Positron Emission Tomography-based Boron Neutron Capture Therapy Using Boronophenylalanine for High-Grade Gliomas: Part

Based on pharmacokinetic findings of fluorine-18labeled L-fluoroboronophenylalanine by positron emission tomography (PET), methods for estimating tumor iOB concentration were devised. In clinical practice of boron neutron capture therapy (BNCT) for high-grade gliomas, a large amount of L-boronophenylalanine (L iOB BPA)-fructose solution is used. Under these conditions, a slow i.v. infusion of L-10B-BPA-fructose solution should be performed for BNCT; therefore, the changes over time in iOB concentration in the target tissue were estimated by convoluting the actual time course of changes in plasma ‘#{176}B concentration with a PET-based weight function including the proper rate constants [K1 (ml/g/min), k2 (min1), k3 (mint), and k4 (min’)]. With this method, the estimated values of ‘#{176}B concentration in gliomas were very close to the ioB levels in surgical specimens. This demonstrated the similarity in pharmacokinetics between fluorine-18-labeled L-fluoroboronophenylalanine and L-’#{176}B-BPA. This method, using the appropriate rate constant, permits the determination of tumor ioB concentration and is widely suitable for clinical BNCT, because the averaged PET data are enough to use in future patients without individual PET study. Received 12/18/97; revised 5/22/98; accepted 7/1/98. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I Supported in part by Grants-in-Aid for Science Research 06282254, 06671411, 07274259, 8671602, and 09671439 from the Ministry of Education, Science, Sports and Culture of Japan. 2 To whom requests for reprints should be addressed, at Department of Neurosurgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo 602-0841, Kyoto, Japan. Phone: 075-251-5543; Fax: 075-251-5544; E-mail: [email protected]. Introduction BNCT3 requires selective delivery of a boron-containing drug to the tumor, followed by irradiation with neutrons (1-5). For estimation of the radiation dose to the tumor, it is essential to know the concentration of boron in the tumor at the time of BNCT. However, direct measurement at the time of BNCT is impossible; therefore, new approaches to the estimation of the boron content of tumors during BNCT are required. When actually performing BNCT, we must reconfirm the tumor level by measuring the L-’#{176}B-BPA in the arterial blood. We administered a large amount of L-’#{176}B-BPA-fructose solution i.v. before BNCT, admitted the patient to the irradiation room, and began neutron irradiation, but the collection of arterial blood was possible for at least 1-2 h, until the beginning of neutron irradiation. Thus, the input function of L-’#{176}B-BPA can be determined by blood sampling during this 1-2 h, and, finally, the neutron dose must be determined based on the tumor lO level. Under these conditions, estimation of ‘#{176}B level based on the incorporation constant (ic*) and the utilization ratio (Ur*; Refs. 6-8) is often inappropriate. In this study, our main purpose is to solve these actual problems. We evaluated the tumor pharmacokinetics ofL-’8F-’#{176}B-FBPA based on comparison with L-’#{176}BBPA using PET and assessed the similarity of L-’8F-’#{176}B-FBPA accumulation to that of L-’#{176}B-BPA. If the ‘#{176}B concentration calculated using the rate constant obtained by PET using L‘#{176}B-FBPA and the actually measured ‘#{176}B input function is close to that in the surgical specimens, similarity in pharmacokinetics between L-’8F-1#{176}B-FBPA and L-’#{176}B-BPA will be confirmed. We also designed a basic method for measuring the tumor concentration of L-’#{176}B-BPA using L-’8F-’#{176}B-FBPA for clinical BNCT. Patients and Methods Clinical Use of L-18F-’#{176}B-FBPA. The performance of L-’8F-’#{176}B-FBPA PET studies on humans and the quality control of L-’8F-’#{176}B-FBPA followed the guidelines established by the PET Committee of Nishijin Hospital (Kyoto, Japan) in January 1991. The synthesis method and purification of L-’8F-’#{176}B-FBPA are detailed in our previous report (9). Preparation of L i B BPA Fructose Complex. L-’#{176}BBPA is relatively insoluble in water. For i.v. administration, we prepared a L-’#{176}B-BPA fructose-complex solution as reported by Yoshino et a!. (10). This complex dissociates and reaches an 3 The abbreviations used are: BNCT, boron neutron capture therapy; PET, positron emission tomography; L-”F-1#{176}B-FBPA, fluorine-l8-labeled L-fluoroboronophenylalanine; L-’#{176}B-BPA, L-boronophenylalanine; GBM, glioblastoma multiforme; ROI, region of interest; All, anaplastic astrocytoma WHO grade II; Am, anaplastic astrocytoma WHO grade III. Research. on April 13, 2017. © 1998 American Association for Cancer clincancerres.aacrjournals.org Downloaded from