Fast track — ArticlesBone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study
Introduction
Hormone-refractory prostate cancer has a propensity to involve the bone marrow at an early stage. Subsequently, this involvement leads to the development of symptomatic skeletal metastases with pain, spinal-cord compression, pathological fracture, and pancytopenia. Bone-targeted treatments such as bisphosphonates (eg, zoledronate) and bone-seeking radioisotopes (eg, 89Sr and ethylenediaminetetramethylene phosphonate (EDTMP)-153Sm) are commonly used to delay skeletal disease progression and relieve pain. Zoledronate reduces the risk of skeletal-related events, but does not extend survival.1 The beta-emitting radioisotopes 89Sr and EDTMP-153Sm have been shown to improve pain control in men with symptomatic, hormone-refractory prostate cancer, with myelosuppression as their dose-limiting toxicity.2, 3
Beta-emitting radioisotopes produce relatively low-energy radiation with a track length in tissues of up to several mm. By contrast, alpha-emitters produce high, linear energy transfer (LET) radiation with a range of less than 100 μm. Compared with 89Sr and EDTMP-153Sm, a bone-seeking alpha-emitter might therefore have an increased anti-tumour effect, by virtue of the densely ionising abilities of high-LET radiation, but with relative sparing of the bone marrow because of its short-track length.
Radium-223 (223Ra) is a bone-seeking alpha-emitter with a half-life of 11·4 days that has been studied extensively in preclinical animal models. In mice, the biodistribution of 223Ra has been shown to correspond with that of 89Sr, targeting of the bony skeleton with retention of its daughter isotopes in the bone matrix.4 Modelling of the dose deposition in relation to tumour deposits in the bone marrow suggests a substantial reduction in dose to the healthy bone marrow with 223Ra compared with 89Sr.4 In a rat model of breast cancer, 223Ra showed pronounced anti-tumour effects in the absence of bone marrow toxic effects.5 After 67 days' follow-up period, two of five animals treated with at least 100 kBq/kg 223Ra survived, whereas none did in the control group. In this model, treatment with bisphosphonates gave no survival benefit.
A phase I trial of one intravenous injection of 223Ra was done recently in 25 patients with metastatic bone disease (15 with hormone-refractory prostate cancer, ten with breast cancer).6 Doses of 50–250 kBq/kg were well tolerated, with grade 3 leucopenia (Common Terminology Criteria for Adverse Events [CTCAE], version 2.0) in three of 25 patients and no grade 2+ thrombocytopenia. No dose-limiting toxic effects were recorded. Gastrointestinal adverse events, most commonly diarrhoea (10 of 25 patients; highest CTCAE grade 2), were most frequent, especially in the highest dose groups. Preferential uptake was seen in skeletal metastases compared with healthy bone, with excretion mainly through the intestinal tract. Preliminary evidence of efficacy was seen with substantial reductions in serum alkaline phosphatase (ALP) concentrations and improved pain control across the dose levels.6 Preliminary data suggested that the effect on ALP was similar across doses, and the lowest tested dose (50 kBq/kg) was selected for future studies.
In a randomised, double-blind, placebo-controlled, multicentre phase II study, we aimed to investigate the effect of repeated 223Ra doses in men with symptomatic, hormone-refractory prostate cancer. Main study objectives were the efficacy of 223Ra treatment with respect to the reduction in bone-specific ALP (bone-ALP) concentration, and time to occurrence of skeletal-related events (SREs).
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Patients
Eligible patients had histologically or cytologically confirmed adenocarcinoma of the prostate; multiple bone metastases or one painful lesion with two consecutive rising amounts of serum prostate-specific antigen (PSA); Eastern Cooperative Oncology Group performance status 0–2; life expectancy of longer than 3 months; adequate haematological (neutrophils ≥1·5×109/L; platelets ≥100×109/L; haemoglobin >100 g/L), renal (creatinine <1·5×upper limit of normal), and hepatic (normal bilirubin [within
Results
64 patients were recruited in 11 centres in Sweden, Norway, and the UK between Feb 11, 2004, and May 3, 2005 (figure 2). 33 patients were assigned external-beam radiotherapy and 223Ra, and 31 to external-beam radiotherapy and placebo. Table 1 shows the baseline values of bone-ALP, haemoglobin, albumin, PSA, age, extent of disease on bone scan,9 and pain score. We recorded no significant difference in external-beam radiotherapy dose fractionation at baseline between the study groups (223Ra,
Discussion
In our randomised study of patients with symptomatic, hormone-refractory prostate cancer, 223Ra was well tolerated with little or no myelotoxic effect, and showed promising evidence of efficacy. One primary endpoint was met, with a significant effect on bone-ALP 4 weeks after last treatment. Efficacy data in this small study suggested a potential beneficial effect of 223Ra on SRE risk, time to PSA progression, and overall survival. The good toxicity profile seen for 223Ra will allow future
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