The Real-World Lifetime Economic Burden of Urothelial Carcinoma by Stage at Diagnosis

Abstract: Urothelial carcinoma (UC) is generally diagnosed early and may incur significant lifetime costs. This study estimated, from the payer’s perspective, the lifetime costs among patients diagnosed with UC according to stage at diagnosis. Methods: This retrospective analysis of the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database identified patients ≥66 years with newly diagnosed UC from 2004-2013. Patients were followed from UC diagnosis to death or last follow-up to estimate lifetime costs. Costs were allocated to three phases: diagnosis (≤ 3 months after diagnosis), terminal (≤ 3 months before death), and continuation (months between diagnosis and terminal phases). Survival-adjusted lifetime costs (total and major UC-related) were estimated for patients with UC based on stage at diagnosis (stages 0 through IV) and in a subgroup of patients receiving ≥1 systemic line of chemotherapy (LOC). Results: The sample included 15,588 patients: 3,446 stage 0 (8% ≥1 LOC; median [IQR] follow-up in months: 44 [23-71]); 3,902 stage I (12% ≥1 LOC; 33 [15-62]); 4,301 stage II (26% ≥1 LOC; 17 [7-39]); 1,612 stage III (25% ≥1 LOC; 17 [7-42]); and 2,327 stage IV (33% ≥1 LOC; 8 [3-18]). Median age was 78 years and 72% were male. Mean lifetime costs were lowest for stage IV patients (stage 0, $151,626; stage I, $150,123; stage II, $149,728; stage III, $190,996; stage IV, $117,503). Hospitalizations not involving a cystectomy contributed about half of lifetime costs across all stages. Cystectomy contributed 2% to 13% of the total lifetime UC costs ($3,356 stage 0; $7,011 stage I; $11,855 stage II; $25,509 stage III; $11,693 stage IV). UC-related office visits contributed 8% to 15% of lifetime costs ($11,717 stage 0; $14,611 stage I; $19,882 stage II; $21,480 stage III; $17,820 stage IV). Conclusion: UC continues to be a costly cancer with stage III patients having highest lifetime costs. Hospitalizations drive most of the lifetime costs across all stages; most of these hospitalizations did not involve costs related to cystectomy. Treatment plans requiring shorter and fewer hospitalizations may lessen the economic burden of UC.

Author Contributions: AA, MB, YD, RS, and CJ were involved in the study conception and design; AA, CJ, VC, and AH were involved in the analysis and interpretation of the data; all authors assisted in the drafting of the manuscript, revising it critically for intellectual content, and approving the final version for publication. All authors agree to be accountable for all aspects of the work described herein.

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Urothelial carcinoma (UC) accounts for 90% of bladder cancer tumors in the United States.^1,2 Approximately 75% of patients present with non-muscle invasive bladder cancer (NMIBC) at diagnosis,^3,4 of whom 30% to 70% will have same stage recurrence⁵ and 10% to 15 % will go on to develop invasive bladder cancer.^4,6 Inclusive of all stages, the overall 5-year survival for bladder cancer is 77% but is as low as 5% in patients with distant disease and is up to 95% for patients with in situ alone disease.⁷ Prognosis, management, and therapeutic aims are dependent on disease invasiveness at each stage. For NMIBC, treatment is directed at reducing recurrences and preventing disease progression; for muscle invasive bladder cancer (MIBC), definitive local therapy, with or without neoadjuvant and/or adjuvant chemotherapy are used for curative intent; for locally advanced (M0) and metastatic disease (M1), the goal is to prolong and maintain quality of life, which can include use of systemic therapy (both chemotherapy and immune checkpoint inhibitors [ICIs]), surgery, and/or radiotherapy.⁸ 

Continuous treatment and surveillance makes bladder cancer one of the most expensive cancer types over the lifetime of a patient^9-11 and, in fact, has been shown to be the costliest cancer when compared to other malignancies.^12-14 Previous studies have reported long-term cost estimates for bladder cancer ranging from $102,700 to $125,541 in the United States.^11,13,15 In UC, similar to other cancers, the trajectory of cost accumulation is not linear but rather U-shaped, exhibiting high costs incurred around diagnosis and death, and relatively lower costs inbetween.^5,16 Lifetime costs of UC are expectedly stage-dependent because patients with early stage UC typically have longer survival and consequently higher costs during their disease journey from diagnosis, treatment, recovery/survivorship, and end of life. There could also be heterogeneity in lifetime costs within each stage, depending on the type and extent of care received. For example, in early stage bladder cancer, patients undergoing more treatment may incur three times as much cost compared with those in the lowest quartile, but the extent of care may not necessarily correlate with improved patient survival.^17,18

Studies to date on the overall economic burden of bladder cancer,^{5,6,10,12,14,19} or more broadly UC, have reported costs per-patient-per month or cumulative costs over the course of patient follow-up rather than distinct phases of disease management, or have estimated costs for specific stages rather than evaluated across all stages of UC. Additionally, most of them covered periods prior to 2011. With the advent of immunotherapy agents in the treatment landscape of advanced UC and ongoing efforts to define their potential role in earlier stages, it will become increasingly relevant to understand the relative cost-effectiveness of immunotherapy-based approaches compared to chemotherapy. To provide a framework for future comparative studies, as more real-world data on immuno-oncology drugs become available over time, the present research provides updated lifetime direct medical costs of managing and treating patients with UC.

Methods

Data Source 

This study was a retrospective database analysis using data from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The SEER registry covers 28% of the US population and consists of 18 state and regional cancer registries,^20,21 while the Medicare database contains administrative health care service claims and associated costs for all covered Medicare beneficiaries, from Medicare eligibility to death.^21,22

Study Population

The study included Medicare beneficiaries aged 66 years or older who were newly diagnosed with histologically confirmed UC from 2004 to 2013 (International Classification of Diseases for Oncology, Third Edition [ICD-O-3] codes 8120/3-8124/3) and who had available Medicare claims data from 2003 to 2014. Patients were followed from UC diagnosis until death, loss to follow-up, end of the study period (December 31, 2014), Health Maintenance Organization (HMO) enrollment, or Medicare disenrollment. Patients were excluded if they received a postmortem UC diagnosis, had an unknown diagnosis date, or had another cancer (except nonmelanoma skin cancer) in the 5 years before UC diagnosis. Additional exclusion criteria included noncontinuous enrollment in Medicare Parts A and B or enrollment in an HMO in the 12 months prior to diagnosis.

Our primary analysis focused on characterizing the lifetime economic burden in all UC patients who met the inclusion criteria by stage at diagnosis. For each stage, these patients will be referred to below as “average cohort patients” to distinguish them from the subgroup of patients who received a systemic line of chemotherapy (LOC) for UC within each stage, which will be referred to as “LOC patients.” This is an important subgroup because these patients are more likely to potentially benefit from the innovative therapies currently being examined in clinical trials that could replace or be used in conjunction with chemotherapy as the standard of care in the future. Of note, by our definition, patients who received neoadjuvant or adjuvant chemotherapy but not any subsequent systemic chemotherapy during their disease course were not considered as part of the “LOC patients” subgroup. Understanding the burden in LOC patients can help with future comparative cost analyses.

Baseline Characteristics

The SEER registries provided the baseline demographic information for the included UC patients. Each patient’s stage at diagnosis was also obtained from the SEER registries based on the TNM stage at time of UC diagnosis (Supplemental Table 1). Comorbidities that occurred up to 12 months prior to UC diagnosis were obtained from Medicare claims and used to calculate the Deyo adaptation of the Charlson Comorbidity Index (CCI).²³ Using a previously validated claims-based prediction model, Medicare claims, specifically on wheelchair use, oxygen use, walking aid, hospital bed, hospice, skilled nursing facility, or hospitalization occurring 12 months prior to UC diagnosis, were used to calculate a proxy indicator (yes/no) variable for poor performance status.²⁴

Lines of Chemotherapy 

Receipt of chemotherapy was identified by Healthcare Common Procedure Coding System (HCPCS) and National Drug Codes (NDC) and included the following agents, either as monotherapy or in combination: carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, ifosfamide, methotrexate, oxaliplatin, paclitaxel, pemetrexed, vincristine, and vinblastine. The LOC recipients may or may not have received prior neoadjuvant or adjuvant chemotherapy (if they had undergone prior cystectomy). Among such patients, the identification of LOC was differentiated from neoadjuvant/adjuvant chemotherapy based on a 6-month gap post-cystectomy. Thus, if systemic chemotherapy was administered after 6 months of cystectomy, it was considered an LOC. Six months was chosen because adjuvant chemotherapy is generally given 4 to 6 weeks after cystectomy for up to four cycles that last over 3 to 4 months.      

Outcomes

Primary outcomes were lifetime and phase-specific direct medical costs by stage at diagnosis for the average patients and the subgroup of LOC patients. Calculated all-cause costs represented actual Medicare payments rather than billed charges or “list price” established by the provider and thus the perspective of this analysis is the payer’s (Medicare) perspective.^25,26 Costs were assessed in two ways: (1) by clinical setting of care as aligned with how Medicare aggregates its claims files, ie, inpatient (MEDPAR), outpatient (Medicare Part B), physician and supplier (NCH), durable medical equipment (DME), home health agency (HHA), hospice, and prescription drug (Medicare Part D); and (2), by health care resource utilization categories. Health care resource utilization categories were identified using codes from the International Classification of Diseases 9th Edition Clinical Modifications Procedure Coding System (ICD-9-PCS), HCPCS, NDC, and Hospital Revenue Centers (Supplemental Table 2) and included hospitalization not involving a cystectomy, cystectomy, UC-related office visit, radiation, and systemic chemotherapy. Costs that did not fall into any of the above categories were lumped into “other” categorization. Costs were inflated to 2017 and presented in US dollars.

Costs over time were allocated into three clinically relevant disease phases: diagnosis phase (ie, from diagnosis up to 3 months post diagnosis), terminal phase (covering the period 3 months before death), and continuation phase (ie, the period between diagnosis and last follow-up date among patients who did not die or start of the terminal phase among patients who died) (Figure 1). Because this study evaluated lifetime costs across all stages of UC, it was important to select an interval period covering diagnosis and terminal phases (ie, 3 months) that was not too long relative to the overall survival for patients with stage IV UC (~12 months).

Statistical Analysis 

Descriptive statistics were used to summarize patient clinical characteristics and LOCs received. Mean, standard deviation (SD), median, and interquartile range (IQR) were reported for all continuous variables. Frequency and percentage were calculated for all categorical variables. The diagnosis and terminal phase-specific costs were reported as mean (and 95% CI) costs over the respective periods, while the continuation phase costs were reported as mean costs per month. Cumulative lifetime costs were survival-adjusted using the time to death event from Kaplan-Meier curves. This approach allows for the estimation of lifetime costs in the presence of heavy censoring and has been shown to be the most robust method used in this situation.²⁷

Results

Patient Characteristics

A total of 15,588 patients met the inclusion criteria
(Figure 2). At diagnosis, 22% of patients were diagnosed as stage 0, 25% were stage I, 28% were stage II, 10% were stage III, and 15% were stage IV. Median age at diagnosis was 78 years, 72% of patients were male, 87% were non-Hispanic white, and 56% were married (Table 1). Over half of the patients had CCI ≥1, and about a quarter had a proxy for poor performance status. Among stage IV patients, 53% were M1, 53% were N1-N3, and 15% were T4/T4b at diagnosis (not mutually exclusive). As expected, median follow-up was lower for advanced stages of disease (44 months for stage 0, 33 months for stage I, 17 months for stage II, 17 months for stage III, 8 months for stage IV). The prevalence of LOC receipt increased with more advanced cancer (8% for stage 0, 12% for stage I, 26% for stage II, 25% for stage III, and 33% for stage IV patients). Very few patients received neoadjuvant or adjuvant chemotherapy only, without further receipt of line of systemic chemotherapy (1% stage 0, 6% stage II, 12% stage III, and 12% stage IV) (Table 1). Of note, more patients of lower stages were non-Hispanic White and married, which may highlight social support, access to care, and cultural beliefs as important determinants of surveillance and early diagnosis of UC.

Costs

Lifetime and Phase-Specific Costs by Stage

The average patient (as defined under the Methods Section, which includes patients irrespective of whether or not they received chemotherapy) diagnosed with earlier stages of UC (stage 0-II) had similar lifetime costs ($151,626 stage 0; $150,123 stage I; $149,728 stage II), while stage III patients had the highest ($190,996) and stage IV had the lowest lifetime cost burden at $117,503 (Table 2). The lifetime costs for the subgroup of LOC patients (as defined under the Methods section) were 6% to 24% higher than the average patient of the same stage. However, stage III LOC patients incurred lower lifetime costs ($166,851) than the average patient within the stage III group ($190,996). Stage IV LOC patients continued to have comparatively the lowest lifetime cost burden ($138,274) among the LOC patients across the four stages, whereas stage 0 LOC patients had the highest cost burden ($188,140) (Table 2).  

Stage III patients had the highest diagnosis phase ($23,404) and continuation phase ($1,110 per month) costs, and the second highest terminal phase ($24,818) costs. Stage IV patients had the second highest diagnosis ($19,290) and the highest terminal phase costs ($26,571) but the lowest continuation phase costs ($554 per month). In the subgroup of LOC patients, stage 0 patients had the highest continuation phase ($1,208 per month) costs, while stage IV patients continued to have the lowest continuation phase ($690 per month) costs (Table 2). Patients diagnosed with earlier stages of UC spent more time in the continuation phase compared to those diagnosed with advanced stages (45.2 months for stage 0, 36.6 months for stage I, 23.3 months for stage II, 24.4 months for stage III, 10.7 months for stage IV) (Supplemental Table 3).

Lifetime Costs by the Setting of Care Provided 

Regardless of the stage at diagnosis, in the average patients, hospitalizations were the primary cost drivers of lifetime costs, comprising more than 50% to 65% of all costs, followed by outpatient costs and physician Part B costs (Figure 3). Hospice accounted for only 2% to 5% of lifetime costs; increased disease stage did not correlate with a gradient of higher lifetime cost attribution for hospice (Figure 3).

Lifetime Costs by Health Care Resource Utilization Categories

Hospitalizations and office visits. Hospitalizations that did not involve a cystectomy accounted for 49% to 53% of lifetime costs in the average patients. The cost burden as a percentage of total lifetime costs was highest for stage III average patients ($100,356; 53%). In the subgroup of LOC patients, hospitalizations that did not involve a cystectomy contributed to 42% to 47% of lifetime costs, with stage IV LOC patients having the highest burden ($64,642; 47%).

UC-related office visits accounted for 8% to 15% of lifetime costs in the average patients. The cost burden as a percentage of total lifetime costs was highest for stage IV average patients ($17,820; 15%). In the subgroup of LOC patients, UC-related office visits contributed to 13% to 22% of lifetime costs, with stage II LOC patients having the highest burden ($34,386; 22%).

Cystectomy, chemotherapy, and radiation. Cystectomy accounted for 2% to 13% of lifetime costs in the average patients. The cost burden as a percentage of total lifetime costs was highest for stage III average patients ($25,509; 13%). In the subgroup of LOC patients, cystectomy contributed to 2% to 5% of lifetime costs, with stage III LOC patients having the highest burden ($8,959; 5%). 

The cost burden of systemic chemotherapy was minimal, contributing only 1% to 4% in the average patients. Stage IV patients accumulated the highest cost of systemic chemotherapy ($4,831 in the average patients and $10,238 in LOC patients). 

Radiation costs accounted for 1% to 5% of lifetime costs in the average patients. The cost burden as a percentage of total lifetime costs was highest for stage II average patients ($7,932; 5%). In the subgroup of LOC patients, radiation contributed to 3% to 9% of lifetime costs, with stage II LOC patients having the highest burden ($14,527; 9%) (Table 3).

Other costs. Costs that are unlikely related to UC accounted for 17% to 40% of lifetime costs in the average patients, with earlier stages having higher costs in that category.  The cost burden as a percentage of total lifetime costs was highest for stage 0 average patients ($60,210; 40%) and lowest for stage IV ($20,547; 17%). In the LOC subgroups, costs that are unlikely related to UC accounted for 19% to 34% of lifetime costs.

Discussion

Communicating the cost of cancer care to patients is becoming increasingly incorporated by clinical oncology organizations as one of the core principles to improve shared decision-making, patient satisfaction, and optimize out-of-pocket spending and outcomes.^28,29 Our study provides a contemporary detailed update of the lifetime economic burden of UC by adopting a phase-based, stage-dependent approach. The study results provide relevant benchmarks and context to further understand and communicate the economic burden of UC as the treatment landscape for UC continues to evolve.^14,18-20 Additionally, this study generalizes to both the average UC patient by stage as well as the subgroup of patients who receive a systemic line of chemotherapy and therefore are assumed to have progressed to advanced disease where systemic chemotherapy is recommended.

Our study found that the trajectory of cost accumulation does not necessarily increase linearly with stage of disease but rather depends on the extent of care received during the diagnosis, continuation, and terminal phases of UC. A recent study by Sloan et al¹⁵ also using the linked SEER–Medicare dataset (1998-2013) demonstrated that the cumulative costs for bladder cancer patients over a 16-year period were higher for patients with lower stages at first diagnosis ($124,320 for localized; $104,161 for regional; and $64,922 for distant disease), which was mostly due to the longer (16 year) survival of patients presenting with lower stage disease (13.3% for localized; 4.4% for regional; and 0.0% for distant disease), possibly reflecting long-term routine surveillance, including imaging, scans, lab tests, and/or other diagnostic procedures in inpatient, outpatient, and office settings.³⁰ Interestingly, and somewhat similar to the estimates by Sloan et al for localized bladder cancer, stage 0 patients in our study treated with LOC generated the greatest lifetime burden ($188,140) as well as continuation costs ($1,208 per month), compared to LOC recipients of higher disease stage. This could possibly be related to greater extent of care, surveillance, and continuous imaging in stage 0 patients who also subsequently progress to more advanced disease over time and get treated with LOC. Similar to the Sloan et al report, costs in our study were high in the first few months of diagnosis, after which they declined over the continuation phase.

Our study found that stage III patients had the highest lifetime costs ($190,996) and stage IV had the lowest lifetime costs ($117,503). Stage III patients had the highest diagnosis, continuation, and second highest terminal costs (second only to stage IV terminal phase costs). One reason why stage III patients may have the highest lifetime costs is the intensity of care received in a potentially curative setting where treatment plans often involve a multidisciplinary approach and multimodal care that may also include cystectomy and/or (neo)-adjuvant therapy.³¹ At the same time, however, stage III LOC recipients had lower lifetime costs than the average stage III patients, mainly attributable to lower costs during the continuation phase. Future studies should causally examine if lower lifetime costs among stage III patients are due to treatment with LOC.

Hospitalizations not related to cystectomy were a major cost driver for all patients in our study, accounting for nearly half of all costs, regardless of stage of disease at diagnosis or phase of treatment (diagnosis, continuation, terminal). This is to be expected as the study cohort represented older patients with a median age of 78 years, close to a quarter of whom had poor performance status and close to 30% with CCI score of 2 and above. Future studies are needed to understand why patients with UC are being admitted to the hospital for reasons other than cystectomy. Some hospitalization costs may have been a result of complications from procedures, which occur especially among older patients and patients with multiple comorbidities.^5,10,11,32 Such complications can result in extended hospital stays and increased costs. As a result, treatment plans that require fewer and shorter hospitalizations can lead the way to lessening the economic burden of UC. Office visit costs were another significant source of economic burden in UC patients. UC has a high risk of recurrence, and as a result continuous follow-up care and/or surveillance is needed. Depending upon their disease burden and disease course and whether they undergo cystectomy, a bladder sparing procedure, or receive chemotherapy, patients are often followed up frequently with lab tests and imaging. For patients with early stage disease and at high risk for disease recurrence, more frequent office visits, cystoscopies, imaging, and possible transurethral resection of bladder tumor are often required.^8,11,30,33  

Our study is not without limitations. First, our study population consisted of Medicare patients with an average age of 78 years; therefore, our results are not generalizable to a younger non-Medicare population. Second, clinical characteristics such as M stage, performance status, and CCI were measured at initial UC diagnosis rather than continuously updated over the follow-up period where changes can impact treatment decisions. For example, a patient could be diagnosed with M0 disease but develop metastasis over time. Third, the use of ICD-9, HCPCS, and Hospital Revenue Center codes to identify health care resources can be subject to potential miscoding. Fourth, it was not possible to identify whether radiation was given for locoregional treatment vs palliative care. Lastly, while our study provides an update to literature estimates, it covers a period (2003-2014) prior to the approval of immune checkpoint inhibitors in bladder cancer.² 

Conclusion

The present study highlights the significant financial burden incurred by UC patients and the health care system alike.^29,34 Our study provides a needed update to the literature on the economic burden incurred by patients with stages 0 to IV UC and comprehensively reports costs by disease phase, the clinical context of care, and by receipt of systemic chemotherapy. Estimates reported here provide a benchmark on cost of care prior to the approval of immuno-oncology therapies and could be helpful in informing patients, payers, and stakeholders alike about the economic burden of UC during shared-decision making discussions with treating physicians.^29,34   

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