Ignite Creation Date:
2024-05-05 @ 11:55 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00179907
Status:
COMPLETED
Last Update Posted:
2015-03-02
First Post:
2005-09-12
Brief Title:
A Phase III Study of the Photon Radiosurgery System
Sponsor:
Ann Robert H Lurie Childrens Hospital of Chicago
Organization:
Ann Robert H Lurie Childrens Hospital of Chicago
Study Overview
Official Title:
A Phase III Study of Reirradiation for Recurrent Pediatric Brain and Spinal Cord Tumors and Primary Glioblastoma Multiforme Using the Photon Radiosurgery System
Status:
COMPLETED
Status Verified Date:
2015-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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 05-15 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 32 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 cGymin 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 345 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 15 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 interstitialsurface 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 35 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 125 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 15 - 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 80 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 andor 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
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 05-15 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 32 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 cGymin 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 345 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 15 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 interstitialsurface 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 35 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 125 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 15 - 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 80 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 andor 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None