Accurate delivery of the prescribed dose during clinical BNCT requires knowledge (or reasonably valid assumptions) about the boron concentrations in tumor and normal tissues. For conversion of physical dose (Gy) into photon-equivalent dose (Gy-Eq), relative biological effectiveness (RBE) and/or compound-adjusted biological effectiveness (CBE) factors are required for each tissue. The BNCT treatment planning software requires input of the following values: the boron concentration in blood and tumor, RBEs in brain, tumor and skin for the high-LET beam components, the CBE factors for brain, tumor, and skin, and the RBE for the gamma component

Capala, J.

Chanana, A. D.

Coderre, J. A.

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BNL-6 4626 A Treatment Planning Comparison of BPA- or BSH-based BNCT of Malignant Gliomas J. Capala', J.A. Coderre and A.D. Chanana Medical Department, Brookhaven National Laboratory, Upton, NY 1 1973, USA Introduction , Accurate delivery of the prescribed dose during clinical BNCT. requires knowledge (or reasonabfy valid assumptions) about the boron concentrations in .tumor and normal tissues. For conversion of physical dqse (Gy) into photon-equivalent dose (Gy-Eq), relative biological effectiveness (RBE) and/or compound-adjusted biological effectiveness (CBE) factors are required for each tissue. The BNCT treatment planning software requires input of the following values: the boron concentration in blood and tumor, RBEs in brain, tumor and skin for the high-LET beam components, the CBE factors for brain, tumor, and skin, and the RBE for the gamma component. In addition to the ongoing clinical BNCT program in Japan using BSH and the planned trial in Europe with BSH, there is interest among several BNCT groups in the USA in BSH-based BNCT. There is some uncertainty in the BNCT community and literature about the parameters to be considered for BSH regarding tumorhlood 'OB concentration ratio (range: 0.5:l to 2.2:l) [1,2], CBE factor in brain (range: 0.37 to 0.5)[3,4], and CBE factor in tumor (range: 1.2 to 2.3 )[5,6]. In the present work, we applied different combinations of these parameters and used BNCT treatment planning software with actual patient geometry for a direct comparison of a BPA-based plan to the plan that would be obtained for patient' treatment with BMRR epitheml neutron beam using BSH. Materials and Methods Treatment plans fer ESE cshg diEerent-cDmbifiations of the iaput parmeters (Tsb!: 1) were prepared and compared to the BPA plan used for a representative glioblastoma patient treated at Brookhaven National Laboratory. Treatment planning procedures and parameters used for estimation of radiation doses delivered during BPA-based BNCT are described in this volume by Capala et al. [7]. All treatment plans used a single-field exposure and were run with a prescribed limit of 12.6 Gy-Eq as the maximum dose to a 1 cm3 volume of normal brain outside of the tumor volume (contrast enhanced volume on MRI scan) delivered in a single fraction. Results and Discussion Results of these simulations are listed in Table 1. Average doses to the whole brain volume were approximately 4 Gy-Eq and were similar with BPA and BSH. The BPA-based treatment delivered a minimum of 38.1 Gy-Eq to the deepest portion of the tumor. The doses to the tumor volume were considerably lower with BSH in all cases except those involving the most favorable I Address for correspondence: Jacek Capala, Medical Department, Brookahaven National Laboratory, Building 490, Upton, NY 11973, USA set of assumptions. Typical dose volume histogram obtained from BPA-based treatment plan was shown in Figure 1 along with examples of dose-volume histograms that resulted from different sets of assumptions regarding ‘?I3 concentration in the blood and ‘93 tumor-to-blood ratio for BSH- based treatment plans (Figure 1). Only the most optimistic BSH-based treatment plan, which assumed CBE values of 0.37 and 2.3 for the brain and the tumor, respectively, ‘OB concentration in the blood of 30 ppm and ‘OB tumor-to-blood ratio of 2: 1,  produced dose-volume histograms comparable to those obtained using BPA as a boron delivery agent. In this work we have, for BSH, used CBE factors and “’B concentrations that, to the best of our knowledge, span the range of published values from both animal experiments and clinical studies. Published reports of BSH biodistribution in animal tumor models have generally shown that the boron concentration in the tumor is only about 50% of that in the blood, i.e. a tumor-to- blood ration of 0.51. A recent report from Japan [l] described BSH biodistribution data from 39 patients. The ‘?I3 concentrations reported for tumor and blood were 26.5 f 3.4 and 12.7 0.8 pg %/g, respectively, for a tumor-to-blood ratio of 2.1 : 1. The tumor-to-blood concentration ratios used for the simulations in this report were varied from 1 : 1 to 2: 1. Treatment plans 1 - 9 (Table l), represent various combinations of the input parameters for BSH. Plan 1 uses the values reported by Hatanaka [ 13. Plans 2-9 use tumor-to-blood ratios of 1 : l(P1ans 2 -5) and 2: 1 (plans 6-9) at two different blood boron concentrations, 20 and 30 ppm. respectively. In addition, at each blood boron concentration, two sets of CBE factors were used as a way of exploring the effect of uncertainty in these parameters. The plans using 0.5 as the CBE factor for brain and 1.2 as the CBE factor for tumor are considered a “worst case”, whereas the combination 0.37 as the CBE factor for brain and 2.3 as the CBE factor for tumor is considered a “best case” scenario for BSH- based BNCT. Our results showed that if BSH were used in the current BNL protocol (BMRR epithermal neutron beam, single fraction), only very optimistic assumptions regarding CBE factors, and ‘?I3 distribution would produce the radiation doses comparable to those obtained using BPA. However, computer simulations are only as good as their input assumptions. It is possible that new approaches to BSH-mediated boron delivery, as reported by Barth et al. [6] or Zfii&k:i-gei ei al. [7] h ehis volume may improve &e, ’% diStiibutiOii. It is also possible that a favorable micro-distribution of BSH-delivered ‘OB in human tumor cells, as reported by Otersen et al. [8], may increase the effectiveness of the treatment. The influence of fractionation and neutron beam characteristics (other than at BMRR) on the doses delivered to tumor and normal tissues during BSH-based BNCT remains to be explored. Aknowledgement This work was supported by the US. Department of Energy under contract # DE-AC02- 76CH00016. References 1. Hatanaka H, Nakagawa Y. Clinical results of long-surviving brain tumor patients who underwent boron neutron capture therapy. Int. J. Radiat. Oncol. Biol. Phys. 1994;28: 1061 - 1066. 2. Kraft SL, Gavin PR, Leathers CW, Dehaan CE, Bauer WF, Miller DL, Dorn RV, and Griebenow ML. Biodistribution of boron in dogs with spontaneous intracranial tumors following borocaptate 4 sodium administration. Cancer. Res. 1994;54: 1259 -1263. 3. Moms, G. M., Coderre, J. A., Hopewell, J. W., Micca, P. L., Nawrocky, M. M., Liu, H. B., and Bywaters, A. Response of the central nervous system to boron neutron capture irradiation: Evaluation using rat spinal cord model. Radiother Oncol. 1994;32:249-255. 4 Huiskamp, R, Gavin, P. R., Coderre, J. A., Phillip, K. H. I., and Wheeler, F. J. Brain tolerance in dogs to boron neutron capture therapy with borocaptate sodium (BSH) or boronophenylalanine (BPA). In: Y. Mishima (ed.) Cancer Neutron Capture Therapy, pp. in press. New York: Plenum Press, 1996. 5.  Coderre, J. A,, Morris, G. M., Micca, P. L., Nawrocky, M. M.,Fisher, C. D., Bywaters, A., and Hopewell, J. W. The therapeutic ratio in boron neutron capture therapy: Assessment using the rat 9L gliosarwma and spinal cord models. In: Y. Mishima (ed.) Cancer Neutron Capture Therapy, pp. 757-762. New York: Plenum Press, 1996. 4. Aizawa 0. Evaluation of Neutron Irradiation Field for Boron Neutron Capture Therapy by Using absorbed Dose in a Phantom. Int. J. Radiat. Oncol. Biol. Phys. 1994; 28: 1061 - 1066. 5. Capala 3, Chadha, Coderre JA, Diaz AZ, Liu KB,Wheeler FJ, Wessol DE, Wielopolski L, Chanana AD. Doses Delivered to Normal Brain Under Different Treatment Protocols at Brookhaven National Laboratory. In this volume. 6. Barth RF, Yang W, Soloway AH, Goodman, JH. Alternative Approaches for Delivery of Boron Containing Agents to Brain Tumors. In this volume. 7. Haselsberger K, Rander H, Pendl G. Systemic Hyaluronidase: a Promissing Adjuvant for BNCT of Glioblastoma with Na2B,, H,,SH (BSH). In this volume. 8. Otersen B, Sierralta W, Haritz D, Grochulla F; Bergman M, Gabel D. Binding and Subcellular Distribution of Na2B,2 H,,SH (BSH) in Tumor Tissue of Glioma Patients. In this volume. 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 responsi- bility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Refer- ence herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recom- 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. Figure Legend Figure 1. Examples of dose volume histograms for normal brain and tumor obtained for BPA (A - plan #lo) or BSH using a range of possible bloodtumor 'OB concentrations and CBE alues (B- plan #1, C - plan #8, D- plan #9, E - plan #6, F - plan #7). .. . Table 1. Summary of results obtained from treatment plans using BPA or BSH. 1 Compound BPA 12.7 44. 1.3 3.8 1 --- - - BSH I 'OB in the blood (ppm) 12.7 30 20 30 20 26.5 20 30 40 60 'OB in the tumor (ppm) CBE in the brain CBE in the tumor Y =E Beam high-LET RBE Time or irradiation at 3 MW reactor power (min) Peak brain dose 0.5 0.5 0.3j 2.3 1 3.2 49 -- - - 12.6 4.2 0.8 2.1 0.6 0.7 28.5 26.0 17.0 4.7 2.0 2.2 17.8 3 0.37 2.3 1 - - 0.37 2.3 1 3.2 -- - 0.5 1.2 1 3.2 - - 0.5 1.2 1 3.2 39 - - - - 12.6 4.0 1.3 1.7 0.5 0.6 19.5 - 17.8 10.7 3.8 1.6 1.8 0.37 2.3 1 3.2 44 - 7 - - 12.6 4.1 1.1 1.9 0.5 0.6 27.1 - 3 1.4 22.7 4.2 1.8 2.0 0.5 1.2 1 3.2 45 - - - - - 12.6 - 4.1 1 .o 2.0 0.5 0.7 17.9 - - 16.4 8.2 4.4 1.8 2.0 12.5 2.3 1.2 1 1 3 -2 3.2 3.2 3.2 49 - 12.6 - 4.2 0.8 2.1 0.6 0.7 3 1.4 - - 43.0 34.0 4.7 2.0 2.2 39 38 51 44 12.6 45 12.6 4.1 1 .o 2.0 0.5 0.7 47.5 24.6 16.4 4.4 1.8 2.0 18.1 6 12.6 12.6 12.6 ~~ Average brain dose of which: boron gamma fast n Peak tumor dose N- 14 4.0 1.3 1.7 0.4 0.6 4 -2 0.7 2.2 0.6 0.7 4.0 1.3 1.7 0.5 0.6 4.1 1.1 1.9 0.5 0.6 59.3 53.4 45.5 4.2 1.8 2.0 37.9 9 35.8 29.3 60.1 - 54.6 47.7 4.9 1.5 1.7 38.1 - 10 32.6 23.3 5.0 2.0 .2.3 28.5 21.3 3.8 1.5 1.8 Average tumor dose of which: boron gamma fast n . .  N-14 IMinimum tumor dose 23.8 13.3 22.3 30.9 20.6 1 7 8 Treatment plan # 2 4 5 I 70 , BPA 'OB in the blood/tumor (ppm): 13/45.5 BNC CBE for brain/ltumor: 1.313.8 20 in Brain 0 0 10 20 30 40 50 60 BNCT Dose (Gy-Eq) 70 n 2 P, 50 E >" : 20 lL" 3 - 40 Y- o 30 S 0 .I CI 10 0 70 - BSH 'OB in the blood/tumor (ppm): 12.7/26.5 BNC CBE for braidtumor: 0.512.3 : B  60 - - - - - - - - - - - - 0 10 20 30 40 50 60 70 BNCT Dose (Gy-Eq) I 70 I 2o C BSH 'OB in the blood/tumoir (ppm): 30/60 BNC CBE for braini'tumor: 0.5/1.2 I I 2 I Brain J 1 Tumor 0 I O  20 30 40 60 70 BNCT Dose (Gy-Eq) 70 60 50 iD 30 ( O I  20 10 0 0 BSH ‘OB in the blood/tumor (ppm): 30/60 BNC CBE for brainhumor: 0.37i2.3 rl ‘ I  I 10 20 30 40 50 60 BNCT Dose (Gy-Eq) 70 ' Y- O 70 Ij/ 50 lli 30 20 10 BSH 'OB in the blood/tumor (ppm): 20/40 BNC CBE for brain/tumor: 0 . M  .2 I I J Tumor \ 0 I O  20 30 40 50 60 70 BNCT Dose (Gy-Eq) I 70 , 3 rc 0 S 0 0 m .- + Lb Brain I O  BSH 'OB in the blood/tumor (ppm): 20/40 BNC CBE for brainhmor: 0.37123 r i Tumor 0 I O  20 30 40 50 60 70 BNCT Dose (Gy-Eq) 

A treatment planning comparison of BPA- or BSH-based BNCT of malignant gliomas

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A treatment planning comparison of BPA- or BSH-based BNCT of malignant gliomas

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