Author's Accepted Manuscript Dynamic prognostication using conditional recurrence and progression estimates for patients with non-muscle invasive bladder cancer Carmen V. Leitner , Ines A. Ederer , Michela de Martino , Sebastian L. Hofbauer , Ilaria Lucca , Aurélie Mbeutcha , Romain Mathieu , Andrea Haitel , Martin Susani , Shahrokh F. Shariat , Tobias Klatte PII: DOI: Reference:

S0022-5347(16)00225-1 10.1016/j.juro.2016.01.102 JURO 13295

To appear in: The Journal of Urology Accepted Date: 20 January 2016 Please cite this article as: Leitner CV, Ederer IA, de Martino M, Hofbauer SL, Lucca I, Mbeutcha A, Mathieu R, Haitel A, Susani M, Shariat SF, Klatte T, Dynamic prognostication using conditional recurrence and progression estimates for patients with non-muscle invasive bladder cancer, The Journal of Urology® (2016), doi: 10.1016/j.juro.2016.01.102. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.

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Dynamic prognostication using conditional recurrence and progression estimates for patients with non-muscle invasive bladder cancer

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Carmen V. Leitner1, Ines A. Ederer1, Michela de Martino1, Sebastian L. Hofbauer1, Ilaria Lucca1, Aurélie Mbeutcha1, Romain Mathieu1, Andrea Haitel2, Martin Susani2, Shahrokh F. Shariat1,3,4, Tobias Klatte1

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Department of Urology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria, 2 Clinical Institute of Pathology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria, 3Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, 4 Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY

Word count: 2498 Tables: 5

*Corresponding author: Tobias Klatte Department of Urology

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Figures: 2

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Medical University of Vienna Währinger Gürtel 18-20

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A-1090 Vienna, Austria

Phone: +43-1-40400-26020 Fax: +43-1-40400-23320

Email: [email protected]

Keywords: recurrence; progression; BCG; mitomycin; risk group

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ABSTRACT Purpose: Conditional estimates provide a dynamic prediction of outcomes, but there are no data

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for non-muscle invasive bladder cancer (NMIBC). The purpose of this study was to assess the changes in conditional recurrence and progression rates after transurethral resection of the bladder (TURB) and to explore the prognostic impact of established factors and risk groups over

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time.

Methods: We retrospectively analyzed data from 1292 consecutive patients with a newly

recurrence and time to progression.

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diagnosed Ta/T1 BC who underwent a TURB. The endpoints of this study were time to first

Results: The 2-year recurrence rate at baseline was 36% and improved as a function of time that the patient had been free of disease recurrence. After 6-, 12-, 24-, 36-, and 48-months, the

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2-year conditional recurrence rate improved to 31% (14% improvement compared with baseline), 22% (39%), 16% (56%), 13% (64%), and 11% (69%), respectively. Comparably, conditional progression rates improved with increasing follow-up, although relative differences were less distinct. The prognostic impact of established factors and the NMIBC risk group

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progressively decreased over time and finally disappeared. BCG, however, had a protective

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effect on progression even after 3 years. We also provide tables with dynamic prognostic information at all analyzed time points. Conclusions: In patients with primary Ta/T1 BC, recurrence and progression rates improve over time. The prognostic impact of established factors and risk groups decreases and finally disappears. The effect of BCG on progression is long-lasting. Conditional outcome estimates may improve patient counseling and individualize surveillance planning.

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INTRODUCTION Bladder cancer (BC) is the second most common urologic malignancy with more than 400,000 new cases worldwide yearly.1 It is expected to remain a significant burden for healthcare

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systems in the next decades because of the aging and continuous growth of the world population as well as the high prevalence of smoking.2 As a measure for the needs of medical care, the 5-year global BC prevalence has been estimated to be more than 1.1 million.3 At initial

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diagnosis, approximately 75% of patients present with a non-muscle invasive BC (NMIBC).4 A risk-based therapeutic approach is recommended for these patients, which is usually comprised

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of transurethral resection of the tumor (TURB) with or without immediate and adjuvant intravesical instillation therapy.5 NMIBC generally carries a high risk of disease recurrence albeit a relatively low risk of disease progression and death.6 Frequent endoscopic therapeutic and surveillance procedures are necessary, making BC the most expensive cancer to treat per

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patient.7

Cancer prognosis is typically assessed at the time of diagnosis and estimated for a certain time interval (e.g. 5-year survival). However, these estimates become less relevant when the followup time increases and the impact of established prognostic factors changes. In contrast to this

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classical concept, conditional survival (CS) accounts for survival time and thereby provides better and more dynamic estimates of outcome probabilities at each follow-up point.8 It

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measures the probability that a patient will survive some additional number of years, given that the patient has already survived for a certain period of time.9 It is thought that CS may help to individualize the prediction of prognosis, patient counseling and postoperative surveillance schedules.9

The benefits of CS estimates have already been demonstrated in large population-based cohorts of patients with various types of cancer.10–12 Further, several studies have investigated the relevance and usefulness of CS in urologic malignancies, including renal cell carcinoma13–15 3

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and penile cancer.16 In BC, there are two reports addressing CS for patients treated with radical cystectomy (RC).8,17 These studies showed that the risk of mortality decreases with the increasing survivorship and that the impact of classical prognostic factors such as tumor stage

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and lymph node metastasis becomes less significant over time. Despite its high prevalence and clinical relevance, however, no data are available on conditional outcomes in patients with NMIBC.

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For this reason, the aim of this study was to evaluate conditional recurrence and progression in a single-center cohort of patients with primary NMIBC and to explore the prognostic impact of

PATIENTS AND METHODS

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Inclusion/exclusion criteria

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established factors and risk groups over time.

We screened our prospectively maintained single-institutional database of 2133 consecutive patients who underwent a TURB of a newly diagnosed bladder tumor between 1993 and 2014

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for inclusion. Patients with a primary urothelial NMIBC classified as either a Ta or T1 lesion were included; therefore, we excluded patients with benign bladder tumors, other malignant tumors

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which histologically were not defined as urothelial BC, primary T2 disease, a T2 tumor on restaging TURB, previous upper tract urothelial carcinoma and those who underwent a RC for primary NMIBC. A total of 1292 patients were finally analyzed.

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Variables A computerized database abstracting clinical and pathological data of these patients was generated. Database variables included age, gender, pathological tumor stage, grade, tumor

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size, number of tumors, immediate and adjuvant instillation therapies, postoperative follow-up interval, recurrence and progression.

TURB specimens were processed according to standard pathological procedures and analyzed

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by two experts in genitourinary pathology (AH, MS). Tumors were classified according to the 2009 UICC classification18 and the tumor grade was assigned according to the 1973 World

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Health Organization scheme. The tumor size was evaluated as categorical variable according to the 3 cm cut-off.6 Based on pathological tumor classification, grade, number of tumors, tumor size and concomitant carcinoma in situ (CIS), patients were further stratified into risk groups

Treatment and follow-up

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according to guidelines.5

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All patients underwent a TURB. Over the years, there was no standard or routine repeat TURB. Among the 526 high-risk cases, 68% had a repeat TURB and 87% had detrusor muscle in the

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specimen. Immediate postoperative and adjuvant instillation therapies were administered at the surgeon’s discretion and according to guideline criteria. Bacillus Calmette-Guérin (BCG) was usually given in case of high-risk NMIBC weekly for 6 weeks followed by one year of maintenance. Patients were generally followed every 3 to 6 months during the first 2 years after diagnosis, biannually up to 5 years, and annually thereafter. Follow-up consisted of a patient’s medical history, physical examination, urinary cytology, cystoscopy, and another TURB if suspicious lesions were detected.

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Statistical analyses The endpoints of this study were the time to first recurrence in the bladder and the time to progression. Progression was defined as disease relapse in the bladder at tumor stage T2 or

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higher or the development of metastases and calculated from the date of first TURB. In our cohort, no patient developed lymph node or distant metastases without local T2 disease. Because patients with NMIBC are at a significant risk of dying from competing causes,

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competing-risks analyses were used to determine the rates of recurrence and progression. Cumulative incidence functions were generated, and conditional recurrence and progression

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rates were obtained using the multiplicative law of probability. Estimates were stratified by clinical and pathological prognostic variables, including age, gender, tumor stage, grade, CIS, size, number of tumors and risk group, and compared using Gray’s tests. Multivariable estimates from Fine-Gray’s regression models were obtained at baseline as subhazard ratios (SHR) and 95% confidence intervals (95% CI), and from landmark multivariable analyses at 6, 12, 24, 36,

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and 48 months. All analyses were conducted with the “survival” and the “cmprsk” package in R 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria). Statistical testing was two-sided

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RESULTS

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and a p-value

Dynamic Prognostication Using Conditional Recurrence and Progression Estimates for Patients with Nonmuscle Invasive Bladder Cancer.

Conditional estimates provide a dynamic prediction of outcomes but to our knowledge there are no data on nonmuscle invasive bladder cancer. We assesse...
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