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•This meta-analysis of 2081 patients from six randomized clinical trials was designed to evaluate overall survival in men with bone metastases from castration-resistant metastatic prostate cancer treated with bone-targeted radioisotopes. In contrast to the individual studies with a lack of significant benefit from radioisotope use, the authors report that an α-emitting radioisotope (radium 223) was significantly associated with higher overall survival and higher symptomatic skeletal event–free survival rates. However, a β-emitting radioisotope (strontium-89) was not associated with similar benefit.
•Due to the significant between-trial heterogeneity, caution should be used when generalizing these results, which showed a survival benefit with bone-targeted α-emitting but not β-emitting radioisotopes in men with castration-resistant metastatic prostate cancer.
– Paul J. Hampel, MD
Importance.
Both α-emitting and β-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and β-emitting RIs.
Objective
To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with β-emitting RIs.
Data Sources.
PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018.
Study Selection
Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data.
Data Extraction and Synthesis
Individual patient data were requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I2 and was accounted by a random-effects (RE) model.
Main Outcomes and Measures
Overall survival; secondary outcomes were symptomatic skeletal event (SSE)-free survival and adverse events.
Results.
Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95% CI, 0.77-0.95; P = .004) with high heterogeneity (χ25 = 24.46; P < .001; I2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06; P = .12; τ2 = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the α-emitting RI 223Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the β-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001) (between-trial heterogeneity: χ23 = 6.51; P = .09; I2 = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99; P = .04; τ2 = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95% CI, 0.69-0.93; P = .004) (between-trial heterogeneity: χ23 = 6.71; P = .08; I2 = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01; P = .06; τ2 = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001).
Conclusions and Relevance.
In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted α-emitting but not β-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity.
JAMA Oncology
Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-Analysis of Individual Patient Data From Randomized Clinical Trials
JAMA Oncol 2019 Dec 12;[EPub Ahead of Print], S Terrisse, E Karamouza, CC Parker, AO Sartor, ND James, S Pirrie, L Collette, BF Tombal, J Chahoud, S Smeland, B Erikstein, JP Pignon, K Fizazi, G Le Teuff
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
"A Novel Prognostic Model Predicting Overall Survival in Patients With mCRPC Receiving Standard Chemotherapy"
