title: Phase I/II trials of186Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival.
abstract: OBJECTIVE
  To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit.
  
  
  METHODS
  Clinical data from 57 patients who received 2.5-5.1 GBq of186Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan-Meier curves, log-rank tests, Cox's proportional hazards model and Pearson's correlation coefficients were used for overall survival (OS) and correlation analyses.
  
  
  RESULTS
  A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10-0.58, P = 0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of186Re-HEDP (P = 0.03) and patient mean absorbed dose (P = 0.01), whilst only the disease volume remained significant in a multivariable analysis (P = 0.004).
  
  
  CONCLUSIONS
  This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated with survival. This study shows the importance of patient stratification to establish absorbed dose-response correlations and indicates the potential to individualise treatment of bone metastases with radiopharmaceuticals according to patient-specific imaging and dosimetry.
authors: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, UK. ana.denisbacelar@icr.ac.uk.
authors: Ana M
authors: AM
authors: Denis-Bacelar
authors: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors: Sarah J
authors: SJ
authors: Chittenden
authors: Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors: David P
authors: DP
authors: Dearnaley
authors: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors: Antigoni
authors: A
authors: Divoli
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors: Joe M
authors: JM
authors: O'Sullivan
authors: Department of Nuclear Medicine, Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.
authors: V Ralph
authors: VR
authors: McCready
authors: Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors: Bernadette
authors: B
authors: Johnson
authors: Department of Nuclear Medicine and PET/CT, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors: Yong
authors: Y
authors: Du
authors: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors: Glenn D
authors: GD
authors: Flux
mesh_terms: D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000556:secondary; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D012968:Etidronic Acid / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy*; D011829:Radiation Dosage; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted; D016019:Survival Analysis; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C101598:rhenium-186 HEDP; D012968:Etidronic Acid
keywords: Bone metastases; Dosimetry; Molecular radiotherapy; Prostate cancer; Radiopharmaceutical; Survival