Abstract
BackgroundMany trials are evaluating therapies for men with metastatic hormone-sensitive prostate cancer (mHSPC). ObjectiveTo systematically review trials of prostate radiotherapy. Design, setting, and participantsUsing a prospective framework (framework for adaptive meta-analysis [FAME]), we prespecified methods before any trial results were known. We searched extensively for eligible trials and asked investigators when results would be available. We could then anticipate that a definitive meta-analysis of the effects of prostate radiotherapy was possible. We obtained prepublication, unpublished, and harmonised results from investigators. InterventionWe included trials that randomised men to prostate radiotherapy and androgen deprivation therapy (ADT) or ADT only. Outcome measurements and statistical analysisHazard ratios (HRs) for the effects of prostate radiotherapy on survival, progression-free survival (PFS), failure-free survival (FFS), biochemical progression, and subgroup interactions were combined using fixed-effect meta-analysis. Results and limitationsWe identified one ongoing (PEACE-1) and two completed (HORRAD and STAMPEDE) eligible trials. Pooled results of the latter (2126 men; 90% of those eligible) showed no overall improvement in survival (HR=0.92, 95% confidence interval [CI] 0.81–1.04, p=0.195) or PFS (HR=0.94, 95% CI 0.84–1.05, p=0.238) with prostate radiotherapy. There was an overall improvement in biochemical progression (HR=0.74, 95% CI 0.67–0.82, p=0.94×10−8) and FFS (HR=0.76, 95% CI 0.69–0.84, p=0.64×10−7), equivalent to ∼10% benefit at 3yr. The effect of prostate radiotherapy varied by metastatic burden—a pattern consistent across trials and outcome measures, including survival (<5, ≥5; interaction HR=1.47, 95% CI 1.11–1.94, p=0.007). There was 7% improvement in 3-yr survival in men with fewer than five bone metastases. ConclusionsProstate radiotherapy should be considered for men with mHSPC with a low metastatic burden. Patient summaryProstate cancer that has spread to other parts of the body (metastases) is usually treated with hormone therapy. In men with fewer than five bone metastases, addition of prostate radiotherapy helped them live longer and should be considered.
Highlights
Four trials were excluded: two because radiotherapy was administered to metastases as well as the prostate ([19] and NCT02913859), one because men did not receive androgen deprivation therapy (ADT) (NCT02680587), and one because surgery or radiotherapy was allowed as local treatment (NCT01751438), leaving three eligible trials (Supplementary Fig. 1)
Based on 90% of all men randomised to prostate radiotherapy plus ADT versus ADT, we have shown that the effect of prostate radiotherapy on survival varies by metastatic burden
Three trials (TROMBONE [ISRCTN 15704862], g-RAMPP [NCT02454543], and SIMCAP [NCT03456843]) are investigating whether radical prostatectomy offers an alternative to radical radiotherapy in this setting, and two trials [19] (NCT[64_TD$IF]02913859) and a new STAMPEDE arm are evaluating the effects of administering radiotherapy to metastatic sites as well as the prostate
Summary
Randomised controlled trials have evaluated, or are currently evaluating, promising therapies for metastatic hormone-sensitive prostate cancer (mHSPC), including prostate radiotherapy [1,2] Systematic reviews of these trial results can help determine effective treatments, but are usually planned after most trials have reported and focus on published results. A new framework for adaptive meta-analysis (FAME) [5] defines review methods prospectively, prior to trial results being published. Results and limitations: We identified one ongoing (PEACE-1) and two completed (HORRAD and STAMPEDE) eligible trials Pooled results of the latter (2126 men; 90% of those eligible) showed no overall improvement in survival (HR = 0.92, 95% confidence interval [CI] 0.81–1.04, p = 0.195) or PFS (HR = 0.94, 95% CI 0.84–1.05, p = 0.238) with prostate radiotherapy.
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