Ra has been shown to not only have a palliative effect but also a survival prolonging effect in metastatic, castration-resistant prostate cancer with bone metastases. This article reviews the different radionuclide-based approaches for targeting bone metastases, with an emphasis on 223 Ra, and key elements of the underlying radiobiology of these that will impact their clinical effectiveness.Consideration is given to the remaining unknowns of both the basic radiobiological and applied clinical effects of 223 Ra as targets for future research.A significant burden is imposed on patients with cancer by osseous metastases; they are common in many forms of malignancy and are often highly symptomatic. In an early autopsy series of 1000 patients dying from disseminated malignancy of various primary sites, Abrams et al 1 found bone metastases present in 27.2% of their series. Metastases have biologically defined tropisms related to their site of origin. Although the biochemical determinants of these tropisms remain poorly understood, their effects are clear in the clinic and mean that certain sites of cancers have a particular preponderance for forming bone metastases. Autopsy data adapted by Coleman 2 show that 73% of patients dying of breast cancer, 68% of patients dying of prostate cancer and 36% of patients dying of lung cancer have bone metastases present at post-mortem. Of those patients with osseous metastases, a significant proportion goes on to develop skeletal-related events (SREs) in relation to their metastases. The precise definition of SREs differs between trials, but they generally refer to any of the following four clinical outcomes: the need for external beam radiotherapy (EBRT) for bone pain, development of malignant spinal cord compression, pathological fracture (symptomatic or asymptomatic) or the need for orthopaedic intervention to bone metastasis. In the context of a lifelimiting illness, any of the above is obviously of huge detriment to a patient's well-being on a number of fronts; pain by its very nature, time spent attending hospital, immobility associated with fracture/surgery etc. In their review of Phase 3 randomized trials of bone-modifying agents, Poon et al 3 show that in the placebo arms of 11 such trials, the percentage of patients with bone metastases experiencing SREs ranged from 23.47% to 67.2%. Thus bone metastases are a common finding in advanced malignancy and within the cohort of patients experiencing them; SREs are a common outcome, with obvious detriment to the quality of life of the patients affected.EBRT is a proven and well-established means of managing pain associated with bone metastases. In their systematic review of studies examining the palliative benefit of EBRT for bone metastases, Chow et al 4 found overall response rates, with regard to pain, of 58% for single fraction and 59% for multiple fraction treatments. The same authors found complete pain response rates of 23% in single fraction and of 24% in multiple fraction treatments. A large determinant of the degree...

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Objectives: The isotope bone scan (IBS) is the gold-standard imaging modality for detecting skeletal metastases as part of prostate cancer staging. However, its clinical utility for assessing skeletal metastatic burden is limited due to the need for subjective interpretation. We designed and tested a novel custom software tool, the Metastatic Bone Scan Tool (MetsBST), aimed at improving interpretation of IBSs, and compared its performance with that of an established software programme. Methods: We used IBS images from 62 patients diagnosed with prostate cancer and suspected bone metastases to design and implement MetsBST in MATLAB by defining thresholds used to identify the texture and size of metastatic bone lesions. The results of MetsBST were compared with those of the commercially available automated Bone Scan Index (aBSI) with regression analysis. Results: There was strong agreement between the MetsBST and aBSI results (R2 = 0.9189). In a subregional analysis, MetsBST quantified the extent of metastatic disease in multiple bone sites in patients receiving multimodality therapy (radium-223 and external beam radiotherapy) to illustrate the differences in bone metastatic response to different treatments. Conclusion: The results of MetsBST and the commercial software aBSI were highly consistent. MetsBST introduces novel clinical utility by its ability to differentiate between the responses of different bone metastases to multimodality therapies. Advances in knowledge: MetsBST reduces the variability in assessment of tumour burden caused by subjective interpretation. Therefore, it is a useful aid to physicians reporting nuclear medicine scans, and may improve decision-making in the treatment of metastatic prostate cancer.

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Purpose: Radium-223 is an alpha-emitting radionuclide associated with overall survival (OS) improvement in metastatic castration-resistant prostate cancer (mCRPC). External beam radiotherapy (EBRT) to prostate extends OS in men with metastatic hormone-sensitive prostate cancer (mHSPC) limited to less than 4 metastases. We hypothesized that combination radium-223 + pelvic EBRT could safely deliver maximal radiotherapy doses to primary and metastatic prostate cancer and may improve disease control. Patients and Methods: Thirty patients with de novo bone metastatic mHSPC who had commenced androgen deprivation therapy (ADT) and docetaxel were recruited to this single-arm, open-label, prospective clinical trial: Neo-adjuvant Androgen Deprivation Therapy, Pelvic Radiotherapy and RADium-223 (ADRRAD; for new presentation T1–4 N0–1 M1B adenocarcinoma of prostate). Study treatments were: ADT, 6 cycles of radium-223 q28 days, conventionally fractionated prostate radiotherapy (74 Gy) and simultaneous integrated boost to pelvic lymph nodes (60 Gy). Results: No grade 4/5 toxicity was observed. Three patients experienced grade 3 leukopenia, and 1 each experienced grade 3 neutropenia and thrombocytopenia; all were asymptomatic. One patient each experienced grade 3 dysuria and grade 3 urinary infection. No grade 3 gastrointestinal (GI) toxicity was observed. On treatment completion, there was a signal of efficacy; 24 (80%) patients had whole-body MRI evidence of tumor response or stability. Twenty-seven (90%) patients showed a reduction in alkaline phosphatase (ALP) compared with pretreatment levels. Median progression-free survival was 20.5 months. Conclusions: This is the first trial of combination ADT, radium-223, and EBRT to pelvis, post docetaxel. The combination was safe, with an efficacy signal. Multicenter randomized controlled trials (RCT) are warranted.

Consideration is given to further preclinical work needed into the mechanism of action of radium-223 and future clinical directions of the drug including combinations with other agents.

<p>Supplementary figure SF4 shows (A) Kaplan-Meier plot to estimate median progression free survival as time from first docetaxel (or trial registration if no docetaxel received) until PSA progression per PCWG. Median progression free survival = 20.5 months. (B) Kaplan Meier plot to estimate median overall survival as time from first docetaxel (or trial registration if no docetaxel received) until death. Median not reached.</p>