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Preclinical Image Guided Irradiation of Pancreatic Cancer Transgenic Mouse Model
Poster Viewing Abstracts S859
Volume 84 Number 3S Supplement 2012
3698 Comparative Study of Biologic Effective Dose for the Beta Emitters 142 Pr and 90Y and Their Applications in Microsphere Brachytherapy of Hepatocellular Carcinoma M. Ferreira, T.K. Podder, and J.W. Jung; East Carolina University, Greenville, NC Purpose/Objective(s): Biologic effective dose (BED) delivered by Praseodymium-142 (142Pr) was evaluated specifically for applications in nonresectable hepatocellular carcinoma (HCC) microsphere brachytherapy and compared with the currently used radionuclide, Yttrium-90 (90Y). Radiobiological aspects and the physical properties of 142Pr were studied for its possible application in microsphere brachytherapy of HCC. Materials/Methods: BED values were calculated using the linearquadratic (LQ) model for both 142Pr and 90Y and for different values of HCC clonogenic doubling times (DTs). BED varies with the radionuclide properties and with the tumor radiobiological factors and DT. The rate of tumor growth can be classified as: slow (DT > 100 days); intermediate (50 days < DT < 100 days); or rapid growing tumors (DT < 50 days). HCC doubling times vary greatly according to the tumor type: well, moderately or poorly differentiated. The distribution of DT values within each group is positively skewed, with tumors presenting very long DT values compared to the mean value. It was considered a range of DT values for each group: well differentiated (38-720 days), moderately differentiated (17-380 days) and poorly differentiated HCCs (20-70 days), based on clinical values obtained in previous studies. An a/b value of 10 Gy (tumoral liver), and a total physical dose (PD) of 150 Gy were used for both radionuclides studied. Total time to deliver 90% of the prescribed dose was also performed for 90Y and 142Pr. Results: The calculated values for BED for both 142Pr and 90Y for the same total physical dose of 150 Gy were: for well differentiated tumors ranged from 143 to 192 Gy for 90Y, and 279 to 300 Gy for 142Pr. For moderately differentiated, the values ranged from 105 to 189 Gy for 90Y and 260 to 298 Gy for 142Pr. And for the last group, poorly differentiated HCC, values ranged from 114 to 163 Gy for 90Y and 265 to 288 Gy for 142 Pr. For all HCC doubling time range studied, 142Pr presented a higher BED than 90Y. It was observed that the difference for BED values is more pronounced for rapid growing tumors, e.g. 142Pr BED is 1.48 times higher than the 90Y BED for a DT of 17 days. The time to deliver 90% of the dose (T90) for 142Pr is approximately 30% shorter than T90 for 90Y. Conclusions: The higher BED calculated for 142Pr might lead to a potential improvement in the treatment effectiveness, especially for rapid growing tumors. 142Pr could deliver T90 faster than 90Y, which is an advantage. The longer the time to deliver the dose, the higher is the risk of dose to healthy tissue due to potential shunting to adjacent organs (especially to lungs) and/or microsphere migration. Author Disclosure: M. Ferreira: None. T.K. Podder: None. J.W. Jung: None.
3699 Preclinical Image Guided Irradiation of Pancreatic Cancer Transgenic Mouse Model H. Korideck,1 S. Yang,1 A. Kimmelman,1 W. Ngwa,2 M. Makrigiorgos,2 and R. Berbeco3; 1Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 2Dana Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 3Dana Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Purpose/Objective(s): The survival rates for patients diagnosed with pancreatic cancer are among the lowest of any cancer. Pre-clinical translational studies of novel combinations of therapies, including radiation, require instruments capable of the same level of accuracy and precision as is found in the human clinic. This includes image-guided localization followed by isocentric irradiation. Here, we report on our pre-clinical image-guided procedure for irradiation of orthotopic pancreas tumors with ex vivo targeting verification.
Materials/Methods: Five pancreatic ductal adenocarcinoma (PDAC) LSL_Kras L/+, P53 L/+, p48 Cre transgenic mice were treated with imageguided irradiation using the Small Animal Radiation Research Platform (SARRP). The entire irradiation procedure was designed to mimic the current therapy for our human patients. One week prior to therapy, subjects with transgenic pancreatic tumors had surgical fiducials implanted within the tumoral mass to be used as a target surrogate. Image-guided setup was performed using the CBCT functionality of the SARRP. Portal images were acquired prior to irradiation to confirm the accuracy of the fiducialbased targeting. Subjects were irradiated in five fractions, separated by at least 48 hours, with 5 Gy per fraction. Post-irradiation, subjects were sacrificed and the tumor samples were sent to confirm radiation damage in situ by histoimmunochemistry using gamma H2Ax. Results: All subjects were successfully irradiated with the full course of therapy. No complications were incurred by the fiducial implantation procedure. The pre-treatment portal images verified setup accuracy to within 1 mm. Post-treatment evaluation further confirmed the accuracy of the irradiation. Conclusion: Accurate pre-clinical image-guided irradiation can be performed for orthotopic pancreas tumors with an accuracy and precision rivaling those found in the human clinic. These procedures will be used to conduct translational pre-clinical studies of novel therapeutics for eventual implementation in the human clinic. Author Disclosure: H. Korideck: None. S. Yang: None. A. Kimmelman: None. W. Ngwa: None. M. Makrigiorgos: None. R. Berbeco: None.
3700 Total Body Irradiation at High-dose-rate Using a LINAC Results in Increased Survival in a Mouse Model Y. Yang, M. Epperly, T.M. Dixon, D.E. Heron, J.S. Greenberger, and M.S. Huq; University of Pittsburgh, Pittsburgh, PA Purpose/Objective(s): Recently one company has introduced a LINAC which facilitates irradiation at conventional as well as high dose rates. Triplicate in vitro clonagenic irradiation survival curves, using Lewis Lung Carcinoma cells, showed no significant difference in D0 or n˜ between beam energies or dose rates. In order to compare how irradiation using high dose rate affects in vivo toxicity, a mouse model has been developed to compare total body irradiation using different dose rates and photon energies. Materials/Methods: C57BL/6NTac mice (N Z 15 to 20) were irradiated to 9.25 Gy total body dose using 300 MU/min with 6 and 10 MV photon beams, 1400 MU/min with a 6 MV photon beam , and 2400 MU/min with 10 MV photon beams. TLDs were placed on top, in between and under the mice to ensure that the mice were receiving the expected total dose. The mice were followed for development of the hematopoietic syndrome at which time they were sacrificed. Results: Significant differences in survival were found when results were compared for different dose rates and photon energies. Mice irradiated at 2400 MU/min using 10 MV photons had a significantly higher survival compared to the other irradiation groups (p Z 0.0218 compared to 300 MU/min with 10 MV photons, p < 0.0001 compared to 300 MU/min with 6 MV photons, and p Z 0.0012 compared to 1400 MU/min with 6 MV photons). Mice irradiated at 300 MU/min using 10 MV had a significantly higher survival with a 50% survival of 14 days compared to mice irradiated at 300 MU with 6 MV photons (p Z 0.0072) and a 50% survival of 11 days. There was no significant difference in survival between mice irradiated at 1400 MU/min with 6 MV photons compared to mice irradiated at 300 MU/min with either 6 or 10 MV photons (p Z 0.2586 or 0.1085, respectively). Conclusions: These results indicate that although the 2400 MU/min may facilitate faster irradiation with fewer side effects, there may be volume dependent biologic differences in some assays. Acknowledgments: This project was supported by U191A168021-01from the NIAID. Author Disclosure: Y. Yang: None. M. Epperly: None. T.M. Dixon: None. D.E. Heron: None. J.S. Greenberger: None. M.S. Huq: None.
Volume 84 Number 3S Supplement 2012
3698 Comparative Study of Biologic Effective Dose for the Beta Emitters 142 Pr and 90Y and Their Applications in Microsphere Brachytherapy of Hepatocellular Carcinoma M. Ferreira, T.K. Podder, and J.W. Jung; East Carolina University, Greenville, NC Purpose/Objective(s): Biologic effective dose (BED) delivered by Praseodymium-142 (142Pr) was evaluated specifically for applications in nonresectable hepatocellular carcinoma (HCC) microsphere brachytherapy and compared with the currently used radionuclide, Yttrium-90 (90Y). Radiobiological aspects and the physical properties of 142Pr were studied for its possible application in microsphere brachytherapy of HCC. Materials/Methods: BED values were calculated using the linearquadratic (LQ) model for both 142Pr and 90Y and for different values of HCC clonogenic doubling times (DTs). BED varies with the radionuclide properties and with the tumor radiobiological factors and DT. The rate of tumor growth can be classified as: slow (DT > 100 days); intermediate (50 days < DT < 100 days); or rapid growing tumors (DT < 50 days). HCC doubling times vary greatly according to the tumor type: well, moderately or poorly differentiated. The distribution of DT values within each group is positively skewed, with tumors presenting very long DT values compared to the mean value. It was considered a range of DT values for each group: well differentiated (38-720 days), moderately differentiated (17-380 days) and poorly differentiated HCCs (20-70 days), based on clinical values obtained in previous studies. An a/b value of 10 Gy (tumoral liver), and a total physical dose (PD) of 150 Gy were used for both radionuclides studied. Total time to deliver 90% of the prescribed dose was also performed for 90Y and 142Pr. Results: The calculated values for BED for both 142Pr and 90Y for the same total physical dose of 150 Gy were: for well differentiated tumors ranged from 143 to 192 Gy for 90Y, and 279 to 300 Gy for 142Pr. For moderately differentiated, the values ranged from 105 to 189 Gy for 90Y and 260 to 298 Gy for 142Pr. And for the last group, poorly differentiated HCC, values ranged from 114 to 163 Gy for 90Y and 265 to 288 Gy for 142 Pr. For all HCC doubling time range studied, 142Pr presented a higher BED than 90Y. It was observed that the difference for BED values is more pronounced for rapid growing tumors, e.g. 142Pr BED is 1.48 times higher than the 90Y BED for a DT of 17 days. The time to deliver 90% of the dose (T90) for 142Pr is approximately 30% shorter than T90 for 90Y. Conclusions: The higher BED calculated for 142Pr might lead to a potential improvement in the treatment effectiveness, especially for rapid growing tumors. 142Pr could deliver T90 faster than 90Y, which is an advantage. The longer the time to deliver the dose, the higher is the risk of dose to healthy tissue due to potential shunting to adjacent organs (especially to lungs) and/or microsphere migration. Author Disclosure: M. Ferreira: None. T.K. Podder: None. J.W. Jung: None.
3699 Preclinical Image Guided Irradiation of Pancreatic Cancer Transgenic Mouse Model H. Korideck,1 S. Yang,1 A. Kimmelman,1 W. Ngwa,2 M. Makrigiorgos,2 and R. Berbeco3; 1Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 2Dana Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 3Dana Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Purpose/Objective(s): The survival rates for patients diagnosed with pancreatic cancer are among the lowest of any cancer. Pre-clinical translational studies of novel combinations of therapies, including radiation, require instruments capable of the same level of accuracy and precision as is found in the human clinic. This includes image-guided localization followed by isocentric irradiation. Here, we report on our pre-clinical image-guided procedure for irradiation of orthotopic pancreas tumors with ex vivo targeting verification.
Materials/Methods: Five pancreatic ductal adenocarcinoma (PDAC) LSL_Kras L/+, P53 L/+, p48 Cre transgenic mice were treated with imageguided irradiation using the Small Animal Radiation Research Platform (SARRP). The entire irradiation procedure was designed to mimic the current therapy for our human patients. One week prior to therapy, subjects with transgenic pancreatic tumors had surgical fiducials implanted within the tumoral mass to be used as a target surrogate. Image-guided setup was performed using the CBCT functionality of the SARRP. Portal images were acquired prior to irradiation to confirm the accuracy of the fiducialbased targeting. Subjects were irradiated in five fractions, separated by at least 48 hours, with 5 Gy per fraction. Post-irradiation, subjects were sacrificed and the tumor samples were sent to confirm radiation damage in situ by histoimmunochemistry using gamma H2Ax. Results: All subjects were successfully irradiated with the full course of therapy. No complications were incurred by the fiducial implantation procedure. The pre-treatment portal images verified setup accuracy to within 1 mm. Post-treatment evaluation further confirmed the accuracy of the irradiation. Conclusion: Accurate pre-clinical image-guided irradiation can be performed for orthotopic pancreas tumors with an accuracy and precision rivaling those found in the human clinic. These procedures will be used to conduct translational pre-clinical studies of novel therapeutics for eventual implementation in the human clinic. Author Disclosure: H. Korideck: None. S. Yang: None. A. Kimmelman: None. W. Ngwa: None. M. Makrigiorgos: None. R. Berbeco: None.
3700 Total Body Irradiation at High-dose-rate Using a LINAC Results in Increased Survival in a Mouse Model Y. Yang, M. Epperly, T.M. Dixon, D.E. Heron, J.S. Greenberger, and M.S. Huq; University of Pittsburgh, Pittsburgh, PA Purpose/Objective(s): Recently one company has introduced a LINAC which facilitates irradiation at conventional as well as high dose rates. Triplicate in vitro clonagenic irradiation survival curves, using Lewis Lung Carcinoma cells, showed no significant difference in D0 or n˜ between beam energies or dose rates. In order to compare how irradiation using high dose rate affects in vivo toxicity, a mouse model has been developed to compare total body irradiation using different dose rates and photon energies. Materials/Methods: C57BL/6NTac mice (N Z 15 to 20) were irradiated to 9.25 Gy total body dose using 300 MU/min with 6 and 10 MV photon beams, 1400 MU/min with a 6 MV photon beam , and 2400 MU/min with 10 MV photon beams. TLDs were placed on top, in between and under the mice to ensure that the mice were receiving the expected total dose. The mice were followed for development of the hematopoietic syndrome at which time they were sacrificed. Results: Significant differences in survival were found when results were compared for different dose rates and photon energies. Mice irradiated at 2400 MU/min using 10 MV photons had a significantly higher survival compared to the other irradiation groups (p Z 0.0218 compared to 300 MU/min with 10 MV photons, p < 0.0001 compared to 300 MU/min with 6 MV photons, and p Z 0.0012 compared to 1400 MU/min with 6 MV photons). Mice irradiated at 300 MU/min using 10 MV had a significantly higher survival with a 50% survival of 14 days compared to mice irradiated at 300 MU with 6 MV photons (p Z 0.0072) and a 50% survival of 11 days. There was no significant difference in survival between mice irradiated at 1400 MU/min with 6 MV photons compared to mice irradiated at 300 MU/min with either 6 or 10 MV photons (p Z 0.2586 or 0.1085, respectively). Conclusions: These results indicate that although the 2400 MU/min may facilitate faster irradiation with fewer side effects, there may be volume dependent biologic differences in some assays. Acknowledgments: This project was supported by U191A168021-01from the NIAID. Author Disclosure: Y. Yang: None. M. Epperly: None. T.M. Dixon: None. D.E. Heron: None. J.S. Greenberger: None. M.S. Huq: None.