Sequencing of Androgen-Deprivation Therapy of Short Duration With Radiotherapy for Nonmetastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials

Abstract

PURPOSE The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT). MATERIALS AND METHODS Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer–specific mortality. RESULTS Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points ( P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer–specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT. CONCLUSION ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

Duration of androgen deprivation with radiotherapy for high-risk or locally advanced prostate cancer: A network meta-analysis

“…In a recent pooled analysis of 12 studies of short-term ADT comparing neoadjuvant/concurrent with concurrent/adjuvant, the authors found that concurrent/adjuvant ADT should be the standard of care when short-term ADT is indicated in combination with RT. 10 In another meta-analysis that compared short with longer ADT duration combined with RT, prolonging the proportion of ADT that follows RT up to 1.5–3 years but not neoadjuvant ADT was associated with improved MFS, regardless of risk group, age, and RT dose delivered. 11…”

Using a Further Planning MRI after Neoadjuvant Androgen Deprivation Therapy Significantly Reduces the Radiation Exposure of Organs at Risk in External Beam Radiotherapy of Prostate Cancer

“…The reduction in prostate size under ADT measured in this study was within the range of other published studies [ 27 , 28 , 29 ]. The timing of starting ADT before or concurrently with radiotherapy is controversial for oncological efficacy [ 30 , 31 ]. However, waiting for the prostate to shrink after a few months of ADT contributes to relief of the organs at risk and to lower toxicity.…”

Reply to A. Abner et al

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We thank Abner and Vicini 1 for their correspondence in response to our article. 2 We agree that those performing meta-analyses and pooled analyses must take measures to account for important limitations inherent to evaluating heterogeneous data sets. However, we disagree with several of the statements made by Abner et al, such as ascribing potential survival benefits observed in this analysis to substantial progress in the delivery of radiation therapy.

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“…That study was not subject to the forms of bias implied by the authors, given it was purely based on randomized evidence from ADT sequencing. The fact that two randomized trials from two different countries, 3-5 a pooled analysis of the two trials, 6 and the SANDSTORM meta-analysis 2 all numerically or significantly favored adjuvant ADT in the setting of PORT lends strong credence to the validity of this effect. None showed any potential benefit of neoadjuvant ADT with PORT.…”