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Treatment Patterns and Outcomes in Stage IV Bladder Cancer in a Community Oncology Setting: 2008-2015

Open AccessPublished:August 10, 2018DOI:https://doi.org/10.1016/j.clgc.2018.07.025

      Abstract

      Introduction

      Current real-world data regarding treatment patterns in advanced bladder cancer in the community setting are limited. This study describes patient characteristics, treatment patterns, and effectiveness outcomes for stage IV bladder cancer in the community setting.

      Methods

      Medical records data of adults diagnosed with stage IV bladder cancer between January 1, 2008 and June 1, 2015 were retrospectively collected from a network of United States community oncology practices. Patient characteristics, treatment patterns, and efficacy outcomes were assessed. Across-group comparisons were conducted using bivariate analyses. Kaplan-Meier and Cox regression analyses of progression-free survival and overall survival (OS) were conducted.

      Results

      Of 508 patients (mean age, 70 ± 11 years), 75.2% were male, 79.1% white, 15.4% black, and 71.5% were ≥ 65 years. The most prevalent comorbidities were diabetes (23.4%) and renal disease (16.5%). Overall, 56% of patients received first-line platinum-based chemotherapy; the most common regimen was gemcitabine/carboplatin (23.6%), followed by gemcitabine/cisplatin (17%). The median OS was 9.4 months from stage IV bladder cancer diagnosis and 8.4 months from start of first-line therapy. Cox regression analysis of OS from diagnosis showed a higher risk of death for patients with no treatment (hazard ratio [HR], 2.06; P < .0001) or other treatment (HR, 1.83; P = .002) versus cisplatin and for patients with impaired performance (HR, 2.05; P < .0001).

      Conclusion

      Platinum-based chemotherapy was the most prescribed treatment for stage IV bladder cancer in the community setting. Several patients were not treated with any chemotherapy, although we did not observe the reason for no treatment. This study highlights an unmet need in this population, particularly in a relapsed/refractory setting, and the need for improvement in outcomes.

      Keywords

      Introduction

      Bladder cancer is the ninth most common cancer in the world, with 430,000 new cases diagnosed in 2012.
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      In 2018, an estimated 81,190 new cases of bladder cancer are expected to be diagnosed in the United States (US), with approximately 17,240 deaths expected during that period.
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      The incidence of bladder cancer increases with age, and the median age at diagnosis in the US is 73 years.
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      Surveillance, Epidemiology, and End Results Program. SEER Cancer Stat Facts: Bladder Cancer.
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      The most common histologic subtype of bladder cancer in the US and Europe is urothelial carcinoma, with a minority being of pure or mixed squamous, adenocarcinoma, micropapillary, plasmacytoid, neuroendocrine, and sarcomatoid histologies.
      National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer, Version 5.2018.
      According to Surveillance, Epidemiology, and End Results (SEER) Program statistics, although the overall 5-year survival rate for any diagnosis of bladder cancer is > 77%, only 5% of patients diagnosed with metastatic bladder cancer survive for 5 years.
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      Surveillance, Epidemiology, and End Results Program. SEER Cancer Stat Facts: Bladder Cancer.
      Treatment decisions and prognosis of bladder cancer are dependent on 2 main factors: depth of invasion into the bladder wall and degree of differentiation of the tumor. Systemic therapy is the preferred treatment for metastatic disease, whereas multimodality treatment is preferred for node-positive disease.
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      Neoadjuvant chemotherapy is recommended for patients with cT2, cT3, and cT4a muscle-invasive bladder cancer without nodal disease and for patients who are cisplatin-eligible.
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      NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer, Version 5.2018.
      The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) for first-line therapy in the metastatic setting include gemcitabine in combination with cisplatin and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) as Category 1 recommendations.
      National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer, Version 5.2018.
      The regimen chosen for first-line therapy in the metastatic bladder cancer setting is often based on the performance status (PS) of the patient. Regimens with lower toxicity profiles are recommended for patients with serious comorbidities or compromised liver or kidney function.
      National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer, Version 5.2018.
      Cisplatin ineligibility is common for reasons including a PS of 2, renal dysfunction, hearing loss, grade ≥ 2 neuropathy, or heart failure. Carboplatin is often substituted for cisplatin in these patients.
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      Cisplatin-ineligible and chemotherapy-ineligible patients should be the focus of new drug development in patients with advanced bladder cancer.
      Until recently, the preferred agents for second-line therapy in the US were single-agent taxanes or gemcitabine. For relapsed or refractory metastatic bladder cancer, the NCCN Guidelines recommend participation in clinical trials of new agents.
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      There has been growing interest in immune checkpoint blockers, such as anti-programmed cell death-1 antibodies (nivolumab and pembrolizumab) and anti-programmed cell death ligand-1 (PD-L1) antibodies (atezolizumab, avelumab, and durvalumab).
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      Atezolizumab was the first immune checkpoint blocker approved in 2016 as systemic treatment for locally advanced or metastatic disease following platinum-based treatment.
      This was followed by approvals for nivolumab, durvalumab, and avelumab in early to mid-2017 for the same population.
      In the first half of 2017, atezolizumab and pembrolizumab were approved as first-line options for cisplatin-ineligible patients, and in mid-2018, the labels for both drugs were updated to limit use in cisplatin-ineligible patients whose tumors cells express high PD-L1 (tumor proportion score ≥ 5% for atezolizumab; combined positive score ≥ 10% for pembrolizumab).
      These novel immunotherapies have been added to the NCCN Guidelines as Category 2A recommendations (with the exception of pembrolizumab in the post-platinum setting, which is a Category 1 recommendation owing to a phase III trial that demonstrated improved overall survival [OS] compared with standard of care).
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      In light of several recent approvals of immunotherapies, it is important to understand current treatment patterns and their associated clinical outcomes, as these data can serve as benchmarks for understanding the impact of immunotherapies in the future. Our study aimed to understand how patients with stage IV bladder cancer are treated in a real-world (defined as not part of a clinical trial
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      ) community oncology setting and to add to the limited data that examine effectiveness outcomes associated with that treatment.

      Patients and Methods

      Study Design, Data Source, and Patient Population

      This was a retrospective observational study using data from Vector Oncology Data Warehouse, a repository that includes electronic medical record data from 10 US community oncology practices, representing more than 30 practice locations. These represent physician-owned practices that draw patients from all 48 contiguous states, with a concentration of patients from the South. In addition to geographic variability, these practices also vary in community settings, with both rural and urban practices being included, and range in size from as small as 2 to as large as 20 physicians. The Vector Oncology Data Warehouse includes provider notes to support the collection of key information not otherwise available in structured electronic medical record fields, such as verification of disease progression. Patients were included if they met the following criteria: age ≥ 18 years and a stage IV bladder cancer diagnosis (T4b, node-positive, or distant metastatic disease; International Classification of Diseases [ICD] code 188.x; ICD code C67.x) between January 1, 2008, and June 1, 2015. Patients were excluded from this study if they had a record of participation in cancer clinical trials. Data were collected from the beginning of each medical record through June 30, 2015, or the end of the medical record, whichever occurred first.

      Procedures

      Potentially eligible patients were identified using Structured Query Language for the aforementioned diagnostic codes. Experienced research nurses reviewed medical records to determine final study eligibility and abstracted key information not otherwise available in structured data fields (eg, tumor location, PS, documented disease progression, etc.). No personal health information or personal identifiers were collected. Study procedures were approved by IntegReview, an institutional review board in Austin, TX.
      Patient demographics included age at diagnosis of stage IV bladder cancer, race, and gender. Clinical characteristics included stage at initial bladder cancer diagnosis, PS, histology, metastatic disease sites, comorbid conditions, and smoking history. Additional characteristics included start and end dates of anticancer treatment following diagnosis of stage IV bladder cancer, dates of disease progression (as documented in the clinical record), and date of death if applicable (from the clinical record or Social Security Death Index).
      Treatment patterns were defined as comprising the first-line (1L) period, the interval from the first treatment following diagnosis of stage IV bladder cancer until progression, and second-line (2L) period, the interval from the start of treatment after progression until the next disease progression. Primary endpoints were progression-free survival (PFS) within the 1L and 2L periods, and OS from the diagnosis of stage IV bladder cancer, from start of 1L treatment, and from start of 2L treatment.

      Statistical Methods

      Descriptive statistics were generated for all demographic and clinical characteristics of interest. Differences in continuous variables were evaluated using analysis of variance or Kruskal-Wallis test. The χ2 test or Fisher exact test was used to test for differences in categorical variables. The Kaplan-Meier product limit estimator was used to descriptively characterize time-to-event outcomes. A log-rank test was used to compare time-to-event endpoints across groups. Cox regression analyses were used to evaluate the influence of demographic and clinical covariates on time-to-event endpoints. The same set of patient-level covariates was included in each model: age group, stage of disease at initial diagnosis, smoking history, presence of comorbidities, gender, race, body mass index, and PS. Treatment category (carboplatin, cisplatin, other chemotherapy, and no therapy) was a covariate in all the models.

      Results

      Demographic and Clinical Characteristics

      We examined the records of 1021 patients with stage IV bladder cancer to arrive at our final study sample of 508 patients. The majority of the patients excluded from the analysis were patients with a diagnosis of stage IV disease outside of the date range of interest (n = 399) followed by patients with inadequate records (n = 41) and those who participated in clinical trials (n = 27). Table 1 shows the overall demographic and clinical characteristics, and by age (< 65 years vs. ≥ 65 years). Patients in the overall study sample had a median age of 71 years, and were mostly male (75.2%) and white (79.1%). The most frequent cancer stage documented at initial diagnosis was stage IV (31.1%), and initial disease stage was undocumented in 35.2% of the sample. Overall, 32.3% of patients received chemotherapy before stage IV diagnosis and more than one-half (58.7%) received surgery. The majority of the patients (76.4%) were current or past smokers. The most frequently observed comorbidities overall were diabetes (23.4%), renal disease (16.5%), and chronic obstructive pulmonary disease (12.4%).
      Table 1Demographic, Clinical, and Treatment Characteristics of Patients, Overall and by Age
      Variable/StatisticOverall (N = 508), n (%)Age GroupP Value
      < 65 Years (n = 145), n (%)≥ 65 Years (n = 363), n (%)
      Demographic and clinical characteristics
       Age at diagnosis of stage IV bladder cancer, y
      Mean (SD)69.7 (11.1)55.7 (6.7)75.3 (6.7)
      Median (min, max)71.0 (35, 92)57.0 (35, 64)75.0 (65, 92)
       Gender.994
      χ2 test.
      Men382 (75.2)109 (75.2)273 (75.2)
       Race.129
      Fisher exact test.
      White402 (79.1)107 (73.8)295 (81.3)
      Black78 (15.4)27 (18.6)51 (14.0)
      Asian1 (0.2)1 (0.7)0 (0.0)
      Latino3 (0.6)2 (0.6)1 (0.3)
      Other/undocumented24 (4.7)8 (5.5)16 (4.4)
       Stage of disease at initial diagnosis.097
      Fisher exact test.
      Stage I38 (7.5)10 (6.9)28 (7.7)
      Stage II63 (12.4)13 (9.0)50 (13.8)
      Stage III47 (9.3)16 (11.0)31 (8.5)
      Stage IV158 (31.1)56 (38.6)102 (28.1)
      Other/unknown23 (4.5)8 (5.5)15 (4.1)
      Undocumented
      Although specific stage of disease was not reported, the majority had early-stage disease as evidenced by a documented record of surgery.
      179 (35.2)42 (29.0)137 (37.7)
       Stage of disease at advanced diagnosis.020
      Fisher exact test.
      Stage IV/M0 (no distant metastasis)152 (29.9)56 (38.6)96 (26.4)
      Stage IV/M1 (distant metastasis)350 (68.9)87 (60.0)263 (72.5)
      Other6 (1.2)2 (1.4)4 (1.1)
       Treatment modalities before stage IV diagnosis
      Surgery
      Surgery refers to any surgery for bladder cancer including radical cystectomy and TURBT.
      298 (58.7)74 (51.0)224 (61.7).027
      χ2 test.
      Chemotherapy/targeted therapy164 (32.3)48 (33.1)116 (32.0).803
      χ2 test.
      Radiation therapy14 (2.8)3 (2.1)11 (3.0).766
      Fisher exact test.
      Concurrent chemoradiation30 (5.9)3 (2.1)27 (7.4).020
      χ2 test.
      Other1 (0.2)0 (0.0)1 (0.3)1.000
      Fisher exact test.
       Smoking history< .001
      χ2 test.
      Current116 (22.8)52 (35.9)64 (17.6)
      Past272 (53.5)49 (33.8)223 (61.4)
      Never/unknown
      Smoking history was unknown in 9 (1.8%) patients overall.
      120 (23.6)44 (30.3)76 (20.9)
       Documentation of PS< .001
      χ2 test.
      Impaired
      Evidence in the medical record of PS impairment ≥ 2 Eastern Cooperative Oncology Group rating.
      79 (15.6)10 (6.9)69 (19.0)
      Not impaired429 (84.4)135 (93.1)294 (81.0)
       Select comorbidities
      Only those comorbidities occurring in ≥ 5% of patients overall are reported. Other conditions examined included those assessed as part of the standard Charlson Comorbidity Index (peripheral vascular disease, hemiplegia, ulcer disease, connective tissue disease such as rheumatoid arthritis or lupus, Alzheimer’s or other dementia, cirrhosis or other serious liver disease, leukemia, lymphoma, metastatic solid tumor [other than bladder], and acquired immune deficiency syndrome).
      Diabetes119 (23.4)27 (18.6)92 (25.3).106
      χ2 test.
      Renal disease84 (16.5)13 (9.0)71 (19.6).004
      χ2 test.
      COPD63 (12.4)10 (6.9)53 (14.6).017
      χ2 test.
      Myocardial infarction41 (8.1)6 (4.1)35 (9.6).040
      χ2 test.
      Congestive heart failure26 (5.1)3 (2.1)23 (6.3).049
      χ2 test.
      Cerebrovascular accident24 (4.7)1 (0.7)23 (6.3).007
      χ2 test.
      Treatment characteristics prior to metastatic disease
       Patients with chemotherapy prior to stage IV/M1 disease19247145
       Received platinum.500
      χ2 test.
      Yes98 (51.0)26 (55.3)72 (49.7)
      No94 (49.0)21 (44.7)73 (50.3)
       Type of platinum agent982672.040
      Fisher exact test.
      Carboplatin34 (34.7)4 (15.4)30 (41.7)
      Cisplatin58 (59.2)20 (76.9)38 (52.8)
       Patients with stage IV/M1 disease414113301
       Surgery types
      TURBT254 (61.4)62 (54.9)192 (63.8).097
      χ2 test.
      Cystectomy
      Cystectomy and cystoprostatectomy categories did not differentiate between patients with or without documentation of radical surgery.
      103 (24.9)35 (31.0)68 (22.6).079
      χ2 test.
      Cystoprostatectomy
      Cystectomy and cystoprostatectomy categories did not differentiate between patients with or without documentation of radical surgery.
      82 (19.8)27 (23.9)55 (18.3).201
      χ2 test.
      Fulguration14 (3.4)4 (3.5)10 (3.3)1.000
      Fisher exact test.
      Nephroureterectomy12 (2.9)3 (2.7)9 (3.0)1.000
      Fisher exact test.
      Other111 (26.8)36 (31.9)75 (24.9).156
      χ2 test.
      Values do not equal 100% in all categories owing to rounding.
      Abbreviations: COPD = Chronic obstructive pulmonary disease; PS = performance status; SD = standard deviation; TURBT = transurethral resection of bladder tumor.
      a Although specific stage of disease was not reported, the majority had early-stage disease as evidenced by a documented record of surgery.
      b Surgery refers to any surgery for bladder cancer including radical cystectomy and TURBT.
      c Smoking history was unknown in 9 (1.8%) patients overall.
      d Evidence in the medical record of PS impairment ≥ 2 Eastern Cooperative Oncology Group rating.
      e Only those comorbidities occurring in ≥ 5% of patients overall are reported. Other conditions examined included those assessed as part of the standard Charlson Comorbidity Index (peripheral vascular disease, hemiplegia, ulcer disease, connective tissue disease such as rheumatoid arthritis or lupus, Alzheimer’s or other dementia, cirrhosis or other serious liver disease, leukemia, lymphoma, metastatic solid tumor [other than bladder], and acquired immune deficiency syndrome).
      f Cystectomy and cystoprostatectomy categories did not differentiate between patients with or without documentation of radical surgery.
      g χ2 test.
      h Fisher exact test.
      A comparison of the study sample characteristics by age (Table 1) showed that a higher proportion of patients aged ≥ 65 years had impaired performance compared with those < 65 years (19.0% vs. 6.9%; P < .001). Patients aged ≥ 65 years had higher rates of renal disease (19.6% vs. 9.0%; P = .004), chronic obstructive pulmonary disease (14.6% vs. 6.9%; P = .017), and congestive heart failure (6.3% vs. 2.1%; P = .049), respectively, compared with patients aged < 65 years. Overall, a higher percentage of older (≥ 65 years) compared with younger (< 65 years) patients had surgery as the primary treatment (61.7% vs. 51.0%; P = .027). Comparison of sample characteristics by treatment category (not shown) indicated significant differences in mean age: cisplatin, age 65 years; carboplatin, age 69 years; other/no treatment, age 73 years (P < .0001). Stage of disease at advanced diagnosis also differed among groups, with the cisplatin group having the lowest percentage of stage IV/M1 disease (54.8%), compared with the carboplatin (73.9%) and other/no treatment (73.5%; P = .001) groups. Impaired PS at stage IV diagnosis was lower in the cisplatin (9.6%) and carboplatin (11.8%) groups versus the other/no treatment group (21.7%; P = .004). In addition, presence of renal disease at advanced diagnosis was lower in the cisplatin group (8.7%) compared with the carboplatin (16.8%) and other/no treatment groups (20.8%; P = .018).
      A subset of the study sample had M1 disease (n = 414) at any point of follow-up. Table 1 summarizes the types of surgeries these patients received prior to M1 diagnosis. Transurethral resection of bladder tumor (61.4%) and cystectomy (24.9%) were the most frequent types of surgery in this setting. Almost one-half of these patients received chemotherapy prior to M1 diagnosis (192/414; 46.4%), and among these, 51% received platinum agents. Cisplatin was the most frequently prescribed platinum agent in this setting (Table 1).

      Treatment Patterns

      For the 501 patients diagnosed with stage IV cancer who had a first disease progression, systemic therapy consisted of platinum-based therapy (56.3%), with the most common regimen being gemcitabine/carboplatin (23.6%) followed by gemcitabine/cisplatin (17.0%). In the 1L treatment period, 35.9% of patients did not receive chemotherapy. Among the 265 patients with a second disease progression, platinum-based therapy was administered to 29.1% of patients. Otherwise, taxane alone, pemetrexed alone, gemcitabine alone, or taxane/gemcitabine were the most frequently used therapies. In the 2L treatment period, 44.5% of patients did not receive chemotherapy. A summary of systemic therapies in the stage IV setting is presented for patients from the 1L and 2L treatment periods in Supplemental Table 1 (in the online version).

      Clinical Outcomes

      PFS and OS were assessed by treatment line, overall, by treatment group, and separately among treated patients. Among 495 patients included in the overall analysis, the median PFS from the start of 1L was 6.4 months (Table 2). By treatment category, the median PFS for 1L was 8.5 months with cisplatin, 6.4 months with carboplatin, 7.5 months with other treatment, and 4.0 months with no treatment. The log-rank test of differences was significant (P = .012) (Figure 1A). In 2L, the overall median PFS was 3.8 months (Table 2). The median PFS for 2L by treatment category was 5.3 months with cisplatin, 3.9 months with carboplatin, 3.3 months with other treatment, and 4.0 months with no treatment (P = .621; data not shown).
      Table 2Kaplan-Meier Analyses of PFS and OS
      Overall
      Overall: The time origin was the start of therapy within 1L or 2L (defined above) or the start of the interval (1: diagnosis to day of first disease progression or 2: day after first disease progression to day of second disease progression) for those who did not receive treatment. For 1L PFS analysis, 7 of 508 patients were omitted owing to early censoring. Six additional patients were omitted from 1L PFS analysis because they received both cisplatin and carboplatin in 1L (these patients were also omitted from 1L OS analysis).
      Treatment
      Patients with treatment: The time origin was the start of therapy within 1L or 2L. Patients with no treatment were excluded from the analysis.
      PFS
       From start of 1L
      Median, mos6.47.5
      95% CI of median5.8-7.46.6-8.2
      Events/patients309/495232/321
       From start of 2L
      Median, mos3.83.7
      95% CI of median3.2-5.13.0-5.3
      Events/patients140/26596/147
      OS
       From start of 1L
      Median, mos8.411.0
      95% CI of median7.5-9.69.7-12.2
      Events/patients425/502263/321
       From start of 2L
      Median, mos4.45.3
      95% CI of median3.6-5.04.5-6.5
      Events/patients236/265130/147
      Abbreviations: 1L = First-line; 2L = second-line; CI = confidence interval; OS = overall survival; PFS = progression-free survival.
      a Overall: The time origin was the start of therapy within 1L or 2L (defined above) or the start of the interval (1: diagnosis to day of first disease progression or 2: day after first disease progression to day of second disease progression) for those who did not receive treatment. For 1L PFS analysis, 7 of 508 patients were omitted owing to early censoring. Six additional patients were omitted from 1L PFS analysis because they received both cisplatin and carboplatin in 1L (these patients were also omitted from 1L OS analysis).
      b Patients with treatment: The time origin was the start of therapy within 1L or 2L. Patients with no treatment were excluded from the analysis.
      Figure thumbnail gr1
      Figure 1Kaplan-Meier Estimates of PFS (A) and OS (B) From Start of 1L. All Patients, by Treatment. The Time Origin Was the Start of Therapy Within 1L or the Date of Diagnosis With Stage IV Bladder Cancer for Those Who did Not Receive Treatment. Seven of 508 Patients Were Omitted From the PFS Analysis Because of Early Censoring. Six Additional Patients Were Omitted From Both PFS and OS Analyses Because They Received Both Cisplatin and Carboplatin
      Abbreviations: 1L = First line; CI = confidence interval; OS = overall survival; PFS = progression-free survival.
      Cox regression analysis in 1L showed no significant difference in PFS between patients who were treated with cisplatin versus carboplatin (hazard ratio [HR], 1.232; P = .153) or other treatment (HR, 1.158; P = .542). Patients with no 1L therapy had, on average, a higher risk of disease progression compared with patients treated with cisplatin (HR, 1.606; P = .005). The model also showed that, on average, patients with impaired PS had a higher risk of disease progression versus unimpaired patients (HR, 1.613; P = .009). No difference in PFS was observed by treatment group in 2L.
      In the subset of 321 treated patients, the median PFS from start of 1L was 7.5 months and from 2L (n = 147) was 3.7 months (Table 2). No differences in PFS were observed by age group or by smoking status in either line. Cox regression analyses among patients with treatment showed no significant predictors of PFS in 1L or 2L, although these models did not include a treatment category variable.
      Among the overall sample of 508 patients, median OS from stage IV bladder cancer diagnosis was 9.4 months (95% confidence interval [CI], 8.3-10.7 months). By treatment category, the median OS from stage IV bladder cancer diagnosis was 14.6 months with cisplatin, 11.3 months with carboplatin, 7.3 months with other treatment, and 4.2 months with no treatment (log-rank: P < .001; data not shown). The median OS from start of 1L was 8.4 months for the overall analysis (n = 502) (Table 2). The median OS from start of 1L by treatment group was 13.3 months in the cisplatin group, 10.6 months in the carboplatin group, 6.8 months in the other treatment group, and 4.2 months in the no treatment group (log-rank: P < .0001; Figure 1B). The overall median OS from start of 2L was 4.4 months (Table 2). By treatment category, the median OS from start of 2L was 6.2 months with cisplatin, 8.0 months with carboplatin, 4.7 months with other treatment, and 2.5 months with no treatment (log-rank: P = .010; data not shown).
      Cox regression analysis of OS from stage IV bladder cancer diagnosis showed, on average, a higher risk of death for patients who received no treatment (HR, 2.057; P < .0001) or other treatment (HR, 1.833; P = .002) compared with patients who received cisplatin. Those with impaired PS were, on average, at greater risk of death versus unimpaired patients (HR, 2.053; P < .0001). Cox regression analysis of OS in the 1L showed no difference in the risk of death for cisplatin-treated patients versus carboplatin-treated patients (HR, 1.107; P = .464). The model showed that, on average, patients with no (HR, 1.859; P < .0001) or other (HR, 1.812; P = .002) 1L therapy had higher risk of death than cisplatin-treated patients. Patients with impaired PS had, on average, a higher risk of death versus unimpaired patients (HR, 2.054; P < .0001). Cox regression analysis of OS from 2L showed that patients with impaired PS had, on average, a higher risk of death versus unimpaired patients (HR, 1.702; P = .022).
      In the subset of treated patients, the median OS from the start of 1L and 2L was 11.0 and 5.3 months, respectively (Table 2). No differences in OS were seen by age group or by smoking status in either line. Cox regression analysis of OS in 1L in the subset of treated patients showed a higher risk of death among men versus women (HR, 1.418; P = .019), and impaired versus unimpaired status (HR, 2.143; P < .001). In 2L, Cox regression analysis showed a higher risk of death among patients of nonwhite or unknown race versus white patients (HR, 1.660; P = .022).

      Discussion

      The results of this real-world, community-based retrospective study in patients with stage IV bladder cancer show that the preferred 1L treatment was platinum-based chemotherapy, which was received by 56.3% of patients. Gemcitabine/cisplatin and gemcitabine/carboplatin were the most commonly observed 1L treatments, and no clear option was observed for 2L. Thirty-six percent of patients received no 1L chemotherapy and 44.5% of patients did not receive 2L chemotherapy. There was no difference in PFS or OS in the 1L or 2L between patients treated with cisplatin or carboplatin. Patients who received no/other therapy in these settings had worse clinical outcomes than those who received cisplatin. Untreated patients (several reasons for non-treatment including physician’s choice, patient’s choice, or creatinine clearance) had the poorest outcomes and demonstrate an unmet need. Our findings reflect that gemcitabine/carboplatin and gemcitabine/cisplatin were the most recent standard of care for 1L chemotherapy in the community oncology setting prior to the recent US Food and Drug Administration approval of immune checkpoint blockers.
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      • Mead G.
      • et al.
      Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986.
      • Kaufman D.
      • Raghavan D.
      • Carducci M.
      • et al.
      Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer.
      • Sternberg C.N.
      • de Mulder P.
      • Schornagel J.H.
      • et al.
      Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours.
      Checkpoint blockers add a new armamentarium of bladder cancer treatment and the hope of novel immunotherapeutic options. With these recent approvals, the NCCN Guidelines now recommend gemcitabine/carboplatin, pembrolizumab, or atezolizumab for 1L therapy in cisplatin-ineligible patients, with pembrolizumab and atezolizumab limited to those patients whose tumors express high PD-L1 (or those ineligible for any platinum-based chemotherapy, regardless of PD-L1 expression).
      National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer, Version 5.2018.
      • Balar A.V.
      • Castellano D.E.
      • O’Donnell P.H.
      • et al.
      Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: results from the total KEYNOTE-052 study population.
      • Balar A.V.
      • Galsky M.D.
      • Rosenberg J.E.
      • et al.
      Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
      There are limited data in the literature to compare PFS and OS outcomes among patients with stage IV bladder cancer treated in a US community oncology setting. The findings presented here provide an opportunity to compare real-world data with data from clinical trials. Our results for median PFS (7.5 months in the 1L among patients receiving chemotherapy) are comparable with previous results from clinical trials comparing platinum-based regimens in advanced bladder cancer, which showed a median PFS of 7.6 months for gemcitabine/cisplatin and 8.3 months for gemcitabine/cisplatin/paclitaxel.
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • et al.
      Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987.
      We show that PFS in the 1L treatment period was shorter in the overall group (6.4 months) compared with patients who were treated, and that patients who did not receive platinum-based therapy had a shorter median PFS than those who received platinum-based therapy. Interestingly, our results for the median OS in 1L (11.0 months) were shorter than those reported in clinical trials of patients who received gemcitabine/cisplatin with (15.8 months) or without (12.7 months) paclitaxel,
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • et al.
      Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987.
      and slightly higher than those reported for patients who were deemed cisplatin-ineligible and were assigned to receive gemcitabine/carboplatin (9.3 months) or methotrexate/carboplatin/vinblastine (8.1 months).
      • Bellmunt J.
      • von der Maase H.
      • Mead G.M.
      • et al.
      Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987.
      We observed differences by chemotherapy treatment category (cisplatin vs. carboplatin vs. no/other chemotherapy) in a small number of patient characteristics such as age and stage of disease at diagnosis. As expected, we observed that patients who received cisplatin were younger, had a better PS, and had a lower percentage of renal disease than those who received carboplatin.
      • Sonpavde G.
      • Galsky M.D.
      • Latini D.
      • et al.
      Cisplatin-ineligible and chemotherapy-ineligible patients should be the focus of new drug development in patients with advanced bladder cancer.
      However, Cox regression models that included these patient-level characteristics showed no difference between the platinum agents in efficacy outcomes and significantly worse outcomes for patients who received other/no treatment versus those who received cisplatin. This study does not answer why the decision was made to not treat patients in 1L or 2L. Treatment decision is an interesting area for future research. A detailed investigation of the demographic and clinical characteristics of patients who are never treated and who have cessation of treatment may shed light on whether outcomes among untreated patients result from a lack of treatment or the underlying characteristics of the patients, revealing what the true unmet need might be.
      Recent findings from an observational study of 5653 patients using the National Cancer Database showed that adjuvant chemotherapy was associated with improved survival in patients with locally advanced bladder cancer.
      • Galsky M.D.
      • Stensland K.D.
      • Moshier E.
      • et al.
      Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer.
      Despite several years of evidence from clinical trials supporting the use of adjuvant chemotherapy,
      • Galsky M.D.
      • Stensland K.D.
      • Moshier E.
      • et al.
      Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer.
      • Clark P.E.
      • Spiess P.E.
      • Agarwal N.
      • et al.
      NCCN Guidelines Insights: Bladder Cancer, Version 2.2016.
      • Leow J.J.
      • Martin-Doyle W.
      • Rajagopal P.S.
      • et al.
      Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials.
      we reviewed the treatment that patients in our study received between their initial and stage IV bladder cancer diagnoses, and the data show that fewer than 50% received chemotherapy. This suggests that change of treatment patterns may be adopted slowly in the real-world setting and underscores the importance of providing real-world evidence.
      Future research should focus on real-world evidence regarding immuno-oncology therapies to gauge the improvement of outcomes in real-world settings. Such research should incorporate analyses of patient characteristics and treatment patterns leading up to stage IV diagnosis. The research presented in this paper is important in helping to lay the foundation for such future studies. Limitations of this study include that physician assessment of disease progression in real-world practice may vary from the Response Evaluation Criteria in Solid Tumors (RECIST) criteria used in clinical trials. Further, the frequency of disease assessment and the standard of care may also differ among practices. These sources of variability are unlikely to introduce systematic bias. This study is retrospective and does not include some agents that have recently become available as treatment options for this patient population, such as immune checkpoint blockers. It will be of interest to examine outcomes when data have matured for newer therapies.

      Conclusions

      Real-world data on current treatment patterns in patients with stage IV bladder cancer are limited. Our research provides a necessary overview of patient characteristics, treatment patterns, and outcomes in this patient population and highlights the unmet need, particularly in the relapsed/refractory setting, for better treatment and improved clinical outcomes in these patients. We show that the recent standard of care for first-line treatment of patients with stage IV bladder cancer in the community oncology setting is platinum-based chemotherapy. There was no clear preferred option for 2L treatment in these patients. As immuno-oncology therapies begin to see uptake in the community oncology setting, future research should focus on real-world evidence of these therapies and should gauge the improvement of newer treatment options in comparison with the current standard of care.

      Clinical Practice Points

      • There are limited available real-world data on current treatment patterns in patients with stage IV bladder cancer.
      • In the US community setting, platinum-based chemotherapy is the recent standard of care for first-line treatment of patients with stage IV bladder cancer.
      • Gemcitabine/cisplatin and gemcitabine/carboplatin were the 2 most commonly observed first-line treatments. There has been no definite second-line treatment option for this patient population.
      • Immuno-oncology therapies are beginning to be introduced in the community oncology setting.

      Disclosure

      Dr Shenolikar is an employee of AstraZeneca and owns stock in the company; Drs Fisher and Miller are employees of Vector Oncology; Dr Walker is an employee of Vector Oncology and receives consultancy fees from Genentech; and Dr Fenton has received consulting fees from AstraZeneca. AstraZeneca sponsored Vector Oncology to conduct this study. AstraZeneca also sponsored the Lockwood Group and Cactus Communications Pvt. Ltd. for support and assistance with submission of the manuscript to the journal.

      Acknowledgments

      The authors thank The Lockwood Group (Stamford, CT) for editorial support, which was in accordance with Good Publication Practice (GPP3) guidelines and funded by AstraZeneca (Wilmington, DE). The authors also thank Michelle Rebello and Shruti Shah (CACTUS Communications) for editorial assistance and submission of the manuscript.

      Supplemental Data

      Supplemental Table 1Systemic Therapy by Line
      Agents1L (N = 501), n (%)2L (N = 265), n (%)
      Gemcitabine + carboplatin only118 (23.6)25 (9.4)
      Gemcitabine + cisplatin only85 (17.0)17 (6.4)
      Carboplatin/taxane26 (5.2)22 (8.3)
      Cisplatin/other25 (5.0)6 (2.3)
      Carboplatin/other14 (2.8)2 (0.8)
      Cisplatin only7 (1.4)2 (0.8)
      Carboplatin only2 (0.4)1 (0.4)
      Cisplatin/taxane2 (0.4)1 (0.4)
      Gemcitabine/cisplatin/taxane2 (0.4)0 (0.0)
      Gemcitabine/carboplatin/taxane1 (0.2)1 (0.4)
      Gemcitabine only19 (3.8)14 (5.3)
      Gemcitabine/taxane2 (0.4)4 (1.6)
      Taxane only6 (1.2)25 (9.4)
      Pemetrexed1 (0.2)16 (6.0)
      Other
      Other: in 1L, included 5-fluorouracil/mitomycin, capecitabine, Bacillus Calmette-Guérin (BCG), methotrexate, temozolomide, and topotecan; in 2L, included taxane/other, doxorubicin, capecitabine/everolimus, ifosfamide, oxaliplatin, and topotecan.
      11 (2.2)11 (4.2)
      No chemotherapy
      Some patients who were not treated in 1L were treated at a later period. The overall proportion of patients who did not receive any chemotherapy was approximately 30%.
      180 (35.9)118 (44.5)
      Abbreviations: 1L = First-line; 2L = second-line.
      a Other: in 1L, included 5-fluorouracil/mitomycin, capecitabine, Bacillus Calmette-Guérin (BCG), methotrexate, temozolomide, and topotecan; in 2L, included taxane/other, doxorubicin, capecitabine/everolimus, ifosfamide, oxaliplatin, and topotecan.
      b Some patients who were not treated in 1L were treated at a later period. The overall proportion of patients who did not receive any chemotherapy was approximately 30%.

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