Sarah J. Chittenden

Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases.

Objective 223Ra is an alpha particle emitter that targets areas of increased bone turnover in bone metastases. Alpha particles account for 95% of the 27.8 MeV emitted per decay. Less than 2% of the emissions are from photons. This means that a high absorbed dose will be delivered locally, although the number of photons for imaging will be low. The purpose of this study was to investigate the possibility of quantitative imaging of 223Ra to enable biodistribution studies. MethodsA Philips Forte gamma camera, equipped with a medium-energy collimator, was used. Basic imaging parameters were determined from phantom studies, and the accuracy of activity quantification was tested in a phantom study and within a patient study. ResultsImaging parameters were determined for the three most suitable photon peaks from the acquired energy spectrum (82, 154 and 270 keV). Camera sensitivity is constant for circular sources with areas greater than 10 cm2. The spatial resolution (full-width at half-maximum) was 1.1 cm for each of the three energy windows. The possibility for quantitative imaging was further investigated for the 82 keV energy window, which showed the highest sensitivity and spatial resolution. A phantom study showed that activity could be quantified to within 10% for a 200 ml volume placed within water containing background activity and to within 50% for a 0.5 ml phantom. Quantification of activity in bone after administrations of 100 kBq/kg of 223Ra-chloride proved the feasibility of quantitative imaging of patients who have received radionuclide therapy. ConclusionBecause of the high-energy deposition of 223Ra, only a low injected activity is required for therapy, which results in a low count rate for the gamma camera. Nevertheless, this study has demonstrated that it is possible to quantify uptake with a sufficient degree of accuracy to obtain clinically relevant information.

High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone

We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates.

Whole-Body Dosimetry for Individualized Treatment Planning of 131I-MIBG Radionuclide Therapy for Neuroblastoma

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 131I-metaiodobenzylguanidine (131I-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 131I-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 patients 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 131I-MIBG therapy on a patient-specific basis.

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

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 223Ra-dichloride in patients with bone metastases due to castration-refractory prostate cancer. Methods: Six patients received 2 intravenous injections of 223Ra-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.

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.

Individualized 131I-mIBG therapy in the management of refractory and relapsed neuroblastoma.

ObjectiveIodine-131-labelled meta-iodobenzylguanidine (131I-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach. Materials and methodsA review of 44 treatments in 25 patients treated with 131I-mIBG therapy was performed. Patients received 131I-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients. ResultsThe mean administered activity was 11089±7222 MBq and the mean whole-body dose for a single administration was 1.79±0.57 Gy. Tumour-absorbed doses varied considerably (3.70±3.37 mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease. ConclusionA highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized 131I-mIBG therapy.

Dosimetry of Intralesional 131I-Monoclonal Antibody (MAb) Therapy in Patients with Recurrent High Grade Gliomas

Six patients have been treated with 131I labelled anti-tenascin (IgG2A) Mab. Administration directly into the solid component of the tumour was achieved via either one or two stereotactically placed catheters. Up to 600 MBq of MAb conjugated 131I was infused at a rate of 50-100 µl/hour. Throughout therapy, urine collection, blood sampling, whole body activity measurements, whole body scans and SPECT scans of the tumour were carried out regularly. Absorbed doses to the bladder, blood, whole body and tumour were calculated according to the MIRD system.

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

Abstract 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.

Reply to 'Single high dose versus repeated bone-targeted radionuclide therapy'

We would like to thank Liepe [1] for his interest in our recent article and giving us the opportunity to further expand upon some additional aspects of the study [2]. The data used for the present study [2] belong to two National Institute of Health (NIH) funded activity escalation phase I [3] and fixed administered activity phase II [4] clinical trials. A total of 57 patients were recruited between 1996 and 2003, before availability of Ra-dichloride or chemotherapy agents such as docetaxel and/or abiraterone. The aims of these trials were to investigate the feasibility and toxicity profile of high administered activities of Re-HEDP and autologous peripheral blood stem cell transplantation (PBSCT) in patients with castration-resistant prostate cancer metastatic to bone (mCRPC). The results of these studies were previously published [3, 4]. Amaximum tolerated activity of 5 GBq of ReHEDP was determined in the phase I trial, with a statistically significant prostate-specific antigen (PSA) improved response in patients receiving activities above 3.5 GBq. The phase II study demonstrated the safe delivery of a fixed 5 GBq of Re-HEDP and PBSCT in a group of 38 patients with mCRPC. The aim of our recent publication was to use the long-term survival and imaging data available to study the potential of imaging and dosimetry to predict response and outcome. Our study did not intend to discuss whether high administered activities and PBSCTare the best treatment strategy for patients with mCRPC [2]. Liepe raises concerns about the lack of a sample size calculation for the overall survival (OS) analysis according to administered activity levels, the capture of patient follow-up, and the inclusion of patients treated with Ra-dichloride or docetaxel. Our post hoc analysis showed a statistically significant difference in survival between the lowand high-activity groups and a sample size calculation was not included, as this was not an end-point to the original trials and not needed for this type of analysis. As stated in our publication [2], followup time was used for OS analysis as the time interval between administration of Re-HEDP and death, which was documented for 50 of the 57 patients. Seven patients were censored at the last point of contact, or at the time they received a treatment prolonging survival. Our results showed a statistically significant difference in overall survival for both groups, with a median OS advantage of 13 months, which could not be explained by differences in baseline prognostic factors. Unfortunately, imaging was not available for all patients, so it was not possible to determine whether patients treated with > 3.5 GBq received higher absorbed doses, which could have affected survival. Nonetheless, this result was considered of potential interest for future studies, particularly in light of newly emerging radiopharmaceuticals also showing a prolonged survival for higher administered activities [5]. This Editorial Commentary refers to the article http://dx.doi.org/10.1007/ s00259-017-3815-0.

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.