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

Abstract

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.

Figure 1.. Overall Survival and Subgroup Analysis of Trials Comparing Patients Receiving Radioisotopes (RIs) With Patients Receiving No RIs by Type of Radiation

A, Overall survival in all trials. τ² values were estimated using the DerSimonian and Laird method. Test for heterogeneity: α-emitting RIs: χ²₁ = 0.53; P = .47; I² = 0%; β-emitting RIs: χ²₃ = 15.67; P < .001; I² = 81%. B, Subgroup analysis of OS. ALSYMPCA indicates Alpharadin in Symptomatic Prostate Cancer Patients; FE, fixed-effects model; HR, hazard ratio; O − E, observed minus expected number of deaths in the experimental arm; PSA, prostate-specific antigen; RE, random-effects model; and RI, radioisotope. To convert PSA to micrograms per liter, multiply by 1; to convert alkaline phosphatase to microkatals per liter, multiply by 0.0167; to convert hemoglobin to grams per liter, multiply by 10. ^aP value corresponds to the test for between-trial heterogeneity. ^bτ². ^cThe trials by Tu et al and Oosterhof et al were excluded because they were considered outliers. ^dData from the Taxane Radioisotope Zoledronic Acid (TRAPEZE) trial were not included in the subgroup analysis of bone metastases at baseline because this information was not available.

Figure 2.. Stratified Survival Curves for Overall Survival (OS) and Symptomatic Skeletal Event (SSE)–Free Survival^a

The absolute differences (95% CIs) at 1 and 2 years are given. RI indicates radioisotope. ^aThe absolute difference at more than 2 years is not reported because of timing lack of precision.

Figure 3.. Symptomatic Skeletal Event (SSE)–Free Survival and Subgroup Analyses of Trials Comparing Patients Receiving Radioisotopes (RIs) With Patients Receiving No RIs by Type of Radiation

A, Symptomatic skeletal event–free survival excluding 2 trials.^, τ² values were estimated using the DerSimonian and Laird method. Test for heterogeneity: α-emitting RIs: χ²₁ = 0.18; P = .67; I² = 0%; β-emitting RIs: χ²₁ = 1.28; P = .26; I² = 22%. B, Subgroup analysis of SSE-free survival. ALSYMPCA indicates Alpharadin in Symptomatic Prostate Cancer Patients; FE, fixed-effects model; HR, hazard ratio; O − E, observed minus expected number of SSEs in the experimental arm; PSA, prostate-specific antigen; RE, random-effects model; and RI, radioisotope. To convert PSA to micrograms per liter, multiply by 1; to convert alkaline phosphatase to microkatals per liter, multiply by 0.0167; to convert hemoglobin to grams per liter, multiply by 10. ^aP value corresponds to the test for between-trial heterogeneity. ^bτ². ^cThe trials by Tu et al and Oosterhof et al were excluded because no information was available for the former and data were not reliable for the latter. ^dData from the Taxane Radioisotope Zoledronic Acid (TRAPEZE) trial were not included in the subgroup analysis of bone metastases at baseline because this information was not requested in this trial.