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• W3002566129 abstract "STAMPEDE is a multi-arm multi-platform randomised controlled trial of treatment for locally advanced, recurrent or hormone-sensitive metastatic prostate cancer, which has energised the UK prostate cancer oncology community. Achieving rapid recruitment, it generated results that have changed systemic therapy practice: docetaxel has been added to lifelong androgen deprivation therapy (ADT) as the standard of care (SoC) in this population, having shown a clinically significant survival advantage [[1]James N.D. Sydes M.R. Clarke N.W. Mason M.D. Dearnaley D.P. Spears M.R. et al.Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.Lancet. 2016; 387: 1163-1177Abstract Full Text Full Text PDF PubMed Scopus (1343) Google Scholar], and abiraterone is currently being evaluated by the National Institute for Health and Care Excellence (NICE) after showing a comparable survival benefit [[2]James N.D. de Bono J.S. Spears M.R. Clarke N.W. Mason M.D. Dearnaley D.P. et al.Abiraterone for prostate cancer not previously treated with hormone therapy.N Engl J Med. 2017; 377: 338-351Crossref PubMed Scopus (1033) Google Scholar,[3]Sydes M.R. Spears M.R. Mason M.D. Clarke N.W. Dearnaley D.P. de Bono J.S. et al.Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.Ann Oncol. 2018; 29: 1235-1248Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar]. Retrospective series suggest radiotherapy to the primary tumour may provide improved overall survival for men with metastatic cancer. This hypothesis has now been tested in Arm K of STAMPEDE [[4]Parker C.C. Sydes M.R. Mason M.D. Clarke N.W. Aebersold D. de Bono J.S. et al.Prostate radiotherapy for men with metastatic disease: a new comparison in the STAMPEDE trial.Clin Oncol. 2013; 25: 318-320Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,[5]Parker C.C. James N.J. Brawley C.D. Clarke N.W. Hoyle A.P. Ali A. et al.Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomized controlled phase 3 trial.Lancet. 2018; 392: 2353-2366Abstract Full Text Full Text PDF PubMed Scopus (656) Google Scholar]. Eligible patients had a diagnosis of metastatic prostate cancer requiring lifelong ADT and no contraindication to radiotherapy. They were randomised 1:1 to either SoC or SoC plus external beam radiotherapy delivered to the prostate ± seminal vesicles. Protocol radiotherapy schedules were 55 Gy in 20 fractions over 4 weeks or 36 Gy in six weekly fractions of 6 Gy, chosen prior to randomisation according to centre or clinician preference. In line with results showing survival benefit for docetaxel treatment in this population, the study protocol was amended to permit this treatment, which was given to about 15% of the trial population. Patients were stratified by hospital, age, performance status, nodal involvement, aspirin/non-steroidal anti-inflammatory drug use and docetaxel use. The primary outcome measure was overall survival, and for interim analyses the primary activity outcome was failure-free survival (FFS), defined as freedom from biochemical failure, local or distant progression or death from prostate cancer. Secondary outcomes were symptomatic local events, progression-free survival, equivalent to FFS but ignoring biochemical events, and metastatic progression-free survival, defined as the time to new metastases, progression of existing metastases or death. The target sample size was 1250 patients, selected on the assumption of 1- and 3.5-year median FFS and overall survival, respectively, for the SoC control group, and 25% relative improvement in hazard ratios for failure and death for patients receiving SoC + radiotherapy. During recruitment it was observed that the two radiotherapy schedules were being used about equally. Therefore, the sample size was increased to 1800 patients, to provide power to detect differences in FFS for each radiotherapy schedule-defined subgroup versus SoC alone. Based on accumulating external results, and without reference to data from STAMPEDE, investigators concluded in May 2018 that any benefit from radiotherapy would be greater in patients with lower metastatic burden, and that this potential benefit could be tested with reasonable power in the subgroup of STAMPEDE patients with lower burden. Survival analysis used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. For the subgroup analysis that tested the effects of prostate radiotherapy by baseline metastatic burden, high burden was defined according to the CHAARTED criteria as four or more bone metastases with one or more outside the vertebral bodies or pelvis, or visceral metastases, or both [[6]Sweeney C.J. Chen Y.H. Carducci M. Liu G. Jarrard D.F. Esenberger M. et al.Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.N Eng J Med. 2015; 373: 737-746Crossref PubMed Scopus (1765) Google Scholar]. Between January 2013 and September 2016, 2061 men newly diagnosed with metastatic prostate cancer were randomised from 117 sites, 1029 to SoC and 1032 to SoC + radiotherapy. The arms were well balanced, 40% and 54% of patients having lower and higher metastatic disease burden, respectively, and 6% having unknown burden. Of the patients allocated to SoC + radiotherapy, 88% received one of the protocol radiotherapy schedules, 6% an alternative schedule and 6% declined treatment. Across the whole patient group, a significant improvement was seen in FFS (hazard ratio 0.76; 95% confidence interval 0.68–0.84; P = 3.4 × 10−7) but not in overall survival (hazard ratio = 0.92; 95% confidence interval 0.80–1.06; P = 0.27) for patients treated using SoC + radiotherapy. In 819 men with lower metastatic disease burden, however, overall survival was significantly better for SoC + radiotherapy (hazard ratio = 0.68; 95% confidence interval 0.52–0.90; P = 0.007), with 3-year survival rates of 73% for SoC versus 81% for SoC + radiotherapy. In 1120 men with a higher metastatic burden, radiotherapy did not improve overall survival (hazard ratio = 1.07; 95% confidence interval 0.90–1.28; P = 0.42) (Figure 1). Both radiotherapy schedules were well tolerated, with no significant difference in rates or latencies of symptomatic local events between patients receiving SoC and SoC + radiotherapy. The STAMPEDE randomised comparison of over 2000 metastatic prostate cancer patients did not find a significant improvement in overall survival for SoC + radiotherapy in the whole patient group. However, a significant overall survival benefit was seen for patients with lower metastatic burden treated using SoC + radiotherapy (P = 0.007) in a subgroup analysis that met proposed credibility criteria [[7]Sun X. Briel M. Walter S.D. Guyatt G.H. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses.BMJ. 2010; 340: c117Crossref PubMed Scopus (492) Google Scholar]. An interaction test indicates that the observed effect was independent of other variables assessed. The HORRAD study of 432 men with metastatic prostate cancer randomised to receive ADT alone or with radiotherapy recently reported no significant improvement in overall survival for the ADT + radiotherapy arm when assessed across all patients, but a trend for improved overall survival in those patients with lower metastatic disease burden treated using ADT + radiotherapy (P = 0.063) [[8]Boevé L.M.S. Hulshof M.C.C.M. Vis A.N. Zwinderman A.H. Twisk J.W.R. WPJ W. et al.Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised trial: data from the HORRAD trial.Eur Urol. 2019; 75: 410-418Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar]. This trend for improved survival in patients with lower metastatic burden receiving SoC + radiotherapy has now been confirmed in the larger STAMPEDE study. STAMPEDE recruited rapidly and consequently its median follow-up (37 months) is currently shorter than the median survival (46 months). Longer-term analysis of STAMPEDE data may provide additional insights for population subsets. Palliative chemotherapy with docetaxel has become SoC for hormone-sensitive metastatic prostate cancer, with a survival benefit comparable with abiraterone therapy until disease progression. Patients receiving docetaxel in this study had the shortest follow-up, and although no significant difference in overall survival or FFS was seen for these patients, this may change with longer follow-up. Improved systemic therapy, providing better control of metastases, may effectively move the border between low and high metastatic disease burden, enabling a greater number of patients to benefit from radiotherapy. At the time of the study, standard curative radiotherapy in the UK was 74 Gy in 37 fractions [[9]Dearnaley D. Jovic G. Syndikus I. Khoo V. Cowan R.A. Graham J.D. et al.Escalated-dose conformal radiotherapy for localised prostate cancer: long-term overall survival results from the MRC RT01 randomised controlled trial.Eur J Cancer. 2011; 47: 11-12Abstract Full Text PDF Google Scholar]. This schedule was felt to be burdensome for patients with metastatic disease and, given emerging evidence that the α/β ratio for prostate cancer was relatively low [[10]Dearnaley D. Syndikus I. Gulliford S. Hall E. Hypofractionation for prostate cancer: time to change.Clin Oncol. 2017; 29: 3-5Abstract Full Text Full Text PDF Scopus (11) Google Scholar], radiotherapy schedules of 55 Gy/20 fractions/26 days and 36/6 fractions/36 days were chosen for the trial. STAMPEDE has shown some evidence of heterogeneity in FFS by radiotherapy schedule (P = 0.072): although a clear FFS benefit was seen for SoC + 55 Gy/20 fractions compared with SoC alone (hazard ratio 0.69; 95% confidence interval 0.59–0.8; P < 10−6), the benefit did not reach significance for SoC + 36 Gy/6 fractions (hazard ratio = 0.85; 95% confidence interval 0.73–0.99; P = 0.033). Longer-term analysis may shed more light on any difference in the effectiveness of the two radiotherapy schedules, potentially guiding identification of an optimised schedule, which future translational research might allow to be personalised. In newly diagnosed patients with prostate cancer and low burden metastatic disease, overall survival was improved by adding prostate radiotherapy to SoC. SoC + radiotherapy should therefore be considered the new SoC for this population. The STAMPEDE authors suggest that radiotherapy might be given as 60 Gy in 20 fractions, the current standard UK external beam radiotherapy schedule for localised prostate cancer [[11]Dearnaley D. Syndikus I. Mossop H. Khoo V. Birtle A. Bloomfield D. et al.Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority phase 3 CHHIP trial.Lancet Oncol. 2016; 17: 1047-1060Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar]. The authors declare no conflicts of interest." @default.
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• W3002566129 title "Radiotherapy to the Primary Tumour for Patients with Metastatic Prostate Cancer: Practice-Changing Results from STAMPEDE" @default.
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