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The value of radiotherapy
adjuvant to surgery was first reported by Walker in 1978.
Great strides have been made
since, including radiosurgery.
Photon, electron, neutron,
and proton radiation beams are all in clinical use. The accuracy has
improved with development of three dimensional techniques and image
fusion.
Radiotherapy
plays a very important role in the management of gliomas, as it can reach
where surgeon's hands do not.
Principles of Radiotherapy:
The higher the dose of radiation
delivered , better is the tumor control.
The lower the dose to the surrounding
normal tissues, the lower is the associated morbidity.
Hypoxic tumor cells, usually in the
center of the tumor, are relatively radioresistant, and the lesser tumor
volume, better is the effectiveness of radiation. Surgical excision of
these tumor cells, and tumor debulking adds to the benefits of
radiotherapy.
Delays between surgery and radiotherapy
should be avoided as it reduces the potential repopulation of tumor
cells.
Forms of Radiotherapy:
The types of radiation are often X-rays
from the linear accelerator, and gamma rays from the decay of certain
radioactive materials like cobalt-60 and cesium-137. Other types include,
use of electron, neutron, and charged particles.
Broadly, radiotherapy can be categorized
into external beam radiation therapy (EBRT) or teletherapy, and
brachytherapy.
Teletherapy(EBRT), the most commonly used
radiotherapy in CNS, refers to the projection through space of x-rays or
gamma rays aimed at a target. The standard machines for
administering teletherapy are the cobalt-60 machine and the linear
accelerator.
When deep X-ray therapy was used, the result were poor and
morbidity was high due to non uniform dose distribution resulting in more
radiation dose to normal brain tissue and bone necrosis due to increased
absorption of radiation by bone. Since the introduction of Telecobalt
there was significant improvement in disease control with drastic
reduction in complication rate. The cobalt-60 machine relies on the
radioactive decay of cobalt for the production of gamma rays. Employing a
system of field-shaping devices and custom designed blocks, the cobalt
machine can also be used to obtain shaped fields for precision treatment.
With the introduction of mega voltage X-ray machine like Linear
Accelerator, results have improved further with even greater
reduction in morbidity. The advantages of mega voltage X-ray machine are
greater beam definition, lesser scatter radiation, increased penetration
resulting in better depth dose and bone and scalp sparing effect.
Radiosurgery
is a recent addition. It refers to the use of an extremely
precise and well delineated beam of radiation that generates lesions
within the brain. Aim of radio surgery is to deliver a very high
single dose of radiation precisely to a well defined target, to produce
blood vessel thrombosis and sclerosis, to promote tissue necrosis
resulting in inactivation of tumor or obliteration of vascular
malformation without physical removal. Stereotaxy is used for
precise localization. When stereo tactic radiation is given as a
large single dose it is called stereotactic radiosurgery.
When stereo tactic radiation is fractionated, it is called stereotactic
radiotherapy.
Stereo tactic treatment can
be given with a gamma knife which is dedicated tele cobalt unit
having multiple pencil beams of gamma irradiation from Co60 source or X-knife
which is a Linear Accelerator with a attachment of special cones to
deliver pencil beams. Localization is done using special head rings fixed
to the head to the patient. Dose varies from 12 -25Gy as a single
fraction.
Many recommend stereotactic
radiosurgery as the first line of treatment for AVMs. Other indications
for Stereotactic radiosurgery are 1. Open surgery risky due to medical
reasons, 2. Recurrent/residual tumors following previous surgery, 3. Open
surgery is risky due to location of lesion, 4. Patient who refuses open
surgery.
Brachytherapy is
another form of radiotherapy used in CNS. It refers to continuous low-dose-rate
irradiation such as that generated from radioisotopes, implanted directly
into tumor, either temporarily or permanently. The most common form of
brachytherapy is the interstitial implantation of radioactive iodine-125
or iridium-192 as a component of the treatment of supratentorial
malignant gliomas. This allows high dose delivery to the target while
minimizing exposure to the surrounding normal tissue. This is limited by
tumor volume and the location. The main indication is the post EBRT
recurrence.
The use of brachytherapy is
controversial, since
the results of stereotactic radiotherapy and brachytherapy are similar.
Intraoperative
Radiotherapy(IORT) is the delivery of a single large dose of radiation
using electron beam or low energy X-rays during surgery. It is indicated
for recurrent tumors as well as primary tumors as a supplement to EBRT.
The dose is determined by the tumor volume and previous radiation. The
preliminary reports are encouraging.
Conformal
three-dimensional radiation uses high-dose radiation beams shaped to
match the shape of the glioma. This technique is highly targeted and, in
certain cases, may even be used for patients who have had previous
radiotherapy.
Hyperfractionated
radiation
uses many small radiation doses to deliver a high total dosage of
radiation.
A balloon
catheter (GliaSite) that delivers radiation to the tumor cavity after
surgery is showing promise.
Radiobiology:
The interaction of ionizing radiation with biological
material proceeds through several stages resulting in wide variety of
biological end effects. Ionizing radiation interact with molecules
producing excitation and ionization. The chemical changes in irradiated
molecule can be direct or indirect. Since water forms > 70% most of
the indirect action involves water molecules. Radiation results in 2
types of cell death. Reproduction death occurs in dividing cells and
interphase death not restricted to proliferative cells. Neurons which are
not capable of cell division undergo interphase death.
Rapidly dividing cells are more radiosensitive compared to
slowly dividing cells. CNS tumor with slowly dividing cells is less
radiosensitive compared to epithelial tumor. Since cells show variety of
sensation in different phases of cell cycle, fractionated radiotherapy is
given in an attempt to attack more and more cells in the sensitive phase
of cell cycle. Fractionation also helps normal cell recovering because of
differential recovery of normal and tumor cells. As the number of
fraction increases the total dose has to be increased because of recovery
of cells from sub lethal damage resulting in wastage of radiation. But
when large single dose is given the damage to normal tissue is the same
as the tumor tissue and hence normal tissue cannot be included with target
volume. This is the basic principle of stereo tactic radio surgery which
involves giving a large single dose to the lesion resulting in necrosis
of the treated area.
Effects of radiation on the brain:
Large single dose or radiation causes brain death within
hours. There is wide spread increase in vascular permeability and
increase in intracranial tension. At dose levels used in therapy the same
phenomenon occurs to a lesser degree.
Acute reaction occur during or immediately
after a course of irradiation (within 2 weeks). There may be headache due
to increased pressure for first few fractions. During the acute phase,
blood vessels, nerve cells and glial cells are injured directly. Vascular
changes contribute to further cell degeneration. There may be reduction
of conscious level and worsening of focal neurological signs. These
phenomena are rarely seen today due to liberal use of Dexamathosone and
due to provision of shunts.
Delayed reaction may be " early
delayed" (subacute) appearing a few weeks to a few months (6-12
weeks) after radiation or "late delayed" starting month or
years (4-40 months) later.
The " early delayed" (subacute) reaction
is usually one of transient demyelination due to temporary depletion of
oligodendroglia. The somnolence syndrome represents an early delayed
radiation reaction in the brain and in characterized by transient period
of exhaustion at 2 weeks, drowsiness, lethargy and anorexia at 4-6 weeks
after radiation. It is usually reversible over a period of 1-2 weeks. 4-8
weeks after radiation, there may be rapidly progressive ataxia, cranial
nerve and focal neuro deficits and nystagmus and takes longer (1-2mths)
to recover.
Late delayed damage is the most feared
complication and vary depending on the region irradiated. This results
from the continuation of oligodendroglial loss and endothelial damage
leading to demyelination and necrosis of while matter. Less severe forms
of late damage may occur in children as cognitive impairment and is age related.
Midline structure like midbrain, brain stem and hypothalamus are
particularly vulnerable CT scan of brain of long term survivors of large
field radiation show generalized atrophy with wide sulci and large
ventricle, but it does not seem to be associated with noticeable
deterioration on patients intellectual status. Most are
irreversible.
Delayed spinal cord damages include, acute ( over several
hours) complete quadriplegia/paraplegia, LMN syndrome (muscle atrophy,
areflexia, fasciculations) developing over weeks, and Chronic progressive
myelitis.
Additional form of delayed radiation injury, is the
development of second malignancy of a different histologic type within
the irradiated field, following years after irradiation.
Pathology: Radiation injury is
characterized by a shrinking and shriveling of the cortex. In the spinal
cord, the cord is thinned out. Histologically there are areas of
confluent coagulative necrosis of the white matter, vascular thickening,
telangiectasia and vascular proliferation.
Imaging: There are no radiographic changes that
are pathognomonic of radionecrosis. Isotope scan may help. However,
histologic confirmation is required in most instances.
Clinical applications:
Goals of radiotherapy are curative and
palliative. In curative radiotherapy. some degree of risk is accepted for
a reasonable probability of permanent eradication of the malignancy. In
medulloblastoma, risks of radiation injury to cognition, a diminution of
bone growth, or other toxicities may be acceptable for a 60%-80%
probability of cure. In palliative radiotherapy, the intent is to
ameliorate the symptoms and it would be a short course avoiding radiation
induced CNS toxicity. Currently, the whole brain radiotherapy
for the treatment of GBM is no longer practiced. Localized field covering
2 - 3cm area around the peritumoral edema is the standard portal up to
45Gy. This is followed by the booster dose to the reduced field with
1.5-2.0cm around the tumor.
Doses of radiation are typically prescribed
in cGy (centiGray). The cGy, a unit of absorbed dose in tissue,
became the standard dose unit of radiation in 1980 when it replaced the
term rad (radiation absorbed dose). Appropriate dose depends on
radiation tolerance of the surrounding normal tissue and the data concerning
the dose response of the tumor to radiation. The dose fraction
limits for brain necrosis are approximately 35 Gy/10 fractions or 60Gy/30
fractions. CNS tissue is late reacting tissue and the reaction is more
related to dose per fraction as well as total dose. Hence in radical
radiotherapy where patient is expected to survive long, daily dose should
not exceed 180-200cGy for adults and 150cGy for children The total dose
should not exceed 60-65 Gy.
Next is the appropriate volume for irradiation (
amount of tissue that needs to be encompassed in the radiation beam).
This is ascertained by appropriate imaging studies, with a margin, and a
sound understanding of the patterns of spread of the tumor. For example,
in medulloblastoma which is known to seed to the spinal axis, the volume
must encompass the entire craniospinal axis.
Finally, one must choose the
right technique. A common technique is parallel opposed lateral
beams directed at the brain. Other techniques include parallel opposed
lateral fields, and a vertex field, arc treatment, or single beams. In
the spinal malignancies, either a single posterior field, parallel
opposed anterior and posterior fields, or various angled fields. A
computer reconstruction of the radiation dose distribution (computerized
dosimetry) is widely employed. This has resulted in better
and accurate dose delivery minimizing the dose to surrounding normal
brain tissue and resulting in fairly uniform dose distribution to the
tumor. Imaging modality like MRI has considerably improved the accuracy
of target volume definition.
3 D
conformal treatment using multiple collimator and stereo
tactic radiation can be considered as the ultimate precision radiotherapy.
No statistically significant
benefit is noted with combined radiotherapy and chemotherapy.
Radiosensitizers: In order to
increase sensitivity to radiation of the same external dose halogenated
pyrimidines can be administered during radiotherapy. These agents
are thymidine antimetabolites, which are incorporated into the DNA of
dividing cells enhancing the radio sensitivity of these cells.
Pyrimidine uptake in tumor cells is higher (high labeling index) than in
normal brain cells thus increasing the radio sensitivity of the
tumor. Treatment can be combined with accelerated fractionation or
hyper fractionation.
BUdR,
IUdR, FUdR, and 5-FU are some the agents
that have been used for sensitizing. Prolonged intravenous or
intra-arterial infusion are equal in their effects. In one study
glioblastomas showed a slightly better response compared to standard
radiation. In patients with anaplastic astrocytoma a MST of more
than 5 years has been reported. It is not clear whether these results are
influenced by other factors. Cytotoxicity is another anti-tumor effect of
these agents.
But prospective
randomized studies showed no significant additional effect of
radiosensitizer. Hyperthermia is being tried as an
adjunct because hyperthermic cytotoxic effects are independent of the
cell-cycle phase.
Radioenhancers: These drugs,
such as topotecan, increase the effects of radiation. Topotecan combined
with other drugs, such as thiotepa and carboplatin, may help children
with neuroblastoma and brain tumors. Efaproxiral, an investigative agent
that increases oxygen in the brain, is showing promise as a
radioenhancer.
Radiotherapy
and tumor types:
Low grade glioma: Low grade astrocytoma after
complete excision do not require post operative radiotherapy. Tumor with
incomplete excision or after open or stereo tactic biopsy require
radiotherapy. Routine post operative radiotherapy of oligodendroglioma
provides marginal survival advantages. Dose of 55-60 Gy.
High grade glioma: Radiotherapy
prolongs survival and improves quality of life. Deficits improve in 1/3
and stabilized in ½. Usually large field radiotherapy is followed by
boost. Giving local boost beyond 70 Gy is being tried but still should be
considered as investigational.
Ependymoma: Post
operative radiotherapy is standard practice. Craniospinal radiotherapy is
controversial and is probably Indicated in high grade tumors.
Brainstem Radiotherapy
may be given even without biopsy confirmation in selected cases; lately,
a stereotactic
biopsy is insisted upon as a prelude.. If tumor is less
than 4 cm, fractionated stereo tactic radiotherapy will minimize dose to
critical areas.
Pineal tumor: It
is necessary to do CSF and serum markers namely B-HCG and AFB +ve markers
are diagnostic of germ cell tumors and radiotherapy and / or chemotherapy
started straight away without biopsy confirmation. If markers are
negative, biopsy confirmation is advisable. If response is good it
indicated germinoma or pineoblastoma and external radiation is continued
to the whole brain for a dose of 36Gy. Hence the pineal dose is 55Gy. For
histologically verified germ cell tumors, a dose of 36Gy is given
to whole brain followed by a boost dose of 20Gy. The risk of developing
spinal metastases is 13%, with brain radiotherapy alone. The risk is
reduced to 5% if spinal irradiation is given. Hence an adult should
receive craniospinal irradiation and in children and young women spinal
radiation is given only if CSF cytology is positive and when major
surgical intervention is done. Pineoblastoma is treated like germinoma
and pineocytoma is treated like glioma when histological proof is
available.
Lymphoma: Treatment
is by whole brain radiation of 36Gy followed by a boost of 20Gy. Spinal
radiation is given when CSF is positive. Median survival is 10-18 months.
Long term cure is rare with radiation alone. Hence lymphoma needs
adjuvant chemotherapy also. More recently chemotherapy is tried after
surgery and radiotherapy is given later and the results are awaited.
Medulloblastoma: Radiotherapy is indicated in
all patients after surgical excision. Craniospinal radiation is essential
because of high incidence of spinal seeding. Whole brain is treated with
a dose of 30-36Gy in 20 fractions followed by a boost of 15-20Gy. Spinal
cord is given a dose of 30-36Gy and in children <5 years a dose of
25-30Gy is given. The value of adjuvant chemotherapy in low risk patients
is not established, but is indicated in high risk patients. Trials are ongoing
in which chemotherapy is given prior to radiotherapy in high risk
patients.
Pituitary lesions: In
craniopharyngioma, tumor control is better with surgery and radiotherapy
than with surgery alone. Dose 50-55Gy in 25-30 fractions. In pituitary
adenomas surgery followed by radiotherapy produces 83% 10 year
progression free survival. A large proportion of patients require hormone
replacement therapy due to progressive pituitary failure. Radiotherapy
can produce optic nerve damage in 1-2%. More recently stereo tactic
radiotherapy is used for tumor of less than 4cm. And the incidence of
optic nerve damage is minimized or eliminated.
Meningioma: After
incomplete excision of begin meningioma, 5 year recurrence rate is 30-40%
and adjuvant radiotherapy reduces it to 10-25%. Radiotherapy for
inoperable tumor results in 50% progression free survival. Malignant
meningioma requires postoperative radiotherapy and the treatment is
similar to that of glioblastoma. Stereotactic biopsy is preferred
whenever possible.
Metastases: Whole
brain radiation produces neurological improvement in 35-70% of patients.
30Gy in 10 fractions, 40Gy in 20 fractions and 50Gy in 25 fractions show
no difference in results. When patient is likely to survive for a longer
time as in metastasis of renal carcinoma or thyroid carcinoma,
conventional fractionation is preferable. Solitary metastasis or
metastases up to 3 numbers may be treated with stereo tactic radio
surgery when the primary is in kidney, malignant melanoma, thyroid,
sarcoma etc.. While brain radiotherapy may be followed by boost
especially when primary is under control and there are no metastases
elsewhere.
Spinal cord tumors: Low grade gliomas in general
are not given postoperative radiotherapy after good surgical excision
without any neurological deficit. The risk of radiation myelopathy is 5%
after radical radiotherapy. The spinal cord tolerance depends upon the
length of cord irradiated. The dose is restricted to 50-55Gy for cord
length of cord irradiated. The dose is restricted to 50-55Gy for cord
length up to 10cm. For longer segments, dose is limited to 45Gy.
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