A Phase I/II Study of the Photon Radiosurgery System
A Phase I/II Study of the Photon Radiosurgery System
The standard treatment for children with brain tumors is surgical removal of the tumor
 followed by radiation to the brain and chemotherapy (medicines) given to shrink any remaining
 tumor or to prevent tumor from growing back. There are very few treatment options available
 for children whose brain tumor grows back after receiving radiation treatment. There is a
 greater risk of complications and side effects when the brain is repeatedly treated with
 external radiation. The side effects of repeat radiation treatment are dependent on the
 amount of the brain that is radiated. Radiation given with PRS during surgery is focused to
 the specific area of the brain where the tumor is located. Therefore, the area of the brain
 affected by the radiation is smaller. It is hoped that this targeted radiation will lessen
 the side effects to the normal brain that is not affected by the tumor. It is also hoped that
 a lower occurrence of side effects will increase the quality of life of children with brain
 tumors.

 The optimal dose of targeted radiation is not known. Therefore, increasing doses will be
 given to treat different patients, starting with the lowest possible dose. The amount of
 radiation to be given will depend on whether or not your child received prior radiation
 therapy and where the tumor is located. The groups of patients will first be divided into 2
 groups: Group A, who are those who received radiation as part of their prior treatment, and
 Group B, who are those who did not receive any radiation treatment. Each group will be then
 divided again into 2 groups depending on the location of the tumor. In each group, if the
 lowest dose is well-tolerated with only minimal side effects by 3 patients, then the next
 higher dose will be given to the next 3 patients.

 The purposes of this research are:

 -  To evaluate the potential side effects of a single high dose of x-rays using the Photon
 Radiosurgery System (PRS) given to a small area of the brain.

 -  To determine the maximum dose of targeted radiation that can be safely given to brain
 tumors with the fewest side effects.

 -  To see how well this treatment works for children with recurrent brain tumors and
 newly-diagnosed glioblastoma multiforme.
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 - 40 Gy. 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.
Inclusion Criteria:

 -  All patients must be between 2 and 32 yrs. of age. Patients who are pregnant or
 lactating will not be included in this study.

 -  Patients must have an estimated survival time of > 3 months, and a Karnofsky
 performance status of > 50% or and ECOG performance status of 0-2.

 -  Patient must have radiographic imaging evidence of tumor recurrence except for
 glioblastoma multiforme.

 -  The recurrent tumor prior to irradiation with PRS must be < 4 cm.

 -  All patients must be > 3 weeks from cytotoxic chemotherapy, except if patient received
 < 1 week of non-myelotoxic chemotherapy. In that case, patient may be enrolled with
 permission of the principal investigator.

 -  All patients must be > 6 weeks from high dose chemotherapy with stem cell rescue.

 -  All patients must be > 3 weeks from prior radiation therapy.

 -  Patients with a history of prior irradiation will be included.

 -  Informed consent must be obtained prior to registration on the study.

 Tumor Sites:

 -  Brain

 -  Spinal Cord

 Tumor Types:

 -  Recurrent Medulloblastoma

 -  Recurrent Ependymoma (recurrence regardless of primary treatment)

 -  Recurrent Glioma

 -  Glioblastoma Multiforme

 -  Recurrent Craniopharyngioma

 -  Recurrent PNET (Primitive Neuroectodermal tumor)

 -  Recurrent Meningioma

 -  Recurrent Pineoblastoma

 Tumor Size:

 -  < 4 cm in maximum diameter