Stig Palm1, Tom Bäck2, Börje Haraldsson3, Lars Jacobsson2, Sture Lindegren2, Per Albertsson4. 1. Department of Radiation Physics, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden stig.palm@gu.se. 2. Department of Radiation Physics, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. 3. Department of Clinical and Molecular Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; and. 4. Department of Oncology, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Abstract
UNLABELLED: A biokinetic model was constructed to evaluate and optimize various intraperitoneal radioimmunotherapies for micrometastatic tumors. The model was used to calculate the absorbed dose to both anticipated microtumors and critical healthy organs and demonstrated how intraperitoneal targeted radiotherapy can be optimized to maximize the ratio between them. METHODS: The various transport mechanisms responsible for the biokinetics of intraperitoneally infused radiolabeled monoclonal antibodies (mAbs) were modeled using a software package. Data from the literature were complemented by pharmacokinetic data derived from our clinical phase I study to set parameter values. Results using the β-emitters (188)Re, (177)Lu, and (90)Y and the α-emitters (211)At, (213)Bi, and (212)Pb were compared. The effects of improving the specific activity, prolonging residence time by introducing an osmotic agent, and varying the activity concentration of the infused agent were investigated. RESULTS: According to the model, a 1.7-L infused saline volume will decrease by 0.3 mL/min because of lymphatic drainage and by 0.7 mL/min because of the transcapillary convective component. The addition of an osmotic agent serves to lower the radiation dose to the bone marrow. Clinically relevant radioactivity concentrations of α- and β-emitters bound to mAbs were compared. For α-emitters, microtumors receive high doses (>20 Gy or 100 Sv [relative biological effect = 5]). Since most of the tumor dose originates from cell-bound radionuclides, an increase in the specific activity would further increase the tumor dose without affecting the dose to peritoneal fluid or bone marrow. For β-emitters, tumors will receive almost entirely nonspecific irradiation. The dose from cell-bound radiolabeled mAbs will be negligible by comparison. For the long-lived (90)Y, tumor doses are expected to be low at the maximum activity concentration delivered in clinical studies. CONCLUSION: According to the presented model, α-emitters are needed to achieve radiation doses high enough to eradicate microscopic tumors.
UNLABELLED: A biokinetic model was constructed to evaluate and optimize various intraperitoneal radioimmunotherapies for micrometastatic tumors. The model was used to calculate the absorbed dose to both anticipated microtumors and critical healthy organs and demonstrated how intraperitoneal targeted radiotherapy can be optimized to maximize the ratio between them. METHODS: The various transport mechanisms responsible for the biokinetics of intraperitoneally infused radiolabeled monoclonal antibodies (mAbs) were modeled using a software package. Data from the literature were complemented by pharmacokinetic data derived from our clinical phase I study to set parameter values. Results using the β-emitters (188)Re, (177)Lu, and (90)Y and the α-emitters (211)At, (213)Bi, and (212)Pb were compared. The effects of improving the specific activity, prolonging residence time by introducing an osmotic agent, and varying the activity concentration of the infused agent were investigated. RESULTS: According to the model, a 1.7-L infused saline volume will decrease by 0.3 mL/min because of lymphatic drainage and by 0.7 mL/min because of the transcapillary convective component. The addition of an osmotic agent serves to lower the radiation dose to the bone marrow. Clinically relevant radioactivity concentrations of α- and β-emitters bound to mAbs were compared. For α-emitters, microtumors receive high doses (>20 Gy or 100 Sv [relative biological effect = 5]). Since most of the tumor dose originates from cell-bound radionuclides, an increase in the specific activity would further increase the tumor dose without affecting the dose to peritoneal fluid or bone marrow. For β-emitters, tumors will receive almost entirely nonspecific irradiation. The dose from cell-bound radiolabeled mAbs will be negligible by comparison. For the long-lived (90)Y, tumor doses are expected to be low at the maximum activity concentration delivered in clinical studies. CONCLUSION: According to the presented model, α-emitters are needed to achieve radiation doses high enough to eradicate microscopic tumors.
Authors: Benjamin B Kasten; Rebecca C Arend; Ashwini A Katre; Harrison Kim; Jinda Fan; Soldano Ferrone; Kurt R Zinn; Donald J Buchsbaum Journal: Nucl Med Biol Date: 2017-01-10 Impact factor: 2.408
Authors: Andreas Hallqvist; Karin Bergmark; Tom Bäck; Håkan Andersson; Pernilla Dahm-Kähler; Mia Johansson; Sture Lindegren; Holger Jensen; Lars Jacobsson; Ragnar Hultborn; Stig Palm; Per Albertsson Journal: J Nucl Med Date: 2019-01-25 Impact factor: 10.057
Authors: Benjamin B Kasten; Abhishek Gangrade; Harrison Kim; Jinda Fan; Soldano Ferrone; Cristina R Ferrone; Kurt R Zinn; Donald J Buchsbaum Journal: Nucl Med Biol Date: 2017-12-24 Impact factor: 2.408
Authors: Anna Gustafsson-Lutz; Tom Bäck; Emma Aneheim; Ragnar Hultborn; Stig Palm; Lars Jacobsson; Alfred Morgenstern; Frank Bruchertseifer; Per Albertsson; Sture Lindegren Journal: EJNMMI Res Date: 2017-04-24 Impact factor: 3.138