In this report we discuss some issues considered in selecting initial protocols for boron neutron capture therapy (BNCT) of human glioblastoma multiforme. First the tolerance of normal tissues, especially the brain, to the radiation field. Radiation doses limits were based on results with human and animal exposures. Estimates of tumor control doses were based on the results of single-fraction photon therapy and single fraction BNCT both in humans and experimental animals. Of the two boron compounds (BSH and BPA), BPA was chosen since a FDA-sanctioned protocol for distribution in humans was in effect at the time the first BNCT protocols were written and therapy studies in experimental animals had shown it to be more effective than BSH

Chanana, A. D.

Coderre, J. A.

Joel, D. D.

Slatkin, D. N.

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Coif - 5% 0 4 u 3  -- 4 BNL-6 36 9 5 Protocols for BNCT of glioblastoma multiforme at Brookhaven: Practical considerations Chanana, AD., Coderre, J A ,  Joel, D.D. and Slatkin, D.N. Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. Introduction T Between September, 1994 and February, 1996 15 patients were treated with BPA- based BNCT at the Brookhaven Medical Research Reactor (BMRR) under two FDA- sanctioned protocols that differed primarily iri the peak dose delivered to a volume of - 1 cm3 of tissue 2 cm deep in the brain, generally located in the region of surgical debulking of the tumor, and in the average dose to - 16 cm3 of brain (See Table 1). In this report we discuss some of the issues considered in the preparation of the initial clinical BNCT protocols and the rationale supporting the specifications adopted. field, particularly the brain. The radiation dose Iimits established were based on results from both human and animal exposures to either single doses of photons [l-31 or single' treatments with BNCT [4,5]. Collectively these studies suggest that the upper limit for a safe dose to the whole brain including the basal ganglia is between IO and 11 Gy. Comparison of multiple fractions to a single fraction photon radiation using the brain tolerance unit formulation [6] supports this conclusion. Smaller volumes of brain (- 14cm3) were found to tolerate doses up to 20 Gy [7]. 12.6 Gy-Eq in 4 patients. The average calculated doses to the whole brain and basal ganglia were less than 3.0 Gy-Eq in all patients. In all BNCT treatments the dose rate was below 26 cGy-Eq/min. Although it was thought that these doses were conservative, it was considered advisable to initiate epithermal neutron-mediated BNCT as safely as possible while still delivering a potentially effective dose to the tumor. photon therapy and single-fraction BNCT both in humans and in experimental animals [8-121. The conclusion drawn from these studies was that 17 to 25 Gy-Eq should provide palliation and some prolongation of life in patients with glioblastoma multiforme but that higher doses may be required for long-term tumor control. In the patients. treated with BNCT under these initial protocols, the nominal minimum tumor dose The first of these issues deals with tolerance of normal tissues within the radiation As shown in Table 1, the prescribed peak dose was 10.5 Gy-Eq in 11 patients and J Estimates of tumor control doses were based on the results of single-fraction A&ress for correspondence: AD. Chanana, Medical Department, Brookhaven National Laboratory, Upton, New York 11973, U.S.A. DISTRMJION OF TH& k ranged from 20 to 37 Gy-Eq while the nominal minimum dose to the target volume (2 cm envelope around the tumor-enhanced MRI image) ranged from 8 to 17 Gy-Eq. In all patients tumor recurred between 3 and 9 months after BNCI'. Brain Tissue Peak dose to - 1 cm3 tissue Average dose to - 16 cm3 tissue Average dose to whole brain Basal ganglia ~ P Table 1. Radiation dose limits to the normal brain in the first BNCT protocols expressed as Gray-equivalent (Gy-F$). The number of patients is in parenthesis. Gy-Eq. 10.5 (11) 12.6 (4) 10.0 (11) 12.0 (4) e 7.5 (15) 7.5 (15) Gy-Eq is equal to the absorbed dose (Gy) times an experimentally determined biological effectiveness factor for each dose component [13] The decision to administer BNCI' in a single fraction was based on the following reasons; 1) To date, all BNCI' in humans has been delivered in a single fraction. 2) The distribution of BPA, particularly to normal brain, following more than one fraction of BNCT is unknown. 3) BNCI' using BPA and the BMRR epithermal neutron beam allows a substantial tumor dose to be delivered without exceeding normal brain radiation tolerance. 4) Animal studies to date have not conclusively demonstrated that fractionation improves tumor control [14] nor have they shown that fractionation provides more than minimal protection to normal brain [15]. In the absence of experimental guidance as to the most effective method for fractionating BPA-mediated BNCI', we considered it prudent to start with single-fraction treatments. rational choice since an FDA-sanctioned protocol for biodistribution in humans was in effect at the time the first BNCT protocols were written and therapy studies in experimental animals had shown it to be more effective than BSH [16]. Further, BPA is a non-toxic, metabolic compound that is actively transported across the blood-brain- barrier (BBB) with the potential for accumulation in islets or streamers of tumor otherwise protected by the BBB. reduce tumor mass and to minimize the impact of post-BNCI' cerebral edema. Maximum tumor depth was determined based on the limited thermal neutron flux to sites deep (> 6 cm) in the brain. A Karnofkky performance status (KPS) score of 2 70 was chosen to minimize potential problems associated with the requirement that patients be able to remain totally still during an exposure period of - 45 minutes without anesthesia. Also, this KPS score is used as a partitioning prognostic factor in analyzing patient survival [17]. Patients with a histopathologically confirmed diagnosis of glioblastoma multiforme were selected because their extraordinarily poor prognosis Of the two boron compounds (BSH and BPA) potentially available, BPA was the Other issues were less controversial. Prior debulking was deemed necessary to DISCLAIMER This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or use- fulness of any information, apparatus, product, or proctss disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any spe- cific commercial product, process, or service by trade name, trademark, manufac- turer, or otherwise does not necessarily constitute or imply its endorsement, mom- mendation, or favoring by the United States Government or any agency thereof. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof. DISCLAIMER Portions of this document may be illegible in electronic image products. Images are produced from the best available original document. justifies their inclusion in an unproven experimental therapy. Patients with prior radiotherapy and/or prior chemotherapy were excluded because of the unknown degree of increased susceptibility of normal brain to BNCI‘ resulting from these treatments. These protocols were closed to patient entry in February, 1996. The major conclusions drawn from these 15 patients were; 1) BNCT, as administered to these patients, was safe. There were no adverse effects associated with the infusion of BPA- fructose at a dose of 250 mg BPA/kg body weight. There was no damage to the scalp other than focal alopecia and no damage to normal brain or other critical organs was observed. 2) Tumor palliation was achieved with a median life span approximately equal to that observed with standard therapies [18]. 3) Tumor recurrence was usually deep in the target volume, an area that received the lowest dose of radiation. 4) A simulation room outside the reactor for patient positioning is very advantageous. Based on this experience a follow-up protocol received FDA sanction in June, 1996. Under the new protocol, radiation doses to tumor and target volume will be increased to 30 Gy-Eq [goal] and 17 Gy-Eq minimum [requirement] respectively. The average dose to the whole-brain and basal ganglia will be maintained at less than 7.5 Gy- Eq. These radiation dose parameters will be achieved by; 1) increasing the aperture size (8 cm to 12 cm) and thickness (7.6 cm to 15.2 cm) of the neutron beam collimator 1191; 2) incorporating bilateral irradiations if necessary to achieve the required dose to the target volume, and; 3) redefining the peak-dose as 12.6 Gy-Eq to less than 1% of the normal brain volume. Acknowledgement: This research was supported in part by the U.S. Department of Energy under Contract DE-ACO2-76CHOOO16. References: 1. Thompson, C.B., Sanders, J.E., Flournoy, N., Buckner, C.D., Thomas, E.D. The Risks of central nervous system relapse and leukoencephalopathy in patients receiving marrow transplants for acute leukemia. Blood 6T105-199; 1986. 2. Kemper, T.L., O’Neil, R., Caveness, W.F. Effects of single dose supervoltage whole brain radiation in macaca mulatta. J. Neuropathol. Exp. Neurol. 36:916- 940; 1977. 3. Fike, J.R., Gobbel, G.T. Central nervous system radiation injury in large animal models. In: Gutin, P.H., Leibel, S.A., Sheline, G.E., eds. Radiation Injury to the Nervous System. New York: Raven Press; 1991:113-135. 4. Huiskamp, R., Gavin, P.R., Coderre, J.A., Phillip K.H.I., Wheeler FJ. Brain tolerance in dogs to boron neutron capture therapy with borocaptate sodium (BSH) or boronophenylalanine @PA). In: Mishima Y, ed. Cancer neutron capture therapy. New York: Plenum Press; 1996591-598. 5. 6. 7. 8. 9. Slatkin, D.N. A history of boron neutron capture therapy of brain tumors: postulation of a brain radiation dose tolerance limit. Brain 114:1609-1629; 1991. Pezner, R.D., Archambeau, J.O. Brain tolerance unit: A method to estimate risk of radiation brain injury for various dose schedule. Int. J. Radiat. Oncol. Biol. Phys. 7:397-402, 1981. Engenhart, R., Kimmig, B.N., Hover, K-H., Wowra, B., Romahn, J., Lorenz, WJ., vanKaick, G., Wannemacher, M. Long-term follow-up for brain metastases treated by percutaneous stereotactic single high-dose irradiation. Cancer 71: 1353- 1361; 1993. Flickinger, J.C., Loeffler, J.S., Larson, D.A. Stereotactic radiosurgery for intracranial malignancies. Oncology 8:81-98; 1994. Colombo, F., Benedetti, A, Pozza, F., Avanzo, R., Chierego, G., Marchetti, C., Dettori, P., Bernardi, L, Pinna, V. Radiosurgery using a 4 MeV linear accelerator. Acta Radiologica, Suppl. 369:603-607; 1986. 10. Coderre, J., Rubin, P., Freedman, A, Hansen, J., Wooding, T.S., Joel, D., Gash, D. Selective ablation of rat brain tumors by boron neutron capture therapy. Int. J. Radiat. Oncol. Biol. Phys. 28:1067-1077; 1994. 11. Coderre, J.A., Button, T.M., Micca, P.L., Fisher, C., Nawrocky, M.M., Liu, H.B. Neutron capture therapy of the 9L rat gliosarcoma using the p -  boronophenylalanine- fructose complex. Int J. Radiat. Oncol. Biol. Phys. 30643- 652, 1994a. 12. Hatanaka, H. Clinical experience of boron neutron capture therapy for gliomas - A comparison with conventional chemo-immuno-radiotherapy. In: Hatanaka, H., ed. Boron-neutron capture therapy for tumors. Niigata: Nishimura Co. Ltd.; 1986~349-379. 13. Coderre, J.A., Makar, M.S., Micca, P.L., Nawrocky, M.M., Liu, H.B., Joel, D.D., Slatkin, D.N., Amos, H.I. Derivation of relative biological effectiveness for the high-LET radiations produced during boron neutron capture irradiations of the 9L rat gliosarcoma in vitro and in vivo. Int. J. Radiat. Oncol. Biol Phys. 27:1121-1129; 1993. 14. Coderre, J.A., Morris, G.M., Micca, P.L, Fisher, C.D. and Ross, G.A. Comparative assessment of single-dose and fractionated neutron capture therapy. Radiat. Res. 144:310-317, 1995. 15. Gavin, P.R., Wheeler, F.I., and Swartz, C.D. Fractionation effects of BNCT on normal tissue tolerance of the canine brain. Abstract; Seventh International Symposium on Neutron Capture Therapy, Zurich, Switzerland, Sept. 4-7, 1996. 1, 16. 17. 18. 19. Coderre, J.A., Morris, G.M., Micca, P.L, Nawrocky, M.M., Fisher, C.D., Bywaters, A. and Hopewell, J.W. The therapeutic ration in BNCT: Assessment using the rat 9L gliosarcoma and spinal cord models. In: Mishima, Y., ed. Cancer Neutron Capture Therapy pp. 757-762 New York, Plenum Press, 1996. Curran, WJ. Jr., Scott, C.B., Horton, J., Nelson, J.S., Weinstein, AS., Fischbach, A.J., Chang, C.H., Rotman, M., Asbell, S.O., Krisch, R.E. and Nelson, D.F. Recursive partitioning analysis of prognostic factors in three radiation therapy oncology group malignant glioma trials. J. Nat. Canc. Inst. 85704-710, 1993. Elowitz, E.H., Chadha, M., Coderre, J.A., Iwai J., Joel, D.D., Slatkin, D.N., Chanana, AD. A phase I/II trial of boron neutron capture therapy (BNCT) for glioblastoma multifome using intravenous boronophenylalanine-fructose complex and epithermal neutrons: early clinical results. Seventh International Symposium of Neutron Capture Therapy 1996;NA. Liu, H.B., Greenberg, D.D., and Capala, J. An improved neutron brain tumor irradiations in clinical boron neutron capture therapy. (in press). I collimator for Med. Physics 

Protocols for BNCT of glioblastoma multiforme at Brookhaven: Practical considerations

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Protocols for BNCT of glioblastoma multiforme at Brookhaven: Practical considerations

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