Fichiers publics: 2017
prostate .pdf
À propos / Télécharger
Nom original: prostate.pdf
Ce document au format PDF 1.7 a été généré par Adobe InDesign CC 2015 (Windows) / Adobe PDF Library 15.0; modified using iTextSharp™ 5.4.1 ©2000-2012 1T3XT BVBA (AGPL-version), et a été envoyé sur fichier-pdf.fr le 15/01/2017 à 20:43, depuis l'adresse IP 149.154.x.x. La présente page de téléchargement du fichier a été vue 720 fois.
Taille du document: 1.3 Mo (111 pages).
Confidentialité: fichier public
NCCN Guidelines Version 1.2016
NCCN Guidelines Index
Prostate Table of Contents
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Version 1.2017 — December 16, 2016
NCCN.org
NCCN Guidelines for Patients® available at www.nccn.org/patients
Version 1.2017, 12/16/16© National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Printed by Merzak Fadlallah on 1/12/2017 5:30:19 PM. For personal use only. Not approved for distribution. Copyright © 2017 National Comprehensive Cancer Network, Inc., All Rights Reserved.
Prostate Cancer Panel Members
* James L. Mohler, MD/Chair ω
Emmanuel S. Antonarakis, MD †
The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Andrew J. Armstrong, MD †
Duke Cancer Institute
Robert R. Bahnson, MD ω
The Ohio State University Comprehensive
Cancer Center - James Cancer Hospital
and Solove Research Institute
Eric Mark Horwitz, MD §
Fox Chase Cancer Center
Michael Hurwitz, MD, PhD †
Yale Cancer Center/Smilow Cancer Hospital
Christopher J. Kane, MD ω
UC San Diego Moores Cancer Center
Michael Kuettel, MD, MBA, PhD §
Joshua M. Lang, MD †
University of Wisconsin Carbone Cancer Center
Stan Rosenfeld ‡
Patient Services Committee Chair
Edward Schaeffer, MD, PhD ω
Robert H. Lurie Comprehensive Cancer
Center of Northwestern University
Ted A. Skolarus, MD ω
Eric J. Small, MD †
UCSF Helen Diller Family
Cheryl Clark, MD Þ
Dana-Farber/Brigham and Women’s
Cancer Center | Massachusetts General
Hospital Cancer Center
Richard J. Lee, MD, PhD †
Cancer Center | Massachusetts General Hospital
Anthony Victor D’Amico, MD, PhD §
David F. Penson, MD, MPH ω
Sandy Srinivas, MD †
Elizabeth R. Plimack, MD, MS † Þ
Seth A. Strope, MD, MPH ω
Siteman Cancer Center at BarnesJewish Hospital and Washington
University School of Medicine
Brian J. Davis, MD, PhD §
Mayo Clinic Cancer Center
James A. Eastham, MD ω
Rodney Ellis, MD §
Case Comprehensive Cancer Center/
University Hospitals Seidman Cancer Center and
Cleveland Clinic Taussig Cancer Institute
Charles A. Enke, MD §
Fred &amp; Pamela Buffett Cancer Center
Thomas A. Farrington ‡
Prostate Health Education Network (PHEN)
Celestia S. Higano, MD † ω
Fred Hutchinson Cancer Research Center/ Seattle
Cancer Care Alliance
Julio M. Pow-Sang, MD ω
Moffitt Cancer Center
David Raben, MD §
University of Colorado Cancer Center
Sylvia Richey, MD †
St. Jude Children’s Research Hospital/
University of Tennessee Health Science Center
Mack Roach, III, MD §
NCCN Guidelines Panel Disclosures
Guru Sonpavde, MD †
Jonathan Tward, MD, PhD §
Huntsman Cancer Institute
at the University of Utah
Przemyslaw Twardowski, MD † ‡
City of Hope Comprehensive Cancer Center
NCCN
Deborah Freedman-Cass, PhD
Dorothy A. Shead, MS
Þ Internal medicine
†	Medical oncology
‡ Patient advocate
§	Radiotherapy/Radiation oncology
ω	Urology
* Discussion Section Writing Committee
NCCN Prostate Cancer Panel Members
Summary of Guidelines Updates
Initial Prostate Cancer Diagnosis (PROS-1)
Very Low-Risk: Initial Therapy, Adjuvant Therapy (PROS-2)
Low-Risk: Initial Therapy, Adjuvant Therapy (PROS-3)
Intermediate-Risk: Initial Therapy, Adjuvant Therapy (PROS-4)
High-Risk: Initial Therapy, Adjuvant Therapy (PROS-5)
Very High-Risk, Regional, and Metastatic Disease: Initial Therapy, Adjuvant Therapy (PROS-6)
Monitoring, Recurrence (PROS-7)
Radical Prostatectomy Biochemical Failure (PROS-8)
Radiation Therapy Recurrence (PROS-9)
Systemic Therapy for Progressive Castration-Naive Disease (PROS-10)
Systemic Therapy for M0 CRPC (PROS-11)
Subsequent Systemic Therapy for M1 CRPC: No Visceral Metastases (PROS-13)
Subsequent Systemic Therapy for M1 CRPC: Visceral Metastases (PROS-14)
Principles of Life Expectancy Estimation (PROS-A)
Principles of Imaging (PROS-B)
Principles of Active Surveillance and Observation (PROS-C)
Principles of Radiation Therapy (PROS-D)
Principles of Surgery (PROS-E)
Principles of Androgen Deprivation Therapy (PROS-F)
Principles of Immunotherapy and Chemotherapy (PROS-G)
Staging (ST-1)
Grade Group Definitions (ST-3)
Clinical Trials: NCCN believes that
the best management for any patient
with cancer is in a clinical trial.
Participation in clinical trials is
especially encouraged.
To find clinical trials online at NCCN
Member Institutions, click here:
nccn.org/clinical_trials/physician.html.
NCCN Categories of Evidence and
Consensus: All recommendations
are category 2A unless otherwise
specified.
See NCCN Categories of Evidence
and Consensus.
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2016.
Prostate Cancer Updates
Updates in Version 1.2017 of the NCCN Guidelines for Prostate Cancer from Version 3.2016 include:
PROS-7
• Changed “Advanced disease” to “Progression to metastatic disease without
• Initial prostate cancer diagnosis, added a bullet for “Family history"
biochemical failure.”
with a new footnote: "The following should be considered: brother or
• N1 or M1, added "on ADT."
father or multiple family members diagnosed with prostate cancer at
• Branches for recurrence after initial definitive therapy and N1 and M1 on ADT
less than 60 years of age, germline DNA repair gene abnormalities,
were separated
especially BRCA2 mutation or Lynch syndrome (germline mutations in
MLH1, MSH2, MSH6, or PMS2) and/or strong family history for breast or • Added “Progression” to bottom branch, with links to PROS-11 and PROS-12.
ovarian cancer (suggests possibility of BRCA2 mutation) or colorectal, PROS-8
• Clarified "abdominal/pelvic" CT or MRI.
endometrial, gastric, ovarian, pancreatic, small bowel, urothelial,
• "Progression" was split into separate pathways depending on previous
kidney, or bile duct cancer (suggests possibility of Lynch syndrome)."
treatment, with links to PROS-10, PROS-11, and PROS-12.
• Modified the following footnote: “Androgen deprivation therapy (ADT)
• Added a new footnote defining "castration-naive." The term "castration-naive"
or radiation therapy (RT) may be considered in selected patients
is used to define patients who are not on ADT at the time of progression.
with high- or very-high-risk disease, where complications, such as
The NCCN Prostate Cancer Panel uses the term "castration-naive" even
hydronephrosis or metastasis, can be expected within 5 y. (See PROS-5
when patients have had neoadjuvant, concurrent, or adjuvant ADT as part of
or PROS-6).
radiation therapy provided they have recovered testicular function.
• Removed text box: “Preferred treatment for any therapy is approved
clinical trial.”
• TRUS biopsy positive, studies negative for distant metastases: added the
• Risk Group - added the ISUP/WHO Grade Groups. (See ST-3)
option for "high-intensity focused ultrasound (HIFU)."
PROS-2, -3, -4, -5, -6
• Not a candidate for local therapy, added "bone scan."
• Modified “Adverse feature(s) and no lymph node metastases.”
• Added a link to PROS-11 for patients who progress while on ADT.
• Added branch “No adverse features or lymph node metastases.”
PROS-10
• Changed “Undetectable PSA or nadir” to “Undetectable PSA after RP or • Systemic therapy for progressive castration-naive disease, M1, removed
“Continuous” from “ADT.”
PSA nadir after RT.”
• Moved the following footnote to the Principles of Androgen Deprivation
• High and very high risk groups, initial therapy, removed “EBRT + ADT
Therapy (PROS-F). “DES has cardiovascular and thromboembolic side
(2-3y) + docetaxel.”
effects at any dose but frequency is dose and agent dependent. DES should
• Modified footnote: “Six cycles of docetaxel every 3 weeks without
be initiated at 1 mg/d and increased, if necessary, to achieve castrate levels
prednisone may be administered after the completion of radiation in
of serum testosterone (&lt;50 ng/dL). Other estrogens delivered topically or
selected patients who are fit for chemotherapy.”
parenterally may have less frequent side effects but data are limited.”
• No metastases, added "Change or maintain current treatment and continue
• Very high risk group, initial therapy, ADT replaced “in select patients”
monitoring."
with “or observation for patients who are not candidates for definitive
• PSA rising, no, added "Maintain current treatment and continue monitoring."
therapy.”
• Added a new footnote "RP + PLND can be considered in younger,
• Removed the following footnote: “For patients who are not candidates for
healthier patients without tumor fixation to the pelvic side-wall."
docetaxel-based regimens.”
• Deleted footnote: “Primary therapy with ADT should be considered only
PROS-12,
PROS-13 and PROS-14
for patients who are not candidates for definitive therapy.”
• Ketoconazole ± hydrocortisone, added a footnote stating "Ketoconazole ±
hydrocortisone should not be used if the disease progressed on abiraterone."
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
UPDATES-1
• Added a new footnote to prior therapy enzalutamide/abiraterone "Limited
data suggest a possible role for AR-V7 testing to help guide selection of
therapy."
PROS-B (2 of 3)
• Added the following bullets:
"Bone scans are helpful to monitor metastatic prostate cancer to
determine the clinical benefit of systemic therapy. However, new lesions
seen on an initial post-treatment bone scan, compared to the pretreatment baseline scan, may not indicate disease progression."
"New lesions in the setting of a falling PSA or soft tissue response and in
the absence of pain progression at that site may indicate bone scan flare
or an osteoblastic healing reaction. For this reason, a confirmatory bone
scan 8–12 weeks later is warranted to determine true progression from
flare reaction. Additional new lesions favor progression. Stable scans
make continuation of treatment reasonable. Bone scan flare is common,
particularly on initiation of new hormonal therapy, and may be observed
in nearly half of patients treated with the newer agents, enzalutamide
and abiraterone. Similar flare phenomenon may exist with other imaging
modalities, such as CT or PET/CT imaging."
"Bone scans and soft tissue imaging (CT or MRI) in men with metastatic
prostate cancer or non-metastatic progressive prostate cancer may be
obtained regularly during systemic therapy to assess clinical benefit.
Bone scans should be performed for symptoms and as often as every
6–12 mo to monitor ADT. The need for soft tissue images remains
unclear. In CRPC, 8- to 12-week imaging intervals appear reasonable."
• Added "Whole body" to PET/CT.
PROS-D (1 of 2)
• Primary brachytherapy
Removed “low dose rate (LDR).”
Modified the last bullet “High dose-rate (HDR) brachytherapy can be
used alone or in combination with EBRT (40–50 Gy) instead of LDR.
Commonly used boost regimens include 9.5 to 11.5 13 to 15 Gy x 1
fraction, 8 to 11.5 Gy x 2 fractions, 5.5 to 7.5 6.5 Gy x 3 fractions, and
4.0 to 6.0 Gy x 4 fractions. A commonly used regimen for HDR treatment
alone includes 9.5 Gy x 4 fractions, 10.5 Gy x 3 fractions, 13.5 Gy x 2
fractions, or 19 Gy x 1 fraction.”
PROS-D (1 of 2) continued
• Salvage brachytherapy
Modified the first bullet, “Permanent LDR or temporary HDR brachytherapy
can be used as treatment for a local recurrence following EBRT or primary
brachytherapy. Radiation dose depends on the original primary external
beam dose and the pattern of recurrence, and ranges from 100 to 110 Gy for
LDR and 9 to 12 Gy x 2 fractions for HDR.
• Post-Prostatectomy Radiation Therapy, added a new bullet "Two years
instead of 6 months of ADT can be considered in addition to RT based on
RTOG 9601 (presented at ASTRO 2015) for men with persistent PSA after RP or
for PSA levels that exceed 1.0 ng/mL at the time of initiation of salvage therapy.
Six months of ADT can be considered coadministered with salvage radiation
based on the results of GETUG-16. An LHRH agonist should be used. For
2-year ADT, there is level 1 evidence to support 150 mg bicalutamide daily but
an LHRH agonist could be considered as an alternative."
PROS-F (1 of 4)
• Added list of ADT agents for clarification.
• Updated text from "There was a trend toward improvement in overall
survival" to “An improvement in overall survival was demonstrated.”
• Changed "Secondary hormonal manipulation" to "Secondary hormone
therapy" for consistency with algorithm pages.
• Modified bullet, "In the setting in which patients are docetaxel-naive and
have no or minimal symptoms, administration of secondary hormonal
therapy including addition of, or switching to, a different anti-androgen
(flutamide, bicalutamide, nilutamide, enzalutamide), addition of adrenal/
paracrine androgen synthesis inhibitors (ketoconazole with or without
hydrocortisone, or abiraterone with prednisone), or use of an estrogen,
such as DES, can be considered. Ketoconazole ± hydrocortisone should not
be used if the disease progressed on abiraterone."
• Added a new bullet, previously on page PROS-11: DES has cardiovascular
and thromboembolic side effects at any dose but frequency is dose and
agent dependent. DES should be initiated at 1 mg/d and increased, if
necessary, to achieve castrate levels of serum testosterone (&lt;50 ng/dL).
Other estrogens delivered topically or parenterally may have less frequent
side effects but data are limited."
• Added a new bullet: "Two randomized clinical trials (STRIVE and
TERRAIN) showed that 160 mg/d enzalutamide improved progression-free
survival compared with 50 mg/d bicalutamide in men with treatment-naïve
CRPC and, therefore, enzalutamide may be the preferred option in this
setting. However, bicalutamide can still be considered in some patients,
given the different side-effect profiles of the agents and the increased cost
of enzalutamide."
PROS-G (1 of 3)
• Added list of chemotherapy and immunotherapy agents for clarification.
• Added "with prednisone" to cabazitaxel.
• Added "Patients who are not candidates for docetaxel or who are
intolerant of docetaxel should be considered for cabazitaxel, based on
recent results that suggest clinical activity of cabazitaxel in mCRPC.
Cabazitaxel was associated with lower rates of peripheral neuropathy than
docetaxel, particularly at 20 mg/m2 (12% vs. 25%) and may be appropriate
in patients with pre-existing mild peripheral neuropathy. Current data do
not support greater efficacy of cabazitaxel over docetaxel."
• Added "Cabazitaxel at 25 mg/m² every 3 weeks with prednisone has been
the standard of care in the post-docetaxel setting, with or without growth
factor support. A recent trial, PROSELICA, compared cabazitaxel 25 mg/
m² every 3 weeks to 20 mg/m² every 3 weeks. Cabazitaxel 20 mg/m² had
less toxicity; febrile neutropenia, diarrhea, and fatigue were less frequent.
Cabazitaxel at 20 mg/m² had a significantly lower PSA response rate but
non-significantly lower radiographic response rate and non-significantly
shorter progression-free and overall survival (13.4 vs 14.5 mo) compared
to 25 mg/m². Cabazitaxel starting dose can be either 20 mg/m² or 25 mg/
m² for men with mCRPC who have progressed despite prior docetaxel
chemotherapy. Cabazitaxel 20 mg/m² with prednisone is recommended
for frail or less chemo-fit men and those at high risk for neutropenic fever.
Cabazitaxel 25 mg/m² with prednisone is recommended for healthy men
who wish to be more aggressive."
Docetaxel retreatment can be attempted for men who have not
demonstrated definitive evidence of progression on prior docetaxel
Several systemic agents have shown palliative and radiographic
response benefits in clinical trials.
Treatment decisions around off-label chemotherapy use in the
treatment-refractory CRPC should be individualized based on
comorbidities and functional status and after informed consent.
No benefits of combination approaches over sequential singleagent therapies have been demonstrated, and toxicity is higher with
combination regimens.
• Removed “Mitoxantrone has not demonstrated a survival improvement
in the post-docetaxel setting but remains a palliative therapeutic option,
particularly in men who are not candidates for cabazitaxel or radium-223
therapy. No chemotherapy regimen to date has demonstrated improved
survival or quality of life after cabazitaxel, and trial participation should
be strongly encouraged. Outside of a clinical trial, several systemic
agents have shown palliative benefits in single-arm studies. Treatment
decisions should be individualized based on comorbidities and
functional status. Finally, for men who have not demonstrated definitive
evidence of progression on prior docetaxel therapy, retreatment with this
agent can be attempted.”
• Removed "Men who have not demonstrated definitive evidence of
progression on prior docetaxel may be retreated with docetaxel."
• Added Grade Group Definitions with references.
INITIAL PROSTATE
INITIAL CLINICAL
Life expectancyb
≤5 y and
• DRE
• PSA
• Gleason primary
and secondary
• Family historya
&gt;5 y or
symptomaticc
aThe
STAGING WORKUPd
RISK GROUP f
No further workup or treatment until symptomatic,
except in high- or very-high-risk groupse
Bone scan if any of these:
• T1 and PSA &gt;20 ng/mL
• Gleason score ≥8
• T3, T4
• Symptomatic
Pelvic CT or MRI if any
of these:
• T1-T2 and nomogram
indicated probability
of lymph node
involvement &gt;10%
All others: no
additional imaging
following should be considered: brother or father or multiple family members diagnosed with prostate cancer
at less than 60 years of age, germline DNA repair gene abnormalities, especially BRCA2 mutation or Lynch
syndrome (germline mutations in MLH1, MSH2, MSH6, or PMS2) and/or strong family history for breast or
ovarian cancer (suggests possibility of BRCA2 mutation) or colorectal, endometrial, gastric, ovarian, pancreatic,
small bowel, urothelial, kidney, or bile duct cancer (suggests possibility of Lynch syndrome).
bSee Principles of Life Expectancy Estimation (PROS-A).
cMen with clinically localized disease may consider the use of tumor-based molecular assays. Retrospective case
cohort studies have shown that molecular assays performed on biopsy or prostatectomy specimens provide
prognostic information independent of NCCN risk groups. These include, but are not limited to, likelihood of death
with conservative management, likelihood of biochemical progression after radical prostatectomy or external
beam therapy, and likelihood of developing metastasis after radical prostatectomy or salvage radiotherapy. See
dSee Principles of Imaging (PROS-B).
eAndrogen deprivation therapy (ADT) or radiation therapy (RT) may be considered in selected patients with high- or
very-high-risk disease, where complications, such as hydronephrosis or metastasis, can be expected within 5 y.
(See PROS-5 or PROS-6).
fPatients with multiple adverse factors may be shifted into the next highest risk group.
Clinically Localized:
Very low:
• T1c
• Gleason score ≤6/grade
• PSA &lt;10 ng/mL
• Fewer than 3 prostate
biopsy cores positive,
≤50% cancer in each core
• PSA density &lt;0.15 ng/mL/g
• T1-T2a
Intermediate:f
• T2b-T2c or
• Gleason score 3+4=7/
grade group II or
grade group III or
• PSA 10–20 ng/mL
High:f
• T3a or
• Gleason score 8/grade
group IV or
• Gleason score 9–10/grade
group V
• PSA &gt;20 ng/mL
Locally Advanced:
Very high:
• T3b-T4 or
• Primary Gleason pattern 5/
grade group V or
• &gt;4 cores with Gleason
score 8–10/grade group lV
or V
Metastatic:
Any T, N1 or
Any T, Any N, M1
See Initial
(PROS-2)
RISK GROUP
SURVIVALb
≥20 yg
• Gleason score ≤6/
grade group I
≤50% cancer in each
• PSA density &lt;0.15 ng/
mL/g
INITIAL THERAPY
• PSA no more often than every 6 mo unless clinically indicated
• DRE no more often than every 12 mo unless clinically indicated
• Repeat prostate biopsy no more often than every 12 mo unless clinically
• Consider mpMRI if anterior and/or aggressive cancer is suspected when
PSA increases and systematic prostate biopsies are negative
EBRTh,i or brachytherapy
Radical prostatectomy (RP)j
± pelvic lymph node
dissection (PLND) if predicted
probability of lymph node
metastasis ≥2%
10–20 yg
&lt;10 y
the increased diagnosis of early prostate cancer from PSA testing. See NCCN
Guidelines for Prostate Cancer Early Detection. Active surveillance is recommended
for these subsets of patients.
hActive surveillance involves actively monitoring the course of disease with the
expectation to intervene with potentially curative therapy if the cancer progresses.
See Principles of Active Surveillance and Observation (PROS-C).
iSee Principles of Radiation Therapy (PROS-D).
jSee Principles of Surgery (PROS-E).
diseasen
See Initial Clinical
See Monitoring (PROS-7)
Adverse feature(s) and no lymph node
metastases:k
EBRT i
Observation l
No adverse features or lymph node metastases
Lymph node metastasis:
ADTm (category 1) ± EBRT i (category 2B)
Active surveillanceh
gThe panel remains concerned about the problems of over-treatment related to
kAdverse
laboratory/pathologic features include: positive margin(s), seminal
vesicle invasion, extracapsular extension, or detectable PSA.
lObservation involves monitoring the course of disease with the expectation to
deliver palliative therapy for the development of symptoms or a change in
exam or PSA that suggests symptoms are imminent. See Principles of Active
Surveillance and Observation (PROS-C).
mSee Principles of Androgen Deprivation Therapy (PROS-F).
nCriteria for progression are not well defined and require physician judgment;
however, a change in risk group strongly implies disease progression. See
RPj ± PLND if predicted
• Repeat prostate biopsy no more often than every 12 mo unless
clinically indicated
• Consider mpMRI if anterior and/or aggressive cancer is suspected
when PSA increases and systematic prostate biopsies are negative
EBRT i or
kAdverse laboratory/pathologic features
include: positive margin(s), seminal
deliver palliative therapy for the development of symptoms or a change in exam or
PSA that suggests symptoms are imminent. See Principles of Active Surveillance
and Observation (PROS-C).
RPj + PLND if
predicted probability
Intermediate:f,o
• T2b-T2c
grade group II
grade group III
≥10 yp
Adverse feature(s) and no
lymph node metastases:k
No adverse features or lymph
node metastases
ADTm (category 1) ± EBRT i
(category 2B)
Undetectable PSA
after RP or PSA
nadir after RT
See Monitoring
See Radical
Biochemical Failure
PSA failure
EBRTi ± ADTm (4–6 mo)
± brachytherapy
or brachytherapy alonei
See Radiation Therapy
Recurrence (PROS-9)
lObservation
involves monitoring the course of disease with the expectation
to deliver palliative therapy for the development of symptoms or a change in
oPatients with favorable intermediate-risk prostate cancer (predominant Gleason
grade 3 [ie, Gleason score 3 + 4 = 7/grade group ll], and percentage of positive
fPatients with multiple adverse factors may be shifted into the next highest risk group. biopsy cores &lt;50 percent, and no more than one NCCN intermediate risk factor)
may be considered for active surveillance. See Discussion section.
pActive surveillance of unfavorable intermediate and high-risk clinically localized
kAdverse laboratory/pathologic features include: positive margin(s), seminal vesicle
cancers is not recommended in patients with a life expectancy &gt;10 years
invasion, extracapsular extension, or detectable PSA.
(category 1).
EBRTi + ADTm (2–3 y; category 1)q
• Gleason score
8/grade group
9–10/grade
EBRTi
+ brachytherapy
RPj + PLND
± ADTm (2–3
y)
See Radical Prostatectomy
lObservation involves monitoring the course of disease with the expectation to deliver
with multiple adverse factors may be shifted into the next highest palliative therapy for the development of symptoms or a change in exam or PSA that
suggests symptoms are imminent. See Principles of Active Surveillance and Observation
risk group.
(PROS-C).
kAdverse laboratory/pathologic features include: positive margin(s), seminal qSix cycles of docetaxel every 3 weeks without prednisone may be administered after
completion of radiation in selected patients who are fit for chemotherapy.
fPatients
EBRTi + ADT m (2–3 y; category 1)q
• Primary Gleason
pattern 5/grade
• &gt;4 cores with
Gleason score
group lV or V
EBRTi + brachytherapy ± ADTm
(2–3 y)
RPj + PLND (in select patients)r
ADTm or observation for patients
who are not candidates for
definitive therapy
Regional:
Any T, N1, M0
Any T,
Any N, M1
EBRTi + ADTm (2–3 y; category 1)
involves monitoring the course of disease with the expectation to deliver
palliative therapy for the development of symptoms or a change in exam or PSA that
qSix cycles of docetaxel every 3 weeks without prednisone may be administered after
kAdverse laboratory/pathologic features include: positive margin(s), seminal rRP + PLND can be considered in younger, healthier patients without tumor fixation to the
pelvic side-wall.
INITIAL MANAGEMENT
OR PATHOLOGY
Failure of PSA to fall to
undetectable levels
(PSA persistence)
Post-RP
Initial definitive therapy
• PSA every 6–12 mo for 5 y,s
then every year
• DRE every year, but may be
omitted if PSA undetectable
PostEBRT
Undetectable PSA after RP with
a subsequent detectable PSA
that increases on 2 or more
determinations (PSA recurrence)
failuret
Positive DRE
Progression to
without biochemical
N1 or M1
on ADT
• Physical exam + PSA every
• Bone scan and for symptoms
as often as every 6–12 mo
See Radiation
Therapy Recurrence
See Systemic Therapy
for Progressive
Castration-Naive
Disease (PROS-10)
Systemic Therapy for
M0 CRPC (PROS-11)
for M1 CRPC (PROS-12)
sPSA as frequently as every 3 mo may be necessary to clarify disease status, especially in high-risk men.
tRTOG-ASTRO (Radiation Therapy Oncology Group - American Society for Therapeutic Radiology and Oncology)
Phoenix Consensus: 1) PSA increase by 2 ng/mL or
more above the nadir PSA is the standard definition for biochemical failure after EBRT with or without HT; and 2) A recurrence evaluation should be considered when
PSA has been confirmed to be increasing after radiation even if the increase above nadir is not yet 2 ng/mL, especially in candidates for salvage local therapy who are
young and healthy. Retaining a strict version of the ASTRO definition allows comparison with a large existing body of literature. Rapid increase of PSA may warrant
evaluation (prostate biopsy) prior to meeting the Phoenix definition, especially in younger or healthier men.
RADICAL PROSTATECTOMY BIOCHEMICAL FAILURE
Failure of PSA to
fall to undetectable
levels (PSA
persistence)
after RP with
a subsequent
detectable PSA that
increases on 2 or
more determinations
(PSA recurrence)
• PSADT
• Consider:
Chest x-rayd
Bone scand
Abdominal/pelvic CT
or MRI and/or TRUSd
C-11 choline PET/CTd
Prostate bed biopsy
(especially if imaging
suggests local
recurrence)
uObservation involves monitoring the course of disease with the
negative for
positive for
expectation to
begin ADT when symptoms develop or PSA changes to suggest symptoms are
imminent. See Principles of Active Surveillance and Observation (PROS-C).
vImaging should include chest x-ray, bone scan, and abdominal/pelvic CT or MRI
EBRTi ± ADTm
Observationu
Progressionv
See Systemic Therapy for
Progressive CastrationNaive Disease
(PROS-10)w
For M0 CRPC (PROS-11)w
Progressive CastrationNaive Disease (PROS-10)w
ADTm ± EBRT to
site of metastases,
if in weightbearing bones, or
symptomatici
with and without contrast. Consider C-11 choline PET/CT.
See Principles of Imaging (PROS-B).
wThe term "castration-naive" is used to define patients who are not on ADT at the
time of progression. The NCCN Prostate Cancer Panel uses the term "castrationnaive" even when patients have had neoadjuvant, concurrent, or adjuvant ADT as
part of radiation therapy provided they have recovered testicular function.
TRUS biopsy
studies negative
for distant
Observation u
RP + PLNDj
High-intensity
ultrasound (HIFU)
Brachytherapyi
RADIATION THERAPY RECURRENCE
Candidate for local
• Original clinical stage
T1-T2, NX or N0
• Life expectancy &gt;10 y
• PSA now &lt;10 ng/mL
• Chest x-rayd
• Bone scand
• Prostate MRId
Abdominal/pelvic
CT/MRId
C-11 choline PET/
Studies positive
Not a candidate
for local therapy
tRTOG-ASTRO (Radiation Therapy Oncology Group - American
Society for
Therapeutic Radiology and Oncology) Phoenix Consensus: 1) PSA increase by
2 ng/mL or more above the nadir PSA is the standard definition for biochemical
failure after EBRT with or without HT; and 2) A recurrence evaluation should
be considered when PSA has been confirmed to be increasing after radiation
even if the increase above nadir is not yet 2 ng/mL, especially in candidates for
salvage local therapy who are young and healthy. Retaining a strict version of
the ASTRO definition allows comparison with a large existing body of literature.
ADTm (especially if
bone scan positive)
See Systemic
Therapy for
CastrationNaive Disease
M0 CRPC
Rapid increase of PSA may warrant evaluation (prostate biopsy) prior to meeting
the Phoenix definition, especially in younger or healthier men.
uObservation involves monitoring the course of disease with the expectation to
SYSTEMIC THERAPY FOR PROGRESSIVE CASTRATION-NAIVE DISEASEw
Orchiectomy
LHRH agonist ± antiandrogenm,x
LHRH antagonistm,x
See Systemic Therapy For M0 CRPC
(PROS-11)
Progressionv,z
LHRH agonist ± antiandrogenm,x ≥7 days to
prevent testosterone flare
LHRH agonist + antiandrogenm,x
ADTm,x and docetaxel 75 mg/m with or
without prednisone for 6 cyclesy
Therapy For M1
CRPC (PROS-12)
Not small cell
Consider biopsy
if small cell
Cisplatin/etoposideaa,bb
Carboplatin/etoposideaa,bb
Docetaxel/carboplatinaa,bb
expectation to begin ADT when symptoms develop or PSA changes to suggest symptoms are imminent.
vImaging should include chest x-ray, bone scan, and abdominal/pelvic CT or MRI with and without contrast. Consider C-11 choline PET/CT. See Principles of Imaging
(PROS-B).
wThe term "castration-naive" is used to define patients who are not on ADT at the time of progression. The NCCN Prostate Cancer Panel uses the term "castrationnaive" even when patients have had neoadjuvant, concurrent, or adjuvant ADT as part of radiation therapy provided they have recovered testicular function.
xIntermittent ADT can be considered for men with M0 or M1 disease to reduce toxicity. See Principles of Androgen Deprivation Therapy (PROS-F)
yHigh-volume disease is differentiated from low-volume disease by visceral metastases and/or 4 or more bone metastases, with at least one metastasis beyond the
pelvis vertebral column. Patients with low-volume disease have less certain benefit from early treatment with docetaxel combined with ADT.
zAssure castrate level of testosterone.
aaSee Principles of Immunotherapy and Chemotherapy (PROS-G).
bbSee NCCN Guidelines for Small Cell Lung Cancer.
SYSTEMIC THERAPY FOR M0 CASTRATION-RECURRENT PROSTATE CANCER
No metastases
(M0)
levels of
• Clinical trial (preferred)
• Observation especially if
PSADT ≥10 mo
• Secondary hormone
therapym especially if PSADT
&lt;10 mo
Antiandrogen
Antiandrogen withdrawal
Ketoconazole ±
DES or other estrogen
vImaging should include chest x-ray, bone scan, and abdominal/pelvic
Change or
maintain current
and continue
Imagingv
Metastases (M1)
PSA rising
treatment and
continue monitoring
CT or MRI with and without contrast. Consider C-11 choline PET/CT.
CRPC,
• Maintain castrate levels of serum
testosterone (&lt;50 ng/dL)
• Consider bone antiresorptive
therapy with denosumab or
zoledronic acid (both category 1) if
bone metastases present
• Immunotherapy with sipuleucel-T
if asymptomatic or minimally
symptomatic, no liver metastases,
life expectancy &gt;6 mo, ECOG
performance status 0–1 (category 1)
(See PROS-G)cc
• Palliative RT for painful bony
• Best supportive care
• Abirateronem with prednisone
(category 1)
• Docetaxelaa,ee with prednisone
• Enzalutamidem (category 1)
• Radium-223 for symptomatic bone
metastases (category 1)ff
• Clinical trial
• Secondary hormone therapym
Ketoconazole ± hydrocortisonegg
• Alternative chemotherapy
(mitoxantrone with prednisone)aa
Progressionv after:
• Abiraterone
• Enzalutamidem
• Docetaxel
See Subsequent Therapy
for M1 CRPC: No Visceral
Metastases (PROS-13)
for M1 CRPC: Visceral
after all other
eeAlthough
CT or MRI
with and without contrast. Consider C-11 choline PET/CT. See Principles of
Imaging (PROS-B).
ccSipuleucel-T has not been studied in patients with visceral metastases.
most patients without symptoms are not treated with chemotherapy, the
survival benefit reported for docetaxel applies to those with or without symptoms.
Docetaxel may be considered for patients with signs of rapid progression or visceral
metastases despite lack of symptoms.
ffRadium-223 is not approved for use in combination with docetaxel or any other
chemotherapy. See Principles of Radiation Therapy (PROS-D, page 2 of 2).
ggKetoconazole ± hydrocortisone should not be used if the disease progressed on
abiraterone.
SUBSEQUENT SYSTEMIC THERAPY FOR M1 CASTRATION-RECURRENT PROSTATE CANCERhh
Prior therapy
enzalutamide/
abirateroneii
No visceral
• Docetaxel with prednisone (category 1)aa
• Radium-223 for symptomatic bone metastases (category 1)ff
• Sipuleucel-T if asymptomatic or minimally symptomatic, no liver metastases, life expectancy &gt;6 mo, ECOG 0–1
• Other secondary hormone therapym
• Enzalutamide (category 1)m
• Abirateronem with prednisone (category 1)
• Cabazitaxel with prednisone (category 1)aa
• Docetaxel rechallengeaa
• Alternative chemotherapy (mitoxantrone with prednisone)aa
ggKetoconazole
ffRadium-223 is not approved for use in combination with docetaxel
or any other
± hydrocortisone should not be used if the disease
progressed on abiraterone.
hhPatients can continue through all treatment options listed. Best
supportive care is always an appropriate option.
iiLimited data suggest a possible role for AR-V7 testing to help guide
selection of therapy.
• Docetaxel with prednisone (category 1aa
mSee
aaSee
Principles of Androgen Deprivation Therapy (PROS-F).
Principles of Immunotherapy and Chemotherapy (PROS-G).
PRINCIPLES OF LIFE EXPECTANCY ESTIMATION
• Life expectancy estimation is critical to informed decision-making in prostate cancer early detection and treatment.
• Estimation of life expectancy is possible for groups of men but challenging for individuals.
• Life expectancy can be estimated using the Social Security Administration tables (www.ssa.gov/OACT/STATS/table4c6.html) or the WHO’s
Life Tables by country (http://apps.who.int/gho/data/view.main.60000?lang=en).
• Life expectancy can then be adjusted using the clinician’s assessment of overall health as follows:
Best quartile of health - add 50%
Worst quartile of health - subtract 50%
Middle two quartiles of health - no adjustment
• Example of 5-year increments of age are reproduced in the NCCN Guidelines for Older Adult Oncology for life expectancy estimation.
PROS-A
PRINCIPLES OF IMAGING
Goals of Imaging
• Imaging is performed for the detection and characterization of disease to
select treatment or guide change in management.
• Imaging studies should be performed based on the best available clinical
evidence and not influenced by business or personal interests of the care
• Imaging techniques can evaluate anatomic or functional parameters.
Anatomic imaging techniques include plain film radiographs, ultrasound,
CT, and MRI.
Functional imaging techniques include radionuclide bone scan, PET/CT,
and advanced MRI techniques, such as spectroscopy and spect (DWI).
Efficacy of Imaging
• The utility of imaging for men with early biochemical failure after RP
depends on risk group prior to operation, pathologic Gleason grade and
stage, PSA, and PSA doubling time (PSADT) after recurrence. Low- and
intermediate-risk groups with low serum PSAs postoperatively have a very
low risk of positive bone scans or CT scans.
• Frequency of imaging should be based on individual risk, age, PSADT,
Gleason score, and overall health.
• Conventional bone scans are rarely positive in asymptomatic men with
PSA &lt;10 ng/mL. The relative risk for bone metastasis or death increases
as PSADT falls. Bone imaging should be performed more frequently when
PSADT ≤8 mo, where there appears to be an inflection point.
Plain Radiography
• Plain radiography can be used to evaluate symptomatic regions in the
skeleton. However, conventional plain x-rays will not detect a bone lesion
until nearly 50% of the mineral content of the bone is lost or gained.
• CT or MRI may be more useful to assess fracture risk as these modalities
permit more accurate assessment of cortical involvement than plain films
where osteoblastic lesions may obscure cortical involvement.
• Ultrasound uses high-frequency sound waves to image small regions of the
Standard ultrasound imaging provides anatomic information.
Vascular flow can be assessed using Doppler ultrasound techniques.
• Endorectal ultrasound is used to guide transrectal biopsies of the prostate.
• Endorectal ultrasound can be considered for patients with suspected
recurrence after RP.
• Advanced ultrasound techniques for imaging of the prostate and
for differentiation between prostate cancer and prostatitis are under
evaluation.
Bone Scan
• The use of the term “bone scan” refers to the conventional technetium99m-MDP bone scan in which technetium is taken up by bone that is
turning over and imaged with a gamma camera using planar imaging or 3-D
imaging with single-photon emission CT (SPECT).
Sites of increased uptake imply accelerated bone turnover and may
indicate metastatic disease.
Osseous metastatic disease may be diagnosed based on the overall
pattern of activity, or in conjunction with anatomic imaging.
• Newer technology using 18F-NaF as the tracer for a PET/CT scan or hybrid
imaging bone scan can be used as a diagnostic staging study. These
tests appear to have greater sensitivity than bone scan. However, there is
controversy about how the results of 18F-NaF PET/CT bone scan should be
acted upon since all phase 3 clinical trials to date have used progression
criteria on bone scans.
• Bone scan is indicated in the initial evaluation of patients at high risk for
skeletal metastases.
T1 disease and PSA ≥20, T2 disease and PSA ≥10, Gleason score ≥8, or
T3/T4 disease
Any stage disease with symptoms suggestive of osseous metastatic
• Bone scan can be considered for the evaluation of the post-prostatectomy
patient when there is failure of PSA to fall to undetectable levels, or when
there is undetectable PSA after RP with a subsequent detectable PSA that
increases on 2 or more subsequent determinations.
• Bone scan can be considered for the evaluation of patients with an
increasing PSA or positive DRE after RT if the patient is a candidate for
additional local therapy or systemic therapy.
Version 1.2017, 12/16/16© National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
PROS-B
Bone Scan (continued)
• Bone scans are helpful to monitor metastatic prostate cancer to determine
the clinical benefit of systemic therapy. However, new lesions seen on an
initial post-treatment bone scan, compared to the pre-treatment baseline
scan, may not indicate disease progression.
• New lesions in the setting of a falling PSA or soft tissue response and in
modalities, such as CT or PET/CT imaging.
• Bone scans and soft tissue imaging (CT or MRI) in men with metastatic
• Bone scans should be performed for symptoms and as often as every 6–12
mo to monitor ADT. The need for soft tissue images remains unclear. In
CRPC, 8- to 12-week imaging intervals appear reasonable.
• CT provides a high level of anatomic detail, and may detect gross
extracapsular disease, nodal metastatic disease, and/or visceral metastatic
CT is generally not sufficient to evaluate the prostate gland.
• CT may be performed with and without oral and intravenous contrast, and
CT technique should be optimized to maximize diagnostic utility while
minimizing radiation dose.
• CT is used for initial staging in select patients (PROS-1)
T3 or T4 disease
Patients with T1 or T2 disease and nomogram-indicated probability of
lymph node involvement &gt;10% may be candidates for pelvic imaging, but
the level of evidence is low.
• CT may be considered in patients after RP when PSA fails to fall to
undetectable levels or when an undetectable PSA becomes detectable and
increases on 2 or more subsequent determinations, or after RT for rising
PSA or positive DRE if the patient is a candidate for additional local therapy
or systemic therapy.
• The strengths of MRI include high soft tissue contrast and characterization,
multiparametric image acquisition, multiplanar imaging capability, and
advanced computational methods to assess function.
MRI can be performed with and without the administration of intravenous
contrast material.
Resolution of MRI images in the pelvis can be augmented using an
endorectal coil.
• Standard MRI techniques can be considered for initial evaluation of highrisk patients.
• MRI may be considered in patients after RP when PSA fails to fall to
undetectable levels or when an undetectable PSA becomes detectable
and increases on 2 or more subsequent determinations, or after RT for
rising PSA or positive DRE if the patient is a candidate for additional local
therapy. MRI-US fusion biopsy may improve the detection of higher grade
(Gleason score &gt;7) cancers.
• Multiparametric MRI (mpMRI) can be used in the staging and
characterization of prostate cancer. mpMRI images are defined as images
acquired with at least one more sequence in addition to the anatomical
T2-weighted images, such as DWI or dynamic contrast-enhanced (DCE)
images.
• mpMRI may be used to better risk stratify men who are considering active
surveillance. Additionally, mpMRI may detect large and poorly differentiated
prostate cancer (ie, Gleason score &gt;7) and detect extracapsular extension
(T staging). mpMRI has been shown to be equivalent to CT scan for pelvic
lymph node evaluation.
Positron Emission Tomography/Computed Tomography
• Whole body PET/CT using C-11 choline tracers may identify sites of
metastatic disease in men with biochemical recurrence after primary
Other choline radiotracers are under evaluation.
Further study is needed to determine the best use of choline PET/CT
imaging in men with prostate cancer.
• Oncologic PET/CT is performed typically using 18F-fluorodeoxyglucose
(FDG), a radioactive analog of glucose.
In certain clinical settings, the use of FDG-PET/CT may provide useful
information, but FDG-PET/CT should not be used routinely since data on
the utility of FDG-PET/CT in patients with prostate cancer is limited.
PRINCIPLES OF ACTIVE SURVEILLANCE AND OBSERVATION
• The NCCN Prostate Cancer Panel and the NCCN Prostate Cancer
Early Detection Panel (See NCCN Guidelines for Prostate Cancer
Early Detection) remain concerned about over-diagnosis and
over-treatment of prostate cancer. The panel recommends that
patients and their physicians (ie, urologist, radiation oncologist,
medical oncologist, primary care physician) consider active
surveillance based on careful consideration of the patient’s
prostate cancer risk profile, age, and health.
• The NCCN Guidelines for Prostate Cancer distinguish between
active surveillance and observation. Both involve no more often
than every-6-month monitoring but active surveillance may
involve surveillance prostate biopsies. Evidence of progression
will prompt conversion to potentially curative treatment in
active surveillance patients, whereas monitoring continues
until symptoms develop or are eminent (ie, PSA &gt;100 ng/mL) in
observation patients, who will then begin palliative ADT.
• Active surveillance is preferred for men with very-low-risk
prostate cancer and life expectancy ≤20 y. Observation is
preferred for men with low-risk prostate cancer with life
expectancy &lt;10 y. See Risk Group Criteria (PROS-2).
• Patients with favorable intermediate-risk prostate cancer
(predominant Gleason grade 3 [ie, Gleason score 3 + 4 = 7], and
percentage of positive biopsy cores &lt;50 percent, and no more
than one NCCN intermediate risk factor) may be considered for
active surveillance. See Discussion section. Active surveillance
involves actively monitoring the course of disease with the
expectation to intervene with curative intent if the cancer
progresses.
• Cancer progression may have occurred if:
Gleason grade 4 or 5 cancer is found upon repeat prostate biopsy
Prostate cancer is found in a greater number of prostate biopsies or
occupies a greater extent of prostate biopsy.
• Observation involves monitoring the course of disease with the
expectation to deliver palliative therapy for the development of
symptoms or change in exam or PSA levels that suggest symptoms
are imminent.
• Patients with clinically localized prostate cancers who are candidates
for definitive treatment and choose active surveillance should have
regular follow-up. Follow-up should be more rigorous in younger men
than in older men. Follow-up should include:
PSA no more often than every 6 mo unless clinically indicated
DRE no more often than every 12 mo unless clinically indicated
Needle biopsy of the prostate should be repeated within 6 mo of
diagnosis if initial biopsy was &lt;10 cores or assessment discordant
(eg, palpable tumor contralateral to side of positive biopsy)
MRI-US fusion biopsy may improve the detection of higher grade
A repeat prostate biopsy should be considered if prostate exam
changes, MRI suggests more aggressive disease, or PSA increases,
but no parameter is very reliable for detecting prostate cancer
progression.
A repeat prostate biopsy should be considered as often as annually
to assess for disease progression, because PSA kinetics may not
be as reliable as monitoring parameters to determine progression of
Repeat prostate biopsies are not indicated when life expectancy is
less than 10 y or appropriate when men are on observation.
PSADT appears unreliable for identification of progressive disease
that remains curable. Although mpMRI is not recommended for
routine use, it may be considered if PSA rises and systematic
prostate biopsy is negative to exclude the presence of an anterior
PROS-C
• Advantages of active surveillance:
About 2/3 of men eligible for active surveillance will avoid
Avoidance of possible side effects of definitive therapy that may
be unnecessary
Quality of life/normal activities potentially less affected
Risk of unnecessary treatment of small, indolent cancers reduced
• Advantages of observation:
Avoidance of possible side effects of unnecessary definitive
therapy and early initiation and/or continuous ADT
• Disadvantages of observation:
Risk of urinary retention or pathologic fracture without prior
symptoms or concerning PSA level
• Disadvantages of active surveillance:
Chance of missed opportunity for cure although very low
About 1/3 of men will require treatment, although treatment delays
do not seem to impact cure rate.
Periodic follow-up prostate biopsies may be necessary.
PRINCIPLES OF RADIATION THERAPY
Primary External Beam Radiation Therapy
• Highly conformal RT techniques should be used to treat prostate cancer.
• Doses of 75.6 to 79.2 Gy in conventional fractions to the prostate (± seminal
vesicles for part of the therapy) are appropriate for patients with low-risk
cancers. For patients with intermediate- or high-risk disease, doses up to
81.0 Gy provide improved PSA-assessed disease control.
• Moderately hypofractionated image-guided IMRT regimens (2.4–4 Gy per
fraction over 4–6 weeks) have been tested in randomized trials reporting
similar efficacy and toxicity to conventionally fractionated IMRT. They can
be considered as an alternative to conventionally fractionated regimens
when clinically indicated.
• Extremely hypofractionated image-guided IMRT/SBRT regimens (6.5
Gy per fraction or greater) are an emerging treatment modality with
single institutional and pooled reports of similar efficacy and toxicity
to conventionally fractionated regimens. They can be considered as
an alternative to conventionally fractionated regimens at clinics with
appropriate technology, physics, and clinical expertise.
• Patients with high-risk and very-high-risk cancers should receive
neoadjuvant/concomitant/adjuvant ADT for a total of 2 to 3 y if
comorbidities allow (category 1). Pelvic lymph node irradiation can be
considered.
• Patients with intermediate-risk cancer may be considered for pelvic lymph
node irradiation and 4- to 6-mo neoadjuvant/concomitant/adjuvant ADT.
• Patients with low-risk cancer should not receive pelvic lymph node
irradiation or ADT.
• The accuracy of treatment should be improved by attention to daily
prostate localization, with techniques of IGRT using CT, ultrasound,
implanted fiducials, electromagnetic targeting/tracking, or an endorectal
balloon to improve oncologic cure rates and reduce side effects.
Primary Brachytherapy
• Brachytherapy as monotherapy is indicated for patients with low-risk
cancers and selected patients with low-volume intermediate-risk cancers.
Intermediate-risk cancers may be treated by combining brachytherapy
with EBRT (40–50 Gy) ± 4 to 6 mo neoadjuvant/concomitant/adjuvant ADT.
Patients with high-risk cancers may be treated with a combination of EBRT
(40–50 Gy) and brachytherapy ± 2 to 3 y neoadjuvant/concomitant/adjuvant
ADT.
• Patients with a very large prostate or very small prostate, symptoms
of bladder outlet obstruction (high IPSS), or a previous TURP are
more difficult to implant and may suffer increased risk of side effects.
Neoadjuvant ADT may be used to shrink the prostate to an acceptable size;
however, increased toxicity would be expected from ADT and prostate size
may not decline in some men despite neoadjuvant ADT. Potential toxicity of
ADT must be balanced against the potential benefit of target reduction.
• Post-implant dosimetry must be performed to document the quality of the
low dose-rate implant.
• The recommended prescribed doses for brachytherapy monotherapy are
145 Gy for Iodine-125 and 125 Gy for Palladium-103. The corresponding
boost doses after 40 to 50 Gy EBRT are 110 Gy and 90 to 100 Gy,
• High dose-rate (HDR) brachytherapy can be used alone or in combination
with EBRT (40–50 Gy). Commonly used boost regimens include 13 to 15 Gy
x 1 fraction, 8 to 11.5 Gy x 2 fractions, 5.5 to 6.5 Gy x 3 fractions, and 4.0
to 6.0 Gy x 4 fractions. Commonly used regimens for HDR treatment alone
include 9.5 Gy x 4 fractions, 10.5 Gy x 3 fractions, 13.5 Gy x 2 fractions, or
19 Gy x 1 fraction.
Salvage Brachytherapy
• Permanent LDR or temporary HDR brachytherapy can be used as treatment
for a local recurrence following EBRT or primary brachytherapy. Radiation
dose depends on the original primary external beam dose and the pattern of
recurrence, and ranges from 100 to 110 Gy for LDR and 9 to 12 Gy x 2 fractions
for HDR.
PROS-D
Post-Prostatectomy Radiation Therapy
• The panel recommends use of nomograms and consideration of age and
comorbidities, clinical and pathologic information, PSA levels, and PSADT to
individualize treatment discussion. The panel also recommends consultation
with the American Society for Therapeutic Radiology and Oncology (ASTRO)
AUA Guidelines. Evidence supports offering adjuvant/salvage RT in most
men with adverse pathologic features or detectable PSA and no evidence of
disseminated disease.
• Indications for adjuvant RT include pT3 disease, positive margin(s), Gleason
score 8–10, or seminal vesicle involvement. Adjuvant RT is usually given
within 1 year after RP and once any operative side effects have improved/
stabilized. Patients with positive surgical margins may benefit the most.
• Indications for salvage RT include an undetectable PSA that becomes
detectable and then increases on 2 subsequent measurements. Treatment is
more effective when pre-treatment PSA is low and PSADT is long.
• The recommended prescribed doses for adjuvant/salvage post-prostatectomy
RT are 64–72 Gy in standard fractionation. Biopsy-proven gross recurrence
may require higher doses.
• Two years instead of 6 months of ADT can be considered in addition to RT
based on RTOG 9601 (presented at ASTRO 2015) for men with persistent
PSA after RP or for PSA levels that exceed 1.0 ng/mL at the time of initiation
of salvage therapy. Six months of ADT can be considered coadministered
with salvage radiation based on the results of GETUG-16. An LHRH agonist
should be used. For 2-year ADT, there is level 1 evidence to support 150 mg
bicalutamide daily but an LHRH agonist could be considered as an alternative.
• The defined target volumes include the prostate bed and may include the
whole pelvis in selected patients.
• Radium-223 is an alpha-emitting radiopharmaceutical that has been shown to
extend survival in men who have castration-recurrent prostate cancer (CRPC)
with symptomatic bone metastases, but no visceral metastases. Radium-223
alone has not been shown to extend survival in men with visceral metastases
or bulky nodal disease greater than 3 to 4 cm. Radium-223 differs from betaemitting agents, such as samarium 153 and strontium 89, which are palliative
and have no survival advantage. Radium-223 causes double-strand DNA
breaks and has a short radius of activity. Grade 3–4 hematologic toxicity (2%
neutropenia, 3% thrombocytopenia, 6% anemia) occurs at low frequency.
• Radium-223 is administered intravenously once a month for 6 months by an
appropriately licensed facility, usually in nuclear medicine or RT departments.
• Prior to the initial dose, patients must have absolute neutrophil count ≥1.5 x
109/L, platelet count ≥100 x 109/L, and hemoglobin ≥10g/dL.
• Prior to subsequent doses, patients must have absolute neutrophil count ≥1 x
109/L and platelet count ≥50 x 109/L (per label, although this may be too low in
practice). Radium-223 should be discontinued if a delay of 6 to 8 weeks does
not result in the return of blood counts to these levels.
• Non-hematologic side effects are generally mild, and include nausea, diarrhea,
and vomiting. These symptoms are likely related to the fact that radium-223 is
predominantly eliminated by fecal excretion.
• At the present time, except on a clinical trial, radium-223 is not intended to
be used in combination with chemotherapy due to the potential for additive
myelosuppression.
• Concomitant use of denosumab or zoledronic acid does not interfere with the
beneficial effects of radium-223 on survival.
Palliative Radiotherapy
• 8 Gy as a single dose should be used instead of 30 Gy in 10 fractions for nonvertebral metastases.
• Widespread bone metastases can be palliated using strontium 89 or samarium
153 with or without focal external beam radiation.
PRINCIPLES OF SURGERY
Pelvic Lymph Node Dissection:
• An extended PLND will discover metastases approximately twice as
often as a limited PLND. Extended PLND provides more complete
staging and may cure some men with microscopic metastases;
therefore, an extended PLND is preferred when PLND is performed.
• An extended PLND includes removal of all node-bearing tissue
from an area bound by the external iliac vein anteriorly, the pelvic
sidewall laterally, the bladder wall medially, the floor of the pelvis
posteriorly, Cooper's ligament distally, and the internal iliac artery
proximally.
• A PLND can be excluded in patients with &lt;2% predicated probability
of nodal metastases by nomograms, although some patients with
lymph node metastases will be missed.
• PLND can be performed using an open, laparoscopic, or robotic
technique.
Radical Prostatectomy:
• RP is an appropriate therapy for any patient with clinically localized
prostate cancer that can be completely excised surgically, who
has a life expectancy of ≥10 years, and has no serious comorbid
conditions that would contraindicate an elective operation.
• High-volume surgeons in high-volume centers generally provide
better outcomes.
• Laparoscopic and robot-assisted RP are used commonly. In
experienced hands, the results of these approaches appear
comparable to open surgical approaches.
• Blood loss can be substantial with RP, but can be reduced by careful
control of the dorsal vein complex and periprostatic vessels.
• Urinary incontinence can be reduced by preservation of urethral
length beyond the apex of the prostate and avoiding damage to
the distal sphincter mechanism. Bladder neck preservation may
decrease the risk of incontinence. Anastomotic strictures increase
the risk of long-term incontinence.
• Recovery of erectile function is directly related to age at RP,
preoperative erectile function, and the degree of preservation of the
cavernous nerves. Replacement of resected nerves with nerve grafts
has not been shown to be beneficial. Early restoration of erections
may improve late recovery.
• Salvage RP is an option for highly selected patients with local
recurrence after EBRT, brachytherapy, or cryotherapy in the
absence of metastases, but the morbidity (ie, incontinence, loss of
erection, anastomotic stricture) is high and the operation should be
performed by surgeons who are experienced with salvage RP.
PROS-E
PRINCIPLES OF ANDROGEN DEPRIVATION THERAPY
Androgen Deprivation Therapy (ADT) for Clinically Localized Disease (PROS-2
through PROS-6), Biochemical Failure Without Metastases OR for Metastatic
Castration-Naïve Disease (PROS-8 through PROS-10):
• LHRH agonist alone
Leuprolide
• LHRH agonist (as above) plus first-generation antiandrogen
LHRH agonist plus nilutamide
LHRH agonist plus flutamide
LHRH agonist plus bicalutamide
• LHRH agonist (as above) plus second-generation antiandrogen
LHRH agonist plus enzalutamide
• LHRH antagonist
Secondary Hormone Therapy for M0 or M1 Castration-Recurrent Disease
(PROS-11 through PROS-14):
• First-generation antiandrogen
• Second-generation antiandrogen
• Ketoconazole
• Ketoconazole plus hydrocortisone
• Corticosteroids (hydrocortisone, prednisone, dexamethasone)
• DES or other estrogen
ADT for Clinically Localized Disease
• Neoadjuvant ADT for RP is strongly discouraged outside of a
• ADT should not be used as monotherapy in clinically
localized prostate cancer.
• Giving ADT before, during, and/or after radiation prolongs
survival in selected radiation-managed patients.
• Studies of short-term (4–6 mo) and long-term (2–3 y)
neoadjuvant ADT all have used complete androgen blockade.
Whether the addition of an antiandrogen is necessary
requires further study.
• In the largest randomized trial to date using the antiandrogen
bicalutamide alone at high dose (150 mg), there were
indications of a delay in recurrence of disease but no
improvement in survival. Longer follow-up is needed.
• In one randomized trial, immediate and continuous use of
ADT in men with positive nodes following RP resulted in
significantly improved overall survival compared to men who
received delayed ADT. Therefore, such patients should be
considered for immediate ADT.
• Many of the side effects of continuous ADT are cumulative
over time on ADT.
Systemic Therapy For M1 Castration-Recurrent Disease
• Second generation antiandrogen
Enzalutamide (category 1; category 2A if prior therapy with abiraterone)
• Androgen biosynthesis inhibitor
Abiraterone + prednisone (category 1; category 2A for initial treatment of
disease with visceral metastases or if prior therapy with enzalutamide)
PROS-F
ADT for Biochemical Failure Without Metastases
• The timing of ADT for patients whose only evidence of cancer
is a rising PSA is influenced by PSA velocity, patient anxiety,
the short- and long-term side effects of ADT, and the underlying
comorbidities of the patient.
• Most patients will have a good 15-year prognosis, but their
prognosis is best approximated by the absolute level of PSA,
the rate of change in the PSA level (PSADT), and the initial
stage, grade, and PSA level at the time of definitive therapy.
• Earlier ADT may be better than delayed ADT, although
the definitions of early and late (what level of PSA) are
controversial. Since the benefit of early ADT is not clear,
treatment should be individualized until definitive studies are
done. Patients with a shorter PSADT (or a rapid PSA velocity)
and an otherwise long life expectancy should be encouraged to
consider ADT earlier.
• Some patients are candidates for salvage after biochemical
failure, which may include radiation after failed operation or RP
or cryosurgery after failed radiation.
• Men with prolonged PSADTs (&gt;12 mo) and who are older are
candidates for observation.
• Men who choose ADT should consider intermittent ADT. A
phase 3 trial that compared intermittent to continuous ADT
showed that intermittent ADT was not inferior to continuous
ADT with respect to survival, and quality of life was better for
the intermittent ADT arm. The 7% increase in prostate cancer
deaths in the intermittent ADT arm was balanced by more
non-prostate cancer deaths in the continuous ADT arm. An
unplanned subset analysis showed that men with Gleason
sum 8–10 prostate cancer in the continuous arm had a median
overall survival that was 14 mo longer (8 y) than those in the
intermittent arm (6.8 y).
ADT for Metastatic Disease
• ADT is the gold standard for men with metastatic prostate cancer.
• A phase 3 trial compared continuous ADT to intermittent ADT, but the
study could not demonstrate non-inferiority for survival. However,
quality-of-life measures for erectile function and mental health were
better in the intermittent ADT arm after 3 months of ADT compared to the
continuous ADT arm.
• In addition, three meta-analyses of randomized controlled trials failed to
show a difference in survival between intermittent and continuous ADT.
• Close monitoring of PSA and testosterone levels and possibly imaging
is required when using intermittent ADT, especially during off-treatment
periods, and patients may need to switch to continuous ADT upon signs
of disease progression.
Optimal ADT
• LHRH agonist or antagonist (medical castration) and bilateral
orchiectomy (surgical castration) are equally effective.
• Combined androgen blockade (medical or surgical castration combined
with an antiandrogen) provides modest to no benefit over castration
alone in patients with metastatic disease.
• Antiandrogen therapy should precede or be co-administered with
LHRH agonist and be continued in combination for at least 7 days for
patients with overt metastases who are at risk of developing symptoms
associated with the flare in testosterone with initial LHRH agonist alone.
• Antiandrogen monotherapy appears to be less effective than medical or
surgical castration and is not recommended.
• No clinical data support the use of finasteride or dutasteride with
combined androgen blockade.
• Patients who do not achieve adequate suppression of serum
testosterone (less than 50 ng/dL) with medical or surgical castration can
be considered for additional hormonal manipulations (with estrogen,
antiandrogens, LHRH antagonists, or steroids), although the clinical
benefit remains uncertain. The optimal level of serum testosterone to
effect “castration” has yet to be determined.
Secondary Hormone Therapy
• Androgen receptor activation and autocrine/paracrine androgen
synthesis are potential mechanisms of recurrence of prostate cancer
during ADT (CRPC). Thus, castrate levels of testosterone should be
maintained while additional therapies are applied.
• Once the tumor becomes resistant to initial ADT, there are a variety of
options that may afford clinical benefit. The available options are based
on whether the patient has evidence of metastases by imaging, M0
CRPC (non-metastatic) vs. M1 CRPC (metastatic), and whether or not
the patient is symptomatic.
• In the setting in which patients have no or minimal symptoms,
administration of secondary hormonal therapy including addition of,
or switching to, a different anti-androgen (flutamide, bicalutamide,
nilutamide, enzalutamide), addition of adrenal/paracrine androgen
synthesis inhibitors (ketoconazole with or without hydrocortisone or
abiraterone with prednisone), or use of an estrogen, such as DES, can
be considered. Ketoconazole ± hydrocortisone should not be used if
the disease progressed on abiraterone.
• DES has cardiovascular and thromboembolic side effects at any dose
but frequency is dose and agent dependent. DES should be initiated
at 1 mg/d and increased, if necessary, to achieve castrate levels of
serum testosterone (&lt;50 ng/dL). Other estrogens delivered topically or
• In a randomized controlled trial in the setting of M1 CRPC prior to
docetaxel chemotherapy, abiraterone (1000 mg daily on an empty
stomach) and low-dose prednisone (5 mg BID) compared to prednisone
alone improved radiographic progression-free survival (rPFS), time
to initiation of chemotherapy, time to onset or worsening of pain, and
time to deterioration of performance status. An improvement in overall
survival was demonstrated. Use of abiraterone and prednisone in this
setting is a category 1 recommendation. The side effects of abiraterone
that require ongoing monitoring include hypertension, hypokalemia,
peripheral edema, atrial fibrillation, congestive heart failure, liver injury,
and fatigue, as well as the known side effects of ADT and long-term
corticosteroid use.
• A phase 3 study of docetaxel-naive men showed that
enzalutamide (160 mg daily) resulted in significant improvement
in rPFS and overall survival. The use of enzalutamide in this
setting is category 1. The side effects of enzalutamide that
require long-term monitoring include fatigue, diarrhea, hot
flashes, headache, and seizures (reported in 0.9% of men on
enzalutamide).
• Both randomized trials of abiraterone and enzalutamide in the
pre-docetaxel setting were conducted in men who had no or
minimal symptoms due to M1 CRPC. How these agents compare
to docetaxel for pain palliation in this population of patients is
not clear. Both drugs have palliative effects in the post-docetaxel
setting. Both abiraterone and enzalutamide are approved in this
setting and have category 1 recommendations. Both drugs are
suitable options for men who are not good candidates to receive
docetaxel.
• In the post-docetaxel CRPC population, enzalutamide and
abiraterone plus prednisone have been shown to extend survival
in randomized controlled trials. Therefore, each agent has a
category 1 recommendation.
• Two randomized clinical trials (STRIVE and TERRAIN) showed
that 160 mg/d enzalutamide improved progression-free survival
compared with 50 mg/d bicalutamide in men with treatment-naïve
CRPC and, therefore, enzalutamide may be the preferred option
in this setting. However, bicalutamide can still be considered
in some patients, given the different side-effect profiles of the
agents and the increased cost of enzalutamide.
• Evidence-based guidance on the sequencing of these agents in
either pre- or post-docetaxel remains unavailable.
Monitor/Surveillance
• ADT has a variety of adverse effects including hot flashes, loss of
libido and erectile dysfunction, shrinkage of penis and testicles,
loss of muscle mass and strength, fatigue, depression, hair loss,
osteoporosis, greater incidence of clinical fractures, obesity, insulin
resistance, alterations in lipids, and greater risk for diabetes and
cardiovascular disease. Patients and their medical providers should
be advised about these risks prior to treatment.
• Screening and treatment for osteoporosis are advised according
to guidelines for the general population from the National
Osteoporosis Foundation (www.nof.org). The National Osteoporosis
Foundation guidelines include recommendations for: 1) supplemental
calcium (1200 mg daily) and vitamin D3 (800–1000 IU daily) for all
men &gt;50 y of age; and 2) additional treatment for men when the
10-y probability of hip fracture is ≥3% or the 10-y probability of a
major osteoporosis-related fracture is ≥20%. Fracture risk can be
assessed using FRAX®, the algorithm recently released by WHO.
ADT should be considered “secondary osteoporosis” when using
the FRAX® algorithm. Treatment options to increase bone density,
a surrogate for fracture risk in men without metastases, include
denosumab (60 mg SQ every 6 mo), zoledronic acid (5 mg IV
annually), and alendronate (70 mg PO weekly).
• A baseline DEXA scan should be obtained before starting therapy
in men at increased risk for fracture based on FRAX® screening.
A follow-up DEXA scan after 1 year of therapy is recommended
by the International Society for Clinical Densitometry, although
there is no consensus on the optimal approach to monitoring the
effectiveness of drug therapy. Use of biochemical markers of bone
turnover to monitor response to therapy is not recommended. The
serum level of 25-hydroxy vitamin D and average daily dietary intake
of vitamin D will assist the nutritionist in making a patient-specific
recommendation for vitamin D supplementation. There are currently
no guidelines on how often to monitor vitamin D levels. However, for
those who require monitoring with DEXA scans, it makes sense to
check the serum vitamin D level at the same time.
• Denosumab (60 mg SQ every 6 mo), zoledronic acid (5 mg IV
annually), and alendronate (70 mg PO weekly) increase bone
mineral density, a surrogate for fracture risk, during ADT for
prostate cancer. Treatment with either denosumab, zoledronic acid,
or alendronate sodium is recommended when the absolute fracture
risk warrants drug therapy.
• Screening for and intervention to prevent/treat diabetes and
cardiovascular disease are recommended in men receiving ADT.
These medical conditions are common in older men and it remains
uncertain whether strategies for screening, prevention, and
treatment of diabetes and cardiovascular disease in men receiving
ADT should differ from the general population.
PRINCIPLES OF IMMUNOTHERAPY AND CHEMOTHERAPY
• Chemotherapy
Docetaxel + prednisone (category 1; category 2A for rechallenge)
Cabazitaxel + prednisone (category 1 post-docetaxel)
• Immunotherapy
Sipuleucel-T (category 1)
◊◊Only for asymptomatic or minimally symptomatic, no liver
metastases, life expectancy &gt;6 mo, ECOG performance status 0-1
• Men with asymptomatic or minimally symptomatic mCRPC may
consider immunotherapy.
Sipuleucel-T has been shown in a phase 3 clinical trial to
extend mean survival from 21.7 mo in the control arm to 25.8
mo in the treatment arm, which constitutes a 22% reduction in
mortality risk.
Sipuleucel-T is well tolerated; common complications include
chills, pyrexia, and headache.
Sipuleucel-T may be considered for men with CRPC who meet
• Men with advanced prostate cancer should be encouraged to participate
the following: (category 1)
in clinical trials and referred early to a medical oncologist.
◊◊Good performance status (ECOG 0-1)
• Men with high-volume, ADT-naïve, metastatic disease should be
◊◊Estimated life expectancy &gt;6 mo
considered for ADT and docetaxel based on the results of the ECOG
◊◊No hepatic metastases
3805 (CHAARTED) trial. In this study, 790 men were randomized to 6
◊◊No or minimal symptoms
cycles of docetaxel at 75 mg/m2 every 3 weeks without prednisone
• Every-3-week docetaxel with or without prednisone is the
with ADT vs. ADT alone. In the majority subset of patients with highpreferred first-line chemotherapy treatment based on phase
volume disease, defined as 4 or more bone metastases including one
3 clinical trial data for men with symptomatic mCRPC.
extra-axial bone lesion or visceral metastases, a 17-month improvement
Radium-223 has been studied in symptomatic patients who are
in overall survival was observed (HR 0.60; P = .0006). Improvements
not candidates for docetaxel-based regimens and resulted in
in PSA response, time to clinical progression, and time to recurrence
improved overall survival. Abiraterone and enzalutamide have
were observed with use of docetaxel. Toxicities of 6 cycles of docetaxel
been shown to extend survival in patients who progressed on
without prednisone included fatigue, neuropathy, stomatitis, diarrhea,
docetaxel. (See PROS-F, 3 of 4). Mitoxantrone and prednisone
and neutropenia with or without fever. The use of white cell growth
may provide palliation but have not been shown to extend
factors should follow NCCN Guidelines based on risk of neutropenic
survival.
fever. Docetaxel should not be offered to men without metastatic
• Only regimens utilizing docetaxel on an every-3-week schedule
prostate cancer or to men with low-volume metastatic prostate cancer,
demonstrated beneficial impact on survival. The duration of
since this subgroup was not shown to have improved survival in either
therapy should be based on the assessment of benefit and
the ECOG study or a similar European (GETUG-AFU 15) trial.
toxicities. In the pivotal trials establishing survival advantage of
docetaxel-based chemotherapy, patients received up to 10 cycles
of treatment if no progression and no prohibitive toxicities were
PROS-G
• Patients who are not candidates for docetaxel or who are intolerant
of docetaxel should be considered for cabazitaxel with prednisone,
based on recent results that suggest clinical activity of cabazitaxel
in mCRPC. Cabazitaxel with prednisone was associated with lower
rates of peripheral neuropathy than docetaxel, particularly at 20
mg/m2 (12% vs. 25%) and may be appropriate in patients with preexisting mild peripheral neuropathy. Current data do not support
greater efficacy of cabazitaxel over docetaxel.
• Rising PSA should not be used as the sole criteria for progression.
Assessment of response should incorporate clinical and
radiographic criteria.
• Men with mCRPC that has progressed following docetaxel-based
chemotherapy should be encouraged to participate in clinical
trials. However, cabazitaxel with prednisone has been shown in a
randomized phase 3 study to prolong overall survival, progressionfree survival, and PSA and radiologic responses when compared
with mitoxantrone and prednisone and is FDA approved in the postdocetaxel second-line setting. Selection of patients without severe
neuropathy and adequate liver, kidney, and bone marrow function is
necessary, given the high risk of neutropenia and other side effects
in this population, with consideration of prophylactic granulocyte
growth factor injections.­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
• Cabazitaxel at 25 mg/m² every 3 weeks with prednisone has been
the standard of care in the post-docetaxel setting, with or without
growth factor support. A recent trial, PROSELICA, compared
cabazitaxel 25 mg/m² every 3 weeks to 20 mg/m² every 3 weeks.
Cabazitaxel 20 mg/m² had less toxicity; febrile neutropenia,
diarrhea, and fatigue were less frequent. Cabazitaxel at 20 mg/m²
had a significantly lower PSA response rate but non-significantly
lower radiographic response rate and non-significantly shorter
progression-free and overall survival (13.4 vs 14.5 mo) compared
to 25 mg/m². Cabazitaxel starting dose can be either 20 mg/m² or
25 mg/m² for men with mCRPC who have progressed despite prior
docetaxel chemotherapy. Cabazitaxel 20 mg/m² with prednisone
is recommended for frail or less chemo-fit men and those at high
risk for neutropenic fever. Cabazitaxel 25 mg/m² with prednisone is
recommended for healthy men who wish to be more aggressive.
• Docetaxel retreatment can be attempted in men who have not
• No chemotherapy regimen to date has demonstrated improved
survival or quality of life after cabazitaxel, and trial participation
should be encouraged. Several systemic agents have shown
palliative and radiographic response benefits in clinical trials.
• Treatment decisions around off-label chemotherapy use in the
• No benefits of combination approaches over sequential singleagent therapies have been demonstrated, and toxicity is higher with
• See NCCN Guidelines for Myeloid Growth Factors for
recommendations on growth factor support.
• In men with CRPC who have bone metastases, denosumab and
zoledronic acid have been shown to prevent disease-related skeletal
complications, which include fracture, spinal cord compression, or
the need for surgery or RT to bone.
When compared to zoledronic acid, denosumab was shown to be
superior in prevention of skeletal-related events.
Choice of agent may depend on underlying comorbidities, whether
the patient has been treated with zoledronic acid previously,
logistics, and/or cost considerations.
◊◊Zoledronic acid is given intravenously every 3 to 4 weeks. The
dose is based on the serum creatinine obtained just prior to
each dose and must be adjusted for impaired renal function.
Zoledronic acid is not recommended for creatinine clearance
&lt;30 mL/min.
◊◊Denosumab is given subcutaneously every 4 weeks.
Although renal monitoring is not required, denosumab is not
recommended in patients with creatinine clearance &lt;30 mL/min.
When creatinine clearance is &lt;60 mL/min, the risk for severe
hypocalcemia increases. Even in patients with normal renal
function, hypocalcemia is seen twice as often with denosumab
than zoledronic acid and all patients on denosumab should be
treated with vitamin D and calcium with periodic monitoring of
serum calcium levels.
Osteonecrosis of the jaw is seen with both agents; risk is
increased in patients who have tooth extractions, poor dental
hygiene, or a dental appliance. Patients should be referred
for dental evaluation before starting either zoledronic acid or
denosumab. If invasive dental procedures are required, bonetargeted therapy should be withheld until the dentist indicates that
the patient has healed completely from all dental procedure(s).
The optimal duration of therapy for either denosumab or
zoledronic acid remains uncertain.
The toxicity profile of denosumab when denosumab is used in
patients who have been treated with zoledronic acid remains
uncertain.
Clinical trials are in progress that assess a role for zoledronic acid
or denosumab in men beginning ADT for bone metastases.
NCCN Guidelines Version 1.2017 Staging
TNM Staging System For Prostate Cancer
Primary Tumor (T)
Primary tumor cannot be assessed
No evidence of primary tumor
T1 Clinically inapparent tumor neither palpable nor visible
by imaging
Tumor incidental histologic finding in 5% or less of
tissue resected
Tumor incidental histologic finding in more than 5%
of tissue resected
Tumor identified by needle biopsy (e.g., because of
elevated PSA)
Tumor confined within prostate*
Tumor involves one-half of one lobe or less
Tumor involves more than one-half of one lobe but
not both lobes
Tumor involves both lobes
Tumor extends through the prostatic capsule**
Extracapsular extension (unilateral or bilateral)
Tumor invades the seminal vesicle(s)
T4 Tumor is fixed or invades adjacent structures other
than seminal vesicles: bladder, levator muscles,
and/or pelvic wall.
*Note:	Tumor found in one or both lobes by needle biopsy, but not palpable or reliably
visible by imaging, is classified as T1c.
**Note:	Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is
not classified as T3, but as T2.
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original
and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010), published
by Springer Science+Business Media, LLC (SBM). (For complete information and data supporting the staging
tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its
primary source. The inclusion of this information herein does not authorize any reuse or further distribution
without the expressed, written permission of Springer SBM, on behalf of the AJCC.
Pathologic(pT)*
Organ confined
pT2a
Unilateral, involving one-half of one side or less
pT2b
Unilateral, involving more than one-half of one side but not
Bilateral disease
Extraprostatic extension
Extraprostatic extension or microscopic invasion of the
bladder neck**
Seminal vesicle invasion
Invasion of bladder, rectum
*Note:	There is no pathologic T1 classification.
**Note:	Positive surgical margin should be indicated by an R1 descriptor (residual
microscopic disease).
Regional Lymph Nodes (N)
Regional lymph nodes were not assessed
No regional lymph node metastasis
Metastasis in regional lymph node(s)
Pathologic
Regional nodes not sampled
No positive regional nodes
Metastases in regional nodes(s)
Distant Metastasis (M)*
No distant metastasis
Distant metastasis
Non-regional lymph node(s)
Bone(s)
Other site(s) with or without bone disease
*Note:	When more than one site of metastasis is present, the most advanced category is
used. pMIc is most advanced.
ANATOMIC STAGE/PROGNOSTIC GROUPS *
Group T
T1a-c
PSA &lt;10
T1-2a
PSA X
PSA ≥10 &lt;20
Any PSA
T1-2
PSA ≥20
T3a-b
Any T
Any N	M1
Gleason ≤6
Gleason X
Gleason 7
Any Gleason
Gleason ≥8
*Note: When either PSA or Gleason is not available, grouping should be determined by
T stage and/or either PSA or Gleason as available.
Histopathologic Type
This classification applies to adenocarcinomas and squamous
carcinomas, but not to sarcoma or transitional cell carcinoma of the
prostate. Adjectives used to describe variants of prostate
adenocarcinomas include mucinous, signet ring cell, ductal,
adenosquamous and neuroendocrine small cell carcinoma.
Transitional cell (urothelial) carcinoma of the prostate is classified as a
urethral tumor. There should be histologic confirmation of the disease.
Histopathologic Grade (G)
Gleason score is recommended because as the grading system
of choice, it takes into account the inherent morphologic heterogeneity
of prostate cancer, and several studies have clearly established its
prognostic value. A primary and a secondary pattern (the range of each
is 1–5) are assigned and then summed to yield a total score. Scores of
2–10 are thus theoretically possible. The vast majority of newly diagnosed
needle biopsy detected prostate cancers are graded Gleason score 6 or
above. (If a single pattern of disease is seen, it should be reported as both
grades. For example, if a single focus of Gleason pattern 3 disease is
seen, it is reported as Gleason score 3 + 3 = 6.) In a radical prostatectomy,
if a tertiary pattern is present, it is commented upon but not reflected in the
Gleason score. It is recommended that radical prostatectomy specimens
should be processed in an organized fashion where a determination can
be made of a dominant nodule or separate tumor nodules. If a dominant
nodule/s is present, the Gleason score of this nodule should be separately
mentioned as this nodule is often the focus with highest grade and/or
stage of disease.
Gleason score cannot be processed
Well differentiated (slight anaplasia)
Moderately differentiated (moderate anaplasia)
Gleason 8-10	Poorly differentiated/undifferentiated
(marked anaplasia)
GRADE GROUP DEFINITIONS
Grade group 1: Gleason score ≤6
Only individual discrete well-formed glands
Grade group 2: Gleason score 3+4=7
Predominantly well-formed glands with lesser component of poorly-formed/fused/cribriform glands
Predominantly poorly-formed/fused/cribriform glands with lesser component of well-formed glands*
Grade group 4: Gleason score 4+4=8; 3+5=8; 5+3=8
• Only poorly-formed/fused/cribriform glands or
• Predominantly well-formed glands and lesser component lacking glands1 or
• Predominantly lacking glands and lesser component of well-formed glands1
Grade group 5: Gleason score 9-10
Lack gland formation (or with necrosis) with or without poorly formed/fused/cribriform glands2
1Poorly-formed/fused/cribriform glands can be a more minor component
2For case with &gt;95% poorly-formed/fused/cribriform glands or lack of glands
on a core or at RP, the component of &lt;5% well-formed glands is not factored into the grade
• Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma:
definition of grading patterns and proposal for a new grading system. Am J Surg Pathol 2016;40:244-252.
• Epstein JI, Zelefsky MJ, Sjoberg DD, et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol 2016;69:428-435.
• Rubin MA, Girelli G, Demichelis F. Genomic correlates to the newly proposed grading prognostic groups for prostate cancer. Eur Urol 2016;69:557-560.
• Loeb S, Folkvaljon Y, Robinson D, et al. Evaluation of the 2015 Gleason grade groups in a nationwide population-based cohort. Eur Urol 2016;69:1135-1141.
This discussion is being updated to correspond with the
newly updated algorithm. Last updated 05/27/16
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN
consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform
NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN
Category 3: Based upon any level of evidence, there is major NCCN
disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Overview ................................................................................................. MS-2
Literature Search Criteria and Guidelines Update Methodology .............. MS-2
Estimates of Life Expectancy .................................................................. MS-2
Risk Stratification..................................................................................... MS-3
Nomograms ......................................................................................... MS-3
Molecular Testing ................................................................................ MS-4
Imaging ................................................................................................... MS-5
Risks of Imaging .................................................................................. MS-6
Observation ............................................................................................. MS-7
Active Surveillance .................................................................................. MS-7
Rationale ............................................................................................. MS-8
Application ........................................................................................... MS-9
Surveillance Program and Reclassification Criteria ............................. MS-9
Radical Prostatectomy........................................................................... MS-11
Operative Techniques and Adverse Effects ....................................... MS-11
Pelvic Lymph Node Dissection .......................................................... MS-12
Radiation Therapy ................................................................................. MS-13
External Beam Radiation Therapy ..................................................... MS-13
Stereotactic Body Radiotherapy ........................................................ MS-14
Brachytherapy ................................................................................... MS-15
Proton Therapy .................................................................................. MS-16
Radiation for Distant Metastases ....................................................... MS-18
Other Local Therapies ........................................................................... MS-18
Androgen Deprivation Therapy .............................................................. MS-19
Types of ADT .................................................................................... MS-19
ADT for Patients with Low-Risk Disease ........................................... MS-20
ADT for Patients with Intermediate-Risk Disease .............................. MS-20
ADT for Patients with High-Risk or Very-High-Risk Disease .............. MS-20
Adjuvant ADT after Radical Prostatectomy ........................................ MS-20
ADT for Biochemical Recurrence ...................................................... MS-21
ADT for Nodal or Metastatic Disease................................................. MS-22
Adverse Effects of Traditional ADT .................................................... MS-23
Hormone Therapy for CRPC ............................................................. MS-24
Chemotherapy and Immunotherapy ...................................................... MS-26
Docetaxel .......................................................................................... MS-26
Cabazitaxel........................................................................................ MS-27
Sipuleucel-T ...................................................................................... MS-27
MS-Agents Related to Bone Health in CRPC .................................... MS-27
NCCN Recommendations ..................................................................... MS-28
Initial Prostate Cancer Diagnosis....................................................... MS-28
Initial Clinical Assessment and Staging Evaluation............................ MS-28
Very Low Risk ................................................................................... MS-29
Low Risk ............................................................................................ MS-29
Intermediate Risk .............................................................................. MS-29
High Risk ........................................................................................... MS-30
Very High Risk ................................................................................... MS-30
Nodal and Metastatic Disease ........................................................... MS-30
Disease Monitoring ............................................................................ MS-30
Adjuvant or Salvage Therapy after Radical Prostatectomy ................ MS-31
Post-Irradiation Recurrence ............................................................... MS-33
Progressive Castration-Naïve Disease .............................................. MS-34
Progression to CRPC ........................................................................ MS-35
CRPC without Signs of Metastasis .................................................... MS-35
Small Cell Carcinoma of the Prostate ................................................ MS-35
Metastatic CRPC ............................................................................... MS-36
Summary ............................................................................................... MS-39
Table 1. Available Tissue-Based Tests for Prostate Cancer Prognosis . MS-40
Table 2. Selected Active Surveillance Experiences in North America ... MS-41
References ............................................................................................ MS-42
Version 1.2017, 12/16/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
An estimated 220,800 new cases of prostate cancer will be diagnosed
in 2015, accounting for 26% of new cancer cases in men.1 However, the
age-adjusted death rates from prostate cancer have declined (-3.8%
annually from 1994–2004). Researchers have estimated prostate
cancer to account for 27,540 deaths in 2015.1 The decreasing and
comparatively low death rate suggests that increased public awareness
with earlier detection and treatment has affected mortality from this
prevalent cancer. The alternative hypothesis is that prostate cancer is
becoming biologically less aggressive, but evidence is lacking. Early
detection can lead to overtreatment of prostate cancers that do not
threaten life expectancy, which results in unnecessary side effects that
impair quality of life and increase health care expenditures. Over the
past several years, the incidence of prostate cancer has declined, likely
in part a result of decreased rates of prostate-specific antigen (PSA)
screening.2,3 Better use of PSA for early detection of potentially fatal
prostate cancer (see the NCCN Guidelines for Prostate Cancer Early
Detection, available at www.NCCN.org) should decrease the risk of
over-detection and over-treatment AND preserve the decrease in
prostate cancer mortality.
Literature Search Criteria and Guidelines Update
An electronic search of the PubMed database was performed to obtain
key literature in prostate cancer published between September 4, 2014
and April 15, 2015, which used the search term prostate cancer, prior to
the update of this version of the NCCN Guidelines® for Prostate
Cancer. The PubMed database was chosen because it remains the
most widely used resource for medical literature and indexes only peerreviewed biomedical literature.
The search results were narrowed by selecting studies in humans
published in English. Results were confined to the following article
types: Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline;
Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and
Validation Studies.
The PubMed search resulted in 97 citations and their potential
relevance was examined. The data from key PubMed articles and
articles from additional sources deemed relevant to these guidelines
and discussed by the panel have been included in this updated
Discussion section. Recommendations for which high-level evidence
was lacking were based on panel review of lower-level evidence and
expert opinion.
The complete details of the Development and Update of the NCCN
Guidelines are available at www.NCCN.org.
Estimates of Life Expectancy
Estimates of life expectancy have emerged as a key determinant of
primary treatment, particularly when considering active surveillance or
observation. Life expectancy can be estimated for groups of men, but it
is difficult to extrapolate these estimates to an individual patient. Life
expectancy can be estimated using the Minnesota Metropolitan Life
Insurance Tables, the Social Security Administration Life Insurance
Tables,4 or the WHO’s Life Tables by Country,5 and adjusted for
individual patients by adding or subtracting 50% based on whether one
believes the patient is in the healthiest quartile or the unhealthiest
quartile, respectively.6 As an example, the Social Security
Administration Life Expectancy for a 65-year-old American man is 17.7
years. If judged to be in the upper quartile of health, a life expectancy of
26.5 years is assigned. If judged to be in the lower quartile of health, a
life expectancy of 8.8 years is assigned. Thus, treatment
recommendations could change dramatically using the NCCN
Guidelines if a 65-year-old man was judged to be in either poor or
excellent health.
Risk Stratification
Optimal treatment of prostate cancer requires assessment of risk: how
likely is a given cancer to be confined to the prostate or spread to the
regional lymph nodes? How likely is the cancer to progress or
metastasize after treatment? How likely is adjuvant or salvage radiation
to control cancer after an unsuccessful radical prostatectomy? Prostate
cancers are best characterized by the digital rectal exam (DRE)- and
radiographically determined clinical T stage, Gleason score and extent
of cancer in the biopsy specimen, and serum PSA level. Imaging
studies (ultrasound, MRI) have been investigated intensively but have
yet to be accepted as essential adjuncts to staging.
The NCCN Guidelines incorporate a risk stratification scheme that uses
a minimum of stage, grade, and PSA to assign patients to risk groups.
These risk groups are used to select the appropriate options that should
be considered and to predict the probability of biochemical failure after
definitive local therapy.7 Risk group stratification has been published
widely and validated, and provides a better basis for treatment
recommendations than clinical stage alone.8,9
The NCCN Guidelines Panel recognized that heterogeneity exists within
each risk group. For example, an analysis of 12,821 patients showed
that men assigned to the intermediate-risk group by clinical stage (T2b–
T2c) had a lower risk of recurrence than men categorized according to
Gleason score (7) or PSA level (10–20 ng/mL).10 A similar trend of
superior recurrence-free survival was observed in men placed in the
high-risk group by clinical stage (T3a) compared to those assigned by
Gleason score (8–10) or PSA level (&gt;20 ng/mL), although it did not
reach statistical significance. Other studies have reported differences in
outcomes in the high-risk group depending on risk factors.11 Evidence
also shows heterogeneity in the low-risk group, with PSA levels and
percent positive cores affecting pathologic findings after radical
prostatectomy.12,13
In a retrospective study, 1024 patients with intermediate-risk prostate
cancer were treated with radiation with or without neoadjuvant and
concurrent ADT.14 Multivariate analysis revealed that primary Gleason
pattern 4, percentage of positive biopsy cores ≥50, and presence of &gt;1
intermediate-risk factors (ie, T2b-c, PSA 10-20ng/mL, Gleason score 7)
were significant predictors of increased incidence of distant metastasis.
The authors used these factors to separate the patients into
unfavorable and favorable intermediate-risk groups and determined that
the unfavorable intermediate-risk group had worse PSA recurrence-free
survival, distant metastasis, and prostate cancer-specific mortality than
the favorable intermediate-risk group.
Nomograms
The more clinically relevant information that is used in the calculation of
time to PSA failure, the more accurate the result. The Partin tables15-17
were the first to achieve widespread use for counseling men with
clinically localized prostate cancer. The tables give the probability (95%
confidence intervals) that a patient with a certain clinical stage, Gleason
score, and PSA will have a cancer of each pathologic stage. A
nomogram is a predictive instrument that takes a set of input data
(variables) and makes predictions about an outcome. Nomograms
predict more accurately for the individual patient than risk groups,
because they combine the relevant prognostic variables, regardless of
value. Nomograms can be used to inform treatment decision-making for
men contemplating active surveillance,18,19 radical prostatectomy,20-23
neurovascular bundle preservation24-26 or omission of pelvic lymph node
dissection (PLND) during radical prostatectomy,27,28 brachytherapy,20,29-31
or external beam radiation therapy (EBRT).20,32 Biochemical
progression-free survival can be reassessed postoperatively using age,
diagnostic serum PSA, and pathologic grade and stage.20,33 Potential
success of adjuvant or salvage radiation therapy (RT) after
unsuccessful radical prostatectomy can be assessed using a
nomogram.20,34
and recommendations for active surveillance as the only option for men
with low-risk prostate cancer and life expectancy less than 10 years or
very-low-risk prostate cancer and life expectancy less than 20 years.
Although risk groups, life expectancy estimates, and nomograms help
inform decisions, uncertainty about the risk of disease progression
persists. American men continue to under-select active surveillance and
their physicians may under-recommend it, likely as a result of this
uncertainty.43
None of the current models predicts with perfect accuracy, and only
some of these models predict metastasis19,20,33,35,36 and cancer-specific
death.21,23,37,38 Given the competing causes of mortality, many men who
sustain PSA failure will not live long enough either to develop clinical
evidence of distant metastases or to die from prostate cancer. Those
with a short PSA doubling time are at greatest risk of death. Not all PSA
failures are clinically relevant; thus, PSA doubling time may be a more
useful measure of risk of death.39 The NCCN Guidelines Panel
recommends that NCCN risk groups be used to begin the discussion of
options for the treatment of clinically localized prostate cancer and that
nomograms be used to provide additional and more individualized
Several tissue-based molecular assays have been developed in an
effort to improve decision-making in newly diagnosed men considering
active surveillance and in treated men considering adjuvant therapy or
treatment for recurrence. Uncertainty about the risk of disease
progression can be reduced if such molecular assays can provide
accurate and reproducible prognostic or predictive information beyond
NCCN risk group assignment and currently available life expectancy
tables and nomograms. Retrospective case cohort studies have shown
that these assays provide prognostic information independent of NCCN
risk groups, which include likelihood of death with conservative
management, likelihood of biochemical recurrence after radical
prostatectomy or radiotherapy, and likelihood of developing metastasis
after operation or salvage radiotherapy.44-48 No randomized controlled
trials have studied the utility of these tests. Several of these assays are
available, and 3 have received positive reviews by the Molecular
Diagnostic Services Program (MolDX) and are likely to be covered by
CMS (Centers for Medicare &amp; Medicaid Services). Several other tests
are under development, and the use of these assays is likely to
increase in the coming years.
Personalized or precision medicine is a goal for many translational and
clinical investigators. The National Academy of Medicine has described
several lessons that should accelerate the development of useful
biomarkers40 to inform men and their physicians about proper choices
for treatment of clinically localized prostate cancer. Dr. Hayes has
warned us that a “bad tumor marker is as bad as a bad drug.”41,42 The
NCCN Prostate Cancer Guidelines Panel takes pride in its leadership
regarding the need for life expectancy estimation, use of nomograms
Table 1 lists these tests in alphabetical order and provides an overview
of each test, populations where each test independently predicts
outcome, and supporting references. These molecular biomarker tests
listed have been developed with extensive industry support, guidance,
and involvement, and have been marketed under the less rigorous FDA
regulatory pathway for biomarkers. Although full assessment of their
clinical utility requires prospective randomized clinical trials, which are
unlikely to be done, the panel believes that men with clinically localized
disease may consider the use of tumor-based molecular assays at this
time. Future comparative effectiveness research may allow these tests
and others like them to gain additional evidence regarding their utility for
better risk stratification of men with prostate cancer.
Imaging techniques are useful for detecting metastases and tumor
recurrence. Anatomic imaging techniques include radiographs,
ultrasound, CT, and MRI. Functional techniques include radionuclide
bone scan (conventional Tc EDTMP scan), PET, and advanced MRI,
such as spectroscopy and diffusion-weighted imaging (DWI). More
details on each technique are outlined under Principles of Imaging.
The guidelines recommend CT or MRI imaging as part of staging
workup for men with longer life expectancies and T3 or T4 disease or
nomogram-predicted probability of lymph node involvement &gt;10%.
Multivariate analysis of retrospective data on 643 men with newly
diagnosed prostate cancer who underwent staging CT found that PSA,
Gleason score, and clinical T stage were associated independently with
a positive finding (P &lt; .05 for all).49 Bone scans are recommended as
part of staging for patients with longer life expectancies and higher
Gleason grade, higher T stage, or higher PSA values as delineated in
the algorithm. Retrospective evidence suggests that Gleason score and
PSA levels are associated with positive bone scan findings.50
Transrectal ultrasonography (TRUS) is the most common technique for
anatomic visualization of the prostate. TRUS is used to guide
transrectal biopsies, and can be considered for patients with
biochemical recurrence after operation or radiation.
The utility of imaging for men with an early biochemical recurrence after
radical prostatectomy depends on disease risk before operation and
pathologic stage, Gleason grade, PSA, and PSA doubling time after
recurrence. Patients with low- and intermediate-risk disease and low
postoperative serum PSA levels have a very low risk of positive bone
scans or CT scans.51,52 In a series of 414 bone scans performed in 230
men with biochemical recurrence after radical prostatectomy, the rate of
a positive bone scan for men with PSA &gt;10 ng/mL was only 4%.53 Serial
PSA measurements can be helpful for stratifying men at highest risk of
progression and metastases. Some men have detectable PSA after
radical prostatectomy due to benign prostate tissue in the prostate
fossa. They have low stable PSAs and a very low risk of prostate
cancer progression.54,55
The use of multiparametric MRI (mpMRI) in the staging and
characterization of prostate cancer has increased in the last few years.
To be considered “multi-parametric,” MRI images must be acquired with
at least one more sequence apart from the anatomical T2-weighted
one, such as DWIs or dynamic contrast-enhanced (DCE) images.
Furthermore, a high-quality mpMRI requires a 3.0 T magnet; the need
for an endorectal coil remains controversial.
Evidence supports the implementation of mpMRI in several aspects of
prostate cancer management. First, mpMRI helps detect large and
poorly differentiated cancers (ie, Gleason score ≥7).56 MpMRI has been
incorporated into MRI-TRUS fusion-targeted biopsy protocols, which
has led to an increase in the diagnosis of high-grade cancers with fewer
biopsy cores, while reducing detection of low-grade and insignificant
cancers.57-59 Second, mpMRI aids in the detection of extracapsular
extension (T staging), with high negative predictive values in low-risk
men.60 MpMRI results may inform decision-making regarding nervesparing operation.61 Third, mpMRI has been shown to be equivalent to
CT scan for staging of pelvic lymph nodes.62,63 Finally, mpMRI outperforms bone scan and targeted x-rays for detection of bone
metastases, with sensitivity 98% to 100% and specificity of 98% to
100% (vs. sensitivity of 86% and specificity of 98%–100% for bone scan
plus targeted x-rays).64
C-11 choline PET/CT has been used to detect and differentiate prostate
cancer from benign tissue.65,66 The sensitivity and specificity of the
technique in restaging patients with biochemical failure were 85% and
88%, respectively.67 C-11 choline PET/CT may be useful to detect
distant metastases in these patients. FDG-PET/CT, in contrast, is not
recommended for routine use for prostate cancer management because
data remain insufficient.
Risks of Imaging
As with any medical procedure, imaging is not without risk. Some of
these risks are concrete and tangible, while others are less clear. Risks
associated with imaging include exposure to ionizing radiation, adverse
reaction to contrast media, false-positive scans, and over-detection.
Deterministic and stochastic are two types of effects from exposure to
ionizing radiation by x-ray, CT, or PET/CT. Deterministic effects are
those that occur at a certain dose level, and include events such as
cataracts and radiation burns. No effect is seen below the dose
threshold. Medical imaging is always performed almost below the
threshold for deterministic effects. Stochastic effects tend to occur late,
increase in likelihood as dose increases, and have no known lower
“safe” limit. The major stochastic effect of concern in medical imaging is
radiation-induced malignancy. Unfortunately, no direct measurements
are available to determine risk of cancer arising from one or more
medical imaging events, so risks are calculated using other models
(such as from atomic bomb survivors). The literature is conflicting with
regards to the precise risk of secondary malignancies in patients
undergoing medical imaging procedures. There is a small but finite risk
of developing secondary malignancies as a result of medical imaging
procedures, and the risk is greatest in young patients. However, the
absolute risk of fatal malignancy arising from a medical imaging
procedure is very low, and is difficult to detect given the prevalence of
cancer in the population and the multiple factors that contribute to
oncogenesis.68 Efforts should be made to minimize dose from these
procedures, which begin with judicious use of imaging only when
justified by the clinical situation. Harm may arise from not imaging a
patient, through disease non-detection or erroneous staging.
Many imaging studies make use of contrast material delivered by oral,
intravenous, or rectal routes. The use of contrast material may improve
study performance, but reactions to contrast material may occur and
they should be used only when warranted. Some patients develop
adverse reactions to iodinated intravenous contrast material. Most
reactions are mild cutaneous reactions (eg, hives, itching) but
occasionally severe reactions can be life-threatening (bronchospasm or
anaphylactoid). The risk of severe reaction is low with non-ionic contrast
materials and may be about 1:170,000 injections.69 Both iodinated CT
contrast material and gadolinium-based MR contrast materials can
affect renal function, particularly when renal function is impaired. MR
contrast materials also have been associated with systemic
nephrogenic sclerosis in patients with impaired renal function. Centers
performing imaging studies with contrast materials should have policies
in place to address the use of contrast in these patients.
Every imaging test has limitations for sensitivity, specificity, and
accuracy, which are modulated further by the expertise of the
interpreting physician. Harm can arise from failure to detect a tumor or
tumor recurrence (ie, false negative), but harm to the patient and added
expense to the medical system also can result from false-positive
scans. Improper interpretation of a benign finding as malignant can lead
to significant patient anxiety, additional and unnecessary imaging, and
invasive procedures that carry their own risks for adverse outcomes.
Accurate and medically-relevant interpretation of imaging studies
requires familiarity and expertise in the imaging modality, attention to
detail in image review, knowledge of tumor biology, and familiarity with
treatment options and algorithms. Challenging cases are best
addressed through direct communication, either physician-to-physician
or in a multidisciplinary tumor board setting.
Medical imaging is a critical tool in the evaluation and management of
patients with malignancy. However, as with any medical procedure,
imaging is not without risks to patients. Inappropriate use of imaging
also has been identified as a significant contributor to health care costs
in the United States and worldwide. Therefore, imaging should be
performed only when medically appropriate, and in a manner that
reduces risk (eg, minimizing radiation dose). An algorithmic approach to
the use of imaging, such as by NCCN and the Appropriateness Criteria
developed by the American College of Radiology,70 can assist medical
decision-making.
Observation involves monitoring the course of prostate cancer with the
expectation to deliver palliative therapy for development of symptoms or
change in exam or PSA that suggests symptoms are imminent.
Observation thus differs from active surveillance. The goal of
observation is to maintain quality of life by avoiding noncurative
treatment when prostate cancer is unlikely to cause mortality or
significant morbidity. The main advantage of observation is avoidance
of possible side effects of unnecessary definitive therapy or ADT.
However, patients may develop urinary retention or pathologic fracture
without prior symptoms or increasing PSA level.
Observation is applicable to elderly or frail men with comorbidity that will
likely out-compete prostate cancer. Johansson and colleagues71
observed that only 13% of men developed metastases 15 years after
diagnosis of T0-T2 disease and only 11% had died from prostate
cancer. Since prostate cancer will not be treated for cure for patients
with shorter life expectancies, observation for as long as possible is a
reasonable option based on physician’s discretion. Monitoring should
include PSA and DRE no more often than every 6 months, but will not
involve surveillance biopsies. When symptoms develop or are imminent,
patients can begin palliative ADT.
Active surveillance (also referred to as watchful waiting, expectant
management, or deferred treatment) involves actively monitoring the
course of the disease with the expectation to deliver curative therapy if
the cancer progresses. Unlike observation, active surveillance is mainly
applicable to younger men with seemingly indolent cancer with the goal
to defer treatment and its potential side effects. Because these patients
have a longer life expectancy, they should be followed closely and
treatment should start promptly should the cancer progress so as not to
miss the chance for cure.
In one study, approximately two thirds of eligible men avoided
treatment, and thus the possible associated side effects of treatment,
after 5 years of active surveillance.72 In another study, 55% of the
population remained untreated at 15 years.73 Although a proportion of
men will eventually undergo treatment, the delay does not appear to
impact cure rates, and several studies have shown active surveillance is
safe.72-76 In fact, a 2015 meta-analysis of 26 active surveillance cohort
studies that included 7627 men identified only 8 prostate cancer deaths
and 5 cases of metastasis.77 In addition, studies have shown that active
surveillance does not adversely impact psychologic well-being or quality
of life.78-81 Possible disadvantages of active surveillance are listed in the
Principles section of these guidelines and include the possible necessity
of follow-up prostate biopsies.
The NCCN Guidelines Panel remains concerned about the problems of
over-treatment related to the increased frequency of diagnosis of
prostate cancer from widespread use of PSA for early detection or
screening (see NCCN Guidelines for Prostate Cancer Early Detection).
The debate about the need to diagnose and treat every man who has
prostate cancer is fueled by the high prevalence of prostate cancer
upon autopsy of the prostate82; the high frequency of positive prostate
biopsies in men with normal DREs and serum PSA values83; the
contrast between the incidence and mortality rates of prostate cancer;
and the need to treat an estimated 37 men with screen-detected
prostate cancer84,85 or 100 men with low-risk prostate cancer86 to
prevent one death from the disease. The controversy regarding overtreatment of prostate cancer and the value of prostate cancer early
detection84-90 has been informed further by publication of the Goteborg
study, a subset of the European Randomized Study of Screening for
Prostate Cancer (ERSPC).91 Many believe that this study best
approximates proper use of PSA for early detection since it was
population-based and involved a 1:1 randomization of 20,000 men who
received PSA every 2 years and used thresholds for prostate biopsy of
PSA &gt;3, and &gt;2.5 since 2005. The follow-up of 14 years is longer than
the European study as a whole (9 years) and Prostate, Lung,
Colorectal, and Ovarian (PLCO) (11.5 years). Prostate cancer was
diagnosed in 12.7% of the screened group compared to 8.2% of the
control group. Prostate cancer mortality was 0.5% in the screened
group and 0.9% in the control group, which gave a 40% absolute
cumulative risk reduction of prostate cancer death (compared to
ERSPC 20% and PLCO 0%). Most impressively, 40% of the patients
were managed initially using active surveillance and 28% were still on
active surveillance at the time these results were analyzed. To prevent
a prostate cancer death, 12 men would need to be diagnosed and
treated as opposed to the ERSPC as a whole where 37 men needed to
be treated. Thus, early detection, when applied properly, should reduce
prostate cancer mortality. However, that reduction comes at the
expense of over-treatment that may occur in as many as 50% of men
treated for PSA-detected prostate cancer.92
The best models of prostate cancer detection and progression estimate
that 23% to 42% of all U.S. screen-detected cancers were overtreated93
and that PSA detection was responsible for up to 12.3 years of leadtime bias.94 The NCCN Guidelines Panel responded to these evolving
data with careful consideration of which men should be recommended
active surveillance. However, the NCCN Guidelines Panel recognizes
the uncertainty associated with the estimation of chance of competing
causes of death, the definition of very-low- or low-risk prostate cancer,
the ability to detect disease progression without compromising chance
of cure, and the chance and consequences of treatment side effects.
Epstein and colleagues95 introduced clinical criteria to predict
pathologically “insignificant” prostate cancer. Insignificant prostate
cancer is identified by: clinical stage T1c, biopsy Gleason score ≤6, the
presence of disease in fewer than 3 biopsy cores, ≤50% prostate
cancer involvement in any core, and PSA density &lt;0.15 ng/mL/g.
Despite the usefulness of these criteria, physicians are cautioned
against using these as the sole decision maker. Studies have shown
that as many as 8% of cancers that qualified as insignificant using the
Epstein criteria were not organ-confined based on postoperative
findings.96,97 A new nomogram may be better.98 Although many
variations upon this definition have been proposed (reviewed by Bastian
and colleagues99), a consensus of the NCCN Guidelines Panel was
reached that insignificant prostate cancer, especially when detected
early using serum PSA, poses little threat to men with life expectancy
less than 20 years. The confidence that Americans with very-low-risk
prostate cancer have a very small risk of prostate cancer death is
enhanced by lead time bias introduced by PSA early detection that
ranges from an estimated 12.3 years in a 55-year-old man to 6 years in
a 75-year-old man.94
The role for active surveillance should increase with the shift towards
earlier-stage diagnosis attributed to PSA testing. However, results from
randomized or cohort studies comparing this deferral strategy with
immediate treatment are mixed, partly due to heterogeneity of the
patient populations (reviewed by Sanda and Kaplan100). Ultimately, a
recommendation for active surveillance must be based on careful
individualized weighing of a number of factors: life expectancy, general
health condition, disease characteristics, potential side effects of
treatment, and patient preference.
Race is emerging as another important factor to consider, particularly
for African-American men. Multiple studies have shown that African
Americans with very-low-risk prostate cancer may harbor high-grade
(Gleason sum ≥7) cancer that is not detected by pre-treatment biopsies.
Compared to Caucasian Americans matched on clinical parameters,
African Americans have been reported to have 1.7- to 2.3-fold higher
change of pathologic upgrading.101,102 Several studies have reported
that, among men with low-risk prostate cancer who are enrolled in
active surveillance programs, African Americas have higher risk of
disease progression to higher Gleason grade or volume cancer than
Caucasian Americans.103-105 African Americans in the low- to
intermediate-risk categories also appear to suffer from an increased risk
of biochemical recurrence after treatment.106 Reasons for these clinical
disparities are under investigation and may include difference in tumor
location within the prostate that may reflect different prostate cancer
subtypes related to differences in gene expression.107-110 Strategies to
improve risk-stratification for African Americans considering active
surveillance may include mpMRI in concert with targeted image-guided
biopsies, which has been reported to improve detection of clinically
significant tumors in some men.111
Surveillance Program and Reclassification Criteria
Each of the major active surveillance series has used different criteria
for reclassification.73,75,112-116 Reclassification criteria were met by 23% of
men with a median follow-up of 7 years in the Toronto experience,114
36% of men with a median follow-up of 5 years in the Johns Hopkins
experience,75 and 16% of men with a median follow-up of 3.5 years in
the University of California, San Francisco (UCSF) experience113 (Table
2). Uncertainty regarding reclassification criteria and the desire to avoid
missing an opportunity for cure have driven several reports in the past
year that have dealt with the validity of commonly used reclassification
criteria. The Toronto group demonstrated that a PSA trigger point of
PSA doubling time &lt;3 years could not be improved upon by using a
PSA threshold of 10 or 20, PSA doubling time calculated in various
ways, or PSA velocity &gt;2 ng/mL/y.117 The Johns Hopkins group used
biopsy-demonstrated reclassification to Gleason pattern 4 or 5 or
increased tumor volume on biopsy as their criteria for reclassification.
Of 290 men on an annual prostate biopsy program, 35% demonstrated
reclassification at a median follow-up of 2.9 years.118 Neither PSA
doubling time (area under the curve [AUC] 0.59) nor PSA velocity (AUC
0.61) was associated with prostate biopsy reclassification. Both groups
have concluded that PSA kinetics cannot replace regular prostate
biopsy, although treatment of most men who demonstrate
reclassification on prostate biopsy prevents evaluation of biopsy
reclassification as a criterion for treatment or reduction of survival. Early
experience supports the utilization of mpMRI in biopsy protocols to
better risk-stratify men under active surveillance.119,120
changes, if mpMRI (if done) suggests more aggressive disease, or if
PSA increases, but no parameter is very reliable for detecting prostate
cancer progression. Repeat biopsy is useful to determine whether
higher Gleason grade elements, which may influence prognosis and
hence the decision to continue active surveillance or to proceed to
definitive local therapy, are evolving although the risk appears small.121
Treatment of all men who developed Gleason pattern 4 on annual
prostate biopsies has thus far resulted in only 2 prostate cancer deaths
among 1298 men (0.15%) in the Johns Hopkins study.75 However, it
remains uncertain whether treatment of all who progress to Gleason
pattern 4 was necessary. Studies remain in progress to identify the best
trigger points when interventions with curative intent may still be
The Toronto group published on 3 patients who died of prostate cancer
in their experience with 450 men.114 These 3 deaths led them to revise
their criteria for offering men active surveillance, because each of these
3 men probably had metastatic disease at the time of entry on active
surveillance. In 450 men followed for a median of 6.8 years, overall
survival was 78.6% and prostate cancer-specific survival was 97.2%.114
Of the 30% (n = 145) of men who progressed, 8% had an increase in
Gleason grade, 14% had PSA doubling time &lt;3 years, 1% developed a
prostate nodule, and 3% were treated because of anxiety. One hundred
thirty-five of these 145 men were treated: 35 by radical prostatectomy,
90 by EBRT with or without androgen deprivation therapy (ADT), and 10
with ADT alone. Follow-up is available for 110 of these men and 5-year
biochemical progression-free survival is 62% for those undergoing
radical prostatectomy and 43% for those undergoing radiation. Longerterm follow-up of this cohort was reported in 2015.73 The 10- and 15year actuarial cause-specific survival rates for the entire cohort were
98.1% and 94.3 %, respectively. Only 15 of 993 (1.5%) patients had
died of prostate cancer, an additional 13 men (1.3%) had developed
metastatic disease, and only 36.5% of the cohort had received
treatment by 10 years.
In comparison, among 192 men on active surveillance who underwent
delayed treatment at a median of 2 years after diagnosis in the Johns
Hopkins experience, 5-year biochemical progression-free survival was
96% for those who underwent radical prostatectomy and 75% for those
who underwent radiation.116 The two groups were similar by pathologic
Gleason grade, pathologic stage, and margin positivity. All men treated
by radical prostatectomy after progression on active surveillance had
freedom from biochemical progression at median follow-up of 37.5
months, compared to 97% of men in the primary radical prostatectomy
group at median follow-up of 35.5 months. A later publication from this
group showed that 23 of 287 men who were treated after active
surveillance (8%) experienced biochemical recurrence, and the rate
was independent of the type of treatment.75 Several studies have shown
that delayed radical prostatectomy does not increase the rates of
adverse pathology.122-125
The panel believes there is an urgent need for further clinical research
regarding the criteria for recommending active surveillance, the criteria
for reclassification on active surveillance, and the schedule for active
surveillance especially as it pertains to prostate biopsies, which pose an
increasing burden. Literature suggests that as many as 7% of men
undergoing prostate biopsy will suffer an adverse event,88 and those
who develop urinary tract infection are often fluoroquinolone-resistant.126
Radical prostatectomy may become technically challenging after
multiple sets of biopsies, especially as it pertains to potency
preservation.127
Radical prostatectomy is appropriate for any patient whose cancer
appears clinically localized to the prostate. However, because of
potential perioperative morbidity, radical prostatectomy should be
reserved for patients whose life expectancy is 10 years or more.
Stephenson and colleagues23 reported a low 15-year prostate cancerspecific mortality of 12% in patients who underwent radical
prostatectomy (5% for patients with low-risk disease), although it is
unclear whether the favorable prognosis is due to the effectiveness of
the procedure or the low lethality of cancers detected in the PSA era.
Radical prostatectomy was compared to watchful waiting in a
randomized trial of 695 patients with early-stage prostate cancer (mostly
T2).128,129 With a median follow-up of 12.8 years, those assigned to the
radical prostatectomy group had significant improvements in disease-
specific survival, overall survival, and risk of metastasis and local
progression.128 The reduction in mortality was confirmed at 23 years of
follow-up, with an absolute difference of 11%.129 Overall, 8 men needed
to be treated to avert one death; that number fell to 4 for men younger
than 65 years of age. The results of this trial offer high-quality evidence
to support radical prostatectomy as a treatment option for clinically
Some patients at high or very high risk may benefit from radical
prostatectomy. In an analysis of 842 men with Gleason scores 8 to 10
at biopsy who underwent radical prostatectomy, predictors of
unfavorable outcome included PSA level over 10 ng/mL, clinical stage
T2b or higher, Gleason score 9 or 10, higher number of biopsy cores
with high-grade cancer, and over 50% core involvement.130 Patients
without these characteristics showed higher 10-year biochemical-free
and disease-specific survival after radical prostatectomy compared to
those with unfavorable findings (31% vs. 4% and 75% vs. 52%,
respectively). Radical prostatectomy is an option for men with high-risk
disease and in select patients with very high-risk disease.
Radical prostatectomy is a salvage option for patients experiencing
biochemical recurrence after primary EBRT, but morbidity
(incontinence, erectile dysfunction, and bladder neck contracture)
remains significantly higher than when radical prostatectomy is used as
initial therapy.131,132 Overall and cancer-specific 10-year survival ranged
from 54% to 89% and 70% to 83%, respectively.131 Patient selection is
important and salvage prostatectomy should only be performed by
highly experienced surgeons.
Operative Techniques and Adverse Effects
Long-term cancer control has been achieved in most patients with both
the retropubic and the perineal approaches to radical prostatectomy;
Télécharger le fichier (PDF)
prostate.pdf (PDF, 1.3 Mo)
Formats alternatifs: ZIP
Partager le document
Faire un lien vers cette page
Le lien permanent vers la page de téléchargement du fichier permet de partager votre document sur les réseaux sociaux (Facebook, LinkedIn), forums en ligne, ou directement par courriel ou messagerie instantanée (Messenger, Whatsapp):
Lien court
Le lien court permet de partager facilement votre document sur Twitter ou par SMS:
Le code suivant permet de faire un lien vers votre document sur un site Web ou un Blog:
Documents similaires
Sur le même sujet..
patients should without therapy cancer prostate comprehensive clinical version national disease network rights guidelines reserved
Pour voir les commentaires déjà publiés ou ajouter un commentaire, Connectez-vous ou Créez un compte.
Ce fichier a été mis en ligne par un utilisateur du site. Identifiant unique du document: 00481473.
Pour plus d'informations sur notre politique de lutte contre la diffusion illicite de contenus protégés par droit d'auteur, consultez notre page dédiée.