Outcomes of localized prostate cancer following conservative management.

Abstract

Most newly diagnosed prostate cancers are clinically localized, and major treatment options include surgery, radiation, or conservative management. Although conservative management can be a reasonable choice, there is little contemporary prostate-specific antigen (PSA)-era data on outcomes with this approach.
To evaluate the outcomes of clinically localized prostate cancer managed without initial attempted curative therapy in the PSA era.
A population-based cohort study of men aged 65 years or older when they were diagnosed (1992-2002) with stage T1 or T2 prostate cancer and whose cases were managed without surgery or radiation for 6 months after diagnosis. Living in areas covered by the Surveillance, Epidemiology, and End Results (SEER) program, the men were followed up for a median of 8.3 years (through December 31, 2007). Competing risk analyses were performed to assess outcomes.
Ten-year overall survival, cancer-specific survival, and major cancer related interventions.
Among men who were a median age of 78 years at cancer diagnosis, 10-year prostate cancer-specific mortality was 8.3% (95% confidence interval [CI], 4.2%-12.8%) for men with well-differentiated tumors; 9.1% (95% CI, 8.3%-10.1%) for those with moderately differentiated tumors, and 25.6% (95% CI, 23.7%-28.3%) for those with poorly differentiated tumors. The corresponding 10-year risks of dying of competing causes were 59.8% (95% CI, 53.2%-67.8%), 57.2% (95% CI, 52.6%-63.9%), and 56.5% (95% CI, 53.6%-58.8%), respectively. Ten-year disease-specific mortality for men aged 66 to 74 years diagnosed with moderately differentiated disease was 60% to 74% lower than earlier studies: 6% (95% CI, 4%-8%) in the contemporary PSA era (1992-2002) compared with results of previous studies (15%-23%) in earlier eras (1949-1992). Improved survival was also observed in poorly differentiated disease. The use of chemotherapy (1.6%) or major interventions for spinal cord compression (0.9%) was uncommon.
Results following conservative management of clinically localized prostate cancer diagnosed from 1992 through 2002 are better than outcomes among patients diagnosed in the 1970s and 1980s. This may be due, in part, to additional lead time, overdiagnosis related to PSA testing, grade migration, or advances in medical care.

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CLINICIAN’S CORNER
ORIGINAL CONTRIBUTION
Outcomes of Localized Prostate Cancer
Following Conservative Management
Grace L. Lu-Yao, MPH, PhD
Peter C. Albertsen, MD
Dirk F. Moore, PhD
Weichung Shih, PhD
Yong Lin, PhD
Robert S. DiPaola, MD
Michael J. Barry, MD
Anthony Zietman, MD
Michael O’Leary, MD, MPH
Elizabeth Walker-Corkery, MPH
Siu-Long Yao, MD
A
cer death in the United States.1When
diagnosed, prostate cancer is con-
tained within the prostate in approxi-
mately 85% of cases,2and standard
treatmentoptionsusuallyincludesur-
gery, radiation, or conservative man-
agement (active surveillance or defer-
ral of treatment until necessitated by
disease signs or symptoms).
Formenyoungerthan65yearswith
clinicallylocalizedprostatecancer,re-
sultsofalarge,randomizedclinicaltrial
have demonstrated that surgery im-
provessurvivalcomparedwithconser-
vative management.3The majority of
men diagnosed with localized pros-
tatecancer,however,areolderthan65
years.4Although not specifically de-
signedtoaddressageeffects,thissame
clinical trial3was unable to demon-
strate a survival benefit for surgery
amongoldermen.3,5Coupledwithdata
showing that the lifetime risk of being
diagnosedwithprostatecancerisabout
MONG MEN, PROSTATE CAN-
ceristhemostcommonnon-
skin cancer and the second
most common cause of can-
17%, while the corresponding risk of
dyingofthisdiseaseisonlyabout3%,6
the evidence suggests that conserva-
tive management may be an impor-
tanttreatmentconsiderationforthesiz-
able majority of men diagnosed with
localized prostate cancer.
Despite its potential as a reasonable
treatment choice, however, conserva-
tivemanagementhasbeenusedinonly
about 10% of patients,7perhaps be-
causeofalimitedunderstandingofand
contemporary data on the anticipated
course and outcomes of this ap-
CME available online at
www.jamaarchivescme.com
and questions on p 1237.
Author Affiliations: The Cancer Institute of New Jer-
sey (Drs Lu-Yao, Moore, Shih, Lin, DiPaola, and Yao);
DepartmentofMedicine,RobertWoodJohnsonMedi-
cal School (Drs Lu-Yao, DiPaola, and Yao) and De-
partment of Biostatistics, The School of Public Health
(DrsMoore,Shih,andLin),UniversityofMedicineand
Dentistry of New Jersey, Piscataway; Department of
Surgery (Urology), University of Connecticut, Farm-
ington(DrAlbertsen);TheDeanandBettyGalloPros-
tate Cancer Center (Drs Lu-Yao and DiPaola), Medi-
cal Practices Evaluation Center (Dr Barry and Ms
Walker-Corkery), and Department of Radiation On-
cology (Dr Zietman), Massachusetts General Hospi-
tal, Boston; Department of Surgery, Harvard Medical
School, Boston (Dr O’Leary); and Schering-Plough
Research Institute, Kenilworth, New Jersey
(Dr Yao).
Corresponding Author: Grace L. Lu-Yao, MPH, PhD,
195 Little Albany St, Room 5534, New Brunswick, NJ
(luyaogr@umdnj.edu).
Context Most newly diagnosed prostate cancers are clinically localized, and major
treatment options include surgery, radiation, or conservative management. Although
conservativemanagementcanbeareasonablechoice,thereislittlecontemporarypros-
tate-specific antigen (PSA)–era data on outcomes with this approach.
Objective To evaluate the outcomes of clinically localized prostate cancer managed
without initial attempted curative therapy in the PSA era.
Design, Setting, and Participants A population-based cohort study of men aged
65 years or older when they were diagnosed (1992-2002) with stage T1 or T2 pros-
tate cancer and whose cases were managed without surgery or radiation for 6 months
after diagnosis. Living in areas covered by the Surveillance, Epidemiology, and End
Results (SEER) program, the men were followed up for a median of 8.3 years (through
December 31, 2007). Competing risk analyses were performed to assess outcomes.
Main Outcome Measures Ten-year overall survival, cancer-specific survival, and
major cancer related interventions.
Results Among men who were a median age of 78 years at cancer diagnosis, 10-year
prostatecancer-specificmortalitywas8.3%(95%confidenceinterval[CI],4.2%-12.8%)
formenwithwell-differentiatedtumors;9.1%(95%CI,8.3%-10.1%)forthosewithmod-
eratelydifferentiatedtumors,and25.6%(95%CI,23.7%-28.3%)forthosewithpoorly
differentiatedtumors.Thecorresponding10-yearrisksofdyingofcompetingcauseswere
59.8%(95%CI,53.2%-67.8%),57.2%(95%CI,52.6%-63.9%),and56.5%(95%CI,
53.6%-58.8%), respectively. Ten-year disease-specific mortality for men aged 66 to 74
yearsdiagnosedwithmoderatelydifferentiateddiseasewas60%to74%lowerthanear-
lierstudies:6%(95%CI,4%-8%)inthecontemporaryPSAera(1992-2002)compared
withresultsofpreviousstudies(15%-23%)inearliereras(1949-1992).Improvedsurvival
wasalsoobservedinpoorlydifferentiateddisease.Theuseofchemotherapy(1.6%)orma-
jor interventions for spinal cord compression (0.9%) was uncommon.
Conclusions Resultsfollowingconservativemanagementofclinicallylocalizedpros-
tate cancer diagnosed from 1992 through 2002 are better than outcomes among pa-
tients diagnosed in the 1970s and 1980s. This may be due, in part, to additional lead
time, overdiagnosis related to PSA testing, grade migration, or advances in medical
care.
JAMA. 2009;302(11):1202-1209
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proach. For example, most long-term
dataonconservativemanagementhave
been acquired either in earlier eras
when PSA testing was not performed
or from areas where prostate-specific
antigen (PSA) testing was uncom-
mon,8-11and cancers diagnosed in the
contemporaryPSAerahavebeenshown
tobesignificantlydifferentfromthose
found in earlier eras.2
Thislackofreliablecontemporaryin-
formation makes it difficult for pa-
tients and their physicians to antici-
pate outcomes, make informed
treatmentdecisions,andinterpretthere-
sults of maturing clinical trials (often
startedinearliereras)thatcompareout-
comestoconservativemanagement.We
assembledalargepopulation-basedco-
hortof14516menwithlocalizedT1or
T2 prostate cancer in order to provide
data on the results of conservatively
managed localized prostate cancer di-
agnosed in the contemporary PSA era.
METHODS
Data Sources
Data were obtained from Medicare in-
surance program files linked to the
population-basedSurveillance,Epide-
miology,andEndResults(SEER)can-
cer registries, which are 98% com-
pleteforcaseascertainment.12TheSEER
regions encompassed approximately
14% of the US population before 2000
and25%thereafter.12TheMedicareda-
tabasecoversapproximately97%ofUS
persons aged 65 years or older. Link-
age to the SEER database is complete
for approximately 93% of the pa-
tients.12Thisstudywasapprovedbythe
University of Medicine and Dentistry
of New Jersey institutional review
board, as well as by the SEER pro-
gram, and the Center for Medicare &
Medicaid Services. Informed consent
was waived by the University of Medi-
cine and Denistry of New Jersey insti-
tutionalreviewboardbecausethedata
did not contain personal identifiers.
Cancerstageandgradeforeachcase
were abstracted from SEER data files.
Well differentiated cancers were char-
acterized by a Gleason score of 2 to 4;
moderately differentiated, 5 to 7, and
poorlydifferentiated,8to10.Informa-
tionabouttreatmentwasobtainedfrom
bothSEERandMedicarefiles.ACharl-
soncomorbidityscorewasderivedfrom
Medicare claims during the year prior
toprostatecancerdiagnosisusingavali-
dated algorithm.13Race was self-
determinedbythepatients.Outcomes
in the pre-PSA era were obtained from
publishedliteratureexceptforthestudy
by Albertsen et al,10for which age-
specific data were obtained directly
fromtheauthors.Inthisstudy,thepre-
PSAerareferstotheperiodbefore1988.
ThecontemporaryPSAerareferstoout-
comes among patients diagnosed in
1992 or thereafter.
Study Participants
Thestudycohortconsistedofmenolder
than 65 years who were SEER resi-
dentsanddiagnosedwithAJCC(Ameri-
can Joint Committee on Cancer) stage
T1 or T2 cancer from 1992 through
2002(N=89877).Thisensuredthatev-
ery patient had at least 12 months of
Medicareclaimsdatatoassesstheirco-
morbidity status prior to cancer diag-
nosis(1991wasthefirstyearMedicare
claims data were available for all can-
cer cases). Men who died within 180
daysofdiagnosis(n=1761),orwhore-
ceivedattemptedcurativetherapysuch
asprostatectomyorradiationwithin180
days of diagnosis were excluded
(n=31485).Patientswhohadothercan-
cers diagnosed either before or after
prostatecancerwereexcluded(n=3965)
toensurethatallcancertherapieswere
for prostate cancer. Men who did not
have both Medicare Part A and Part B
as their primary health insurance cov-
erage during the study period were ex-
cluded (n=34777) because their can-
cer treatment history might be
incomplete. Men with missing data
(n=2995), an unknown cancer grade
(n=255),orwhoreceivedandrogendep-
rivation therapy prior to diagnosis
(n=123) were also excluded. In this
study, we classified T1c cancer as de-
tectedbyPSAscreeningresultsandthe
restasanonscreendetectedcancer.Re-
sults(bothmortalityandsecondarycan-
certherapies)remainedsimilarwhenpa-
tients receiving attempted curative
therapy more than 180 days after diag-
nosis were excluded.
Outcomes Assessment
Overall survival was available through
December31,2007,andprostatecancer–
specificsurvival,throughDecember31,
2005. Underlying causes of death were
obtained from the SEER database. Pre-
vious studies have shown high agree-
ment(87%-92%)betweencauseofdeath
in the SEER database and that deter-
mined through medical record re-
view.14,15Follow-up cancer therapies
were identified from SEER and Medi-
careclaimsdatathroughtheendof2005.
External beam radiation that consisted
oflessthan20visitswithina6-weekpe-
riod was considered palliative, whereas
brachytherapy or external beam radia-
tion delivered over 20 visits within 6
weeks was considered attempted cura-
tive therapy. Chemotherapy use was
identified through previously pub-
lished algorithms (? ?0.73 compared
with medical record review).16A vali-
datedalgorithmwasusedtoidentifyan-
drogen deprivation therapy.17,18We de-
veloped and validated a new algorithm
to identify palliative surgery or radia-
tion for spinal cord compression, im-
pending cord compression, or painful
metastasis based on chart review.
Statistical Analyses
Theprimarystudyendpointsweretime
to death from prostate cancer and time
todeathfromothercauses,stratifiedby
patientage,cancergrade,andstageatdi-
agnosis. Our study had more than 95%
powertodetectachangeof10percent-
age points in the prostate cancer death
rate estimates compared with previ-
ouslyreportedrates.Fortheanalysisof
competingrisks,wetabulatedthenum-
bers of men with each of the 3 out-
comesofinterest(alive,deadfrompros-
tatecancer,anddeadfromothercauses)
for each of the age-grade-stage combi-
nations.ResultsformenwithT1andT2
well-differentiated cancers were com-
bined because of limited sample sizes.
Confidence intervals (CIs) for the
current study were based on 95% per-
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centilesof1000bootstrapreplications
ofthecompetingrisksmodelfordeath
from either prostate cancer or other
causes.19Confidence intervals for Al-
bertsen et al were estimated using a
Weibull survival model that matched
the5-and10-yearprostatecancerdeath
rates reported in that article. The rest
of the CIs were extracted from pub-
lishedliterature.Ourstudy,withmuch
larger sample sizes than the study by
Albertsen et al,10had more than 95%
powertodetectachangeof10percent-
agepointsintheprostatecancerdeath
rate estimates over rates for moder-
atelydifferentiateddiseasereportedby
Albertsen et al and more than 80%
power for poorly differentiated dis-
ease, based on simulations with 1000
replications.Confidencesintervalswere
based on percentiles of 1000 boot-
strapreplicationsofthecompetingrisks
model for the 3 outcomes.19
Estimates of competing risks and P
values were computed using cumula-
tive incidence functions.20For the
analysisofcompetingrisksforsecond-
ary cancer therapy, we computed the
competing risks of each outcome in-
dependently, with death treated as a
competing risk, because 1 individual
could have had more than 1 second-
ary treatment. To provide more stable
estimatesofthesurvivalcurves,weused
a nearest neighbor hazard smoother
with an Epanechnikov kernel21as
implemented in the R statistical sys-
tem(RFoundationforStatisticalCom-
puting, Vienna, Austria). All P values
were 2 sided. P ?.05 were considered
statistically significant.
RESULTS
Baseline characteristics of the study
populationaresummarizedinTABLE1.
Seventy-sixpercentofthemenhadGlea-
sonscoresof5to7(n=10988)and4493
men (31%) had screen detected cancer
(T1c). Palpable disease (T2) at diagno-
sis was present in 42% of the cases, and
most men (~70%) did not have signifi-
cant comorbid conditions. The median
age at diagnosis was 78 years and me-
dian follow-up was 8.3 years.
At the end of the study period, most
menwereeitheraliveorhaddiedofother
causes(TABLE2).Duringthefirst10years,
amongthe222patientsdiagnosedwith
well-differentiatedprostatecancer,15died
ofprostatecancerand133diedofother
causes.Amongthe10988patientsdiag-
nosedwithmoderatelydifferentiatedpros-
tate cancer, 642 died of prostate cancer
and5005diedofothercauses.Amongthe
3306patientsdiagnosedwithpoorlydif-
ferentiated prostate cancer, 684 died of
prostate cancer and 1652 died of other
causes.Ten-yearprostatecancer–specific
mortalitywas8.3%(95%CI,4.2%-12.8%)
for men with well-differentiated, 9.1%
(95%CI8.3%-10.1%)moderatelydiffer-
entiated, and 25.6% (95% CI, 23.7%-
28.3%)poorlydifferentiatedtumors.The
corresponding10-yearrisksofdyingof
causes other than prostate cancer were
59.8% (95% CI, 53.2%-67.8%), 57.2%
(95%CI,52.6%-63.9%),and56.5%(95%
CI, 53.6%-58.8%) for each respective
group.TheFIGUREillustrates the com-
petingriskofdeathaccordingtoageat
diagnosis,cancerstage,andgrade.Re-
sultsforwell-differentiatedtumorswere
notshownbecausesamplesizesweretoo
small for reliable estimates. When the
analyseswererestrictedtomenwithout
androgendeprivationtherapywithin6
monthsofcancerdiagnosis,theresults
werecomparableorevenmorefavorable
than those shown in the Figure.
Survival results in our contemporary
PSA era study cohort were more favor-
ablethanresultspreviouslyreported.For
example, in the current study, 10-year
prostatecancer–specificmortalitywas6%
(95% CI, 4%-8%) in the contemporary
PSAera(1992-2002)comparedwithre-
sults of previous studies (15%-23%) in
earliereras(1949-1992)formenaged65
to 74 years diagnosed with moderately
differentiated disease (TABLE 3). Im-
provementinsurvivalamongmenwith
older age or poorly differentiated dis-
ease was also observed.
TABLE 4 summarizes 10-year cumu-
lative risks of various secondary cancer
therapiesbasedontheanalysesofcom-
petingrisks.Overall,androgendepriva-
tiontherapyusewashigh:about60%to
83%within10years.Forty-onepercent
of our cohort received androgen depri-
vation therapy within 6 months of can-
cerdiagnosis;amongtheremainingco-
hort members, 28.4% with moderately
and45.4%withpoorlydifferentiatedcan-
cer received androgen deprivation
therapy within 10 years. Relatively few
patientsreceivedchemotherapy(n=237,
1.6%), or underwent spinal surgery or
radiationformetastaticdisease(n=134,
0.9%).Ten-yearcumulativerisksofpal-
liativetherapy(palliativeradiation,che-
motherapy, or spinal surgery or radia-
tion) were 4.1% and 6.9% among older
Table 1. Characteristics of Men Without
Initial Attempted Curative Therapy for
Clinically Localized (T1 or T2) Prostate Cancera
Characteristics
Age at diagnosis, median
(IQR), y
Follow-up, median (IQR), mo
Black raceb
Married at diagnosis
Urban residence
Zip code-level income, median
(IQR), US $
SEER regions
Northeast
North-central
West
South
Cancer grade, Gleason score
Well-differentiated, 2-4
Moderately-differentiated,
5-7
Poorly differentiated, 8-10)
Clinical stagec
T1a or T1b
T1c
T2
Charlson comorbidity scored
0
1
?2
Year of diagnosis
1992-1996
1997-2002
Use of primary androgen
deprivation therapy
Vital status at last follow-up
Alive as of December
31, 2007
Abbreviations: IQR, interquartile range; SEER, Surveil-
lance, Epidemiology, and End Results.
aData are presented as number (percentage) unless oth-
erwise indicated. Percentages may not sum to 100 due
to rounding.
bRace was self-determined by the patients.
cSEER clinical extension information was used to deter-
mine cancer stage (T1a, T1b, T1c, T2).
dCharlson comorbidity score was derived from Medicare
claims during the year before prostate cancer diagnosis
by using a validated algorithm.13
Participants
(N=14516)
78 (73-82)
100 (77-137)
1577 (10.9)
9070 (62.5)
12553 (86.5)
42924
(33677–57315)
1302 (9.0)
3930 (27.1)
8807 (60.7)
477 (3.3)
222 (1.5)
10988 (75.7)
3306 (22.8)
3972 (27.4)
4493 (31.0)
6051 (41.7)
10127 (69.8)
2807 (19.3)
1582 (10.9)
4623 (31.9)
9893 (68.2)
6041 (41.6)
5814 (40.1)
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patients (?75 years) with nonscreen-
detected moderately and poorly differ-
entiatedcancer,respectively.Youngerage
wasassociatedwithhigheruseofpallia-
tivetherapy(P?.001).Outcomeswere
similarwhenanalyseswererestrictedto
relatively healthy men (comorbidity
score, 0).
COMMENT
The appropriate treatment of men with
clinicallylocalizedprostatecancerdiag-
nosed in the PSA era has been a subject
ofgreatcontroversy.Forthemajorityof
men older than 65 years who are diag-
nosed with localized disease, random-
izedclinicaltrialdatahavenotbeenable
to demonstrate a survival benefit for
surgery3orforanyotherapproachcom-
pared with conservative manage-
ment.26Despite these data raising the
possibility that conservative manage-
ment may be a reasonable treatment
choice,littledataexistthatdescribeout-
comes following conservative manage-
ment in the contemporary PSA era.27-30
To address this lack of data, we ex-
amined 14516 men with localized T1
or T2 prostate cancer without initial
attempted curative therapy and found
that 10-year prostate cancer–specific
mortality declined by more than
60% compared with previous studies
(Table 3). We also found that for the
majority of men managed without
initial attempted curative therapy (ie,
those ?65 years with moderately dif-
ferentiatedcancer),onlyalimitedpro-
portion (4%-11%) used palliative ra-
Table 2. Sample Sizes by Age and Vital Status as of December 31, 2005, Among 14516 Patients With Clinically Localized Prostate Cancera
Characteristic
Age at Diagnosis, y, No. (%)
66-69
(n = 1450 )
70-74
(n = 3005 )
Well-Differentiated Cancer
75-79
(n = 4376 )
?80
(n = 5685 )
All Ages
(N=14516)
Gleason 2-4, stages I and II
Overall sample size
Died of prostate cancer
Died of other cause
Alive
27 (100)
NA
NA
16 (59)
53 (100)
NA
NA
21 (40)
63 (100)
8 (13)
37 (59)
18 (29)
79 (100)
8 (10)
62 (78)
9 (11)
222 (100)
17 (8)
141 (64)
64 (29)
Moderately Differentiated Cancer
Gleason 5-7, T1a and T1b
Overall sample size
Died of prostate cancer
Died of other cause
Alive
Gleason 5-7, T1c
Overall sample size
Died of prostate cancer
Died of other cause
Alive
Gleason 5-7, T2
Overall sample size
Died of prostate cancer
Died of other cause
Alive
345 (100)
NA
NA
258 (75)
713 (100)
21 (3)
252 (35)
440 (62)
946 (100)
40 (4)
411 (43)
495 (52)
1231 (100)
79 (6)
738 (60)
414 (34)
3235 (100)
143 (4)
1485 (46)
1607 (50)
415 (100)
9 (2)
66 (16)
340 (82)
818 (100)
26 (3)
190 (23)
602 (74)
1127 (100)
64 (6)
311 (28)
752 (67)
1199 (100)
75 (6)
501 (42)
623 (52)
3559 (100)
174 (5)
1068 (30)
2317 (65)
431 (100)
32 (7)
94 (22)
305 (71)
891 (100)
54 (6)
277 (31)
560 (63)
1336 (100)
105 (8)
498 (37)
733 (55)
1536 (100)
160 (10)
756 (49)
620 (40)
4194 (100)
351 (8)
1625 (39)
2218 (53)
Poorly Differentiated Cancer
Gleason 8-10, T1a and T1b
Overall sample size
Died of prostate cancer
Died of competing cause
Alive
Gleason 8-10, T1c
Overall sample size
Died of prostate cancer
Died of competing cause
Alive
Gleason 8-10, T2
Overall sample size
Died of prostate cancer
Died of competing cause
Alive
Abbreviation: NA, not available because Surveillance Epidemiology, and End Results (SEER)−Medicare privacy rules prohibit disclosure of numbers of less than 5 in any specific cell;
therefore, numbers in those rows do not sum.
aSEER clinical extension information was used to determine cancer stage (T1, T2).
32 (100)
9 (28)
12 (38)
11 (34)
80 (100)
23 (29)
27 (34)
30 (38)
164 (100)
41 (25)
72 (44)
51 (31)
370 (100)
106 (29)
193 (52)
71 (19)
646 (100)
179 (28)
304 (47)
163 (25)
70 (100)
6 (9)
15 (21)
49 (70)
160 (100)
32 (20)
48 (30)
80 (50)
294 (100)
49 (17)
96 (33)
149 (51)
41 (100)
66 (16)
179 (44)
165 (40)
934 (100)
153 (16)
338 (36)
443 (47)
130 (100)
38 (29)
30 (23)
62 (48)
290 (100)
51 (18)
108 (37)
131 (45)
446 (100)
98 (22)
184 (41)
164 (37)
860 (100)
171 (20)
438 (52)
251 (30)
1726 (100)
358 (21)
760 (44)
608 (35)
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diation therapy, chemotherapy, or
treatments for spinal cord compres-
sion over the ensuing 10 years follow-
ing diagnosis. In contrast, use of an-
drogen deprivation therapy was quite
common.
Thesubstantialimprovementinsur-
vivalthatweobservedinourstudycom-
paredwithpreviousreports10,11,24might
beexplained,inpart,byadditionallead
time,overdiagnosisrelatedtoPSAtest-
ing,orgrademigration,amongotherfac-
tors.31Prostate-specific antigen testing
identifies disease 6 to 13 years before it
presentsclinically.32Contemporarypa-
tients identified through such testing
wouldbeexpectedtoliveatleast6to13
yearslongerbecauseofthisleadtime.32
Inaddition,previouslydocumentedsys-
tematic upgrading of modern tumors
comparedwithearliereras33makesmore
recentlygradedtumorsappeartohavea
morebenigncourse,resultinginlonger
survivals.31Finally,itisalsopossiblethat
advancementsinmedicalcaremighthave
ledtoimprovedoutcomes.Thenetover-
alleffectisthatoutcomesfollowingcon-
servative management are now signifi-
cantlybetterthanthosereportedinpre-
viouseras;therefore,physiciansandtheir
patientsmayneedtoreconsiderthisman-
agement option, particularly in light of
randomizedtrialdatafromthepre-PSA
erasuggestinglittleifanybenefittomore
aggressive intervention.
Our documentation of a major im-
provementinconservativemanagement
outcomesisimportant,notonlybecause
itprovidesupdatedinformationforphy-
siciansandpatientsbutalsobecausethe
results may color the interpretation of
maturingrandomizedclinicaltrials.For
example,inthewidelycitedScandina-
vianrandomizedstudyofprostatectomy
vs conservative management, disease-
specificsurvivalintheconservativeman-
agementgroup(~85%at10-year)3was
found to be very similar to that docu-
mentedinseveralobservationalcohort
studies of conservative management
fromthesamepre-PSAorearlyPSAera
(~87%,24~86%,34and~83%35).Theuse
ofradicalprostatectomyresultedinan
approximate5.3%absolutepercentage
pointincreasetoabout90%incancer-
specific survival in this study.
The results of our study, however,
demonstrated that 10-year cancer-
specificsurvivalwithconservativeman-
agementhasnowincreasedfromabout
83%to87%inthepre-PSAorearlyPSA
eratoabout94%inthePSAera,which
is now beyond the approximate 90%
Figure. Competing Risk of Death by Age at Diagnosis, Cancer Stage, and Grade
100
60
40
80
20
0 100
60
40
80
20
0
100
60
40
80
20
0 100
60
40
80
20
0
Stage T1c
100
60
40
80
20
0
0286 1040286
Years Following Diagnosis
1040286 1040286 104
100
60
40
80
20
0
Stage T2
Probability of being alive
Nonprostate cancer mortality
Prostate cancer mortality
Deceased, %
Deceased, %
Alive, %
Alive, %
100
60
40
80
20
0 100
60
40
80
20
0
100
60
40
80
20
0 100
60
40
80
20
0
Stage T1c
100
60
40
80
20
0 100
60
40
80
20
0
Stage T2
66 to 69 70 to 7475 to 79
≥80
Stage T1a or b
Moderately Differentiated Cancer
Age at Diagnosis, y
66 to 6970 to 74 75 to 79
≥80
Stage T1a or b
Poorly Differentiated Cancer
Age at Diagnosis, y
PROSTATE CANCER OUTCOMES AND CONSERVATIVE MANAGEMENT
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Page 6

10-yearcancer-specificsurvivalratefor
asimilarpopulationofmentreatedwith
prostatectomy in the pre-PSA or early
PSA era Scandinavian trial (ie, those
aged 66-74 years with moderately-
differentiated cancer; Table 3). The
roomavailableforadditionalimprove-
mentwhen10-yearcancer-specificsur-
vival is already close to 94% with con-
servativemanagementmaybelimited,
and the absolute benefit of surgery in
the Scandinavian trial may be difficult
toreproduceinsimilarstudieslikethe
USProstateCancerInterventionvsOb-
servationTrial(PIVOT),inwhichmost
men were diagnosed through PSA
screening.36Nevertheless,theonlytrue
way to determine whether this will be
the case is to await the results of con-
temporary randomized studies like
PIVOT, and it is not our intent to sug-
gestthatbenefitforthemajorityofmen
withlocalizedprostatecancer(ie,those
?65 years old) can be excluded based
on our results and those of the Scan-
dinavianstudy.3Ontheotherhand,for
men with poorly differentiated dis-
Table 3. Ten-Year Competing Risk of Dying of Prostate Cancer According to Cancer Grade and Age Group for Men Aged 65 to 74 Years
Without Initial Attempted Curative Therapy
Year of Cancer
Diagnosis
1992-2002
1992-2002
1971-1984
1977-1984
1983-1992
1949-1989
1978-1982
Cancer Grade, % (95% Confidence Interval)
Moderately Differentiated,
Gleason 5-7, Age at Diagnosis, y
Poorly Differentiated, Gleason
8-10, Age at Diagnosis, y
65-69
2 (1-4)
6 (4-8)
21 (10-32)
15 (4-26)
23 (20-26)
16 (11-20)
16 (9-23)
70-74
5 (3-7)
6 (5-8)
23 (13-34)
15 (4-26)
23 (20-26)
16 (11-20)
16 (9-23)
65-69 70-74
Current study, stage T1a
Current study, stage T1 or T2a
Albertsen et al,102005b
Johansson et al,222004c
Lu-Yao et al,231997d
Chodak et al,241994e
Adolfsson et al,251992f
aCurrent study, patients aged 66 through 69 years and 70 through 74 years. Comparison limited to men aged 66 through 74 years because most other studies had a median age
approximately 70 years and had very limited data on men older than 75 years.
bAuthors provided age-specific and Gleason score–specific data to calculate weighted averages for moderately differentiated cancer. Confidence intervals (CIs) were estimated
using a parametric bootstrap with 100 replications based on the mortality estimates provided by the authors.
cAge-specific data not available. Data taken from the article’s Table 2,22moderately differentiated cancer. The mean age was not provided. Data for men with poorly differentiated
cancer not presented due to small sample size.
dMean age for moderately and poorly differentiated cancer was 71 and 72 years, respectively. Data taken from the article’s Table 2,23intention to treat analyses.
eAge-specific data not available. Data taken from the article’s Table 524for well-differentiated or moderately differentiated cancer (men aged ?61 years), and poorly differentiated
cancer (mean age, 70 years).
fAge-specific data not available. Mean age 68 years. All patients had well- or moderately-differentiated cancer.
38 (27-54)
61 (42-79)
25 (20-31)
50 (31-69)
55 (49-60)
66 (50-81)
55 (49-60)
66 (50-81)
Table 4. Ten-Year Cumulative Risk of Selected Secondary Cancer Treatments After Diagnosis in Patients With Localized Prostate Cancer
Without Initial Attempted Curative Therapy
Moderately Differentiated, Gleason 5-7 (95% Confidence Interval)d
Treatments
66-74 Years at Diagnosis
?75 Years at Diagnosis
Screen Detected T1c
(n = 1233)
Nonscreen Detected
(n = 2377)
Screen Detected T1c
(n = 2324)
Nonscreen Detected
(n = 5047)
No. of
Events
257
590
109
10-y Risk
(95% CI)a
23.7 (21.2-26.9)
60.3 (56.7-64.4)
10.9 (9.2-13.3)
No. of
Events
257
962
168
10-y Risk
(95% CI)a
13.0 (11.2-14.3)
51.4 (47.9-53.6)
9.3 (7.6-10.8)
No. of
Events
113
1457
83
10-y Risk
(95% CI)a
5.9 (4.9-7.1)
73.8 (67.4-77.9)
5.0 (3.7-6.6)
No. of
Events
119
2477
160
10-y Risk
(95% CI)a
2.9 (2.3-3.6)
58.2 (55.3-60.3)
4.1 (3.6-4.8)
Attempted curative therapyb
Androgen deprivation therapy
Palliative radiation,
chemotherapy, or spinal
surgery or radiationc
Poorly Differentiated, Gleason 8-10, % (95% Confidence Interval)d
Screen-Detected, T1c
(n = 230)
2414.1 (9.5-20.1)
15781.8 (75.1-97.4)
35 30.1 (16.1-51.1)
Nonscreen Detected
(n = 532)
64 14.5 (11.4-17.9)
38780.7 (68.4-89.5)
7817.0 (13.2-20.2)
Screen-Detected, T1c
(n = 703)
376 6.3 (4.7-8.5)
58083.1 (74.9-94.7)
498.1 (6.1-10.4)
Nonscreen Detected
(n = 1839)
46 3.0 (2.3-4.0)
1442 83.7 (77.8-86.6)
1066.9 (5.6-9.0)
Attempted curative therapyb
Androgen deprivation therapy
Palliative radiation,
chemotherapy, or spinal
surgery or radiationc
aThe cumulative risks were derived from competing risk models and may be different from raw rate (Event No./No. person at risk).
bRadical prostatectomy, or at least 20 visits for radiation therapy during a 6-week period, and/or brachytherapy.
cLess than 20 visits for radiation therapy during a 6-week period. Due to small numbers of chemotherapy and spinal surgery, these categories are not presented separately.
dConfidence intervals were estimated using a bootstrap with 1000 replications.
PROSTATE CANCER OUTCOMES AND CONSERVATIVE MANAGEMENT
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Page 7

ease managed conservatively, the 10-
year cancer-specific survival was sub-
stantiallylower(~58%-74%)thanwhat
was reported in the Scandinavian trial
and, therefore, the potential for ben-
efit with attempted curative therapy
may be greater for these men.
Ourstudyhadsomelimitations.The
men in our study, like the majority of
patients with prostate cancer, were 65
yearsorolderandourresultsmightnot
apply to younger patients. In addi-
tion, we were limited to data available
in the SEER registries. For example,
PSA values at diagnosis were not col-
lectedduringthestudyperiodandGlea-
son 5, 6, and 7 tumors were grouped
together as moderately differentiated
disease. Consequently, the results for
moderately differentiated disease as a
whole may overestimate survival for
Gleason 7 tumors and underestimate
survival for Gleason 5 tumors. In ad-
dition, there may be unmeasured pa-
tient or disease characteristics beyond
age, tumor stage, and tumor grade
unique to patients selecting conserva-
tive management that effect results so
thattheymaynotapplytopatientswith
more aggressive disease characteris-
tics not captured in the database. An-
otherlimitationisthelengthoffollow-
up.Becauseoftheprotractednatureof
the disease, longer follow-up data are
needed for men with a life expectancy
of greater than 10 years.
Finally,asinotherobservationaland
randomizedtrialsandstudies,thesec-
ondaryendpointsweresupportive,ex-
ploratory,andlessrobustthanthepri-
maryendpoints.Forexample,although
theMedicaredatabaseisgenerallyable
to capture the initiation of secondary
therapy accurately (surgery, radia-
tion,androgendeprivationtherapy,and
chemotherapy, etc), the actual accu-
racy may vary somewhat from proce-
duretoprocedureand,therefore,com-
parisons between rates of secondary
therapiesmaybelessexact.12,16,37Inad-
dition,theMedicaredatabasedoesnot
consistently capture the use of oral
agents,suchastheantiandrogens,that
may be used for androgen deprivation
therapy. In the case of antiandrogens,
however, data from the CAPSURE
(Center of the Prostate Strategic Uro-
logic Research Endeavor) database38
have shown that the use of antiandro-
gens as sole treatment for localized
prostate cancer is uncommon (~2%)
and,therefore,itisunlikelythattheuse
of hormonal therapy would be signifi-
cantly underestimated. Irrespective of
the strengths and limitations of each
secondaryendpoint,however,itisim-
portant to recognize that the purpose
oftheseadditionalanalyseswastopro-
videadditionalinsightandcontextfor
the interpretation of the primary end
pointsofcancer-specificandoverallsur-
vival and not necessarily for these end
pointstostandaloneasdefinitivecon-
clusions.
In addition to the study’s limita-
tions, there were also some important
strengths. The study was population-
based, and all-inclusive in the regions
studied, rather than limited to specific
institutions or networks. Conse-
quently, the results are more likely to
apply more broadly. Furthermore, the
study was much larger than previous
studies and, therefore, provided more
stable estimates on which to base fu-
ture clinical decisions. In particular,
conservativemanagementisoftenanes-
pecially relevant treatment choice for
men aged 75 years or older. However,
data on this older population are rare
andthisgroupisoftenexcludedorun-
derrepresented in randomized trials.
Ourstudy,withmorethan10061men
aged 75 years or older, provided cru-
cial information to fill this important
knowledge gap.
In summary, our findings suggest
that outcomes following conservative
managementofcontemporaryPSAera
patients with localized prostate can-
cer are substantially more favorable
than in studies from earlier eras, and
patients with well- or moderately dif-
ferentiateddiseasemanagedconserva-
tivelyaregenerallyevenmorelikelyto
die of causes other than prostate can-
cer.9,10,24,34Considering favorable 10-
year outcomes following conservative
management, men with a life expec-
tancyoflessthan10yearsmaywishto
consider an active surveillance or
watchful waiting protocol as an alter-
native to immediate attempted cura-
tive therapy.10,24,30,34,39
Author Contributions: Dr Lu-Yao had full access to
all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Studyconceptanddesign:Lu-Yao,Albertsen,DiPaola,
Barry, Zietman, Yao.
Acquisition of data: Lu-Yao, Walker-Corkery.
Analysisandinterpretationofdata:Lu-Yao,Albertsen,
Moore, Shih, Lin, Barry, Zietman, O’Leary, Yao.
Draftingofthemanuscript:Lu-Yao,Albertsen,Lin,Yao.
Critical revision of the manuscript for important in-
tellectual content: Lu-Yao, Albertsen, Moore, Shih,
DiPaola, Barry, Zietman, O’Leary, Walker-Corkery,
Yao.
Statistical analysis: Lu-Yao, Moore, Shih, Lin.
Obtained funding: Lu-Yao.
Administrative, technical, or material support:
Albertsen, DiPaola, Barry, Walker-Corkery, Yao.
Studysupervision:Lu-Yao,Shih,DiPaola,O’Leary,Yao.
Financial Disclosures: Dr Barry reported that he be-
camethepresidentofthenot-for-profitFoundationfor
InformedMedicalDecisionMakingonAugust1,2009.
Dr Anthony Zietman reported that he will receive a sti-
pend for becoming the cochair of the National Cancer
Institute Genitourinary Steering Committee. In addi-
tion, during the past 5 years, the following authors re-
ported that they have received financial support and
maintainedaffiliations:DrG.Lu-Yaohasreceivedclini-
calresearchfundingfromtheOhlFoundation,NewJer-
sey Commission on Cancer Research, the Agency for
HealthcareResearchandQuality,andemploymentwith
HealthStat; Dr Albertson has received clinical research
fundingfromSanofi-Aventisandconsultationfeesfrom
Blue Cross/Blue Shield; Dr Shih has received clinical re-
search funding from Myriad; Dr Moore has contrib-
uted to a consulting project with Innocentive Inc and
has received funding from the National Cancer Insti-
tute and the National Institute of Diabetes and Diges-
tive and Kidney Diseases; Dr Barry has received fund-
ing from the Agency for Healthcare Research and
Quality, the National Cancer Institute, the National In-
stituteonAging,theNationalInstituteofDiabetesand
DigestiveandKidneyDiseases,andtheFoundationfor
Informed Medical Decision Making (a not-for-profit);
Ms Walker-Corkery has received funding from the
Agency for Healthcare Research and Quality, the Na-
tionalCancerInstitute,andtheNationalInstituteofDia-
betes and Digestive and Kidney Diseases; Dr S.-L. Yao
has been employed by Sanofi-Aventis and Schering-
Plough in the area of clinical cancer research. None of
these entities contributed funding, or played any role
whatsoever in the design, interpretation, or drafting of
our study or manuscript.
Funding/Support:Thestudywassupportedbythefol-
lowing grants and awards: award DAMD17-01-1-
0755 from the US Army Medical Research Acquisi-
tionActivity,FortDetrick,MD,DepartmentofDefense
award W81XWG-05-1-0235, Ohl Foundation, and
grants R01 CA116399 and CINJ core grant CA-
72720-10 from the National Cancer Institute.
RoleofSponsor:TheDepartmentofDefense,OhlFoun-
dation, and National Cancer Institute provided fund-
ingforthisstudy.TheDepartmentofDefenseandOhl
Foundationdidnotplayanyroleinthedesignandcon-
ductofthestudy;collection,management,analysis,and
interpretation of the data; and preparation, review, or
approval of the manuscript. The National Cancer Insti-
tute did not play any role in the design and conduct of
the study; analysis and interpretation of the data; and
preparationofthemanuscript,butdidcollectandman-
age the data as well as reviewed and approved the
manuscript.
PROSTATE CANCER OUTCOMES AND CONSERVATIVE MANAGEMENT
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Page 8

Disclaimer: This study used the linked SEER-Medicare
database.Theinterpretationandreportingofthesedata
are the sole responsibility of the authors. The content
of the information does not necessarily reflect the po-
sition or the policy of the Government or the employ-
ers, and no official endorsement should be inferred.
Additional Contributions: We acknowledge the ef-
forts of the Applied Research Branch, Division of Can-
cer Prevention and Population Science, National Can-
cerInstitute,theOfficeofInformationServices,andthe
OfficeofStrategicPlanning,CenterforMedicare&Med-
icaid Services; Information Management Services Inc,
and the SEER Program tumor registries in the creation
of the SEER-Medicare database. We thank Thanusha
Puvananayagam,MPH,anassistantstaffwithsalarysup-
port from the Cancer Institute of New Jersey, for out-
standing administrative and technical assistance.
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