title: Dosimetry and toxicity of Quadramet for bone marrow ablation in multiple myeloma and other haematological malignancies.
abstract: Standard treatment regimens for haematological malignancies include myeloablative chemoradiotherapy and subsequent rescue by stem cell transplantation. However, these treatment regimens have significant associated mortality and morbidity, and disease recurrence remains a problem. One alternative approach is the targeted delivery of radiotherapy to the marrow using a bone-seeking agent labelled with an appropriate radioisotope, with the aim of delivering a potentially ablative radiation dose to marrow while minimising non-haematological toxicity. Pharmacokinetics and radiation dosimetry for a commercial preparation of samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP; Quadramet) were evaluated in 43 tracer (average dose 740 MBq) studies of 42 patients with haematological malignancies. Measurements of 24-h retention were also available following infusion of 18-48 GBq in 15 patients. Quadramet cleared rapidly from the tissue, with a median biological half-life of 1.4 h. Activity taken up by the skeleton was firmly bound, with activity decreasing according to physical half-life at 24 h in 29 of the 43 cases. The percentage activity retained in the skeleton at 24 h with tracer doses was high (62%+/-13%), although this decreased to approximately 30% with therapy infusions. Because of this decrease in retention, the maximum feasible therapy activity for this formulation of Quadramet is 35 GBq. Median absorbed marrow radiation dose was 0.78 Gy/GBq in tracer studies: the decreased retention at high activities means that this corresponds to a median dose of 12 Gy for 35 GBq administered activity. It is possible to use 24-h retention as a rough guide to marrow dose in individual patients. In tracer studies, median bladder radiation dose was 0.22 Gy/GBq and radiation dose to the liver was very conservatively estimated at 0.2 Gy/GBq. After therapy infusions of up to 50 GBq in 37 patients, non-haematopoietic toxicity was not seen in any patient. In addition, myelosuppression was achieved without evidence of myelofibrosis. The residual dose rate to marrow fell to a level acceptable for stem cell re-infusion by 2 weeks after administration.
authors.affiliation: Department of Nuclear Medicine, Royal Brisbane Hospital, Herston, Queensland, Q4209, Australia. marissa_bartlett@health.qld.gov.au
authors.forename: Marissa L
authors.initials: ML
authors.lastname: Bartlett
authors.forename: Myles
authors.initials: M
authors.lastname: Webb
authors.forename: Simon
authors.initials: S
authors.lastname: Durrant
authors.forename: A James
authors.initials: AJ
authors.lastname: Morton
authors.forename: Roger
authors.initials: R
authors.lastname: Allison
authors.forename: David J
authors.initials: DJ
authors.lastname: Macfarlane
mesh_terms: D001853:Bone Marrow / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005260:Female; D019337:Hematologic Neoplasms / Q000378:metabolism / Q000532:radiotherapy / Q000601:surgery; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D009101:Multiple Myeloma / Q000378:metabolism* / Q000532:radiotherapy* / Q000601:surgery; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011829:Radiation Dosage; D011874:Radiometry / Q000379:methods*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D019172:Transplantation Conditioning / Q000379:methods; D016896:Treatment Outcome; D014915:Whole-Body Counting
chemical_list: D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D019275:Radiopharmaceuticals; C061972:samarium Sm-153 lexidronam