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Management of localized or locally advanced prostate cancer

Updated 2016 Jan 18 07:39:00 AM: addition of chemotherapy with docetaxel plus
estramustine to ADT may increase relapse-free survival in men with treatment-naive high-risk
localized prostate cancer (Lancet Oncol 2015 Jul) view update Show more updates
Recommendations Editor
Deputy Editor
Allen Shaughnessy, PharmD, M Med Ed, FCCP Kevin R. Loughlin, MD

Related Summaries:
Prostate cancer screening
Prostate biopsy
Prostate cancer staging and imaging
Management of biochemical relapse of localized prostate cancer
Overview:
risk stratification and decision making
risk stratification based on combination of clinical characteristics and laboratory tests
very low risk - prostate-specific antigen (PSA) < 10 ng/mL, PSA density < 0.15
ng/mL/g, < 3 positive cores with 50% involvement, Gleason score 6, AND
clinical stage T1c
low risk - PSA < 10 ng/mL AND Gleason score 6 AND clinical stage T1-T2a
intermediate risk - PSA 10-20 ng/mL OR Gleason score 7 OR clinical stage T2b
National Comprehensive Cancer Network (NCCN) and European Association of
Urology (EAU) also consider T2c as intermediate risk
high risk - PSA > 20 ng/mL OR Gleason score 8-10 OR clinical stage T3-T4
National Institute for Health and Care Excellence (NICE) also considers T2c as
high risk
NCCN and EAU consider T3b-T4 as very high risk
risk stratification and decision making tools aim to help patients make informed choices
about treatments to pursue
symptom scales and performance status tools also help decision making for treatment
and assess response to treatment
conservative management options
watchful waiting - for men with life expectancy < 10 years and with very low, low, or
intermediate risk (NCCN Category 2A) or those unwilling to accept side effects of active
treatment (EAU Grade A, Level 1b)
active surveillance - for men with life expectancy 10 years and very low or low risk
(NCCN Category 2A, EAU Grade A, Level 2a) and those with intermediate risk who want
to avoid immediate radical therapy
radical prostatectomy
consider life expectancy in decision to have surgical resection
indications
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men with low or intermediate risk and life expectancy 10 years (NCCN
Category 2A, EAU Grade A, Level 1b)
men with high risk (NCCN Category 2A)
select men with very high risk (NCCN Category 2A, EAU Grade C, Level 3)
technique may be open (radical or perineal) or minimally invasive (laparoscopic or
robot-assisted laparoscopic)
possible complications include urinary incontinence, erectile dysfunction, alteration
of sexual experience (including loss of sexual function), potential loss of ejaculation
and fertility, and bladder neck contracture
pelvic lymph node dissection should be performed in high risk or very high risk or
lower risk categories if predicted risk of lymph node metastases 2%-5%
radiation therapy
initial (definitive) treatment
men with very low risk and life expectancy 20 years may have external beam
radiation therapy (EBRT) (NCCN Category 2A)
men with low risk and life expectancy 10 years may have EBRT (NCCN
Category 2A)
men with intermediate risk may have EBRT, with or without 4-6 months
androgen deprivation therapy (ADT) and with or without brachytherapy or
option of brachytherapy alone for men with favorable prognostic factors (NCCN
Category 2A)
men with high risk or very high risk, options include EBRT plus 2-3 years ADT
(NCCN Category 1) or an EBRT plus brachytherapy and with or without 2-3
years ADT (NCCN Category 2A)
adjuvant treatment - EBRT immediately after radical prostatectomy (or within 1
year) for men with pathologic stage T3, positive surgical margins, Gleason 8-10,
seminal vesicle invasion, prostate-specific antigen (PSA) doubling times < 9 months,
or extracapsular invasion (NCCN Category 2A, EAU Grade A, Level 1b)
focal therapy not recommended as therapeutic alternative outside of clinical trial (EAU
Grade A)
hormone therapy (androgen deprivation therapy [ADT])
options include surgical castration or medical castration
ADT before radical prostatectomy not recommended
primary ADT not recommended except in men not eligible for definitive therapy
adjuvant ADT (before, during, and/or after EBRT) should be considered for men
with
intermediate-risk cancer, options include
EBRT, with or without 4-6 months ADT and with or without brachytherapy
(NCCN Category 2A)
short-term ADT before and during EBRT (EAU Grade A, Level 1b)
localized high-risk cancer, options include
EBRT plus 2-3 years ADT (NCCN Category 1)
EBRT plus brachytherapy, with or without 2-3 years ADT (NCCN Category
2A)
long-term ADT before and during EBRT (EAU Grade B, Level 2a)
very high-risk cancer, options include
EBRT plus 2-3 years ADT (NCCN Category 1, EAU Grade A, Level 1b)
EBRT plus brachytherapy with or without 2-3 years ADT (NCCN Category
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2A)
ADT for patients not eligible for definitive therapy (NCCN Category 2A)
comparative efficacy
radical prostatectomy may reduce prostate cancer mortality and might reduce
overall mortality compared to watchful waiting in patients with symptomatic stage
T2 prostate cancer (level 2 [mid-level] evidence)
radical prostatectomy may not reduce all-cause mortality compared to watchful
waiting in men with asymptomatic stage T1c prostate cancer, but may have benefit
for men with PSA > 10 ng/mL (level 2 [mid-level] evidence)
brachytherapy associated with improved health-related quality of life compared to
radical prostatectomy in men with low-risk prostate cancer (level 2 [mid-level]
evidence)
brachytherapy appears to have similar rate of biochemical failure in patients with
localized prostate cancer, but brachytherapy may have increased biochemical
recurrence compared to radical prostatectomy in men with intermediate- or
high-risk prostate cancer (level 3 [lacking direct] evidence)
external beam radiation therapy and radical prostatectomy appear to have similar
biochemical recurrence-free survival in men with low- to intermediate-risk localized
prostate cancer (level 3 [lacking direct] evidence)
external beam radiation therapy plus androgen deprivation therapy associated with
reduced biochemical failure compared to radical prostatectomy in men with high-risk
localized prostate cancer (level 3 [lacking direct] evidence)
limited data available comparing radiation therapy, active surveillance, and focal
therapies
follow-up after treatment involves regular monitoring such as
measure PSA at least every 6-12 months for first 5 years, then once every year
(unless if high risk of recurrence, then every 3 months) (NCCN Category 2A)
perform digital rectal exam (DRE) every year (may be unnecessary if PSA
undetectable) (NCCN Category 2A)
Risk Stratification and Decision Making
Risk stratification:
relative survival rate for patients with localized prostate cancer is 99.5% at 10 years
(Surveillance, Epidemiology, and End Results (SEER) Survival Monograph 2007 PDF)
initial risk stratification may involve several clinical characteristics or test results, including
prostate-specific antigen (PSA) levels, number of positive cores, and clinical tumor stage (1,
2)
risk stratification systems for local or locally advanced prostate cancer

National Comprehensive Cancer Network (NCCN)
very low risk if all of the following
prostate-specific antigen (PSA) < 10 ng/mL (10 mcg/L) and PSA density <
0.15 ng/mL/g
< 3 positive cores and 50% prostate cancer involvement in any core
Gleason score 6
clinical stage T1c
low risk - PSA < 10 ng/mL (10 mcg/L) AND Gleason score 6 AND clinical stage
T1-T2a
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intermediate risk - PSA 10-20 ng/mL (10-20 mcg/L) OR Gleason score 7 OR

clinical stage T2b-T2c
high risk - PSA > 20 ng/mL (20 mcg/L) OR Gleason score 8-10 OR clinical stage
T3a
very high risk - primary Gleason pattern 5 OR > 4 cores with Gleason score 8-10
AND clinical stage T3b-T4 (locally advanced)
Reference - NCCN 2014 Oct from NCCN website (free registration required)
European Association of Urology (EAU)
low risk - PSA < 10 ng/mL (10 mcg/L) AND Gleason score < 7 AND clinical stage
T1-T2a
clinical stage T2b
high risk
localized - PSA > 20 ng/mL (20 mcg/L) OR Gleason score > 7 OR clinical
stage T2c
locally advanced - clinical stage T3-T4 with any PSA or Gleason score OR
lymph node positive
Reference - EAU 2015 Mar PDF
National Institute for Health and Care Excellence (NICE)
low risk - PSA < 10 ng/mL (10 mcg/L) AND Gleason score 6 AND clinical stage
T1-T2a
clinical stage T2b
high risk - PSA > 20 ng/mL (20 mcg/L) OR Gleason score 8-10 OR clinical stage
T2c
Reference - NICE 2014 Jan:CG175 PDF
nomogram or Partin tables may also be used to identify patients with low risk of lymph
node metastases(1)
see Prostate cancer staging and imaging for additional information
Identification of clinically insignificant prostate cancer:
among 561 patients > 65 years old who died and had premortem diagnosis of prostate
cancer, 53% died WITH prostate cancer and 42% died FROM prostate cancer (J Clin
Epidemiol 2004 Jul;57(7):721)
Epstein criteria for clinically insignificant prostate cancer
clinical stage T1c
biopsy Gleason score 6
presence of disease in < 3 biopsy cores
50% prostate cancer involvement in any biopsy core
prostate-specific antigen (PSA) density < 0.1 ng/mL/g (or PSA density 0.1-0.15
ng/mL/g with low-to-intermediate grade cancer < 3 mm found in only 1 biopsy core)
Reference - JAMA 1994 Feb 2;271(5):368
Epstein criteria may be more accurate for predicting organ-confined disease
than for clinically insignificant prostate cancer (level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review of 6 studies validating Epstein criteria for prediction of insignificant
prostate cancer in 979 patients
overall analysis limited by substantial clinical heterogeneity
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clinical heterogeneity due to differences in number of biopsies taken,

interpretation of biopsies, calculations of PSA densities, and surgical methods
no studies used Epstein criteria in complete accordance with original definitions,
and application of Epstein criteria varies across studies
Gleason scoring system was modified in 2005, 5 studies published after 2005 did
not specify Gleason scoring system used
reference standards for clinically insignificant disease were not explained
sensitivities and specificities were not reported
range of overall diagnostic accuracy of Epstein criteria
80%-96.9% for predicting organ-confined prostate cancer
37%-84% for predicting insignificant prostate cancer
Reference - BJU Int 2011 Aug;108(4):518
EBSCOhost Full Text
8% of patients meeting Epstein criteria may have prostate cancer not confined
to prostate
based on 2 cohort studies without clinical outcomes
366 patients who had radical prostatectomy and met Epstein criteria for clinically
insignificant prostate cancer were evaluated
88 (24%) had Gleason 7-10 prostate cancer at radical prostatectomy
30 (8.2%) had non-organ-confined prostate cancer
Reference - Eur Urol 2008 Dec;54(6):1306
237 men who had radical prostatectomy and met Epstein criteria for clinically
insignificant prostate cancer were evaluated
8.4% had non-organ-confined prostate cancer
modification of Epstein biopsy criteria did not improve detection of non-organconfined prostate cancer
Reference - Cancer 2004 Nov 1;101(9):2001 full-text
11%-33% of patients appear to be incorrectly classified by 16 currently used
low-risk or active surveillance criteria (level 2 [mid-level] evidence)
based on retrospective cohort study with unclear blinding
1,070 patients with prostate cancer were assessed with 16 currently used definitions
of low-risk or active surveillance prostate cancer
77 had insignificant cancers and 578 had unfavorable histopathological criteria
proportion of individuals who were selected by specific criterion and were proven by
final pathology to have concordant Gleason grading, pT2, N0, or Nx status ranged
from 67.7% to 89.1%
Reference - BJU Int 2012 Sep;110(6 Pt B):E172
EBSCOhost Full Text, editorial
can be found in BJU Int 2012 Sep;110(6 Pt B):E182
EBSCOhost Full Text
Decision making:
multiple oncology organizations recommend against initiating treatment in patients with
low-risk prostate cancer without first discussing active surveillance, including
Canadian Oncology Societies (Choosing Wisely Canada 2014 Oct 29)
American Society for Radiation Oncology (Choosing Wisely 2014 Sep 15)
prostate cancer risk tools for men contemplating various treatments for local or locally
advanced prostate cancer include
Partin tables to predict risk of extraprostatic extension, seminal vesicle involvement,
and lymph node involvement
pretreatment nomogram for predicting biochemical recurrence after radical
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prostatectomy or external beam radiation therapy (J Clin Oncol 1999

Jan;17(1):168 full-text)
pretreatment nomogram for predicting the presence of small, moderately
differentiated, confined tumors (J Urol 2003 Nov;170(5):1792)
pretreatment nomograms for predicting risk of progression after radical prostatectomy
or brachytherapy (Memorial Sloan Kettering Cancer Center Pretreatment)
nomogram predicting risk of biochemical recurrence in men who have had radical
prostatectomy (Memorial Sloan Kettering Cancer Center Post-Radical Prostatectomy)
nomogram predicting treatment success of salvage radiation therapy in men having
recurrence after radical prostatectomy (Memorial Sloan Kettering Cancer Center
Salvage Radiation Therapy)
patient decision aids have limited evidence for guiding treatment decisions in
men with low-risk prostate cancer (level 2 [mid-level] evidence)
based on systematic review with incomplete reporting of trial quality
systematic review of 3 randomized trials, 10 nonrandomized controlled trials
evaluating patient decision aids for patients with low-risk prostate cancer
3 randomized controlled trials with 494 patients included in review were rated poor or
good quality but quality assessment not reported
meta-analysis could not be performed due to clinical heterogeneity
authors could draw no conclusions due to differences in treatment options offered,
types of decision aids, and assessed outcomes
Reference - CA Cancer J Clin 2009 Nov-Dec;59(6):379 full-text
nomogram using findings from multiparametric magnetic resonance imaging
might help rule out candidates for active surveillance (level 2 [mid-level]
evidence)
based on prognostic cohort study without validation
85 men (mean age 60 years) with prostate cancer had baseline multiparametric
magnetic resonance imaging (MRI) and those with lesions that could be biopsied had
12-core transrectal ultrasound (TRUS) biopsy and target MRI/ultrasound fusion biopsy
all men were considered initial candidates for active surveillance based on (PSA)
density 0.15, 2 positive biopsy cores, 50% tumor in any core, Gleason score
6, and clinical stage T1c
60 men (70.6%) remained eligible for continued active surveillance based on biopsy
results
nomogram derived using MRI findings significantly associated with continued active
surveillance
number of lesions
highest MRI lesion suspicion (low, moderate, or high)
ratio of total lesion volume to whole prostate volume
diagnostic performance of nomogram for predicting men likely to remain candidates
for active surveillance
positive predictive value range 30%-70%
negative predictive value range 80%-90%
Reference - Cancer 2013 Sep 15;119(18):3359
Symptom scales and performance status:
International Prostate Symptom Score (IPSS) questionnaire
score range 0-35
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symptom category scores

mild 7
moderate 8-19
severe 20-35
performance status evaluation to aid treatment decisions
Eastern Cooperative Oncology Group (ECOG) or World Health Organization
(WHO) Performance Status Scale:
Grade
Criteria
Fully active, able to carry on all predisease performance without restriction
Restricted in physically strenuous activity but ambulatory and able to carry out
work of a light or sedentary nature (such as light house work or office work)
Ambulatory and capable of all self-care but unable to carry out any work
activities; up and about > 50% of waking hours
Capable of only limited self-care, confined to bed or chair > 50% of waking
hours
Completely disabled; cannot carry on any self-care; totally confined to bed or

chair
Dead
Reference - Am J Clin Oncol 1982 Dec;5(6):649.
Karnofsky Performance Status Scale:

Definitions
Rating
Criteria
Able to carry on normal

activity; no special care
needed
100%
Normal, no complaints, no evidence of disease
90%
Able to carry on normal activity; minor signs

or symptoms of disease
80%
Normal activity with effort; some signs or

symptoms of disease
70%
Cares for self; unable to carry on normal
Unable to work; able to live

at home and care for most
personal needs; varying
amount of assistance needed
Unable to care for self;
activity or to do active work

60%
Requires occasional assistance, but is able to

care for most personal needs
50%
Requires considerable assistance and frequent

medical care
40%
Disabled; requires special care and assistance
References - J Gerontol 1991 Jul;46(4):M139, Cancer 1994 Apr 15;73(8):2087.
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Definitions
requires equivalent of
institutional or hospital care;
disease may be progressing
rapidly
Rating
Criteria
30%
Severely disabled; hospital admission is

indicated although death not imminent
20%
Very sick; hospital admission necessary; active

supportive treatment necessary
10%
Moribund; fatal processes progressing rapidly
0%
Dead
References - J Gerontol 1991 Jul;46(4):M139, Cancer 1994 Apr 15;73(8):2087.

Conservative Management
General information:
incidence of small, localized, well-differentiated prostate cancer increasing due to screening
with prostate-specific antigen (PSA), but many men with localized prostate cancer may not
benefit from curative treatment(3)
about 45% of men with prostate cancer detected by PSA may be candidates for
conservative management(3)
watchful waiting and active surveillance are 2 conservative management options that may
be considered for patients who are unlikely to benefit from curative treatments (1, 2, 3)
elderly men with prostate cancer and Gleason score 2-4 receiving conservative
management appear to have similar life expectancy as general population (level
2 [mid-level] evidence)
based on retrospective cohort study
451 men aged 65-75 years with prostate cancer diagnosed by palpable nodule or
prostatic hypertrophy (before PSA testing was available) were analyzed for
age-adjusted survival after mean follow-up of 15.5 years
compared to general population
no significant difference in life expectancy for men with Gleason score 2-4
maximum estimated loss of life expectancy
4-5 years for men with Gleason score 5-7
6-8 years for men with Gleason score 8-10
Reference - JAMA 1995 Aug 23-30;274(8):626, commentary can be found in JAMA
1996 Jan 3;275(1):31, commentary can be found in JAMA 1996 Jan 3;275(1):31
Watchful waiting:
watchful waiting (also called deferred treatment or symptom-guided treatment) involves
observation that may or may not involve routine patient contact
palliative treatment deferred until development of local or systemic progression with
or without symptoms
once symptoms develop, patient treated palliatively with transurethral resection of
prostate (TURP) or other procedures for urinary tract obstruction, and hormonal
therapy or radiation therapy for palliation of metastatic lesions
indications for patients with local or locally advanced prostate cancer
men with life expectancy < 10 years and very low-, low-, or intermediate-risk
according to risk stratification (NCCN Category 2A)(1)
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men not eligible for local curative treatment and those with short life expectancy (EAU
Grade A, Level 1b)(3)
base decision to begin noncurative treatment on symptoms and disease progression (EAU
Grade B)(3)
monitor prostate-specific antigen (PSA) level at least annually and offer isotope bone scans
to asymptomatic men at high risk of developing bone complications (2)
prostate cancer-specific mortality for T1 or T2 prostate cancer reported to be
between 8%-26% following watchful waiting for 6 months (level 2 [mid-level]
evidence)
based on prognostic cohort study
14,516 men 65 years old diagnosed with stage T1 or T2 prostate cancer in 1992 to
2002 managed without curative treatment (surgery or radiation) for 6 months were
followed for median 8.3 years
76% had Gleason scores between 5 and 7
10-year prostate cancer-specific mortality by Gleason score
8.3% for Gleason 2-4
10-year mortality due to other cause by Gleason score
consistent results after excluding men receiving curative treatment > 6 months after
diagnosis
Reference - JAMA 2009 Sep 16;302(11):1202 full-text, commentary can be found in
JAMA 2010 Jan 6;303(1):33
Active surveillance:
active surveillance (also called active monitoring) involves active management of patient
with regularly scheduled follow-up(3)
active decision not to treat immediately
patient remains under close surveillance, with curative treatment triggered by
predefined thresholds
indications for patients with local or locally advanced prostate cancer
life expectancy 10 years and very low risk or low risk according to NCCN risk
stratification (NCCN Category 2A)(1)
life expectancy > 10 years and lowest risk of cancer progression (EAU Grade A, Level
2a), such as those with(3)
clinical stage T1-T2
prostate-specific antigen (PSA) 10 ng/mL (10 mcg/L)
biopsy Gleason score 6 (at least 10 cores)
2 positive biopsies
minimal biopsy core involvement ( 50% cancer per biopsy)
patient desire to avoid immediate radical prostatectomy or radical radiation therapy
with intermediate risk, or patients with low risk according to NICE risk stratification(2)
not recommended for men with life expectancy > 10 years and intermediate risk or high
risk according to NCCN risk stratification (NCCN Category 1)
protocol and schedule recommendations
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National Comprehensive Cancer Network (NCCN) recommends active surveillance

schedule intervals, unless additional assessments are clinically indicated (NCCN
Category 2A)(1)
PSA level 6 months
digital rectal exam (DRE) 12 months
repeat prostate biopsy 12 months
European Association of Urology (EAU) considerations for active surveillance
monitoring(3)
follow-up based on DRE, PSA, and repeated biopsies
optimal timing for follow-up still unclear (yearly or every 2 years) (EAU Grade A,
Level 2a)
active treatment may be offered to patients with a change in Gleason score, an
increase in number of positive biopsy cores, an increase in biopsy core
involvement, an increase in T-stage, or on patient request
multiparametric magnetic resonance imaging (MRI) at baseline (if not previously
performed)
PSA level every 3-4 months for 1 year, then every 3-6 months for years 2-4, then
every 6 months
monitor PSA kinetics (PSA doubling time and velocity) throughout active
surveillance
digital rectal exam every 6-12 months for 4 years, then every 12 months
multiparametric MRI and/or rebiopsy at any time if clinical or PSA changes
radical treatment should be offered to patients with evidence of disease
progression
decision analysis for active surveillance vs. initial treatment for men with low-risk prostate
cancer based on hypothetical cohorts of 65-year-old men can be found in JAMA 2010 Dec
1;304(21):2373, correction can be found in JAMA 2011 May 11;305(18):1862
in men with low-risk prostate cancer, active surveillance rates appear to be low
189,768 men with biopsy-proven N0/M0 prostate cancer from 2010-2011 United
States National Cancer Data Base evaluated
low-risk disease (defined by Klotz, D'Amico, and modified Epstein criteria) considered
eligible for active surveillance management
proportion of men with NO/MO prostate cancer eligible for active surveillance 39.8%
by Klotz criteria, 28.5% by D'Amico criteria, and 10.7% by modified Epstein criteria
proportion of eligible men who received active surveillance 6.5% (Klotz criteria), 7.4%
(D'Amico criteria), 12.1% (modified Epstein criteria)
Reference - JAMA Intern Med 2015 Sep 1;175(9):1569
in men with low- or intermediate-risk prostate cancer receiving active
surveillance, 10-year prostate cancer specific survival reported to be
96%-100%
based on systematic review with limited search
systematic review of 10 cohort studies evaluating active surveillance in 3,550 men
with low- or intermediate-risk prostate cancer
10-year prostate cancer specific survival 96%-100%
Reference - J Surg Oncol 2014 Jun;109(8):830
in men with low-risk prostate cancer receiving active surveillance, 10-year
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prostate cancer mortality reported to be < 3%

450 patients with low-risk prostate cancer managed with active surveillance until
PSA or histologic progression
low-risk criteria included
Gleason score 6 and PSA 10 ng/mL
age > 70 years with Gleason 3 + 4 or PSA 15 ng/mL
overall survival 78.6% during median 6.8-year follow-up
prostate cancer-specific survival
99.7% at 5 years
97.2% at 10 years
Reference - J Clin Oncol 2010 Jan 1;28(1):126 full-text, commentary can be
found in J Clin Oncol 2010 Jun 1;28(16):e265, Eur Urol 2010 Jul;58(1):179
in men with prostate cancer receiving active surveillance, low-risk and
intermediate-risk categories associated with similar 10-year disease-specific
survival
based on prospective cohort study
509 men (median age 67.6 years) screened for prostate cancer were managed with
active surveillance and followed for median 7.4 years
381 men (75%) had low-risk prostate cancer (stage T1/T2, PSA 10 ng/mL, PSA
density < 0.2 ng/mL/mL, Gleason score 6, and 2 positive biopsy cores)
128 men (25%) had intermediate-risk prostate cancer (PSA 10-20 ng/mL,
Gleason score = 7, or 3 positive biopsy cores)
method and timing of follow-up treatment was at discretion of treating physician
deferred treatment (after median 2.6 years) in
39.9% of low-risk patients
53.9% of intermediate-risk patients
calculated 10-year outcomes comparing low-risk patients vs. intermediate-risk patients
disease-specific survival 99.1% vs. 96.1% (not significant)
overall survival 79% vs. 64.5% (p = 0.003)
active therapy-free survival 49.7% vs. 30.3% (p = 0.005)
Reference - BJU Int 2012 Dec;110(11):1672
EBSCOhost Full Text
active surveillance reported to not decrease quality of life in men with low-risk
prostate cancer (level 3 [lacking direct] evidence)
based on case series
124 patients in Finland with low-risk localized prostate cancer having active
surveillance were followed for 1 year
60% completed baseline and 1-year follow-up questionnaires
no significant differences at 1 year compared to baseline in mental and physical
health-related quality of life, urinary function, or erectile function
Reference - BJU Int 2012 Jun;109(11):1614
EBSCOhost Full Text
prostate-specific antigen doubling time not associated with progression on
biopsy in patients with low-risk prostate cancer being managed with active
surveillance
250 men with low-risk prostate cancer based on risk stratification being managed with
active surveillance had PSA measured before each surveillance biopsy and were
followed for median 3 years
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26% had progression on biopsy (defined as any change from diagnostic biopsy)
PSA doubling time not associated with biopsy progression using predictive accuracy of
models analysis
PSA velocity weakly associated with biopsy progression
Reference - BJU Int 2013 Mar;111(3):396
EBSCOhost Full Text
Radical Prostatectomy
involves removal of entire prostate gland and resectioning of seminal vesicles, may include
bilateral pelvic lymph node dissection(3)
life expectancy should be considered as part of risk stratification and decision making for
surgical treatment(3)
goal in patients with life expectancy 10 years is eradication of disease without
causing incontinence or (when possible) impotence
no age threshold at which point surgery is denied based on age alone
prostatectomy primarily used for men with 10 years life expectancy when tumor is
clinically confined to prostate(1)
some patients with locally advanced disease may also benefit from prostatectomy
surgery from high-volume surgeons in high-volume centers may have better outcomes
10-year biochemical-free progression rate for men having radical prostatectomy and with (1,
3)
high- or very high-risk disease reported to range 24% to 39%, depending on

prognostic factors, such as clinical stage, prostate-specific antigen (PSA) level, and
Gleason score at biopsy
locally advanced disease reported to range from 43% to 51%
in men receiving radical prostatectomy, higher surgical volumes or experience
associated with lower recurrence and complication rates (level 2 [mid-level]
evidence)
based on 3 cohort studies
7,765 patients treated with radical retropubic prostatectomy by one of 72 surgeons at
4 United States academic medical centers
greater surgeon experience (greater number of prior surgeries) associated with
lower risk of prostate cancer recurrence (p < 0.001)
decreasing recurrence risk with increasing number of prior radical prostatectomies
did not plateau until about 250 prior radical prostatectomies
5-year recurrence rates
10.7% (95% CI 7.1%-15.9%) for patients treated by surgeons performing
250 prior radical prostatectomies
17.9% (95% CI 12.1%-25.6%) for patients treated by surgeons performing
10 prior radical prostatectomies
absolute risk difference 7.2% (95% CI 4.6%-10.1%)
Reference - J Natl Cancer Inst 2007 Aug 1;99(15):1171 full-text
Medicare claims records of 11,522 men > 65 years old who had prostatectomy in
1992-1996 analyzed by hospital volume and surgeon volume (estimated by quartiles
of patient cohort)
comparing very high-volume hospitals (114-252 patients per hospital over 5
years) vs. low-volume hospitals (1-33 patients per hospital over 5 years)
incidence of potentially life-threatening events during 30 days after surgery
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27% vs. 32% (p = 0.03)

incidence of late urinary complications (bladder-neck obstruction, urethral or
ureteral strictures, intestinal or vesical fistulas, pelvic abscess, or treatment
for incontinence) 20% vs. 28% (p < 0.001)
comparing very high-volume surgeons (33-121 patients per surgeon over 5 years)
vs. low-volume surgeons (1-10 patients per surgeon over 5 years)
incidence of potentially life-threatening events during 30 days after surgery
26% vs. 32% (p < 0.001)
incidence of late urinary complications (bladder-neck obstruction, urethral or
ureteral strictures, intestinal or vesical fistulas, pelvic abscess, or treatment
for incontinence) 20% vs. 28% (p < 0.001)
incidence of incontinence > 1 year after surgery16% vs. 20% (p = 0.04)
Reference - N Engl J Med 2002 Apr 11;346(15);1138, editorial can be found in N
Engl J Med 2002 Apr 11;346(15):1161, commentary can be found in N Engl J Med
2002 Aug 29;347(9):693
Medicare claims data from 2,292 men > 65 years old who had radical prostatectomy
in 1997-1998
comparing high-volume surgeons ( 40 surgeries/year) vs. low-volume surgeons
(< 40 surgeries/year)
complication rate 11.8% vs. 21.9% (p < 0.01)
length of hospital stay 4.1 days vs. 5.2 days (p = 0.03)
Reference - J Clin Oncol 2003 Feb 1;21(3):401 full-text, editorial can be found in
J Clin Oncol 2003 Feb 1;21(3):393, commentary can be found in Eur Urol 2010
Feb;57(2):355
Indications for prostatectomy:
National Comprehensive Cancer Network (NCCN) recommendations based on NCCN risk
stratification(1)
very low risk and life expectancy 20 years (NCCN Category 2A)
low or intermediate risk and life expectancy 10 years (NCCN Category 2A)
high risk (NCCN Category 2A)
very high risk in selected patients with no fixation to adjacent organs (NCCN Category
2A)
European Association of Urology (EAU) recommendations based on EAU risk stratification(3)
indicated in men with low or intermediate risk and life-expectancy > 10 years (EAU
Grade A, Level 1b)
indicated in men with high-risk localized prostate cancer and life-expectancy > 10
years as part of multimodal treatment approach(EAU Grade A, Level 2a)
option for selected men with locally advanced (T3a) disease and life-expectancy > 10
years as part of multimodal treatment approach (EAU Grade B, Level 2b)
option for highly selected men with locally advanced (Tcb-T3 N0 or any T N1) disease
as part of multimodal treatment approach (EAU Grade C, Level 3)
National Institute for Health and Care Excellence (NICE) recommendations based on NICE
risk stratification(2)
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radical treatment recommended for men with localized prostate cancer receiving
active surveillance who have evidence of disease progression
radical prostatectomy or radiation therapy recommended for men with intermediate
risk, or men with high risk and realistic prospect of long-term disease control
Prostatectomy techniques:
possible approaches(1, 3)
open - radical retropubic or perineal
minimally invasive - laparoscopic radical prostatectomy (LRP) or robot-assisted
laparoscopic prostatectomy (RALP)
robot-assisted prostatectomy appears to have similar safety and efficacy
outcomes compared to retropubic radical prostatectomy or laparoscopic radical
prostatectomy, and robot-assisted prostatectomy may result in reduced need
for transfusion (level 2 [mid-level] evidence)
based on 3 systematic reviews of mostly observational studies
comparing robotic radical prostatectomy and retropubic radical prostatectomy
robot-assisted radical prostatectomy associated with reduced
need for transfusion in analysis of 14 studies with 5,289 men (odds ratio
7.55, 95% CI 3.65-15.64) (Eur Urol 2012 p. 431)
blood loss in analysis of 4 studies with 809 men (weighted mean difference
582.77 mL, 95% CI 435.25-730.29 mL) (Eur Urol 2012 p. 431)
no significant differences in
operative time in analysis of 6 studies with 781 men (Eur Urol 2012 p. 431)
complication rate in analysis of 12 studies with 5,288 men (Eur Urol 2012 p.
431)
positive surgical margin rates in analysis of 18 studies with 8,158 men (Eur
Urol 2012 p. 382)
biochemical recurrence-free survival in analysis of 5 studies 4,781 men (Eur
Urol 2012 p. 382)
comparing robotic radical prostatectomy and laparoscopic radical prostatectomy
no significant differences in risk of
urinary incontinence at 12 months in analysis of 10 studies (HTA 2012)
infection in analysis of 12 studies (HTA 2012)
operative time in analysis of 4 studies with 1,182 men (Eur Urol 2012 p. 431)
complication rate in analysis of 8 studies with 1,720 men (Eur Urol 2012 p.
431)
biochemical recurrence-free survival in analysis of 2 studies with 1,212 men
(Eur Urol 2012 p. 382)
inconsistent results in terms of risk of positive surgical margin rates
robotic prostatectomy associated with reduced risk of postsurgical positive
margins in analysis of 37 studies (odds ratio 0.69, 95% CI 0.51-0.96) (HTA
2012)
no significant difference in positive surgical margin rates in analysis of 11
studies with 2,514 men (Eur Urol 2012 p. 382)
inconsistent results in relation to blood loss
no significant difference in risk of blood loss in analysis of 4 studies with
1,182 men (Eur Urol 2012 p. 431)
robot-assisted radical prostatectomy associated with reduced need for
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transfusion in analysis of 8 studies with 1,780 men (odds ratio 2.56, 95% CI
1.32-4.96) (Eur Urol 2012 p. 431)
robotic prostatectomy associated with reduced risk of organ injury in analysis of
17 studies (odds ratio 0.16, 95% CI 0.03-0.76) (HTA 2012)
References
HTA 2012 - systematic review and network meta-analysis of 1 randomized trial
and 57 observational studies evaluating robotic radical prostatectomy and
laparoscopic radical prostatectomy in 19,064 men with clinically localized prostate
cancer (Health Technol Assess 2012;16(41):1 full-text)
Eur Urol 2012 p. 431 - systematic review of 111 observational studies evaluating
surgical approaches for short-term and long-term outcomes in men with prostate
cancer (Eur Urol 2012 Sep;62(3):431), commentary can be found in Eur Urol
2013 Mar;63(3):e38
Eur Urol 2012 p. 382 - systematic review of 129 observational studies evaluating
different techniques for robot-assisted radical prostatectomy or comparing robotassisted radical prostatectomy to other surgical approaches for short-term and
long-term outcomes (Eur Urol 2012 Sep;62(3):382), commentary can be found in
Eur Urol 2013 Feb;63(2):e27
consistent results for safety and efficacy outcomes in more recent cohort study,
conducted after more widespread dissemination of robot-assisted radical
prostatectomy (J Clin Oncol 2014 May 10;32(14):1419)
robot-assisted laparoscopic radical prostatectomy might reduce risk of
postoperative erectile dysfunction but not urinary incontinence compared to
open retropubic radical prostatectomy (level 2 [mid-level] evidence)
based on nonrandomized trial
2,625 men (median age 63 years) with prostate cancer in Sweden were assigned to
robot-assisted laparoscopic radical prostatectomy vs. open retropubic radical
prostatectomy and followed for 12 months
70% had robot-assisted laparoscopic prostatectomy and 30% had open prostatectomy
93% were evaluable after surgery and included in analyses
patient-reported erectile dysfunction in 75% with robot-assisted laparoscopic
prostatectomy vs. 79% with open prostatectomy (adjusted odds ratio 0.75, 95% CI
0.58-0.96, NNT 25), but analyses not adjusted for treatment of erectile dysfunction
no significant differences in patient-reported urinary incontinence (assessed by
frequency of pad change, leakage, and/or urinary discomfort) or rate of positive
surgical margins
Reference - Eur Urol 2015 Aug;68(2):216 full-text, editorial can be found in Eur Urol
2015 Aug;68(2):226
open and laparoscopic radical prostatectomy appear similarly effective for
pathological and functional outcomes (level 2 [mid-level] evidence)
339 men with localized prostate cancer who had radical prostatectomy without
neoadjuvant hormonal therapy (50% with open retropubic prostatectomy and 50%
with laparoscopic prostatectomy) were assessed
mean follow-up 24 months
comparing open prostatectomy vs. laparoscopic prostatectomy
overall positive surgical margins in 22.2% vs. 26.5% (not significant)
positive surgical margins in 10.5% vs. 17.5% (p = 0.006, NNT 15) in subgroup of
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34 patients with organ-confined disease

no significant differences in rates of urinary incontinence or erectile dysfunction
Reference - BMC Urol 2014 Feb 7;14:18 full-text
overall rate of positive surgical margins about 27% after radical prostatectomy,
but risk of positive margins and need for retreatment appear lower with robotassisted radical prostatectomy than with open surgery
2,175 men who had radical prostatectomy in Australia and had available surgical
margin status data were assessed
27.2% had positive surgical margins after radical prostatectomy
compared to open surgery
robot-assisted radical prostatectomy associated with decreased risk of
positive surgical margins (odds ratio [OR] 0.69, 95% CI 0.55-0.87)
additional treatment within 12 months (OR 0.59, 95% CI 0.39-0.88)
laparoscopic radical prostatectomy associated with nonsignificant decrease in risk
of positive surgical margins (OR 0.73, 95% CI 0.53-1.01)
Reference - BJU Int 2014 Nov;114(5):680
EBSCOhost Full Text
Perioperative considerations:
pelvic lymph node dissection
technique
should be performed using extended technique that removes all node-containing
tissue from area bounded by external iliac vein anteriorly, pelvic side wall
laterally, bladder wall medially, floor of pelvis posteriorly, Cooper's ligament
distally, and internal iliac artery proximally(1)
may be performed using open, laparoscopic, or robot-assisted approaches, with
complication rates reported to be similar for each approach(1)
limited lymph node dissection should not be performed, due to risk of missing at least
half of involved lymph nodes (EAU Grade A, Level 2a)
indications for pelvic lymph node dissection during radical prostatectomy
National Comprehensive Cancer Network (NCCN) recommendations based on
NCCN risk stratification(1)
very low risk, low risk, or intermediate risk if predicted risk of lymph node
metastases 2% (NCCN Category 2A)
high risk or very high risk (NCCN Category 2A)
European Association of Urology (EAU) recommendations based on EAU risk
stratification(3)
intermediate risk if estimated risk for positive lymph nodes > 5% (EAU Grade
B, Level 2b), or high risk (EAU Grade A, Level 2b)
unnecessary for low risk (EAU Grade A, Level 2b)
other considerations
adjuvant hormone therapy after radical prostatectomy shows no survival advantage at
10 years (EAU Grade A, Level 1a)(3)
National Institute for Health and Care Excellence (NICE) recommends not offering
adjuvant hormonal therapy or immediate postoperative radiation therapy, even in men
with margin-positive disease (except in clinical trial)(2)
nerve-sparing surgery may be attempted in preoperatively potent patients at low risk
based on EAU risk stratification (EAU Grade B, Level 2b)(3)
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multiparametric magnetic resonance imaging (MRI) may help in decision to perform

nerve-sparing procedures in intermediate- and high-risk cancer (EAU Grade B, Level
2b)(3)
preoperative MRI may not reduce rate of positive surgical margins in men
having robot-assisted laparoscopic prostatectomy (level 3 [lacking direct]
evidence)
based on nonclinical outcome from randomized trial with incomplete blinding of
outcome assessors
485 men (mean age 63 years) with prostate cancer having robot-assisted
laparoscopic prostatectomy in Norway were randomized to preoperative MRI vs.
no MRI
54.6% had stage cT1, 41.8% had stage cT2, and 3.6% had stage cT3 disease on
preoperative digital rectal examination and transrectal ultrasound
MRI radiologists were not blinded to patient characteristics including cT stage,
prostate-specific antigen levels, or Gleason score
10% excluded from analyses (2.3% withdrew and 7.7% had no surgery or
surgery performed in another country)
minimum clinically important difference between groups defined as 20%
difference in positive surgical margin rates
positive surgical margin rates comparing preoperative MRI vs. no MRI
19% vs. 23% overall (not significant)
16% vs. 27% in subgroup of patients with cT1 disease (p = 0.035)
24% vs. 18% in subgroup of patients with cT2-3 disease (not significant)
Reference - Eur Urol 2015 Sep;68(3):487 full-text
bupivacaine wound infiltration plus diclofenac perioperatively appears to
reduce pain and postoperative tramadol use in men having prostatectomy (level
2 [mid-level] evidence)
based on randomized trial with allocation concealment not stated
96 men having radical retropubic prostatectomy with general anesthesia randomized
to bupivacaine 0.5% wound infiltration at surgical closure plus diclofenac 75 mg
intramuscularly vs. saline infiltration plus saline intramuscularly (placebo) and followed
to 24 hours postoperatively
all patients had postoperative analgesia with patient-controlled tramadol IV
pain score assessed using verbal rating scale (range 0-10, with higher number
indicating greater pain severity)
comparing bupivacaine plus diclofenac vs. placebo
median pain score in postanesthesia care unit 2 vs. 4 (p < 0.05)
median pain score at 24 hours 1 vs. 2 (p < 0.05)
cumulative tramadol consumption in postanesthesia care unit 0.3 mg vs. 12 mg
(p < 0.001)
cumulative tramadol consumption at 24 hours 184 mg vs. 270 mg (p < 0.001)
need for rescue analgesic in 13% vs. 36% (p < 0.05)
Reference - Urology 2011 Dec;78(6):1281, editorial can be found in Urology 2011
Dec;78(6):1285
tranexamic acid reduces perioperative blood transfusions in adults having
radical retropubic prostatectomy (level 2 [mid-level] evidence)
based on randomized trial with baseline differences
200 adults having radical retropubic prostatectomy randomized to 1 of 2 groups
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tranexamic acid IV (loading dose of 500 mg given 20 minutes before surgery

followed by continuous infusion of tranexamic acid at 250 mg/hour during
surgery)
saline
at baseline, tranexamic acid group had higher use of antiplatelets (p = 0.05) and
calcium channel blockers (p = 0.01) compared to placebo group
comparing tranexamic acid vs. placebo
blood transfusions during hospital stay in 34% vs. 55% (p = 0.004, NNT 5)
mean intraoperative blood loss 1,103 mL vs. 1,335 mL (p = 0.02)
thromboembolic events at 6 months in 2% vs. 5% (not significant)
Reference - BMJ 2011 Oct 19;343:d5701 full-text, commentary can be found in BMJ
2011 Nov 22;343:d7520
recombinant factor VIIa 40 mcg/kg IV administered early in retropubic
prostatectomy might reduce blood loss and need for transfusion (level 2
[mid-level] evidence)
based on small randomized trial
36 men having retropubic prostatectomy for prostate cancer or Millin prostatectomy
for prostate hypertrophy were randomized to recombinant factor VIIa (40 mcg/kg vs.
20 mcg/kg) IV bolus vs. placebo and followed for 10 days
interventions were administered after lymph node biopsy or placement of guiding
sutures
comparing recombinant factor VIIa 40 mcg/kg vs. placebo
median total blood loss 1,089 mL vs. 2,688 mL (p = 0.001)
transfusion needed in 0% vs. 58% (p = 0.001, NNT 2)
comparing recombinant factor VIIa 20 mcg/kg vs. placebo
median total blood loss 1,235 mL vs. 2,688 mL (p = 0.001)
transfusion needed in 38% vs. 58% (not significant)
Reference - Lancet 2003 Jan 18;361(9353):201
EBSCOhost Full Text, correction
can be found in Lancet 2003 Mar 29;361(9363), commentary can be found in Lancet
2003 May 17;361(9370):1745
statin use after radical prostatectomy reported to be associated with lower rates of
biochemical recurrence in some patients in subgroup analysis of retrospective cohort study
(BJU Int 2014 Nov;114(5):661
EBSCOhost Full Text)
Complications:
possible complications(1, 2, 3)
urinary incontinence
erectile dysfunction
alteration of sexual experience, including loss of sexual function
potential loss of ejaculation and fertility
bladder neck contracture
hospitalization and procedure rates following radical prostatectomy or radiation therapy
32,465 men with localized prostate cancer who had radical prostatectomy (49%) or
radiotherapy (51%) were analyzed
5-year cumulative incidence rates
any hospital admission for treatment-related complication 2.2%
hospital admission for patients with length of stay > 1 day 2.4%
urologic procedure 32%
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rectal or anal procedure 13.7%

open surgical procedure 0.9%
second primary malignancy 3%
Reference - Lancet Oncol 2014 Feb;15(2):223
prostatectomy associated with increased risk of urinary incontinence and
erectile dysfunction at 2-5 years compared to radiation therapy but not at 15
years in men with localized prostate cancer (level 2 [mid-level] evidence)
1,655 men aged 55-74 years with localized prostate cancer diagnosed in 1994-1995
were followed up to 15 years
70% had prostatectomy
30% had radiation therapy
all patients received treatment (prostatectomy or radiation therapy) within 1 year of
diagnosis with or without androgen deprivation therapy
mortality 27.7% with prostatectomy and 50.3% with radiation therapy at 15 years
follow-up among living men 87.5% at 2 years and 60.3% at 15 years
comparing radical prostatectomy vs. radiation therapy at 2 years
urinary incontinence in 9.6% vs. 3.2% (adjusted odds ratio [OR] 6.22, 95% CI
1.92-20.29)
erectile dysfunction in 78.8% vs. 60.8% (adjusted OR 3.46, 95% CI 1.93-6.17)
bowel urgency in 13.6% vs. 34% (adjusted OR 0.39, 95% CI 0.22-0.68)
results at 5 years similar to results at 2 years
at 15 years, no significant between-group difference for rates of urinary incontinence,
erectile dysfunction, or bowel urgency
Reference - N Engl J Med 2013 Jan 31;368(5):436
radical prostatectomy associated with increased risk for erectile dysfunction
and urinary leakage but decreased risk for urinary obstruction compared to
watchful waiting (level 2 [mid-level] evidence)
based on post hoc analysis of randomized trial
326 patients from SPCG-4 trial of radical prostatectomy vs. watchful waiting with
questionnaire at 1-7.5 years after randomization (mean 4 years) were evaluated
comparing radical prostatectomy vs. watchful waiting
seldom or never had sufficient erectile function for intercourse in 80% vs. 45%
(relative risk [RR] 1.8, 95% CI 1.5-2.2, NNH 2)
at least some urinary leakage in 62% vs. 35% (RR 1.8, 95% CI 1.4-2.3, NNH 3)
regular dependence on diaper or urine bag in 14% vs. 1% (RR 21.5, 95% CI
2.9-157 NNH 7)
moderate-to-severe obstructive urinary symptoms (on American Urological
Association Symptom Index) in 35% vs. 49% (RR 0.7, 95% CI 05-0.9, NNT 8)
Reference - N Engl J Med 2002 Sep 12;347(11):790, editorial can be found in N Engl J
Med 2002 Sep 12;347(11):839, commentary can be found in Evidence-Based Medicine
2003 Mar-Apr;8(2):41
consistent results at median 12.2-year follow-up (Lancet Oncol 2011 Sep;12(9):891,
editorial can be found in Lancet Oncol 2011 Sep;12(9):832)
minimally invasive radical prostatectomy associated with fewer initial
complications but higher rates of urinary incontinence and erectile dysfunction
than open retropubic radical prostatectomy (level 2 [mid-level] evidence)
based on cohort study
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8,837 men with prostate cancer had minimally invasive or open retropubic radical
prostatectomy and were followed for median 2.8 years
comparing minimally invasive vs. open retropubic radical prostatectomy in adjusted
analysis
median length of stay 2 vs. 3 days (p < 0.001)
blood transfusion in 2.7% vs. 20.8% (p < 0.001, NNT 6)
postoperative respiratory complications in 4.3% vs. 6.6% (p = 0.004, NNT 44)
miscellaneous surgical complications in 4.3% vs. 5.6% (p = 0.03, NNT 77)
anastomotic stricture in 5.8% vs. 14% (p < 0.001, NNT 13)
genitourinary complications in 4.7% vs. 2.1% (p = 0.001, NNH 38)
urinary incontinence rate 15.9 per 100 person-years vs. 12.2 per 100
person-years (p = 0.02, NNT 27 per year)
erectile dysfunction rate 26.8 per 100 person-years vs. 19.2 per 100 person-years
(p = 0.009, NNT 14 per year)
Reference - JAMA 2009 Oct 14;302(14):1557 full-text, editorial can be found in JAMA
2009 Oct 14;302(14):1590, commentary can be found in JAMA 2010 Feb
17;303(7):619
Interventions to reduce complications:
Urinary complications:
periprocedural considerations
single- and double-layer urethrovesical anastomosis have similar rates of
early postoperative urinary incontinence (level 1 [likely reliable] evidence)
based on randomized trial
116 consecutive patients having robotic prostatectomy randomized to
reconstruction of rhabdosphincter and puboprostatic collar (double-layer
anastomosis) vs. no reconstruction (single-layer anastomosis)
comparing postoperative urinary incontinence (0-1 pad used daily) in single-layer
vs. double-layer anastomosis (no significant differences)
26% vs. 34% on day 1
49% vs. 46% on day 2
51% vs. 54% on day 7
74% vs. 80% on day 30
Reference - J Urol 2008 Sep;180(3):1018, commentary can be found in J Urol
2009 Mar;181(3):1500
high single- and double-layer urethrovesical anastomosis associated with
similar long-term functional urinary outcomes (level 2 [mid-level] evidence)
based on secondary analysis of randomized trial above
mean postoperative follow-up 23.5 months
no significant difference in urine leakage amounts, pad usage, or long-term
prostate symptom scores
Reference - Urology 2010 Nov;76(5):1102, editorial can be found in Urology 2010
Nov;76(5):1107
complete bladder neck preservation during radical prostatectomy may
improve postoperative urinary continence (level 2 [mid-level] evidence)
based on randomized trial without intention-to-treat analysis
208 men (mean age 64 years) having radical prostatectomy randomized to
complete bladder neck preservation vs. no bladder neck preservation
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no patients had history of incontinence or transurethral prostate resection

9 men (5%) did not have successful bladder neck preservation and were excluded
from analyses
comparing complete bladder neck preservation vs. no bladder neck preservation
mean daily urine loss at 6 months 5.5 g vs. 44.4 g (p < 0.001)
mean daily urine loss at 1 year 3.1 g vs. 25.4 g (p < 0.001)
social continence (use of 1 security pad/day) at 6 months in 89.5% vs.
74.8% (p = 0.05)
social continence at 1 year in 94.7% vs. 81.4% (p = 0.027, NNT 8)
objective continence (urine loss 50 g/day) at 1 year in 91.6% vs. 79.4% (p
= 0.035, NNT 9)
complete bladder neck preservation associated with improved patient-reported
quality of life at 3, 6, and 12 months (p 0.016 for each)
Reference - J Urol 2013 Mar;189(3):891, commentary can be found in Eur Urol
2013 Aug;64(2):338, J Urol 2013 Aug;190(2):815
anterior suspension combined with posterior reconstruction during robotassisted laparoscopic prostatectomy associated with earlier return of
urinary continence in men with localized prostate cancer (level 2
72 men with localized prostate cancer randomized to anterior suspension and
posterior reconstruction during robot-assisted laparoscopic prostatectomy (RALP)
vs. standard RALP and followed for 6 months
analyses included 86% at 1 month, 79% at 3 months, and 63% at 6 months
comparing anterior suspension and posterior reconstruction during RALP vs.
standard RALP
continence in
26.5% vs. 7.1% at 1 month (p = 0.047, NNT 5)
45.2% vs. 15.4% at 3 months (p = 0.016, NNT 4)
65.4% vs. 57.9% (not significant)
no significant difference in complications or median duration of hospital stay
Reference - BJU Int 2012 Sep;110(6):875
EBSCOhost Full Text,
commentary can be found in Urol Oncol 2013 Feb;31(2):272
suprapubic cystostomy drainage associated with reduced urinary symptoms
compared to urethral Foley catheter in men having prostatectomy (level 2
based on small randomized trial with unclear randomization sequence generation
65 men (mean age 63 years) having total retropubic prostatectomy were
randomized to suprapubic cystostomy drainage (42 patients) vs. urethral Foley
catheter (23 patients) were followed for 12 months
comparing suprapubic cystostomy drainage vs. urethral Foley catheter
urinary symptoms during catheterization in 14% vs. 91% (p < 0.001, NNT 2)
painful urination after catheter removal in 31% vs. 65% (p < 0.01, NNT 3)
Reference - Int J Urol 2012 Jun;19(6):587
commentary can be found in Eur Urol 2014 Mar;65(3):597
intrafascial technique during nerve-sparing endoscopic extraperitoneal
radical prostatectomy associated with better early continence and potency
outcomes in men 65 years old (level 2 [mid-level] evidence)
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based on randomized trial with unclear blinding of outcome assessors

400 patients having nerve-sparing endoscopic extraperitoneal radical
prostatectomy randomized to intrafascial vs. standard interfascial technique
phosphodiesterase-5 inhibitor use allowed for potency concerns
comparing intrafascial vs. standard techniques
continence (0-1 pads) at 3 months in 74% vs. 63% (p = 0.003)
continence at 6 months in 87.9% vs. 76.2% (p = 0.04)
potency (positive reaction to sexual encounter questionnaire) at 12 months
in 82.8% vs. 64.8% (p = 0.005)
positive surgical margin in 9% vs. 9.5% (no p value reported)
no significant between-group differences in potency at 6 or 12 months in
subgroup of patients > 65 years old
Reference - Urology 2010 Sep;76(3):743, editorial can be found in Urology 2010
Sep;76(3):749; discussion 749
modified apical dissection improves early continence rate compared to
standard laparoscopic radical prostatectomy (level 1 [likely reliable]
evidence)
based on randomized trial
104 patients having laparoscopic radical prostatectomy randomized to modified
technique (simplified apical dissection to avoid damage to external striated
urethral sphincter complex) vs. standard technique
postoperative continence defined as no pad use, or use of liner for security
reasons only
comparing modified apical dissection vs. standard technique
postoperative continence at 3 days in 66% vs. 28% (p < 0.01, NNT 3)
postoperative continence at 30 days in 85% vs. 55% (p < 0.01, NNT 4)
postoperative continence at 90 days in 96% vs. 91% (not significant)
Reference - J Cancer Res Clin Oncol 2010 Apr;136(4):511
medications
duloxetine
duloxetine may reduce postprostatectomy stress urinary incontinence
when added to pelvic floor muscle training but may increase
incontinence when medicine is stopped (level 2 [mid-level] evidence)
based on randomized trial without blinding
112 men with postprostatectomy stress urinary incontinence randomized to
pelvic floor muscle training (PFMT) plus duloxetine 40 mg orally twice daily
vs. PFMT plus placebo for 16 weeks
study investigators not blinded to treatment group
after 16 weeks, patients continued PFMT alone for 8 weeks
daily incontinence episode frequency decreased from baseline in both groups
comparing complete continence (0 absorptive pads used) with duloxetine vs.
placebo
78% vs. 52% (p = 0.007, NNT 4) at week 16
46% vs. 73% (p = 0.008, NNH 4) at week 20 (4 weeks with medication
discontinued)
62% vs. 78% (p = 0.08) at week 24 (8 weeks with medication
discontinued)
15.2% duloxetine and 1.8% placebo group (p = 0.01) dropped out due to
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adverse events
Reference - Eur Urol 2007 Jun;51(6):1559
duloxetine may reduce incontinence episodes in men with
postprostatectomy stress urinary incontinence (level 2 [mid-level]
evidence)
based on small randomized trial
31 men aged 53-81 years with stress urinary incontinence post radical
prostatectomy had 2-week placebo run-in period then randomized to
duloxetine 80 mg/day vs. placebo for 3 months
comparing duloxetine vs. placebo
change in incontinence episodes frequency -52% vs. 19% (p < 0.0001)
fatigue in 50% vs. 13% (p value not reported)
duloxetine group had improvement in Incontinence Impact Questionnaire
Short Form total score (p = 0.006) and Urogenital Distress Inventory Short
Form total score (p = 0.02)
Reference - Eur Urol 2011 Jan;59(1):148, commentary can be found in J Urol
2012 Jun;187(6):2156
duloxetine reported to reduce stress urinary incontinence after
prostatectomy, but 65% of men discontinued treatment (level 3
[lacking direct] evidence)
94 men with mild-to-moderate postprostatectomy stress urinary incontinence
who were treated with duloxetine were examined 1 month after treatment
all men required 5 absorptive pads/day before treatment (baseline)
all men received duloxetine 30 mg orally once daily for 1 week, then 60
mg orally once daily
at 1 month after beginning of duloxetine treatment
daily pad usage reduced from 2.9 to 1.6 (p < 0.05)
scores in incontinence impact questionnaire and linear satisfaction
improved
duloxetine discontinued in 65% of men due to lack of efficacy or intolerable
adverse events (including fatigue, light-headedness, insomnia, nausea, and
dry mouth)
Reference - Can Urol Assoc J 2013 May-Jun;7(5-6):E260 full-text
tamsulosin may reduce risk of acute urinary retention in patients with
prostate cancer after robot-assisted laparoscopic radical prostatectomy
(level 2 [mid-level] evidence)
based on randomized trial with unclear blinding
236 patients with prostate cancer who had robot-assisted laparoscopic radical
prostatectomy randomized to tamsulosin 0.4 mg/day from 1 day pre- to 14 days
postoperatively vs. no tamsulosin
urethral catheter was removed on postoperative day 5
acute urinary retention defined as painful, palpable, or percussible bladder and
inability to pass any urine
218 patients (92%) were included in analysis of acute urinary retention
acute urinary retention after removal of urethral catheter in 7.3% with tamsulosin
vs. 17.4% with no tamsulosin (p = 0.018, NNT 10)
Reference - Int J Urol 2014 Feb;21(2):164
EBSCOhost Full Text
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solifenacin succinate may slightly improve urinary continence after robotassisted radical prostatectomy for localized prostate cancer (level 2
640 men (mean age 61 years) with urinary incontinence 7-21 days after catheter
removal following robot-assisted radical prostatectomy for localized prostate
cancer were randomized to solifenacin succinate 5 mg orally once daily vs.
placebo for 12 weeks
solifenacin succinate dose could be doubled to 10 mg once daily at week 4
based on efficacy and safety
urinary incontinence defined as need for 2-10 pads per day for 7 consecutive
days
97% took 1 study medication dose and were included in analyses
patient-reported urinary continence defined as need for 0 pads per day or dry
security pad for 3 consecutive days
comparing solifenacin succinate vs. placebo
continence in 29% vs. 21% (p = 0.04)
mean decrease in pads per day 3.2 vs. 2.9 (p = 0.03)
1 treatment-emergent adverse events in 33.2% vs. 30.3% (no p value
reported)
dry mouth in 6.1% vs. 0.6% (no p value reported)
no significant difference in time from first dose to urinary continence or quality of
life between groups
Reference - J Urol 2015 Apr;193(4):1305, editorial can be found in J Urol 2015
Apr;193(4):1310
pelvic floor muscle training (PFMT) for urinary incontinence following radical prostatectomy
pelvic floor muscle training (with or without biofeedback) may decrease long-term
urinary incontinence after radical prostatectomy or transurethral resection of prostate
if started prior to prostate surgery (level 2 [mid-level] evidence)
initiation of pelvic floor muscle training preoperatively may not shorten time to achieve
continence compared with postoperative pelvic floor muscle training in men having
radical prostatectomy (level 2 [mid-level] evidence)
physical therapist guidance in pelvic floor muscle exercises may not increase
continence after radical prostatectomy compared to verbal instruction of exercises
combination of PFMT and bladder control strategies improves continence in men with
persistent incontinence after radical prostatectomy (level 1 [likely reliable] evidence)
see Behavioral interventions for urinary incontinence for details
handout on pelvic floor muscle training for men from University of California Los
Angeles Urology Department PDF
electrical therapy
electrical stimulation with nonimplanted electrodes has inconsistent
evidence for effect on urinary incontinence after radical prostatectomy
based on Cochrane review of trials with methodologic limitations
systematic review of 6 randomized trials evaluating electrical stimulation with
nonimplanted electrodes in 544 men with urinary incontinence
all trials in men with radical prostatectomy
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all trials had 1 limitation including

unclear allocation concealment
unclear blinding
small sample size
electrical stimulation plus pelvic muscle floor training (PMFT) significantly
decreased urinary incontinence through 6-month follow-up vs. sham stimulation
plus PMFT in 1 moderate quality trial with 56 men
comparing electrical stimulation plus PFMT to PFMT with or without biofeedback
no significant difference in urinary incontinence at 3 months in analysis of 4
low-quality trials with 395 men, results limited by significant heterogeneity
electrical stimulation plus PFMT associated with increased adverse effects
(risk ratio 7.04, 95% CI 1.51-32.94) in analysis of 2 trials with 238 men,
results limited by significant heterogeneity
electrical stimulation plus PFMT significantly reduced quality of life in 1 trial
with 129 men
Reference - Cochrane Database Syst Rev 2013 Jun 6;(6):CD001202
electrical stimulation may reduce urinary incontinence after radical
prostatectomy (level 2 [mid-level] evidence)
based on Cochrane review with limited evidence
systematic review of 50 randomized trials evaluating conservative interventions
for treatment or prevention of urinary incontinence after prostatectomy in 4,717
men
45 trials included men having radical prostatectomy
4 trials included men having transurethral resection of prostate (TURP)
1 trial included men after either operation
controls included no treatment, sham therapy, and verbal instruction
11 trials evaluated electric or magnetic therapy (anal electrical stimulation,
perineal electrical stimulation, transcutaneous electrical nerve stimulation, or
extracorporeal magnetic innervation) for treatment of urinary incontinence after
electrical stimulation associated with reduced urinary incontinence at < 3
months compared to control in analysis of 2 trials with 96 men
risk ratio 0.77 (95% CI 0.6-0.98)
NNT 3-60 with urinary incontinence in 84% of control group
results consistent at 3-6 months, 6-12 months, and > 12 months
urinary incontinence at < 3 months in 82.9% with pelvic floor muscle training
(PFMT) plus biofeedback plus anal electrical stimulation vs. 94.1% with no
treatment (p < 0.05, NNT 9) in 1 trial with 138 men
no significant difference in urinary incontinence at < 3 months with addition
of anal electrical stimulation to PFMT in analysis of 2 trials with 177 men
significantly improved quality of life with addition of
biofeedback plus electrical stimulation to PFMT in 1 trial with 76 men
extracorporeal magnetic innervation to PFMT in 1 trial with 24 men
4 trials evaluated electric or magnetic therapy for prevention of urinary
incontinence after radical prostatectomy
comparing postoperative PFMT plus biofeedback plus anal electrical
stimulation vs. control in 1 trial with 60 men
urinary incontinence at 3-6 months in 20% vs. 66.7% (p < 0.05, NNT 2)
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urinary incontinence at 6-12 months in 3.3% vs. 33.3% (p < 0.05, NNT
4)
addition of transcutaneous electrical stimulation plus biofeedback to
postoperative PFMT significantly reduced urinary incontinence at 6-12
months but had no effect at < 6 months in 1 trial with 54 men
urinary incontinence through 12 months comparing postoperative
transcutaneous electrical stimulation vs. postoperative PFMT in 1 trial
with 52 men
urinary incontinence quality of life with addition of preoperative anal
electrical stimulation to preoperative PFMT in 1 trial with 32 men
Reference - Cochrane Database Syst Rev 2015 Jan 20;(1):CD001843
Erectile dysfunction:
recovery of erectile function may be related to age at prostatectomy, preoperative erectile
function, and degree of preservation of cavernous nerves(1)
phosphodiesterase-5 inhibitors may be effective for erectile dysfunction in men
with nonmetastatic prostate cancer (level 2 [mid-level] evidence)
systematic review of 11 randomized trials evaluating interventions for sexual
dysfunction as complication of cancer treatment in 1,743 patients
10 trials were in men after treatment with 1 of following for nonmetastatic prostate
cancer
nerve-sparing prostatectomy in 4 trials with 652 patients
radical retropubic prostatectomy in 2 trial with 687 patients
radical prostatectomy in 1 trial with 184 patients
radiation therapy in 2 trial with 120 patients
methodologic limitations included
unclear allocation concealment in all trials
unclear method of randomization in 9 trials
unclear blinding of assessor in 7 trials
no assessment of attention control by authors in 5 trials where blinding not
possible - 4 trials with counseling intervention and 1 trial using vacuum
constriction device
phosphodiesterase-5 inhibitors associated with
improvement in erections (odds ratio [OR] 10.09, 95% CI 6.2-16.43) in analysis
of 2 trials with 415 patients
NNT 2-3 with improvement of 17% in controls
68% phosphodiesterase-5 inhibitor vs. 17% placebo patients had improvement in
erections in analysis of 2 trials with 415 patients (p < 0.0001, NNT 2)
adverse events were rare and usually mild-to-moderate headaches or flushing, except
in 1 trial that reported 6 events of tachycardia and 6 events of chest pain
other interventions with limited evidence suggesting benefit
combination of phosphodiesterase-5 inhibitors with acetyl-L-carnitine and
propionyl-L-carnitine
sexual counselling to improve self-administration of prostaglandin intracavernous
injection
transurethral alprostadil
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vacuum constriction device

Reference - Cochrane Database Syst Rev 2007 Oct 17;(4):CD005540
sildenafil may be effective for erectile dysfunction after radical prostatectomy
based on systematic review without assessment of trial quality
review failed to identify any randomized controlled trials and noted heterogeneity
among 14 observational studies analyzing effect of sildenafil on postradical
prostatectomy erectile dysfunction
Reference - Eur Urol 2009 Feb;55(2):334
on-demand sildenafil may be as effective as nightly sildenafil in men after
nerve-sparing radical prostatectomy (level 2 [mid-level] evidence)
based on randomized trial with high dropout rate and baseline differences
100 men (mean age 54 years) having nerve-sparing minimally invasive radical
prostatectomy were randomized to 1 of 2 treatments for 12 months followed by
1-month washout
nightly sildenafil 50 mg orally plus on-demand placebo
on-demand sildenafil 50 mg orally (maximum 6 tablets/month) plus nightly
placebo
men had no preoperative erectile dysfunction (International Index of Erectile FunctionErectile Function domain [IIEF-EF] score 26)
26% did not complete treatment, but all patients included in intention-to-treat analysis
at baseline, mean nerve-sparing score (range 0-8, with higher scores indicating better
nerve preservation) was 6.5 in nightly sildenafil group vs. 7.1 in on-demand sildenafil
group (p = 0.033)
in unadjusted analysis
no significant difference in IIEF-EF scores or percentage of patients returning to
baseline IIEF-EF during treatment at any time point evaluated
nightly sildenafil associated with lower IIEF-EF scores and lower percentage of
patients returning to baseline after washout period (p = 0.022)
no significant differences in assessment of potency, sexual function, or sexual bother
Reference - BJU Int 2013 Oct;112(6):844
EBSCOhost Full Text
tadalafil prophylaxis may not reduce risk of erectile dysfunction in men having
radiation therapy for prostate cancer (level 2 [mid-level] evidence)
based on randomized trial with high dropout rate
242 men with prostate cancer and intact spontaneous erectile function randomized
within 7 days of initiating radiation therapy to tadalafil 5 mg orally daily vs. placebo for
24 weeks and followed to 1 year
63% received external radiotherapy and 73% brachytherapy
trial sample size calculations assumed 85% completion rate per protocol overall and
intact erectile function at 28-30 weeks in 20% in placebo group
72% completed trial per protocol, and 91% were included in analysis
comparing tadalafil vs. placebo
erectile dysfunction at 28-30 weeks in 21% vs. 26% (not significant)
erectile dysfunction at 1 year in 28% vs. 29% (not significant)
no significant differences in overall sexual function or satisfaction
Reference - JAMA 2014 Apr 2;311(13):1300
tadalafil once daily may improve erectile function in men with organ-confined
prostate cancer having nerve-sparing radical prostatectomy (level 2 [mid-level]
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evidence)
based on randomized trial with unclear clinical significance
423 men 68 years old (mean age 58 years) with organ-confined prostate cancer
(Gleason score 7) who had nerve-sparing radical prostatectomy were randomized to
1 of 3 treatments for 9 months
tadalafil 5 mg once daily plus placebo on demand up to 3 times/week
placebo once daily plus tadalafil 20 mg on demand
placebo once daily plus placebo on demand
all patients had normal erectile function before surgery
erectile function assessed with IIEF-EF scores (range 0-30, minimal clinically important
difference defined as 4 points)
rate of unassisted erectile function (IIEF-EF score 22)
25.2% with tadalafil 5 mg once daily (p = 0.016 vs. placebo, NNT 10)
19.7% with tadalafil 20 mg on demand (not significant vs. placebo)
14.2% with placebo
mean improvement in IIEF-EF score compared to placebo
2.8 points with tadalafil 5 mg once daily (p < 0.05 vs. placebo)
1.6 points with tadalafil 20 mg on demand (not significant vs. placebo)
compared to placebo, tadalafil 5 mg once daily associated with significantly improved
self-reported sexual function
Reference - REACTT trial (Eur Urol 2014 Mar;65(3):587)
tadalafil once daily may reduce penile length loss in men with organconfined prostate cancer having nerve-sparing radical prostatectomy (level
3 [lacking direct] evidence)
based on nonclinical outcome from post hoc secondary analysis of REACTT trial
all patients with organ-confined prostate cancer who were randomized to tadalafil
5 mg once daily vs. tadalafil 20 mg on demand vs. placebo after nerve-sparing
radical prostatectomy were assessed
mean decrease in stretched penile length
2.2 mm with tadalafil 5 mg once daily (p = 0.032 vs. placebo) (p = 0.003 vs.
tadalafil 20 mg on demand)
7.9 mm with tadalafil 20 mg on demand (not significant vs. placebo)
6.3 mm with placebo
absence of morning erections in (p = 0.045 among groups)
34.2% with tadalafil 5 mg once daily
50% with tadalafil 20 mg on demand
56.5% with placebo
tadalafil 5 mg once daily associated with significant increase in frequency of
successful sexual intercourse (assessed on Sexual Encounter Profile questionnaire
questions 1-3) compared to placebo
Reference - Urology 2015 May;85(5):1090
early pelvic-floor muscle exercise intervention associated with improved sexual
function after radical prostatectomy (level 2 [mid-level] evidence)
72 men (mean age 65 years) with severe sexual dysfunction after radical
prostatectomy for prostate cancer were randomized to pelvic-floor muscle exercise
training twice daily in 3 positions vs. control (not taught exercises, did not receive
biofeedback training, or informational DVD) for 3 months
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control group given same intervention at 3 months

62 patients (86%) completed trial and included in analyses
early pelvic-floor muscle exercise intervention associated with significantly improved
mean sexual function score at 6 and 12 months
Reference - Cancer Nurs 2012 Mar-Apr;35(2):106
review of erectile dysfunction following radical prostatectomy (noting that transient erectile
dysfunction for up to 2 years is common following nerve-sparing prostatectomy) can be
found in JAMA 2005 Jun 1;293(21):2648
Radiation Therapy
Indications:
Initial (definitive) treatment:
National Comprehensive Cancer Network (NCCN) recommendations for indications for any
radiation therapy based on NCCN risk stratification(1)
for men with very low risk with life expectancy 20 years (NCCN Category 2A),
external beam radiation therapy (EBRT) with dose 75.6-79.2 Gy in conventional
fractions to prostate (with or without irradiation of seminal vesicles for part of
therapy) is appropriate
for men with low risk with life expectancy 10 years (NCCN Category 2A), EBRT with
dose 75.6-79.2 Gy in conventional fractions to prostate (with or without irradiation of
seminal vesicles for part of therapy) is appropriate
for men with intermediate risk, options include (NCCN Category 2A)
EBRT, with or without 4-6 months androgen deprivation therapy (ADT) and with
or without brachytherapy
brachytherapy alone for men with favorable factors (clinical stage T1c, Gleason
score 7, low prostate volume)
for men with high risk or very high risk, options include
EBRT plus brachytherapy with or without 2-3 years ADT (NCCN Category 2A)
EBRT is an option for all risk groups with nonmetastatic disease (EAU Grade A, Level
2a)
intensity-modulated radiation therapy (IMRT) recommended modality for definitive
treatment by EBRT (EAU Grade A, Level 2a)
for men with low risk, total dose recommended 74-78 Gy (EAU Grade A, Level 1a)
for men with intermediate risk or high risk, total dose recommended 76-78 Gy plus
androgen deprivation therapy (ADT)
for 4-6 months in those with intermediate risk (EAU Grade A, Level 1b)
for 2-3 years in those with high risk (EAU Grade A, Level 1b)
for men with locally advanced N0 disease, radiation therapy must be given in
combination with androgen deprivation therapy (ADT) for 2-3 years (EAU Grade A,
Level 1a)
for men with node positive disease, pelvic external radiation can be given in
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combination with immediate long-term (2-3 years) androgen deprivation therapy

(ADT) (EAU Grade B, Level 2b)
for low-risk men with prostate volume 50 mL, no previous transurethral resection of
prostate (TURP), and with good International Prostate Symptom Score (IPSS),
alternative treatment may be radiation therapy by low-dose rate brachytherapy (EAU
Grade A, Level 2a)
National Institute for Health and Care Excellence (NICE) recommendations(2)
offer radical treatment to men with localized prostate cancer being managed by active
surveillance who have evidence of disease progression
offer radical radiation therapy plus 6 months ADT before, during, or after radiation
treatment to men with intermediate- or high-risk cancer on NICE risk stratification
(when realistic prospect of long-term disease control)
consider pelvic radiation therapy in men with locally advanced prostate cancer who
have > 15% risk of pelvic lymph node involvement and who will have EBRT and
neoadjuvant ADT
Adjuvant therapy:
National Comprehensive Cancer Network (NCCN) recommendations(1)
indications for adjuvant EBRT after radical prostatectomy and pelvic lymph node
dissection in men with lymph node metastases based on NCCN risk stratification
for men with very low risk disease and life expectancy 20 years (NCCN
Category 2B)
for men with intermediate risk disease and life expectancy 10 years in
combination with androgen deprivation therapy (ADT) (NCCN Category 2B)
for men with high risk disease or very high risk disease with no fixation in
combination with ADT (NCCN Category 2B)
indications for EBRT after radical prostatectomy (usually within 1 year) for any risk
category disease include the following adverse features (NCCN Category 2A)
pathologic stage T3
positive surgical margins (especially if > 10 mm margin involvement or 3 sites
of positivity or if associated with persistent serum PSA levels)
Gleason score 8-10
seminal vesicle invasion
PSA doubling times < 9 months
extracapsular invasion
postprostatectomy adjuvant radiation therapy doses are 64-72 Gy in standard
fractionation
target adjuvant radiation therapy to prostate bed, pelvic lymph nodes may also be
irradiated, but pelvic radiation unnecessary
EAU recommendation(3)
for men with tumor stage T3 N0 M0, adjuvant EBRT immediately after radical
prostatectomy may improve biochemical and clinical disease-free survival, especially
for men with positive margins (EAU Grade A, Level 1a)
Brachytherapy:
General Information:
radioactive sources with low- or high-dose-rate implanted into prostate tissue
low-dose-rate
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seed implants placed permanently

short-range radiation emitted to prostate, but excessive irradiation of bladder and
rectum avoided
advantages
treatment may be completed in 1 day
for low-risk tumors, cancer-control rates reported to be comparable to radical
prostatectomy ( 90%)
risk of incontinence is minimal in patients with previous transurethral resection of
prostate (TURP)
short-term erectile function maintained
disadvantages
general anesthesia required
risk of acute urinary retention (risk of incontinence is higher after TURP)
irritative voiding symptoms may persist for up to 1 year after implantation
high-dose-rate
temporary insertion of radiation source, provides "boost" dose to men with high
recurrence risk having external-beam radiation therapy (EBRT)
combination of high-dose-rate brachytherapy plus EBRT allows dose escalation while
minimizing acute or late toxicity in patients with high-risk localized or locally advanced
cancer
reported to have lower risk of urinary frequency, urgency, rectal pain, and erectile
dysfunction compared to low-dose-rate brachytherapy
Reference - NCCN 2014 Oct from NCCN website (free registration required)
Indications:
National Comprehensive Cancer Network (NCCN) recommendations for indications for
brachytherapy based on NCCN risk stratification - any of(1)
as monotherapy
very low risk with life expectancy 20 years (NCCN Category 2A)
low risk with life expectancy 10 years (NCCN Category 2A)
intermediate risk with low prostate volume (NCCN Category 2A)
in combination with EBRT with or without ADT in patients with intermediate risk, high
risk, or very high risk (NCCN Category 2A)
European Association of Urology (EAU) recommendations for indications for low-dose rate
brachytherapy - all of(3)
low risk on EAU risk stratification
50% prostate cancer involvement in any core
prostate volume < 50 cm3
no previous TURP
International Prostate Symptom Score (IPSS) 12
consider high-dose rate brachytherapy plus EBRT for men with intermediate- or
high-risk cancer on NICE risk stratification
10-year biochemical-free progression rate for men having brachytherapy reported to range
from 65% to 85%(3)
Techniques:
isotopes and doses
low-dose-rate monotherapy
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145 Gy for iodine-125

125 Gy for palladium-103
low-dose-rate after 40-50 Gy external-beam radiation therapy (EBRT)
110 Gy for iodine-125
90-100 Gy for palladium-103
high-dose-rate monotherapy, commonly used regimens
9.5-11.5 Gy x 2 fractions
5.5-7.5 Gy x 3 fractions
4-6 Gy x 4 fractions
high-dose-rate after 40-50 Gy EBRT, 13.5 Gy x 2 fractions
Reference - NCCN 2014 Apr from NCCN website (free registration required)
Efficacy:
brachytherapy reported to have high biochemical progression-free survival in
hormone-naive men with low-risk prostate cancer (level 3 [lacking direct]
evidence)
108 hormone-naive patients 54 years old (range 45-54 years) had permanent
interstitial brachytherapy for clinical stage T1c-T2c NXM0 prostate cancer and were
followed for mean 5.3 years
biochemical progression-free survival defined as prostate-specific antigen (PSA) level
0.4 ng/mL
96% actuarial 8-year biochemical progression-free survival
Reference - BJU Int 2006 Aug;98(2):324
EBSCOhost Full Text
high-dose rate brachytherapy given as monotherapy reported to have
biochemical control rate of 94% at 60 months in men with clinically organconfined prostate cancer (level 2 [mid-level] evidence)
351 consecutive patients with clinically localized prostate cancer who were treated
with transrectal ultrasound-guided high-dose rate brachytherapy (38.0 Gy in 2
implants of 2 fractions of 9.5 Gy each with a 14-day interval between implants)
evaluated after mean follow-up of 59.3 months
biochemical control (PSA increase 2 ng/mL above nadir PSA)
98% at 36 months
94% at 60 months
metastasis-free survival
99% at 36 months
98% at 60 months
acute grade 3 genitourinary toxicity 4.8%
acute grade 3 gastrointestinal toxicity 0%
late grade 3 genitourinary toxicity 3.4%
late grade 3 gastrointestinal toxicity 1.4%
Reference - Radiat Oncol 2013 May 8;8(1):115
addition of brachytherapy to low-dose external beam radiation therapy may not
increase overall survival in men with localized prostate cancer (level 2
based on systematic review of trials with methodologic limitations
systematic review of 36 randomized trials evaluating management options for men
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with localized prostate cancer

management options included radiation therapy (brachytherapy and/or external beam
radiation therapy [EBRT]) and nonpharmacological therapies (radical prostatectomy,
high intensity focused ultrasound, cryotherapy, active surveillance, or watchful
waiting), each with or without adjuvant hormone therapy
no or unclear allocation concealment
no or unclear blinding
no significant difference in overall survival comparing low-dose EBRT plus
brachytherapy to low-dose EBRT alone in analysis of 2 trials with 320 patients
Reference - Eur J Cancer 2015 Nov;51(16):2345 full-text
addition of high-dose rate brachytherapy to EBRT may increase biochemical
disease-free survival in patients with localized prostate cancer (level 3 [lacking
direct] evidence)
based on nonclinical outcome from randomized trial
220 patients with organ-confined prostate cancer were randomized to 1 of 2
interventions and followed for median 30 months
EBRT (35.75 Gy in 13 fractions) plus high-dose rate (HDR) brachytherapy (17 Gy
in 2 fractions over 24 hours)
EBRT alone (55 Gy in 20 fractions)
comparing EBRT plus HDR brachytherapy vs. EBRT alone
mean biochemical relapse-free survival 5.1 years vs. 4.3 years (p = 0.03)
improved quality of life (measured by Functional Assessment of Cancer Therapyprostate [FACT-P] score at 12 weeks) (p = 0.02)
no significant between-group differences overall survival or late toxicity rates
Reference - Radiother Oncol 2007 Aug;84(2):114
Adverse effects of brachytherapy and their management:
key adverse effects include urinary incontinence and erectile dysfunction
see Radiation therapy for prostate cancer for details
External beam radiation:
external-beam radiation therapy of primary tumor may have several advantages over
avoids surgical complications
lowers risk of urinary incontinence and stricture
good chance of short-term preservation of erectile function
disadvantages of external-beam radiation therapy
treatment course 8-9 weeks
> 50% of men have some temporary bladder or bowel symptoms during treatment
low but definite risk of protracted rectal symptoms due to radiation proctitis
risk of erectile dysfunction increases over time
in case of recurrence, salvage prostatectomy has higher risk of complications than
primary radical prostatectomy
contraindications to radiation therapy
absolute
prior pelvic irradiation
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active inflammatory disease of rectum

permanent indwelling Foley catheter
relative
very low bladder capacity
chronic moderate or severe diarrhea
bladder outlet obstruction requiring suprapubic catheter
inactive ulcerative colitis
Reference - NCCN 2014 Apr from NCCN website (free registration required)
Indications:
National Comprehensive Cancer Network (NCCN) recommendations for indications for
external beam radiation therapy (EBRT) based on NCCN risk stratification(1)
very low risk with life expectancy 20 years (NCCN Category 2A)
low risk with life expectancy 10 years (NCCN Category 2A)
intermediate risk, options include EBRT, with or without 4-6 months androgen
deprivation therapy (ADT) and with or without brachytherapy (NCCN Category 2A)
high risk or very high risk, options include
EBRT plus long-term ADT (NCCN Category 1)
EBRT recommended for all risk groups (EAU Grade A, Level 2a)
intensity-modulated radiation therapy (IMRT) recommended modality for definitive
treatment by EBRT (EAU Grade A, Level 2a)
for men with low risk, total dose recommended 74-78 Gy (EAU Grade A, Level 1a)
for men with intermediate risk or high risk, total dose recommended 76-78 Gy plus
androgen deprivation therapy
for 4-6 months for intermediate risk (EAU Grade A, Level 1b)
2-3 years for high risk (EAU Grade A, Level 1b)
for men with locally advanced N0 disease, radiation therapy must be given in
combination with androgen deprivation therapy for 2-3 years (EAU Grade A, Level 1a)
for men with N+ disease, pelvic external radiation can be given in combination with
immediate long-term (2-3 years) androgen deprivation therapy (EAU Grade B, Level
2b)
National Institute for Health and Care Excellence (NICE) recommends offering EBRT plus at
least 6 months ADT (before, during, or after) to men with intermediate- or high-risk cancer
on NICE risk stratification(2)
Techniques:
intensity-modulated radiation therapy (IMRT) with or without image-guided radiation
therapy (IGRT) is routinely used in clinical practice
use of linear accelerator and computerized techniques
allow for more complex distribution of radiation delivery dose within treatment field
provide concave isodose curves (particularly useful for sparing rectum)
3-dimensional conformal radiation therapy
uses a multi-leaf collimeter to adjust radiation beam such that it conforms to the size
and shape of the tumor, with a prespecified safety margin surrounding the tumor
reported to improve local control through dose escalation, without increasing risk of
morbidity
IGRT
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allows visualization of organ movement and correction in real time

optimum method for visualization and correction still undefined
tomotherapy
uses linear accelerator mounted on ring gantry that rotates as dose is delivered
through center of ring
may be an alternative technique for correction of organ movement in the future
Efficacy:
adjuvant radiation therapy after radical prostatectomy
patients with pT3 disease and positive surgical margins may have most benefit of
adjuvant radiation therapy after radical prostatectomy (EAU Level 1a)(3)
adjuvant radiation therapy following radical prostatectomy may reduce
local recurrence at 5 and 10 years, might reduce metastases and overall
mortality at 10 years, but may increase risk for urethral stricture and
urinary incontinence at 10 years (level 2 [mid-level] evidence)
based on Cochrane review of trials without blinding and with incomplete data
reporting
systematic review of 3 randomized trials comparing adjuvant radiation therapy
following radical prostatectomy to radical prostatectomy alone in 1,815 men with
prostate cancer
EORTC trial 22911 with 1,005 men < 76 years old with high-risk localized
prostate cancer
SWOG 8794 trial with 425 men aged 43-79 years
ARO 96-02 trial with 385 men aged 50-77 years
radiotherapy given as external beam radiotherapy to a radical dose of 60 Gy or
the biological equivalent of using 2-dimensional, 3- dimensional computed
tomography (CT) planning, IMRT or novel techniques
overall survival, distant metastases, and local recurrence were not reported for
entire cohort of randomized men
at 5 years
adjuvant radiation therapy associated with
lower incidence of local recurrence (5% vs. 14.7%, p < 0.0001, NNT 11)
in 1 trial with 1,005 men
lower incidence of biochemical relapse (risk difference -15%, 95% CI
-20% to -11%) in analysis of 3 trials with 1,737 men
overall survival (risk difference 0%, 95% CI -2% to 3%) in analysis of 3
trials with 1,737 men
incidence of metastases (risk difference -1%, 95% CI -3% to 1%) in
analysis of 3 trials with 1,737 men
incidence of urethral stricture in 1 trial with 307 men
incidence of urinary incontinence in 1 trial with 100 men
at 10 years in 1 trial with 425 men, adjuvant radiation therapy associated with
fewer deaths (41.1% vs. 52.1%, p = 0.022, NNT 9) in analysis of 425 men,
but no significant difference in overall survival in analysis with longer
follow-up
lower incidence of metastases (43.5% vs. 54%, p = 0.028, NNT 10) in
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analysis of 425 men

lower incidence of local recurrence (7.9% vs. 21.7%, p = 0.00013, NNT 8) in
analysis of 374 men
lower incidence of biochemical relapse (35% vs. 64%, p < 0.0001, NNT 4) in
analysis of 347 men
higher incidence of urethral stricture (17.8% vs. 9.5%, p = 0.012, NNH 12)
in analysis of 425 men
nonsignificant increase in incidence of urinary incontinence (6.5% vs. 2.8%,
p = 0.07) in analysis of 425 men
Reference - Cochrane Database Syst Rev 2011 Dec 7;(12):CD007234
adjuvant radiation therapy may reduce locoregional progression in patients
with risk factors after radical prostatectomy (level 2 [mid-level] evidence)
based on randomized trial without blinding (included in Cochrane review)
1,005 patients < 76 years old with high-risk localized prostate cancer following
radical retropubic prostatectomy (N0M0 but capsule perforation, positive surgical
margins, or seminal vesicle invasion) were randomized to external irradiation (60
Gy over 6 weeks) starting within 16 weeks of surgery vs. wait-and-see policy
wait-and-see policy included delay of subsequent treatment (irradiation or other)
until biochemical or clinical relapse
biochemical progression defined as increase in prostate-specific antigen (PSA)
concentration > 0.2 mcg/L measured on 2 occasions 2 weeks apart
median follow-up 5 years
comparing adjuvant radiation therapy vs. wait-and-see policy
biochemical progression-free survival in 74% vs. 52.6% (NNT 5)
clinical/radiographic progression-free survival in 91.2% vs. 81% (NNT 10)
locoregional failure at 5 years in 5.4% vs. 15.4% (NNT 10)
distant failure in 6.1% vs. 6.3%
overall survival 93.1% vs. 92.3%
comparing adjuvant radiation therapy vs. wait-and-see policy
grade 2 or 3 late effects in 30% vs. 15% (NNH 6)
grade 3 late effects in 4.2% vs. 2.6% (NNH 62)
14 patients (3.1%) stopped radiation therapy early due to toxicity
no grade 4 toxicity reported
Reference - EORTC trial 22911 (Lancet 2005 Aug 13;366(9485):572
EBSCOhost Full Text), editorial can be found in Lancet 2005 Aug
13-19;366(9485):524
EBSCOhost Full Text
adjuvant radiation therapy after radical prostatectomy may decrease risk of
biochemical or clinical progression at 10 years (level 2 [mid-level]
evidence)
based on follow-up of EORTC trial 22911
100% completed median 10.6-year follow-up
comparing radiation therapy vs. wait-and-see policy at 10 years
biochemical progression, clinical progression, or death in 39.4% vs. 61.8% (p
< 0.0001, NNT 5)
clinical progression or death in 31.3% vs. 36% (p = 0.054)
all-cause mortality 25.9% vs. 22.95% (not significant)
adverse events in 70.8% vs. 59.7% (p = 0.001, NNH 9)
Reference - Lancet 2012 Dec 8;380(9858):2018, editorial can be found in Lancet
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2012 Dec 8;380(9858):1974

adjuvant radiation therapy after radical prostatectomy for locally advanced
prostate cancer associated with reduced risk of disease recurrence (level 2
based on randomized trial without blinding (included in Cochrane review)
425 men with pT3N0M0 prostate cancer who had radical prostatectomy within 16
weeks, negative bone scan, negative lymph nodes on pelvic lymphadenectomy,
and at least 1 extraprostatic disease finding (extracapsular tumor extension,
positive surgical margins, or seminal vesicle invasion) were randomized to
radiation therapy (60-64 Gy to pelvic fossa in 30-32 fractions) vs. observation and
usual care
mean follow-up 10.9 years (median 10.6 years), 416 patients had at least 5 years
of follow-up
70 patients who were in observation group received radiotherapy at various
stages (median 2 years) after randomization
comparing adjuvant radiation therapy vs. observation
median metastasis-free survival 14.7 years vs. 13.2 years (p = 0.06)
metastases or death in 35.5% vs. 43.1% (p = 0.06, NNT 14)
metastases in 7.9% vs. 16.6% (not significant)
death in 33.2% vs. 39.3% (not significant)
median recurrence-free survival (not counting PSA elevation as recurrence)
13.8 years vs. 9.9 years (p = 0.001)
disease recurrence or death in 39.3% vs. 52.6% (p = 0.001, NNT 8)
median overall survival 14.7 years vs. 13.8 years (not significant)
complications in 23.8% vs. 11.9% (p = 0.002, NNH 8)
urethral stricture in 17.8% vs. 9.5% (p = 0.02, NNH 12)
rectal complications such as proctitis or rectal bleeding in 3.3% vs. 0% (p =
0.02, NNH 30)
total urinary incontinence in 6.5% vs. 2.8% (p = 0.11)
Reference - JAMA 2006 Nov 15;296(19):2329, commentary can be found in JAMA
2007 Mar 7;297(9):950, Nat Clin Pract Urol 2007 Aug;4(8):416
addition of radiation therapy to androgen deprivation therapy (ADT)
addition of radiation therapy to ADT may improve survival in patients with
locally advanced prostate cancer (level 2 [mid-level] evidence)
1,205 men (median age 70 years) with locally advanced prostate cancer were
randomized to lifelong ADT plus radiation therapy vs. ADT alone
patients had locally advanced (T3 or T4) disease or high-risk organ-confined (T2)
disease (defined as prostate-specific antigen [PSA] > 40 ng/mL or PSA 20-40
ng/mL plus Gleason score 8)
comparing ADT plus radiation therapy vs. ADT alone
10-year overall survival 55% vs. 49% (p = 0.001, NNT 17)
median overall survival 10.9 years vs. 9.7 years (p < 0.001)
prostate cancer-specific mortality 32% vs. 52% (p < 0.001, NNT 5)
10-year biochemical progression-free survival 74% vs. 46% (p < 0.05)
no significant differences in other disease-specific mortality causes
ADT plus radiation therapy associated with increased bowel-related adverse
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events (no p value reported)

Reference - J Clin Oncol 2015 Jul 1;33(19):2143 full-text
addition of radiation therapy to ADT may reduce mortality in elderly men
with locally advanced or screen-detected high-risk prostate cancer (level 2
31,451 men 65 years old with stage cT1-T3 prostate cancer having radiation
therapy plus systemic ADT or ADT alone were grouped into 1 of 3 cohorts
cohort 1 consisted of 12,924 men aged 65-75 years with stage cT2 disease
plus Gleason score 5-10 or with stage cT3 disease plus any Gleason score
(64% had radiation therapy plus ADT)
cohort 2 consisted of 14,340 men aged 76-85 years with stage cT2 plus
Gleason score 5-10 or stage cT3 disease with any Gleason score (39% had
radiation therapy plus ADT)
cohort 3 consisted of 4,277 men aged 65-85 years with screen-detected
stage cT1c disease plus Gleason score 8-10 (53% had radiation therapy plus
ADT)
comparing radiation therapy plus ADT vs. ADT alone in cohort 1
7-year cause-specific mortality 4.4% vs. 9.8% (adjusted hazard ratio 0.43,
95% CI 0.37-0.49)
7-year all-cause mortality 24.6% vs. 39.2% (adjusted hazard ratio 0.63, 95%
CI 0.59 to 0.67)
consistent results in cohorts 2 and 3
Reference - J Clin Oncol 2015 Mar 1;33(7):716, editorial can be found in J Clin
Oncol 2015 Mar 1;33(7):676, commentary can be found in BMJ 2015 Jan
7;350:h84
radiation therapy with rectangular fields may reduce risk of locoregional
progression or distant metastasis compared to conformal fields in patients with
high-risk prostate cancer (level 2 [mid-level] evidence)
based on post hoc secondary analysis of randomized trial
266 men with prostate cancer were randomized to radiation therapy (66 Gy to
prostate and seminal vesicles in 33 fractions) with rectangular vs. conformal radiation
elds
164 high-risk (prostate-specific antigen > 20 mcg/L, poor differentiation, or T3
tumors) patients were evaluated
median follow-up 34 months for surviving patients
comparing rectangular vs. conformal radiation elds
locoregional progression or distant metastasis in 11.4% vs. 28.2% (p = 0.012,
NNT 6)
regional progression or distant metastasis in 8.9% vs. 22.4% (p = 0.025, NNT 8)
Reference - Radiother Oncol 2013 May;107(2):134
Dosage ranges:
National Comprehensive Cancer Care Network recommendations based on NCCN risk
stratification(1)
definitive treatment
dose 75.6-79.2 Gy in conventional fractions (plus or minus seminal vesicles for
part of therapy) for men with low-risk cancer
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dose up to 81 Gy for men with intermediate- or high-risk cancer

moderately hypofractionated image-guided intensity-modulated radiation therapy
regimens (2.4-4 Gy per fraction over 4-6 weeks) may be considered alternative
when clinically indicated
extremely hypofractionated image-guided intensity-modulated radiation
therapy/stereotactic body radiation therapy regimens ( 6.5 Gy per fraction) at
clinics with appropriate technology, physics, and clinical expertise may be
considered cautious alternative
adjuvant treatment
dose 64-72 Gy in standard fractionation after prostatectomy
target adjuvant radiation therapy to prostate bed and pelvic lymph nodes in
intermediate and high-risk patients, and may include whole pelvis in some
patients
National Institute for Health and Care Excellence (NICE) recommendations
offer men having radical external beam radiation therapy for localized prostate cancer
minimum dose 74 Gy at 2 Gy per fraction(2)
escalated-dose conformal radiation therapy associated with increased
biochemical progression-free survival (level 3 [lacking direct] evidence) but
similar overall survival (level 2 [mid-level] evidence) compared to control-dose
conformal radiotherapy at 10 years in men with prostate cancer
based on follow-up of randomized trial without blinding
843 men with histologically confirmed T1b-T3a, N0, M0 prostate cancer and prostate
specific antigen < 50 ng/mL were randomized 1 of 2 conformal radiation therapy
dosages
escalated dose (74 Gy in 37 fractions)
control dose (64 Gy in 32 fractions)
all patients received neoadjuvant androgen deprivation therapy for 3-6 months before
start of conformal radiation therapy and continued until the end of radiation therapy
biochemical progression-free survival defined as time to biochemical failure, prostate
cancer-related death, or development of local, nodal, or metastatic disease
overall mortality 28% during median 10-year follow-up
comparing escalated dose vs. control dose
10-year biochemical progression-free survival 55% vs. 43% (p = 0.0003, NNT 9)
10-year overall survival 71% vs. 71% (not significant)
Reference - Lancet Oncol 2014 Apr;15(4):464
high-dose radiation therapy may reduce biochemical failure (level 3 [lacking
direct] evidence), but increase gastrointestinal and genitourinary toxicities
(level 2 [mid-level] evidence) compared to conventional dose in patients with
prostate cancer
systematic review of 6 randomized trials comparing high-dose radiation therapy
(HDRT) vs. conventional dose radiation therapy (CDRT) in 2,822 patients with prostate
cancer
HDRT total dose ranged from 74 to 80 Gy, CDRT total dose ranged from 64 to 70.2 Gy
HDRT associated with
decreased biochemical failure at 10 years in analysis of 5 trials with 2,327
patients
odds ratio (OR) 0.61 (95% CI 0.51-0.74)
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NNT 8-16 with biochemical failure in 34% of CDRT group

increased late grade 2 gastrointestinal toxicity in analysis of 5 trials with 2,507
patients
OR 1.72 (95% CI 1.42-2.08)
NNH 7-16 with late grade 2 gastrointestinal toxicity in 19% of CDRT group
increased late grade 2 genitourinary toxicity in analysis of 5 trials with 2,507
patients
OR 1.24 (95% CI 1.01-1.52)
NNH 13-651 with late grade 2 genitourinary toxicity in 19% of CDRT group
10-year overall survival in analysis of 4 trials with 2,026 patients
10-year prostate cancer-specific survival in analysis of 5 trials with 2,327 patients
quality of life in 2 trials
Reference - J Cancer Res Clin Oncol 2015 Jun;141(6):1063
consistent findings for overall survival comparing low-dose to high-dose external beam
radiation therapy in analysis of 3 trials with 1,363 patients with localized prostate
cancer in systematic review (Eur J Cancer 2015 Nov;51(16):2345 full-text)
higher external beam radiation therapy doses may reduce risk of biochemical
treatment failure (level 3 [lacking direct] evidence)
based on 1 systematic review and 3 randomized trials
higher dose external beam radiation therapy associated with lower risk of
biochemical treatment failure than lower dose external beam radiation
therapy (level 3 [lacking direct] evidence)
based on nonclinical outcomes of systematic review of mostly moderate-quality
observational studies
systematic review of 10 randomized trials and 65 cohort studies evaluating
radiation treatments for clinically localized prostate cancer
no randomized trials found comparing radiation therapy to no treatment
higher dose EBRT (78-79 Gy) associated with reduced risk of biochemical failure
at 5 and 10 years compared with lower dose EBRT (68-70 Gy) in analysis of 3
randomized trials and 11 cohort studies but no meta-analysis performed and no
statistics given
Reference - Ann Intern Med 2011 Aug 2;155(3):171
EBSCOhost Full Text
external beam radiation therapy at 80 Gy associated with decreased risk of
biochemical relapse but increased risk of urinary toxicity compared to 70 Gy
306 patients (mean age 67 years) with localized prostate cancer were randomized
to 3-dimensional conformal EBRT at 80 Gy vs. 70 Gy and followed for median 61
months
toxicity graded using the Radiation Therapy Oncology Group 1991 criteria and
late effects on normal tissues-subjective, objective, management, analytic scales
(LENT-SOMA) scales
comparing 80 Gy vs. 70 Gy
biochemical relapse in 28% vs. 39% (p = 0.036, NNT 9)
urinary toxicity grade 2 in 17.5% vs. 10% (p = 0.046, NNH 13 for 80 Gy)
rectal toxicity grade 2 in 19.5% vs. 14% (not significant)
no significant differences in mortality or quality of life
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Reference - GETUG 06 trial (Int J Radiat Oncol Biol Phys 2011 Jul 15;80(4):1056)
high-dose radiation may reduce risk of local and biochemical failure
compared with conventional-dose radiation (level 3 [lacking direct]
evidence)
based on nonclinical outcome from randomized trial
393 patients with stage T1b-T2b prostate cancer and PSA levels < 15 ng/mL were
randomized to high dose (79.2 Gy) vs. conventional dose (70.2 Gy) of EBRT and
followed for median 5.5 years
comparing high dose vs. conventional dose
freedom from biochemical failure (increasing PSA level) at 5 years in 80.4%
vs. 61.4% (p < 0.001, NNT 6)
freedom from local failure at 5 years in 67.2% vs. 47.6% (p < 0.001, NNT 6)
acute grade 2 gastrointestinal morbidity in 57% vs. 41% (p = 0.004, NNH 6)
late grade 2 gastrointestinal morbidity in 17% vs. 8% (p = 0.005, NNH 11)
no significant differences in overall survival, genitourinary morbidity, or grade 3
gastrointestinal morbidity
Reference - PROG 9509 (JAMA 2005 Sep 14;294(10):1233 full-text), correction in
JAMA 2008 Feb 27;299(8):899, editorial can be found in JAMA 2005 Sep
14;294(10):1274, commentary can be found in JAMA 2008 Feb 27;299(8):898
high-dose conformal radiation may reduce risk of biochemical treatment
failure at 5 years (level 3 [lacking direct] evidence)
based on nonclinical outcome in randomized trial without blinding
669 patients with stage T1b-4 prostate cancer randomized to high-dose (78 Gy)
vs. conventional-dose (68 Gy) of EBRT and followed for median 50.7 months
patients with metastases or previous malignancy except basal cell carcinoma were
excluded
neoadjuvant or adjuvant hormone therapy allowed but not recommended
comparing high-dose vs. conventional-dose
freedom from biochemical or local failure at 5 years in 64% vs. 54% (p =
0.02, NNT 10)
freedom from clinical failure at 5 years in 76% vs. 76% (not significant)
overall survival at 5 years 83% vs. 82% (not significant)
Reference - J Clin Oncol 2006 May 1;24(13):1990 full-text, editorial can be found
in J Clin Oncol 2006 May 1;24(13):1975, commentary can be found in Nat Clin
Pract Urol 2007 Jan;4(1):18
patients with PSA < 8 ng/mL may not benefit from high-dose conformal
radiation
based on subgroup analysis of randomized trial
6-year freedom from failure comparing high dose vs. conventional dose
in patients with PSA 1-7.99 ng/mL 64% vs. 73% (not significant)
in patients with PSA 8-18 ng/mL 70% vs. 52% (p = 0.008, NNT 6)
in patients with PSA > 18 ng/mL 50% vs. 43% (not significant)
Reference - Radiother Oncol 2010 Jul;96(1):13
hypofractionated external beam radiation therapy does not appear to reduce
biochemical and/or clinical disease failure compared to conventional external
beam radiation therapy (level 2 [mid-level] evidence)
307 men with prostate cancer randomized to 1 of 2 EBRT regimens
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70.2 Gy in 26 fractions at 2.7 Gy per fraction (hypofractionated EBRT, equivalent

of 84.4 Gy in 2 Gy fractions)
76 Gy in 38 fractions at 2 Gy per fraction (conventional EBRT)
all patients with high-risk disease received long-term androgen deprivation therapy
303 men (99%) were included in analyses
median follow-up 68.4 months
5-year biochemical and/or clinical disease failure in 23.3% with hypofractionated EBRT
vs. 21.4% with conventional EBRT (not significant)
no significant differences in local or distant failure, prostate cancer-specific mortality,
all-cause mortality, or late toxicity
Reference - J Clin Oncol 2013 Nov 1;31(31):3860, editorial can be found in J Clin
Oncol 2013 Nov 1;31(31):3849
Adverse effects of external beam radiation therapy and their management:
key adverse effects include
urinary symptoms, including nocturia, dysuria, urinary urgency
gastrointestinal symptoms, including proctitis and rectal bleeding
see Radiation therapy for prostate cancer for details
Pelvic lymph node irradiation:
pelvic lymph node irradiation should be considered for men with intermediate- or high-risk
cancer based on NCCN risk stratification, but not those with low-risk cancer(1)
prophylactic pelvic radiation may not improve long-term survival in patients
with nonmetastatic prostate cancer treated with prostate radiation therapy
444 patients (mean age 68 years) with localized prostate cancer (stage T1b-T3, N0
pNx, M0) were randomized to pelvic and prostate external beam radiation therapy vs.
prostate radiation therapy and followed for median 42.1 months
comparing pelvic and prostate radiation therapy vs. prostate radiation therapy
5-year progression-free survival 66% vs. 65.3% (not significant)
5-year overall survival 86.5% vs. 88.3% (not significant)
no significant differences in acute and late digestive toxicities or quality-of-life
outcomes
Reference - J Clin Oncol 2007 Dec 1;25(34):5366 full-text, commentary can be
found in J Clin Oncol 2008 Apr 20;26(12):2055
Proton beam radiation therapy:
American Society for Radiation Oncology does not routinely recommend proton beam
therapy for prostate cancer outside of a prospective clinical trial or registry (Choosing
Wisely 2014 Sep 15)
proton beam radiation therapy is an option, but no data support use of proton beam
radiation therapy over usual therapies(1, 2, 3)
proton beam radiation therapy has insufficient evidence to support use for prostate cancer
3 randomized trials found evaluating particle beam radiation therapy in prostate
cancer, none reported significant differences in overall or cancer-specific survival
(AHRQ Technical Brief 2009 Sep:1 PDF)
systematic review found 1 of 2 randomized trials of proton irradiation as boost
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following conventional radiation therapy for prostate cancer, reported improved

biochemical control with higher dose (Radiother Oncol 2007 May;83(2):123)
proton beam therapy for prostate cancer does not appear cost-effective (Singapore
Health Technology Assessment 2008 May PDF, J Clin Oncol 2007 Aug
20;25(24):3603 full-text)
Focal Therapies
Recommendations:
European Association of Urology (EAU) criteria and recommendations based on EAU risk
stratification(3)
focal therapy for prostate cannot be recommended as therapeutic alternative outside
of clinical trial (EAU Grade A)
cryosurgery indicated in men who are not candidates for surgery or radiation therapy
(EAU Grade C)
lack of long-term (> 10 years) comparative outcome data for high intensity focused
ultrasound (HIFU) should be discussed with the patient (EAU Grade C)
National Institute for Health and Care Excellence (NICE) recommends not offering
cryotherapy or HIFU to men with localized prostate cancer except in context of clinical
trial(2)
Cryotherapy:
cryotherapy (also called cryosurgery or cryoablation), is a minimally invasive focal therapy
that achieves tumor tissue damage by local freezing(1, 3)
cryotherapy technique(3)
involves placement of 12-15 17 gauge cryoneedles in prostate with transrectal
ultrasound (TRUS) guidance, placement of thermosensors at external sphincter and
bladder neck, and insertion of urethral warmer
2 freeze-thaw cycles gives temperature of -40 degree C (104 degree F) in mid-gland
and at neurovascular bundle
5-year biochemical disease-free survival rates for cryotherapy(3)
at prostate-specific antigen (PSA) threshold 1 ng/mL (1 mcg/L) reported to be
76% for low-risk cancer
71% for intermediate-risk cancer
61% for high-risk cancer
at PSA threshold < 0.5 ng/mL (0.5 mcg/L) reported to be
cryotherapy complication rates reported to be(3)
erectile dysfunction in about 80%
incontinence in 4.4%
tissue sloughing in about 3%
urinary retention in about 2%
pelvic pain in 1.4%
High intensity focused ultrasound (HIFU):
high intensity focused ultrasound (HIFU) technique(3)
uses focused ultrasound waves to damage tissue through mechanical, thermal, and
cavitation effects
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performed under general or spinal anesthesia

10 g prostate tissue treated per hour
8-year biochemical disease-free survival rates for high intensity focused ultrasound
reported to be(3)
Hormonal Therapy
National Comprehensive Cancer Network (NCCN) recommendations on optimal androgen
deprivation therapy (ADT)(1)
surgical castration and medical castration are equally effective
antiandrogen monotherapy may be less effective than medical or surgical castration
and is not recommended as primary ADT
men who do not have adequate serum testosterone suppression (< 50 ng/dL) with
medical or surgical castration may be considered for additional hormonal treatments
(estrogen, antiandrogen, or steroids), though clinical benefit uncertain (optimal level
of serum testosterone suppression has yet to be defined)
Indications:
National Comprehensive Cancer Network (NCCN) recommendations for androgen
deprivation therapy (ADT) based on NCCN risk stratification(1)
ADT before radical prostatectomy strongly discouraged outside of clinical trials
ADT should not be used as monotherapy in clinically localized disease
for men with intermediate-risk cancer, options include external beam radiation therapy
(EBRT), with or without 4-6 months ADT and with or without brachytherapy (NCCN
Category 2A)
for men with localized high-risk cancer, options include
EBRT plus brachytherapy, with or without 2-3 years ADT (NCCN Category 2A)
for men with very high-risk cancer, options include
ADT for patients not eligible for definitive therapy (NCCN Category 2A)
adjuvant ADT after radical prostatectomy and pelvic lymph node dissection indicated
for men with lymph node metastases if
very low risk disease and life expectancy 20 years as monotherapy (NCCN
Category 1) or in combination with EBRT (NCCN Category 2B)
low risk disease and life expectancy 10 years as monotherapy (NCCN Category
1) or in combination with radiation therapy (NCCN Category 2B)
intermediate risk disease and life expectancy 10 years as monotherapy (NCCN
Category 1) or in combination with EBRT (NCCN Category 2B)
high risk disease and very high risk disease with no fixation as monotherapy
(NCCN Category 1) or in combination with EBRT (NCCN Category 2B)
European Association of Urology (EAU) recommendations(3)
androgen suppression monotherapy is an option for high-risk men with all of the
following criteria (EAU Grade A)
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who are not candidates for any form of local treatment or who are unwilling to
undergo local treatment
with PSA doubling time < 12 months
with PSA > 50 ng/ml
with a poorly differentiated tumor
for men with node positive disease after extended lymph node dissection
offer adjuvant androgen deprivation therapy (ADT) (EAU Grade A)
immediate long-term androgen deprivation therapy (ADT) may be given in
combination with pelvic external beam radiation (EAU Grade B)
adjuvant androgen deprivation therapy (ADT) plus additional radiation therapy
may be an option (EAU Grade B)
do not offer ADT plus radical prostatectomy, even in men with margin-positive
disease, except in clinical trial
indications for ADT based on NICE risk stratification
radical radiation therapy plus 6 months ADT before, during, or after treatment or
radical prostatectomy recommended for men with intermediate risk or men with
high risk and realistic prospect of long-term disease control
consider ADT for up to 3 years for men with high-risk cancer
Techniques:
Bilateral orchiectomy (surgical castration):
bilateral orchiectomy (surgical castration)(1, 4)
quick reduction of testosterone
can be performed under local anesthesia
Luteinizing-hormone releasing hormone agonists or antagonists (medical
castration):
Agonists:
also called
luteinizing-hormone releasing hormone (LHRH) analogs
gonadotropin-releasing hormone (GnRH) agonists
GnRH agonists
LHRH agonists cause medical castration by inhibiting release of gonadotropins (1, 4)
initially, LHRH agonist stimulates luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) and leads to a testosterone surge
clinical flare with symptoms (including bone pain, acute bladder outlet obstruction,
renal obstruction, spinal cord compression, or cardiovascular events), may be
associated with testosterone surge
available LHRH agonists
goserelin (Zoladex) 3.6 mg subcutaneous implant every 4 weeks or 10.8 mg
subcutaneous implant every 12 weeks
histrelin (Vantas) 50 mg subcutaneous implant every 12 months
leuprolide (Eligard, Lupron, Lupron Depot, Viadur)
Eligard 7.5 mg subcutaneously once monthly
Lupron 1 mg subcutaneously once daily
Lupron Depot
7.5 mg intramuscularly once monthly or
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22.5 mg intramuscularly once every 12 weeks

triptorelin (Trelstar)
3.75 mg intramuscularly every 4 weeks (28 days)
11.25 mg intramuscularly every 12 weeks
22.5 mg intramuscularly every 24 weeks
buserelin (Suprefact, CinnaFact) in Canada, South Africa, and United Kingdom; not
available in United States
Antagonists:
also called luteinizing-hormone releasing hormone (LHRH) antagonists or gonadotropinreleasing hormone (GnRH) antagonists
avoids testosterone surge that occurs with starting LHRH agonists(1, 3)
LHRH antagonists bind immediately to LHRH receptors in pituitary
rapid drop in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and
testosterone
hormonal adverse effects similar to LHRH agonists(4)
available LHRH antagonists
degarelix (Firmagon) FDA approved dose for treatment of advanced prostate cancer
initial dose 240 mg (given as 2 subcutaneous injections of 120 mg at
concentration of 40 mg/mL, administered at 2 different injection sites)
maintenance dose 80 mg (1 subcutaneous injection at concentration of 20
mg/mL) every 28 days, starting 28 days after initial dose
abarelix (Plenaxis) for palliative treatment in men with advanced prostate cancer
(withdrawn in United States in 2005, only available in Germany) (Trends Endocrinol
Metab 2009 Jan;20(1):43)
Complete androgen blockade (CAB):
also called combined androgen blockade or total androgen blockade (1, 2)
includes both(1)
reduction of testosterone via medical or surgical castration
antiandrogen treatment to block androgen activity at testosterone receptors in
prostate cells
Antiandrogens:
primary mechanism of action of antiandrogens is competing with testosterone at androgen
receptor(1)
nonsteroidal antiandrogens
drugs include
bicalutamide (Casodex) 50 mg orally once daily
nilutamide (Nilandron) 300 mg orally once daily for 30 days, then 150 mg orally
once daily
flutamide (Eulexin) 250 mg orally every 8 hours
enzalutamide (Xtandi) 160 mg (4 capsules) orally once daily
adverse effects include
liver toxicity (occasionally fatal) - liver enzymes must be regularly monitored
gynecomastia
breast pain
Reference - European Association of Urology 2015 Guidelines on Prostate Cancer PDF
steroidal antiandrogens
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drugs include
cyproterone acetate
medroxyprogesterone acetate
megestrol acetate
adverse effects include
liver toxicity (occasionally fatal) - liver enzymes must be regularly monitored
cardiovascular toxicity
gynecomastia (rarely)
impotence
loss of libido
Estrogens:
decrease pituitary gonadotropins by down-regulating LHRH secretion(1, 3)
regimens FDA approved for palliative treatment of androgen-dependent advanced prostate
carcinoma
estradiol (Estrace) 1-2 mg orally 3 times daily, available in 0.5 mg, 1 mg, and 2 mg
scored tablets
estradiol valerate (Delestrogen) 30 mg intramuscularly every 1-2 weeks; available in
10 mg/mL, 20 mg/mL, and 40 mg/mL strengths
esterified estrogens (Menest) 1.25-2.5 mg orally 3 times daily; available in 0.3 mg,
0.625 mg, 1.25 mg, and 2.5 mg tablets
diethylstilbestrol (DES, Stilboestrol) (not available in United States)
1-3 mg orally once daily
reported to be as effective as bilateral orchiectomy but associated with cardiovascular
adverse effects
contraindication is known cardiovascular disease, due to cardiotoxicity of estrogen
therapy(3)
Primary androgen deprivation therapy (ADT):
Efficacy:
addition of dutasteride to active surveillance may reduce progression in men
with low-risk prostate cancer (level 2 [mid-level] evidence)
based on randomized trial with inadequate statistical power
302 men aged 48-82 years with low-risk prostate cancer having active surveillance
randomized to dutasteride 0.5 mg once daily vs. placebo for 3 years
inclusion criteria
clinically diagnosed low-risk prostate cancer (T1c-T2a)
Gleason score of 6 (no Gleason pattern score of 4)
serum prostate-specific antigen (PSA) of 11 ng/mL
life expectancy of > 5 years
patients and investigators were not blinded to prostate-specific antigen concentrations
time to prostate cancer progression defined as time to either pathological progression
or therapeutic progression (start of medical therapy)
pathological progression defined as meeting 1 of predefined criteria
4 cores involved
50% of any one core involved
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Gleason pattern score of 4

95% in dutasteride group and 88% in placebo group had 1 postbaseline biopsy
96% had 1 biopsy after baseline or therapeutic progression and were included in
primary analysis
comparing dutasteride vs. placebo at 3 years
prostate cancer progression (pathologic or therapeutic) in 38% vs. 48% (p =
0.009, NNT 10)
pathological progression in 29% vs. 33% (p = 0.079)
therapeutic progression in 7.5% vs. 12.3% (p = 0.074)
no evidence of cancer at final biopsy (in 91%) in 36% vs. 23% (p = 0.024, NNT
8)
Reference - REDEEM trial (Lancet 2012 Mar 24;379(9821):1103), editorial can be
found in J Urol 2012 Jul;188(1):110, commentary can be found in Nat Rev Urol 2012
Feb 14;9(3):119, Lancet 2012 Mar 24;379(9821):1078, Eur Urol 2012 Jun;61(6):1265,
Aktuelle Urol 2013 Jan;44(1):8 (German), Eur Urol 2013 Jul;64(1):167
DynaMed commentary -- definition of therapeutic progression may overestimate
progression rates in men receiving active surveillance alone, since some men may
seek treatment due to anxiety of not actively treating their disease
primary androgen deprivation therapy may increase mortality compared with
watchful waiting for patients > 65 years old with T1-T2 prostate cancer (level 2
based on 2 cohort studies of Surveillance, Epidemiology, and End Results (SEER)
Medicare data using different statistical methods for adjusted analyses
19,271 men > 66 years old who had T1-T2 prostate cancer and did not have surgery
or radiation therapy in first 180 days from diagnosis were evaluated
7,867 had primary androgen deprivation therapy (PADT, either luteinizinghormone releasing hormone [LHRH] agonist or orchiectomy) as primary cancer
therapy (median age 79 years)
11,404 had watchful waiting (did not receive surgery, radiation, or PADT)
(median age 77 years)
median follow-up 81 months
comparing PADT vs. watchful waiting
all-cause mortality 11.9 vs. 9.5 per 100 person-years (p < 0.05, NNH 41.7
person-years)
prostate cancer mortality 2.6 vs. 1.3 per 100 person-years (p < 0.05, NNH
76.9 person-years)
in statistical analysis adjusting for regional variations in PADT use
no significant association with all-cause mortality
PADT still associated with increased prostate cancer mortality
Reference - JAMA 2008 Jul 9;300(2):173 full-text, correction can be found in
JAMA 2009 Jan 7;301(1):38, commentary can be found in JAMA 2009 Jan
7;301(1):35, Nat Clin Pract Urol 2008 Dec;5(12):648
compared to watchful waiting, primary androgen deprivation therapy may
reduce survival in men > 65 years old with localized prostate cancer (level 2
analysis of SEER Medicare data for 16,535 men aged 65-80 years with organconfined well-differentiated or moderately-differentiated prostate cancer who
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survived > 1 year and did not have prostatectomy or radiation therapy within 6
months of diagnosis (watchful waiting)
4,316 (25.5%) had PADT (LHRH agonist or bilateral orchiectomy) during first 6
months after diagnosis
median overall survival 8.26 years with PADT vs. 10 years with watchful waiting
(adjusted hazard ratio 1.19, 95% CI 1.13-1.27)
Reference - Eur Urol 2009 Oct;56(4):609 full-text
Timing of ADT:
in patients not suitable for curative therapy, immediate androgen deprivation
therapy associated with reduced mortality compared to deferred androgen
deprivation therapy at time of symptomatic progression (level 2 [mid-level]
evidence)
based on randomized trial with confidence intervals including clinically unimportant
differences
985 patients (median age 73 years) with localized prostate cancer (T0-4, N0-2, M0)
not suitable for local curative treatment randomized to immediate vs. deferred
androgen ablation (at time of symptomatic disease progression or serious
complications)
median follow-up 7.8 years with median time of starting deferred treatment 7 years
in deferred treatment arm
44% died
25.6% died without ever needing androgen deprivation
immediate ADT associated with improved overall survival compared to deferred
(hazard ratio 1.25, 95% CI 1.05-1.48)
Reference - J Clin Oncol 2006 Apr 20;24(12):1868 full-text, commentary can be found
in Eur Urol 2006 Aug;50(2):384, Nat Clin Pract Urol 2006 Sep;3(9):474, J Clin Oncol
2006 Nov 10;24(32):5172
consistent findings at 10 years
985 patients were followed for median 12.8 years
all-cause mortality 78% and prostate cancer-related mortality 27%
mean duration of exposure to androgen deprivation therapy 87 months in
immediate group vs. 27 months in deferred group (p < 0.0001)
comparing immediate vs. deferred androgen deprivation therapy
10-year mortality 64% vs. 74% (hazard ratio 1.21, 95% CI 1.05-1.39, NNT
10)
mortality at end of follow-up 76% vs. 80% (no p value reported)
10-year disease progression 30% vs. 42% (p < 0.05)
no significant difference in time to castration-resistant disease
Reference - Eur Urol 2014 Nov;66(5):829
early androgen suppression for advanced prostate cancer might increase overall
survival at 10 years but not associated with earlier survival benefit (level 2
based on Cochrane review with incomplete assessment of trial quality
systematic review of 4 randomized trials evaluating timing of androgen as referenced
in suppression in 2,167 patients with advanced prostate cancer (local disease too
advanced for curative treatment or metastatic disease)
1 trial evaluated ADT after radical prostatectomy and pelvic lymphadenectomy for
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local disease, and found to have microscopic evidence of nodal metastases on

pathological examination
3 trials evaluated primary ADT
all trials conducted prior to use of PSA testing
trial quality assessment did not include loss to follow-up
androgen suppression therapies studied included orchiectomy, goserelin, or other
LHRH analog, and diethylstilbestrol
early androgen suppression defined as treatment immediately at time of diagnosis or
immediately following surgery or for clinically localized but pathologically advanced
disease
deferred androgen suppression defined as therapy withheld until symptoms, clinical
signs, or radiologic progression
comparing early vs. delayed androgen suppression
no significant differences in overall survival at
1 year in analysis of 4 trials with 2,167 patients
3 years in analysis of 4 trials with 2,012 patients
5 years in analysis of 4 trials with 1,572 patients
early androgen suppression associated with increased 10-year overall survival
(odds ratio 1.5, 95% CI 1.04-2.16) in analysis of 4 trials with 982 patients
Reference - Cochrane Database Syst Rev 2002;(1):CD003506
Comparative efficacy:
nonsteroidal antiandrogen monotherapy may have similar effect on survival but
different adverse effect profile compared to luteinizing hormone-releasing
hormone agonists or surgical castration in men with nonmetastatic prostate
cancer (level 2 [mid-level] evidence)
systematic review of 11 randomized trials comparing nonsteroidal antiandrogen
monotherapy vs. luteinizing hormone-releasing hormone agonists or surgical
castration monotherapy (control) in 3,060 men with advanced prostate cancer
nonsteroidal antiandrogen monotherapies included flutamide and bicalutamide
luteinizing hormone-releasing hormone agonists included goserelin, triptorelin,
and leuprorelin
unclear or no allocation concealment
lack of blinding of outcome assessor
7 trials included men with nonmetastatic prostate cancer
no significant differences in clinical progression, survival, and serious adverse events
nonsteroidal antiandrogen monotherapy associated with increased breast pain,
gynecomastia, vomiting, and asthenia but decreased hot flashes, hemorrhage,
nocturia, fatigue, loss of sexual interest, and urinary frequency
Reference - Cochrane Database Syst Rev 2014 Jun 30;(6):CD009266
gonadotropin-releasing hormone antagonists and standard androgen
suppression therapy associated with similar mortality and risk of progression
and treatment failure in men with advanced prostate cancer (level 2 [mid-level]
evidence)
based on systematic review of trials without blinding
systematic review of 13 trials (10 randomized and 3 nonrandomized trials) comparing
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gonadotropin-releasing hormone (GnRH) antagonists vs. standard androgen

suppression therapy in 4,107 men with advanced prostate cancer
GnRH antagonists included abarelix 100 mg intramuscularly (6 trials) and
degarelix initial dose 240 mg then maintenance dose 80 or 160 mg
subcutaneously (7 trials)
follow-up ranged from 27 days to 1 year
overall mortality in analysis of 9 trials with 3,020 patients
prostate-specific antigen progression in analysis of 7 trials with 2,489 patients
treatment failure in analysis of 7 trials with 2,200 patients
urinary symptom-specific quality of life in analysis of 3 trials with 461 patients
risk of serious adverse events (7 trials), severe/life-threatening adverse events (5
trials), or discontinuation due to adverse events (8 trials)
GnRH antagonists associated with improved prostate symptom-specific quality of life
(mean score difference -1.84, 95% CI -3 to -0.69) in analysis of 3 trials with 459
patients
Reference - BMJ Open 2015 Nov 13;5(11):e008217 full-text
in patients with prostate cancer ineligible for radical treatment, degarelix
appears as effective for decreasing prostate volume and may reduce lower
urinary tract symptoms compared to goserelin plus bicalutamide (level 2
182 men (mean age 73 years) with prostate cancer ineligible for radical treatment
randomized to degarelix vs. goserelin once monthly for 3 months
first dose of degarelix 240 mg subcutaneously followed by second and third
doses of 80 mg subcutaneously
goserelin doses 3.6 mg subcutaneously plus patients received bicalutamide
50 mg/day orally for 28 days for flare protection
60% had localized or locally advanced disease and 29% had metastatic disease
comparing degarelix vs. goserelin
decrease in total prostate volume 37.2% vs. 39% (not significant)
clinically relevant relief of lower urinary tract symptoms (defined as 3-point
decrease in International Prostate Symptom Score) in 61% vs. 44.3% (p =
0.02, NNT 6)
adverse events in 39% vs. 48% (not significant)
no significant difference in total prostate volume
EBSCOhost Full Text
degarelix may be as effective as leuprolide for maintaining low testosterone
levels over 1-year period in patients with prostate cancer (level 3 [lacking
direct] evidence) without increased risk for cardiovascular events (level 2
based on randomized trial with clinical outcomes limited to secondary analysis
610 men 18 years old with adenocarcinoma of prostate were randomized to 1
of 3 treatments for 12 months
degarelix 240 mg at baseline, then maintenance dose of degarelix 80
mg/month subcutaneously
degarelix 240 mg subcutaneous at baseline, then maintenance dose of
degarelix 160 mg/month subcutaneously
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leuprolide 7.5 mg/month intramuscularly

no significant differences in treatment response, defined as suppression of
testosterone to 0.5 ng/mL at all monthly measurements
97% with degarelix 80 mg
98% with degarelix 160 mg
96% with leuprolide
commentary can be found in BJU Int 2009 Jan;103(2):145
EBSCOhost Full
Text, Eur Urol 2009 Jun;55(6):1488
consistent results for testosterone and PSA suppression at median follow-up 27.5
months (J Urol 2011 Sep;186(3):889)
comparing pooled degarelix groups vs. leuprolide in secondary analysis, no
significant differences in
serious arrhythmias (2% vs. 5%)
ischemic heart disease (4% vs.10%)
prolongation of QT interval
Reference - J Urol 2010 Dec;184(6):2313 full-text
addition of chemotherapy with docetaxel plus estramustine to ADT may
increase relapse-free survival in men with treatment-naive high-risk localized
prostate cancer (level 2 [mid-level] evidence)
413 men (median age 63 years) with treatment-naive high-risk localized prostate
cancer in France were randomized to chemotherapy plus ADT vs. ADT alone for 3
years
chemotherapy regimen was docetaxel 70 mg/m2 IV on day 2 every 3 weeks plus
estramustine 10 mg/kg/day orally on days 1-5 every 3 weeks for 4 cycles; doses
could be reduced by 25% in any subsequent cycle if neutropenic fever or grade 4
neutropenia for 6 days
ADT regimen was goserelin 10.8 mg subcutaneously every 3 months plus
investigator's choice of androgen receptor inhibitor for first 3 weeks
adjunctive local treatment with radiation therapy or prostatectomy was allowed at
3 months after start of systemic therapy
median follow-up 8.8 years
relapse defined as biochemical failure, onset of metastases on imaging, local relapse,
need for salvage treatment, or death
comparing chemotherapy plus ADT vs. ADT alone
8-year relapse-free survival in 62% vs. 50% (p = 0.017, NNT 9)
secondary cancer in 13% vs. 11% (not significant)
long-term side effect grade 2 in 21% vs. 18% (not significant) in subgroup of
396 patients having adjunctive radiation therapy
no treatment-related deaths reported
Reference - GETUG 12 trial (Lancet Oncol 2015 Jul;16(7):787), editorial can be found
in Lancet Oncol 2015 Jul;16(7):741, commentary can be found in Nat Rev Urol 2015
Jul;12(7):358
Adjuvant ADT after prostatectomy:
adjuvant hormone therapy does not appear to improve overall survival at 5
years in patients with localized or locally advanced prostate cancer treated with
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prostatectomy, and may decrease overall survival at 10 years (level 2

based on Cochrane review of trials with methodological limitations
21 studies with 11,149 patients who received neoadjuvant or adjuvant hormone
therapy for localized or locally advanced prostate cancer reviewed
methodological limitations included
unclear method of randomization in 15 studies
absence of blinding of intervention allocation and outcome assessment in 20
studies
comparing adjuvant hormone therapy after prostatectomy to prostatectomy alone in
analysis of 2 trials with 407 patients
no significant difference in overall survival at 5 years
adjuvant hormone therapy after prostatectomy associated with
decreased overall survival at 10 years
(odds ratio [OR] 0.53, 95% CI 0.33-0.84), results limited by significant
heterogeneity
NNH 3-24 with 64.4% survival in controls
increased disease-free survival at 5 years
OR 3.73 (95% CI 2.3-6.03)
NNT 4-6 with 60.6% survival in controls
increased disease-free survival at 10 years
OR 2.06 (95% CI 1.34-3.15)
NNT 4-15 with 37% survival in controls
Adjuvant ADT after radiation therapy:
Efficacy:
addition of hormone therapy to radiation therapy associated with improved
survival in patients with localized or locally advanced prostate cancer (level 2
based on 3 systematic reviews and 3 randomized trials with heterogeneity or
methodologic limitations
adjuvant hormone therapy may improve overall survival and diseasespecific survival in patients with localized or locally advanced prostate
cancer treated with radiation therapy (level 2 [mid-level] evidence)
based on Cochrane review limited by heterogeneity
systematic review of 21 randomized trials in 11,149 patients with localized or
locally advanced prostate cancer
trials heterogeneous for type of hormonal therapy and staging of disease
compared to radiation therapy alone, adjuvant hormone therapy during or after
radiation therapy associated with
increased overall survival at 5 years in analysis of 4 trials with 2,844 patients
odds ratio (OR) 1.29 (95% CI 1.07-1.56)
increased overall survival at 10 years in analysis of 2 trials with 1,059
patients
OR 1.44 (95% CI 1.13-1.84)
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increased disease-specific survival at 5 years in analysis of 2 trials with 1,392

patients
OR 2.1 (95% CI 1.53-2.88)
increased disease-free survival at 10 years in analysis of 2 trials with 1,059
patients
OR 1.96 (95% CI 1.49-2.56)
addition of adjuvant hormone therapy to low-dose external beam radiation
therapy associated with increased overall survival in men with localized
based on systematic review of trials with methodologic limitations
systematic review of 36 randomized trials evaluating management options for
men with localized prostate cancer
management options included radiation therapy (brachytherapy and/or external
beam radiation therapy [EBRT]) and nonpharmacological therapies (radical
prostatectomy, high intensity focused ultrasound, cryotherapy, active surveillance,
or watchful waiting), each with or without adjuvant hormone therapy
no or unclear allocation concealment
no or unclear blinding
low-dose EBRT plus adjuvant hormone therapy associated with increased overall
survival compared to low-dose EBRT alone in analysis of 6 trials with 3,936
patients
risk ratio 1.21 (95% CI 1.12-1.3)
NNT 8-18, with overall survival 46.6% in EBRT alone group
Reference - Eur J Cancer 2015 Nov;51(16):2345 full-text
addition of hormone therapy to radiation therapy associated with improved
survival in locally advanced prostate cancer (level 2 [mid-level] evidence)
systematic review of 7 randomized trials comparing radiation therapy plus
hormone therapy to radiation therapy alone in 4,387 patients with locally
advanced prostate cancer
radiation therapy plus hormone therapy associated with
decreased biochemical failure in analysis of 7 trials with 3,956 patients
relative risk (RR) 0.76 (95% CI 0.7-0.82, NNT 10)
results limited by significant heterogeneity
improved clinical progression-free survival in analysis of 5 trials with 4,020
patients
RR 0.81 (95% CI 0.71-0.93, NNT 13)
results limited by heterogeneity
improved cancer-specific survival (RR 0.76, 95% CI 0.69-0.83, NNT 18) in
analysis of 6 trials with 4,266 patients
improved overall survival (RR 0.86, 95% CI 0.8-0.93, NNT 20) in analysis of
6 trials with 4,266 patients
decreased local relapse rate (RR 0.64, 95% CI 0.54-0.75, NNT 11) in analysis
of 4 trials with 2,650 patients
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decreased distant relapse rate (RR 0.72, 95% CI 0.65-0.81, NNT 11) in
no significant differences in toxicity or cardiac deaths
Reference - Cancer 2009 Aug 1;115(15):3446 full-text
addition of long-term androgen suppression to radiation therapy associated
with increased 10-year survival in prostate cancer patients with high
metastatic risk (level 2 [mid-level] evidence)
415 patients < 80 years old with newly diagnosed prostate cancer with high
metastatic risk randomized to radiation therapy alone (external radiation once
daily 5 days/week for 7 weeks) vs. radiation therapy plus immediate androgen
suppression
high metastatic risk defined as World Health Organization (WHO) histologic grade
3 or T3-T4 disease and WHO performance status of 0-2
androgen suppression with goserelin acetate subcutaneously every 4 weeks for 3
years and cyproterone acetate given for 1 month starting 1 week before first
goserelin injection
comparing radiation therapy plus immediate androgen suppression vs. radiation
therapy alone
10-year clinical disease-free survival 47.7% vs. 22.7% (p < 0.0001, NNT 4)
10-year overall survival 58.1% vs. 39.8% (p = 0.0004, NNT 6)
10-year prostate cancer mortality 10.3% vs. 30.4% (p < 0.0001, NNH 5)
no significant difference in cardiovascular mortality
Reference - Lancet Oncol 2010 Nov;11(11):1066, editorial can be found in Lancet
Oncol 2010 Nov;11(11):1016, commentary can be found in Nat Rev Urol 2010
Dec;7(12):644
addition of androgen deprivation therapy to radiation therapy may improve
survival in patients with localized prostate cancer but unclear if benefit
significant for all risk groups (level 2 [mid-level] evidence)
2,028 patients (median age 70 years) with stage T1b, T1c, T2a, or T2b prostate
adenocarcinoma and prostate-specific antigen (PSA) level 20 ng/mL were
randomized to radiation therapy plus androgen deprivation therapy (ADT) for 4
months (starting 2 months before radiation therapy) vs. radiation therapy alone
ADT was flutamide 250 mg orally 3 times daily plus either goserelin 3.6
mg/month subcutaneously or leuprolide 7.5 mg/month intramuscularly
49 patients were ineligible, withdrew consent, or did not have pretreatment data;
1,979 patients (98%) analyzed
risk stratification
685 patients were low risk (defined as Gleason score 6, PSA level 10
ng/mL, and clinical stage T1 or T2a)
1,068 patients were intermediate risk (defined as Gleason score 7 or Gleason
score 6 with PSA level 10-20 ng/mL or clinical stage T2b)
226 patients were high risk (defined as Gleason score 8-10)
comparing ADT plus radiation therapy vs. radiation therapy alone
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10-year disease-specific mortality 4% vs. 8% (p = 0.001, NNT 25)

10-year rate of biochemical failure 26% vs. 41% (p < 0.001, NNT 7)
10-year cumulative incidence of distant metastases 6% vs. 8% (p = 0.04,
NNT 50)
10-year mortality from causes other than prostate cancer 34% vs. 37% (not
significant)
positive findings on repeat prostate biopsy at 2 years in 20% vs. 39% (p <
0.001, NNT 6) in analysis of 843 patients
no significant difference in acute or late radiation-induced toxic effects
post hoc subgroup analysis by risk stratification
comparing ADT plus radiation therapy vs. radiation therapy alone in low-risk
patients
no significant difference in
10-year overall survival (67% vs. 64%)
10-year disease-specific mortality (3% vs. 1%)
positive findings on repeat prostate biopsy at 2 years in 12% vs. 35%
comparing ADT plus radiation therapy vs. radiation therapy alone in
intermediate-risk patients
10-year disease-specific mortality 3% vs. 10% (p = 0.004, NNT 15)
comparing ADT plus radiation therapy vs. radiation therapy alone in high-risk
patients
10-year overall survival (53% vs. 51%)
10-year disease-specific mortality (12% vs. 14%)
10-year rate of biochemical failure 31% vs. 53% (p = 0.002, NNT 5)
Reference - N Engl J Med 2011 Jul 14;365(2):107, editorial can be found in N
Engl J Med 2011 Jul 14;365(2):169
addition of androgen suppression therapy to radiation therapy may increase
survival in clinically localized prostate cancer (level 2 [mid-level] evidence)
206 men with clinically localized prostate cancer (T1b to T2b, NX, M0) and 1
advanced feature were randomized to 3-dimensional conformal radiation therapy
70 Gy plus androgen suppression therapy vs. radiation therapy alone for 6
months
advanced features defined as any of
PSA level 10-40 ng/mL
Gleason score 7
magnetic resonance imaging evidence of extraprostatic disease
androgen suppression therapy included flutamide 250 mg orally every 8
hours starting 1-3 days before either of
leuprolide acetate (7.5 mg/month or 22.5 mg every 3 months
intramuscularly)
goserelin (3.6 mg/month or 10.8 mg every 3 months subcutaneously)
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comparing radiation therapy plus androgen suppression therapy vs. radiation
therapy alone (counting 4 dropouts as survivors)
estimated 5-year overall survival 88% vs. 78% (p = 0.04, NNT 10)
deaths due to prostate cancer 0% vs. 6% (p = 0.02, NNT 17)
gynecomastia in 18 cases vs. 3 cases (p = 0.002)
grade 3 impotence among previously potent men in 26 cases vs. 21 cases (p
= 0.02)
Reference - JAMA 2004 Aug 18;292(7):821 full text, editorial can be found in
JAMA 2004 Aug 18;292(7):864, commentary can be found in JAMA 2004 Nov
3;292(17):2084, JAMA 2004 Dec 1;292(21):2581
DynaMed commentary -- trial not included in systematic reviews above because it
examines hormone treatment before, during, and after primary treatment when
compared to primary treatment alone rather than when given after radiation
therapy
consistent results for overall survival and death due to prostate cancer at median
follow-up 7.6 years
therapy alone
estimated overall survival 85% vs. 57.7% (p = 0.01, NNT 4)
death due to prostate cancer in 4% vs. 13.5% (p = 0.01, NNT 11)
mortality in subgroup of men with no or minimal comorbidity in 10.8%
vs. 29.8% (p < 0.001, NNT 6)
no significant difference in mortality in subgroup of men with moderate or
severe comorbidity
Reference - JAMA 2008 Jan 23;299(3):289 full-text
consistent findings in older men at median follow-up 7.6 years
based on post hoc subgroup analysis of randomized trial above
102 patients older than median patient age (72.4 years for men with no or
minimal comorbidity, 73 years for men with moderate or severe comorbidity)
were assessed
radiation therapy plus androgen suppression therapy associated with
decreased mortality in older men with no or minimal comorbidity
increased mortality in men with moderate or severe comorbidity
Reference - Int J Radiat Oncol Biol Phys 2010 Feb 1;76(2):337
consistent findings for overall survival in men with no or mild comorbidity at
overall survival comparing radiation therapy plus androgen suppression
therapy vs. radiation therapy alone in men with no or mild comorbidity
90.9% vs. 85.8% at 7 years in patients with intermediate risk (p =
0.009, NNT 20)
88.9% vs. 51.2% at 7 years in patients with high risk (p = 0.007, NNT
3)
no significant difference in overall survival in men with moderate or severe
comorbidity
Reference - Int J Radiat Oncol Biol Phys 2010 Jul 15;77(4):1046
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addition of androgen deprivation therapy to radiation therapy may

reduce long-term mortality in men with mild or no comorbidity, but may
increase mortality in men with moderate or severe comorbidity (level 2
based on follow-up of randomized trial above
all patients were followed for median 16.2 years
therapy alone
all-cause mortality
67.9% vs. 72.2% in men with no or minimal comorbidity (p = 0.04,
NNT 24)
95.8% vs. 92% in men with moderate or severe comorbidity (p =
0.001, NNH 26)
prostate cancer mortality
6.4% vs. 25.3% in men with no or minimal comorbidity (p = 0.004,
NNT 6)
4.2% vs. 12% in men with moderate or severe comorbidity (not
significant)
Reference - JAMA 2015 Sep 22-29;314(12):1291
hormonal therapy after radiation therapy reported to decrease quality-adjusted
life expectancy in men with high-risk prostate cancer and prior myocardial
infarction (level 3 [lacking direct] evidence)
based on cohort analysis of data from randomized trials without direct statistical
comparison
men with localized high-risk or locally advanced prostate cancer who received
radiation therapy with or without hormonal therapy in either of 2 randomized trials
were analyzed
quality-adjusted life expectancy in men with prior myocardial infarction at starting age
50 years (no p values reported)
3.3 years with no hormonal therapy
3.2 years with hormonal therapy for 6 months
2.8 years with hormonal therapy for 3 years
consistent results in men with prior myocardial infarction at starting age 60 years and
those at starting age 70 years
in men without previous myocardial infarction and < 4 cardiac risk factors, hormonal
therapy for 3 years after radiation therapy was reported to have higher qualityadjusted life expectancy compared to hormonal therapy for 6 months or no hormonal
therapy in all age groups evaluated
Reference - Cancer 2013 May 15;119(10):1808, correction can be found in Cancer
2013 Jun 15;119(12):2358
addition of ADT to radiation therapy may not increase cardiovascular mortality
in patients with localized prostate cancer (level 2 [mid-level] evidence)
based on post hoc secondary analysis of randomized trial
1,979 patients with stage T1b-2b prostate cancer and PSA levels < 20 ng/mL were
assessed for cardiovascular mortality
10-year cardiovascular mortality 10% with ADT plus radiation therapy vs. 11% with
radiation therapy alone (not significant)
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Reference - Eur Urol 2016 Feb;69(2):204

lack of prostate-specific antigen complete response following hormonal therapy
plus radiation therapy associated with reduced disease-specific survival and
increased risk of distant metastasis in patients with localized prostate cancer
based on cohort analysis of data from randomized trial
1,070 patients (84% of those randomized) with localized prostate cancer who received
hormonal therapy plus radiation therapy (prostate-only or whole pelvis) with available
data were analyzed
70% had prostate-specific antigen complete response (PSA-CR, defined as PSA 0.3
ng/mL) following hormonal therapy
compared to PSA-CR, no PSA-CR associated with
reduced disease-specific survival (hazard ratio [HR] 2.03, 95% CI 1.38-2.97)
reduced disease-free survival (HR 1.28, 95% CI 1.09-1.5)
increased risk of distant metastasis (HR 1.92, 95% CI 1.37-2.69)
Reference - Cancer 2013 Jun 1;119(11):1999 full-text
Duration of ADT:
8-36 months of adjuvant hormonal treatment associated with decreased risk of
biochemical failure, local recurrence, and distant metastases compared with 3-6
months of therapy in patients with locally advanced prostate cancer treated
with radiation therapy (level 2 [mid-level] evidence)
systematic review of 5 randomized trials evaluating duration of hormone therapy in
3,424 patients with locally advanced prostate cancer
shorter durations were 3-6 months, longer durations were 8-36 months
median follow-up 3.7-10 years
all analyses limited by statistical heterogeneity
longer duration of hormonal therapy associated with
decreased rate of biochemical failure (relative risk [RR] 1.32, 95% CI 1.09-1.6,
NNT 9-10) in analysis of 5 trials with 3,424 patients
reduced risk of local recurrence (RR 1.87, 95% CI 1.22-2.86, NNT 9) in analysis
reduced risk of distant metastasis (RR 1.77, 95% CI 1.16-2.69, NNT 9) in analysis
overall survival in analysis of 4 trials with 3,128 patients
prostate cancer-specific survival in analysis of 4 trials with 3,128 patients
Reference - BMC Cancer 2010 Dec 9;10:675
EBSCOhost Full Text full-text
continued androgen suppression therapy with LHRH agonist for 2-2.5 years
after short-term androgen suppression therapy plus radiation therapy may
increase survival in men with locally advanced prostate cancer (level 2
based on 3 randomized trials without blinding
355 patients (median age 72 years) with T1c-T3b N0M0 prostate adenocarcinoma
were randomized to high-dose radiation therapy 76-82 Gy in 2-Gy daily fractions plus
long-term ADT vs. high-dose radiation therapy plus short-term ADT
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ADT consisted of goserelin 3.6 mg subcutaneously in first month then 10.8 mg

every 3 months plus flutamide 750 mg/day or bicalutamide 50 mg/day orally
during first 2 months
all patients had short-term ADT 2 months before and 2 months combined with
radiation therapy, patients in long-term ADT group had ADT for additional 24
months after radiation therapy
all patients had intermediate- or high-risk factors according to National
Comprehensive Cancer Network criteria
comparing long-term ADT vs. short-term ADT
5-year biochemical disease-free survival 90% vs. 81% (p = 0.01, NNT 12)
5-year metastasis-free survival 94% vs. 83% (p = 0.01)
cardiovascular events in 20% vs. 14% (no p value reported)
no significant differences between groups in rates of late rectal or urinary
toxicities grade 2
significant increase in survival outcomes in high-risk patients, but not in
intermediate-risk patients
Reference - Lancet Oncol 2015 Mar;16(3):320, editorial can be found in Lancet
Oncol 2015 Mar;16(3):244, commentary can be found in Nat Rev Urol 2015
Apr;12(4):181
1,554 patients with T2c-T4 prostate cancer with no extra pelvic lymph node
involvement and prostate-specific antigen > 150 ng/mL were randomized to goserelin
3.6 mg/month subcutaneously for 24 months vs. no additional therapy and followed
for 5 years
prior to randomization all patients received
radiation therapy consisting of 45 Gy to pelvic nodes and 65-70 Gy to
prostate
4 months of goserelin and flutamide before and during radiation therapy
comparing continued androgen suppression therapy vs. no additional therapy
disease-free survival 46.4% vs. 28.2% (p < 0.001, NNT 6)
overall survival 80% vs. 78.5% (not significant)
Reference - J Clin Oncol 2003 Nov 1;21(21):3972
consistent results for overall survival at 10-year follow-up
overall survival 51.6% with long-term androgen suppression therapy vs.
53.9% with no additional therapy (not significant)
Reference - J Clin Oncol 2008 May 20;26(15):2497
970 men with locally advanced prostate cancer who previously received external beam
radiation therapy plus 6 months of androgen suppression randomized to luteinizing
hormone-releasing hormone (LHRH) agonist for 2.5 additional years vs. no further
treatment
patients followed median 6.4 years
71.7% on long-term androgen suppression completed therapy
comparing long-term vs. short-term therapy
5-year overall mortality 15.2% vs. 19% (p < 0.05, NNT 27)
5-year prostate-specific mortality 3.2% vs. 4.7% (p = 0.002, NNT 67)
Reference - N Engl J Med 2009 Jun 11;360(24):2516, editorial can be found in N
Engl J Med 2009 Jun 11;360(24):2572 (correction can be found in N Engl J Med
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2009 Jul 9;361(2):217), commentary can be found in N Engl J Med 2009 Sep
17;361(12):1212
addition of short-term or intermediate-term androgen suppression to radiation
therapy, with or without zoledronic acid, associated with similar prostate
cancer-specific mortality (level 2 [mid-level] evidence)
randomized to 1 of 4 treatment groups starting 5 months before radiation therapy
leuprorelin 22.5 mg intramuscularly every 3 months for 6 months (short-term
androgen suppression [STAS])
STAS followed by leuprorelin 22.5 mg intramuscularly every 3 months for 12
months after radiation therapy (intermediate-term androgen suppression [ITAS])
STAS plus concurrent zoledronic acid 4 mg IV every 3 months for 18 months
ITAS plus concurrent zoledronic acid for 18 months
prostate cancer-specific mortality
4.1% with STAS alone
7.4% with ITAS alone (not significant vs. STAS alone)
7.8% with STAS plus zoledronic acid (not significant vs. STAS alone)
4.3% with ITAS plus zoledronic acid (not significant vs. STAS alone)
no significant differences in all-cause mortality, local progression, or distant
progression among groups
Reference - RADAR trial (Lancet Oncol 2014 Sep;15(10):1076), editorial can be found
in Lancet Oncol 2014 Sep;15(10):1041, commentary can be found in Nat Rev Clin
Oncol 2014 Oct;11(10):559
18 months and 36 months of androgen blockade associated with similar survival
and relapse rates in patients with node-negative high-risk prostate cancer
treated with pelvic radiation therapy (level 2 [mid-level] evidence)
based on unpublished randomized trial (available as meeting abstract)
630 patients with node-negative high-risk prostate cancer (T3-4, PSA > 20 ng/mL, or
Gleason score > 7) were treated with pelvic radiation therapy and randomized to 18
months vs. 36 months of androgen blockade
androgen blockade (neoadjuvant, concomitant, and adjuvant) was bicalutamide 50 mg
for 1 month plus goserelin 10.8 mg every 3 months
comparing androgen blockade for 18 months vs. 36 months
overall mortality 23.8% vs. 22.9% (not significant)
5-year overall survival 86.8% vs. 92.1% (p = 0.052)
5-year disease-specific survival 96.4% vs. 97.6% (not significant)
10-year overall survival 63.2% vs. 63.6% (not significant)
10-year disease-specific survival 87.2% vs. 87.2% (not significant)
no significant differences in rates of biochemical, regional, or distant failure
Reference - PCS IV trial (J Clin Oncol 2013 Feb 20;31(6 suppl):3)
Neoadjuvant ADT:
neoadjuvant hormone therapy may increase overall survival in patients with
non-metastatic prostate cancer (level 2 [mid-level] evidence)
based on systematic review of trials with methodological limitations
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systematic review of 15 randomized trials evaluating addition of neoadjuvant hormone

therapy to traditional therapy in 5,194 patients with non-metastatic prostate cancer on
cytological and pathological examination
most trials had 3.7 year follow-up
traditional therapy defined as radiotherapy or radical prostatectomy
unclear methods of randomization
unclear allocation concealment
addition of neoadjuvant hormone therapy to traditional therapy associated with
increased overall survival in analysis of 5 trials with 2,086 patients
odds ratio (OR) 1.51 (95% CI 1.22-1.87)
NNT 8-23 with survival in 65% with traditional therapy alone
decrease in positive surgical margin in analysis of 9 trials with 2,119 patients
OR 0.3 (95% CI 0.24-0.38)
NNT 4-5 with positive surgical margin in 48% with traditional therapy alone
improved biochemical disease-free survival (OR 1.95, 95% CI 1.13-3.39) in
Reference - World J Surg Oncol 2015 Feb 22;13:73 PDF
neoadjuvant hormone therapy before radiation therapy may improve clinical
disease-free survival in patients with localized or locally advanced prostate
cancer (level 2 [mid-level] evidence)
studies
comparing neoadjuvant hormone therapy before radiation therapy to radiation therapy
alone
neoadjuvant hormone therapy before radiation therapy associated with
increased clinical disease-free survival in analysis of 2 trials with 991 patients
odds ratio (OR) 1.86 (95% CI 1.43-2.4)
NNT 5-13 with 32% survival in controls
increased biochemical disease-free survival in analysis of 3 trials with 1,097
patients
OR 1.93, 95% CI 1.45-2.56), but results may be limited by significant
heterogeneity
no significant difference in disease-specific survival in analysis of 2 trials with 991
patients
neoadjuvant ADT for 6 months associated with reduced mortality compared to
radiation therapy alone in men with locally advanced prostate cancer (level 2
based on 10-year follow-up of TROG 96.01 trial (included in Cochrane above)
818 men with locally advanced (T2b, T2c, T3, and T4 N0 M0) prostate cancer
randomized to 1 of 3 groups and followed for 10 years
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neoadjuvant androgen deprivation therapy (ADT) with goserelin 3.6 mg/month

subcutaneously plus flutamide 250 mg orally 3 times daily starting 2 months
before radiation therapy (as below) for 3 months
same neoadjuvant ADT regimen starting 5 months before radiation therapy for 6
months
radiation therapy alone as 66 Gy in 33 fractions of 2 Gy/day for 6.5-7 weeks
compared to radiation therapy alone, continuation of neoadjuvant ADT for 6 months
associated with decreased risk of
prostate cancer-specific mortality (hazard ratio [HR] 0.49, 95% CI 0.32-0.74)
all-cause mortality (HR 0.63, 95% CI 0.48-0.83)
Reference - Lancet Oncol 2011 May;12(5):451, editorial can be found in Lancet Oncol
2011 May;12(5):411, commentary can be found in Asian J Androl 2011 Jul;13(4):624
neoadjuvant hormone therapy before prostatectomy does not appear to
improve overall survival at 5 years in patients with localized or locally advanced
studies
comparing neoadjuvant hormone therapy before prostatectomy to prostatectomy
alone, no significant differences in
overall survival in analysis of 3 trials with 827 patients
disease-free survival at 5 years in analysis of 4 trials with 1,129 patients
neoadjuvant hormonal therapy may be associated with increased risk for
all-cause mortality in men with presence of or risk factors for coronary artery
disease (level 2 [mid-level] evidence)
based on 2 retrospective cohort studies
neoadjuvant hormonal therapy associated with increased risk for all-cause
mortality in men with history of myocardial infarction or coronary artery
disease-induced heart failure (level 2 [mid-level] evidence)
5,077 men (median age 69.5 years) with localized or locally advanced prostate
cancer received radiation therapy
30% received neoadjuvant hormonal therapy for median 4 months prior to
radiation therapy
median follow-up about 5 years
overall mortality 8.3%
All-cause Mortality and Neoadjuvant Hormonal Therapy:
Subgroup
Proportion of
Cohort
All-cause
Mortality with
Neoadjuvant
All-cause
Mortality
without
Hormonal
Neoadjuvant
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Therapy
Hormonal
Therapy
No comorbidity
52%
9.6%
6.7%
Single CAD risk

factor
43%
10.7%
7%
26.3%*
11.2%
MI- or
5%
CAD-induced heart
failure
Abbreviations: CAD, coronary artery disease; MI, myocardial infarction.

* p = 0.04 for comparison without neoadjuvant hormonal therapy.
Reference - JAMA 2009 Aug 26;302(8):866, commentary can be found in JAMA
2010 Jan 6;303(1):32
neoadjuvant hormonal therapy associated with increased risk of all-cause
death in men with low-risk prostate cancer and 1 coronary artery disease
risk factor (level 2 [mid-level] evidence)
11,166 men (median age 71 years) with prostate cancer (48% with low-risk
cancer) who had brachytherapy were analyzed
45.4% received neoadjuvant hormonal therapy for median duration 4
months and 31% received supplemental external beam radiation therapy
50% had 1 coronary artery disease (CAD) risk factor including diabetes,
hypercholesterolemia, or hypertension
median follow-up 4.1-4.6 years among groups
comparing neoadjuvant hormonal therapy vs. no neoadjuvant hormonal therapy
neoadjuvant hormonal therapy associated with increased risk of all-cause
death in men with low-risk prostate cancer and 1 CAD risk factor (adjusted
hazard ratio 1.36, 95% CI 1.07-1.74)
no significant differences in all-cause death in men with
low-risk prostate cancer and no CAD risk factors
intermediate- or high-risk prostate cancer
Reference - Eur Urol 2014 Jan;65(1):177
addition of short-term or intermediate-term androgen suppression to radiation
therapy, with or without zoledronic acid, associated with similar prostate
cancer-specific mortality (level 2 [mid-level] evidence)
randomized to 1 of 4 treatment groups starting 5 months before radiation therapy
leuprorelin 22.5 mg intramuscularly every 3 months for 6 months (short-term
androgen suppression [STAS])
STAS followed by leuprorelin 22.5 mg intramuscularly every 3 months for 12
months after radiation therapy (intermediate-term androgen suppression [ITAS])
STAS plus concurrent zoledronic acid 4 mg IV every 3 months for 18 months
ITAS plus concurrent zoledronic acid for 18 months
prostate cancer-specific mortality
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4.1% with STAS alone

7.4% with ITAS alone (not significant vs. STAS alone)
7.8% with STAS plus zoledronic acid (not significant vs. STAS alone)
4.3% with ITAS plus zoledronic acid (not significant vs. STAS alone)
no significant differences in all-cause mortality, local progression, or distant
progression among groups
Reference - RADAR trial (Lancet Oncol 2014 Sep;15(10):1076), editorial can be found
in Lancet Oncol 2014 Sep;15(10):1041, commentary can be found in Nat Rev Clin
Oncol 2014 Oct;11(10):559
extending androgen suppression therapy from 8 to 28 weeks prior to radiation
therapy may not improve survival in men with intermediate-risk prostate cancer
1,579 men with intermediate-risk prostate cancer were randomized to androgen
suppression therapy with luteinizing hormone-releasing hormone (LHRH) analog
agents for 8 weeks vs. 28 weeks prior to radiation therapy
all patients continued androgen suppression therapy for 8 weeks after initiation of
radiation therapy
all patients had concomitant treatment with bicalutamide 50 mg orally once daily
or flutamide 250 mg orally 3 times daily starting within 14 days of androgen
suppression therapy initiation and continuing until last day of radiation therapy
94.3% completed follow-up and were included in analyses
comparing androgen suppression therapy for 8 weeks vs. 28 weeks
10-year disease-specific survival 95% vs. 96% (not significant)
no significant differences in 10-year cumulative incidences of locoregional progression,
prostate-specific antigen (PSA)-based recurrence, or distant metastasis
Reference - J Clin Oncol 2015 Feb 1;33(4):332, editorial can be found in J Clin Oncol
2015 Feb 1;33(4):301
neoadjuvant androgen suppression therapy before external beam radiation
therapy for 4 months associated with similar overall survival as 8 months of
androgen suppressive therapy in men with localized prostate cancer (level 2
276 men (median age 66 years) with localized prostate cancer randomized to
neoadjuvant androgen suppression therapy with LHRH agonist triptorelin 3.75 mg
intramuscularly once monthly plus antiandrogen flutamide 250 mg orally 3 times daily
for 4 months prior to external beam radiation therapy (EBRT) vs. for 8 months prior to
EBRT
comparing neoadjuvant androgen suppression therapy for 4 months vs. 8 months
5-year biochemical failure-free survival 66% vs. 63% (not significant)
no significant difference in prostate cancer-specific survival (overall or at 5 years)
Reference - Int J Radiat Oncol Biol Phys 2011 Sep 1;81(1):35
Adverse effects of ADT and their management:
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key adverse effects include

increased risk of fracture
hot flashes
cardiovascular events and diabetes
see Androgen deprivation therapy for prostate cancer for details
Comparative Efficacy
Conservative management comparisons:
Watchful waiting compared to curative treatment:
radical prostatectomy may reduce prostate cancer mortality and might reduce
overall mortality compared to watchful waiting in patients with symptomatic
stage T2 prostate cancer (level 2 [mid-level] evidence)
based on Cochrane review with limited evidence
systematic review of randomized or quasi-randomized trials comparing radical
prostatectomy vs. watchful waiting for localized prostate cancer found only 2 trials
1 poor-quality trial with 142 patients found no significant difference in overall mortality
at 15-year follow-up
1 high-quality trial with 695 patients (described in detail below) found nonsignificant
reduction in overall mortality and significant reductions in prostate cancer-specific
mortality and distant metastases at most time points
statistical significance of results varied with method of analysis
Reference - Cochrane Database Syst Rev 2010 Nov 10;(11):CD006590
DynaMed commentary -- conclusions may not be generalizable to patients with
screening-detected prostate cancer
consistent findings for prostate cancer-specific survival and overall survival in
systematic review of 18 randomized trials and 473 observational studies evaluating
treatments and reporting clinical or biochemical outcomes in men with localized
prostate cancer (Ann Intern Med 2008 Mar 18;148(6):435
EBSCOhost Full
Text full-text)
details of high-quality trial (SPCG-4 trial) with 695 patients
695 men < 75 years old with newly diagnosed prostate cancer of International
Union against Cancer clinical stage T1b, T1c or T2, well-differentiated to
moderately well-differentiated tumor, and life expectancy > 10 years were
randomized to radical prostatectomy vs. watchful waiting
most men (74%-78%) had cancer of stage T2 and were symptomatic
5.2% men had prostate cancer detected by screening
T1b indicates incidental histologic finding on resected tissue
T1c indicates needle biopsy due to elevated serum prostate-specific antigen (PSA)
level
T2 indicates palpable or visible carcinoma confined within prostate
patients with distant metastases unresponsive to treatment at autopsy were
classified as having death attributed to prostate cancer
during follow-up, 30 men in watchful waiting group (8.6%) had surgery with
curative intent and 25 men in radical prostatectomy group (7.2%) did not receive
radical treatment
outcomes at median follow-up 6.2 years, comparing radical prostatectomy vs.
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watchful waiting in intention-to-treat analysis

all-cause mortality in 15.3% vs. 17.8% (not significant)
death attributed to prostate cancer in 4.6% vs. 8.9% (p = 0.02, NNT 24),
absolute differences in favor of radical prostatectomy were 2% at 5 years
(not significant) and 6.6% at 8 years (NNT 16)
rates of distant metastases were similar at 5 years but favored radical
prostatectomy by absolute 14% at 8 years (NNT 8)
Reference - SPCG-4 trial (N Engl J Med 2002 Sep 12;347(11):781), editorial can
be found in N Engl J Med 2002 Sep 12;347(11):839, commentary can be found in
N Engl J Med 2003 Jan 9;348(2):170, CMAJ 2003 Jan 7;168(1):67, J Fam Pract
2003 Jan;52(1):22
EBSCOhost Full Text, Am Fam Physician 2003 Feb
1;67(3):599
overall mortality in 23.9% vs. 30.5% (p = 0.04, NNT 16)
death due to prostate cancer in 8.6% vs. 14.4% (p = 0.01, NNT 18),
difference apparent only in men < 65 years old
distant metastases in 14.4% vs. 22.7% (p = 0.004, NNT 12)
local progression in 18.4% vs. 42.8% (p < 0.001, NNT 5)
Reference - N Engl J Med 2005 May 12;352(19):1977, commentary can be
found in CMAJ 2005 Jun 21;172(13):1682 full-text, Ann Intern Med 2005 Aug
2;143(3):232
EBSCOhost Full Text, Am Fam Physician 2005 Sep
1;72(5):878, N Engl J Med 2005 Sep 22;353(12):1298, ACP J Club 2005
Nov-Dec;143(3):57
EBSCOhost Full Text
outcomes at longer follow-up, comparing radical prostatectomy vs. watchful
waiting in intention-to-treat analysis
overall mortality at median follow-up 10.8 years in 39.4% vs. 44.8% (p =
0.09)
death due to prostate cancer at median follow-up 10.8 years in 13.5% vs.
19.5% (p < 0.05, NNT 17)
death due to prostate cancer at median follow-up 12 years in 12.5% vs.
17.9% (p = 0.03, NNT 19)
distant metastases at median follow-up 12 years in 19.3% vs. 26% (p =
0.006, NNT 15)
Reference - J Natl Cancer Inst 2008 Aug 20;100(16):1144 full-text, editorial
can be found in J Natl Cancer Inst 2008 Aug 20;100(16):1123 full-text,
commentary can be found in J Natl Cancer Inst 2009 Jan
21;101(2):124 full-text, Nat Clin Pract Urol 2009 Jan;6(1):12, Eur Urol 2009
Apr;55(4):989
overall mortality in 46.1% vs. 52.7% (p = 0.007, NNT 15)
death due to prostate cancer in 14.6% vs. 20.7% (p = 0.01, NNT 17)
distant metastases in 21.7% vs. 33.4% (p < 0.001, NNT 9)
Reference - N Engl J Med 2011 May 5;364(18):1708, editorial can be found
in N Engl J Med 2011 May 5;364(18):1770
reduction in mortality associated with radical prostatectomy compared to
active surveillance appears to be limited to men < 65 years old
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based on follow-up of SPCG-4 trial at median 13.4 years

follow-up ranged from 3 weeks to 23.2 years
comparing radical prostatectomy vs. watchful waiting in men < 65 years old
overall mortality 40% vs. 65.6% (p < 0.001, NNT 4)
prostate cancer-specific mortality 18.3% vs. 34.1% (p = 0.002, NNT 7)
distant metastases in 28.7% vs. 44.5% (p < 0.001, NNT 7)
comparing radical prostatectomy vs. watchful waiting in men 65 years old
overall mortality 69.8% vs. 71.7% (not significant)
prostate cancer-specific mortality 17.3% vs. 23.9% (not significant)
distant metastases in 23.8% vs. 32.7% (p = 0.04)
Reference - N Engl J Med 2014 Mar 6;370(10):932
Society of General Internal Medicine (SGIM) Bottom Line concludes "Use of
radical prostatectomy among men diagnosed with early prostate cancer led to a
significant mortality reduction in men younger than 65 and in those with intermediate
tumor risk. There was no difference in mortality in those older than 65 or those in the
lowest-risk group." with High-quality evidence and provides 2-page quick summary
(SGIM Bottom Line 2014 Oct 1 PDF)
radical prostatectomy may not reduce all-cause mortality compared to watchful
waiting in men with asymptomatic stage T1c prostate cancer, but may have
benefit for men with PSA > 10 ng/mL (level 2 [mid-level] evidence)
based on randomized trial with low adherence
731 men 75 years old (mean age 67 years) with localized prostate cancer were
randomized to radical prostatectomy vs. observation
all men had PSA < 50 ng/mL and life expectancy of 10 years at baseline
about 50% of patients in each group had stage T1c disease (not palpable, detected by
PSA testing)
median follow-up 10 years (maximum 15 years)
77.2% of radical prostatectomy group and 79.6% of observation group received
allocated treatment, all men included in intention-to-treat analysis
comparing radical prostatectomy vs. observation in overall analysis
all-cause mortality 47% vs. 49.9% (not significant)
prostate cancer-related mortality 5.8% vs. 8.4% (p = 0.09)
comparing radical prostatectomy vs. observation in subgroup analysis of 251 men with
PSA > 10 ng/mL at baseline
all-cause mortality 48.4% vs. 61.6% (p < 0.05, NNT 8)
prostate cancer-related mortality 5.6% vs. 12.8% (p < 0.05, NNT 14)
Reference - PIVOT trial (N Engl J Med 2012 Jul 19;367(3):203), correction can be
found in N Engl J Med 2012 Aug 9;367(6):582, editorial can be found in N Engl J Med
2012 Jul 19;367(3):270
radiation therapy and watchful waiting appear to have similar health-related
quality of life at 10 years (level 2 [mid-level] evidence)
based on small post hoc secondary analysis of randomized trial
54 patients from randomized trial (33% of those randomized) who completed healthrelated quality-of-life questionnaire were included in analysis
no significant between-group differences in health-related quality of life or symptom
scores
Reference - Scand J Urol Nephrol 2009;43(2):119
EBSCOhost Full Text
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curative treatment may increase 10-year prostate cancer-specific survival

compared to palliative treatment in men with high-risk prostate cancer (level 2
11,380 men 75 years old with high-risk prostate cancer (serum PSA levels 20-100
ng/mL) were analyzed
3,904 patients had curative treatment (28.2% had radical prostatectomy and 68% had
radiation therapy) and 7,476 patients had palliative treatment
all men were free of distant metastases at baseline
10-year prostate cancer-specific mortality 13% with curative treatment vs. 36% with
palliative treatment (p < 0.01)
Reference - BJU Int 2013 Mar;111(3):381
EBSCOhost Full Text
treatment with surgery or radiation may be associated with higher survival than
watchful waiting in localized prostate cancer (level 2 [mid-level] evidence)
based on observational cohort study
retrospective study of 44,630 men aged 65-80 years diagnosed with organ-confined,
well- or moderately-differentiated prostate cancer 1991-1999 and who had survived at
least 1 year after diagnosis
32,022 patients treated with radical prostatectomy or radiation therapy within 6
months of diagnosis (treated patients) were compared with 12,608 patients who did
not receive radical prostatectomy, radiation or hormonal therapy (untreated patients)
patients followed until death or end of 2002
overall mortality 23.8% treated vs. 37% untreated patients
survival differences remained statistically significant after adjusting for recognized
confounders
Reference - JAMA 2006 Dec 13;296(22):2683 full-text, editorial can be found in JAMA
2006 Dec 13;296(22):2733, correction can be found in JAMA 2007 Jan 3;297(1):42,
commentary can be found in Nat Clin Pract Urol 2007 Aug;4(8):420, Eur Urol 2007
Jun;51(6):1751, JAMA 2007 Apr 18;297(15):1651
prostatectomy appears to improve 10-year disease-specific survival compared
to watchful waiting in men with grade 2-3 prostate cancer (level 2 [mid-level]
evidence)
59,876 men aged 50-79 with clinically localized prostate cancer were evaluated
10-year disease-specific survival rates for
grade 1 cancer were
94% (95% CI 91%-95%) with prostatectomy
90% (95% CI 87%-92%) with radiation therapy
93% (95% CI 91%-94%) with conservative management
grade 2 cancer were
grade 3 cancer were
Reference - Lancet 1997 Mar 29;349(9056):906
EBSCOhost Full Text, editorial
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can be found in Lancet 1997 Mar 29;349(9056):892
EBSCOhost Full Text
Active surveillance compared to curative treatment:

limited evidence for comparative effectiveness of active surveillance and radical
prostatectomy or radiation therapy in men with localized prostate cancer
based on systematic review with clinical heterogeneity
systematic review of 195 papers, 2 evidence reports and associated articles, and 2
economic assessments evaluating strategies for observational management (active
surveillance or watchful waiting), and comparative efficacy of observational
management vs. immediate treatment with curative intent (radical prostatectomy or
radiation therapy) in men with localized prostate cancer
nonstandardized use of the terms active surveillance and watchful waiting prevalent,
and observational treatment objectives (curative and palliative) frequently combined
within studies
active surveillance defined as observational management with curative intent
watchful waiting defined as observational management with palliative intent
no studies found comparing active surveillance with radical prostatectomy or radiation
therapy in men with localized disease
comparisons not made between active surveillance and watchful waiting observational
strategies
Reference - Ann Intern Med 2012 Apr 17;156(8):582
EBSCOhost Full
Text full-text, also published in AHRQ Evidence Report 2011 Dec 6:204 PDF
DynaMed commentary -- most randomized trials conducted before PSA screening and
may have now limited applicability
Radical prostatectomy comparisons:
Prostatectomy compared to brachytherapy:
brachytherapy associated with improved health-related quality of life compared
to radical prostatectomy in men with low-risk prostate cancer (level 2
based on small randomized trial with high dropout rate and prospective cohort study
of 190 men (median age 60 years) with low-risk prostate cancer (stage T1-T2a with
Gleason score 6, prostate-specific antigen [PSA] < 10 ng/mL) who attended
multidisciplinary educational session to promote informed patient decisions
34 men randomized to brachytherapy vs. radical prostatectomy
94 men chose to have brachytherapy
62 men chose to have radical prostatectomy
168 men responded to survey at median follow-up 5.2 years
41% of randomized patients lost to follow-up
randomized groups and men who chose therapy were combined for analysis
brachytherapy associated with higher health-related quality-of-life scores for urinary
function (p = 0.02), sexual function (p = 0.001), and patient satisfaction (p < 0.001)
no significant between-group difference in bowel function
Reference - J Clin Oncol 2011 Feb 1;29(4):362
brachytherapy may be as effective as radical prostatectomy at preventing
biochemical failure in patients with localized prostate cancer (level 3 [lacking
direct] evidence)
based on systematic review without clinical outcomes
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systematic review of 13 case series and 3 cohort studies

no randomized trials identified
rates of freedom from biochemical failure varied considerably and were highly
dependent on tumor stage, grade and pretreatment serum PSA levels
results in patients with favorable tumors (T1 or T2 tumor, Gleason score 6, serum
PSA level 10 ng/mL) were comparable to radical prostatectomy
adverse outcomes
1%-14% rates of acute urinary retention
< 5% rates of long-term sequelae including urinary incontinence, cystitis, urethral
strictures, and proctitis
4%-14% impotence
Reference - CMAJ 2001 Apr 3;164(7):975 full-text, commentary can be found in CMAJ
2001 Oct 16;165(8):1003
brachytherapy associated with increased biochemical recurrence compared to
radical prostatectomy in men with intermediate- or high-risk prostate cancer
(level 3 [lacking direct] evidence)
1,872 men treated with radical prostatectomy or interstitial radiation (seed implant)
with or without neoadjuvant androgen deprivation therapy or external beam radiation
therapy (EBRT) evaluated
compared to radical prostatectomy, interstitial radiation therapy associated with
increased 5-year PSA outcome in
high-risk patients (stage 2c or PSA levels > 20 ng/mL, or Gleason score 8)
(relative risk 3, 95% CI 1.8-5 respectively), and still significant with addition of
androgen deprivation therapy
intermediate-risk patients (stage 2b, Gleason score 7, or PSA level > 10 and 20
ng/mL) (relative risk 3.1, 95% CI 1.5-6.1), but no longer significant with addition
of androgen deprivation therapy
no significant differences in 5-year PSA outcome in low-risk patients (stage T1c or
T2a, PSA level 10 ng/mL, and Gleason score 6)
Reference - JAMA 1998 Sep 16;280(11):969 full-text, editorial commentary can be
found in JAMA 1998 Sep 16;280(11):1008, commentary can be found in JAMA 1999
May 5;281(17):1583
Prostatectomy compared to external beam radiation therapy:
radical prostatectomy associated with lower mortality than radiation therapy in
men with nonmetastatic prostate cancer (level 2 [mid-level] evidence)
34,515 men who received treatment for prostate cancer in Sweden from 1996 to 2010
(62.4% with radical prostatectomy and 37.6% with radiation therapy) were analyzed
metastatic disease in 3.5%
prostate cancer-related mortality 3%
comparing radical prostatectomy vs. radiation therapy in men without metastatic
disease
prostate cancer-related mortality 1.4% vs. 4.9% (p < 0.001)
other mortality 4.5% vs. 8.7% (p < 0.001)
Reference - BMJ 2014 Feb 26;348:g1502
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prostatectomy associated with increased long-term survival compared to

radiation therapy or watchful waiting in patients with localized prostate cancer
based on observational cohort study
844 patients diagnosed with localized prostate cancer (stage T1-T3 and M0) in
Geneva, Switzerland 1989-1998 were evaluated
treatments included prostatectomy (158 patients), radiation therapy (205 patients),
watchful waiting (378 patients), hormone therapy (72 patients), and other types of
therapy (31 patients)
10-year survival rates
83% with prostatectomy
75% with radiation therapy (p < 0.001 vs. prostatectomy, NNT 13 favoring
prostatectomy)
72% with watchful waiting (p < 0.001 vs. prostatectomy, NNT 9 favoring
prostatectomy)
mortality differences primarily found in
patients < 70 years old
patients with poorly differentiated tumors (Gleason score 7)
Reference - Arch Intern Med 2007 Oct 8;167(18):1944 full-text, commentary can be
found in Arch Intern Med 2008 Jun 23;168(12):1351
external beam radiation therapy and radical prostatectomy appear to have
similar biochemical recurrence-free survival in men with low- to
intermediate-risk localized prostate cancer (level 3 [lacking direct] evidence)
based on retrospective cohort study without clinical outcomes
505 men with low- to intermediate-risk prostate cancer were treated with radical
prostatectomy or EBRT
biochemical relapse defined as PSA level 0.4 ng/mL (for radical prostatectomy) or
nadir PSA +2 (for EBRT 72 Gy)
5-year biochemical recurrence-free survival in 79% with radical prostatectomy vs.
86% with EBRT (not significant)
Reference - Ann Surg Oncol 2011 Oct;18(10):2980
DynaMed commentary -- definition cutoff for biochemical relapse of PSA level 0.4
ng/mL is higher than standard definition
external beam radiation therapy plus androgen deprivation therapy associated
with reduced biochemical failure compared to radical prostatectomy in high-risk
localized prostate cancer (level 3 [lacking direct] evidence)
based on retrospective cohort study without clinical outcomes
284 patients with high-risk localized prostate cancer were treated with EBRT plus
androgen deprivation therapy or radical prostatectomy
high risk defined by National Comprehensive Cancer Center Network criteria as any of
baseline Gleason score 8
initial or pretreatment PSA > 20 ng/mL
clinical Stage T3
presence of 2 negative clinical factors (such as stage T2c, baseline Gleason
score 7, and/or initial PSA 1120 ng/mL).
comparing EBRT vs. radical prostatectomy, 3-year freedom from biochemical failure in
86.8% vs. 69.8% (p = 0.001, NNT 6)
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Reference - Int J Radiat Oncol Biol Phys 2009 Nov 15;75(4):975

prostatectomy might reduce risk of treatment failure compared to external
beam radiation therapy in men with localized prostate cancer (level 2
based on systematic review with limited evidence
systematic review found 18 randomized trials and 473 observational studies evaluating
treatments and reporting clinical or biochemical outcomes in localized prostate cancer
only 3 randomized trials compared effectiveness between primary treatments for
localized prostate cancer
prostatectomy associated with reduced treatment failure (elevated acid phosphatase
or appearance of bony or parenchymal disease) at 5 years vs. external beam radiation
therapy in 1 low-quality trial of 106 patients
no trials found in patients with prostate cancer primarily detected with PSA testing
all treatments (including androgen deprivation, radical prostatectomy, and radiation
therapy) caused urinary, bowel, or sexual dysfunction at varying levels
Reference - Ann Intern Med 2008 Mar 18;148(6):435
EBSCOhost Full
Text full-text, correction can be found in Ann Intern Med 2008 Jun 3;148(11):888,
commentary can be found in Evid Based Med 2008 Oct;13(5):139
Cryoablation comparisons:
external beam radiation therapy and cryoablation might have similar diseasespecific survival and overall survival at 8 years in patients with prostate cancer
based on small randomized trial with early termination
63 patients (median age 70 years) with stage T2c-T3a prostate cancer were
randomized to external beam radiation therapy (EBRT) at 2 Gy/day 5 days/week for
6.5 weeks vs. cryoablation and followed for mean 37 months
all patients received goserelin for 6 months beginning 3 months prior to treatment
trial terminated early due to slow accrual after enrolling 42.7% of planned patients
median follow-up 105.2 months
comparing EBRT vs. cryoablation
8-year disease-specific survival 69% vs. 64% (not significant)
Reference - J Urol 2012 Oct;188(4):1170
DynaMed commentary -- trial accrual halted due to shift in practice toward
longer-term adjuvant hormonal therapy at time of original study
consistent results in 62 patients who completed trial and were followed for median
8.75 years (J Urol 2012 Oct;188(4):1170)
Follow-Up
National Comprehensive Cancer Network (NCCN) recommendations(1)
measure serum prostate-specific antigen (PSA) every 6-12 months for first 5 years,
then once every year, unless high risk of recurrence (in which case measure every 3
months) (NCCN Category 2A)
perform digital rectal exam (DRE) every year, but may not be necessary if PSA
undetectable (NCCN Category 2A)
in men with brachytherapy, perform postimplant dosimetry to document quality of
implant
European Association of Urology (EAU) recommendations(3)
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routine follow-up after treatment with curative intent for asymptomatic patients every
3 months for 6 months, then every 6 months until 3 years, then every year to include
(EAU Grade B)
disease-specific history
PSA level
DRE
palpable nodule or PSA > 0.2 ng/mL (0.2 mcg/L) may be associated with residual or
recurrent disease after radical prostatectomy (EAU Grade B)
palpable nodules and rising serum PSA are signs of local recurrence (EAU Grade B)
imaging studies for detection of local recurrence only recommended if findings will
affect treatment (biopsy not necessary before second-line therapy in most cases) (EAU
Grade B)
routine bone scans and other imaging studies not recommended in asymptomatic men
with no signs of biochemical relapse; if man has bone pain or other symptoms,
consider restaging regardless of serum PSA (EAU Grade B)
PSA level > 0.2 ng/mL is associated with residual or recurrent disease after radical
prostatectomy
for all men having radical treatment, check PSA levels 6 weeks after treatment, then
every 6 months for first 2 years, then once per year
do not routinely offer DRE to men whose PSA remains at baseline levels
Quality Improvement
Choosing Wisely:
American Society for Radiation Oncology recommends against initiating management of
low-risk prostate cancer without discussing active surveillance (Choosing Wisely 2014 Sep
15)
American Society for Radiation Oncology does not routinely recommend proton beam
therapy for prostate cancer outside of a prospective clinical trial or registry (Choosing
Wisely 2014 Sep 15)
Choosing Wisely Canada:
Canadian Oncology Societies recommend against starting management in patients with
low-risk prostate cancer (T1-T2, prostate-specific antigen [PSA] < 10 ng/mL, and Gleason
score < 7) without first discussing active surveillance (Choosing Wisely Canada 2014 Oct
29)
Guidelines and Resources
Guidelines:
International guidelines:
Royal Marsden Hospital/Radiation Therapy Oncology Group (RMH/RTOG) consensus
guidelines and contouring atlas on pelvic node delineation in prostate and pelvic node
intensity modulated radiation therapy can be found in Int J Radiat Oncol Biol Phys 2015 Jul
15;92(4):874
International Society of Geriatric Oncology (SIOG) recommendations on management of
prostate cancer in older men can be found in BJU Int 2010 Aug;106(4):462
EBSCOhost Full Text
International Society of Urological Pathology (ISUP) consensus conference statement on
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handling and staging of radical prostatectomy specimens can be found in Adv Anat Pathol
2011 Jul;18(4):301
United States guidelines:
National Institutes of Health (NIH) State-of-the-Science conference statement on role of
active surveillance in management of localized prostate cancer can be found in Ann Intern
Med 2012 Apr 17;156(8):591
EBSCOhost Full Text or at National Guideline
Clearinghouse 2012 Nov 19:37616
American Urological Association (AUA)
American Urological Association (AUA) guideline on early detection of prostate cancer
can be found in J Urol 2013 Aug;190(2):419 full-text or at National Guideline
Clearinghouse 2013 Nov 18:46426, commentary can be found in J Urol 2013
Aug;190(2):427, J Urol 2013 Sep;190(3):1134, Eur Urol 2013 Nov;64(5):857, or in Eur
Urol 2014 Jun;65(6):1218
AUA guideline on management of clinically localized prostate cancer can be found at
AUA 2007 PDF or at National Guideline Clearinghouse 2007 Dec 3:11446
AUA guideline on PSA testing for pretreatment staging and posttreatment
management of prostate cancer can be found at AUA 2013 PDF
AUA best practice policy statement on cryosurgery for treatment of localized prostate
cancer can be found at AUA 2009 PDF
AUA best practice policy statement on urological surgery antimicrobial prophylaxis can
be found at AUA 2007 PDF or at National Guideline Clearinghouse 2008 Apr 28:12210
American Cancer Society (ACS) guideline on early detection of prostate cancer (2010
update) can be found in CA Cancer J Clin 2010 Mar-Apr;60(2):70 full-text
American Cancer Society (ACS) guideline on nutrition and physical activity for cancer
prevention can be found in CA Cancer J Clin 2012 Jan-Feb;62(1):30 full-text
American Cancer Society (ACS) guideline on nutrition and physical activity for cancer
survivors can be found in CA Cancer J Clin 2012 Jul;62(4):242 full-text or at National
Guideline Clearinghouse 2012 Oct 8:37279
American Cancer Society (ACS) review of guidelines and issues on cancer screening can be
found in CA Cancer J Clin 2012 Mar-Apr;62(2):129 full-text
American Society of Clinical Oncology (ASCO) guideline on initial hormonal management of
androgen-sensitive metastatic, recurrent or progressive prostate cancer can be found in J
Clin Oncol 2007 Apr 20;25(12):1596
National Academy of Clinical Biochemistry (NACB) guideline on use of tumor markers in
testicular, prostate, colorectal, breast, and ovarian cancers can be found in Clin Chem 2008
Dec;54(12):e11 full-text
American College of Radiology (ACR) Appropriateness Criteria for
pretreatment detection, staging, and surveillance of prostate cancer can be found at
ACR 2012 PDF or in J Am Coll Radiol 2013 Feb;10(2):83 or at National Guideline
Clearinghouse 2013 Aug 5:43879
high-dose-rate brachytherapy for prostate cancer can be found at ACR 2013 PDF or at
National Guideline Clearinghouse 2014 May 5:47697
definitive external beam irradiation in stage T1 and T2 prostate cancer can be found
at ACR 2013 PDF or at National Guideline Clearinghouse 2014 May 5:47696
locally advanced high-risk prostate cancer can be found at ACR 2011 PDF or at
National Guideline Clearinghouse 2011 Aug 1:32604 or in Clin Oncol (R Coll Radiol)
2012 Feb;24(1):43
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permanent source brachytherapy for prostate cancer can be found at ACR 2010 PDF
or at National Guideline Clearinghouse 2011 Aug 8:32605
postradical prostatectomy irradiation in prostate cancer can be found at ACR 2010 PDF
or at National Guideline Clearinghouse 2011 Mar 7:23841
external beam radiotherapy treatment planning for clinically localized prostate cancer
can be found at ACR 2011 PDF or at National Guideline Clearinghouse 2012 May
7:35164
post-treatment follow-up of prostate cancer can be found at ACR 2011 PDF or at
National Guideline Clearinghouse 2011 Sep 12:32610
American Brachytherapy Society (ABS) consensus guideline on high-dose-rate prostate
brachytherapy can be found in Brachytherapy 2012 Jan-Feb;11(1):20 full-text
ABS consensus guideline on transrectal ultrasound-guided permanent prostate
brachytherapy can be found in Brachytherapy 2012 Jan-Feb;11(1):6
American College of Radiology/American Society for Radiation Oncology (ACR/ASTRO)
guideline on intensity modulated radiation therapy can be found in Am J Clin Oncol 2012
Dec;35(6):612 or at ACR 2011 PDF
American Institute of Ultrasound in Medicine (AIUM) practice guideline on performance of
ultrasound evaluation of prostate (and surrounding structures) can be found in J
Ultrasound Med 2011 Jan;30(1):156
National Comprehensive Cancer Network (NCCN) practice guidelines on
prostate cancer can be found at NCCN website (free registration required)
prostate cancer early detection can be found at NCCN website (free registration
required)
Digestive Disease Institute expert panel consensus on screening and diagnosis of prostate
cancer in patients with ileal pouch-anal anastomosis can be found in Am J Gastroenterol
2011 Feb;106(2):186
Pasadena Consensus Panel recommendations for robot-assisted radical prostatectomy as
technique to treat localized prostate cancer can be found in Eur Urol 2012 Sep;62(3):368
American Urological Association/American Society for Radiation Oncology (AUA/ASTRO)
guideline on adjuvant and salvage radiotherapy after prostatectomy can be found in J Urol
2013 Aug;190(2):441 or at National Guideline Clearinghouse 2013 Dec 30:46418 or in Int J
Radiat Oncol Biol Phys 2013 Aug 1;86(5):822
American Heart Association/American Cancer Society/American Urological Association
science advisory on androgen-deprivation therapy in prostate cancer and cardiovascular
risk can be found in Circulation 2010 Feb 16;121(6):833 full-text, also published in CA
Cancer J Clin 2010 May-Jun;60(3):194 full-text
United Kingdom guidelines:
National Institute for Health and Care Excellence (NICE) guideline on diagnosis and
treatment of prostate cancer can be found at NICE 2014 Jan:CG175 PDF or at National
Guideline Clearinghouse 2014 Jun 9:47764, summary can be found in BMJ 2014 Jan
8;348:f7524
NICE guidance on cabazitaxel for hormone-refractory metastatic prostate cancer
previously treated with docetaxel-containing regimen can be found at NICE 2012
May:TA255 PDF
National Institute for Health and Care Excellence (NICE) guideline on denosumab for
prevention of skeletal-related events in adults with bone metastases from solid tumors
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can be found at NICE 2012 Oct:TA265 PDF or at National Guideline Clearinghouse

2013 Jan 7:38576
Consensus Panel statement on role of transrectal ultrasonography (TRUS) in focal therapy
of prostate cancer can be found in BJU Int 2012 Oct;110(7):942
EBSCOhost Full Text
Canadian guidelines:
Alberta Health Services (AHS) clinical practice guideline on prostate cancer can be found at
AHS 2013 Sep PDF or at National Guideline Clearinghouse 2014 Jul 7:47847
Alberta Health Services/Toward Optimized Practice (AHS/TOP) primary care guide on
evaluation and referral for prostate cancer can be found at TOP 2010 PDF
Cancer Care Ontario (CCO) Program in Evidence-Based Care guidelines on
active surveillance for management of localized prostate cancer can be found at CCO
2014 Dec 10 PDF
low-dose rate brachytherapy for patients with low- or intermediate-risk prostate
cancer can be found at CCO 2012 Oct 31 PDF or at National Guideline Clearinghouse
2014 May 19:47791
role of IMRT in prostate cancer can be found at CCO 2010 Oct 27 PDF or at National
Guideline Clearinghouse 2012 Nov 26:35102
adjuvant radiotherapy following radical prostatectomy for pathologic T3 or marginpositive prostate cancer can be found at CCO 2010 Jul PDF or at National Guideline
Clearinghouse 2011 Feb 28:24139
risk reduction of prostate cancer with drugs or nutritional supplements can be found at
CCO 2012 May 17 PDF or at National Guideline Clearinghouse 2013 Dec 30:45882
Cancer Care Ontario/Genitourinary Cancer Disease Site Group (CCO/GU DSG)
evidence-based guideline recommendations on low-dose rate brachytherapy in patients
with low- or intermediate-risk prostate cancer can be found in Can Urol Assoc J 2013
May-Jun;7(5-6):E411 full-text
Androgen Deprivation Therapy Survivorship Working Group recommendations on androgen
deprivation therapy for prostate cancer can be found in J Sex Med 2010 Sep;7(9):2996
European guidelines:
European Association of Urology (EAU) guidelines
European Association of Urology (EAU) guideline on prostate cancer can be found at
EAU 2015 Mar PDF
European Association of Urology (EAU) guideline on robotic and single-site surgery in
urology can be found at EAU Mar 2014 PDF
European Association of Urology (EAU) guideline on urinary incontinence can be found
at EAU 2014 Apr PDF
European Association of Urology (EAU) guideline on pain management in urological
cancers can be found at EAU 2014 PDF
European Association of Urology (EAU) guideline on pain management and palliative
care can be found at EAU 2014 PDF
Spanish Society of Medical Oncology (SEOM) clinical guideline on treatment of prostate
cancer can be found in Clin Transl Oncol 2012 Jul;14(7):520
European Society for Medical Oncology (ESMO) clinical practice guideline on diagnosis,
treatment and follow-up of prostate cancer can be found in Ann Oncol 2013 Jun 27 early
online full-text
French Association of Urology (AFU) statement on lymphadenectomy and prostate cancer
can be found in Prog Urol 2012 Jul;22(9):510 [French]
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AFU expert guideline on treatment of prostate cancer in elderly men can be found in Prog
Urol 2009 Dec;19(11):810, commentary can be found in Prog Urol 2009 Dec;19(11):818
[French]
French expert recommendations on best practice for prostate biopsy can be found in Prog
Urol 2011 Jan;21(1):18
Haute Autorit de Sant conseils pour cancer de la prostate se trouvent sur le site Haute
Autorit de Sant 2008 Sep [French]
French expert consensus recommendation on prostate cancer can be found in Prog Urol
2010 Nov;20 Suppl 4:S217 [French]
Asian guidelines:
Japanese Urological Association (JUA) 2006 Clinical guideline on prostate cancer can be
found at Minds guideline listing (
) [Japanese
]
Mexican guidelines:
Grupos de Desarrollo de las Instituciones Pblicas del Sistema Nacional de Salud de Mxico
(Secretara de Salud, IMSS, ISSSTE, SEDENA, SEMAR, DIF, PEMEX) guas de prctica
clnica en prevencin y deteccin temprana del cncer de prstata en el primer nivel de
atencin se pueden encontrar en Secretara de Salud-Mxico 2008 PDF [Spanish]
Australian and New Zealand guidelines:
Australian and New Zealand Faculty of Radiation Oncology Genito-Urinary Group consensus
guideline on definitive external beam radiotherapy for prostate carcinoma can be found in J
Med Imaging Radiat Oncol 2010 Dec;54(6):513
EBSCOhost Full Text
Middle Eastern guidelines:
National Comprehensive Cancer Network (NCCN) guideline on prostate cancer modified for
Middle East and North Africa region can be found in J Natl Compr Canc Netw 2010 Jul;8
Suppl 3:S26
Review articles:
review of prostate cancer can be found in Ann Intern Med 2015 Dec 1;163(11):ITC1
EBSCOhost Full Text
review of treatment options for localized prostate cancer can be found in Can Fam
Physician 2013 Dec;59(12):1269
Agency for Healthcare Research and Quality (AHRQ) comparative effectiveness review on
therapies for clinically localized prostate cancer can be found at AHRQ Comparative
Effectiveness Review 2014 Dec:146 PDF
review of ablative therapy for localized prostate cancer can be found in Health Technol
Assess 2015 Jul;19(49):1 PDF
review of localized prostate cancer can be found in N Engl J Med 2007 Dec
27;357(26):2696
review of magnetic resonance imaging in diagnosis and management of prostate cancer
can be found in BJU Int 2013 Nov;112 Suppl 2:6
EBSCOhost Full Text
review of penile rehabilitation after radical prostatectomy: what the evidence really says
can be found in BJU Int 2013 Nov;112(7):998
EBSCOhost Full Text
review of radical prostatectomy in high-risk prostate cancer can be found in Int J Urol 2013
Mar;20(3):290
EBSCOhost Full Text
review of prostate cancer treatment can be found in JAMA 2009 May
27;301(20):2141 full-text, commentary can be found in JAMA 2009 Oct 14;302(14):1529
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review of low-dose rate and high-dose rate brachytherapy can be found at J Contemp
Brachytherapy 2013 Mar;5(1):33 full-text
review of gonadotropin-releasing-hormone-receptor antagonists can be found in Lancet
2001 Nov 24;358(9295):1793
EBSCOhost Full Text
review of androgen deprivation therapy (medical or surgical castration) can be found in
JAMA 2005 Jul 13;294(2):238 full-text
review of screening and treatment can be found in Adv Stud Med 2003 Jul-Aug;3(7):391
PDF, commentary can be found in Adv Stud Med 2003 Nov-Dec;3(10):579 PDF
review of treatment options for localized prostate cancer can be found in Am Fam
Physician 2011 Aug 15;84(4):413 full-text, previous version can be found in Am Fam
Physician 2005 May 15;71(10):1915, editorial can be found in Am Fam Physician 2005 May
15;71(10):1871
review of minimally invasive radical prostatectomy can be found in Mayo Clin Proc 2004
Sep;79(9):1169
review of high-dose-rate brachytherapy in the curative treatment of patients with localized
prostate cancer can be found in Mayo Clin Proc 2008 Dec;83(12):1364
review of endorectal balloons in prostate radiotherapy can be found in Radiother Oncol
2010 Jun;95(3):277
review of external-beam radiotherapy for localized prostate cancer can be found in N Engl
J Med 2006 Oct 12;355(15):1583, commentary can be found in N Engl J Med 2007 Jan
18;356(3):308
review of external beam radiation therapy (EBRT) for localized prostate cancer can be
found in N Engl J Med 2006 Oct 12;355(15):1583, commentary can be found in N Engl J
Med 2007 Jan 18;356(3):308
review of intensity-modulated radiotherapy can be found in Lancet Oncol 2008
Apr;9(4):367, correction can be found in Lancet Oncol. 2008 Jun;9(6):513
review of fecal incontinence following radiotherapy for prostate cancer can be found in
Radiother Oncol 2011 Feb;98(2):145
review of clinically localized prostate cancer can be found in BMJ 2006 Nov
25;333(7578):1102 full-text
editorial discussion of cryotherapy and high intensity focused ultrasound for prostate
cancer can be found in BMJ 2008 Dec 1;337:a2540
review of tissue ablation technologies for localized prostate cancer can be found in Mayo
Clin Proc 2004 Dec;79(12):1547
editorial discussion of treatments for localized prostate cancer can be found in BMJ 2000
Jan 8;320(7227):69
review of androgen deprivation therapy can be found in J Clin Endocrinol Metab 2012
Feb;97(2):360
review series on androgen deprivation therapy (ADT) can be found in Asian J Androl 2012
Mar;14(2)
review of adverse effects of ADT in men with prostate cancer can be found in Asian J
Androl 2012 Mar;14(2):222
review of quality of life issues in men undergoing ADT can be found in Asian J Androl
2012 Mar;14(2):226
review of cognitive changes associated with ADT can be found in Asian J Androl 2012
Mar;14(2):232
review of indications and prevalence can be found in Asian J Androl 2012
Mar;14(2):177
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review of hematologic changes during ADT can be found in Asian J Androl 2012
Mar;14(2):187
review of ADT-associated vasomotor symptoms can be found in Asian J Androl 2012
Mar;14(2):193 full-text
review of impact of ADT on sexual function can be found in Asian J Androl 2012
Mar;14(2):198
review of muscle function, physical performance, and body composition changes in
men with prostate cancer undergoing ADT can be found in Asian J Androl 2012
Mar;14(2):204
editorial can be found in Asian J Androl 2012 Mar;14(2):175
review of prostate cancer treatment can be found in JAMA 2009 May 27;301(20):2141,
commentary can be found in JAMA 2009 Oct 14;302(14):1529
review of improving management of patients with prostate cancer receiving long-term
androgen deprivation therapy can be found in BJU Int 2012 Jun;109 Suppl 6:13
EBSCOhost Full Text
literature review of combination of hormonal therapy and radiation therapy in high-risk
prostate cancer can be found in Prostate 2010 May 15;70(7):701
review of maintaining bone health in patients with prostate cancer receiving androgen
deprivation therapy can be found in Med J Aust 2006 Feb 20;184(4):176 full-text
case presentation of androgen deprivation treatment in prostate cancer can be found in
BMJ 2013 Jan 8;346:e8555
MEDLINE search:
to search MEDLINE for (Locally advanced prostate cancer) with targeted search (Clinical
Queries), click therapy, diagnosis, or prognosis
Patient Information
prostate cancer
handout on prostate cancer from American Academy of Family Physicians or in
Spanish
handout on early prostate cancer can be found in Am Fam Physician 2005 May
15;71(10):1929
handout from Patient UK PDF
web-based interactive booklet from NCCN Guidelines for Patients
handout from National Cancer Institute PDF
handout from MacMillan Cancer Support
handout on treatment from National Cancer Institute PDF
considerable information from Prostate Cancer Education Council
information from CancerHelp UK
handout on healthcare after cancer treatment can be found in Am Fam Physician 2005 Feb
15;71(4):713
ICD-9/ICD-10 Codes
ICD-9 codes:
185 malignant neoplasm of prostate
790.93 elevated prostate-specific antigen (PSA)
ICD-10 codes:
C61 malignant neoplasm of prostate
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References
General references used:
1. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate Cancer. Version 1. 2015. In:
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology
(NCCN Guidelines). NCCN 2014 Oct from NCCN website (free registration required)
2. National Institute for Health and Care Excellence (NICE). Prostate cancer: diagnosis and
treatment. NICE 2014 Jan:CG175 PDF, summary can be found in BMJ 2014 Jan
8;348:f7524
3. Mottet N, Bellmunt J, Briers E, et al; European Association of Urology (EAU). Guidelines
on prostate cancer. EAU 2015 Mar PDF
4. Schrder F, Crawford ED, Axcrona K, Payne H, Keane TE. Androgen deprivation therapy:
past, present and future. BJU Int. 2012 Jun;109 Suppl 6:1-12
EBSCOhost Full Text
Recommendation grading systems used:
European Association of Urology (EAU) grading system for recommendations
grades of recommendation (which may be changed if panel consensus)
Grade A - based on clinical studies of good quality and consistency addressing the
specific recommendations and including at least 1 randomized trial
Grade B - based on well-conducted clinical studies, but without randomized
clinical trials
Grade C - made despite the absence of directly applicable clinical studies of good
quality
levels of evidence
Level 1a - meta-analysis of randomized trials
Level 1b - 1 randomized trial
Level 2a - 1 well-designed controlled study without randomization
Level 2b - 1 other type of well-designed quasi-experimental study
Level 3 - well-designed nonexperimental studies, such as comparative studies,
correlation studies, and case reports
Level 4 - expert committee reports or opinions or clinical experience of respected
authorities
References
EAU guideline or prostate cancer (EAU 2014 Mar PDF)
National Comprehensive Cancer Network (NCCN) categories of evidence and consensus
Category 1 - based on high-level evidence, there is uniform NCCN consensus that
intervention is appropriate
Category 2A - based on lower-level evidence, there is uniform NCCN consensus that
Category 2B - based on lower-level evidence, there is NCCN consensus that
Category 3 - based on any level of evidence, there is major NCCN disagreement that
Reference - NCCN Categories of Evidence and Consensus
Synthesized Recommendation Grading System for DynaMed Plus:
DynaMed systematically monitors clinical evidence to continuously provide a synthesis of
the most valid relevant evidence to support clinical decision-making (See 7-Step
Evidence-Based Methodology).
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Guideline recommendations summarized in the body of a DynaMed topic are provided with
the recommendation grading system used in the original guideline(s), and allow DynaMed
users to quickly see where guidelines agree and where guidelines differ from each other
and from the current evidence.
In DynaMed Plus (DMP), we synthesize the current evidence, current guidelines from
leading authorities, and clinical expertise to provide recommendations to support clinical
decision-making in the Overview & Recommendations section.
We use the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) to classify synthesized recommendations as Strong or Weak.
Strong recommendations are used when, based on the available evidence,
clinicians (without conflicts of interest) consistently have a high degree of confidence
that the desirable consequences (health benefits, decreased costs and burdens)
outweigh the undesirable consequences (harms, costs, burdens).
Weak recommendations are used when, based on the available evidence, clinicians
believe that desirable and undesirable consequences are finely balanced, or
appreciable uncertainty exists about the magnitude of expected consequences
(benefits and harms). Weak recommendations are used when clinicians disagree in
judgments of relative benefit and harm, or have limited confidence in their judgments.
Weak recommendations are also used when the range of patient values and
preferences suggests that informed patients are likely to make different choices.
DynaMed Plus (DMP) synthesized recommendations (in the Overview & Recommendations
section) are determined with a systematic methodology:
Recommendations are initially drafted by clinical editors (including 1 with
methodological expertise and 1 with content domain expertise) aware of the best
current evidence for benefits and harms, and the recommendations from guidelines.
Recommendations are phrased to match the strength of recommendation. Strong
recommendations use "should do" phrasing, or phrasing implying an expectation to
perform the recommended action for most patients. Weak recommendations use
"consider" or "suggested" phrasing.
Recommendations are explicitly labeled as Strong recommendations or Weak
recommendations when a qualified group has explicitly deliberated on making such
a recommendation. Group deliberation may occur during guideline development.
When group deliberation occurs through DynaMed-initiated groups:
Clinical questions will be formulated using the PICO (Population, Intervention,
Comparison, Outcome) framework for all outcomes of interest specific to the
recommendation to be developed.
Systematic searches will be conducted for any clinical questions where systematic
searches were not already completed through DynaMed content development.
Evidence will be summarized for recommendation panel review including for each
outcome the relative importance of the outcome, the estimated effects comparing
intervention and comparison, the sample size, and overall quality rating for the
body of evidence.
Recommendation panel members will be selected to include at least three
members that together have sufficient clinical expertise for the subject(s)
pertinent to the recommendation, methodological expertise for the evidence
being considered, and experience with guideline development.
All recommendation panel members must disclose any potential conflicts of
interest (professional, intellectual, and financial), and will not be included for the
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specific panel if a significant conflict exists for the recommendation in question.

Panel members will make Strong recommendations if and only if there is
consistent agreement in a high confidence in the likelihood that desirable
consequences outweigh undesirable consequences across the majority of
expected patient values and preferences. Panel members will make Weak
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Special acknowledgements:
Allen Shaughnessy, PharmD, M Med Ed, FCCP (Professor of Family Medicine and Director
of Master Teacher Fellowship, Tufts University Family Medicine Residency; Cambridge
Health Alliance; Massachusetts, United States) provides peer review.
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of Surgery (Urology), Harvard Medical School, Boston, United States) provides peer review.
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panel for the Prostate Cancer Early Detection 2014 guideline.
E. David Crawford, MD (Professor of Surgery and Radiation Oncology and Head of Urologic
Oncology, University of Colorado Health Sciences Center; Colorado, United States) provides
peer review.
Dr. Crawford declares receiving consulting fees from Ferring, Dendreon, and MdX.
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Management of localized or locally advanced prostate cancer

Allen Shaughnessy, PharmD, M Med Ed, FCCP Kevin R. Loughlin, MD

risk stratification systems for local or locally advanced prostate cancer

intermediate risk - PSA 10-20 ng/mL (10-20 mcg/L) OR Gleason score 7 OR

clinical heterogeneity due to differences in number of biopsies taken,

prostatectomy or external beam radiation therapy (J Clin Oncol 1999

symptom category scores

Fully active, able to carry on all predisease performance without restriction

Completely disabled; cannot carry on any self-care; totally confined to bed or

Reference - Am J Clin Oncol 1982 Dec;5(6):649.

Karnofsky Performance Status Scale:

Able to carry on normal

Normal, no complaints, no evidence of disease

Able to carry on normal activity; minor signs

Normal activity with effort; some signs or

Cares for self; unable to carry on normal

Unable to work; able to live

Unable to care for self;

activity or to do active work

Requires occasional assistance, but is able to

Requires considerable assistance and frequent

Disabled; requires special care and assistance

References - J Gerontol 1991 Jul;46(4):M139, Cancer 1994 Apr 15;73(8):2087.

Severely disabled; hospital admission is

Very sick; hospital admission necessary; active

Moribund; fatal processes progressing rapidly

References - J Gerontol 1991 Jul;46(4):M139, Cancer 1994 Apr 15;73(8):2087.

National Comprehensive Cancer Network (NCCN) recommends active surveillance

prostate cancer mortality reported to be < 3%

high- or very high-risk disease reported to range 24% to 39%, depending on

27% vs. 32% (p = 0.03)

34 patients with organ-confined disease

multiparametric magnetic resonance imaging (MRI) may help in decision to perform

tranexamic acid IV (loading dose of 500 mg given 20 minutes before surgery

rectal or anal procedure 13.7%

no patients had history of incontinence or transurethral prostate resection

based on randomized trial with unclear blinding of outcome assessors

all trials had 1 limitation including

vacuum constriction device

control group given same intervention at 3 months

combination with immediate long-term (2-3 years) androgen deprivation therapy

seed implants placed permanently

145 Gy for iodine-125

with localized prostate cancer

active inflammatory disease of rectum

allows visualization of organ movement and correction in real time

analysis of 425 men

2012 Dec 8;380(9858):1974

events (no p value reported)

dose up to 81 Gy for men with intermediate- or high-risk cancer

NNT 8-16 with biochemical failure in 34% of CDRT group

70.2 Gy in 26 fractions at 2.7 Gy per fraction (hypofractionated EBRT, equivalent

following conventional radiation therapy for prostate cancer, reported improved

performed under general or spinal anesthesia

22.5 mg intramuscularly once every 12 weeks

Gleason pattern score of 4

local disease, and found to have microscopic evidence of nodal metastases on

gonadotropin-releasing hormone (GnRH) antagonists vs. standard androgen

leuprolide 7.5 mg/month intramuscularly

prostatectomy, and may decrease overall survival at 10 years (level 2

increased disease-specific survival at 5 years in analysis of 2 trials with 1,392

10-year disease-specific mortality 4% vs. 8% (p = 0.001, NNT 25)