A Phase I/II Study of the Photon Radiosurgery System
Condition: Brain Tumor, Recurrent; Glioblastoma Multiforme
MeSH terms: Glioblastoma; Brain Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Photon Radiosurgery System (Intrabeam)
Intervention type(s): Procedure
Intervention description(s): 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
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment