Evaluation of Cancer-Specific Mortality with Surgery Versus Radiation as Primary Therapy for Localized High-Grade Prostate Cancer in Men Younger than 60 Years Old - Beyond the Abstract

High-grade prostate cancer more adversely affects mortality in younger men who have longer life expectancies and lower comorbidities, whereas older men are more likely to die with, rather than from the disease. Currently, there is a lack of consensus over which local therapy, radical prostatectomy (RP) or radiation therapy (RT), is optimal for first-line treatment of high-grade localized prostate cancer. Level I evidence regarding the superiority between RP vs. RT is not established, with randomized trials accruing poorly to answer this question. In this study, we used the SEER database to assess the impact of initial RP and RT on survival outcomes for localized Gleason score 8-10 prostate cancer in men under 60 years.We found that upfront surgery demonstrated a significant decrease in prostate cancer-specific and overall mortality versus RT (HR 0.37; 95% CI 0.19 – 0.74; p = 0.005 and HR 0.41; 95% CI 0.24 – 0.70; p = 0.001 respectively) in a multivariate analysis that controlled for age, Gleason score, clinical T-stage, and PSA.
 
Urotoday 2018 BTA Kaplan Meier survival curve radiation vs surgery
Figure 1. Kaplan-Meier survival curve for (A) prostate cancer-specific mortality and (B) overall mortality in patients with localized high-grade prostate cancer treated with initial surgery vs. radiation

Univariate and UroToday Multivariate Cox proportional hazards models
Table 1. Univariate and Multivariate Cox proportional hazards models of prostate cancer-specific mortality for primary treatment with surgery vs. radiation therapy

These improved mortality outcomes by the surgery arm were confirmed using inverse-probability treatment weighting analysis (HR 0.28, 95% CI 0.17 – 0.46, p < 0.001 and HR 0.57, 95% CI 0.43 – 0.76, p < 0.001). We also performed subgroup analyses to compare outcomes of men treated with initial surgery, external beam radiation therapy (EBRT), and combination external beam radiation therapy with brachytherapy (EBRT+BT). We found no significant difference in prostate cancer-specific mortality (HR 0.74, 95% CI 0.26 – 1.86, p = 0.5) between the EBRT and EBRT+BT groups, but EBRT+BT was associated with reduced overall mortality versus EBRT alone (HR 0.40, 95% CI 0.15 – 0.89, p = 0.02). Comparison of EBRT+BT and RP groups did not show any significant difference in prostate cancer-specific and overall mortality (HR 0.41, 95% CI 0.13 – 1.65, p = 0.2 and HR 0.96, 95% CI 0.31 – 4.10, p = 0.9).

Our study represents a contemporary source of evidence comparing survival outcomes in RP vs RT for a younger cohort. Due to its retrospective nature and reliance on a cancer registry, further prospective studies are needed to confirm these results.

A few noteworthy points are worth mentioning. First, our analysis showed that EBRT+BT was superior to EBRT alone for overall mortality but not cancer-specific mortality in our analysis. Recent data has shown that brachytherapy provides benefit in terms of disease recurrence. The ASCENDE-RT trial, which compared dose-escalated EBRT vs EBRT with low-dose rate brachytherapy boost in high-risk prostate cancer, showed that men treated with EBRT alone were twice as likely to experience a biochemical recurrence than those treated with EBRT+BT.2 In addition, multiple non-comparative series have reported favorable outcomes with brachytherapy boost.3 However, there are currently no randomized trials comparing survival outcomes of brachytherapy boost with contemporary dose-escalated EBRT.3 Second, we found no significant differences in survival outcomes between surgery and EBRT+BT. This is in contrast to a recent multi-institutional observational study by Kishan et al. with Gleason 9-10 cancer, which demonstrated that men treated with EBRT+BT had lower prostate cancer-specific and all-cause mortality than both surgery and EBRT groups at 7.5 years of follow-up.4

In our study, we acknowledge that splitting the RT arm into an EBRT and EBRT+BT group may not be sufficiently powered for a comparison between EBRT+BT and RP, as our EBRT+BT group made up 8.3% of our total sample size. Despite this limitation, without evidence from a randomized trial, it is still uncertain whether EBRT+BT will show improved outcomes compared to surgery. Until prospective randomized trials are completed to confirm the long-term outcomes of these treatment approaches, further observational studies should be pursued to elucidate the existing data.  

Written By: Hubert Huang and  Mohummad Minhaj Siddiqui M.D., Division of Urology, Department of Surgery, University of Maryland Medical Center, Baltimore, Maryland

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References:
1. Huang H, Muscatelli S, Naslund M et al: Evaluation of Cancer-Specific Mortality with Surgery Versus Radiation as Primary Therapy for Localized High-Grade Prostate Cancer in Men Younger than 60 Years Old. J Urol 2018. 
2. Morris WJ, Tyldesley S, Rodda S et al: Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer. Int J Radiat Oncol Biol Phys 2017; 98: 275.
3. Mendez LC, Morton GC: High dose-rate brachytherapy in the treatment of prostate cancer. Transl Androl Urol 2018; 7: 357.
4. Kishan AU, Cook RR, Ciezki JP et al: Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer. JAMA 2018; 319: 896.