Proxima Therapeutics' Gliasite Radiation Therapy System: Newly FDA Approved for Malignant Brain Tumors

Reprinted from Select Review in Neuro-oncology 2: 2, 2001 with permission.

Stephen B. Tatter, M.D., Ph.D.
Department of Neurosurgery, Wake Forest University Baptist Medical Center, Winston-Salem, NC

The Gliasite RTS¹ is one of only three new treatments approved for malignant gliomas in the last 20 years. It consists of an inflatable balloon catheter that is placed in the resection cavity at the time of an otherwise-indicated tumor debulking. Internal radiation is delivered with an aqueous solution of organically-bound ¹²⁵I (Iotrex).[Stubbs, 2000] A 2, 3, or 4 cm diameter GliaSite RTS catheter is implanted. 1-2 weeks later, the device is filled with Iotrex and saline for 3-6 days, whereupon the Iotrex is retrieved. Prescription doses from 40-60 Gy at 0.5-1 cm from the balloon surface have been used in small series of patients with previously-radiated, recurrent, malignant gliomas without the need for reoperation for radiation necrosis.² Initial clinical use demonstrates excellent conformance of brain to the semi-rigid spherical balloon placed in the resection cavity allowing a high radiation dose to be delivered to the volume at greatest risk of recurrence.²

The arguments for delivering additional local radiation to malignant gliomas without necessitating a high rate of reoperation for radiation necrosis are compelling but not yet overwhelming. They include:

• Radiation is by far the most effective treatment for malignant gliomas but presumably due to increasing normal tissue injury there is no net benefit achieved by delivering additional fractionated, external-beam, radiation dose.
• Global control cannot be achieved without achieving local control. 80-90% of recurrences are within 2 cm of the resection cavity margin..[Lee, 1999; Sneed, 1994; Wallner, 1989]
• There is a dose response for seed based brachytherapy in the local control of malignant gliomas.[Sneed, 1996] Due to the inhomogeneity of radiation dose delivered by seed based techniques reported rates of reoperation for radiation necrosis are 26-64%.[Ling, 1979; Saw, 1989; Prados, 1992; Scharfen, 1992; Bernstein, 1994; Wen, 1994] This suggests that there is little room for further refinement of the older technology. It may also explain why seed based brachytherapy has frequently but not uniformly been found to be beneficial.[Laperriere, 1998; Videtic, 1999; Halligan, 1996; Gaspar, 1999; Prados, 1992; Scharfen 1992; Wen, 1994]
• The last more subtle argument is that the rarely observed long-term survival of patients with malignant gliomas is likely at least in part achieved by activating host (presumably immune) defenses. Most of these patients have had multiple recurrences and have undergone multimodal therapy before achieving long-term remission. Among current long-term survivors many have had seed based brachytherapy. Some have had bacterial infections that may have lead to more efficient immune activation. Local tumor killing with radiation has the benefit of allowing tumor antigens to be presented to the immune system which might sometimes result in recognition of the glioma cells as malignant.

The Gliasite RTS offers the potential to improve quality of life during treatment by avoiding the need for external hardware. While FDA approval is based on device performance and safety data and the historically documented benefit of brachytherapy, the Gliasite RTS also offers potential efficacy advantages. Chief among these is the potential for quantitatively studying and optimizing dose. This possibility is unique to the Gliasite RTS among brachytherapy modalities because the catheter functions as a single point source of radiation eliminating spacial distribution of radiation sources as a dependent variable that cannot be studied and optimized.[Dempsey, 1998; Monroe, 2001]

Although tested against recurrent malignant gliomas (anaplastic astrocytoma, anaplastic oliogodendroglioma, anaplastic mixed oligoastrocytoma, and gliobalstoma multiforme) the Gliasite RTS has been approved by the US FDA for use against "malignant brain tumors." Trials are underway for isolated brain metastases and for newly diagnosed glioblastoma. The case for use of the Gliasite RTS for metastases in order to avoid or delay whole brain radiation is particularly compelling for those of us who have seen patients die of radiation induced dementia in the setting of tumor remission.

In summary, the GliaSite RTS performs safely and efficiently in initial clinical use. Brain conformance to the device after the resection of recurrent malignant gliomas is excellent allowing delivery of a readily-quantifiable radiation dose to the tissue at highest risk for recurrence. This device preserves quality-of-life better than older brachytherapy techniques. Applications are anticipated in a variety of newly-diagnosed, metastatic, and recurrent brain tumors.

References

1. Proxima Therapeutics
   Alpharetta, Georgia, U.S.A.
   Phone: 1-770-753-4848
   WWW: http://www.proximatherapeutics.com/
2. New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium Study 98-01. Prelinarily reported as: Tatter SB, Shaw EG, deGuzman AF, Rosenblum ML, Mikkelson T, Olivi A, S. G: Brachytherapy in re-resected malignant glioma cavities using the Gliasite Radiotherapy System. A phase I safety and device performance trial. Proc Am Soc Clin Oncol 2000, 19:169a.
3. Bernstein M, Laperriere N, Glen J, Leung P, Thomason C, Landon AE: Brachytherapy for recurrent malignant astrocytoma. International Journal of Radiation Oncology, Biology, Physics 1994, 30: 1213-1217.
4. Dempsey JF, Williams JA, Stubbs JB, Patrick TJ, Williamson JF: Dosimetric properties of a novel brachytherapy balloon applicator for the treatment of malignant brain-tumor resection-cavity margins. International Journal of Radiation Oncology, Biology, Physics 1998, 42: 421-429.
5. Gaspar LE, Zamorano LJ, Shamsa F, Fontanesi J, Ezzell GE, Yakar DA: Permanent ¹²⁵iodine implants for recurrent malignant gliomas. International Journal of Radiation Oncology, Biology, Physics 1999, 43: 977-982.
6. Halligan JB, Stelzer KJ, Rostomily RC, Spence AM, Griffin TW, Berger MS: Operation and permanent low activity ¹²⁵I brachytheraphy for recurrent high-grade astrocytomas. International Journal of Radiation Oncology, Biology, Physics 1996, 35: 541-547.
7. Ling CC, Anderson LL, Shipley WU: Dose inhomogeneity in interstitial implants using 125-I seeds. International Journal of Radiation Oncology, Biology, Physics 1979, 5: 419-423.
8. Lee SW, Fraass BA, Marsh LH, Herbort K, Gebarski SS, Martel MK, Radany EH, Lichter AS, Sandler HM: Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. International Journal of Radiation Oncology, Biology, Physics 1999, 43: 79-88.
9. Laperriere NJ, Leung PM, McKenzie S, Milosevic M, Wong S, Glen J, Pintilie M, Bernstein M: Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma. International Journal of Radiation Oncology, Biology, Physics 1998, 41: 1005-1011.
10. Monroe JI, Dempsey JF, Dorton JA, Mutic S, Stubbs JB, Markman J, Williamson JF: Experimental validation of dose calculation algorithms for the GliaSite RTS, a novel ¹²⁵I liquid-filled balloon brachytherapy applicator. Medical Physics 2001, 28: 73-85.
11. Prados MD, Gutin PH, Phillips TL, Wara WM, Sneed PK, Larson DA, Lamb SA, Ham B, Malec MK, Wilson CB: Interstitial brachytherapy for newly diagnosed patients with malignant glioma. The UCSF experience. International Journal of Radiation Oncology, Biology, Physics 1992, 24: 593-597.
12. Saw CB, Suntharalingam N, Ayyangar KM, Tupchong L: Dosimetric considerations of stereotactic brain implants. International Journal of Radiation Oncology, Biology, Physics 1989, 17: 887-891.
13. Scharfen CO, Sneed PK, Wara WM, Larson DA, Phillips TL, Prados MD, Weaver KA, Malec M, Acord P, Lamborn KR: High activity iodine-125 interstitial implant for gliomas . International Journal of Radiation Oncology, Biology, Physics 1992, 24: 583-591.
14. Sneed PK, Lamborn KR, Larson DA, Prados MD, Malec MK, McDermott MW, Weaver KA, Phillips TL, Wara WM, Gutin PH: Demonstration of brachytherapy boost dose-response relationships in glioblastoma multiforme. International Journal of Radiation Oncology, Biology, Physics 1996, 35: 37-44.
15. Sneed PK, Gutin PH, Larson DA, Malec MK, Phillips TL, Prados MD, Scharfen CO, Weaver KA, Wara WM: Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost. International Journal of Radiation Oncology, Biology, Physics 1994, 29: 719-727.
16. Stubbs JB, Strickland AD, Frank RK, Simon J, McMillan K, Williams JA: Biodistribution and dosimetry of an aqueous solution containing sodium 3-(¹²⁵I)iodo-4-hydroxybenzenesulfonate (Iotrex) for brachytherapy of resected malignant brain tumors. Cancer Biotherapy & Radiopharmaceuticals 2000, 15: 645-656.
17. Videtic GM, Gaspar LE, Zamorano L, Fontanesi J, Levin KJ, Kupsky WJ, Tekyi-Mensah S: Use of the RTOG recursive partitioning analysis to validate the benefit of iodine-125 implants in the primary treatment of malignant gliomas. International Journal of Radiation Oncology, Biology, Physics 1999, 45: 687-692.
18. Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG: Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. International Journal of Radiation Oncology, Biology, Physics 1989, 16: 1405-1409.
19. Wen PY, Alexander E, 3rd, Black PM, Fine HA, Riese N, Levin JM, Coleman CN, Loeffler JS: Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas. Cancer 1994, 73: 3029-3036.

• The Wake Forest Neurosurgery Brain Tumor Index Comprehensive Internet links to information about brain tumors
• The New WHO Classsification of Central Nervous System Tumors
• Astrocytic Tumor Grading Systems
• Mutations in Astrocytic Lineage Tumors
• Benign brain and spine tumors such as meningioma, epidermoid, dermoid, hemangioblastoma, , colloid cyst, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, and craniopharyngioma.
• Acoustic neuroma and other cerebellopontineangle (cpa) and skull base tumors
• Pituitary tumor (adenoma, carcinoma) information
• Neurofibromatosis (type I, Von Recklinghausen's disease) information
• Tuberous sclerosis resources
• Von Hippel-Lindau disease resources
• Spine tumorinformation