title: Biokinetic Modeling and Dosimetry for Optimizing Intraperitoneal Radioimmunotherapy of Ovarian Cancer Microtumors.
abstract: 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.
  
  
  CONCLUSIONS
  According to the presented model, α-emitters are needed to achieve radiation doses high enough to eradicate microscopic tumors.
authors.affiliation: Department of Radiation Physics, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden stig.palm@gu.se.
authors.forename: Stig
authors.initials: S
authors.lastname: Palm
authors.affiliation: Department of Radiation Physics, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Tom
authors.initials: T
authors.lastname: Bäck
authors.affiliation: Department of Clinical and Molecular Medicine, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Börje
authors.initials: B
authors.lastname: Haraldsson
authors.affiliation: Department of Radiation Physics, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Jacobsson
authors.affiliation: Department of Radiation Physics, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sture
authors.initials: S
authors.lastname: Lindegren
authors.affiliation: Department of Oncology, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Albertsson
mesh_terms: D000512:Alpha Particles; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001610:Beta Particles; D001853:Bone Marrow / Q000528:radiation effects; D002196:Capillaries / Q000378:metabolism; D004322:Drainage; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008208:Lymphatic System / Q000378:metabolism; D015233:Models, Statistical; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000628:therapy*; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019275:Radiopharmaceuticals
keywords: alpha-emitters; intraperitoneal therapy; ovarian cancer; radioimmunotherapy; targeted alpha therapy