Use of Potentially Curative Therapies for Muscle-invasive Bladder Cancer in the United States: Results from the National Cancer Data Base

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1 EUROPEAN UROLOGY 63 (2013) available at journal homepage: Platinum Priority Bladder Cancer Editorial by Peter C. Black on pp of this issue Use of Potentially Curative Therapies for Muscle-invasive Bladder Cancer in the United States: Results from the National Cancer Data Base Phillip J. Gray a,b, Stacey A. Fedewa c, William U. Shipley a, *, Jason A. Efstathiou a, Chun Chieh Lin c, Anthony L. Zietman a, Katherine S. Virgo c,d a Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; b Harvard Radiation Oncology Program, Boston, MA, USA; c Health Services Research Program, American Cancer Society, Atlanta, GA, USA; d Department of Health Policy & Management, Emory University, Atlanta, GA, USA Article info Article history: Accepted November 7, 2012 Published online ahead of print on November 19, 2012 Keywords: Bladder cancer Genitourinary cancer Bladder-sparing therapy Radical cystectomy Abstract Background: Despite its lethal potential, many patients with muscle-invasive bladder cancer (MIBC) do not receive aggressive, potentially curative therapy consistent with established practice standards. Objective: To characterize the treatments received by patients with MIBC and analyze their use according to sociodemographic, clinical, pathologic, and facility measures. Design, setting, and participants: Using the National Cancer Data Base, we analyzed patients with MIBC (stages II IV) treated between 2004 and 2008, excluding those with ct4b tumors or distant metastases. Treatments included radical or partial cystectomy with or without chemotherapy (CT), chemoradiotherapy (CRT), radiation therapy (RT), or CT alone and observation following biopsy. Aggressive therapy (AT) was defined as radical or partial cystectomy or definitive RT/CRT (total dose 50 Gy). Outcome measurements and statistical analysis: AT use and correlating variables were assessed by multivariable, generalized estimating equation models adjusted for facility clustering. Results and limitations: According to the database, 52.5% of patients received AT; 44.9% were treated surgically, 7.6% received definitive CRT or RT, and 25.9% of patients received observation only. AT use decreased with advancing age (odds ratio [OR]: 0.34 for age yr vs 50 yr; p < 0.001). AT use was also lower in racial minorities (OR: 0.74 for black race; p < 0.001), the uninsured (OR: 0.73; p < 0.001), Medicaid-insured patients (OR: 0.81; p=0.01), and at low-volume centers (OR: 0.64 vs high-volume centers; p < 0.001). Use of AT was higher with increasing tumor stage (OR: 2.23 for T3/T4a vs T2; p < 0.001) and nonurothelial histology (OR: 1.25 and 1.43 for squamous and adenocarcinoma, respectively; p < 0.001). Study limitations include retrospective design and lack of information about patient and provider motivations regarding therapy selection. Conclusions: AT for MIBC appears underused, especially in the elderly and in groups with poor socioeconomic status. These data point to a significant unmet need to inform policy makers, payers, and physicians regarding appropriate therapies for MIBC. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Radiation Oncology, Massachusetts General Hospital, 55 Fruit Street, Cox 3, Boston, MA 02114, USA. Tel ; Fax: address: wshipley@partners.org (W.U. Shipley) /$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

2 824 EUROPEAN UROLOGY 63 (2013) Introduction Despite continued reduction in high-risk behaviors such as tobacco consumption, cancer of the urinary bladder remains the fourth most common cancer in men in the United States with an estimated new cases in both sexes diagnosed in 2012 [1]. Approximately 25% of patients present with muscle-invasive disease at diagnosis [2]. While noninvasive bladder cancer can be effectively managed with transurethral resection of the bladder tumor (TURBT) or localized therapies such as intravesical bacillus Calmette-Guérin, muscle-invasive bladder cancer (MIBC) has a high propensity for rapid growth and distant spread if not managed aggressively. The National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU) have recommended both radical cystectomy (RC) and radiation therapy (RT) (with the addition of chemotherapy [CT] if possible) as appropriate, curative, primary treatments for patients with MIBC [3,4]. RT is recognized as an effective and potentially curative treatment for MIBC in patients deemed unfit for surgery [5]. Additionally, use of this approach is a viable alternative to RC in carefully selected patients [3,4,6]. The use of chemoradiotherapy (CRT) or RT alone appears inferior to RC in some reports; however, these reports rarely define doses, timing, and intent of such therapy [3,7,8]. Indeed, other studies have shown similar 5-yr survival rates for patients treated with CRT or RT compared to cystectomy, though a prospective comparison has never been performed [9 11]. Use of RC and recent trends in surgical process of care measures derived from the National Cancer Data Base (NCDB) have recently been reported [12]. This report identified significant underuse of cystectomy in potentially eligible patients. Other reports have identified similar findings [7]. We hypothesized that decreased use of cystectomy may be due to more widespread adoption of RT-based approaches as supported by international guidelines. As such, our study seeks to provide a more in-depth look at the use of all aggressive and potentially curative therapies in patients with MIBC. 2. Patients and methods The NCDB, jointly sponsored by the American College of Surgeons and the American Cancer Society, is a hospital-based cancer registry that serves as a comprehensive, clinical, surveillance resource for cancer care in the United States [12,13]. The NCDB captures approximately 75% of new cancers in the United States each year. Data coding methods have been described previously [12]. For the purposes of this report, we extracted data from the NCDB on individuals receiving all or part of their first treatment course for MIBC at the reporting institution between January 1, 2004, and December 31, Patients with American Joint Committee on Cancer (AJCC) stage II IV cancer of the urinary bladder were included. Those with clinical or pathologic evidence of distant metastatic disease or those with clinical T4b tumors were excluded given the low cure rate in these patients, supporting a palliative approach to treatment. A total of patients met all of the study criteria. Of these, 528 patients with data missing on sex (n=10), facility type (n=202), region (n=54), insurance (n=95), or anatomic radiation treatment site (n=167) were excluded, leaving patients available for analysis. Demographic variables included patient sex and age at diagnosis. Race was categorized as non-hispanic white, Hispanic, black, other, or missing. Region of residence was recorded as one of four regions according to the US Census: Northeast, Midwest, South, and West [14]. Patient insurance was categorized as private, Medicaid (the US government health program for low-income individuals administered by individual states), young (aged yr) Medicare (the US government health program for the disabled and elderly), older Medicare (aged 65 yr), uninsured, or missing. Modified Charlson-Deyo scores (a measure of comorbidity across multiple organ sites, which can be captured using International Classification of Diseases, 9th revision, Clinical Modification [ICD-9-CM] codes) were calculated for each patient excluding their diagnosis of MIBC [15]. Hydronephrosis and hydroureter (identified using ICD-9-CM codes and ) were considered separately as comorbidities in our analysis. Facility type was categorized as community cancer center, comprehensive community cancer center, teaching/research institution, and US National Cancer Institute (NCI)- designated cancer center, as described previously [16]. Facility volume categories were created by dividing the number of patients with bladder cancer treated by an institution into hospital-specific tertiles of equal size, and for the purposes of this study are defined as low (1 137), medium ( ) and high ( ). Treatment modality was recorded according to Facility Oncology Registry Data standards. Primary modalities included RC, partial cystectomy (PC), RT or CT. The use of CT with RC or PC was divided into neoadjuvant or adjuvant based on receipt before or after surgery within 180 days respectively. RT was subdivided into definitive RT (total dose 50 Gy) and palliative RT (<50 Gy). When CT was used within 180 days of definitive RT this was defined as definitive CRT. Observation was defined as any patient who did not receive RC, PC, CT or RT and includes those treated with one or more TURBT. Any patient without full data regarding treatments received was labeled missing. Aggressive therapy (AT) was defined as any therapy with a reasonable likelihood of providing cure as supported by international guidelines. For the purposes of this study, this included (1) RC or PC with or without the use of CT or (2) any definitive radiotherapy-based regimen. Primary-field radiation does and any boost or cone-down dose (dose to the primary delivered with a reduction in field size) was summed and only total dose is reported. Multivariable generalized estimating equation models were used identify independent variables associated with the receipt of AT. Patients with unknown or missing treatment details were excluded from the models (n=2902). An exchangeable correlation matrix was used to adjust for patient clustering within an individual facility (n=1325 facilities) using the SAS Genmod procedure, as described previously [17]. Statistical comparison of data was performed using a two-tailed chisquare test. Statistical analysis was performed using SAS v.9.2 (SAS Institute Inc., Cary, NC, USA). 3. Results Treatments received by the patients analyzed are shown in Table 1. RC without the use of pre- or postoperative CT was the most common treatment received (28.7%). Neoadjuvant CT was used in only 1.9% of cases; adjuvant CT was recorded in 10.7% of patients. Only 3.7% of patients underwent PC and the use of CT with PC was rare. In total, 44.9% of patients received some form of open or laparoscopic surgical therapy. Definitive CRT was used in 5.3% of cases; RT alone was used in 3.8% of cases: 2.3% of patients received definitive RT (dose 50 Gy) and 1.5% received low-dose palliative RT. CT alone (with or without palliative radiation) was used in 10% of patients; 7432

3 EUROPEAN UROLOGY 63 (2013) Table 1 Muscle-invasive bladder cancer treatments, Treatment type No. % Radical cystectomy Without chemotherapy With neoadjuvant chemotherapy With adjuvant chemotherapy Partial cystectomy Without chemotherapy With neoadjuvant chemotherapy With adjuvant chemotherapy Radiotherapy Definitive with chemotherapy Definitive without chemotherapy Palliative Chemotherapy (with or without palliative radiotherapy) Observation Missing Aggressive therapy a Nonaggressive therapy Total a Surgical resection or any radiotherapy-based regimen with a total dose 50 Gy. patients (25.9%) received observation only. Patients with missing treatment variables made up 10.1% of the cohort. Most in this category had missing CT variables (n=1988; 70%). Overall, 52.5% of the analyzed cohort received aggressive potentially curative therapy for their MIBC. The median age of the analyzed cohort was 72 years. Use of AT varied significantly with age. Younger patients were much more likely to receive AT (Fig. 1). Of patients aged yr, 35% were treated aggressively, and <15% of those aged >90 yr received AT. There was an increase in the use of RT-based regimens with age, whereas the use of surgery and CT alone decreased steadily with age. CT use by year is shown in Figure 2. Over the 5-yr study period, use of CT alone increased from 8.7% to 11.3% and the use of perioperative CT increased from 11.8% to 15.9% ( p < for trend). The use of definitive RT alone fell [(Fig._1)TD$FIG] during the study period from 2.9% to 1.9%; CRT use remained flat at just >5% during this time. Multivariable models analyzing patient sociodemographic, clinical, and facility characteristics associated with receipt of AT are shown in Table 2. Black patients were less likely to receive AT than white patients (OR: 0.74; p < 0.001). Patients without insurance, Medicaid beneficiaries, and young Medicare patients were less likely to receive AT compared to those with private insurance (OR: 0.73, 0.81, and 0.86, respectively; p < 0.001, 0.01, and 0.04, respectively). Receipt of AT did not vary by study year, but was more common in the Midwest compared to the Northeast (OR: 1.46; p < 0.001). Patients with a Charlson- Deyo comorbidity score of 1 were more likely to receive AT (OR: 1.09; p=0.01), whereas patients with a score 3 were less likely to receive AT (OR: 0.82; p=0.01). The presence of hydronephrosis/hydroureter was associated with decreased receipt of AT (OR: 0.69; p < 0.001). Patients with AJCC stage III (T3/T4a) and stage IV (node positive) disease were twice as likely to receive AT than patients with stage II (T2) disease (OR: 2.23 and 1.96, respectively; p < 0.001). The receipt of observation varied by stage, with 33.2% of T2 patients receiving observation compared to 16.2% of T3/T4a patients and 8.6% of nodepositive patients. Patients with squamous cell or adenocarcinoma histology were also more likely to receive AT (OR: 1.26 and 1.43, respectively; p < 0.001). Treatment at an NCIdesignated cancer center was associated with increased receipt of AT compared to teaching/research institutions (OR: 2.49; p < 0.001), whereas treatment at a community center or community comprehensive cancer center was associated with reduced receipt of AT (OR: 0.67 and 0.79, respectively; p < 0.001). Similarly, receipt of AT was less common at low- or medium-volume centers compared to high-volume centers (OR: 0.64 and 0.74, respectively; p < 0.001). For patients receiving CT alone as primary treatment, 23% also received palliative RT. RT dose varied Fig. 1 Distribution of primary therapies received by patients with muscle-invasive bladder cancer by age group. Aggressive therapies are shown in solid colors, nonaggressive therapies are shown in striped colors.

4 826 [(Fig._2)TD$FIG] EUROPEAN UROLOGY 63 (2013) Fig. 2 Chemotherapy use in patients with muscle-invasive bladder cancer by year of treatment. p for trend < significantly between the treatment groups. Those receiving definitive CRT and definitive RT had similar median total doses of 65 Gy and 64 Gy, respectively. Patients treated with palliative RT had a median total dose of 32 Gy. Given the high number of patients with missing treatment details, we conducted a sensitivity analysis of missing data. Patients with missing treatment details were overall more similar in their distribution of age, race, insurance type, and comorbidity score to patients receiving non-at. Patients with missing treatment information were somewhat more common at high-volume centers and were also more likely to have advanced disease. 4. Discussion This study seeks to build upon recently published data from the NCDB identifying underuse of RC for patients with MIBC [12]. One potential explanation for these earlier findings was a shift towards the use of potentially curative bladdersparing techniques such as definitive CRT or RT. Data from this analysis show, however, that only 7.6% of patients received CRT or RT in a manner consistent with established practice guidelines [3,4]. Recent data from the BC2001 trial published in 2012 demonstrated CRT to be superior to RT alone [18]; as the time period analyzed precedes this publication, however, we did include high-dose RT in the category of AT. The choice of 50 Gy is consistent with doses historically delivered at large European centers [10,19]. Overall, <3% of patients received RT alone and its use declined over the study period while use of CRT remained flat. While CT has been shown to improve outcomes when combined with RT or RC, CT treatment alone is not considered adequate therapy for potentially curable patients with MIBC. This is based on data showing pathologic response rates of only 20 40% for patients treated with neoadjuvant CT before cystectomy [20 22]. Our data show trends towards increasing use of perioperative CT over time, and also CT alone over time. Despite more convincing data supporting the use of neoadjuvant CT versus adjuvant CT for MIBC, CT was delivered adjuvantly nearly six times as often. One of the most striking findings from this analysis is the high proportion of patients receiving observation (including serial TURBT) as an initial therapy. TURBT alone for MIBC has been used selectively at some centers [23]. There have been single-institution experiences describing outcomes comparable to cystectomy in patients with negative repeat biopsies following initial TURBT [24,25]. In general, MIBC treated in this way has a high chance of recurrence, requiring later definitive therapy, and selecting this approach initially appears appropriate in <10% of patients [26 28]. By comparison, treatment with observation in our cohort exceeded 25% for patients aged yr and was nearly 40% for those aged yr. While many of these patients likely had comorbid disease and reduced performance status limiting therapeutic options, age alone should not disqualify these patients from receipt of potentially curative therapy. Indeed, many prospective trials of both CRT and RC have treated patients in these age groups successfully [6,18,29]. Our data also demonstrate decreased receipt of AT in disadvantaged populations such as racial minorities. Poor access to quality health care in these populations has been well documented [30]. Our data also show that those without insurance or insurance through state-run Medicaid programs are less likely to receive AT. Similar findings have been shown in other cancers [31,32]. Interestingly, older patients with Medicare were equally likely to receive AT compared to those with private insurance. The finding that younger Medicare patients were less likely to receive RT may be related to the high level of disability required to obtain Medicare coverage before age 65 yr. The increased use of AT at NCI-designated cancer centers and teaching/ research hospitals likely is partially driven by referral bias,

5 EUROPEAN UROLOGY 63 (2013) Table 2 Likelihood of receiving aggressive therapy for patients with bladder cancer stages II IV Variable No. (%) OR a 95% CI p value b Age group, yr (6.1) (15.5) (25.5) (29.9) < (20.1) <0.001 > (2.9) <0.001 Sex Male (71.1) 1 Female 7460 (28.9) Race Non-Hispanic white (79.7) 1 Hispanic 683 (2.7) Black 1693 (6.6) <0.001 Other 528 (2.1) Missing 2320 (9.0) Insurance type Private 7632 (29.6) 1 Uninsured 726 (2.8) <0.001 Medicaid 940 (3.6) Medicare, younger c 937 (3.6) Medicare, older (58.6) Missing 444 (1.7) US geographic region Northeast 5677 (22.0) 1 Midwest 6886 (26.7) <0.001 South 9049 (35.1) West 4177 (16.2) TNM stage T (64.5) 1 T3 or T4a 5618 (21.8) <0.001 Any T, N (13.8) <0.001 Histology Urothelial (89.3) 1 Squamous 1188 (4.61) <0.001 Adenocarcinoma 732 (2.8) <0.001 Carcinoma NOS 755 (2.9) Other 84 (0.3) Charlson score (67.8) (21.3) (7.7) I3 843 (3.3) Hydronephrosis/hydroureter Absent (90.0) 1 Present 2570 (10.0) <0.001 Facility type Teaching/research 4326 (16.8) 1 Community cancer center (48.6) <0.001 Comprehensive cancer center 5997 (23.3) <0.001 NCI Network center 2936 (11.4) <0.001 Facility volume High (65.9) 1 Medium 6576 (25.5) <0.001 Low 2222 (8.6) <0.001 OR = odds ratio; CI = confidence interval; NOS = not otherwise specified; NCI = National Cancer Institute. a ORs are also adjusted for education level, tumor grade, and diagnosis year. b Values in bold are statistically significant at p < c Comprises patients aged yr. Older Medicare patients were aged 65 yr. especially for cystectomy. Despite this, many patients in remote areas may not have the means to travel to such centers for treatment, putting them at increased risk of receiving substandard care [7]. Our study is limited by the nature of the NCDB, which includes only information on treatments received and not on those offered or discussed with the patient. Our data do not, therefore, capture patient or provider treatment preferences and motivations. The NCDB is also limited to data from Commission on Cancer-accredited facilities, which tend to be located in urban areas. Additionally, the NCDB captures only the initial course of treatment,

6 828 EUROPEAN UROLOGY 63 (2013) though it reliably records the initial treatment delivered up to 1 yr from diagnosis. Despite this, patients receiving serial TURBT who go on to have cystectomy years later may not be captured. Even so, our identified use rates are similar to studies using other large databases [7]. Finally, using a cut-off of 50 Gy for defining definitive versus palliative RT may inappropriately exclude patients who were offered definitive therapy but stopped treatment early due to side effects, though this number is low based on our experience [6]. 5. Conclusions This study provides further insight into the treatment of patients with MIBC in the United States. AT in line with established practice guidelines are significantly less likely to be received by the elderly, racial minorities, those with inadequate insurance coverage, and patients seen at lowvolume centers. Our study is the largest to date to fully explore the variety of treatments used for patients with MIBC in this century and can be used to inform payers, policy makers, and physicians regarding the appropriate selection of treatments for patients with MIBC. Author contributions: William U. Shipley had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Shipley, Gray, Virgo, Efstathiou, Fedewa. Acquisition of data: Virgo, Fedewa. Analysis and interpretation of data: Shipley, Gray, Virgo, Efstathiou, Fedewa, Zietman, Lin. Drafting of the manuscript: Shipley, Gray, Virgo, Efstathiou, Fedewa, Zietman, Lin. Critical revision of the manuscript for important intellectual content: Shipley, Gray, Virgo, Efstathiou, Fedewa, Zietman, Lin. Statistical analysis: Fedewa, Virgo, Lin. Obtaining funding: Fedewa, Virgo. Administrative, technical, or material support: None. Supervision: Shipley, Virgo. Other (specify): None. Financial disclosures: William U. Shipley certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: This studywas supported in part by American Cancer Society Intramural Research Funding. The American Cancer Society was involved in data collection and management. Acknowledgment statement: We thank Dr. W. Scott McDougal for his helpful review of this manuscript. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at eururo References [1] Siegel R, Naishadham D, Jemal A. 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