Vol. 293 No. 17, May 4, 2005

20-Year Outcomes Following Conservative Management of Clinically
Localized Prostate Cancer
Peter C. Albertsen, MD, MS; James A. Hanley, PhD; Judith Fine, BA
JAMA. 2005;293:2095-2101.

ABSTRACT  

Context  The appropriate therapy for men with clinically localized
prostate cancer is uncertain. A recent study suggested an increasing
prostate cancer mortality rate for men who are alive more than 15 years
following diagnosis.
Objective  To estimate 20-year survival based on a competing risk
analysis of men who were diagnosed with clinically localized prostate
cancer and treated with observation or androgen withdrawal therapy
alone, stratified by age at diagnosis and histological findings.
Design, Setting, and Patients  A retrospective population-based cohort
study using Connecticut Tumor Registry data supplemented by hospital
record and histology review of 767 men aged 55 to 74 years with
clinically localized prostate cancer diagnosed between January 1, 1971,
and December 31, 1984. Patients were treated with either observation or
immediate or delayed androgen withdrawal therapy, with a median
observation of 24 years.
Main Outcome Measures  Probability of mortality from prostate cancer
or other competing medical conditions, given a patient's age at
diagnosis and tumor grade.

Results  The prostate cancer mortality rate was 33 per 1000
person-years during the first 15 years of follow-up (95% confidence
interval [CI], 28-38) and 18 per 1000 person-years after 15 years of
follow-up (95% CI, 10-29). The mortality rates for these 2 follow-up
periods were not statistically different, after adjusting for
differences in tumor histology (rate ratio, 1.1; 95% CI, 0.6-1.9). Men
with low-grade prostate cancers have a minimal risk of dying from
prostate cancer during 20 years of follow-up (Gleason score of 2-4, 6
deaths per 1000 person-years; 95% CI, 2-11). Men with high-grade
prostate cancers have a high probability of dying from prostate cancer
within 10 years of diagnosis (Gleason score of 8-10, 121 deaths per 1000
person-years; 95% CI, 90-156). Men with Gleason score of 5 or 6 tumors
have an intermediate risk of prostate cancer death.
Conclusion  The annual mortality rate from prostate cancer appears to
remain stable after 15 years from diagnosis, which does not support
aggressive treatment for localized low-grade prostate cancer.

To determine the need for treatment of localized prostate cancer,
patients and physicians must understand the natural history of this
disease. A recent study by Johansson et al1 documented 20-year outcomes
for a population-based cohort of 223 men diagnosed with localized
prostate cancer between 1977 and 1984. The authors noted a substantial
increase in prostate cancer mortality among the 49 men who were alive
more than 15 years following diagnosis.
In 1998, we published a competing risk analysis of 767 men aged 55 to 74
years with clinically localized prostate cancer at diagnosis who were
treated with observation or androgen-withdrawal therapy alone.2 The
purpose of that analysis was to provide an estimate of the natural
progression of prostate cancer if treated conservatively. Because these
men have been followed up continuously by the Connecticut Tumor Registry
(CTR), we had an opportunity to extend our follow-up to 20 years to
determine whether prostate cancer mortality rates declined, remained
constant, or increased after 15 years.

METHODS  

Patients followed up in this analysis were the same patients described
in our 1998 study.2 The original study population consisted of 767 men
identifiedfrom the CTR database who were Connecticut residents when
diagnosed with prostate cancer between January 1, 1971, and December 31,
1984. Of these men, 610 died before March 1, 1997, after a median
follow-up of 15.4 years. Since then, 107 patients have died. The year of
last contact for the remaining 50 men was 1987 (n = 1), 1998
(n = 2), 2001 (n = 1), 2002 (n = 2), 2003 (n = 41), 2004
(n = 3). The final censoring date was October 8, 2004.
The original research was approved in 1990 to 1992 with a waiver of
informed consent by the institutional review boards of the Connecticut
Department of Public Health (DPH), as well as 24 acute care hospitals
and the 2 Veterans Affairs medical centers in Connecticut that had
institutional review boards at the time. Administrative approval waiving
informed consent was obtained in the remaining 11 hospitals. This study
was approved in 2004 by the Connecticut DPH Human Investigation
Committee and the institutional review board of the University of
Connecticut Health Center.
Charts were abstracted onsite to confirm the date of diagnosis,
metastatic evaluations completed, method of treatment, and any
associated comorbidities. Patients who had undergone surgery, received
either radiation therapy or brachytherapy, or who were known to have
metastatic disease were excluded. In addition, patients with concomitant
cancers and those surviving less than 6 months after diagnosis were also
excluded. Study personnel performing chart abstraction were blinded to
the long-term outcome of the patients as recorded by the CTR. Original
histology slides that were used to secure the patients' diagnoses were
retrieved from hospital pathology departments and mailed to a referee
pathologist who was also blinded to the long-term outcome.2 Standardized
grading was performed using the Gleason classification system. This
system grades prostate cancers into 1 of 5 morphological patterns
according to the tumors' glandular differentiation and growth pattern as
assessed under low-power magnification, with 1 indicating
well-differentiated disease and 5 indicating poorly differentiated
disease. The Gleason score represents the sum of the pattern numbers of
the 2 most common patterns by volume. Scores range from 2 to 10, with a
Gleason score of 10 being the most poorly differentiated and aggressive
tumors.3
Accurate staging information was lacking for many men. Bone scan tests
were performed on only 30% of patients and serum acid phosphatase levels
were confirmed as normal in only 53% of patients. The proportion of
patients without evidence of testing for metastatic disease ranged from
33% for men with a Gleason score of 2 to 4 disease to 15% for men with a
Gleason score of 7 and 8 to 10 disease. No information was available
concerning prostate-specific antigen (PSA) levels at diagnosis because
this population had prostate cancer diagnosed before the clinical
application of this test. Approximately 71% of patients were diagnosed
with prostate cancer following transurethral resection or open
prostatectomy, 26% of patients were diagnosed by needle biopsy of the
prostate, and 3% of patients were diagnosed by other or unknown methods.
Outcome Assessment
On March 1, 1997, and again on October 8, 2004, the vital status of each
patient was obtained from the CTR, which is located in the Connecticut
DPH. The CTR is the oldest state cancer registry and has functioned as
one of the sites of the National Cancer Institute's Surveillance,
Epidemiology, and End Results program since 1973. The CTR uses a variety
of sources to obtain follow-up data for registered patients, including
hospital tumor registrars who rely on hospital records and physician and
patient contact, as well as periodic searches of the DPH Vital Records
Section files. The CTR database is linked annually with files of the
Center for Medicare & Medicaid Services, formerly the Health Care
Financing Administration, to ascertain deaths of men enrolled in
Medicare. If a man is not known to be dead, a date of last contact is
assigned that corresponds with the date of the last Center for Medicare
& Medicaid Services/Health Care Financing Administration linkage. The
Connecticut Department of Motor Vehicles files are linked annually and
the National Death Index Plus files are linked every 1 or 2 years to
obtain cause of death for patients known to be dead.
For all men who died since the last analysis, information coded from
death certificates was obtained to classify them as having died from
prostate cancer or another cause. A patient was determined to have died
from prostate cancer if any of the 3 causes listed on part 1 of the
death certificate reported prostate cancer. If prostate cancer did not
appear on 1 of these 3 lines, the patient's death was attributed to
competing medical conditions. For some patients, only information
concerning the date of death was available. Patients who were not
followed up until death were considered alive until the date of last
contact and their subsequent survival time was censored.

Statistical Analysis

The primary outcomes of our study were probability of mortality from
prostate cancer or other competing causes, given a patient's age at
diagnosis and tumor grade. For the competing risk analysis, we tabulated
the numbers of men with each of the 3 outcomes of interest (alive,
deceased from prostate cancer, and deceased from other causes) for each
of the 20 age-histology combinations. Because of the variable length of
follow-up and the small numbers in some cells, we also performed a
second competing risk analysis based on 2 inputs: the rate of mortality
from prostate cancer and from other causes, both fitted as smooth
functions of age at diagnosis, Gleason score, and year of follow-up.
These smoothed estimates were derived from regression models and
incorporated the duration of follow-up and the patterns of outcomes in
neighboring cells to allow more stable estimates for all cells.
The regression models used to construct the smoothed competing risk
analysis required information concerning both the date of death and the
cause of death for all patients. For 25 (3.5%) of the 717 men who died,
only the date of death was available. We imputed the cause of death for
each of these 25 men separately for each histology score category
according to the ratio of the deaths of known causes for the other men
with the same histology scores.2 The rates of mortality from prostate
cancer and other competing medical conditions were estimated
respectively using separate Poisson regression analyses from the 7429
person-years of follow-up by using the Poisson link in the GENMOD
procedure in SAS statistical software version 6.12 (SAS Institute, Cary,
NC), which allowed noninteger numbers of events. P<.05 was considered
statistically significant.
To estimate the proportions of men who died from prostate cancer or
other competing medical conditions, or who were still alive 20 years
following diagnosis, we applied the fitted rates of prostate cancer
death and other causes of death to the proportion of men still alive at
the beginning of each successive follow-up interval. This was plotted
for each age-histology stratum. Prostate cancer mortality rates in each
of the 5-year intervals after diagnosis were calculated using the
numbers of deaths divided by the number of person-years of follow-up in
the interval; rates were expressed as the number of prostate cancer
deaths per 1000 person-years. The confidence intervals (CIs) for these
mortality rates were calculated by multiple imputation. Because the
distribution of tumor histology among survivors after 15 years was more
favorable than the entire cohort at the time of diagnosis, we also
compared the mortality rates before and after 15 years of follow-up,
adjusting for tumor grade and age at diagnosis using Poisson regression.

RESULTS  

The median observation period was 24 years (range, 16-33 years); for 87%
of the men, it was longer than 20 years. Of the 107 men who died since
our previous study, we determined the date of death for all 107 men and
the cause of death for 95 men. We were able to obtain the cause of death
for an additional 44 men for whom this information was unavailable at
the end of the first study.2 A description of the original study
population, including information gathered concerning cause of death
during the past 6 years, is shown in Table 1.
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Table 1. Characteristics of Patients With Clinically Localized Prostate
Cancer (Nv7)
The distributions of outcomes at the end of this follow-up are shown in
Table 2. The table stratifies men by 2 key factors that influence
long-term survival: age at diagnosis and the histology score of the
biopsy specimen classified according to the Gleason system. To
standardize the follow-up and provide more stable estimates of the
mortality rates from prostate cancer or other competing conditions,
smoothed estimates are presented as 20-year outcomes as a function of
time from diagnosis (Figure). The results follow the same trends as
noted in 1998. Few men with low-grade tumors identified by prostate
biopsy had progression leading to prostate cancer death within 20 years,
although most men with high-grade tumors died from the cancer regardless
of their age at diagnosis. Among men with a comorbidity score of 0 to 1,
26%, 15%, and 8% survived at least 15, 20, and 25 years, respectively.
Among men with a comorbidity score of more than 1, 11%, 6%, and 3%
survived at least 15, 20, and 25 years, respectively.
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Table 2. Age Distribution, Comorbidity Scores, and 20-Year Outcome of
767 Patients With Clinically Localized Prostate Cancer Followed Up for a
Median of 24 Years
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Figure. Survival and Cumulative Mortality From Prostate Cancer and Other
Causes Up to 20 Years After Diagnosis, Stratified by Age at Diagnosis
and Gleason Score
Prostate cancer–specific mortality rates were unchanged after 15 years
of follow-up (Table 3). The prostate cancer mortality rate was 33 per
1000 person-years during the first 15 years (95% CI, 28-38) and 18 per
1000 person-years after 15 years of follow-up (95% CI, 10-29). These
rates were not statistically different after adjusting for the more
favorable histology profiles among men who survived more than 15 years
from diagnosis (rate ratio, 1.1; 95% CI, 0.6-1.9).
View this table:
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Table 3. Unadjusted Prostate Cancer Death Rates by Period of Follow-up,
Age at Diagnosis, and Tumor Grade at Diagnosis

COMMENT  

Considerable controversy surrounds the appropriate treatment of newly
diagnosed prostate cancer. Widespread testing for PSA has introduced
lead time and length time effects that further complicate the task of
determining the efficacy of treatment. Although some of the cancers
identified by contemporary biopsy techniques are destined to progress to
clinically significant disease, trends in population-based incidence and
mortality rates suggest that a significant number of prostate cancers
identified by PSA testing are unlikely to be clinically symptomatic.4
Johansson et al1 recently published 20-year follow-up data of a
population-based cohort of men diagnosed with prostate cancer between
1977 and 1984, a period of time very similar to our patient series. They
reported an unexpected 3-fold increase in prostate cancer mortality
rates for the 49 patients who were still alive 15 years after diagnosis.
A 20-year analysis of our cohort does not support that finding. Two
factors may contribute to this difference: histology classification and
cause of death determination.
Despite recent advances in genomics, tumor histology still remains the
most powerful predictor of disease progression. Patients in the study by
Johansson et al1 underwent an aspiration biopsy and the results were
classified according to the World Health Organization grading system.
Our study used the Gleason score grading system, which relies on
glandular architecture to classify specimens. Although both systems show
good correlation between grade and survival, they are based on
fundamentally different criteria and may result in different
classifications, especially among men with moderately differentiated
disease.3, 5
Both studies agree that men with well-differentiated tumors rarely die
from their disease and that men with poorly differentiated tumors
frequently die within 5 to 10 years of diagnosis, often despite
aggressive interventions. Men with moderately differentiated tumors have
the greatest variation in outcomes. Based on only 8 prostate cancer
deaths from years 15 to 20, Johansson et al1 reported that the prostate
cancer mortality rate for the entire cohort increased from 15 to 44
deaths per 1000 person-years. We found that men with Gleason scores of
5, 6, and 7 had mortality rates of 12, 30, and 65 deaths per 1000
person-years, respectively, during a 20-year follow-up. These rates were
unchanged from those rates at 15 years. The increased mortality rate
reported by Johansson et al1 may therefore reflect a classification
artifact involving a small number of patients.
A second distinction between these 2 studies is cause of death
determination. Prostate cancer mortality statistics rely on an accurate
determination of whether a patient died of his disease or from a
competing medical condition. This can be difficult to determine when
patients have multiple chronic diseases, such as heart disease or other
malignancies (eg, lung cancer or colon cancer).
Johansson et al1 relied on medical record review to determine cause of
death and validated their findings with information recorded in the
Swedish Death Register. We relied on information reported on part 1 of
the death certificate to classify patients as having died from prostate
cancer or a competing medical condition. Although death certificates are
often an unreliable source for identifying a specific cause of death, we
have determined through 2 independent validation studies that prostate
cancer mortality can be classified reliably (concordance with medical
record review of 87%-96%) when cause of death is recorded as a
dichotomous variable (ie, the patient died from prostate cancer or a
competing medical condition).6-7 The misclassification of a small number
of patients in either study may explain the different findings at years
15 and 20. Overall, the prostate cancer mortality rates determined in
both studies are remarkably similar.
The clinical implications of both studies should be the same. Men with
well-differentiated disease rarely require treatment, while men with
poorly differentiated disease treated with androgen deprivation alone
will usually die from prostate cancer. Radical prostatectomy may reduce
disease-specific mortality by half.8 However, for those men who have PSA
recurrence following surgery, there is a high probability of disease
progression during a period of 10 to 15 years; this most commonly occurs
in men who have poorly differentiated disease.9
Counseling men who have moderately differentiated disease (Gleason score
of 5-6 and/or World Health Organization grade 2) and a life expectancy
of more than 15 years poses the greatest challenge. A majority of these
men will die from competing medical conditions during a period of 15 to
20 years. Until better prognostic markers are developed, physicians will
continue to recommend aggressive treatments at the time of diagnosis.
Repeated PSA testing is exacerbating this dilemma by introducing a lead
time of many years. The data from our study and Johansson et al1 are
derived from patients diagnosed with prostate cancer before the advent
of PSA testing. Based on data collected by the Rotterdam section of the
European Randomized Study of Screening for Prostate Cancer, Draisma et
al4 have developed models that estimate the impact of PSA testing on
lead time and the probability of detecting clinically insignificant
disease. These depend on a man's age at screening. For a single PSA
screening test at age 55 years, the estimated lead time was 12.3 years
(range, 11.6-14.1 years) and the likelihood of detecting clinically
insignificant disease was 27% (range, 24%-37%). At age 75 years, the
estimated lead time was only 6.0 years (range, 5.8-6.3 years), but the
likelihood of detecting clinically insignificant disease increased to
56% (range, 53%-61%). Draisma et al4 estimated that annual PSA testing
from ages 55 to 67 years would yield insignificant cancers in
approximately half of all men diagnosed with localized prostate cancers
and would increase a person's lifetime risk of being diagnosed with
prostate cancer by 80%.
Thompson et al10 have recently demonstrated that the pool of subclinical
prostate cancer is much larger than prostate cancer mortality statistics
would suggest. After analyzing data from a large chemoprevention study
comparing finasteride with placebo, they found that the prevalence of
prostate cancer was 6.6% among men whose PSA was consistently less than
0.5 ng/mL and as high as 26.9% among men whose PSA was between 3.1 and
4.0 ng/mL. It is unclear whether these tumors will progress at the same
rate as described by our study and Johansson et al.1 Length time bias
would result in PSA testing preferentially identifying slower growing
tumors. Evidence supporting the impact of length time bias is found in a
recent study by Stamey et al11 who reviewed pathology specimens from
1317 consecutive men undergoing radical prostatectomy at Stanford
University during the past 20 years. They found that the size of the
prostate cancers identified by PSA testing has decreased steadily since
1983 and that an increased PSA level in 2004 more commonly reflects
benign prostate enlargement rather than prostate cancer.
A limitation of our study is that many of the patients did not undergo a
complete metastatic evaluation and the actual stage of the disease at
diagnosis may have been worse than our classification. Before the advent
of contemporary transrectal ultrasound–guided biopsies, which often
include 10 to 12 cores, 40% of patients with newly diagnosed disease had
clinical evidence of extracapsular disease.12 Catalona et al13 have
shown that more than half of all patients presenting with a serum PSA
level of more than 10 mg/mL have pathological evidence of extracapsular
disease. Because none of the patients included in our series underwent
PSA testing, there is a high probability that the series contains a
number of men with extracapsular disease. Therefore, our results most
likely underestimate survival for contemporary patients with localized
prostate cancer.
Extended follow-up of our competing risk analysis suggests that prostate
cancer progression rates do not increase after 15 years of follow-up.
Men with low-grade prostate cancer have only a small risk of prostate
cancer progression even after 20 years of management by observation or
androgen withdrawal therapy alone. These results do not support
aggressive treatment of localized low-grade prostate cancer. Men with
poorly differentiated disease (Gleason scores of 7 and 8-10) have a high
risk of death from prostate cancer; only 3 men were alive after 20
years. Men with moderate-grade disease (Gleason scores of 5-6) have an
intermediate cumulative risk of prostate cancer progression after 20
years of follow-up. Our data provide what are likely overestimates of
prostate cancer progression when men are treated by observation or
androgen withdrawal therapy alone. Only through randomized controlled
trials designed to measure the efficacy of screening and treatment for
prostate cancer can we answer questions concerning which patients may
truly benefit. Such trials are currently under way in Sweden, England,
and the United States.14-17

AUTHOR INFORMATION  

Corresponding Author: Peter C. Albertsen, MD, MS, Division of Urology,
University of Connecticut Health Center, 263 Farmington Ave, Farmington,
CT 06030-3955 (albertsen{at}nso.uchc.edu).
Author Contributions: Dr Albertsen 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.
Study concept and design: Albertsen.
Acquisition of data: Albertsen, Fine.
Analysis and interpretation of data: Albertsen, Hanley.
Drafting of the manuscript: Albertsen, Hanley.
Critical revision of the manuscript for important intellectual content:
Albertsen, Hanley, Fine.
Statistical analysis: Hanley.
Obtained funding: Albertsen, Fine.
Administrative, technical, or material support: Albertsen, Fine.
Study supervision: Albertsen.
Financial Disclosures: None reported.
Funding/Support: This study was funded by grant HS09578 from the Agency
for Healthcare Research and Quality.
Role of the Sponsor: The Agency for Healthcare Research and Quality had
no role in the design and conduct of the study; in the collection,
management, analysis, and interpretation of the data; or in the
preparation, review, or approval of the manuscript. Certain data used in
this study were obtained from the Connecticut Tumor Registry in the
Connecticut Department of Public Health. The authors assume full
responsibility for analyses and interpretation of these data.
Author Affiliations: Division of Urology, University of Connecticut
Health Center, Farmington (Dr Albertsen and Ms Fine); and Department of
Epidemiology and Biostatistics, McGill University, Montreal, Quebec (Dr
Hanley).

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knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."
http://community.webtv.net/PALMER_ENT/doc