side effects has been shown for up to 96 mg of dexamethasone and
500 mg of methylprednisolone daily. The effects of corticosteroids
include, reduction of tumor mass, reduction of peritumoral edema,
decrease in permeability of the blood-brain barrier, and increase in cell
cycle time.
All
patients with a history of seizures should receive anticonvulsants.
The
prophylactic use of anticonvulsants is controversial similar to the use
pre operative antibiotics.
Position
of the patient at surgery is most important.
The
site of lesion, the familiarity of the surgeon should be taken into
account.
Osmodiuretic
therapy is very useful in both an emergency and a peri-operative
situation.
A
surface marking of sagittal sinus, central sulcus and sylvian fissure
will help in their protection at surgery.
Sylvian
fissure - a line drawn from nasion to
lambda (approximately corresponds to EOP).
Rolandic
fissure - a line perpendicular to the midpoint of a
line drawn from outer margin of the eyebrow and the tragus.
It
is then possible to outline the frontal, parietal, and the temporal
lobes.
Posterior
to a line from the lambda to the posterior mastoid is the occipital lobe.
Individual
variations is the rule.
The
scalp incision should provide sufficient exposure of the relevant
cranium, maintain adequate blood supply to the scalp flap and minimize
cosmetic deformity. Traditionally, various classical flaps have been
described.
Infiltration
of 2% xylocaine and adrenaline (1:200,000) mixture, if permitted by the
anesthetist, in the connective tissue overlying the galea helps in
dissection as well as controlling the blood loss.
Bone
removal
should preserve blood supply to the bone plate, avoid air sinuses, remove
sufficient bone to permit identification of cranial and parenchymal
landmarks, achieve brain retraction without compression, and avoid
extensive exposure of uninvolved cortex. Most surgeons advise a generous
craniotomy for gliomas.
In
the author's experience, a generous craniotomy do not add to benefits.
A
dural flap is turned towards the venous sinus closest to the exposure,
taking precautions to avoid the cortical veins.
Use
of a quality microscope in tumor removal from this stage is the
order of the day.
Neuroendoscope
assisted microsurgery is becoming popular, and helps in exploring the
corners with minimal brain retraction.
'En
bloc resection' may be achieved in a surface (lobar) tumor an area that
is either clinically silent or already non-functional. Technical
refinements in surgery with subpial dissection or transsulcal approaches
with brain mapping and awake craniotomy has helped for tumors at eloquent
areas.
In
lesions over the sulci, the transit vessels must be preserved as they may
be supplying the normal brain.
A
subcortical tumor can be identified by distortion of neuroanatomical
landmarks.
The
overlying gyri may be flattened and pale due to paucity of
vascularity.
Gentle
palpation and /or needling with a brain cannula may help in the absence
of surface changes.
A
glioblastoma is softer, whereas a low grade glioma would be firmer with
respect to the surrounding parenchyma.
Alternatively,
delineation of the subcortical dimensions by real-time B-mode
ultrasonography, or performing a cortical incision under stereotactic
guidance, if available, may be carried out.
Overlying
cortex may be removed in 'non eloquent' areas and the tumor may be
debulked from inside out.
Piecemeal
excision is preferred. The common oncologic principles of surgical
excision cannot be applied to brain tumors; clearance margin of 1.5 to 5
cms around the tumor margin cannot be given in most brain tumors in view
of risk of severe morbidity. The surgeon is forced to enter the tumor and
debulk it before excising the capsule.
The
site of the cortical incision and the angle and depth of the
transparenchymal approach are determined by the location and shape of the
tumor with respect to eloquent cortex, major fiber tracts and deep nuclei
as well as bone prominences, dural septa, vascular structures and
ventricles.
Intratumoral
bleeding may be a problem, and will stop only with tumor excision.
Intratumoral
resection is needed to avoid eloquent areas such as, Pre and Postcentral
gyrus,
Calcarine gyri bilaterally
Dominant posterior inferior frontal gyrus,
Posterior superior temporal gyrus, Inferior parietal lobule,
and Nondominant superior parietal lobule.
In
the rare instance in which an eloquent gyrus must be incised, the
incision should be made transversely to its axis.
The
tumor is facilitated by suction, bipolar coagulation and microscissors,
and , if available by, ultrasonic aspiration, and laser. Disruption of
uninvolved tracts of white matter, or opening the ventricle must be
avoided.
The
goal is maximal tumor removal without creation of new neurological
deficits.
Recent
advances have made removal of a strategically located tumor
possible.
Successful
excision of deep seated (thalamus and basal ganglia) gliomas through
trans sylvian-trans insular approach, trans callosal approach, and
trans cortical-trans ventricular approach, have been reported with image
guided surgery.
Lobectomy
in addition to gross total tumor excision, may be useful for large
temporal and frontotemporal tumors.
Lobectomy
with partial tumor excision has no benefit.
Associated
hydrocephalus may need a
drainage procedure.
Postoperative CT scan or MRI
scan with and without contrast material within 48 hours after surgery is
recommended to study the residual tumor, if any. After 48 hours, post
operative changes may mask the residual tumor mass in a scan.
Reoperation:
Advances
in surgical glioma management suggest that reoperation of malignant
tumors may be justified by the palliative effect of tumor mass reduction,
which in turn enhances the cytotoxic effect of adjuvant therapy.
Reoperation
should be considered when a substantial mass of tumor can be removed and
the patient’s age, response to earlier surgery, and performance status
suggest the potential for improvement of quality of life.
The
rationale for reoperation is the same as for the original operation
(confirmation of tumor histology and reduction of tumor mass).
Tumor Biopsy:
Biopsy
is performed when open surgery is not planned any reason. Blind burrhole
biopsy is outdated.
Stereotactic
frames
provide a rigid, three-dimensional (3D) coordinate system for accurate
targeting of brain lesions identified on CT or MRI scans. Stereotaxy is
particularly well-suited for obtaining tissue for biopsy from tumors
located in deep structures, such as the thalamus, basal ganglia, and
brainstem, or in other sites where aggressive tissue removal would
produce unacceptable neurologic deficits .
A limitation of stereotactic
biopsy is that small volumes of tissue are obtained, and tissue
sampling errors may result in failure to reach a correct diagnosis.
Stereotactic biopsy may be nondiagnostic in about 10 of cases and has a
surgical morbidity of approximately 5%.
Controversies exist in
the timing and nature of Glioma surgery.
Patient's
age and general condition, neurological status, and location and presumed
nature of the tumor are the deciding factors.
Surgery
is widely recommended, when the tumor is associated with raised ICP, and
progressive neurological deficit, or intractable epilepsy. Easily
accessible tumors in the 'non eloquent' areas may be excised.
The
controversy is in a radiologically low grade tumor in an eloquent
area, with no raised ICT or neurological deficit.
When
to operate?
Infiltrative
nature of most gliomas, multifocality of gliomas, varied biological
behavior of the tumors, potential deficits and complications related to
surgery, and the widely accepted, though controversial, view that
interventions may provoke progression to a higher grade, are the
arguments against surgery. Additionally, it has been claimed that this
line of treatment leaves ample time for the toxic effects of radiotherapy
and chemotherapy to manifest.
The
patients are offered only symptomatic treatment with or without a biopsy.
However, theses patients need regular follow ups.
The
advocates of early surgery argue that CT and MRI, despite recent
advances, do not give an accurate pathological diagnosis. The surgeon is
better equipped with a tissue diagnosis to arrange for further therapy.
Contrast enhancement is not reliable, and these days of medico legal
problems, a tissue diagnosis is a must.
How
much to remove?
Most
studies, all of which are retrospective, suggest that a gross total
excision of a low grade glioma and incomplete excision followed by
radiotherapy prolong the survival. Moreover, it has been suggested that
extent of surgery is an important factor in predicting recurrence, and
that the recurrent tumors show higher grade. The advocates for radical
surgery claim that extensive surgery may favorably influence the
recurrence rates, modify tumor behavior, and ultimately prolong the
survival. Gross total excision may control the seizures. Large
tumor tissue avoids sampling error as in stereotactic biopsy, and helps
in molecular study. Some gliomas ( pilocytic astrocytomas) are 'curable'
by surgery alone. These studies are not randomized or even case
controlled trials.
Another
group of surgeons feel total resection, given the infiltrative and
multifocal nature of these gliomas, do not provide any additional
benefit. They recommend a tissue diagnosis and appropriate radiotherapy
and chemotherapy.
The
author recommends that the decision has to be individualized, taking into
account of the patient condition and the surgeon's surgical skills, and
that radiotherapy may be with held after gross total excision in low
grade tumors.
Deep
seated radiologically high grade gliomas with no significant
raised ICP or neurological deficit, surgery may not be recommended
despite all the surgical advances. A stereotactic biopsy and appropriate
radiotherapy and chemotherapy is widely practiced. The tumor cells
infiltrate far beyond the visible tumor margins, and the radiology may
reveal only about 505 to 60% of the tumor, it has been suggested. Even
lobectomy has not shown any survival benefit is high grade tumors.
Some
surgeons have reported longer survival times with total excision. They
consider a gross total resection to be more beneficial than a partial
resection or biopsy. Some others found no correlation between the degree
of cytoreductive surgery and survival.
This
issue has never been investigated in a prospective randomized manner.
Radical
resection, in addition to establishing the histological diagnosis,
provides immediate palliation, reestablishes the intracranial CSF
dynamics, reactivates immunological self defence, enhances the effect of
adjuvant therapy by removing resistant cells, and moving cells into more
vulnerable phases of the cell cycle, and also by reducing the target
(tumor) load.
It
has been generally agreed that > 98 % resection results in prolonged
survival, and < 94 % resection is only diagnostic & symptomatic
benefit, but no statistical survival benefit.
The
author recommends gross total excision for all radiologically high grade
tumors in non eloquent areas, provided the patient's age and general
condition permits. Tumors in eloquent areas with neurological deficits,
may also be excised, as it will improve the existing neurological
deficit, and the quality of life, though temporarily.
Photodynamic
therapy:
Photodynamic
(Photoradiation) therapy has been in use for certain cases of cancer of
the esophagus and non-small cell lung cancer, and most recently, to
treat actinic keratosis, a precancerous skin condition. It is a form of
treatment that depends on the selective retention of a photosenstizer
followed by laser treatment with light of an appropriate wavelength. The theoretical
advantage is that it is a two component or binary system which generates
singlet oxygen capable of selectively killing tumor cells only when
combined together, presumably avoiding significant damage to normal
tissues. It has long been known that hematoporphyrin has a propensity to
localize in tumor tissue. This accumulation has been linked to the degree
of vascularity, the number of low density lipoprotein receptors on the
tumor plasma membrane, the decreasing extracellular pH, and uptake by
non-viable cells in necrotic regions.
Irradiation
of a cell incorporating a photosenstizer, such as hematoporphyrin
derivatives, by low power visible light induces photochemical reactions
which lead to cell death. HpDs1, and in particular, a purified component
called Photofrin (HpD-II), are currently being used in clinical trials.
The blood brain barrier (BBB)
is not permeable for hematoporphrin, thus normal brain does not take up
HpD-II and there is selective killing of tumor cells, that are not
resected at surgery.
Following
tumor excision, the tumor bed is cleared off hematoma and hemostatic
agents, and filled with photosenstizer uniformly. The laser beam, as
calculated, is applied for about 30 to 60 minutes. The usual post
operative management is carried out in a dark room. The radiotherapy is
started after four weeks, as HpDs1 may remain for some time in small
vessels.
The
safety and effectiveness of this therapy need further studies.
Radiotherapy is discussed elsewhere.
Adjuvant Therapy:
At
the time of diagnosis most glioblastomas have a tumor mass of
approximately 100g with an estimated cell content of 1011. After
surgery and radiotherapy 102 or 103 cells will
remain. The immune system is able to cope with 105.
The
remaining 1023 cells are the goal of adjunctive therapies, in
order to control local tumor growth.
Chemotherapy: Chemotherapy
is the only established adjuvant treatment, but still many questions
concerning clinical effectiveness exist. In pediatric brain tumor
treatment chemotherapy has found wider application.
As
an attempt to avoid the effects of radiotherapy in those under 3 years of
age, preirradiation chemotherapy is being tried.
It
is indicated for high-grade malignant gliomas as an adjuvant to surgery
and radiotherapy or surgery in recurrent tumors. Reports suggest that the
median survival time (MST) with surgery alone is 14 weeks, and with
radiotherapy it is 36 weeks, and that single agent chemotherapy improves
MST to 51-73 weeks. It is discussed
elsewhere.
In recent years, minimizing the side
effects of chemotherapy, and radiotherapy is an important consideration.
A better understanding of the molecular events leading to tumor
development has provided an opportunity to intervene with experimental
modalities, such as, genetherapy, immunotherapy, and angiostatic therapy.
In addition, other investigatory
agents include,
Retinoids. Retinoids are
vitamin A derivatives and act as differentiating agents in cancer
treatments. That is, they can convert immature, dividing tumor cells into
mature cells, stopping tumor growth. In one study, retinoic acid appeared
to have modest clinical activity against recurrent malignant gliomas,
with tolerable side effects. Other studies indicate that retinoic acid
has no significant effect as a single agent, but combinations with
radiotherapy and other drugs may hold promise. For example, one study
reported some success in treating high-grade malignant gliomas with
radiotherapy and concurrent use of interferon and retinoic acid. Another
showed promise against recurrent gliomas using combinations of retinoic
acid and arabinoside, a chemotherapeutic drug.
Inactivated Viruses. Investigators
are finding that certain viruses may prove to be valuable fighters of
brain cancers. In a 2001 study, a genetically designed poliovirus was
able to target and destroy glioma cells. The virus is altered so that it
does not cause polio. Other viruses are being investigated. A drug based
on this model is years away, however.
Toxins. Agents are
being developed that use toxins to kill malignant brain cells.
One promising agent employs diphtheria
(TransMID-107R). This drug is now in late clinical trials for recurring
cancer but is also being investigated for newly diagnosed and metastatic
brain cancers.
A mushroom toxin (irofulven) is a potent
cancer-cell killer and is in second-phase clinical trials.
Chlorotoxin, a substance derived from
scorpions, is being investigated in early-phase studies.
Imatinib (Gleevac). Imatinib
inhibits an enzyme called Bcr-Abl kinase, which is produced by certain
leukemia cancer cells and has been approved for these leukemias. Although
Gleevac is an unproven treatment for brain tumor, early trials on
recurrent malignant glioma are under way.
Taurolidine. Taurolidine is
a unique agent that prevents tumor formation and growth in animals. An
early clinical trial in patients with high-grade gliomas is under way.
Protein-Blocking Drug. Another
development is the discovery of a protein called BEHAB (brain-enriched
hyaluronan binding protein). BEHAB is produced only by invasive glioma
tumor cells, not by normal brain tissue or noninvasive tumor cells.
Breakdown of BEHAB releases a substance called HABD (hyaluronan-binding
domain), which appears to give glioma cells the ability to invade other
areas of the brain. Both BEHAB and HABD represent potential targets for
new therapies.
Terminal
care:
Inevitably, the surgeon is faced with
the terminal phase of a glioma patient at some stage. Easily treatable,
reversible cause of neurological deterioration, such as, uremia and
electrolyte disturbances should be ruled out before the terminal
care begins. Honesty, understanding, and compassion of the
health professionals form the basis for terminal care.
The comfort of the patient should become
the goal.
The futility of any further anticancer
therapy, investigations and interventions should be acknowledged.
High quality nursing is most essential,
with special attention to bed, bowel and bladder care.
Opiods can be used liberally for pain;
'fentnyl' patch is a good alternative.
Sedation can be used to combat
agitation, anxiety, fear, and mental distress.
Antiemetics are useful, in anticipation
of vomiting.
Convulsions can be controlled with
rectal diazepam.
Intravenous route is avoided; rectal,
transdermal, and subcutaneous routes are preferred.
There are many ethical issues
involved in terminal care. Good communication and interdisciplinary
involvement are the essential part of the terminal phase. The
patient should be involved in all decisions, if possible.
To maintain dignity, the patients
must be able to do things in their own way, and preside over their own
dying.
Conclusion:
Glioma
management is a team management. Goals of management should be realistic,
with a strong emphasis on palliative care, and the every member of the
team should be aware of the goal.
While
mortality statistics for brain tumors have not changed significantly over
the past 10 years for most primary brain tumors, morbidity and our
understanding of the molecular basis for tumor development have.
Despite enormous strides in diagnostics,
surgical tools, and other adjuvant treatment modalities in our
armamentarium,
the etiology, pathogenesis, and
biological behavior of the brain tumors still remain unknown.
There is no consensus on treatment, and
the prognosis of brain tumors continues to be dismal.
Although a prospective randomized study
seems unlikely, retrospective, matched studies, and prospective,
observational trials can improve our understanding. New strategies aimed
at targeted sites on tumors are now in development.
The future, hopefully, is in molecular
biology, genetics, and biotechnology.
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