Phase I/II trials of 186Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival

Abstract

Purpose: 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 of ¹⁸⁶Re-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 of ¹⁸⁶Re-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).

Conclusion: 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.

Keywords: Bone metastases; Dosimetry; Molecular radiotherapy; Prostate cancer; Radiopharmaceutical; Survival.

Fig. 1

Box plot representing the intra- and inter-patient variability of the lesion volumes (a) and absorbed doses (b) for the sub-cohort of 22 patients. For any given patient, the whiskers display the minimum and maximum values. The patient mean absorbed dose and mean lesion volume are shown with full diamond symbols

Fig. 2

Relationships of the patient mean absorbed dose (a), the whole-body absorbed dose (b) and the baseline level of ALP (c) with the disease volume variable for the sub-cohort of 22 patients. The dotted lines represent the 95 % confidence intervals

Fig. 3

Maximum change in PSA (a) and ALP (b) levels from baseline in the subgroup of 22 patients. Patients that received a patient mean absorbed dose (AD) below and above 19 Gy are shown in dark and light grey, respectively

Fig. 4

Kaplan–Meier estimates of overall survival for the cohort of 57 patients divided according to administered activities below and above 3.5 GBq of ¹⁸⁶Re-HEDP (a); and for the sub-cohort of 22 patients grouped according to median values of disease volume (b), patient mean absorbed dose (c), whole-body absorbed dose (d), and baseline levels of ALP (e) and PSA (f). Five patients were censored at the time of treatment with ²²³Ra or docetaxel (black squares) and two patients were censored at the last known follow-up (grey squares)