Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.

BACKGROUND: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. METHODS: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476. FINDINGS: Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy). INTERPRETATION: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.

Sector analysis provides additional spatial information on the permanent prostate brachytherapy learning curve.

PURPOSE: To evaluate the permanent prostate brachytherapy (PPB) learning curve using postimplant multisector dosimetric analysis and to assess the correlation between sector -specific dosimetry and patient-reported outcome measures (PROMs). METHODS AND METHODS: First 200 patients treated with (125)I PPB monotherapy (145 Gy) at a single institution were assessed. Postimplant dosimetry (PID) using CT was evaluated for whole prostate (global) and 12 sectors, assessing minimum dose to 90% of prostate (D90) and dose to 0.1 cm(3) of rectum (D0.1cc). Global and sector PID results were evaluated to investigate changes in D90 with case number. Urinary and bowel PROMs were assessed using the International Prostate Symptom Score and the Expanded Prostate Cancer Index Composite questionnaire. The correlation between global and individual sector PID and urinary/bowel PROMs was also evaluated. RESULTS: Linear regression confirmed a significant improvement in global D90 with case number (r(2) = 0.20; p = 0.001) at a rate of 0.11 Gy/case. Postimplant D90 of base sectors increased at a rate of 0.11-0.15 Gy/case (p = 0.0001) and matched global improvement. The regression lines of midgland and apex sectors were significantly different from global D90 (p = 0.01). Posterior midgland sectors showed a significant reduction in D90 with case number at a rate of 0.13-0.19 Gy/case (p = 0.01). Dose to posterior midgland sectors correlated with rectal D0.1cc dose but not bowel PROMs. Dose to posterior midgland sectors correlated with urinary International Prostate Symptom Score change, which was not apparent when global D90 alone was considered. CONCLUSIONS: Sector analysis provided increased spatial information regarding the PPB learning curve. Furthermore, sector analysis correlated with urinary PROMs and rectal dose.