# Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden: A Real-World Observational Study From the French National Healthcare System Database

Aldéric Masoandro Fraslin, Simone Benhamou, Thierry Lebret, François Radvanyi, Yves Allory, Maryam Karimi, Julia Bonastre

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Aldéric Masoandro Fraslin, Simone Benhamou, Thierry Lebret, François Radvanyi, Yves Allory, et al. Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden: A Real-World Observational Study From the French National Healthcare System Database. Clinical Genitourinary Cancer, 2025, 23 (3), pp.102344. 10.1016/j.clgc.2025.102344. inserm-05057444

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# Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden: A Real-World Observational Study From the French National Healthcare System Database

Aldéric Masoandro Fraslin,<fnref n="1" />,<fnref n="2" /> Simone Benhamou,<fnref n="1" />,<fnref n="2" /> Thierry Lebret,<fnref n="3" />
François Radvanyi,<fnref n="4" /> Yves Allory,<fnref n="4" /> Maryam Karimi,<fnref n="1" />,<fnref n="2" />,# Julia Bonastre<fnref n="1" />,<fnref n="2" />,#

## Abstract

We analyzed claims data to study the incidence, healthcare pathways and medical costs of bladder cancer patients in France. In 2017, 24,737 French patients were hospitalized for first-time bladder cancer; 12.3% had a cystectomy within 6 months. A clustering analysis identified 8 care trajectory groups of patients, with mean first-year costs per patient ranging from €4435 to €25,636.

**Purpose:** To assess the incidence (all lesions) of bladder cancer (BC) in France, describe patient characteristics and healthcare pathways during the first year after diagnosis, and estimate medical costs. **Methods:** All adult patients with an initial BC diagnosis (ICD-10 codes: C67, D09.0, D41.4) in 2017 were selected from the French National Healthcare System Database. Patients were classified according to the most invasive surgical procedure they underwent. Treatments included cystectomy, transurethral resection of bladder tumor (TURBT), intravesical therapy, chemotherapy, and radiotherapy. Healthcare pathways were analyzed as sequences and grouped using hierarchical clustering. Medical costs during the first year of the disease were estimated for each cluster. **Results:** Out of 24,737 incident BC patients selected, the median age at diagnosis was 72 years, and 80.2% were men. Nearly 20% had received treatment for a cancer other than BC in the previous year. The majority (n = 9501, 38.4%) underwent TURBT only with a mean medical cost of €4435 [95% CI: 4322; 4548]. A total of 3037 patients (12.3%) underwent cystectomy as their initial treatment. The estimated costs for the group receiving intravesical instillations following a single TURBT (€6129 [5994; 6264]) were lower than those for the group with repeated TURBT (€9357 [9086; 9628]). Costs for patients who received systemic treatment after cystectomy were the highest at €25,636 [24,519; 26,752]. **Conclusion:** Our study estimates the incidence of BC in France, describes healthcare pathways at the national level, and analyses the associated economic burden.

Clinical Genitourinary Cancer, Vol. 23, No.xxx, 102344 © 2025 The Author(s). Published by Elsevier Inc.
This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/))
**Keywords:** Clustering, Costs, Electronic claims databases, Treatment patterns, Urothelial carcinoma

## Introduction

Bladder cancer (BC) ranks ninth in cancer site incidence worldwide, with higher incidence rates in southern, northern, and western Europe.<fnref n="1" /> In France, BC is the fourth most common cancer in men but is much less frequent in women. In 2017, approximately 13,150 new cases and 5000 deaths from BC were estimated.<fnref n="2" /> However, this incidence estimate was based on data from French local cancer registries, which did not systematically include noninvasive papillary carcinoma (Ta) and carcinoma in situ (Tis). These tumors may represent up to 50% to 60% of all bladder tumors.<fnref n="3" />⁻⁵

BC treatment options differ significantly between early-stage/non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). Transurethral removal of bladder tumor (TURBT) serves

<footnote n="1">¹Department of Biostatistics and Epidemiology, Gustave Roussy, University Paris-Saclay, Villejuif, France</footnote>

<footnote n="2">²University Paris-Saclay, Oncostat U1018, INSERM, Labeled Ligue Contre le Cancer, Villejuif, France</footnote>

<footnote n="3">³Department of Urology, Hôpital Foch, Suresnes, France</footnote>

<footnote n="4">⁴Department of Pathology, Université Paris-Saclay, UVSQ, Institut Curie, Paris, France</footnote>

<footnote>Submitted: Aug 22, 2024; Revised: Mar 31, 2025; Accepted: Mar 31, 2025; Epub: 2 April 2025</footnote>

<footnote>Address for correspondence: Aldéric Masoandro Fraslin, Department of Biostatistics and Epidemiology, Gustave Roussy, University Paris-Saclay, [114, rue Edouard] Vaillant, Villejuif 94800, France.</footnote>

<footnote>E-mail contact: alderic.fraslin@gustaveroussy.fr</footnote>

<footnote>* Co-last authors.</footnote>
# Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden

both diagnostics and treatment purposes. For early-stage BC (stage 0-I), TURBT can be the sole care, possibly repeatedly, and may be combined with intravesical therapy for high-grade tumors. MIBC is treated with cystectomy. Cisplatin-based chemotherapy, either as neoadjuvant or adjuvant therapy, is a standard treatment option for MIBC-fit patients. NMIBC recurrence rates can be as high as 50 to 70%,⁶ and half of MIBC patients will experience recurrence within 5 years.⁷ Therefore, treatments aimed at preventing recurrence by combining surgery with other therapies (eg, intravesical therapy or systemic chemotherapy) according to risk classification guidelines.⁷,⁸ However, there is substantial variability in practices, which is essential to describe for assessing the quality and performance of the healthcare system.

In France, data on BC incidence, treatment patterns, and costs in routine practice are scarce and limited to selected patient populations.⁹,¹⁰ Using patient-level data from the French National Healthcare System Database (SNDS), our objective was to estimate incidence, describe patient characteristics and healthcare pathways during the first year after diagnosis, and assess the associated economic burden for all BC patients.

## Materials and Methods

### Data Source

The SNDS covers 98.8% of the French population. This medical administrative database gathers information for all inpatient and outpatient services.¹¹ It provides the total cost (regardless of the payer) of healthcare resources that are at least partially covered by French national health insurance. Data included patient age, gender, zip code of the town of residence, hospital stay characteristics (hospital identification, ICD-10 diagnosis codes, procedure codes, diagnosis-related group (DRG), date and length of stay), ICD-10 code for long-term illness coverage (LTI), health insurance scheme, area-based deprivation index (quintiles),¹² date of death, drugs and BC medical costs.

### Study Population

Updating an existing algorithm to identify BC patients,¹³ we extracted all hospital stays for adult patients hospitalized for BC (using ICD-10 codes as described in supplementary materials: C67 for malignant neoplasms of the bladder, D09.0 for carcinoma in situ of the bladder and D41.4 for neoplasms of uncertain behavior of the bladder) between January 1 and December 31, 2017. To select incident patients, we excluded those who presented former BC ICD-10 codes either from hospitalizations (up to 2005) or from LTI coverage (before 2016). In addition, to select patients with exhaustive healthcare information, we excluded patients living outside France or with missing health insurance coverage. Patients who had previously undergone cystectomy (even without BC ICD-10 code) were also excluded. The index date was defined for each patient as the date of the first occurrence of a BC ICD-10 code (mainly for TURBT) among hospital stays. Patients who did not receive surgery (TURBT or cystectomy) within 6 months following the index date were excluded from our analysis. Patient selection is summarized in Figure 1 and detailed in supplementary materials.

### Identification of Treatments

BC inpatient treatments and sessions (chemotherapy and radiotherapy) were selected among all hospital stays in 2017 with any BC ICD-10 code for the study population. Initial BC surgery was classified as either TURBT or cystectomy based on procedure codes. In-hospital chemotherapy and radiotherapy were identified through ICD-10 codes, while outpatient radiotherapy was identified using procedure codes. Intravesical therapy (BCG or mitomycin) can be delivered either in a day hospital (with a chemotherapy ICD-10 code) or in an outpatient setting. When available, we used the procedure code for instillation to identify intravesical therapy sessions in both settings. In addition, to handle missing procedure codes for instillation, we developed an algorithm to identify intravesical therapy sessions among chemotherapy sessions or in the outpatient setting based on the rhythm and the time interval between chemotherapy sessions and/or urologist visits (Supplemental Materials). For patients who underwent cystectomy, systemic chemotherapy was considered as neoadjuvant therapy if performed before cystectomy or as adjuvant therapy if initiated within 3 months after cystectomy, in both cases without any metastatic-related ICD-10 code as a related diagnosis. All procedure codes used to identify BC treatments are provided in supplementary materials.

### Data Analysis

Cystectomy was considered the initial surgery if performed within the 6 months following the index date. Otherwise, initial surgery was defined as the first TURBT. For each patient, the Charlson comorbidity index score¹⁴ was calculated on comorbidity information (ICD-10 codes and drugs) in the year preceding the index date.¹⁵ Vulnerable patients were identified through specific ICD-10 codes (supplementary materials). The deprivation index was considered for the residence area at the index date. To characterize hospitals, we used 2 variables: hospital volume defined by the number of cystomies performed in 2017 (low volume: < 10, intermediate volume: ≥ 10 and < 30, high volume: ≥ 30) and hospital profile (private-for-profit and public or private non-for-profit hospitals). Age- and sex- standardized incidence rates by French regions were estimated using the area code of residence of the patient at the index date.

Sequential analysis was performed to describe different healthcare pathways in the first year of the disease and the associated economic burden.¹⁶,¹⁷ BC treatments were transformed into an ordered sequence of states for each patient. Seven states were considered: TURBT, cystectomy, intravesical therapy, chemotherapy, radiotherapy, radiochemotherapy, and no treatment. A time interval of 1 week was used. Similarities between sequences were computed using the Optimal Matching of spell of transitions (OMstran) with a low expansion cost method. This method ensures that the succession of states remains a crucial determinant of differences in pathways while still accounting for time spent in each state. It enables pathways with the same BC treatments (in the same order) to be grouped despite different administration schemes.¹⁸

Homogeneous healthcare pathways (clusters) were then built from the similarity matrix using hierarchical Ward clustering,¹⁹ and the final number of clusters was chosen upon visual inspection of the dendrogram and the largest vertical distance between clusters,
<figure><img src="image_4.png" /><figcaption>**Figure 1** Flow chart of patient selection (incident cases of bladder cancer in 2017).</figcaption></figure>

indicating a significant drop in similarity. Because prognosis and
possible associated treatment options differ mainly depending on
the initial surgery, clustering was performed separately for patients
who underwent cystectomy and patients who did not. To simplify
computation, patients who had only a TURBT (with no additional
treatment) in the first year following diagnosis were not included
in the clustering analysis because they are numerous and consti-
tute a homogenous group of patients. Finally, all hospital costs for
stays with a BC ICD-10 code, as well as costs of outpatient services
(radiotherapy and intravesical therapy) in the first year of the disease,
were estimated from an all-payer perspective. Costs are described
for each cluster using mean per-patient cost and 95% confidence
interval (CI). An additional cost of €157 corresponding to BCG-
MEDAC was accounted for intravesical therapy sessions performed
in the outpatient setting. Statistical analyses were performed using
SAS Enterprise Guide Software (SAS Institute Inc., Cary, NC, USA,
version 9.4) and R (TRAMineR package²⁰).

Results

A total of 24,737 BC patients who underwent surgery at 1 of 612
hospitals were identified for the year 2017, among whom 21,700
underwent TURBT only, and 3037 underwent cystectomy within
6 months after the index date (Figure 1). Most patients were men
(80.3%) with a median age of 72 years (Table 1). Distant metastases
at the index date or in the following 3 months were present among
9.1% of patients who underwent cystectomy and 2.0% of patients
who did not. BC patients had high comorbidity scores (18.8% of
patients with a Charlson index ≥ 3), and 19.9% had been treated
for cancer other than BC in the year before the index date.

For the TURBT-only group, most surgeries were performed
in private for-profit hospitals of intermediate volume. Cystec-
tomies were mainly performed in high-volume hospitals, although
15.7% were conducted in low-volume hospitals. Cystoprostatec-
tomies accounted for 65.3% of interventions.

Standardized incidence rates ranged from 30 to 96.8 cases
per 100,000 inhabitants among French regions, with higher rates
observed in the Southeast and the Northeast (Figure 2).

Among patients who did not undergo cystectomy, 37.3% received intravesical therapy, 7.5% underwent chemotherapy, and 3.6% received radiotherapy (Table 2). The majority of patients (90.4%) who underwent cystectomy had at least 1 previous TURBT. The average hospitalization duration for cystectomy was 18.9 days, with 9% of cases requiring postoperative intensive care unit admission. Regarding systemic treatments in patients who underwent cystectomy, 638 (21.0%) received neoadjuvant chemotherapy, and 187 (6.2%) received adjuvant chemotherapy. Radiotherapy was a less common treatment option in the year following diagnosis, with only 2.7% of patients irradiated among patients undergoing cystectomy.

The main group comprised patients who had 1 TURBT as
their sole care in the first year after BC diagnosis (n = 9501
patients). For the rest of the population, the sequence analysis
identified 7 clusters. The main cluster for patients with initial
cystectomy gathered 2027 patients (66.7%) without systemic
treatment. Among patients who did not undergo initial cystec-
tomy, a cluster of 1119 patients (5.2%) still received systemic
treatments. A visualization of healthcare pathways is shown in
Figure 3.
Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden

<table><caption>**Table 1** Patient and Hospital Characteristics</caption><thead><tr><th></th><th>TURBT</th><th>Cystectomy</th><th>Total</th></tr></thead><tbody><tr><td>N (% Total)</td><td>21,700 (87.7)</td><td>3037 (12.3)</td><td>24,737 (100)</td></tr><tr><td>Gender, n (%)</td><td></td><td></td><td></td></tr><tr><td>Male</td><td>17,428 (80.3)</td><td>2408 (79.3)</td><td>19,836 (80.2)</td></tr><tr><td>Female</td><td>4272 (19.7)</td><td>629 (20.7)</td><td>4901 (19.8)</td></tr><tr><td>Age at index date, years, median (IQR)</td><td>72 (64; 80)</td><td>70 (63; 77)</td><td>72 (64; 80)</td></tr><tr><td>Age groups, years, n (%)</td><td></td><td></td><td></td></tr><tr><td>&lt;40</td><td>258 (1.2)</td><td>21 (0.7)</td><td>279 (1.1)</td></tr><tr><td>40-49</td><td>590 (2.7)</td><td>84 (2.8)</td><td>674 (2.7)</td></tr><tr><td>50-59</td><td>2249 (10.4)</td><td>354 (11.6)</td><td>2603 (10.5)</td></tr><tr><td>60-69</td><td>5892 (27.2)</td><td>997 (32.8)</td><td>6889 (27.9)</td></tr><tr><td>70-79</td><td>6651 (30.6)</td><td>1023 (33.7)</td><td>7674 (31.0)</td></tr><tr><td>≥80</td><td>6060 (27.9)</td><td>558 (18.4)</td><td>6618 (26.8)</td></tr><tr><td>Charlson comorbidity index score at index date, n (%)</td><td></td><td></td><td></td></tr><tr><td>0</td><td>9367 (43.2)</td><td>1411 (46.5)</td><td>10,778 (43.6)</td></tr><tr><td>1-2</td><td>8257 (38.0)</td><td>1049 (34.5)</td><td>9306 (37.6)</td></tr><tr><td>≥3</td><td>4076 (18.8)</td><td>577 (19.0)</td><td>4653 (18.8)</td></tr><tr><td>Diabetes in the past year, n (%)</td><td>3794 (17.5)</td><td>493 (16.2)</td><td>4287 (17.3)</td></tr><tr><td>Other cancer in the past year, n (%)</td><td>4277 (19.7)</td><td>656 (21.6)</td><td>4933 (19.9)</td></tr><tr><td>Distant metastasis at index date<sup>a</sup>, n (%)</td><td>443 (2.0)</td><td>276 (9.1)</td><td>719 (2.9)</td></tr><tr><td>Primary diagnosis ICD-10 code at index date, n (%)</td><td></td><td></td><td></td></tr><tr><td>C67</td><td>18,409 (84.8)</td><td>2911 (95.8)</td><td>21,320 (86.2)</td></tr><tr><td>D09.0 (in situ)</td><td>1148 (5.3)</td><td>36 (1.2)</td><td>1184 (4.8)</td></tr><tr><td>D41.4</td><td>2143 (9.9)</td><td>90 (3.0)</td><td>2233 (9.0)</td></tr><tr><td>Low income patients<sup>b</sup> in 2017, n (%)</td><td>518 (2.4)</td><td>82 (2.7)</td><td>600 (2.4)</td></tr><tr><td>Vulnerable<sup>c</sup> patients, n (%)</td><td>503 (2.3)</td><td>112 (3.7)</td><td>615 (2.5)</td></tr><tr><td>Insurance scheme, n (%)</td><td></td><td></td><td></td></tr><tr><td>General scheme</td><td>17,725 (81.8)</td><td>2511 (82.7)</td><td>20,236 (81.9)</td></tr><tr><td>Agricultural scheme</td><td>1255 (5.8)</td><td>171 (5.6)</td><td>1426 (5.8)</td></tr><tr><td>Self-employed workers scheme</td><td>1480 (6.8)</td><td>192 (6.3)</td><td>1672 (6.8)</td></tr><tr><td>Other schemes</td><td>1221 (5.6)</td><td>162 (5.3)</td><td>1383 (5.6)</td></tr><tr><td>Deprivation index, n (%)</td><td></td><td></td><td></td></tr><tr><td>First quintile (least deprived)</td><td>4041 (19.0)</td><td>529 (17.8)</td><td>4570 (18.9)</td></tr><tr><td>Second quintile</td><td>4042 (19.0)</td><td>531 (17.8)</td><td>4573 (19.0)</td></tr><tr><td>Third quintile</td><td>4386 (20.7)</td><td>635 (21.3)</td><td>5021 (20.7)</td></tr><tr><td>Fourth quintile</td><td>4365 (20.6)</td><td>656 (22.0)</td><td>5021 (20.7)</td></tr><tr><td>Fifth quintile (most deprived)</td><td>4393 (20.7)</td><td>628 (21.1)</td><td>5021 (20.7)</td></tr><tr><td>Missing</td><td>473</td><td>58</td><td>531</td></tr><tr><td>Hospital profile (initial surgery), n (%)</td><td></td><td></td><td></td></tr><tr><td>Private for profit</td><td>12,645 (58.3)</td><td>1594 (52.5)</td><td>14,239 (57.6)</td></tr><tr><td>Public/Private non for profit</td><td>9055 (41.7)</td><td>1443 (47.5)</td><td>10,498 (42.4)</td></tr><tr><td>Hospital volume (initial surgery, n (%)</td><td></td><td></td><td></td></tr><tr><td>Low volume (&lt; 10 cystectomy in 2017)</td><td>6708 (30.9)</td><td>478 (15.7)</td><td>7186 (29.0)</td></tr><tr><td>Intermediate volume (≥ 10 and &lt; 30)</td><td>10,632 (49.0)</td><td>1701 (56.0)</td><td>12,333 (49.9)</td></tr><tr><td>High volume (≥30)</td><td>4360 (20.1)</td><td>858 (28.3)</td><td>5,218 (21.1)</td></tr></tbody></table>

Abbreviations: IQR = inter quartile range; TURBT = trans urethral removal of bladder tumor.

<footnote><sup>a</sup> In the first 3 months following index date.</footnote>

<footnote><sup>b</sup> Beneficiaries of a complementary universal health insurance for low-income households.</footnote>

<footnote><sup>c</sup> Presence of at least 1 vulnerability diagnosis at initial surgery.</footnote>
<figure><img src="image_5.png" /><figcaption>**Figure 2** Age- and sex- sex-standardized incidence rates of bladder cancer per 100,000 inhabitants per region in 2017.</figcaption></figure>

The mean cost per patient in the year following BC diagnosis varied from €4435 to €25,636 across clusters (Table 3). The cluster of patients whose only care was a TURBT was associated with the lowest per-patient cost, €4435 (95% CI: €4322; €4548). The addition of intravesical therapy to TURBT was less costly (mean per-patient cost of €6129 in the cluster with a standard treatment scheme) than repeated TURBTs without other treatment (€9357). Among patients who did not undergo cystectomy, the cluster of patients treated with chemotherapy or radiotherapy was associated with the highest economic burden (mean per-patient cost amounting to €19,136). Regarding patients who underwent cystectomy, the mean per-patient cost was €22,975 (95% CI: €22,537; €23,412), and it rose to €25,636 in the cluster of patients treated with chemotherapy after surgery.

Discussion

In our study, we identified a cohort of 24,737 patients newly diagnosed with BC, for which we describe healthcare pathways and associated costs based on real-life nationwide data. Unlike previous studies, we considered all BC patients, including those with noninvasive lesions treated with TURBT only. The incident population is twice as large as the one described by French cancer registries. This highlights the importance of the often overlooked less advanced forms of BC. Regional incidence is consistent with tobacco consumption in France. Medical costs in the first year of the disease were mostly driven by surgical interventions. When treatment was not limited to the initial TURBT, receiving intravesi-

cal therapy was the least costly option, particularly compared to repeated TURBT.

Our study relies on national real-world data covering the whole French population, providing comprehensive information on healthcare resource use and reflecting the diversity of clinical practices. We employed an innovative framework of sequence analysis to describe healthcare pathways and define homogeneous clinically relevant clusters. This clustering method could be applied to other real-world studies to describe treatment modalities in a given target population. This flexible methodology allows for the definition of clusters on treatments as well as other criteria (eg, patient characteristics or treatment schemes) if a more detailed analysis is sought.

Overall, our results are consistent with other studies describing BC in France, both in terms of patient characteristics and initial care. The proportion of women was higher in our study than in a French study focusing on patients who underwent radical cystectomy because, unlike this study, we included procedure codes for pelvectomy associated with ICD-10 BC codes.¹⁰ Cystoprostatectomies were less frequent in our study compared to the French prospective COBLANCE cohort⁹ because we included low-volume hospitals handling less complex patients. Our cost estimates are also consistent with previous studies²¹⁻²³ when focusing on 1-year costs or specific care. Lifetime costs estimated from these studies for advanced BC amounted to $200,000 for patients diagnosed between 2004 and 2013 in the US²² and reached even higher figures when considering emerging therapies.²³
# Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden

<table><caption>**Table 2** Bladder Cancer Treatments According to Initial Care Surgery</caption><thead><tr><th colspan="2">Patients Without Cystectomy (N = 21,700)</th></tr></thead><tbody><tr><td>Number of TURBT in the first 6 months, n (%)</td><td></td></tr><tr><td>1</td><td>16,258 (74.9)</td></tr><tr><td>2</td><td>4960 (22.9)</td></tr><tr><td>≥ 3</td><td>482 (2.2)</td></tr><tr><td>Time between 2 first TURBT (in days, when applicable): mean (SD)</td><td>77.9 (44.4)</td></tr><tr><td>Intravesical therapy, n (%)</td><td>8104 (37.3)</td></tr><tr><td>Chemotherapy, n (%)</td><td>1621 (7.5)</td></tr><tr><td>Radiotherapy, n (%)</td><td>787 (3.6)</td></tr></tbody><thead><tr><th colspan="2">Patients with cystectomy (N = 3037)</th></tr></thead><tbody><tr><td>Number of previous TURBT, n (%)</td><td></td></tr><tr><td>0</td><td>291 (9.6)</td></tr><tr><td>1</td><td>2323 (76.5)</td></tr><tr><td>≥ 2</td><td>423 (13.9)</td></tr></tbody><thead><tr><th colspan="2">Type of cystectomy, n (%)</th></tr></thead><tbody><tr><td>Cystoprostatectomy (males)</td><td>1982 (65.3)</td></tr><tr><td>Anterior pelvectomy (females)</td><td>451 (14.8)</td></tr><tr><td>Radical cystectomy (males)</td><td>289 (9.5)</td></tr><tr><td>Radical cystectomy (females)</td><td>123 (4.1)</td></tr><tr><td>Partial cystectomy/diverticulectomy</td><td>192 (6.3)</td></tr><tr><td>Length of hospital stay (in days) for cystectomy: mean (SD)</td><td>18.9 (12.2)</td></tr><tr><td>Postoperative intensive care unit admission for cystectomy: n (%)</td><td>272 (9.0)</td></tr><tr><td>Any chemotherapy, n (%)</td><td>1145 (37.7)</td></tr><tr><td>Neoadjuvant chemotherapy, n (%)</td><td>638 (21.0)</td></tr><tr><td>Adjuvant chemotherapy, n (%)</td><td>187 (6.2)</td></tr><tr><td>Radiotherapy, n (%)</td><td>81 (2.7)</td></tr></tbody></table>

Abbreviations: TURBT = trans urethral removal of bladder tumor; SD = standard deviation.

<table><caption>**Table 3** Per Patient Cost of Treatment (in €) in the First Year After Index Date by Cluster, All payers' Perspective With Additional BCG Cost</caption><thead><tr><th>Cluster description (N, NA<sup>a</sup>)</th><th>The mean cost per patient (in €) [95% CI]</th></tr></thead><tbody><tr><td>TURBT as sole care (N = 9501, NA: 26)</td><td>4435 [4322; 4548]</td></tr><tr><td>Patients without cystectomy, TURBT in combination with other treatments (N = 12,199, NA: 9):</td><td>9040 [8899; 9182]</td></tr><tr><td>CI. 1: TURBT + intravesical therapy (n = 4252, NA: 2)</td><td>6129 [5994; 6264]</td></tr><tr><td>CI. 2: Repeated TURBT, isolated treatment (n = 3740, NA: 6)</td><td>9357 [9086; 9628]</td></tr><tr><td>CI. 3: Repeated TURBT + intravesical therapy (n = 3089, NA: 0)</td><td>9012 [8799; 9226]</td></tr><tr><td>CI. 4: TURBT + CT or RT, eventual late CYS (n = 1118, NA: 1)</td><td>19,136 [18,431; 19,841]</td></tr><tr><td>Patients with cystectomy (N = 3037, NA: 9)</td><td>22,975 [22,537; 23,412]</td></tr><tr><td>CI. 1: TURBT + CYS or CYS alone (N = 2020, NA: 7)</td><td>22,010 [21,448; 22,571]</td></tr><tr><td>CI. 2: TURBT + neoadjuvant CT + CYS (N = 665, NA: 2)</td><td>24,493 [23,665; 25,320]</td></tr><tr><td>CI. 3: TURBT + CYS or CYS alone + CT ± RT (N = 352, NA: 0)</td><td>25,636 [24,519; 26,752]</td></tr></tbody></table>

Our study has some limitations. Firstly, our study does not provide a comprehensive estimation of the economic burden of bladder cancer. We chose to focus on treatment costs directly attributable to bladder cancer for the first year after diagnosis. We did not include follow-up costs (urologist visits, imaging, biological procedures, etc.) or transportation costs, which are more difficult to fully attribute to bladder cancer as no ICD-10 codes are available for these services in the French National Healthcare System Database. However, treatment costs are the main cost drivers for BC and account for most of the economic burden in the first year of the disease. Secondly and more importantly, our study uses data from the year 2017 and therefore does not include recent therapies, namely immunotherapy agents which have been approved and reimbursed in France in the metastatic setting (pembrolizumab, and

<footnote><sup>a</sup> NA: 44 patients had missing cost data and were not considered for costs calculation (no valuation of hospitalization in the database); Abbreviations: CI. 1 = cluster 1; CT = chemotherapy; CYS = cystectomy; RT = radiotherapy.</footnote>
<figure><img src="image_6.png" /><figcaption>**Figure 3** Most frequent healthcare pathways of clusters. This figure displays the 10 most frequent pathways of the 7 clusters identified. Each block represents a week and is colored depending on the treatment received this week. The percentage indicates the proportion of patients in each cluster to follow 1 of the 10 displayed trajectories (Ex: 2.5% of the 3089 patients in cluster "Repeated TURBT + intravesical therapy" follow one of the displayed trajectories for this cluster). CYS = cystectomy; CT = chemotherapy; RT = radiotherapy.</figcaption></figure>

avelumab) and the adjuvant setting (nivolumab).²⁴ However, we expect a relatively limited impact of these changes on clustering and healthcare costs in most clusters. The targeted populations of these drugs are quite limited (a maximum 1000 patients per year for the adjuvant setting²⁴) and reimbursement in France has occurred very recently (in 2019 in second-line metastatic patients, 2022 in first-line metastatic patients and in the adjuvant setting) though unlikely to significantly impact healthcare costs in the short term. As our study focuses on the first year after diagnosis, metastatic patients eligible to immunotherapy are very few (< 2%). Regarding patients undergoing cystectomy, it is likely that clustering would identify an additional cluster for patients receiving immunotherapy in the adjuvant setting with higher cost (the average cost of nivolumab in the adjuvant setting has been estimated at €42,000 per patient²⁴). In the near future, it will be relevant to update cost estimates in this patient population and also consider new antibody-drug conjugate therapies such as enfortumab vedotin or even more costly emerging treatments that have already been approved in the US. In addition, the Food and Drug Administration has approved the use of pembrolizumab combined with BCG in BCG-unresponsive, high-risk, NMIBC patients in the US. The efficacy of such PD(L)1 inhibitors in NMIBC patients is currently being investigated in France through phase III clinical trials.²⁵ The higher number of patients who might be eligible for such therapy highlights the need for rigorous economic evaluations to anticipate cost increases for the French health system. In the meantime, our study provides reliable

data that can be useful for cost-effectiveness analyses of new drugs currently under development. Finally, describing healthcare from administrative databases depends on information retrievability. As these databases do not provide data on tumor characteristics, caution is needed when considering characteristics such as metastatic status, especially in a population frequently subject to other cancers, as the ICD-10 code for metastasis does not indicate the tumor origin.

## Conclusion

Our study provides an estimation of BC incidence in France, a comprehensive description of healthcare pathways, and the associated economic burden. In addition, we provide a classification of healthcare pathways in BC using clustering analysis applied to medico-administrative data collected in routine practice.

### Clinical Practice Points

* With the recent approval of immunotherapy agents in bladder cancer (BC) treatment and with a constantly evolving landscape, it is of primary importance to understand treatment patterns and corresponding costs before these approvals.

* This study on real-world French data analyzes both differences in healthcare pathways and treatment costs among all BC patients

* The use of exhaustive national data from the French National Healthcare Database gives an overview of practice variability for BC treatment
# Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden

* We studied 24,737 patients who underwent surgery at 1 of 612 hospitals, 80.3% of whom were men, with a median age of 72.

* Healthcare pathways were derived from the main treatments identified in European guidelines. 12.3% of patients underwent cystectomy. About 37.3% of patients with no cystectomy received intravesical therapy.

* Despite encouraging guidelines prior to the introduction of immunotherapy, only 37.7% of patients who underwent cystectomy received chemotherapy. Clusters of patients receiving chemotherapy had the highest mean per-patient costs up to €25,636.

* This study provides comparative data for future research analyzing the introduction of new therapy options.

## Disclosures

TL reports personal honoraria from Ipsen and Bristol Myers Squibb and support for attending meetings or travel from Pfizer JB reports honoraria from Bristol Myers Squibb, Roche and MSD

YA reports invitations as speaker by AstraZeneca, Astellas, Bristol Myers Squibb, IPSEN, Janssen, MSD and Pfizer; expert boards held by Pfizer and Janssen

## CRediT authorship contribution statement

**Aldéric Masoandro Fraslin:** Writing – review & editing, Writing – original draft, Visualization, Resources, Methodology, Formal analysis, Data curation, Conceptualization. **Simone Benhamou:** Writing – review & editing, Validation, Resources, Project administration, Funding acquisition, Conceptualization. **Thierry Lebret:** Writing – review & editing, Validation, Project administration, Funding acquisition, Conceptualization. **François Radvanyi:** Writing – review & editing, Validation, Project administration. **Yves Allory:** Writing – review & editing, Validation, Project administration, Investigation, Funding acquisition, Conceptualization. **Maryam Karimi:** Writing – review & editing, Validation, Supervision, Methodology, Conceptualization. **Julia Bonastre:** Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization.

## Acknowledgments

This work was funded by Institut National du Cancer (INCA, France) [grant number 2019-1-PL SHS-01-IGR-1].

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.clgc.2025.102344.

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