Central nervous system tumors account for approximately 20% of all childhood neoplasms.
The treatment modalities used in the primary management of brain tumors are surgery,
radiation therapy and chemotherapy. In recent years, considerable progress has been made
in each of these therapeutic approaches. In spite of these advancements local tumor
recurrence continues to be an important reason for treatment failure in these children.
The local tumor recurrence rate varies according to the primary tumor type, treatment
technique and tumor-stage at initial presentation. After conventional treatment, the
local tumor recurrence rate ranges from 10%
- - 40% in tumors like medulloblastoma,
craniopharyngioma, ependymoma and low-grade gliomas .
However in aggressive tumors like
glioblastoma multiforme the tumor recurrence rate in spite of the best modern treatments
remains at 80-100%.
Radiation therapy has always played a key role in the management of adult and pediatric
brain tumors. There has been considerable interest in treating brain tumors using
stereotactic radiosurgery (SRS) using the Gamma knife or Linear accelerator and
stereotactic radiotherapy (SRT). The goal of stereotactic treatment is to deliver a high
dose of radiation with high geometric precision to a discrete tumor located in the brain.
This is accomplished by the use of rigid immobilization skull frames and CT / MRI
information for treatment planning and tumor targeting. Presently there are several
therapeutic options available for children with recurrent brain tumors. Reirradiation has
been employed in recurrent gliomas, medulloblastomas and ependymomas with stereotactic
radiosurgery stereotactic radiation and brachytherapy . Following reirradiation, tumor
control rates of 50-70% have been obtained. The radiosurgery doses used in children with
radiation recurrent tumors have ranged from 10-24 Gy. The reirradiation has been
generally well tolerated with retreatment complications like transient edema, cranial
neuropathy or radiation necrosis observed in 10-15% of children. The results with high
dose chemotherapy and bone marrow / stem cell transplantation in children with recurrent
malignant gliomas, medulloblastoma and ependymoma have been disappointing with
significant morbidity and mortality. Intraoperative radiation has also been utilized for
the treatment of primary and recurrent brain tumors. In a report from Japan, 17 patients
including two children with radiation recurrent malignant brain tumors were treated with
intraoperative radiation to doses of 20
Intraoperative radiation was delivered
using special applicators and electron beams. The radiation was delivered after tumor
resection and doses of 23
- - 40 Gy were delivered to depths of 0.5-1.5 cm.
The median
survival for patients with malignant gliomas and other tumors (ependymoma,
oligodendroglioma) was 12 months and 51 months respectively. The two children with
ependymoma were cured and are currently alive at 134 and 88 months after intraoperative
radiation. Three patients developed symptomatic brain necrosis, two of them had relief of
symptoms with surgery and one patient died. Three patients also developed postoperative
meningitis. In another report from University of Nebraska Medical Center, 49 patients
with glioblastoma multiforme were treated with interstitial Cobalt 60 high dose-rate
irradiation to a dose of 20 Gy to the tumor with a 1-cm margin. The patients with no
prior radiation therapy (Group I) received an additional 40 Gy of external irradiation.
Nineteen of these patients (Group II) had been previously irradiated, and they received
only interstitial irradiation. The Cobalt 60 probe was guided into the tumor using CT
scans and a stereotactic frame. This treatment was well tolerated, one patient had a
dural leak and another had a subdural hematoma. There were no cases of meningitis or
radiation necrosis. The median survival for Group I and Group II patients were 7 months
and 6 months respectively.
The photon radiosurgery system (PRS) is an intraoperative irradiation device that is
capable of delivering high radiation doses to brain tumors. This system has recently been
approved for clinical use by the Food and Drug Administration (FDA).
Photon Radiosurgery System (PRS)
The Photon Radiosurgery System (PRS) incorporates a miniature, 40 KeV x-ray source
capable of delivering a prescribed radiation dose directly to a target volume. The PRS
consists in part of an electron beam-activated x-ray source with a sealed vacuum tube
that is 10 cm long and 3.2 mm in outer diameter that is designed for insertion into the
body. This vacuum tube incorporates an electron beam target on the inside surface of its
tip. When an accelerated electron beam is generated and sent down the tube to strike the
target, Bremsstrahlung and line x-rays are emitted from the tip of the tube in a nearly
isotropic pattern.
Measurements of dose-rate in a water phantom have determined that the x-ray beam emanates
essentially, from a point source, with a nominal dose rate of 150 cGy/min at 10 mm, for a
beam current of 40 uA and a voltage of 40 kV. The absolute dose is estimated to be + 10%.
The dose distribution in water falls off approximately as a function of the third power
of the distance from the power source. The generator is light weighed, only 3.45 lbs. The
radiation dose is adjusted by accelerating voltage (ranging from 30 to 50kV), beam
current (ranging from 5 to 40 uA) and treatment time (0-60 minutes) through the control
console that weighs only 40lbs. The lightweight of PRS system readily allows us to carry
the device to the laboratory and the operating room.
For use of the PRS as an adjuvant treatment, treatment applicators made from a rigid
biocompatible plastic (ULTEM 1000) with known x-ray transmission characteristics are
used. The inside is hollowed out to allow introduction of the PRS x-ray probe to the
epicenter of the applicator so that the dose at its outer surface is uniform. The end of
the applicators is spherical with its diameter ranging from 1.5 cm to 4 cm. Treatment
applicators will be sterilized prior to each use. The applicator is inserted into the
tumor-resected cavity to deliver the prescribed dose of radiation.
The operation and dose characteristics of the PRS combine advantages of external beam
radiosurgery with those of brachytherapy (implantation of radiation seeds). As with
brachytherapy, the PRS can be located very precisely within the target volume, and can
improve the delivery of conformal therapy by irradiating the target volume precisely,
with little or no scatter of radiation. Due to its very rapid dose fall-off, the PRS
significantly reduces the radiation dose delivered to healthy tissues as compared with
external beam radiation and radiosurgery. Like radiosurgery, however, the PRS has a very
high dose rate and can deliver high radiation doses to the target volume. Another
distinct advantage of the PRS system is the ability to significantly decrease the
radiation dose to the normal structures in the brain adjacent to the tumor. All of the
radiation treatment techniques presently available deliver 10-50% of prescribed dose to
the normal brain. Intraoperative irradiation using PRS because of its direct application
into the tumor or tumor bed limits the dose to the normal tissue. This approach could
result in a significant decrease in radiation induced complications in vital structures
such as the optic pathway, brain stem and cerebral blood vessels. Another advantage of
PRS is that unlike other types of therapy, the PRS does not require the use of a
radiation-shielded room. To summarize, the advantages of the interstitial/surface
application of radiation using the PRS are:
1. Direct access to the surgical bed of the tumor. 2. Accurate delivery of a high single dose of radiation to the tumor. 3. Superior protection of adjacent brain, cranial nerves or other critical structures
by the use of intraoperative shielding or intraoperative displacement of these
organs. 4. Superior radiobiological effectiveness (RBE) of low energy X-rays. 5. Tumor dose inhomogeneity similar to brachytherapy and Gamma knife radiosurgery, with
the center of the tumor receiving a higher dose than the peripheral region that is
adjacent to normal structures.
Results of studies carried out with the PRS in brain tumors have demonstrated it to be
capable of delivering a lethal dose of radiation, in a single application to intracranial
tumors with minimal side effects. It has been used to treat primary and metastatic brain
tumors. In a report from Massachusetts General Hospital, 14 adults with primary and
metastatic brain tumors < 3.5 cm in greatest diameter were treated with a single fraction
of irradiation using PRS. The treated tumor diameter ranged from 10mm
- - 35 mm (mean
21mm), and the tumor edge prescribed dose ranged from 10-20 Gy (average 12.5 Gy).
The
average treatment time was 23 minutes (range, 7-45 minutes). Local control was obtained
in 10 of the 13 patients with a follow-up of 1.5
- - 36 months (mean 12 months).
All
patients tolerated the procedure well, and most patients were discharged home the day
after treatment. No new neurological deficits were noted after irradiation. This study
aims at determining the maximum tolerated dose of irradiation using PRS in recurrent
pediatric brain tumors.
Dose Selection.The radiation dose delivered by the PRS and radiosurgery are similar with regard to
dose-rate and total dose. The RTOG (Radiation Therapy Oncology Group) has performed a
dose escalation study to assess the maximum tolerated dose of radiosurgery in adults with
previously irradiated brain tumors and brain metastases. Based on acute and late
toxicity, the maximum tolerated radiosurgery doses were 24 Gy, 18 Gy and 15 Gy for tumors
< 20 mm, 21-30 mm and 31-40 mm respectively.
In this study we had intended to perform a similar dose escalation study with doses
ranging from 10-19 Gy, 10-16 Gy and 10
- - 14 Gy for tumors < 20 mm, 21-25 mm and 26-40 mm
respectively.
These doses are lower than the established maximum tolerated doses for
brain reirradiation in adults with radiosurgery. These doses are also lower than the
20-40 Gy doses utilized for intraoperative irradiation of adult brain tumors with
electrons and Cobalt 60 sources.
An interim analysis of patients entered on the study was performed. Based on the
occurrence of treatment -related complications in ONE patient who required 2 applicators
and in another patient in whom the dose was prescribed to 5 mm depth, the protocol has
been modified as follows:
1. No patient will have PRS treatment using more than one applicator. 2. The depth of prescribed dose should not exceed 2 mm. 3. Patients who have received prior RT and those who have not received prior RT would
be classified into Group A and Group B respectively.
4. The dose levels will for these two groups would be as shown in the table in Section
8.0. The dose escalation for non-brainstem (10-19 Gy) remains the same, but dose
escalation will no longer be stratified by tumor size. The dose levels for sites
adjacent to the brainstem and/or cranial nerves (10-14 Gy) also remain the same. A
minimum of 3 patients will have to be accrued in each dose level and only if there
are no complications observed, accrual at the next dose level would begin.
Dose escalation will be based on the incidence of acute CNS toxicity defined by RTOG
criteria. Unacceptable toxicity will be considered to be irreversible grade 3 (severe),
any grade 4 (life threatening) or grade 5 (fatal) RTOG CNS toxicity occurring within 3
months of reirradiation. If no patient developed an unacceptable CNS toxicity as defined
below, the dose for that tumor size was then escalated.
The brain stem is very important part of the brain that controls most bodily functions
like blood pressure, respiration etc. In this study, we have adopted a gentler dose
escalation scheme for tumors in and around the brain stem. The three doses to be studied
for tumors in this location are10 Gy, 12 Gy and 14 Gy. These doses will be delivered
independent of tumor size.
