EURURO Vol. 71 No. 5

767 844

1. Introduction
Nearly 15% of the 238 590 men diagnosed with prostate
cancer (CaP) in the USA every year have high-risk disease
(defined as clinical T-stage 3, initial prostate-specific
antigen [PSA] > 20 ng/ml, or Gleason score [GS] 8–10)
. The National Comprehensive Cancer Network and
European Association of Urology/European Society for
Radiotherapy & Oncology/International Society for Geriatric
Oncology guidelines for managing high risk CaP suggest that
radical prostatectomy (RP) and external beam radiotherapy
(EBRT) with androgen deprivation therapy (ADT), with or
without a brachytherapy boost (BT), are acceptable options
. However, recently published series comparing out-
comes of RP versus RT have reached conflicting conclusions
regarding efficacy . Some suggest that RP offers
superior local control and allows tailored adjuvant therapy.
Others feel these comparative series are biased because of
the use of anachronistic EBRT treatment strategies, an
inability to properly adjust for important confounders such
as age and disease burden, and an imbalance using salvage
therapies Emerging data indeed suggest that dose-
escalation affords increased survival for patients with high-
risk CaP , and several randomized trials have
demonstrated the superiority of long-term ADT .
The aforementioned studies included all high-risk CaP
patients, though this group is heterogeneous. Specifically,
the GS is the most important prognostic factor and
evidence suggests that patients with GS 9–10 disease have
inferior outcomes—including more frequent biochemical
recurrences (BCRs) and distant metastases (DMs) .
Indeed, the new International Society of Urological Pathol-
ogy grading system separates GS 9–10 disease as a distinct
entity with poorer outcomes . The purpose of this
multi-institutional study was to compare the long-term
outcomes of patients with biopsy GS (bGS) 9–10 CaP treated
with RP, EBRT, or extremely dose-escalated RT (as
represented by EBRT + BT) in the modern era. The EBRT + BT
cohort was chosen as the paradigm for extremely dose-
escalated RT given the availability of long-term outcomes
data. We hypothesized that the combination of extremely
dose-escalated RT and ADT would lead to superior clinical
outcomes in the EBRT + BT cohort.
2. Materials and methods
2.1. Patient population
The study population consisted of 487 consecutively treated men with
bGS 9–10 CaP who were treated at the University of California, Los
Angeles and its affiliated institutions, the California Endocurie Therapy
Center, and Fox Chase Cancer Center between January 2000 and
November 2013. Patients were identified using institutional registries.
Institutional review board approval was obtained for all institutions.
Patients diagnosed before adoption of the 2005 International Society of
Urologic Pathology consensus conference guidelines were included
if they would have been scored as having bGS 9–10 CaP in modern times.
All ADT was pharmacologic, primarily with combined androgen
blockade followed by leuprolide monotherapy. One-hundred-and-
seventy patients had a RP, 230 had definitive EBRT ADT, and 87 had
EBRT + BT ADT. Of the EBRT + BT patients, 84 had high dose rate BT (HDR-
BT) and three had low dose rate BT (LDR-BT).
2.2. Classification of failures and deaths
Patients undergoing RP were classified as experiencing BCRs either
when their postoperative PSA became 0.2 ng/ml or at initiation of
salvage RT (SRT) or salvage ADT. Patients receiving RT were classified
as experiencing a BCR either when their PSA was nadir + 2 ng/ml
or at initiation of local salvage or salvage ADT. Patients were
classified as having DMs when they had imaging evidence of lesions
that were clinically or pathologically diagnosed as metastatic.
Typically, imaging to detect DMs was performed at the time of
BCR or for subsequent PSA increases after an initial BCR. Prostate-
cancer specific mortality (PCSM) was defined based on either clinical
documentation or inclusion of CaP as a primary cause of death on a
death certificate. One-hundred-and-two out of 107 patients who were
deceased at last follow-up (95.3%) had either form of PCSM
determination available.
2.3. Statistical analysis
A two-tailed Student t test was used to evaluate differences in age and
ADT duration between the cohorts, and the Wilcoxon rank-sum test
was used to evaluate differences in initial PSA. Two-tailed chi-square
tests (or Fisher’s exact test) were used to evaluate differences in
categorical variables. Outcomes of interest included BCR-free survival
(BCRFS), DM-free survival (DMFS), cancer-specific survival (CSS), and
overall survival (OS), which were defined by intervals from the end of
treatment to BCR, DM, PCSM, and death, respectively. Follow-up was
defined from the end of local treatment (ie, date of surgery or date of
completion of RT) rather than from diagnosis in order to avoid
introduction of bias stemming from the different lengths of
treatments between cohorts. Kaplan-Meier survival analysis was
used to evaluate outcomes at 5 yr and 10 yr of follow-up. Patients
were censored at the time of the defined outcome or at last follow-up.
The log-rank test was used to compare survival curves at 5 yr and
10 yr. Multivariate Cox regression was used to estimate the hazard
ratios of these outcomes between treatment cohorts, adjusted for
patient age, bGS, clinical T-stage, initial PSA, year of treatment, local
salvage (with time to salvage as a covariate), and systemic salvage
(with time to salvage as a covariate). All analyses were performed
with SAS version 9.4 (SAS Institute, Cary, NC, USA).
Patient summary: While some prostate cancers are slow-growing requiring many years,
sometimes decades, of follow-up in order to compare between radiation and surgery, high-
risk and very aggressive cancers follow a much shorter time course allowing such compar-
isons to be made and updated as treatments, especially radiation, rapidly evolve. We showed
that radiation-based treatments and surgery, with contemporary standards, offer equivalent
survival for patients with very aggressive cancers (defined as Gleason score 9–10). Extremely-
dose escalated radiotherapy with short-course androgen deprivation therapy offered the
least risk of developing metastases, and equivalent long term survival.
# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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