Commentary: Opportunities for research in molecular radiotherapy

Cancer has been treated with radiopharmaceuticals for 80 years. A recent National Cancer Research Institute report from the Clinical and Translational Radiotherapy Research Working Group reviews the current status of molecular radiotherapy and has highlighted the barriers to and opportunities for increased research activities. The report recommends a number of actions to promote this field, which in the dawning age of personalized medicine and theragnostics is of increasing importance, particularly with the clinical introduction of a range of new commercial radiotherapeutics at costs in line with those seen for conventional chemotherapeutics. These recommendations recognize the importance of a multidisciplinary approach to the development of molecular radiotherapy and the particular need for investment in radiopharmacies and personalized dosimetry. There are many areas to be investigated including adaptive treatment planning, the use of radiosensitizers and translational radiation biology. Progress in these areas will result in significant patient benefit and more cost-effective use of increasingly expensive therapeutic radiopharmaceuticals. A concerted effort from the community, from funding bodies and from health service providers is now needed to address the scientific and logistical changes necessary to realize the potential offered by this currently underused treatment modality

Characterisation of the attenuation properties of 3D-printed tungsten for use in gamma camera collimation

Abstract Background The aim of this work was to characterise the attenuation properties of 3D-printed tungsten and to assess the feasibility for its use in gamma camera collimator manufacture. Method 3D-printed tungsten disks were produced using selective laser melting (SLM). Measurements of attenuation were made through increasing numbers of disks for a Tc-99m (140 keV) and I-131 (364 keV) source. The technique was validated by repeating the measurements with lead samples. Resolution measurements were also made with a SLM tungsten collimator and compared to Monte Carlo simulations of the experimental setup. Different collimator parameters were simulated and compared against the physical measurements to investigate the effect on image quality. Results The measured disk thicknesses were on average 20% above the specified disk thicknesses. The measured attenuation for the tungsten samples were lower than the theoretical value determined from the National Institute of Standards and Technology (NIST) cross-sectional database (Berger and Hubbell, XCOM: photon cross-sections on a personal computer, 1987). The laser scan strategy had a significant influence on material attenuation (up to 40% difference). Results of these attenuation measurements indicate that the density of the SLM material is lower than the raw tungsten density. However, an improved performance compared to a lead collimator was observed. The SLM tungsten collimator was adequately simulated as 80% density and 110% septal thickness. Scatter and septal penetration were 17% less than a similar lead collimator and 33% greater than tungsten at 100% density. Conclusions SLM manufacture of tungsten collimators is feasible. Attenuation properties of SLM tungsten are superior to the lead alternative and the opportunity for bespoke collimator design is appealing

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

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

A Phase I Open Label Study of the biodistribution, pharmacokinetcis and dosimetry of Ra223 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 Ra-223-dichloride in patients with bone metastases due to castration-refractory prostate cancer. Methods: Six patients received 2 intravenous injections of Ra-223-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 a 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

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

Dosimetry of yttrium-labelled radiopharmaceuticals for internal therapy: 86Y or 90Y imaging?

This paper reviews issues concerning (86)Y positron emission tomography (PET), (90)Y PET and (90)Y bremsstrahlung imaging. Specific methods and corrections developed for quantitative imaging, for application in preclinical and clinical studies, and to assess (90)Y dosimetry are discussed. The potential imaging capabilities with the radioisotopes (87)Y and (88)Y are also considered. Additional studies required to assess specific unaddressed issues are also identified