1. Institute of Nuclear Engineering and Science National Tsing Hua University Institute of Nuclear Engineering and Science National Tsing Hua University BNCT Treatment Planning for Superficial and Deep-Seated Tumors : Experience from Clinical Trial of Recurrent Head and Neck Cancer at THOR C.T. Chang a, L.Y. Yeh a, Y-W H. liu a, L.W. Wang b a Institute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu, Taiwan, ROC b Department of Oncology Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC June, 2014

2. Institute of Nuclear Engineering and Science National Tsing Hua University Outline Purpose Material & Method － Calculation tools － Calculation assumptions Case discussion － Treatment plannings for different tumor locations ◎ Patient 17 & Patient 16 Conclusion 2

3. Institute of Nuclear Engineering and Science National Tsing Hua University Purpose Oral cancer is the fifth of the top ten cancers announced in 2013 by Department of Health in Taiwan Currently, there is no effective treatment for recurrence head-and-neck cancer Under the collaboration between National Tsing Hua University and Taipei Veterans General Hospital, clinical trial of recurrent head-and-neck cancer using BNCT at Tsing Hua open-pool reactor(THOR) started on August 11, 2010 Up to January of 2014, 17 patients were treated This study shows the selection of treatment setup based on experience on patients with superficial and deep-seated tumors 3

4. Institute of Nuclear Engineering and Science National Tsing Hua University Material & Method Calculation tools Treatment Planning System THORplan MCNP 5 Boron drug : BPA Treatment planning assumptions Reactor power = 1.2MW Boron-10 in blood = 25ppm Target tumor dose ： GTV D80 = 20Gy(W) RBE = 3.2 for neutron = 1 for gamma ray 4 CBE = 3.8 for tumor = 4.9 for mucosa = 2.5 for skin = 1.3 for other normal tissues

5. Institute of Nuclear Engineering and Science National Tsing Hua University Patient 17 (1st irradiation) Tumor volume : 73 cc The patient is in sitting position during irradiation Irradiated at 45 degrees (right and front) Tumor location (measured from the direction of irradiation) - tumor center to skin = 2.5 cm - deepest distance to skin = 5.5 cm Treatment Planning for Superficial tumor 45 〫 5

6. Institute of Nuclear Engineering and Science National Tsing Hua University Treatment Planning for Superficial tumor 6 Two conditions (1) Using patient collimator 16-10-1 cm (2) No collimator (direct irradiation) Source-to-tumor center distance = 20.5 cm

7. Institute of Nuclear Engineering and Science National Tsing Hua University Flux(cm -2 -s -1 ) Flux comparison for superficial tumor treatment 7 Flux(cm -2 -s -1 ) axis (cm) Using collimator causes fluxes to be higher inside the patient collimator, up to 4.5 cm depth

8. Institute of Nuclear Engineering and Science National Tsing Hua University Patient 17-1 Direct IrradiationPatient Collimator Flux (cm -2 s -1 ) ThermalEpi.FastPhotonThermalEpi.FastPhoton GTV- D80 3.36E+84.15E+82.12E+74.88E+73.95E+81.20E+85.13E+67.42E+7 At maximum dose point GTV (3.92) 8.04E+83.35E+81.22E+79.20E+79.26E+84.93E+81.74E+71.12E+8 Mucosa6.78E+81.75E+86.40E+68.20E+76.87E+82.31E+88.52E+69.33E+7 Brain3.74E+85.55E+72.18E+65.56E+72.01E+81.70E+71.17E+64.47E+7 Rt eyeball 4.52E+81.69E+85.36E+65.31E+72.34E+83.93E+71.69E+64.23E+7 Using collimator : gives higher thermal n fluxes for tissues inside the irradiation field ( +18% for GTV); gives lower thermal n fluxes for tissues outside the irradiation field (-46%, eyeball & brain). Thermal n flux at mucosa remains about the same Flux Comparison for Superficial tumor treatment 8 (↑ 18%) (↑ 15%) (↑ 1%) (↓ 46%) (↓ 48%)

9. Institute of Nuclear Engineering and Science National Tsing Hua University Dose Rate Comparison for Superficial Tumor Treatment Using collimator results in higher dose rate (+16%) at GTV-D80 (& GTV max), therefore shorter irradiation time The increase of max dose rate at mucosa is only 2%; for brain and Rt eyeball, the max dose rate decrease by ~40%. Therefore, the maximum dose of mucosa, brain and Rt eyeball decrease. For superficial tumor, using patient collimator helps to protect the normal tissues especially those outside the irradiation field Patient 17-1 Direct Irradiation (Irradiation time = 32.94 min) Patient Collimator (Irradiation time = 28.47 min) Dose Gy(W) Dose Rate (Gy(W) s -1 ) Dose Gy(W) Dose Rate (Gy(W) s -1 ) PhotonB10H1N14TotalPhotonB10H1N14Total GTV- D80 20.0 2.97E-49.08E-34.62E-42.43E-41.01E-2 20.0 4.93E-41.07E-22.12E-42.85E-41.17E-2 At maximum dose location GTV (3.92) 46.10 5.84E-42.18E-23.77E-45.79E-42.33E-2 46.00 7.54E-42.50E-24.63E-46.66E-42.69E-2 Mucosa14.86 5.45E-46.10E-32.41E-46.10E-47.52E-3 13.16 6.42E-46.13E-32.92E-46.13E-47.70E-3 Brain3.05 3.65E-48.95E-41.01E-41.77E-41.54E-3 1.59 2.87E-44.85E-46.11E-59.58E-59.33E-4 Rt eyeball 4.26 3.58E-41.07E-31.61E-45.50E-42.16E-3 2.08 2.89E-45.59E-47.53E-52.86E-41.22E-3 (↑ 16%) (↑ 15%) (↑ 2%) (↓ 39%) (↓ 44%) 9

10. Institute of Nuclear Engineering and Science National Tsing Hua University 10 Treatment Planning for Patient 17 Target: GTV D80 = 27 Gy(W) Boron concentration in blood =25ppm Reactor power =1.2 MW Irradiation time = 38.4 minutes Max. Dose Gy(W) Dose Limit Gy(W) Skin9.8111 Mucosa17.7710 Rt eyeball2.8010 Mucosa over dose limit < 10.6 cc GTVMeanMax.Min. Gy(W)37.962.112.9 In order to limit the volume of mucosa over 10 Gy(W) less than 10 cc, GTV D80 was set to 27Gy(W) during treatment planning The boron concentration in blood was assumed to be 25ppm For reactor power of 1.2 MW, the estimated irradiation time was 38 minutes Except for mucosa, dose of normal tissues were expected to be within the dose limits Volume of mucosa over 10 Gy is < 10 cc

11. Institute of Nuclear Engineering and Science National Tsing Hua University 11 Final Treatment of Patient 17 GTV D80 = 26.5 Gy (W) Reactor power = 1.62 MW Boron concentration in blood = 30ppm Irradiation time = 23.4 minutes Max. Dose Gy(W) Skin9.09 Mucosa17.11 Rt eyeball2.53 Mucosa over dose limit < 9.5 cc GTVMeanMax.Min. Gy(W)37.361.312.6 The boron concentration of patient was measured to be 30 ppm. The treatment was done using reactor power =1.6 MW. The irradiation time is 23 Minutes. The GTV D80 is 26.5 Gy (W), very closed to the prescribed dose 27 Gy (W).

12. Institute of Nuclear Engineering and Science National Tsing Hua University 12 DVH for Patient 17

13. Institute of Nuclear Engineering and Science National Tsing Hua University Patient 16 (1st irradiation) Tumor volume : 8.2 cc Irradiated from left-hand side Tumor location (measured from the direction of irradiation) - tumor center to skin = 6.5 cm - deepest distance to skin = 7.7 cm Treatment Planning for Deep-seated tumor 13

14. Institute of Nuclear Engineering and Science National Tsing Hua University Consider three conditions -- I. Direct irradiation -- II. Patient collimator 10 (long)-10(exit diameter)-1.5 cm (thickness) -- III. Lithium pad 2.5cm thick natural Li 2 CO 3 (size 40*40 cm) + 0.5cm thick enriched Li 2 CO 3 (size 5*5 cm) Source to tumor center distance =19 cm Source to skin distance = 12.5 cm Treatment Planning for Deep-seated tumor 14

15. Institute of Nuclear Engineering and Science National Tsing Hua University 15 Flux comparison for Deep-seated tumor along the beam direction Axis (cm) Flux(cm -2 -s -1 ) For deep-seated tumors, the situation is different. When using collimator, the thermal neutron flux at GTV decrease.

16. Institute of Nuclear Engineering and Science National Tsing Hua University Patient 16-1 Condition I. Direct irradiationCondition II. Patient Collimator Flux (cm -2 s -1 ) ThermalEpi.FastPhotonThermalEpi.FastPhoton GTV-D804.39E+83.55E+73.01E+69.31E+74.04E+83.03E+72.95E+61.03E+8 At maximum dose point GTV (2.72)8.06E+81.13E+85.72E+61.25E+88.00E+81.14E+85.78E+61.37E+8 Skin1.09E+95.06E+82.02E+71.24E+81.11E+95.21E+82.05E+71.38E+8 Mucosa7.56E+81.58E+86.87E+61.05E+87.46E+81.56E+86.98E+61.17E+8 Brain1.21E+94.23E+81.55E+71.40E+81.26E+94.41E+81.58E+71.58E+8 Lt eyelens3.91E+82.56E+81.13E+76.20E+73.57E+81.98E+89.34E+67.10E+7 (↓ 8%) (↓ 1%) (↑ 2%) (↓ 1%) (↑ 4%) (↓ 9%) When using collimator, the thermal neutron flux at GTV-D80 decreases by 8%. Thermal neutron flux of most of the normal tissues change only 1~2% Flux Comparison for Deep-seated tumor 16

17. Institute of Nuclear Engineering and Science National Tsing Hua University When using collimator, the dose rate at GTV-D80 is lower by 6%, results in longer irrad. time Dose rates of normal tissues either increases or decreases only slightly. Therefore, max dose of most of the normal tissues increase. For deep-seated tumors, using collimator has no benefits Dose rate Comparison for Deep-seated tumor Patient 16-1 Condition I. Direct irradiation (Irradiation time = 35.02 min) Condition II. Patient Collimator (Irradiation time = 37.34 min) Dose Gy(W) Dose Rate (Gy(W) s -1 ) Dose Gy(W) Dose Rate (Gy(W) s -1 ) PhotonB10H1N14TotalPhotonB10H1N14Total GTV- D80 20.0 5.97E-48.43E-31.56E-43.23E-49.52E-3 20.0 6.87E-47.77E-31.54E-42.98E-48.93E-3 At maximum dose point GTV (2.72) 35.85 8.34E-41.54E-22.61E-45.89E-41.71E-2 38.22 9.55E-41.52E-22.63E-45.84E-41.71E-2 Skin15.49 8.61E-44.97E-35.28E-49.75E-47.37E-3 17.18 1.00E-35.09E-35.37E-49.98E-47.67E-3 Mucosa17.87 7.03E-46.82E-32.79E-46.82E-48.51E-3 19.08 8.21E-46.72E-32.83E-46.71E-48.51E-3 Brain10.38 9.66E-42.87E-35.07E-45.66E-44.94E-3 11.81 1.14E-32.99E-35.18E-45.90E-45.27E-3 Lt eyelens 4.48 4.15E-49.22E-42.99E-44.73E-42.13E-3 4.63 5.03E-48.39E-42.72E-44.30E-42.07E-3 (↓ 6%) (↑ 4%) (↑ 7%) (↓ 3%) 17

18. Institute of Nuclear Engineering and Science National Tsing Hua University Using Lithium Pad for Skin Protection 18 The maximum dose for normal tissues is still high for the direct irradiation condition Li 2 CO 3 is used to reduce the skin maximum dose 2.5cm thick natural Li 2 CO 3 (size 40*40 cm) + 0.5cm thick enriched Li 2 CO 3 (size 5*5 cm)

19. Institute of Nuclear Engineering and Science National Tsing Hua University Using lithium pad results in much lower fluxes for all tissues compared to direct irradiation Thermal neutron flux at GTV D80 decreases by 30% For skin and mucosa, thermal neutron fluxes decrease more than GTV D80 Patient 16-1 Condition I. Direct irradiation Condition III. Natural lithium pad + Enriched lithium Flux (cm -2 sec -1 ) ThermalEpi.FastPhotonThermalEpi.FastPhoton GTV- D80 4.39E+83.55E+73.01E+69.31E+7 3.06E+82.67E+72.47E+67.91E+7 At maximum dose point GTV (2.72) 8.06E+81.13E+85.72E+61.25E+8 5.44E+88.04E+74.50E+61.02E+8 Skin 1.09E+95.06E+82.02E+71.24E+8 7.04E+83.59E+81.54E+71.00E+8 Mucosa 7.56E+81.58E+86.87E+61.05E+8 5.15E+81.15E+85.35E+68.58E+7 Brain 1.22E+94.44E+81.63E+71.40E+8 7.92E+83.05E+81.18E+71.11E+8 Lt eyelens 3.91E+82.56E+81.13E+76.20E+7 2.56E+81.86E+88.58E+65.33E+7 (↓ 30%) (↓ 33%) (↓ 35%) (↓ 32%) (↓ 35%) Flux Comparison for Deep-seated tumor 19

20. Institute of Nuclear Engineering and Science National Tsing Hua University Dose rate Comparison for Deep-seated tumor Patient 16-1 Condition I. Direct irradiation (Irradiation time = 35.02 min) Condition III. Natural lithium pad + Enriched lithium (Irradiation time = 49.29 min) Dose Gy(W) Dose Rate (Gy(W) s -1 ) Dose Gy(W) Dose Rate (Gy(W) s -1 ) PhotonB10H1N14TotalPhotonB10H1N14Total GTV-D80 20.00 5.97E-48.43E-31.56E-43.23E-49.52E-3 20.0 5.37E-45.86E-31.30E-42.25E-46.76E-3 At maximum point GTV (2.72) 35.85 8.34E-41.54E-22.61E-45.89E-41.71E-2 34.57 7.04E-41.04E-22.10E-43.98E-41.17E-2 Skin 15.49 8.61E-44.97E-35.28E-49.75E-47.37E-3 14.88 7.24E-43.22E-34.18E-46.32E-45.03E-3 Mucosa 17.87 7.03E-46.82E-32.79E-46.82E-48.51E-3 17.62 6.05E-44.64E-32.24E-44.65E-45.96E-3 Brain 10.51 9.64E-42.91E-35.22E-45.74E-45.00E-3 10.32 7.97E-41.89E-34.02E-43.73E-43.49E-3 Lt eye lens 4.48 4.15E-49.22E-42.99E-44.73E-42.13E-3 4.61 3.84E-46.07E-42.37E-43.12E-41.56E-3 (↓ 29%) (↓ 32%) (↓ 30%) (↓ 27%) The dose rate reduction at GTV-D80 is 29%, the irradiation time is longer. The dose rate reduction at skin is 32%, therefore the maximum dose of skin is lower. Using lithium pad has protection effect for normal tissues 20

21. Institute of Nuclear Engineering and Science National Tsing Hua University 21 Final Treatment of Patient 16 GTV D80 = 19 Gy(W) Reactor power = 1.8 MW Boron concentration in blood =21ppm Irradiation time = 35 minutes Max. Dose Gy(W) Skin14.75 Mucosa17.11 Lt eyelens4.81 Skin over dose limit < 2.8 cc Mucosa over dose limit < 24 cc GTVMeanMax.Min. Gy(W)22.633.215.6 Mucosa max.

22. Institute of Nuclear Engineering and Science National Tsing Hua University Conclusions The preferred patient setups are different for tumors at different depth For superficial tumors, using patient collimator is better than direct irradiation On the other hand, for deep-seated tumors, direct irradiation or attaching lithium pads at beam exit are better choices Tumor response of Patient 17 (superficial tumor) is PR, of Patient 16 (deep-seated tumor) is CR Minimum dose of GTV of patient 16 is 15.6 Gy (W), higher then patient 17 (12.6 Gy (W)). 22

23. Institute of Nuclear Engineering and Science National Tsing Hua University 23 References H.S. Li, Y-W H. Liu, C.Y. Lee, T.Y Lin, F.Y. Hsu, “Verification of the accuracy of BNCT treatment planning system THORplan”, Appl. Radiat. Isot. 67 (2009), S122–S125. T.Y Lin, Y-W H. Liu, “Development and verification of THORplan—A BNCT treatment planning system for THOR”, Appl. Radiat. Isot. 69 (2011) 1878– 1881. H.T. Yu, Y-W. H. Liu, T.Y. Lin, L.W. Wang, “BNCT treatment planning of recurrent head-and-neck cancer using THORplan”, Appl. Radiat. Isot. 69 (2011) 1907–1910. Ling-Wei Wang, Yi-Wei Chen, Ching-Yin Ho, Yen-Wan Hsueh Liu, Fong-In Chou, Yuan-Hao Liu, Hong-Ming Liu, Jinn-Jer Peir, Shiang-Huei Jiang, Chi- Wei Chang, Ching-Sheng Liu, Shyh-Jen Wang, Pen-Yuan Chu, Sang-Hue Yen, Fractionated BNCT for locally recurrent head and neck cancer: Experience from a phase I/II clinical trial at Tsing Hua Open-Pool Reactor, Appl. Radiat. Isot. (in press)

24. Institute of Nuclear Engineering and Science National Tsing Hua University 24 Thanks for your attention

25. Institute of Nuclear Engineering and Science National Tsing Hua University Patien t 16-1 Condition I. Direct irradiation Condition III. Natural lithium pad + Enriched lithium pad Max. Dose (Gy(W)) Dose Component (Gy(W)) Max. Dose (Gy(W)) Dose Component (Gy(W)) PhotonB10H1N14OtherPhotonB10H1N14Other Mucosa17.871.47814.3290.5861.4330.04817.621.79013.7350.6621.3740.055 Brain10.512.0276.1061.0961.2050.07710.322.3585.5831.1881.1030.085 Lt eyelens 4.480.8731.9380.6290.9940.0514.611.1351.7970.7000.9220.057 Mucosa max. The use of lithium pad helps to reduce the boron doses but the photon doses also increase For eyelens, though the maximum dose is higher when using lithium pad, it is still under the dose limitation (5Gy) The maximum dose of mucosa can not be easily reduced since it locates nearby the tumor Dose Component (at GTV D80=20 Gy(W)) 25

26. Institute of Nuclear Engineering and Science National Tsing Hua University 26 Mucosa dose Maximum point for Superficial Tumor Direct irradiationPatient collimator

27. Institute of Nuclear Engineering and Science National Tsing Hua University 27 Standard deviation Neutron < 1% Gamma < 2% Computer time (1 core) Patient 16 =3.5 hours Patient 17 = 17 hours

28. Institute of Nuclear Engineering and Science National Tsing Hua University 28 Boron dose %