Clinical–Pathologic Stage Discrepancy in Bladder Cancer Patients Treated With Radical Cystectomy: Results From the National Cancer Data Base

doi:10.1016/j.ijrobp.2014.01.001

International Journal of Radiation OncologyBiologyPhysics

Volume 88, Issue 5, 1 April 2014, Pages 1048-1056

https://doi.org/10.1016/j.ijrobp.2014.01.001 Get rights and content

Purpose

To examine the accuracy of clinical staging and its effects on outcome in bladder cancer (BC) patients treated with radical cystectomy (RC), using a large national database.

Methods and Materials

A total of 16,953 patients with BC without distant metastases treated with RC from 1998 to 2009 were analyzed. Factors associated with clinical–pathologic stage discrepancy were assessed by multivariate generalized estimating equation models. Survival analysis was conducted for patients treated between 1998 and 2004 (n=7270) using the Kaplan-Meier method and Cox proportional hazards models.

Results

At RC 41.9% of patients were upstaged, whereas 5.9% were downstaged. Upstaging was more common in females, the elderly, and in patients who underwent a more extensive lymphadenectomy. Downstaging was less common in patients treated at community centers, in the elderly, and in Hispanics. Receipt of preoperative chemotherapy was highly associated with downstaging. Five-year overall survival rates for patients with clinical stages 0, I, II, III, and IV were 67.2%, 62.9%, 50.4%, 36.9%, and 27.2%, respectively, whereas those for the same pathologic stages were 70.8%, 75.8%, 63.7%, 41.5%, and 24.7%, respectively. On multivariate analysis, upstaging was associated with increased 5-year mortality (hazard ratio [HR] 1.80, P<.001), but downstaging was not associated with survival (HR 0.88, P=.160). In contrast, more extensive lymphadenectomy was associated with decreased 5-year mortality (HR 0.76 for ≥10 lymph nodes examined, P<.001), as was treatment at an National Cancer Institute–designated cancer center (HR 0.90, P=.042).

Conclusions

Clinical–pathologic stage discrepancy in BC patients is remarkably common across the United States. These findings should be considered when selecting patients for preoperative or nonoperative management strategies and when comparing the outcomes of bladder sparing approaches to RC.

Introduction

Cancer of the urinary bladder is a common cancer, with 72,570 new cases estimated in the United States in 2013 (1). Although most cases of non-muscle-invasive bladder cancer are managed effectively with transurethral resection and intravesical therapy, up to 40% of patients develop treatment-refractory disease (2). For these patients and all patients with muscle invasion at diagnosis, radiation therapy (RC) is the most common treatment received (3). Despite this, nonoperative strategies, especially chemoradiation therapy , are widely practiced, with long-term outcomes comparable to those with cystectomy in many series 4, 5, 6.

Accurate clinical staging is vital for preoperative risk stratification and proper selection for neoadjuvant chemotherapy. Accurate clinical stage is even more vital to appropriately select patients for nonoperative management strategies such as chemoradiation therapy. By definition, such therapies do not have the benefit of determining final pathologic stage. As such, the success of such therapies and the design of clinical trials to test novel nonoperative treatments are wholly dependent on the accuracy of the assigned clinical stage. Several previous reports have suggested high rates of clinical–pathologic stage discrepancy in bladder cancer patients 7, 8, 9, 10, 11, 12, 13, 14. These series, however, typically contain limited numbers of patients treated at a single large academic center where therapy and outcomes can vary significantly compared with nationwide practices 3, 15, 16. Additionally, most prospective cystectomy series fail to report survival by initial clinical stage. We sought to investigate the accuracy of clinical staging and its effect on outcome in bladder cancer patients treated with RC using the National Cancer Data Base (NCDB).

Section snippets

Data source

The NCDB, jointly sponsored by the American College of Surgeons and the American Cancer Society, is a hospital-based registry that serves as a comprehensive clinical surveillance resource that derives its data from the 1500 Commission on Cancer–accredited programs in the United States and Puerto Rico. As such, the NCDB captures approximately 70% of incident cancers in the United States each year, making it one of the most powerful and generalizable cancer databases in the world. Ongoing

Patient characteristics

Patient characteristics are shown in Table 1. Median patient age was 67 years. The majority (74.3%) of patients received RC alone. Postoperative chemotherapy was used in 21.9% of patients, whereas 3.8% received preoperative chemotherapy.

Staging and stage discrepancy

Discrepancies in overall AJCC stage were common (Fig. 1A, B; tabulated data available in Table e1, available online). Stage discrepancy was found in 47.8% of patients: 41.9% upstaging and 5.9% downstaging. Upstaging rates for clinical stage 0, I, II, and III

Discussion

Using contemporary data from the NCDB, including data from academic and community centers, we present here the largest study to date describing clinical staging in bladder cancer. We identify that nearly half of bladder cancer patients undergoing RC have a pathologic stage discordant with their clinical stage. This high level of discrepancy has important implications for prognostication, therapy selection, and risk stratification in the design of clinical trials investigating novel nonoperative

Conclusions

Accurate clinical staging is a matter of concern in all cancers for which limited pathologic information may be available (eg, biopsy sampling for prostate cancer, sentinel LN biopsy in breast cancer, nodal staging in lung cancer) and/or where preoperative therapy has become commonplace (eg, rectal adenocarcinoma, locally advanced breast cancer, tumors of the head and neck). Our study provides strong evidence confirming that current clinical staging in bladder cancer is inadequate, resulting in

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Cited by (72)

The Rate of Prostatic Involvement in Men Treated With Radical Cystectomy for Muscle Invasive Bladder Cancer
2023, Practical Radiation Oncology
Radical cystoprostatectomy (RC) is one standard treatment for muscle-invasive bladder cancer (MIBC) in male patients. Another therapeutic option is trimodal therapy. Including the prostate in the trimodal therapy radiation therapy volume is based on MIBC surgical series showing prostatic stromal (PS) involvement. Our aim was to establish the rate of pathologic PS involvement by preoperative T stage in men treated with RC for MIBC.
We conducted a retrospective review of men with MIBC treated with RC between 2006 and 2019. Electronic medical records were reviewed, and preoperative clinical staging data were collected. χ² test was done to test for a statistically significant difference in the rate of prostatic involvement between clinical tumor (cT) stages. Preoperatively identified carcinoma in situ, lymph node involvement, tumor location, and urethral involvement were also analyzed to see if they conferred a higher risk of PS involvement. Multivariate analysis using multiple logistic regression was performed.
We identified 283 men with bladder cancer treated with RC. Patients with non-MIBC or incomplete medical data were excluded (n = 72). We analyzed 211 patients, and 46 (22%) had pathologic PS involvement. PS involvement by preoperative T stage was cT2 = 18%, cT3 = 23%, and cT4 = 48%. Twenty-nine (12%) patients had clinical lymph node involvement, of whom 19 (76%) had PS involvement. Thirty-four (16%) had urethral involvement, of whom 17 (50%) had PS involvement. Sixteen percent and 17% of percent of clinical T2 and T3 patients had bladder neck/trigone tumors, of whom 57% and 50% had prostatic involvement. Clinical T2 and T3 were not statistically different with regards to PS involvement (P = .385). Preoperative urethral involvement, lymph node involvement, cT4, and bladder neck/trigone location were statistically significant predictors of pathologic PS involvement (all P < .05). On multivariate analysis, only clinical urethral involvement was significant (P < .0001).
The high rate of pathologic PS involvement seen in cT2 patients and the lack of ability of cT stage to predict PS involvement support routinely treating the prostate in trimodal therapy. Patients with preoperatively identified bladder neck/trigone tumors, urethral involvement, positive lymph nodes, or prostatic involvement are a subset at even higher risk of having pathologic PS involvement.
Incidence and Clinical Impact of Inflammatory Fluorodeoxyglucose Positron Emission Tomography Uptake After Neoadjuvant Pembrolizumab in Patients with Organ-confined Bladder Cancer Undergoing Radical Cystectomy
2021, European Urology Focus
Data regarding the incidence and prognostic impact of immune-related imaging changes, assessed by ¹⁸[F] fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan, in patients receiving immune-checkpoint inhibitors (ICIs) are lacking. We relied on the population of patients enrolled in the PURE-01 study to evaluate such changes.
To evaluate the role of PET/CT to visualize the immune-related adverse events (irAEs) following pembrolizumab.
From February 2017 to August 2019, in 103 patients with nonmetastatic, clinical T2–4aN0M0 bladder cancer, PET/CT scan was performed before and after neoadjuvant pembrolizumab (N = 206 scans), before radical cystectomy.
PET/CT before and after neoadjuvant pembrolizumab, before radical cystectomy.
We analyzed the occurrence of irAEs, evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, against the development of inflammatory FDG uptake described at PET/CT (irAEs + PET/CT). Logistic regression analyses evaluated the association between irAEs + PET/CT and the pathological response to pembrolizumab. Kaplan-Meier curves tested their association with progression-free survival (PFS) after pembrolizumab and radical cystectomy.
Forty patients (39%) developed irAEs + PET/CT in several target organs. The most frequent target organs were the thyroid (N = 18), stomach (N = 14), mediastinal lymph nodes (N = 9), and lung (N = 5). These changes were clinically evident in 18 (45%) and were not associated with the pathological response, neither in terms of complete response (ypT0N0, p = 0.07) nor as downstaging to ypT≤1N0 disease (p = 0.1), although ypT0N0 responses were numerically more frequent in patients with irAEs+ PET/CT (47.5% vs 32%). Furthermore, irAE+ PET/CT events were associated with longer, not statistically significant, 24-mo PFS: 88.3% versus 76.5% (p = 0.5). Our results warrant further validation in larger datasets.
We presented unique surrogate data of PET/CT that could help improve our understanding of nonclinically evident effects of ICI administration, especially in patients at the early disease stage.
We evaluated the utility of PET/CT to visualize the occurrence of inflammatory changes after pembrolizumab in patients with localized bladder cancer without metastases. After immunotherapy, 39% of the patients developed ¹⁸[F] fluorodeoxyglucose uptake consistent of inflammatory changes. Overall, our data improve our knowledge on the effects induced by immunotherapy, which may have a clinical impact at longer follow-up.
Take Home Message
● In the PURE-01 study, T2–4N0M0 muscle-invasive bladder cancer patients were staged with fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) before and after pembrolizumab.
● PET/CT after pembrolizumab revealed inflammatory FDG uptake in 39% of patients, but only 45% of these cases of uptake corresponded to clinically evident adverse events.
● The development of inflammatory uptake was associated with a higher pathological complete response rate and longer progression-free survival, although these differences were not statistically significant.
[18F]Fluoro-Deoxy-Glucose positron emission tomography to evaluate lymph node involvement in patients with muscle-invasive bladder cancer receiving neoadjuvant pembrolizumab
2021, Urologic Oncology: Seminars and Original Investigations
Data regarding the role of positron emission tomography/computed tomography (PET/CT) to stage lymph nodes in patients receiving neoadjuvant immunotherapy before radical cystectomy are lacking. The aim of this study is to evaluate the role of PET/CT to predict the pathologic lymph node involvement (LNI) in patients with MIBC receiving neoadjuvant pembrolizumab within the PURE-01 trial (NCT02736266).
Three courses of pembrolizumab were administered before radical cystectomy and extended pelvic lymph node dissection in clinical T2-4aN0M0 MIBC based on contrast-enhanced CT scan. LNI was also assessed with PET/CT before and after treatment. PET/CT results were compared with histopathological findings. The ability of baseline and post-therapy PET/CT to evaluate LNI was assessed, and univariate logistic regression analyses were performed.
From February 2017 to August 2019, a total of 108 patients and 105 patients had evaluable baseline and post-pembrolizumab scans, respectively. The sensitivity to detect LNI was 27% and 37.5% for pre- and post-pembrolizumab PET/CT, and specificity was 97% and 98%, respectively. In total, 4 of 7 patients (57%) showing baseline FDG-uptake had LNI vs. 11 of 101 (11%) with no baseline uptake. All but 1 of the 7 patients did not respond to pembrolizumab. Both pre- and post-pembrolizumab PET/CT significantly predicted LNI (P = 0.004 and P < 0.001) at univariate analyses. Our results warrant further validation in larger datasets.
PET/CT performance does not justify its use in routine practice for cN0 MIBC. However, our preliminary data revealed opportunities for the use of baseline PET/CT, within clinical trials, to optimally select patients with MIBC who are best suited for neoadjuvant immunotherapy strategies. Validation in larger datasets, as well as a cost analysis, are needed.
Diagnostic Accuracy of Multiparametric MRI for Local Staging of Bladder Cancer: A Systematic Review and Meta-Analysis
2020, Urology
To evaluate diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI) for local staging of urothelial bladder carcinoma (UBC), a systematic review was performed. Of 2369 records, 20 studies met the inclusion criteria (n=1724). We found a pooled sensitivity and specificity for differentiating between stages ≤T1 and ≥T2 of 0.92 (95% CI 0.88-0.95) and 0.88 (95% CI 0.78-0.94). mpMRI shows high sensitivity and specificity for the differentiation between non-muscle invasive and muscle invasive bladder cancer, but does not appear to be useful for staging per T-stage. It can be used for confirmation when muscle invasive disease is suspected at initial diagnosis.
Extended Lymph Node Dissection for Bladder Cancer: Do Clinical Trials Rule Out a Benefit?
2020, European Urology Focus
Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study
2020, European Urology
Citation Excerpt :
Radical cystectomy (RC), possibly preceded by neoadjuvant chemotherapy, represents the standard of care for treating nonmetastatic, muscle-invasive bladder cancer (MIBC) [1,2]. The radiological assessment of response to neoadjuvant therapies in MIBC has historically experienced major limitations [3–7]. These limitations are mainly related to the profound changes in bladder wall anatomy caused by the transurethral resection of the bladder tumor (TURBT), which generates a surgical defect with inflammatory reaction that usually precedes radiological imaging assessments.
In the PURE-01 study, pembrolizumab was given preoperatively before radical cystectomy in clinical T2-4aN0M0 patients. An accurate clinical response assessment may be useful for developing new perioperative strategies in these patients.
To evaluate the association between bladder multiparametric magnetic resonance imaging (mpMRI) findings after pembrolizumab and the pathological complete response (CR; pT0).
Patients were staged using bladder mpMRI whereby radiologists were asked to characterize the following parameters: residual disease at T1- and T2-weighted images (step 1: yes/no), presence of hyperintense spots within the bladder wall on diffusion-weighted imaging (step 2: yes/no), and presence of pathological contrast enhancement (step 3: yes/no), before and after three cycles of pembrolizumab. Examinations were internally assessed by two senior radiologists and externally evaluated by a third senior radiologist.
To evaluate bladder tumor response after neoadjuvant pembrolizumab, mpMRI was used.
The primary objective was to predict the pT0 after neoadjuvant pembrolizumab by relying on the mpMRI findings. Cohen’s kappa statistics was used to assess interobserver variability. Univariable analyses for pT0 were performed including internal and external post-therapy mpMRI steps.
From February 2017 to October 2018, 82 patients (164 total mpMRI assessments) were analyzed. The agreement between the internal and external mpMRI assessments after therapy was acceptable (κ values ranging from 0.5 to 0.76). Each mpMRI step was significantly associated with pT0 in both internal and external assessments. In patients with CR/no evidence of residual disease (NED) in all internally evaluated mpMRI steps (N = 37), the pT0 was seen in 23 (62%), compared with 19 of 26 externally evaluated NED patients (73%).
In post-pembrolizumab muscle-invasive bladder cancer, mpMRI sequence assessment had acceptable interobserver variability and represented the basis for the proposal of a radiological CR/NED status definition predicting the pT0 response to pembrolizumab. After validation of these findings with external datasets, we propose this tool for developing bladder-sparing immunotherapy maintenance therapies.
Assessment of the extent of disease in patients with muscle-invasive bladder cancer using conventional imaging yields serious limitations. In the PURE-01 study, we evaluated the potential of bladder multiparametric magnetic resonance imaging (MRI) to predict the pathological complete response to neoadjuvant pembrolizumab. After validation with larger datasets, the proposed stepwise assessment incorporating multiparametric MRI sequences will be used at our center to develop bladder-sparing approaches in future studies.

View all citing articles on Scopus

: Conflicts of interest: A.M.K. serves as a consultant for Sanofi.

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Clinical InvestigationClinical–Pathologic Stage Discrepancy in Bladder Cancer Patients Treated With Radical Cystectomy: Results From the National Cancer Data Base

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Data source

Patient characteristics

Staging and stage discrepancy

Discussion

Conclusions

Eur Urol

Eur Urol

Urol Oncol

J Urol

J Urol

J Urol

J Urol

Urol Oncol

Urology

Urology

J Urol

Cancer statistics, 2013

CA Cancer J Clin

Intravesical bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: Ten-year follow-up of a prospective randomized trial

J Clin Oncol

Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer

N Engl J Med

Combined-modality treatment and selective organ preservation in invasive bladder cancer: Long-term results

J Clin Oncol

Discrepancy between clinical and pathological stage: External validation of the impact on prognosis in an international radical cystectomy cohort

BJU Int

Clinicopathological outcomes after radical cystectomy for clinical T2 urothelial carcinoma: Further evidence to support the use of neoadjuvant chemotherapy

BJU Int

Clinical Investigation
Clinical–Pathologic Stage Discrepancy in Bladder Cancer Patients Treated With Radical Cystectomy: Results From the National Cancer Data Base