title: Radiobiologic optimization of combination radiopharmaceutical therapy applied to myeloablative treatment of non-Hodgkin lymphoma.
abstract: Combination treatment is a hallmark of cancer therapy. Although the rationale for combination radiopharmaceutical therapy was described in the mid-1990s, such treatment strategies have only been implemented clinically recently and without a rigorous methodology for treatment optimization. Radiobiologic and quantitative imaging-based dosimetry tools are now available that enable rational implementation of combined targeted radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobiologic normal-organ tolerance while optimizing the ratio of 2 different radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypothetical myeloablative treatment of non-Hodgkin lymphoma (NHL) patients using (131)I-tositumomab and (90)Y-ibritumomab tiuxetan.
  
  
  METHODS
  The range of potential administered activities (AAs) is limited by the normal-organ maximum-tolerated biologic effective doses (MTBEDs) arising from the combined radiopharmaceuticals. Dose-limiting normal organs are expected to be the lungs for (131)I-tositumomab and the liver for (90)Y-ibritumomab tiuxetan in myeloablative NHL treatment regimens. By plotting the limiting normal-organ constraints as a function of the AAs and calculating tumor biologic effective dose (BED) along the normal-organ MTBED limits, we obtained the optimal combination of activities. The model was tested using previously acquired patient normal-organ and tumor kinetic data and MTBED values taken from the literature.
  
  
  RESULTS
  The average AA value based solely on normal-organ constraints was 19.0 ± 8.2 GBq (range, 3.9-36.9 GBq) for (131)I-tositumomab and 2.77 ± 1.64 GBq (range, 0.42-7.54 GBq) for (90)Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal-organ kinetics for the 2 radiopharmaceuticals. Results included AA ranges that would deliver 95% of the maximum tumor BED, allowing for informed inclusion of clinical considerations, such as a maximum-allowable (131)I administration.
  
  
  CONCLUSIONS
  A rational approach for combination radiopharmaceutical treatment has been developed within the framework of a proven 3-dimensional (3D) personalized dosimetry software, 3D-RD, and applied to the myeloablative treatment of NHL. We anticipate that combined radioisotope therapy will ultimately supplant single radioisotope therapy, much as combination chemotherapy has substantially replaced single-agent chemotherapy.
authors.affiliation: Department of Radiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21231, USA. rhobbs3@jhmi.edu
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hobbs
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wahl
authors.forename: Eric C
authors.initials: EC
authors.lastname: Frey
authors.forename: Yvette
authors.initials: Y
authors.lastname: Kasamon
authors.forename: Hong
authors.initials: H
authors.lastname: Song
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003198:Computer Simulation; D004307:Dose-Response Relationship, Radiation; D004360:Drug Therapy, Computer-Assisted / Q000379:methods*; D006801:Humans; D008954:Models, Biological; D019653:Myeloablative Agonists / Q000008:administration & dosage*; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage; D011879:Radiotherapy Dosage; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D019653:Myeloablative Agonists; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C422802:ibritumomab tiuxetan; C119496:tositumomab I-131
keywords: BED; dosimetry; lymphoma; radiopharmaceutical therapy; treatment planning
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