- Email: [email protected]
Female, Black, and Unmarried Patients Are More Likely to Present With Metastatic Bladder Urothelial Carcinoma
Original Study
Female, Black, and Unmarried Patients Are More Likely to Present With Metastatic Bladder Urothelial Carcinoma Zachary Klaassen, John M. DiBianco, Rita P. Jen, Austin J. Evans, Lael Reinstatler, Martha K. Terris, Rabii Madi Abstract To identify the demographic and clinical factors associated with bladder urothelial carcinoma metastasis at diagnosis, patients diagnosed from 2004 to 2010 were identified in the SEER database. Factors associated with metastasis at diagnosis included female gender, black race, unmarried, unemployed, and foreign-born status. Clinicians should be aware of these potential health care disparities in order to improve early care. Background: Although there are well-established risk factors for the diagnosis of bladder cancer, there is no consensus regarding risk factors for presentation of advanced or metastatic disease at diagnosis. The objective of this study was to identify the demographic and clinical factors associated with metastasis at diagnosis in patients with bladder urothelial carcinoma. Patients and Methods: Patients diagnosed with bladder urothelial carcinoma from 2004 to 2010 were identified in the Surveillance, Epidemiology, and End Results (SEER) database (n ¼ 108,417). The primary outcome was metastatic disease at the time of diagnosis. Demographic and socioeconomic variables were analyzed, and multivariable logistic regression models were performed to generate odds ratios (OR) for factors associated with metastasis at diagnosis. Results: Of patients with bladder cancer, 3018 (2.8%) had metastasis at diagnosis and 105,399 (97.2%) had nonmetastatic disease. Patients with metastatic disease at diagnosis were more frequently female (29.6% vs. 23.6%, P < .001), black (9.4% vs. 5.0%, P < .001), and unmarried (44.1% vs. 32.5%, P < .001) compared to patients with nonmetastatic disease. On multivariable analysis, the following characteristics were confirmed to be independently associated with metastatic disease at diagnosis: female gender (vs. male, OR 1.21), black race (vs. white, OR 1.71), unmarried (vs. married, OR 1.46), unemployed (OR 1.02), and foreign-born status (OR 1.01). Conclusion: Female gender, black race, unmarried, unemployed, and foreign-born status are independently associated with metastasis at diagnosis for bladder urothelial carcinoma. All clinicians should be aware of these potential health care disparities in order to involve social services and other support mechanisms in efforts to improve early care. Clinical Genitourinary Cancer, Vol. 14, No. 5, e489-92 ª 2016 Elsevier Inc. All rights reserved. Keywords: Bladder cancer, Marital status, Metastasis, Metastasis at diagnosis, SEER
Introduction Bladder cancer is the ninth most common malignancy worldwide, with an estimated 430,000 new cases diagnosed each year.1 The majority of cases are diagnosed as non-muscle-invasive disease, with a 5-year survival rate of 88% that decreases to 15% when there is metastatic Section of Urology, Medical College of Georgia, Augusta University, Augusta, GA Submitted: Dec 16, 2015; Revised: Apr 5, 2016; Accepted: Apr 11, 2016; Epub: Apr 29, 2016 Address for correspondence: Zachary Klaassen, MD, Department of Surgery, Section of Urology Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912 Fax: (706) 721-2548; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2016.04.006
progression.2 Furthermore, poor performance status and the presence of visceral metastasis are factors associated with worse prognosis in patients undergoing treatment for metastatic bladder urothelial carcinoma.3,4 These points emphasize the importance of early detection, stringent surveillance, adequate social work infrastructure, and identification of atrisk patients for metastases. Although there are well-established risk factors for the diagnosis of bladder cancer,5 there is no consensus regarding risk factors for presentation of advanced or metastatic disease at diagnosis. Previous studies have demonstrated that black race imparts a higher risk for metastasis at the time of diagnosis.6 However, other socioeconomic variables have not been investigated. Additionally, health care disparities continue to exist for bladder cancer despite interventions
Clinical Genitourinary Cancer October 2016
- e489
Metastatic Bladder Urothelial Carcinoma aimed at improving these inequalities.7,8 The objective of this study was to use a population-based cohort to identify demographic and socioeconomic factors associated with metastatic disease at diagnosis in patients with bladder urothelial carcinoma.
Materials and Methods
Variable
Study Population
Age, years, median (IQR)
Patients diagnosed with bladder cancer from 2004 to 2010 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The SEER database reports cancer-specific outcomes from specific geographic areas representing 28% of the US population.9 Patients 18 years of age with bladder urothelial carcinoma were identified utilizing the primary site codes C67.0 to C67.9, and International Classification of Diseases for Oncology, 9th edition (ICD-O), codes 8210/3, 8122/3, 8123/3, 8130/3, and 8131/3 (urothelial carcinoma) for a study cohort of 108,417 patients. Patients were divided into those with metastatic disease and those with nonmetastatic disease at the time of diagnosis.
Gender, n (%)
Description of Covariates Demographic variables of interest included age at diagnosis, gender, race (white vs. black vs. other), and marital status (married vs. single/ divorced/widowed [SDW]). Socioeconomic variables included county data for family income, percentage of persons living in poverty, educational attainment (percentage with less than ninth-grade education), percentage unemployment, and percentage foreign-born status. Insurance status (insured vs. any government insurance vs. uninsured) was also investigated for data available from 2007 to 2010.
Statistical Analysis Descriptive statistics for demographic and socioeconomic variable comparisons were performed by the Student t test for continuous variables and the chi-square test for categorical variables. Multivariable logistic regression models were performed to generate odds ratios (OR) for the identification of factors associated with metastasis at diagnosis. The model was constructed and analyses were performed using backward selection, removing all insignificant variables until the best-fit model was achieved. Models were assessed for confounding and interaction. Statistical analyses were performed by SAS 9.4 (SAS Institute, Cary, NC). All tests were 2 sided; statistical significance was defined as P < .05.
Results Population Sociodemographics There were 3018 patients (2.8%) who had metastasis at diagnosis and 105,399 patients (97.2%) who had nonmetastatic disease. Patients with metastatic disease were more often female (29.6% vs. 23.6%, P < .001), black (9.4% vs. 5.0%, P < .001), and had SDW marital status (44.1% vs. 32.5%, P < .001) compared to patients with nonmetastatic disease at diagnosis (Table 1). Furthermore, patients with metastatic disease at diagnosis were more frequently residing in a county with a higher percentage of people living in poverty (P ¼ .001), unemployed (P < .001), poorly educated (P < .001), and foreign born (P < .001) (Table 2). Patients with metastatic disease at diagnosis were also less likely to have medical insurance (81.4 vs. 86.3%) and more likely to have government insurance (12.5 vs. 6.2%) compared to those without metastatic disease (P < .001).
e490
Table 1 Demographics of Patients With Bladder Urothelial Carcinoma Stratified by Metastasis at Diagnosis
-
Clinical Genitourinary Cancer October 2016
Female
Metastasis at No Metastasis at Diagnosis Diagnosis (n [ 3018) (n [ 105,399) 72 (17)
72 (17) 24,906 (23.6)
2125 (70.4)
80,493 (76.4)
White
2610 (86.5)
94,668 (89.8)
Black
283 (9.4)
5268 (5.0)
Other
122 (4.0)
4010 (3.8)
3 (0.1)
1453 (1.4)
<.001
Race, n (%)
Unknown
<.001
Marital Status, n (%) Married
1576 (52.2)
63,936 (60.7)
SDW
1332 (44.1)
34,224 (32.5)
110 (3.7)
7239 (6.8)
Unknown
.80 <.001
893 (29.6)
Male
P
Abbreviations: IQR ¼ interquartile range; SDW ¼ single, divorced, widowed.
Factors Associated With Metastatic Disease at Diagnosis Independent factors associated with metastasis at diagnosis included female gender (vs. male; OR, 1.21; 95% confidence interval [CI], 1.11-1.32; P < .001), black race (vs. white; OR 1.71; 95% CI, 1.50-1.95; P < .001), SDW status (vs. married; OR, 1.46; 95% CI, 1.35-1.58; P < .001), being unemployed (OR, 1.02; 95% CI, 1.00-1.03; P ¼ .02) and being foreign born (OR, 1.01; 95% CI, 1.00-1.01; P < .001) (Table 3).
Table 2 Socioeconomic Data of Patients With Bladder Urothelial Carcinoma Stratified by Metastasis at Diagnosis
Variable Family income, $, median (IQR) % Persons < poverty, median (IQR)
Metastasis at No Metastasis at Diagnosis Diagnosis (n [ 3018) (n [ 105,399)
P
67,450 (22,350) 68,880 (23,420)
.02
13.01 (5.77)
12.74 (6.38)
<.001
% Unemployed, median (IQR)
9.19 (2.34)
9.02 (2.13)
<.001
Percentage with less than ninth-grade education, median (IQR)
6.13 (5.91)
5.76 (5.19)
<.001
16.40 (16.39)
14.38 (16.22)
<.001
% Foreign born, median (IQR)
<.001
Insurance Status, n (%)a Insured Any government insurance
1479 (81.4)
52,908 (86.3)
227 (12.5)
3818 (6.2)
Uninsured
52 (2.9)
999 (1.6)
Unknown
58 (3.2)
3612 (5.9)
Abbreviation: IQR ¼ interquartile range. a Data from 2007-2010 (n ¼ 1816 for metastasis at diagnosis; n ¼ 61,337 for no metastasis at diagnosis).
Zachary Klaassen et al Discussion The current SEER analysis found that 2.8% of patients with bladder urothelial carcinoma present with metastatic disease. Among these patients, female gender, black race, unmarried status, unemployed, and foreign-born status were independent factors associated with metastasis at diagnosis. These results for bladder cancer, in contrast to other neoplastic diseases, failed to correlate age with advanced disease.10-12 Male gender, which has been associated with advanced disease at the time of diagnosis for both urologic and nonurologic cancers,5 also failed to correlate with metastatic disease in patients with bladder urothelial carcinoma. Previous reports have suggested that women diagnosed with bladder cancer more commonly have invasive disease13-15 and may have worse cancer-specific outcomes compared to men.2,16 However, despite women having more advanced tumor stage, nodal metastasis, and a greater likelihood of receiving adjuvant chemotherapy, Soave et al15 reported similar stage-specific survival among 517 European men and women undergoing radical cystectomy. A number of studies have suggested that delayed hematuria evaluation has contributed to more advanced disease stages in women.16,17 Garg et al17 analyzed 35,646 patients > 65 years of age in the SEEReMedicare database with a hematuria claim in the year before bladder cancer diagnosis. They found that time to a urology visit was longer for women (hazard ratio, 0.9; 95% CI, 0.87-0.92) and that women were more likely to have a delayed (> 30 day) hematuria evaluation (OR, 1.13; 95% CI, 1.07-1.21) compared to men. Although these studies suggest that delay in diagnosis may contribute to poorer outcomes,16,17 they do not specifically address patients with metastatic disease at diagnosis. The current study found that female gender was an independent factor for metastasis at diagnosis and may offer an alternative suggestion that the poorer prognosis for female patients may be associated with advanced disease at presentation. These reasons are likely multifactorial and may include the lower incidence of bladder cancer in women and a lower index of suspicion by physicians because of the high number of women with voiding symptoms unrelated to malignancy. African American race has historically been accepted as a risk factor for advanced disease at diagnosis for multiple neoplasms,18-22 predominantly as a result of poor access to care due to
Table 3 Factors Associated With Metastatic Disease at Diagnosis Odds Ratio (95% Confidence Interval)a
P
Age
0.99 (0.99-1.01)
.25
Female vs. male
1.21 (1.11-1.32)
<.001
Black vs. white
1.71 (1.50-1.95)
<.001
Other vs. white
1.05 (0.87-1.28)
.03
SDW vs. married
1.46 (1.35-1.58)
<.001
% Unemployed
1.02 (1.00-1.03)
.02
% Foreign born
1.01 (1.00-1.01)
<.001
Variable
Race
Abbreviation: SDW ¼ single, divorced, widowed. a Adjusted for age, gender, race, marital status, percentage unemployed, and percentage foreign born.
socioeconomic status.6,7 Indeed, in a SEER study from 1975 to 2005 assessing stage- and grade-specific outcomes stratified by race, blacks presented with higher-stage disease and had worse diseasespecific survival (70.2% vs. 82.8%) compared to whites.21 Furthermore, a National Cancer Data Base study of patients with bladder urothelial carcinoma from 1993 to 2007 reported that black and female patients had a higher proportion of muscle-invasive malignancies and poorer survival outcomes compared to male and white patients.22 The current study is consistent with previous studies, finding black race to be an independent factor for metastasis at diagnosis for bladder urothelial carcinoma. Despite knowledge of these racial disparities, further work and intervention are required to improve these outcomes.7,8 The role of marital status has been well established as a prognostic factor for cancer patients including bladder cancer.23-26 Compared to unmarried patients, married patients have improved outcomes and are less likely to present with advanced disease.10,23,27 Pruthi et al26 proposed that married individuals present earlier in the course of their disease because their partners prompt them to seek care, thus leading to earlier diagnosis and treatment. The current study contributes support to this hypothesis, as patients with metastasis at diagnosis were more often unmarried compared to patients without metastasis. Health care providers caring for unmarried patients with bladder cancer should be aware of advanced disease in these patients, as careful questioning may reveal a more extensive duration of symptoms and raise suspicion of metastatic disease, prompting earlier staging studies. Uninsured and/or government-funded (ie, Medicaid) patients may also be at risk for advanced disease at diagnosis.10-12,19,28,29 Similarly, we found a greater proportion of patients with metastatic disease at diagnosis had government insurance or were uninsured. Additionally, patients with metastasis at diagnosis were more likely to reside in counties with higher unemployment and were more likely to be foreign born. These results may indicate that uninsured patients, poorly educated patients, and patients of lower socioeconomic status may not receive appropriate evaluation and/or follow-up care necessary for diagnosing and treating bladder cancer.7,30 Increasingly, urology practices are choosing to deny treatment of certain patients because of financial implications, resulting in patient referrals to government-sponsored and indigent-care facilities. Delays in bladder cancer treatment have been previously shown to result in inferior outcomes.31 This transfer of care requires a level of administrative vigilance that may lead to evaluation and treatment delays if this infrastructure is not present. Furthermore, this highlights the necessity for early implementation of social support systems and clinical navigators to obtain medical records, confirm appointments, and communicate with patients facing numerous financial and social roadblocks accessing care. Ultimately, all clinicians should be aware of risk factors associated with underserved patients and consider a higher level of suspicion and vigilance when evaluating and treating bladder cancer.12 The strengths of the current study include the large sample size and sufficient data to permit exploration of multivariable analysis for factors associated with metastasis at diagnosis in patients with bladder urothelial carcinoma. However, this study is not without limitations. First, as with any other retrospective analysis of a large administrative database, SEER does not identify known risk factors
Clinical Genitourinary Cancer October 2016
- e491
Metastatic Bladder Urothelial Carcinoma for bladder cancer, in particular smoking status and occupational exposure. Second, the SEER database does not contain information relating to patient comorbidities, which may be an unaccounted confounding factor in the causal association between the identified risk factors in this study and metastasis at diagnosis. Third, for marital status, the SEER database does not provide sufficient data to the length of marriage, marital satisfaction, unmarried cohabitation relationships, or long-term same-sex relationships. Finally, the socioeconomic factors analyzed are based on county-level data as a proxy for individual patients.
Conclusion Female gender, black race, unmarried status, unemployed, and foreign-born status are independently associated with metastasis at the time of diagnosis for bladder urothelial carcinoma. Consistent with other nonurologic malignancies, surrogates of poor socioeconomic status are associated with metastatic disease at presentation. Clinicians should be aware of the correlation between these risk factors and presentation of advanced disease at diagnosis, highlighting potential health care disparities and providing an opportunity to involve social services and other support mechanisms in an effort to improve early care.
Clinical Practice Points Although there are well-established risk factors for the diagnosis
of bladder cancer, there is no consensus regarding risk factors for presentation of advanced or metastatic disease at diagnosis. Patients with metastatic disease at diagnosis were more frequently female, black, and unmarried compared to patients with nonmetastatic disease. On multivariable analysis, female gender, black race, unmarried, unemployed, and foreign-born status were independently associated with metastatic disease at diagnosis. All clinicians should be aware of these potential health care disparities in order to involve social services and other support mechanisms in efforts to improve early care.
Disclosure The authors have stated that they have no conflict of interest.
References 1. Cancer Research UK. Worldwide cancer incidence map. 2011. Available at: http:// publications.cancerresearchuk.org/downloads/product/CS_INFOG_WORLD_INC. pdf. Accessed: June 5, 2015. 2. Lynch CF, Davila JA, Platz CE. Cancer of the urinary bladder. In: Ries YJ, Keel GE, Eisner MP, et al, eds. SEER Survival Monograph: Cancer Survival Among Adults: US SEER Program, 1988-2001, Patient and Tumor Characteristics. Bethesda, MD: National Cancer Institute, SEER Program; 2007. 3. Taguchi S, Nakagawa T, Hattori M, et al. Prognostic factors for metastatic urothelial carcinoma undergoing cisplatin-based salvage chemotherapy. Jpn J Clin Oncol 2013; 43:923-8.
e492
-
Clinical Genitourinary Cancer October 2016
4. Galsky MD, Moshier E, Krege S, et al. Nomogram for predicting survival in patients with unresectable and/or metastatic urothelial cancer who are treated with cisplatin-based chemotherapy. Cancer 2013; 119:3012-9. 5. Wood DP. Urothelial tumors of the bladder. In: Wein AJ, Kavoussi LR, Novick AC, eds. Campbell-Walsh Urology. 10th ed. Philadelphia, PA: Elsevier Saunders; 2012:2309-34. 6. Prout GR Jr, Wesley MN, Greenberg RS, et al. Bladder cancer: race differences in extent of disease at diagnosis. Cancer 2000; 89:1349-58. 7. Jacobs BL, Montgomery JS, Zhang Y, et al. Disparities in bladder cancer. Urol Oncol 2012; 30:81-8. 8. Aizer AA, Wilhite TJ, Chen MH, et al. Lack of reduction in racial disparities in cancer-specific mortality over a 20-year period. Cancer 2014; 120:1532-9. 9. National Cancer Institute. Surveillance, Epidemiology and End Results program. Available at: http://seer.cancer.gov/. Accessed: May 8, 2016. 10. Smith EC, Ziogas A, Anton-Culver H. Association between insurance and socioeconomic status and risk of advanced stage Hodgkin lymphoma in adolescents and young adults. Cancer 2012; 118:6179-87. 11. Marlow NM, Halpern MT, Pavluck AL, et al. Disparities associated with advanced prostate cancer stage at diagnosis. J Health Care Poor Underserved 2010; 21:112-31. 12. Macleod U, Mitchell ED, Burgess C, et al. Risk factors for delayed presentation and referral of symptomatic cancer: evidence for common cancers. Br J Cancer 2009; 101(suppl 2):S92-101. 13. Mungan NA, Aben KK, Schoenberg MP, et al. Gender differences in stageadjusted bladder cancer survival. Urology 2000; 55:876-80. 14. Brookfield KF, Cheung MC, Gomez C, et al. Survival disparities among African American women with invasive bladder cancer in Florida. Cancer 2009; 115: 4196-209. 15. Soave A, Dahlem R, Hansen J, et al. Gender-specific outcomes of bladder cancer patients: a stage-specific analysis in a contemporary, homogenous radical cystectomy cohort. Eur J Surg Oncol 2015; 41:368-77. 16. Cohn JA, Vekhter B, Lyttle C, et al. Sex disparities in diagnosis of bladder cancer after initial presentation with hematuria: a nationwide claims-based investigation. Cancer 2014; 120:555-61. 17. Garg T, Pinheiro LC, Atoria CL, et al. Gender disparities in hematuria evaluation and bladder cancer diagnosis: a population based analysis. J Urol 2014; 192: 1072-7. 18. Sun M, Abdollah F, Liberman D, et al. Racial disparities and socioeconomic status in men diagnosed with testicular germ cell tumors: a survival analysis. Cancer 2011; 117:4277-85. 19. Roetzheim RG, Pal N, Tennant C, et al. Effects of health insurance and race on early detection of cancer. J Natl Cancer Inst 1999; 91:1409-15. 20. Chow WH, Shuch B, Linehan WM, et al. Racial disparity in renal cell carcinoma patient survival according to demographic and clinical characteristics. Cancer 2013; 119:388-94. 21. Yee DS, Ishill NM, Lowrance WT, et al. Ethnic differences in bladder cancer survival. Urology 2011; 78:544-9. 22. Mallin K, David KA, Carroll PR, et al. Transitional cell carcinoma of the bladder: racial and gender disparities in survival (1993 to 2002), stage and grade (1993 to 2007). J Urol 2011; 185:1631-6. 23. Harvei S, Kravdal O. The importance of marital and socioeconomic status in incidence and survival of prostate cancer. An analysis of complete Norwegian birth cohorts. Prev Med 1997; 26:623-32. 24. Gore JL, Kwan L, Saigal CS, et al. Marriage and mortality in bladder carcinoma. Cancer 2005; 104:1188-94. 25. Sammon JD, Morgan M, Djahangirian O, et al. Marital status: a genderindependent risk factor for poorer survival after radical cystectomy. BJU Int 2012; 110:1301-9. 26. Pruthi RS, Lentz AC, Sand M, Kouba E, Wallen EM. Impact of marital status in patients undergoing radical cystectomy for bladder cancer. World J Urol 2009; 27: 573-6. 27. Meng L, Maskarinec G, Wilkens L. Ethnic differences and factors related to breast cancer survival in Hawaii. Int J Epidemiol 1997; 26:1151-8. 28. DeSantis C, Jemal A, Ward E. Disparities in breast cancer prognostic factors by race, insurance status, and education. Cancer Causes Control 2010; 21:1445-50. 29. Philips BU Jr, Gong G, Hargrave KA, et al. Correlation of the ratio of metastatic to non-metastatic cancer cases with the degree of socioeconomic deprivation among Texas counties. Int J Health Geogr 2011; 10:12. 30. Bjurlin MA, Cohn MR, Freeman VL, et al. Ethnicity and smoking status are associated with awareness of smoking related genitourinary diseases. J Urol 2012; 188:724-8. 31. Gore JL, Lai J, Setodji CM, et al. Mortality increases when radical cystectomy is delayed more than 12 weeks: results from a Surveillance, Epidemiology, and End ResultseMedicare analysis. Cancer 2009; 115:988-96.
Female, Black, and Unmarried Patients Are More Likely to Present With Metastatic Bladder Urothelial Carcinoma Zachary Klaassen, John M. DiBianco, Rita P. Jen, Austin J. Evans, Lael Reinstatler, Martha K. Terris, Rabii Madi Abstract To identify the demographic and clinical factors associated with bladder urothelial carcinoma metastasis at diagnosis, patients diagnosed from 2004 to 2010 were identified in the SEER database. Factors associated with metastasis at diagnosis included female gender, black race, unmarried, unemployed, and foreign-born status. Clinicians should be aware of these potential health care disparities in order to improve early care. Background: Although there are well-established risk factors for the diagnosis of bladder cancer, there is no consensus regarding risk factors for presentation of advanced or metastatic disease at diagnosis. The objective of this study was to identify the demographic and clinical factors associated with metastasis at diagnosis in patients with bladder urothelial carcinoma. Patients and Methods: Patients diagnosed with bladder urothelial carcinoma from 2004 to 2010 were identified in the Surveillance, Epidemiology, and End Results (SEER) database (n ¼ 108,417). The primary outcome was metastatic disease at the time of diagnosis. Demographic and socioeconomic variables were analyzed, and multivariable logistic regression models were performed to generate odds ratios (OR) for factors associated with metastasis at diagnosis. Results: Of patients with bladder cancer, 3018 (2.8%) had metastasis at diagnosis and 105,399 (97.2%) had nonmetastatic disease. Patients with metastatic disease at diagnosis were more frequently female (29.6% vs. 23.6%, P < .001), black (9.4% vs. 5.0%, P < .001), and unmarried (44.1% vs. 32.5%, P < .001) compared to patients with nonmetastatic disease. On multivariable analysis, the following characteristics were confirmed to be independently associated with metastatic disease at diagnosis: female gender (vs. male, OR 1.21), black race (vs. white, OR 1.71), unmarried (vs. married, OR 1.46), unemployed (OR 1.02), and foreign-born status (OR 1.01). Conclusion: Female gender, black race, unmarried, unemployed, and foreign-born status are independently associated with metastasis at diagnosis for bladder urothelial carcinoma. All clinicians should be aware of these potential health care disparities in order to involve social services and other support mechanisms in efforts to improve early care. Clinical Genitourinary Cancer, Vol. 14, No. 5, e489-92 ª 2016 Elsevier Inc. All rights reserved. Keywords: Bladder cancer, Marital status, Metastasis, Metastasis at diagnosis, SEER
Introduction Bladder cancer is the ninth most common malignancy worldwide, with an estimated 430,000 new cases diagnosed each year.1 The majority of cases are diagnosed as non-muscle-invasive disease, with a 5-year survival rate of 88% that decreases to 15% when there is metastatic Section of Urology, Medical College of Georgia, Augusta University, Augusta, GA Submitted: Dec 16, 2015; Revised: Apr 5, 2016; Accepted: Apr 11, 2016; Epub: Apr 29, 2016 Address for correspondence: Zachary Klaassen, MD, Department of Surgery, Section of Urology Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912 Fax: (706) 721-2548; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2016.04.006
progression.2 Furthermore, poor performance status and the presence of visceral metastasis are factors associated with worse prognosis in patients undergoing treatment for metastatic bladder urothelial carcinoma.3,4 These points emphasize the importance of early detection, stringent surveillance, adequate social work infrastructure, and identification of atrisk patients for metastases. Although there are well-established risk factors for the diagnosis of bladder cancer,5 there is no consensus regarding risk factors for presentation of advanced or metastatic disease at diagnosis. Previous studies have demonstrated that black race imparts a higher risk for metastasis at the time of diagnosis.6 However, other socioeconomic variables have not been investigated. Additionally, health care disparities continue to exist for bladder cancer despite interventions
Clinical Genitourinary Cancer October 2016
- e489
Metastatic Bladder Urothelial Carcinoma aimed at improving these inequalities.7,8 The objective of this study was to use a population-based cohort to identify demographic and socioeconomic factors associated with metastatic disease at diagnosis in patients with bladder urothelial carcinoma.
Materials and Methods
Variable
Study Population
Age, years, median (IQR)
Patients diagnosed with bladder cancer from 2004 to 2010 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The SEER database reports cancer-specific outcomes from specific geographic areas representing 28% of the US population.9 Patients 18 years of age with bladder urothelial carcinoma were identified utilizing the primary site codes C67.0 to C67.9, and International Classification of Diseases for Oncology, 9th edition (ICD-O), codes 8210/3, 8122/3, 8123/3, 8130/3, and 8131/3 (urothelial carcinoma) for a study cohort of 108,417 patients. Patients were divided into those with metastatic disease and those with nonmetastatic disease at the time of diagnosis.
Gender, n (%)
Description of Covariates Demographic variables of interest included age at diagnosis, gender, race (white vs. black vs. other), and marital status (married vs. single/ divorced/widowed [SDW]). Socioeconomic variables included county data for family income, percentage of persons living in poverty, educational attainment (percentage with less than ninth-grade education), percentage unemployment, and percentage foreign-born status. Insurance status (insured vs. any government insurance vs. uninsured) was also investigated for data available from 2007 to 2010.
Statistical Analysis Descriptive statistics for demographic and socioeconomic variable comparisons were performed by the Student t test for continuous variables and the chi-square test for categorical variables. Multivariable logistic regression models were performed to generate odds ratios (OR) for the identification of factors associated with metastasis at diagnosis. The model was constructed and analyses were performed using backward selection, removing all insignificant variables until the best-fit model was achieved. Models were assessed for confounding and interaction. Statistical analyses were performed by SAS 9.4 (SAS Institute, Cary, NC). All tests were 2 sided; statistical significance was defined as P < .05.
Results Population Sociodemographics There were 3018 patients (2.8%) who had metastasis at diagnosis and 105,399 patients (97.2%) who had nonmetastatic disease. Patients with metastatic disease were more often female (29.6% vs. 23.6%, P < .001), black (9.4% vs. 5.0%, P < .001), and had SDW marital status (44.1% vs. 32.5%, P < .001) compared to patients with nonmetastatic disease at diagnosis (Table 1). Furthermore, patients with metastatic disease at diagnosis were more frequently residing in a county with a higher percentage of people living in poverty (P ¼ .001), unemployed (P < .001), poorly educated (P < .001), and foreign born (P < .001) (Table 2). Patients with metastatic disease at diagnosis were also less likely to have medical insurance (81.4 vs. 86.3%) and more likely to have government insurance (12.5 vs. 6.2%) compared to those without metastatic disease (P < .001).
e490
Table 1 Demographics of Patients With Bladder Urothelial Carcinoma Stratified by Metastasis at Diagnosis
-
Clinical Genitourinary Cancer October 2016
Female
Metastasis at No Metastasis at Diagnosis Diagnosis (n [ 3018) (n [ 105,399) 72 (17)
72 (17) 24,906 (23.6)
2125 (70.4)
80,493 (76.4)
White
2610 (86.5)
94,668 (89.8)
Black
283 (9.4)
5268 (5.0)
Other
122 (4.0)
4010 (3.8)
3 (0.1)
1453 (1.4)
<.001
Race, n (%)
Unknown
<.001
Marital Status, n (%) Married
1576 (52.2)
63,936 (60.7)
SDW
1332 (44.1)
34,224 (32.5)
110 (3.7)
7239 (6.8)
Unknown
.80 <.001
893 (29.6)
Male
P
Abbreviations: IQR ¼ interquartile range; SDW ¼ single, divorced, widowed.
Factors Associated With Metastatic Disease at Diagnosis Independent factors associated with metastasis at diagnosis included female gender (vs. male; OR, 1.21; 95% confidence interval [CI], 1.11-1.32; P < .001), black race (vs. white; OR 1.71; 95% CI, 1.50-1.95; P < .001), SDW status (vs. married; OR, 1.46; 95% CI, 1.35-1.58; P < .001), being unemployed (OR, 1.02; 95% CI, 1.00-1.03; P ¼ .02) and being foreign born (OR, 1.01; 95% CI, 1.00-1.01; P < .001) (Table 3).
Table 2 Socioeconomic Data of Patients With Bladder Urothelial Carcinoma Stratified by Metastasis at Diagnosis
Variable Family income, $, median (IQR) % Persons < poverty, median (IQR)
Metastasis at No Metastasis at Diagnosis Diagnosis (n [ 3018) (n [ 105,399)
P
67,450 (22,350) 68,880 (23,420)
.02
13.01 (5.77)
12.74 (6.38)
<.001
% Unemployed, median (IQR)
9.19 (2.34)
9.02 (2.13)
<.001
Percentage with less than ninth-grade education, median (IQR)
6.13 (5.91)
5.76 (5.19)
<.001
16.40 (16.39)
14.38 (16.22)
<.001
% Foreign born, median (IQR)
<.001
Insurance Status, n (%)a Insured Any government insurance
1479 (81.4)
52,908 (86.3)
227 (12.5)
3818 (6.2)
Uninsured
52 (2.9)
999 (1.6)
Unknown
58 (3.2)
3612 (5.9)
Abbreviation: IQR ¼ interquartile range. a Data from 2007-2010 (n ¼ 1816 for metastasis at diagnosis; n ¼ 61,337 for no metastasis at diagnosis).
Zachary Klaassen et al Discussion The current SEER analysis found that 2.8% of patients with bladder urothelial carcinoma present with metastatic disease. Among these patients, female gender, black race, unmarried status, unemployed, and foreign-born status were independent factors associated with metastasis at diagnosis. These results for bladder cancer, in contrast to other neoplastic diseases, failed to correlate age with advanced disease.10-12 Male gender, which has been associated with advanced disease at the time of diagnosis for both urologic and nonurologic cancers,5 also failed to correlate with metastatic disease in patients with bladder urothelial carcinoma. Previous reports have suggested that women diagnosed with bladder cancer more commonly have invasive disease13-15 and may have worse cancer-specific outcomes compared to men.2,16 However, despite women having more advanced tumor stage, nodal metastasis, and a greater likelihood of receiving adjuvant chemotherapy, Soave et al15 reported similar stage-specific survival among 517 European men and women undergoing radical cystectomy. A number of studies have suggested that delayed hematuria evaluation has contributed to more advanced disease stages in women.16,17 Garg et al17 analyzed 35,646 patients > 65 years of age in the SEEReMedicare database with a hematuria claim in the year before bladder cancer diagnosis. They found that time to a urology visit was longer for women (hazard ratio, 0.9; 95% CI, 0.87-0.92) and that women were more likely to have a delayed (> 30 day) hematuria evaluation (OR, 1.13; 95% CI, 1.07-1.21) compared to men. Although these studies suggest that delay in diagnosis may contribute to poorer outcomes,16,17 they do not specifically address patients with metastatic disease at diagnosis. The current study found that female gender was an independent factor for metastasis at diagnosis and may offer an alternative suggestion that the poorer prognosis for female patients may be associated with advanced disease at presentation. These reasons are likely multifactorial and may include the lower incidence of bladder cancer in women and a lower index of suspicion by physicians because of the high number of women with voiding symptoms unrelated to malignancy. African American race has historically been accepted as a risk factor for advanced disease at diagnosis for multiple neoplasms,18-22 predominantly as a result of poor access to care due to
Table 3 Factors Associated With Metastatic Disease at Diagnosis Odds Ratio (95% Confidence Interval)a
P
Age
0.99 (0.99-1.01)
.25
Female vs. male
1.21 (1.11-1.32)
<.001
Black vs. white
1.71 (1.50-1.95)
<.001
Other vs. white
1.05 (0.87-1.28)
.03
SDW vs. married
1.46 (1.35-1.58)
<.001
% Unemployed
1.02 (1.00-1.03)
.02
% Foreign born
1.01 (1.00-1.01)
<.001
Variable
Race
Abbreviation: SDW ¼ single, divorced, widowed. a Adjusted for age, gender, race, marital status, percentage unemployed, and percentage foreign born.
socioeconomic status.6,7 Indeed, in a SEER study from 1975 to 2005 assessing stage- and grade-specific outcomes stratified by race, blacks presented with higher-stage disease and had worse diseasespecific survival (70.2% vs. 82.8%) compared to whites.21 Furthermore, a National Cancer Data Base study of patients with bladder urothelial carcinoma from 1993 to 2007 reported that black and female patients had a higher proportion of muscle-invasive malignancies and poorer survival outcomes compared to male and white patients.22 The current study is consistent with previous studies, finding black race to be an independent factor for metastasis at diagnosis for bladder urothelial carcinoma. Despite knowledge of these racial disparities, further work and intervention are required to improve these outcomes.7,8 The role of marital status has been well established as a prognostic factor for cancer patients including bladder cancer.23-26 Compared to unmarried patients, married patients have improved outcomes and are less likely to present with advanced disease.10,23,27 Pruthi et al26 proposed that married individuals present earlier in the course of their disease because their partners prompt them to seek care, thus leading to earlier diagnosis and treatment. The current study contributes support to this hypothesis, as patients with metastasis at diagnosis were more often unmarried compared to patients without metastasis. Health care providers caring for unmarried patients with bladder cancer should be aware of advanced disease in these patients, as careful questioning may reveal a more extensive duration of symptoms and raise suspicion of metastatic disease, prompting earlier staging studies. Uninsured and/or government-funded (ie, Medicaid) patients may also be at risk for advanced disease at diagnosis.10-12,19,28,29 Similarly, we found a greater proportion of patients with metastatic disease at diagnosis had government insurance or were uninsured. Additionally, patients with metastasis at diagnosis were more likely to reside in counties with higher unemployment and were more likely to be foreign born. These results may indicate that uninsured patients, poorly educated patients, and patients of lower socioeconomic status may not receive appropriate evaluation and/or follow-up care necessary for diagnosing and treating bladder cancer.7,30 Increasingly, urology practices are choosing to deny treatment of certain patients because of financial implications, resulting in patient referrals to government-sponsored and indigent-care facilities. Delays in bladder cancer treatment have been previously shown to result in inferior outcomes.31 This transfer of care requires a level of administrative vigilance that may lead to evaluation and treatment delays if this infrastructure is not present. Furthermore, this highlights the necessity for early implementation of social support systems and clinical navigators to obtain medical records, confirm appointments, and communicate with patients facing numerous financial and social roadblocks accessing care. Ultimately, all clinicians should be aware of risk factors associated with underserved patients and consider a higher level of suspicion and vigilance when evaluating and treating bladder cancer.12 The strengths of the current study include the large sample size and sufficient data to permit exploration of multivariable analysis for factors associated with metastasis at diagnosis in patients with bladder urothelial carcinoma. However, this study is not without limitations. First, as with any other retrospective analysis of a large administrative database, SEER does not identify known risk factors
Clinical Genitourinary Cancer October 2016
- e491
Metastatic Bladder Urothelial Carcinoma for bladder cancer, in particular smoking status and occupational exposure. Second, the SEER database does not contain information relating to patient comorbidities, which may be an unaccounted confounding factor in the causal association between the identified risk factors in this study and metastasis at diagnosis. Third, for marital status, the SEER database does not provide sufficient data to the length of marriage, marital satisfaction, unmarried cohabitation relationships, or long-term same-sex relationships. Finally, the socioeconomic factors analyzed are based on county-level data as a proxy for individual patients.
Conclusion Female gender, black race, unmarried status, unemployed, and foreign-born status are independently associated with metastasis at the time of diagnosis for bladder urothelial carcinoma. Consistent with other nonurologic malignancies, surrogates of poor socioeconomic status are associated with metastatic disease at presentation. Clinicians should be aware of the correlation between these risk factors and presentation of advanced disease at diagnosis, highlighting potential health care disparities and providing an opportunity to involve social services and other support mechanisms in an effort to improve early care.
Clinical Practice Points Although there are well-established risk factors for the diagnosis
of bladder cancer, there is no consensus regarding risk factors for presentation of advanced or metastatic disease at diagnosis. Patients with metastatic disease at diagnosis were more frequently female, black, and unmarried compared to patients with nonmetastatic disease. On multivariable analysis, female gender, black race, unmarried, unemployed, and foreign-born status were independently associated with metastatic disease at diagnosis. All clinicians should be aware of these potential health care disparities in order to involve social services and other support mechanisms in efforts to improve early care.
Disclosure The authors have stated that they have no conflict of interest.
References 1. Cancer Research UK. Worldwide cancer incidence map. 2011. Available at: http:// publications.cancerresearchuk.org/downloads/product/CS_INFOG_WORLD_INC. pdf. Accessed: June 5, 2015. 2. Lynch CF, Davila JA, Platz CE. Cancer of the urinary bladder. In: Ries YJ, Keel GE, Eisner MP, et al, eds. SEER Survival Monograph: Cancer Survival Among Adults: US SEER Program, 1988-2001, Patient and Tumor Characteristics. Bethesda, MD: National Cancer Institute, SEER Program; 2007. 3. Taguchi S, Nakagawa T, Hattori M, et al. Prognostic factors for metastatic urothelial carcinoma undergoing cisplatin-based salvage chemotherapy. Jpn J Clin Oncol 2013; 43:923-8.
e492
-
Clinical Genitourinary Cancer October 2016
4. Galsky MD, Moshier E, Krege S, et al. Nomogram for predicting survival in patients with unresectable and/or metastatic urothelial cancer who are treated with cisplatin-based chemotherapy. Cancer 2013; 119:3012-9. 5. Wood DP. Urothelial tumors of the bladder. In: Wein AJ, Kavoussi LR, Novick AC, eds. Campbell-Walsh Urology. 10th ed. Philadelphia, PA: Elsevier Saunders; 2012:2309-34. 6. Prout GR Jr, Wesley MN, Greenberg RS, et al. Bladder cancer: race differences in extent of disease at diagnosis. Cancer 2000; 89:1349-58. 7. Jacobs BL, Montgomery JS, Zhang Y, et al. Disparities in bladder cancer. Urol Oncol 2012; 30:81-8. 8. Aizer AA, Wilhite TJ, Chen MH, et al. Lack of reduction in racial disparities in cancer-specific mortality over a 20-year period. Cancer 2014; 120:1532-9. 9. National Cancer Institute. Surveillance, Epidemiology and End Results program. Available at: http://seer.cancer.gov/. Accessed: May 8, 2016. 10. Smith EC, Ziogas A, Anton-Culver H. Association between insurance and socioeconomic status and risk of advanced stage Hodgkin lymphoma in adolescents and young adults. Cancer 2012; 118:6179-87. 11. Marlow NM, Halpern MT, Pavluck AL, et al. Disparities associated with advanced prostate cancer stage at diagnosis. J Health Care Poor Underserved 2010; 21:112-31. 12. Macleod U, Mitchell ED, Burgess C, et al. Risk factors for delayed presentation and referral of symptomatic cancer: evidence for common cancers. Br J Cancer 2009; 101(suppl 2):S92-101. 13. Mungan NA, Aben KK, Schoenberg MP, et al. Gender differences in stageadjusted bladder cancer survival. Urology 2000; 55:876-80. 14. Brookfield KF, Cheung MC, Gomez C, et al. Survival disparities among African American women with invasive bladder cancer in Florida. Cancer 2009; 115: 4196-209. 15. Soave A, Dahlem R, Hansen J, et al. Gender-specific outcomes of bladder cancer patients: a stage-specific analysis in a contemporary, homogenous radical cystectomy cohort. Eur J Surg Oncol 2015; 41:368-77. 16. Cohn JA, Vekhter B, Lyttle C, et al. Sex disparities in diagnosis of bladder cancer after initial presentation with hematuria: a nationwide claims-based investigation. Cancer 2014; 120:555-61. 17. Garg T, Pinheiro LC, Atoria CL, et al. Gender disparities in hematuria evaluation and bladder cancer diagnosis: a population based analysis. J Urol 2014; 192: 1072-7. 18. Sun M, Abdollah F, Liberman D, et al. Racial disparities and socioeconomic status in men diagnosed with testicular germ cell tumors: a survival analysis. Cancer 2011; 117:4277-85. 19. Roetzheim RG, Pal N, Tennant C, et al. Effects of health insurance and race on early detection of cancer. J Natl Cancer Inst 1999; 91:1409-15. 20. Chow WH, Shuch B, Linehan WM, et al. Racial disparity in renal cell carcinoma patient survival according to demographic and clinical characteristics. Cancer 2013; 119:388-94. 21. Yee DS, Ishill NM, Lowrance WT, et al. Ethnic differences in bladder cancer survival. Urology 2011; 78:544-9. 22. Mallin K, David KA, Carroll PR, et al. Transitional cell carcinoma of the bladder: racial and gender disparities in survival (1993 to 2002), stage and grade (1993 to 2007). J Urol 2011; 185:1631-6. 23. Harvei S, Kravdal O. The importance of marital and socioeconomic status in incidence and survival of prostate cancer. An analysis of complete Norwegian birth cohorts. Prev Med 1997; 26:623-32. 24. Gore JL, Kwan L, Saigal CS, et al. Marriage and mortality in bladder carcinoma. Cancer 2005; 104:1188-94. 25. Sammon JD, Morgan M, Djahangirian O, et al. Marital status: a genderindependent risk factor for poorer survival after radical cystectomy. BJU Int 2012; 110:1301-9. 26. Pruthi RS, Lentz AC, Sand M, Kouba E, Wallen EM. Impact of marital status in patients undergoing radical cystectomy for bladder cancer. World J Urol 2009; 27: 573-6. 27. Meng L, Maskarinec G, Wilkens L. Ethnic differences and factors related to breast cancer survival in Hawaii. Int J Epidemiol 1997; 26:1151-8. 28. DeSantis C, Jemal A, Ward E. Disparities in breast cancer prognostic factors by race, insurance status, and education. Cancer Causes Control 2010; 21:1445-50. 29. Philips BU Jr, Gong G, Hargrave KA, et al. Correlation of the ratio of metastatic to non-metastatic cancer cases with the degree of socioeconomic deprivation among Texas counties. Int J Health Geogr 2011; 10:12. 30. Bjurlin MA, Cohn MR, Freeman VL, et al. Ethnicity and smoking status are associated with awareness of smoking related genitourinary diseases. J Urol 2012; 188:724-8. 31. Gore JL, Lai J, Setodji CM, et al. Mortality increases when radical cystectomy is delayed more than 12 weeks: results from a Surveillance, Epidemiology, and End ResultseMedicare analysis. Cancer 2009; 115:988-96.