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1 fax (615) 936-8291
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3 david.penson @vanderbilt.edu
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5 Word Count: 3604 Abstract: 299 Number of Tables: 2 Number of Figures: 3
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ABSTRACT
care to men with early-stage prostate cancer, but mortality risks associated with
Objective: To determine the impact of age, comorbidity, and tumor risk on other-cause
twelve major comorbid conditions, tumor characteristics, initial treatment, and overall
and disease-specific mortality through 14-year follow up. Survival analyses accounting
Results: Fourteen-year cumulative other-cause mortality was 24%, 33%, 46%, and 57%,
for men with comorbidity counts of 0, 1, 2, and 3+, respectively. For men diagnosed at
age 65, subhazard ratios (95%CI) for other-cause mortality among men with 1, 2, or 3+
comorbidities (vs. none) were 1.2 (1.0–1.5), 2.0 (1.6–2.4), and 2.6 (2.1–3.2), respectively.
With each decade increase in age, the subhazard of other-cause mortality associated
with each comorbidity count doubled; in men with 3+ comorbidities, subhazard ratios
(95%CI) for ages 65 and 75 (vs. 55) were 2.0 (1.6–2.5) and 4.0 (2.7–6.1). In men with
3+ comorbidities, ten-year other-cause mortality rates were 26%, 40%, and 71% for
those aged ≤60, 61–74, and ≥75 at diagnosis, respectively. Prostate cancer mortality
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disease(18%) and did not vary by co-morbidity count will all groups having 10-11%
Conclusions: Older men with multiple major comorbidities are at high risk of other-cause
mortality within ten years of diagnosis. Such men should consider this information when
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INTRODUCTION
Men with a new diagnosis of clinically localized prostate cancer are faced with numerous
treatment options, ranging from no initial therapy (watchful waiting or active surveillance)
to aggressive therapy with surgery and radiation. The first question a newly diagnosed
the survival benefits of aggressive treatment for low- and intermediate-risk disease are
delayed for eight to ten years (1), clinical guidelines recommend that men with a life
expectancy of shorter than ten years be spared the morbidity and expense of aggressive
treatment (2,3).
making for men with prostate cancer, physicians remain poor judges of prognosis (4);
this often leads to inappropriate treatment decisions. Recent retrospective data have
shown that men with Charlson scores of 3 or greater are treated aggressively with
surgery or radiation more often than not, despite a 70% other-cause mortality rate at
eight years after diagnosis (5). This practice may be due to several reasons. First, the
long-term risk of other-cause mortality associated with different ages and comorbidity
states remains unclear. The current data on risk of other-cause mortality associated with
comorbidity are either from institutional case series (6-9) or from populations treated
with only one treatment modality(10); to our knowledge, to date there has been no true
comorbidity in U.S. prostate cancer patients. Second, the current instruments used to
clinical setting. Lastly, little data simultaneously integrate risk assessment for both
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cancer-specific and other-cause mortality and include relevant variables to predict both,
In this study, we sought to characterize the association of comorbidity, age, and tumor
our comorbidity assessment to a count of twelve major conditions to allow for easy
translation to the clinical setting. We hoped to identify groups of men that have a high
risk of other-cause mortality and low risk of prostate cancer-specific mortality, so that
these men might better understand the risks and benefits of various therapeutic
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METHODS
Study Participants
men diagnosed with prostate cancer ascertained from the National Cancer Institute
Surveillance, Epidemiology, and End Results (SEER) program. Details of the PCOS
have been published previously (11). In brief, the study includes men diagnosed with
prostate cancer between October 1, 1994 and October 31, 1995 who resided in an area
covered by one of six SEER tumor registries: the states of Connecticut; Utah; and New
Mexico; and the metropolitan areas of Atlanta, Georgia; Los Angeles County, California;
and King County, Washington (Seattle). All men aged 39 to 89 years were eligible
except in King County, where inclusion was limited to men aged 60 to 89 years. Subjects
were identified within 6 months of diagnosis using a Rapid Case Ascertainment System.
Population attrition is reported in Appendix Figure 1. A total of 3,533 (62%) of the eligible
men completed the 6 or 12 month survey. The institutional review board of each
For the current analysis, we included all men in PCOS with non-metastatic prostate
cancer at diagnosis. We excluded men with nodal or distant metastases, those without
Data Collection
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All patients included in this analysis completed a baseline survey within 6 months of
Medical record data. All participants underwent a review of their medical records at one
and five years after diagnosis. Abstractors obtained demographic information, clinical
Specific Antigen (PSA), Gleason score, and clinical stage), and primary treatment type.
Treatment types were defined as aggressive therapy (surgery, external beam radiation
treatment, and vital status were collected from the SEER registries.
Comorbidity Index (12). In the current analysis, comorbidity was expressed as a count of
the following twelve major conditions at the time of diagnosis: Diabetes, bleeding
gastrointestinal ulcer, chronic lung disease, congestive heart failure (CHF), stroke,
bowel disease, hypertension, and depression. Subjects answered yes/no for each of
these comorbidities on the baseline survey. Responses were not validated by chart
review.
Tumor characteristics. Tumors were stratified by clinical and pathological features using
the widely accepted D’Amico criteria, which utilize diagnostic PSA level, Gleason score,
and clinical stage at diagnosis to predict risk of progression, overall mortality, and
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cancer-specific mortality. Tumors are classified as low- (PSA < 10, clinical stage ≤ T2a,
and Gleason score ≤ 6), intermediate- (PSA 10-20, clinical stage T2b, or Gleason score
7), or high-risk (PSA > 20, clinical stage ≥ T2c, or Gleason score ≥ 8) (13, 14). Tumors
are categorized into higher risk strata by having at least one of the characteristics of that
stratum.
Vital status. Vital status and underlying cause of death were determined through 14
Statistical Analysis
We first grouped patients by comorbidity count (0, 1, 2, and 3+) and compared baseline
characteristics using the analysis of variance for continuous variables and chi-square
test for categorical variables. Cumulative incidence rates were computed for overall,
competing risk (15). A competing event eliminates a possibility of the primary event of
interest, and treating it as a mere censored observation would violate the non-
distributional hazard. As summarized by Dignam et. al, both approaches are valid and
informative, and the choice often depends on questions of interest (16). We choose to
use Fine and Gray model, which applies a regression modeling directly on a cumulative
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incidence function (CIF) and allows for estimation of the effect of covariates on the
CIF.We included comorbidity count, age, race, SEER site, D’Amico tumor risk, and
treatment type as covariates. An interaction term between age and comorbidity count
Fine and Gray (15). A weak evidence of violation of the assumption on the categorized
comorbidity counts was found for other-cause mortality (p=0.04); however, closer
seems to hold except for the very end of the study period (13+ years) where the data are
scarce. Similar trend was found for D’Amico tumor risk (p=0.02); only 94 patients were
categorized into the unknown group that causes assumption violation. For prostate
cancer mortality, proportional hazard assumption was likely to be violated for comorbidity
counts (p < 0.01), as well as age, SEER site, tumor risk and treatment type; however, for
this secondary endpoint we still present average subhazard ratios (18) to denote its
survival among men with higher comorbidity counts, we further analyzed the potential
level of 0.05 was used to denote statistical significance, and all tests were two-sided.
Statistical analyses were performed using R 2.14 (19), with cmprsk package (20) for
Funding Source
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This study was funded by grant R01CA114524 from the National Cancer Institute of the
National Institutes of Health. Dr. Daskivich is supported by grants from the Robert Wood
Johnson Clinical Scholars Foundation and American Urological Association. The various
funding sources had no role in the design, conduct, analysis, or decision to publish the
study.
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RESULTS
Baseline characteristics of the sample after stratification by comorbidity count are shown
in Table 1. Older men, and African American race/ethnicity, and those with higher tumor
risks tended to have higher comorbidity counts. Men with higher comorbidity counts
tended to be treated aggressively less often than those with lower comorbidity counts.
However, 256 of 419 men (61%) with comorbidity counts of 3 or greater were treated
Table 2. At fourteen years of follow-up, other-cause mortality estimates were 24%, 33%,
46%, and 57% for men with comorbidity counts of 0, 1, 2, and 3+, respectively.
other-cause mortality with higher comorbidity count. Accounting for age, race, SEER site,
tumor risk stratum, and type of treatment, the subhazards of other-cause mortality for
men with 1, 2, or 3+ comorbidities were 1.2 (95% CI 1.0–1.4), 1.7 (95% CI 1.4–2.0), and
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In order to illustrate the impact of increasing age on risk of other-cause mortality in men
mortality rates for men with three or more comorbidities across different age strata.
Among those with three or more comorbidities, men aged <60 years, 61-74 years, and
>75 years at diagnosis had ten-year other-cause mortality rates of 26% (17 of 65 men),
risk categories and comorbidity count—after stratification into younger (age <60),
intermediate (age 60–70), and older (age >70) groups—are illustrated in Figures 2 and 3.
In all age groups, the risk of other-cause mortality increased with greater comorbidity
count, and the risk of prostate cancer mortality increased with higher tumor risk-stratum.
In concordance with our multivariable models, the absolute impact of comorbidity on risk
of other-cause mortality was markedly less pronounced in men younger than 60,
compared with older men. Across the entire cohort, prostate cancer mortality was low in
men with low- (3%) and intermediate-risk (7%) disease but appreciable in men with high-
risk disease (18%). Proportions of men treated aggressively vs. non-aggressively within
each age/tumor risk subgroup are reported in Appendix Table 3. The risk of prostate
cancer mortality associated with tumor risk was similar across age groups.
disease. These treatments may, however, not be of as much value in men with more
comorbid conditions. Men with zero or one comorbidity who were managed
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conservatively had 2.4 (95% CI 1.6–3.5) and 2.2-fold (95% CI 1.5–3.3) increase
respectively in the subhazard of prostate cancer mortality compared with men treated
aggressively. Men with two or three or more comorbidities who were managed
conservatively did not have a statistically significant increase in prostate cancer mortality
we recapitulated our analysis including men who elected ADT as primary therapy in the
aggressive management group, effectively exploring the decision of any therapy vs none
whatsoever. The results were virtually the same, with the exception the competing risks
model analyzing the subhazard of prostate cancer mortality associated with no treatment
whatsoever. While men with no comorbid conditions still had a increased risk (hazard
ratio: 2.0, 95% CI 1.3-3.0), men with 1, 2 or 3+ co-morbid conditions were not at
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DISCUSSION
These results illustrate the contemporary long-term risks of other-cause and prostate
cancer mortality associated with age at diagnosis, comorbidity, and tumor risk in a
for men with newly diagnosed prostate cancer, since they are not limited by the selection
bias incurred by using single institutional (6-9) or modality-specific data (10). In fact,
several studies have shown that the risk of other-cause mortality associated with a given
comorbidity score increases in a stepwise manner when comparing men treated with
radical prostatectomy, radiation therapy, and watchful waiting (6, 21). Since men who
undergo surgery are generally younger, have better functional status, and have less
severe manifestations of disease than men who choose radiation therapy (and even
more so compared with those who choose watchful waiting), other-cause mortality rates
among men receiving surgery may be lower for a given comorbidity score than those
who choose radiation or watchful waiting. Using a population-based sample of men who
are balanced in age, tumor characteristics, and primary treatment will provide a more
population-based cohort best mimics the relevant clinical scenario: counseling a man
with newly diagnosed with clinically localized prostate cancer who has not yet made a
treatment decision.
Our data also verify the strong prognostic utility of comorbidity in predicting risk of other-
cause mortality and show that its prognostic strength persists even when comorbidity
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such as the Charlson comorbidity index (12), provide better risk stratification than a mere
count of comorbidities, but our data suggest that a count may be sufficient for assessing
may be essential for widespread application of these findings to the clinical setting.
We also found that the subhazard of other-cause mortality associated with a given
comorbidity count doubles with each decade of age at diagnosis above 55 years.
with double the risk compared with a man having an equal number of comorbidities but
aged 55 years at diagnosis. A man aged 75 years at diagnosis with 3+ comorbidities has
quadruple the risk of a similar 55-year-old. A simple frequency analysis mirrors this
relationship, showing 10-year other-cause mortality rates of 26%, 40%, and 71% for men
with 3 or greater comorbidities aged <60, 61 to 74, and >75 years at diagnosis,
respectively.
These data provide benchmarks for evaluating risk of prostate and other-cause mortality
among men with different baseline comorbidity, age, and tumor features. The decision of
individual's knowledge of and personal attitudes about potential benefits and harms;
therefore, the optimal risk ratio of prostate cancer vs. other-cause mortality may differ
from individual to individual. Regardless, our data provide a framework upon which all
patients can apply their own attitudes and assess their likelihood of treatment-related
benefit based on their age, comorbidity, and disease characteristics. However, from a
Services Task Force recommendations on cessation of screening and treatment for men
greater than 75 years (22) has established that men with less than a 10-year life
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expectancy (i.e. populations with greater than 50% other-cause mortality at ten years)
garner little or no benefit from aggressive treatment. Applying a similar cutoff for
comorbidity and age, our data show that men with 3+ comorbidities aged 60 and older
approach 50% mortality at 10 years after diagnosis. Therefore, given the low likelihood
of short-term prostate cancer mortality and high likelihood of other-cause mortality, older
men with more than 3 major comorbidities should strongly weigh the risk of dying from
other causes prior to realizing any potential survival benefit from aggressive therapy
an increased risk of prostate cancer mortality among comorbidity groups suggested that
men with two or more comorbidities may derive little survival benefit from aggressive
treatment. Men with two or more comorbidities did not have a statistically significant
with men treated aggressively, although we had limited power to discern differences.
Men with fewer than two comorbidities, however, did have a significant increase in risk.
men older than 65 who were treated aggressively vs. conservatively, which suggested a
survival benefit with aggressive treatment that persisted after correction for comorbidity
(23). This study also showed a benefit in prostate cancer-specific survival with
aggressive treatment after correction for propensity scoring alone, but propensity scores
should be treated as exploratory given that the analysis has limited power, that there is
likely a selection bias between groups treated aggressively and non-aggressively and
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Our study is limited by several methodological issues. First, the comorbidity assessment
physicians. However, numerous studies have shown that patient report of co-morbid
conditions, particularly common ones like those assessed here, is fairly reliable (24).
Second, because self-reporting of conditions does not allow for a detailed assessment of
comorbidity severity, a broad spectrum of disease is subsumed under each of the twelve
major comorbidity categories. Men with mild (or severe) disease manifestations may
have lower (or higher) rates of other-cause mortality than those estimated by our raw
other cancers at the time of diagnosis was not collected at the time of enrollment in
PCOS, so It is not included in our comorbidity count. Third, since the intake
questionnaire was completed within six months of diagnosis, it is possible that some
comorbid conditions may not have been present before treatment. However, the majority
of our twelve designated conditions are chronic in nature and should have been
apparent at the time of diagnosis. Fourth, a small proportion of men (32 men) were too
sick or lacked the capacity to fill out the intake questionnaire and were excluded from
PCOS; this may result in underestimation of other-cause mortality in the sickest men.
Fifth, since the majority of the cohort was treated aggressively for prostate cancer, rates
of prostate cancer mortality may be lower than if these men had been managed
conservatively, especially at more distant time points and for men with high-risk tumors.
However, for men with low- and intermediate-risk tumors, our estimates will
underestimate prostate cancer-specific mortality by less than 10% at ten years, based
men in a randomized controlled trial (1). Sixth, we did not collect information on length of
time from diagnosis to baseline survey and could not, therefore, conduct sensitivity
analyses on the assumption that no temporal bias related to comorbidity reporting was
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introduced into the study. Lastly, although current randomized controlled trial data
suggests that there is no significant survival benefit with aggressive treatment of early-
stage prostate cancer until 8 to 10 years after local therapy (1), further data on efficacy
When considering these data, the reader may be inclined to inappropriately apply the
results of these findings to the decision as to whether or not to screen for prostate
cancer screening (25). Unfortunately, these data do not inform this decision and should
not be used to decide whether or not to screen. While the risk of overtreatment (which is
driven primarily by the morbidity associated with aggressive therapy) is cited as one of
the risks of screening that led the panel to their conclusion, they do not state in their
recommendation that men who have been diagnosed with prostate cancer should or
should not undergo treatment. We strongly believe that the decisions to screen or to
treat prostate cancer are two separate entities and should always be considered
individually.
In summary, because the potential for morbidity is high, men with a new diagnosis of
prostate cancer should first understand the likely benefit vs. potential harm associated
with aggressive treatment. These data provide a basis upon which to counsel men
regarding their risk of prostate cancer-specific and other-cause mortality. Our data are
based on simple variables that are commonly available to the clinician at the time of
treatment decision: age, number of major comorbidities at diagnosis, and tumor risk.
Older men with multiple major comorbid conditions should be informed of their higher
probability of death from other causes before deriving a survival benefit from surgery or
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radiation therapy for low- and intermediate-risk disease. The information provided herein
aims to make the competing risks of mortality clearer to both patients and their
physicians.
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ACKNOWLEDGEMENTS
We wish to thank the men who participated in PCOS who, by their participation, have
We also thank the physicians in the six Surveillance, Epidemiology and End Results
areas who assisted us in the collection of data from their patients and from medical
records. We thank all the study managers and chart abstractors for their outstanding
efforts in data collection. Finally, we thank all the staff in the six cancer registries for their
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Address for Reprint Requests:
Timothy J. Daskivich, MD
Robert Wood Johnson Clinical Scholars
University of California, Los Angeles
7th Floor, Suite 710
10940 Wilshire Blvd
Los Angeles, CA 90024
Kang-Hsien Fan, MS
Vanderbilt University
571 Preston Research Building
Nashville, Tennessee 37232-6848
Peter C. Albertsen, MD
Chief and Program Director, Division of Urology
University of Connecticut Health Center
263 Farmington Avenue
Farmington, CT 06030– 3955
22
Associate Professor of Research, University of Southern California
Health Services Campus
SSB 318E
M/C 9239
Los Angeles, CA 90089-9239
Reproducible Research Statement: The authors of this study are commited to the
concept of reproducibility of medical research. Our methods section details our research
protcol and our statistical code was provided to the statisticians at Annals in order to
validate our results. Our detailed research protocol and statistical code may be made
available at the discretion of the corresponding author. Use of our dataset is restricted to
members of the PCOS study team and their designates.
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TABLE AND FIGURE LEGENDS
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