Nilsson 2007

Methods	Double blind randomised trial.
Participants	N = 64 patients with prostate cancer. Patients had to have multiple bone metastases or one painful lesion with two consecutive rising amounts of serum PSA. (33 on 223Ra, 31 on placebo).
Interventions	1. 223Ra in dose 50kBq administered iv every 4 weeks during 12 weeks (total 4 injections) + external beam radiotherapy. 2. Placebo administered iv every 4 weeks during 12 weeks (total 4 injections) + external beam radiotherapy. Treatment injection administered on the first day of radiotherapy. External beam radiotherapy administered at the most painful site, either one fraction of 8 Gy or a fractionated course of 20 Gy over 1 week in 5 fractions, or 30 Gy over 2 weeks in 10 fractions. Follow up: 4 months.
Outcomes	Skeletal related events defined as: • 25% increase in pain severity index, computed from patients' assessment of pain on Brief Pain Inventory forms (scale 0–10). • Increased analgesic consumption based on the WHO ladder for cancer pain. • Neurological symptoms secondary to skeletal manifestations of prostate cancer. • New pathological bone fractures (vertebral and non‐vertebral). • Tumour‐related orthopaedic surgical intervention. • Subsequent external‐beam radiation to relieve skeletal pain. • Use of radioisotopes to relieve new skeletal‐related symptoms. • Use of corticosteroids for skeletal pain palliation. • Use of chemotherapy, bisphosphonates, or hormones to treat progression of skeletal disease. Bone serum alkaline phosphatase. Safty and toxicity assessed 2 weekly up to 4 weeks and at 6, 9, 12, 18 and 24 months.
Notes	4 patients were not evaluable on the 223Ra group, 9 patients were not evaluable on the placebo group. All patients withdrawn before week 16 of study (4 weeks of treatment + 12 weeks follow up).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomisation was done centrally with a random number generator stratified by centre".
Allocation concealment (selection bias)	Low risk	"Randomisation was done centrally with a random number generator stratified by centre",
Blinding (performance bias and detection bias) Patients	Low risk	"An individual from the nuclear medicine department at every centre was responsible for study treatment preparation and labelling".
Blinding (performance bias and detection bias) Study researchers	Low risk	"An individual from the nuclear medicine department at every centre was responsible for study treatment preparation and labelling. Researchers remained masked to treatment allocation."
Blinding (performance bias and detection bias) Outcome assessment	Unclear risk	Not described.
Incomplete outcome data (attrition bias) All outcomes	Low risk	"All patients followed for survival irrespective of study status." "Patients who received at least one dose of study drug were included in the analysis and all results were analyzed by intention to treat."