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To examine the association of major types of comorbidity with late-stage prostate cancer, a random sample of 11,083 men diagnosed with prostate cancer during 2002-2007 was taken from the Florida Cancer Data System. Individual-level covariates included demographics, primary insurance payer, and comorbidity following the Elixhauser Index. Socioeconomic variables were extracted from Census 2000 data and merged to the individual level data. Provider-to-case ratio at county level was alsocomputed. Multilevel logistic regression was used to assess associations between these factors and late-stage diagnosis of prostate cancer. Higher odds of late-stage diagnosis was significantly related to presence of comorbidities, being unmarried, current smoker, uninsured, and diagnosed in not-for-profit hospitals. The study reported that the presence of certain comorbidities, specifically 10 out of the 45, was associated with late-stage prostate cancer diagnosis. Eight out of 10 significant comorbid conditions were associated with greater risk of being diagnosed at late-stage prostate cancer. On the other hand, men who had chronic pulmonary disease, and solid tumor without metastasis, were less likely to be diagnosed with late-stage prostate cancer. Late-stage diagnosis was associated with comorbidity, which is often associated with increased health care utilization. The association of comorbidity with late-stage prostate cancer diagnosis suggests that individuals with significant comorbidity should be offered routine screening for prostate cancer rather than focusing only on managing symptomatic health problems.
Prostate cancer is the most common solid malignancy and the second leading cause of cancer-related death for American men. It has been estimated that there will be 233,000 new cases and 29,480 deaths from this disease in the United States in 2014 (American Cancer Society, 2013). The State of Florida ranks second behind California for both incidence (16,590 estimated new cases) and mortality (2,170 estimated deaths) from prostate cancer in 2014 (American Cancer Society, 2013).
Striking racial and ethnic differences in incidence and mortality persist in the United States and the State of Florida. Racial differences are greater for prostate cancer than for any other major cancer sites (e.g., colorectal and lung). Prostate cancer incidence rates are approximately 60% higher for African Americans than for non-Hispanic Whites, and death rate are twice higher for African Americans than any other racial/ethnic group (American Cancer Society, 2013).
Previous studies attempted to explain racial differences in prostate cancer incidence and mortality. Tumor grade, stage of disease at diagnosis, and differences in access to definitive and adjuvant treatment contribute to mortality (Marlow, Halpern, Pavluck, Ward, & Chen, 2010; Shavers & Brown, 2002; Shavers et al., 2004; Tewari et al., 2005). Diet and cooking practices, selenium intake, exposure to pesticides and fertilizers, physical activity, use of health care services, genetic susceptibility, and both individual-level and area-level socioeconomic status (SES) are linked to racial difference in prostate cancer incidence (Brawley, Knopf, & Thompson, 1998; Klassen et al., 2004; Klassen & Platz, 2006; M. N. Oliver, Smith, Siadaty, Hauck, & Pickle, 2006). A growing body of evidence supports the association of prostate cancer risk to farming due to exposure to toxic chemicals, especially pesticides (Alavanja et al., 2003; Meyer, Coker, Sanderson, & Symanski, 2007; Settimi, Masina, Andrion, & Axelson, 2003). Geographical disparities in late-stage diagnosis have been associated with poor access to primary health care, lack of health insurance, and difference in coverage (Mandelblatt, Yabroff, & Kerner, 1999; Mullins, Blatt, Gbarayor, Yang, & Baquet, 2005; Roetzheim et al., 1999; Talcott et al., 2007).
Another important correlate of late-stage diagnosis is the presence and severity of comorbidity. Comorbidity is the co-occurrence of one or more diseases or disorders in an individual (Bartsch et al., 1992; Siu, Lau, Tam, & Shiu, 2002). Comorbidity reflects the aggregate effect of all clinical conditions a patient might have, excluding the disease of primary interest (Arcangeli, Smith, Ratliff, & Catalona, 1997). In other cancer sites, comorbidity was reported to be an important consideration in both screening and early detection as well as treatment decision making (Siddiqui & Gwede, 2012). Effective management of chronic diseases such as prostate cancer often presents enormous challenges (Boeglin, Wessels, & Henshel, 2006). Clinicians and patients alike can be overwhelmed by the need to address comorbid chronic conditions in addition to patients’ prostate cancer–specific treatment goals. Ignoring concurrent disease management, however, can lead to ineffective control of prostate cancer-specific risk factors and may miss opportunities to improve patients’ functioning and quality of life and to decrease mortality risk (Knapp, Quist, Walton, & Miller, 2005).
To our knowledge, no retrospective studies have investigated the risk of late-stage prostate cancer taking into consideration individual characteristics including comorbidities, area-level characteristics, and availability of health care resources. Although a previous study examined the disparities in prostate cancer diagnosis among racial/ethnic groups and across Florida for the period 1996-2002 (Xiao, Tan, & Goovaerts, 2011), the study did not account for comorbidity, which may have an impact on stage of diagnosis and, subsequently, affect treatment and outcomes. The objective of this study was to examine association of major types of comorbidity with late-stage prostate cancer in Florida, using both individual- and area-level characteristics.
Men aged 40 years or older who were diagnosed with prostate cancer in the State of Florida between January 1, 2002 and December 31, 2007, were the focus of this study.
The study used data from four sources. First, prostate cancer incidence data for years 2002-2007 were obtained from the State of Florida Department of Health, which contracts with Florida Cancer Data System (FCDS) housed at the University of Miami. The FCDS was established as the state central cancer registry in 1981 and is the largest single population-based cancer incidence registry in the nation (Florida Department of Health, 2014). The FCDS contains 2.3 million cancer records, 3.5 million discharge records, and 3.1 million mortality records. The FCDS has been part of the Centers for Disease Control and Prevention National Program of Cancer Registries since 1996. The FCDS has met or exceeded the highest standard of completeness, quality, and timeliness set by the North American Association of Central Cancer Registries since 2002. The FCDS collects information on patient demographics, residence, prostate tumor characteristics, and other information such as tobacco use and primary payer of health insurance.
Second, data on sociodemographic characteristics and presence of farmhouse were extracted at the census tract level from the U.S. Census Bureau (Census 2000, Summary File 3) public use files for the State of Florida.
Third, health provider information by county was obtained from the Florida Department of Health Division of Medical Quality Assurance to calculate provider-to-case ratios. Specifically, the number of primary health providers and urologists was divided by the number of diagnosed prostate cancer cases for each county during 2002-2007. This measure was used to capture provider availability.
Fourth, comorbidity data were obtained from the Florida Agency for Health Care and Administration (AHCA). AHCA maintains two databases (Hospital Patient Discharge Data and Ambulatory Outpatient Data) on all patient encounters within hospitals and freestanding ambulatory surgical and radiation therapy centers in Florida. Comorbidity was computed following the Elixhauser Index method (Elixhauser, Steiner, Harris, & Coffey, 1998) based on diagnoses information from AHCA. Comorbidity index for prostate cancer patients linking state cancer registry with inpatient and outpatient data was constructed, and further details on the linkage process are provided elsewhere (Xiao et al., 2013). The version of the comorbidity software provided by the Healthcare Cost and Utilization Project was valid for the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and diagnosis-related groups (DRGs) effective October 1, 2000. To capture comorbidity condition, the analysis started on January 1, 2002. A time window of 1 year before and 1 year after prostate cancer diagnosis date was used to capture inpatient admissions and outpatient visits for any diseases other than prostate cancer or its complications. All diagnoses of diseases independent of prostate cancer and its possible complications during this 2-year time window were included for comorbidity computation (Xiao et al., 2013). The following rule was adopted to distinguish if a metastatic cancer should or should not be considered as a comorbidity: If prostate stage is localized, then any metastatic cancer in AHCA data is a comorbidity; if prostate stage is late, then metastatic cancers of the lymph nodes (ICD-9 code: 196), bone (spine and ribs, 198.5), brain (198.3), and lung (197.0) in AHCA data should not be considered as a morbidity (Xiao et al., 2013).
The study used a total of 45 conditions, including 29 from the Elixhauser Index plus 16 new additional conditions based on prevalent clinical characteristics of the study population. A detailed list of those conditions can be found in another publication from the same authors (Xiao et al., 2013). Data obtained from the four sources were merged into a single data set for analyses, representing one record per patient.
Characteristics of the study population were examined using descriptive statistics. Bivariate associations between diagnosis stage and other covariates were assessed using chi-square or Fisher’s exact test. The associations between major comorbidity categories and late-stage prostate cancer diagnosis in Florida were assessed using a multilevel logistic model.
The response variable in logistic regression was stage of prostate cancer diagnosis, categorized as early or late. Surveillance Epidemiology and End Results summary staging was used to classify prostate cancer stages based on FCDS coding. If the patient was diagnosed with localized prostate cancer, tumor stage was labeled as earlystage, whereas if the patient was diagnosed with regional or distant then tumor stage was labeled as late-stage. Explanatory variables were available at three levels (individual, census tract, and county). Individual-level characteristics included age, race, marital status, tobacco use, health insurance, year of diagnosis, comorbidity, and characteristics of the medical facility where the patient was diagnosed. Using the primary payer code, each case was allocated to one of the following three health insurance types: public, private, and uninsured. If the primary payer was Medicare, Medicaid, Department of Defense (tricare), military personnel (military), Veterans Affairs, or Indian/Public Health Service then health insurance type was defined as public health insurance. Private insurance includes managed care, health maintenance organization, preferred provider organization or fee-for-services. If the patient did not have public insurance or private insurance at the time of diagnosis then this person was categorized as uninsured. At the census tract level, median household income expressed in thousands of dollars and presence of farmhouse was included. Presence of farmhouse was used to capture some aspects of the agricultural exposure to potential toxic substance. Last, provider availability was computed at the county level as the ratio of primary health providers and urologists to prostate cancer cases.
To account for heterogeneity across counties and across census tracts, a census tract-level random intercept as well as a county-level random intercept were included in the logistic regression model. The chance of prostate cancer late-stage diagnosis was then modeled through the following equation:
where pijk = P(Yijk = 1) is the probability that diagnosis was late-stage, and Yijk is the stage outcome of the kth person from the jth census tract located in the ith county. In the above model, represents covariate vector measured at three geographical levels (i.e., individual, census tract and county), the regression coefficient vector is β, and vi and uij denote the county-level and census tract-level random intercepts, respectively. The random intercepts vi and uij were assumed to be independent realizations of zero-mean normal distributions with variance and , respectively. The two distributions were assumed to be independent.
Likelihood ratio test was used for assessing whether uij and vi should be dropped from the model; this is equivalent to testing whether an independent logistic model is appropriate. The model with county and census tract random intercepts significantly improved model with independent observation assumption (χ2 = 8.90, p = .0043). This suggests that a logistic regression model with independent observation assumption would not be adequate. Therefore, county and census tract random intercepts were included in the final model. Odds ratios for explanatory variables were calculated. The statistical analyses were performed using SAS/STAT® software, Version 9.3, of the SAS System for Windows. GLIMMIX procedure was used for multilevel modeling.
Demographic characteristics of the study population and bivariate associations with diagnosis stage are summarized in Table 1. A total of 11,083 men diagnosed with prostate cancer in Florida during 2002-2007 were included in the study, among which 1,404 were diagnosed as late-stage, and 8,653 patients had at least one coexisting condition in the study population. Average age at diagnosis for patients with early-stage diagnosis was 66.31 years and that for patients with late-stage diagnosis was 66.30 years. Among early-stage patients 1,119 were Black and among late-stage patients 221 were Black, which generated a significantly higher proportion of Black patients in the late-stage diagnosis category (p < .0001). Most cases were married (n = 7,758 for early stage, n = 1,018 for late stage) and self-reported as noncurrent smokers (n = 8,201 for early stage, n = 1,108 for late stage). The majority of the sample used public insurance (n = 5,531 for early stage, n = 789 for late stage) and were diagnosed in not-for-profit facilities (n = 7,034 for early stage, n = 1,091 for late stage). The majority of cases were diagnosed in hospitals (n = 9,390 for early stage, n = 1,397 for late stage).
Results of multilevel logistic regression are reported in Table 2. At the individual level, being unmarried, current tobacco user, and uninsured were associated with elevated odds of late-stage diagnosis. Cases diagnosed at non–profit-taking facilities were more likely to be late-stage diagnoses. Compared with men diagnosed in hospital, those who were diagnosed in ambulatory settings were 76% less likely to be diagnosed with late-stage prostate cancer (odds ratio [OR] = 0.240, p = .0004).
At the census tract level, individuals living in a poor neighborhood were associated with a higher likelihood of late-stage prostate cancer diagnosis (OR = 0.996, p = .0576), although the p value of this effect was not significant. Specifically, the odds of being diagnosed with late-stage prostate cancer were 0.4% lower per additional $1,000 in median household income.
Among all comorbidities considered, presence of congestive heart failure, metastatic cancer, fluid and electrolyte disorders, deficiency anemias, infection, skin and subcutaneous tissue disease, musculoskeletal and connective tissue disease, and brain and other neurological disorders were associated with higher odds of late-stage prostate cancer. Presence of chronic pulmonary circulation disease (OR = 0.760, p = .0115), and solid tumor without metastasis (OR = 0.404, p < .0001) were associated with reduced odds of late-stage diagnosis. None of the interactions tested was significant; hence they were not included in the model.
Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States (American Cancer Society, 2013). The association between comorbidity and prostate cancer has been a public health issue for a long time (Alibhai, Naglie, Nam, Trachtenberg, & Krahn, 2003; Post et al., 1999). This study attempted to explain whether the presence of comorbid conditions is associated with prostate cancer stage at diagnosis by using a population-based registry linked with disease diagnosis information for prostate cancer patients.
The study reported that presence of certain comorbidities, specifically 10 out of the 45, was associated with late-stage prostate cancer diagnosis. Eight out of 10 significant comorbid conditions were associated with greater risk of being diagnosed at late-stage. On the other hand, men who had chronic pulmonary disease and solid tumor without metastasis were less likely to be diagnosed with late-stage prostate cancer. Some comorbidities in the Elixhauser Index, such as weight loss, may be etiologically related to other comorbid conditions or late-stage prostate cancer. Such variables were included in the list of comorbidities because the administrative data provided by the AHCA did not provide information to discern the etiology of these conditions. Comorbidity has important implications for prostate cancer screening and management, particularly for older men, who commonly have multiple health conditions. However, the mechanisms behind the relationship between comorbidities and late-stage prostate cancer diagnosis are unclear. It might be possible that individuals with severe comorbidities are more likely to be engaged with the health care system and may be more likely to be tested for prostate cancer. On the other hand individuals with significant comorbidity may not be offered routine screening, including for prostate cancer. The focus may be toward management of existing health problems rather than routine screening (Siddiqui & Gwede, 2012). Additionally, comorbidities could cover symptoms of prostate cancer, and delay earlier diagnosis. The relationship between comorbidity and PCa screening warrant further investigation in light of the U.S. Preventive Services Task Force (2013) recommendation against prostate-specific antigen screening, on the basis that there is moderate or high certainty that the harms outweigh the benefits (U.S. Preventive Services Task Force, 2013).
A particular strength of the study is the linkage of cancer registry data with patient diagnosis information in addition to prostate cancer. The linkage enabled the researchers to have a whole picture of patients in terms of their disease profile instead of just cancer diagnosis. This provided additional data modifiers, including comorbid conditions, improved follow-up, socioeconomic details, and health care access information.
Married men were less likely to be diagnosed at late-stage compared with unmarried men. This finding suggests that being married confers a substantial protective effect in preventing late-stage prostate cancer diagnosis. The unfavorable effect of unmarried marital status on disease stage has been confirmed in prostate cancer and several other malignancies (Abdollah et al., 2011; Campbell et al., 2001; Osborne, Ostir, Du, Peek, & Goodwin, 2005; Wang, Wilson, Stewart, & Hollenbeak, 2011).
Our findings on smoking confirm the detrimental effect of tobacco use on late-stage prostate cancer diagnosis. The relation between smoking and many cancers is established, but its role in prostate cancer is not clear (U.S. Department of Health and Human Services, 2014). The tobacco-related biologic mechanisms most commonly considered to explain how smoking could cause or accelerate the course of prostate cancer involve cadmium. Cadmium is thought to be present in tobacco smoke due to the use of phosphate fertilizers that contain cadmium on tobacco plants. However, this relationship is not clearly established (Chen et al., 2009; Verougstraete, Lison, & Hotz, 2003).
Consistent with past studies (Bennett et al., 1998; Halpern et al., 2008; Jones et al., 2008; Vijayakumar, Weichselbaum, Vaida, Dale, & Hellman, 1996), men without health insurance had worse diagnoses than those with coverage. This finding reinforce the fact that having health insurance is a crucial factor for receiving appropriate cancer screening and timely access to medical care (Fedewa, Etzioni, Flanders, Jemal, & Ward, 2010; Marlow et al., 2010).
Other studies reported that hospital characteristics play an important role in the variations in the early diagnosis of prostate cancer cases as well as outcomes from the disease (Barbiere et al., 2012; Chornokur, Dalton, Borysova, & Kumar, 2011; Jayadevappa, Chhatre, Johnson, & Malkowicz, 2011). Men diagnosed in for–profit facilities were less likely to be diagnosed at late-stage. The study indicated that patients diagnosed with prostate cancer in ambulatory settings were 76% less likely to have late-stage diagnosis (OR = 0.240, p = .0004). The data elements that we had in our possession did not allow distinguishing between private and public hospitals. However, a study reported that being diagnosed in private hospital is associated with early-stage prostate cancer diagnosis, higher use of surgery, and lower use of radiotherapy (Barbiere et al., 2012). Research on the effects of hospital characteristics and ownership on prostate cancer diagnosis is needed to confirm our findings.
At the census tract level, higher median household income was associated with lower likelihood of late-stage diagnosis, which confirms findings from other studies (Clegg et al., 2009). Because low SES is known to affect access to care, income level has been hypothesized to explain the observed difference in stage at diagnosis for prostate cancer (Bennett et al., 1998; J. A. S. Oliver, Grindel, DeCoster, Ford, & Martin, 2011). Opportunities for early detection of prostate cancer are suggested to be lower for low-income men because of financial, cultural, and social factors and distance to care (Barber et al., 1998; Holmes et al., 2012; Steele, Miller, Maylahn, Uhler, & Baker, 2000).
The current study has a number of limitations. Census tract and county-level data were used due to lack of some individual-level information that would have provided richer information for the analyses. Large databases like the FCDS, however, are not without limitations. The data used for this study were from cases diagnosed from 2002 through 2007; therefore the observations made in this analysis may not necessarily reflect the most current trends.
In conclusion, disparities in late-stage diagnosis based on race, SES, and comorbidities continue to exist in prostate cancer. Racial and socioeconomic disparities may partly be explained by the lack of access to care and problems of delayed diagnosis. This research identifies segments of the population that may benefit from targeting interventions. Efforts to narrow these disparities must include earlier diagnosis of prostate cancer in Black men, uninsured men, smokers, men of low SES, and those who have certain comorbid conditions. Comorbidity information must be incorporated into the mainstream of prostate cancer clinical research and in clinical trials to evaluate cancer treatment options for older men.
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by Grant #RSGT-10-082-01-CPHPS from the American Cancer Society.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.