Trends of Muscle Invasive Bladder Cancer: Evidence from the SEER Database, 1988 to 2013

Background: Guidelines for Muscle-Invasive Bladder cancer (MIBC) recommends that patients receive neoadjuvant chemotherapy with radical cystectomy or chemoradiotherapy, as treatment over radical cystectomy alone. Though trends and practice patterns of MIBC have been defined using the National Cancer Database, data using the Surveillance, Epidemiology, and End Results (SEER) have been poorly described. Methods: Using the SEER database, we collected data of MIBC according to the AJCC (American Joint Commission on Cancer). We considered differences in patient demographics and tumor characteristics based on three treatment groups: chemotherapy with radical cystectomy, radical cystectomy alone, and chemoradiotherapy. Multinomial logistic regression was performed to compare likelihood ratios. Temporal trends of each treatment were compared. Results: Of 16,728 patients, 10,468 patients received radical cystectomy alone, 3,236 received radical cystectomy plus chemotherapy, and 3,024 received chemotherapy plus radiation. Patients who received chemoradiotherapy tended to be older and African American compared to radical cystectomy alone (<.001); stage III patients tended to be divorced (<.001). Patients who received chemotherapy with radical cystectomy tended to be males (<.001); stage II patients were less likely to be Asian than White (<.001). Stage III patients were less likely to receive chemoradiotherapy as a treatment option than stage II (<.001). Chemotherapy with radical cystectomy and chemoradiotherapy are both used less frequently as treatment, though increasingly utilized (<.001). Conclusion: Radical cystectomy alone is still the most commonly used treatment for muscle-invasive bladder cancer based on temporal trends. Significant disparities exist in those who receive chemoradiotherapy over radical cystectomy for treatment.


Background
In the United States for 2019, Bladder cancer (BC) is expected to account for 80,470 new cancer cases according to the National Cancer Institute. 1 BC based on the TNM stage system can be described into three chief groups: non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, and metastatic bladder cancer. Non-muscle-invasive bladder cancer is classified as stage I (Ta, Tis, T1) and accounts for approximately 75% of cases. 2− 3 The rest of cases are either considered muscle-invasive bladder cancer (MIBC), classified as stage II to III, or metastatic bladder cancer, classified as stage IV. 3− 4 Primary treatments for MIBC, based on NCCN guidelines, differs based on stage. For stage II tumors, treatment consists of: 1) NAC plus radical cystectomy 2) NAC plus partial cystectomy (for highly selected patients) 3) radical cystectomy and 4) concurrent chemoradiotherapy. 1 For stage III, NCCN lists treatment guidelines as: 1) NAC plus radical cystectomy and 2) concurrent chemoradiotherapy. 1 NAC plus radical cystectomy become the standard treatment for MIBC over radical cystectomy alone. The first study of NAC plus radical cystectomy was conducted by the Medical Research Council/European Organisation for Research and Treatment of Cancer in 1999. 5 In this phase III trial, roughly half of the 976 patients with high grade T2-T4a, N0-NX, M0 urothelial carcinoma were selected for either radical cystectomy alone or three cycles of neoadjuvant chemotherapy (CMV: cisplatin, methotrexate, and vinblastine, with folinic acid rescue) plus radical cystectomy and/or radiation therapy. 5 An 8-year follow up showed a statistically significant 16% improvement in survival outcome. 6 In a 2003 randomized phase III trial from the Southwest Oncology Group (SWOG), 317 patients considered to have muscle-invasive bladder cancer (stage T2-T4a) were randomly assigned to either radical cystectomy alone or three cycles of neoadjuvant chemotherapy (MVAC: methotrexate, vinblastine, doxorubicin, and cisplatin) followed by radical cystectomy. 7 Compared to NAC plus radical cystectomy, patients who received radical cystectomy alone were associated with a 33 percent greater risk of death (hazard ratio, 1.33; 95% CI). 7 Despite CMV and MVAC being used in the phase III trials, healthcare providers have preferred the combination of gemcitabine and cisplatin (GC) in clinical setting due to its better tolerability and similar efficacy. 8 A non-randomized retrospective study comparing GC to MVAC has shown similar likelihood of downstaging primary tumors and eliminating muscle-invasive disease while also showing less toxicity. 9 Bladder preservation therapy that consists of chemoradiation therapy has traditionally been considered a regimen for highly-selected patients with MIBC who are poor candidates for radical cystectomy or for quality of life purposes (ie those who prefer to preserve their native bladder). 10 While no randomized trials of patients with MIBC have directly compared radical cystectomy and bladder preservation therapy, meta-analysis has shown similar overall 5-year and 10-year survival rates. 11 The purpose of our study is to compare trends in three major options of care for MIBC using SEER: radical cystectomy alone, radical cystectomy plus chemotherapy, and chemoradiotherapy with and without TURBT. Previous studies have investigated, using the National Cancer Database (NCDB), tumor characteristics and patient demographic in NAC in combination with radical cystectomy. 12− 17 This the first study to our knowledge to use SEER, a more appropriate database for considering sociodemographic disparities. 18 This is the largest study to directly compare utilization of radical cystectomy with or without chemotherapy to a bladder-preservation approach for MIBC, though the second largest to look at tumor characteristics and patient demographics between these two groups. 19,20 We hypothesize that the use of radical cystectomy alone will decline in lieu of the rise in popularity of alternative treatments.

Methods
SEER is a national cancer database in the United States, a part of the National Cancer Institute, that provides cancer incidence and survival. SEER contains information not available in other national registries including stage of cancer. 21 Our study was based on incident cases of bladder cancer diagnosed among patients of 18 geographic regions, which included the chemotherapy recode, covered by the SEER program (November 2015 submission). Eligible bladder cancer cases were identified using Descriptive statistics were compiled using the statistical package for the social sciences (SPSS) in order to summarize patient demographics, TNM stage and grade, and treatment characteristics. Associations of cases were compared using chi-squared as well as multinomial logistic regression, due to more than two sample groups. Usage rate was compared using 5-year intervals in order to better group the data.

Results
Between the years 1988 and 2013, there were 360,559 cases of bladder cancer in the SEER program that were initially queried for our study. Within each group there resulted in 10,468 radical cystectomy cases, 3,236 radical cystectomy plus chemotherapy cases, and 3,024 chemotherapy plus radiation cases for a total of 16,728 cases that met selection criteria ( Fig. 1). Patients were stratified based on stage in order to control for progression of the cancer. The SEER program does not provide a specific patient age, but instead provides age ranges of 5-years. To calculate median ages of each treatment, averages were created for each patient. After separating by stage, there were significant differences between the groups according to patient demographics and tumor characteristics (Tables 1 & 2). Patients were also compared based on the treatment groups between stage II and III (Table 3). Patients in both stage II and III who received chemoradiotherapy were older (median age: stage II were 72.1 years old and stage III were 71.9 years old) compared to radical cystectomy (median age: stage II were 66.2 years old and stage III 68.9 years old) or radical cystectomy plus chemotherapy (median age: stage II were 63.8 years old and stage III were 65.5 years old) with highly significant p-values (< .001). There was also a difference in the number of patients who received chemoradiotherapy. Although 2,443 stage II cases (26.4%) received chemoradiotherapy for treatment of MIBC, only 581 stage III cases (7.8%) received the same treatment. The values of chemoradiotherapy as a treatment option between stage II and III showed high levels of significance (< .001).
A multinomial logistic regression for each stage was performed in order to compare likelihood of patient demographic or tumor characteristic listed to receive any of three treatments (    28 Their study similar to our own showed an increase in chemotherapy for radical cystectomy due to NAC. 28 Although their study considered many similar patient demographics as the present study and included more patients, our own study controlled for stage when considering patient demographics. 28 In the Cahn et al. study, the authors looked at contemporary use trends between radical cystectomy and bladder preservation therapy for MIBC that included 32,300 from the NCDB between 2004 to 2013. 13 Their study included more patients in radical cystectomy and bladder preservation therapy, when looking at patient and tumor characteristics. Cahn et al., however, did not include a group for chemotherapy with radical cystectomy or control by stage. 13,20,25 Compared to all previous studies, ours looked at greater temporal trends in using data from 1988-2013.
Our study uniquely found a drop in chemoradiotherapy in stage III tumors.
While NAC with radical cystectomy is the preferred treatment for MIBC, a significant portion of the bladder cancer population may be ineligible to receive chemotherapy.
Several retrospective studies have shown that approximately 40% of patients who received radical cystectomy were ineligible to receive cisplatin chemotherapy treatment due to poor renal function. 26,27 Other co-morbidities including hearing loss and cardiac dysfunction may similarly prevent patients from receiving standard cisplatin-based chemotherapy. 28 The usage of a bladder-preservation approach with chemoradiotherapy for MIBC may be used less frequent for the same reason. Moreover, data has identified basal and luminal subgroups of MIBC based on survival and chemotherapy response. 29 A study has shown that the basal subtype of MIBC derive the most benefit from NAC while luminal nonimmune infiltrated may not derive any benefit. 30 The identification of molecular markers in these subtypes of MIBC may pave the way for neoadjuvant immunotherapies with radical cystectomy and in the future more personalized medicine.

Limitations
As an analysis of a national oncologic registry, our study has several limitations that extends to all cohort studies. Our study is limited in the patients that are recorded in the registry. The SEER database itself has several limitations especially on radiotherapy and chemotherapy information. Data stemming from radiotherapy and chemotherapy treatment can be underreported. As both radiotherapy and chemotherapy are commonly administered in outpatient settings, the SEER database may not capture all data especially being driven by hospital-based registries. The SEER database also lacks radiotherapy doses and intent of treatment as either curative or palliative regimens. Data submitted to SEER in terms of chemotherapy options are limited, being listed solely as either "yes" or "no-unknown." 21 While there is confidence that a patient received chemotherapy after the box was marked as "yes," there is less confidence that a patient who was marked as "no-unknown" did not actually receive chemotherapy. For this reason, the data for radical cystectomy alone would be most affected as the patients may actually have received chemotherapy. We are unable to know whether a patient received neoadjuvant compared to adjuvant chemotherapy.

Conclusions
Although considered the standard treatment prior to 2003, radical cystectomy is still the most commonly utilized treatment for MIBC. NAC with radical cystectomy and chemoradiotherapy are still used less frequently as treatment despite category 1 evidence. Differences in chemoradiotherapy as a treatment option were especially noticeable between stage II and III tumors, with stage III cases less likely to receive this treatment. Significant disparities exist in those who receive chemoradiotherapy over radical cystectomy for treatment especially age and race. More research is still needed to understand what treatment delivers better survival outcomes.

Declarations
No conflict of interest exists in the submission of this manuscript, and the manuscript has been approved by all authors for publication. The work described herin is original research that has not been published previously and is not under consideration for publication elsewhere, in whole or in part. All authors of the manuscript have read and agreed to its content are are accountable for all aspects of the accuracy and integrity of the manuscript in accordance with ICMJE criteria, and all agree to the terms of the BioMed Central License Agreement and Open Data Policy.

ACKNOWLEDGMENTS
Not applicable.

Funding
None.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

AUTHOR'S CONTRIBUTIONS
VC made substantial contributions to conception and design of the study; acquisition, analysis and interpretation of data; and drafted and revised the manuscript. MLB and HZ analysis and interpretation of data; assisted with drafting and revising the manuscript. PS contributed to conception and design of the study and acquisition of data; conception and design of the study; analysis and interpretation of data; assisted with drafting and revised the manuscript critically for important intellectual content.

Ethics approval and consent to participate
The study was not primary research involving humans or animals but was instead a secondary analysis of human subject data available in the public domain.

Consent for publication
Not applicable.

Competing interests
The authors declare that they have no competing interests.