Compartmental Model for 223Ra-Dichloride in Patients With Metastatic Bone Disease From Castration-Resistant Prostate Cancer.

PURPOSE: 223Ra-Dichloride is used for treatment of patients with metastatic bone disease from castration-resistant prostate cancer. The uptake and mechanism of action of 223Ra-Dichloride is not well understood. The aim of this work was to develop a compartmental model for 223Ra-Dichloride in patients to improve understanding of the underlying mechanisms. METHODS AND MATERIALS: A compartmental model was developed based on activity retention data from 6 patients (2 treatments of 110 kBq/kg 223Ra-Dichloride) for plasma, bone surfaces, small intestines, large intestines, and excretion data. Rate constants were extracted. Rate constant variability between patients and treatments was assessed. A population model was proposed and compared with the established International Commission on Radiological Protection-67 compartmental model. RESULTS: A single bone compartment cannot accurately describe activity retention in the skeleton. The addition of a second bone compartment improved the fit to skeleton retention data, and the Akaike information criterion decreased. Mean rate constants of 4.0 (range, 1.9-10.9) and 0.15 (0.07-0.39) h-1 were obtained for transport from plasma to first bone compartment and vice versa. Rate constants from first to second bone compartment and back of 0.03 (0.02-0.06) and 0.008 (0.003-0.011) h-1 were calculated. Rate constants for individual patients showed no significant difference between patients and treatments. CONCLUSIONS: The developed compartmental model suggests that 223Ra-Dichloride initially locates at the bone surface and is then incorporated into the bone matrix relatively quickly. This observation could have implications for dosimetry and understanding of the effects of alpha radiation on normal bone tissue. Results suggest that a population model based on patient measurements is feasible.

Bone lesion absorbed dose profiles in patients with metastatic prostate cancer treated with molecular radiotherapy.

OBJECTIVE: The aim of this study was to calculate the range of absorbed doses that could potentially be delivered by a variety of radiopharmaceuticals and typical fixed administered activities used for bone pain palliation in a cohort of patients with metastatic castration-resistant prostate cancer (mCRPC). The methodology for the extrapolation of the biodistribution, pharmacokinetics and absorbed doses from a given to an alternative radiopharmaceutical is presented. METHODS: Sequential single photon emission CT images from 22 patients treated with 5 GBq of 186Re-HEDP were used to extrapolate the time-activity curves for various radiopharmaceuticals. Cumulated activity distributions for the delivered and extrapolated treatment plans were converted into absorbed dose distributions using the convolution dosimetry method. The lesion absorbed doses obtained for the different treatments were compared using the patient population distributions and cumulative dose-volume histograms. RESULTS: The median lesion absorbed doses across the patient cohort ranged from 2.7 Gy (range: 0.6-11.8 Gy) for 1100 MBq of 166Ho-DOTMP to 21.8 Gy (range: 4.5-117.6 Gy) for 150 MBq of 89Sr-dichloride. 32P-Na3PO4, 153Sm-EDTMP, 166Ho-DOTMP, 177Lu-EDTMP and 188Re-HEDP would have delivered 41, 32, 85, 20 and 64% lower absorbed doses, for the typical administered activities as compared to 186Re-HEDP, respectively, whilst 89Sr-dichloride would have delivered 25% higher absorbed doses. CONCLUSION: For the patient cohort studied, a wide range of absorbed doses would have been delivered for typical administration protocols in mCRPC. The methodology presented has potential use for emerging theragnostic agents. Advances in knowledge: The same patient cohort can receive a range of lesion absorbed doses from typical molecular radiotherapy treatments for patients with metastatic prostate cancer, highlighting the need to establish absorbed dose response relationships and to treat patients according to absorbed dose instead of using fixed administered activities.

Excretion and whole-body retention of radium-223 dichloride administered for the treatment of bone metastases from castration resistant prostate cancer.

OBJECTIVE: The aim of the study was to determine the fraction of administered activity that was excreted and retained by a small cohort of patients who each received treatment with radium-223 dichloride (Ra). Ra is an α-emitting radionuclide that has been approved for use in the treatment of bone metastases that are secondary to castration resistant prostate cancer. PATIENTS AND METHODS: Six patients received two weight-based administrations of Ra 6 weeks apart. Activity excreted in the urine and faeces during the first 48 h following each treatment was assessed by direct counting of the excreta. During the same period the whole-body retention of Ra was also determined using a single probe counting system. The results of the excreta counting and the whole-body counting were compared to determine whether whole-body counting was a suitable surrogate for assessing excretion. Further whole-body retention counts were made at around 3, 4, 7 and 42 days following treatment. RESULTS: Patterns of excretion and retention of Ra varied significantly between patients, but were similar for each patient's pair of treatments. The cumulative maximum activity excreted in the initial 8-h period following the Ra administration was 2.6% that increased to 39% at 48 h. The median excreted activity at ~1 and 6 weeks after treatment was 70 and 86%, respectively. Skeletal retention of Ra at 6 weeks ranged from 11 to 60% of the administered activity.

The potential of 223Ra and 18F-fluoride imaging to predict bone lesion response to treatment with 223Ra-dichloride in castration-resistant prostate cancer.

PURPOSE: The aims of this study were to calculate bone lesion absorbed doses resulting from a weight-based administration of 223Ra-dichloride, to assess the relationship between those doses and corresponding 18F-fluoride uptake and to assess the potential of quantitative 18F-fluoride imaging to predict response to treatment. METHODS: Five patients received two intravenous injections of 223Ra-dichloride, 6 weeks apart, at 110 kBq/kg whole-body weight. The biodistribution of 223Ra in metastatic lesions as a function of time after administration as well as associated lesion dosimetry were determined from serial 223Ra scans. PET/CT imaging using 18F-fluoride was performed prior to the first treatment (baseline), and at week 6 immediately before the second treatment and at week 12 after baseline. RESULTS: Absorbed doses to metastatic bone lesions ranged from 0.6 Gy to 44.1 Gy. For individual patients, there was an average factor difference of 5.3 (range 2.5-11.0) between the maximum and minimum lesion dose. A relationship between lesion-absorbed doses and serial changes in 18F-fluoride uptake was demonstrated (r2 = 0.52). A log-linear relationship was demonstrated (r2 = 0.77) between baseline measurements of 18F-fluoride uptake prior to 223Ra-dichloride therapy and changes in uptake 12 weeks after the first cycle of therapy. Correlations were also observed between both 223Ra and 18F-fluoride uptake in lesions (r = 0.75) as well as between 223Ra absorbed dose and 18F-fluoride uptake (r = 0.96). CONCLUSIONS: There is both inter-patient and intra-patient heterogeneity of absorbed dose estimates to metastatic lesions. A relationship between 223Ra lesion absorbed dose and subsequent lesion response was observed. Analysis of this small group of patients suggests that baseline uptake of 18F-fluoride in bone metastases is significantly correlated with corresponding uptake of 223Ra, the associated 223Ra absorbed dose and subsequent lesion response to treatment.

A radiobiological model of metastatic burden reduction for molecular radiotherapy: application to patients with bone metastases.

Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: 83-105 Gy), whilst a median of 183 Gy (interquartile range: 107-247 Gy) was found necessary to eradicate all metastases in a given patient. The absorbed dose required to eradicate all the lesions was strongly correlated with the variability of the absorbed doses delivered to multiple lesions in a given patient (r = 0.98, P < 0.0001). The metastatic burden reduction curves showed a potential large reduction in metastatic burden for a small increase in absorbed dose in 91% of patients. The results indicate the range of absorbed doses required to potentially obtain a significant survival benefit. The metastatic burden reduction method provides a simple tool that could be used in routine clinical practice for patient selection and to indicate the required administered activity to achieve a predicted patient mean absorbed dose and reduction in metastatic tumour burden.

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.

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.

A Phase 1, Open-Label Study of the Biodistribution, Pharmacokinetics, and Dosimetry of 223Ra-Dichloride in Patients with Hormone-Refractory Prostate Cancer and Skeletal Metastases.

UNLABELLED: The aim of this single-site, open-label clinical trial was to determine the biodistribution, pharmacokinetics, absorbed doses, and safety from 2 sequential weight-based administrations of (223)Ra-dichloride in patients with bone metastases due to castration-refractory prostate cancer. METHODS: Six patients received 2 intravenous injections of (223)Ra-dichloride, 6 wk apart, at 100 kBq/kg of whole-body weight. The pharmacokinetics and biodistribution as a function of time were determined, and dosimetry was performed for a range of organs including bone surfaces, red marrow, kidneys, gut, and whole body using scintigraphic imaging; external counting; and blood, fecal, and urine collection. Safety was assessed from adverse events. RESULTS: The injected activity cleared rapidly from blood, with 1.1% remaining at 24 h. The main route of excretion was via the gut, although no significant toxicity was reported. Most of the administered activity was taken up rapidly into bone (61% at 4 h). The range of absorbed doses delivered to the bone surfaces from α emissions was 2,331-13,118 mGy/MBq. The ranges of absorbed doses delivered to the red marrow were 177-994 and 1-5 mGy/MBq from activity on the bone surfaces and from activity in the blood, respectively. No activity-limiting toxicity was observed at these levels of administration. The absorbed doses from the second treatment were correlated significantly with the first for a combination of the whole body, bone surfaces, kidneys, and liver. CONCLUSION: A wide range of interpatient absorbed doses was delivered to normal organs. Intrapatient absorbed doses were significantly correlated between the 2 administrations for any given patient. The lack of gastrointestinal toxicity is likely due to the low absorbed doses delivered to the gut wall from the gut contents. The lack of adverse myelotoxicity implies that the absorbed dose delivered from the circulating activity may be a more relevant guide to the potential for marrow toxicity than that due to activity on the bone surfaces.

A dose-effect correlation for radioiodine ablation in differentiated thyroid cancer.

PURPOSE: The aim of this study was to determine the range of absorbed doses delivered to thyroid remnants, blood, and red marrow from fixed administrations of radioiodine and to ascertain whether the success of ablation is more dependent on these absorbed doses than on the administered activity. METHODS: Twenty-three patients received 3,000 MBq radioiodine following near-total thyroidectomy. The maximum absorbed dose to remnants was calculated from subsequent single photon emission tomography scans. Absorbed doses delivered to blood and red marrow were calculated from blood samples and from whole-body retention measurements. The protein bound iodine (PBI) was also calculated. RESULTS: Maximum absorbed doses to thyroid remnants ranged from 7 to 570 Gy. Eighteen of the 23 patients had a successful ablation. A significant difference was seen between the absorbed doses delivered to thyroid remnants, blood, and red marrow for those patients that had a successful ablation compared to those with a failed ablation (p = 0.030, p = 0.043 and p = 0.048, respectively). The difference between the PBI values acquired at day 1 and day 6 were also indicative of response (p = 0.074). CONCLUSIONS: A successful ablation is strongly dependent on the absorbed dose to the thyroid remnant. Dosimetry-based personalized treatment can prevent both sub-optimal administrations, which entails further radioiodine therapy, and excessive administration of radioactivity, which increases the potential for radiation toxicity.

Whole-body dosimetry for individualized treatment planning of 131I-MIBG radionuclide therapy for neuroblastoma.

UNLABELLED: The aims of this study were to examine the relationship between whole-body absorbed dose and hematologic toxicity and to assess the most accurate method of delivering a prescribed whole-body absorbed dose in (131)I-metaiodobenzylguanidine ((131)I-MIBG) therapy for neuroblastoma. METHODS: A total of 20 children (1-12 y), 5 adolescents (13-17 y), and 1 adult (20 y) with stage 3 or 4 neuroblastoma were treated to a prescribed whole-body absorbed dose, which in most cases was 2 Gy. Forty-eight administrations of (131)I-MIBG were given to the 26 patients, ranging in activity from 1,759 to 32,871 MBq. For 30 administrations, sufficient data were available to assess the effect of whole-body absorbed dose on hematologic toxicity. Comparisons were made between the accuracy with which a whole-body absorbed dose could be predicted using a pretherapy tracer study and the patient's most recent previous therapy. The whole-body absorbed dose that would have been delivered if the administered activity was fixed (7,400 MBq) or determined using a weight-based formula (444 MBq.kg(-1)) was also estimated. RESULTS: The mean whole-body absorbed dose for patients with grade 4 Common Terminology Criteria for Adverse Events (CTCAE) neutropenia after therapy was significantly higher than for those with grade 1 CTCAE neutropenia (1.63 vs. 0.90 Gy; P = 0.05). There was no correlation between administered activity and hematologic toxicity. Absorbed whole-body doses predicted from previous therapies were within +/-10% for 70% of the cases. Fixed-activity administrations gave the largest range in whole-body absorbed dose (0.30-3.11 Gy). CONCLUSION: The results indicate that even in a highly heterogeneous and heavily pretreated patient population, a whole-body absorbed dose can be prescribed accurately and is a more accurate predictor of hematologic toxicity than is administered activity. Therefore, a whole-body absorbed dose can be used to deliver accurate and reproducible (131)I-MIBG therapy on a patient-specific basis.

Optimization of equipment and methodology for whole body activity retention measurements in children undergoing targeted radionuclide therapy.

Accurate measurements of whole-body activity retention of patients during radionuclide therapy are essential for two reasons: First, they enable the correct radiation protection advice to be given and second, they permit the accurate determination of the absorbed whole-body dose delivered during therapy. This, in turn, allows treatment planning to be carried out for future radionuclide therapy on an individual patient basis, and also enables the investigation of the potential correlation of absorbed dose with treatment outcome in groups of patients. There are significant difficulties associated with taking whole-body retention measurements of children, especially when they are very young and/or unwell. It is essential to carry these out in a way that minimises disturbance to the child while still providing good quality data. To accomplish this, we have aimed to optimize the following aspects of the procedure: (i) the environment in which the measurements are performed; (ii) the equipment--which includes the recent installation of a specially designed whole-body activity monitoring system for these patients; and (iii) the methodology for calculating the absorbed dose. These improvements have allowed large numbers of accurate and reproducible whole-body measurements to be collected following patient administrations. This has enabled the identification of more phases of radionuclide excretion during therapy than had previously been observed. These data have been used for radiation protection advice and treatment planning. Two (2) patients were given multiple radionuclide treatments and we were able to compare the whole-body doses delivered.

A model-based method for the prediction of whole-body absorbed dose and bone marrow toxicity for 186Re-HEDP treatment of skeletal metastases from prostate cancer.

In high-activity rhenium-186 hydroxyethylidene diphosphonate ((186)Re-HEDP) treatment of bone metastatic disease from prostate cancer the dose-limiting factor is haematological toxicity. In this study, we examined the correlation of the injected activity and the whole-body absorbed dose with treatment toxicity and response. Since the best response is likely to be related to the maximum possible injected activity limited by the whole-body absorbed dose, the relationship between pre-therapy biochemical and physiological parameters and the whole-body absorbed dose was studied to derive an algorithm to predict the whole-body absorbed dose prior to injection of the radionuclide. The whole-body retention of radioactivity was measured at several time points after injection in a cohort of patients receiving activities ranging between 2,468 MBq and 5,497 MBq. The whole-body absorbed dose was calculated by fitting a sequential series of exponential phases to the whole-body time-activity data and by integrating this fit over time to obtain the whole-body cumulated activity. This was then converted to absorbed dose using the Medical Internal Radiation Dose (MIRD) committee methodology. Treatment toxicity was estimated by the relative decrease in white cell (WC) and platelet (Plt) counts after the injection of the radionuclide, and by their absolute nadir values. The criterion for a treatment response was a 50% or greater decrease in prostate-specific antigen (PSA) value lasting for 4 weeks. Alkaline phosphatase (AlkPh), chromium-51 ethylene diamine tetra-acetate ((51)Cr-EDTA) clearance rate and weight were measured before injection of the radionuclide. The whole-body absorbed dose showed a significant correlation with WC and Plt toxicity ( P=0.005 and 0.003 for the relative decrease and P=0.006 and 0.003 for the nadir values of WC and Plt counts respectively) in a multivariate analysis which included injected activity, whole-body absorbed dose, pre-treatment WC and Plt baseline counts, PSA and AlkPh values, and the pre-treatment Soloway score. The injected activity did not show any correlation with WC or Plt toxicity, but it did correlate with PSA response ( P=0.005). These results suggest that the administration of higher activities would be likely to generate a better response, but that the quantity of activity that can be administered is limited by the whole-body absorbed dose. We have derived and evaluated a model that estimates the whole-body absorbed dose on an individual patient basis prior to injection. This model uses the level of injected activity and pre-injection measurements of AlkPh, weight and (51)Cr-EDTA clearance. It gave good estimates of the whole-body absorbed dose, with an average difference between predicted and measured values of 15%. Furthermore, the whole-body absorbed dose predicted using this algorithm correlated with treatment toxicity. It could therefore be used to administer levels of activity on a patient-specific basis, which would help in the optimisation of targeted radionuclide therapy. We believe that algorithms of this kind, which use pre-injection biochemical and physiological measurements, could assist in the design of escalation trials based on a toxicity-limiting whole-body absorbed dose, rather than using the more conventional activity escalation approach.

Absorbed dose ratios for repeated therapy of neuroblastoma with I-131 mIBG.

Patients undergoing targeted radionuclide therapy (TRT) may receive a series of two or more treatment administrations at varying intervals. However, the level of activity administered and the frequency of administration can vary widely from centre to centre for the same therapy. Tumour dosimetry is seldom employed to determine the optimum treatment plan mainly due to the potential inaccuracies of image quantification. In this work 3D dose distributions obtained from repeated therapies have been registered to enable the dose ratios to be determined. These ratios are independent of errors in image quantification and, since the same target volume can be transferred from one distribution to the next, independent of inconsistencies in outlining these volumes. These techniques have initially been applied to ten sets of I-131 mIBG therapy scan data from five patients, each undergoing two therapies. It was found that where a similar level of activity was administered for the second therapy, a similar tumour dose was delivered, and in two cases where a higher level of activity was administered for the second treatment, a correspondingly higher absorbed dose was delivered. This justifies an approach of administering activities based on individual patient kinetics rather than administering standard activities to all patients.