O ff i c e - b a s e d M a n a g e m e n t o f Nonmuscle Invasive Bladder Cancer Joshua J. Meeks, MD, PhDa, Harry W. Herr, MDb,* KEYWORDS  Bladder cancer  Office-based management  Surveillance  Recurrence  Fulguration

KEY POINTS  Office-based management of the bladder can be used in low risk-stratified patients to reduce costs and burden of care.  Smoking cessation and narrow-band imaging may play important underevaluated roles in the future management of bladder cancer.

Bladder cancer is the fifth most common malignancy in the United States, but it is estimated to be the most expensive lifetime cancer due to the high cost of surveillance. In select patients with a history of low-grade and noninvasive tumors, office-based surveillance may be oncologically safe, with significant reductions in cost and complications from operating room transurethral resection (TUR). This article attempts to identify the ideal candidates, as well as management and surveillance strategies of low-grade bladder tumors in the office-based setting.

NATURAL HISTORY OF NONINVASIVE BLADDER CANCER Over 2.7 million people live with bladder cancer,1 and over 380,000 incident bladder tumors were identified annually worldwide in 2008,2 including 73,000 tumors in the United States.3 In fact, bladder cancer is the fifth most common cancer in the United States. The worldwide age-

standardized rate (ASR) for bladder cancer is 10.1 cases per 100,000 men and 2.5 cases per 100,000 women, with a mortality rate of 4 deaths per 100,000 men and 1.1 deaths per 100,000 women.4 Most bladder tumors identified are nonmuscle invasive (75%–85%). Of nonmuscle invasive bladder tumors, 70% are stage pTa; 20% are stage pT1, and 10% are carcinoma in situ (CIS).5 The overall rate of recurrence for nonmuscle invasive bladder cancer is 48%,6 with a range of 31% to 78% at 5 years, ranging from low to high risk.6,7 In a prospective study of 215 patients from Memorial Sloan-Kettering Cancer Center (MSKCC), low-grade bladder tumors were found to have a recurrence rate of 31% (papilloma), 52% (papillary urothelial neoplasm of low malignant potential [PUNLMP]), and 72% (TaLG), with a median time of recurrence of 72 months for PUNLMP and 18 months for TaLG.8 Progression occurred in 8% of TaLG patients, with those progressing more likely to have multiple tumors, more frequent recurrences, and require more operative TUR procedures. Progression by grade occurred in 3% of cases, and progression by

Disclosures: None. Funding: Dr Herr is supported by the Sidney Kimmel Center for Prostate and Urologic Cancers. Conflicts: None. a Department of Urology, Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue, Tarry 16-703, Chicago, IL 60611, USA; b Department of Surgery, Urology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering, 353 East 68th Street, New York, NY 10065, USA * Corresponding author. E-mail address: [email protected] Urol Clin N Am 40 (2013) 473–479 http://dx.doi.org/10.1016/j.ucl.2013.07.004 0094-0143/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

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INTRODUCTION

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Meeks & Herr stage (T1) occurred in 5% of cases. Progression was heralded by conversion from negative to positive cytology in 71% of cases (12/17).8 Risk factors for progression include >1 tumor (2-fold increase),9 recurrence at 3-month cystoscopy,8,10,11 prior recurrence rate of >1 recurrence per year,12 and size of tumor >3 cm.13,14 No patients with PUNLMP or papillomas progressed.8 Thus, lowgrade bladder cancer has a low risk of progression despite a high rate of recurrence.

COST OF MANAGEMENT OF LOW-GRADE BLADDER CANCER Depending on the model and breadth of features included, bladder cancer has been estimated as the most expensive cancer to health care systems, with a mean cost to Medicare of $96,000 to $187,000 per patient in 2001.15 In the United States, the total estimated cost in 2006 was $206 billion, with predicted productivity loss of $17.9 billion, and cancer-related morbidity of $110 billion.16 The majority of the cost for bladder cancer is hospitalbased transurethral resection of a bladder tumor (TURBT), estimated to be responsible for 71% of the cost of bladder cancer in the United Kingdom.17 In a single-institution study, the mean cost per patient with bladder cancer from a period of 1991 to 1999 was $65,158 measured at MD Anderson. The main expense per patient was due to admission ($16,778, 26%) and surgical procedures ($15,781, 24%), with the remaining costs due to surveillance.18 These prices could be dramatically reduced if patients were managed in the office setting. In a comparison of outpatient TUR (estimated to cost between $2666 and $2113), office fulguration was estimated at only $1167. Routine use of office-based fulguration could mitigate the role of single-dose intravesical therapy after TURBT. Single instillation of postoperative chemotherapy decreases recurrence rates by up to 13%, with possible complications including chemical cystitis. Using Markov state transitional modeling, the cost of office-based fulguration was compared with inpatient TURBT.19 The cost for outpatient fulguration without perioperative chemotherapy was $1115.21, compared with $3436.34 for inpatient TUR. Using sensitivity analysis, the authors found that with a recurrence rate of >14%, the use of repeated office fulgurations was more costeffective than perioperative intravesical chemotherapy instillation.

IDENTIFICATION OF PATIENTS FOR OFFICEBASED MANAGEMENT OF BLADDER CANCER The critical factor to determine the suitability of office-based management of bladder cancer is

an accurate assessment of risk of progression. Although the initial identification of bladder cancer occurs in the office, the authors recommend outpatient TUR with examination under anesthesia for complete and accurate staging. Based on TUR pathology, tumors amenable to office-based management are papillomas, PUNLMP, and TaLG tumors. The main concern with office-based management is missing progression to higher stage or grade, which would warrant greater resection and/ or intravesical therapy. No prospective trials have determined the best candidates for office-based fulguration. Donat and colleagues20 described successful management of low-grade tumors with no recurrence within 6 months of their initial TUR. All tumors were smaller than 0.5 cm, with a negative urine cytology. The risk of progression in this group is approximately 8%.8 Using data from 2596 patients from 7 European Organisation for Research and Treatment of Cancer (EORTC) trials, risk for individual patients can be calculated. The Donat criteria would suggest a yearly progression risk of 1%, and by 5 years, a progression of 6% (intermediate risk of progression based on http://www.eortc.be/tools/bladdercalculator/).6 Thus, patients with a risk score of 6 or less would be potential candidates for office-based management. One of the most important elements of officebased management is the accurate visual diagnosis of papillary or low-stage and -grade tumors. Urologists were able to predict low-grade and -stage tumors using flexible cystoscopy in 93% of cases with 99% accuracy if cytology was included in a study of 144 tumors.21 In a larger study of over 500 patients, only 5% of tumors were inaccurately categorized as noninvasive by flexible cystoscopy.22 Yet, series from other institutions suggest that urologists have a lower accuracy to predict grade, with only 26 of 49 (53%) predicted accurately by cystoscopy.23 Thus, the correct determination of risk by nomograms and visual observation plays a pivotal role in choosing patients for office-based fulguration. The experience of the urologist is a critical factor for successful outpatient management of low-grade papillary bladder tumors.

EFFECTIVENESS AND TOLERABILITY OF OFFICE-BASED MANAGEMENT Herr described the use of office-based cystoscopy with fulguration in 69 patients with both high- and low-grade lesions, some of which demonstrated invasion.24 Of the 32% of patients who required TUR, 5 had CIS, and 3 had muscle invasion. Office-based fulguration was the only intervention in 68% of

Office Management of Bladder Cancer patients, with 30% of patients requiring repeat treatment. In a prospective study of 267 patients carefully selected (as per the Donat criteria), officebased fulguration was the only intervention required in 60% of patients,20 with a median follow-up of 6.8 years and 2.2% dying of bladder cancer. Patients who underwent TUR (higher risk) had no difference in progression compared with cystodiathermy, suggesting appropriate risk-based management. In a series of 91 patients treated with office-based fulguration with local anesthetic, 12% found it painful, but 90% of procedures were completed within 5 minutes, with none lasting longer than 10 minutes.25 At 15 weeks, 59% of patients had no recurrence, and only 6% of patients had recurrence at the site of treatment. Wedderburn and colleagues26 described 103 patients managed with cystodiathermy, with an overall recurrence rate of 49% and 12% recurring at or near the site of treatment. When rated for discomfort, an average visual analog pain scale of mild or negligible was reported by 80% of patients. These data suggest that in carefully selected patients, office-based cystodiathermy can be performed safely and comfortably with reasonable recurrence outcomes.

WATCHFUL WAITING OF IDENTIFIED BLADDER TUMORS Some patients with small or low-grade bladders tumors may be watched without the need for TUR or cystodiathermy after identification of new tumors. Soloway and colleagues27 described observation of 32 patients with a mean duration of 10.8 months, and patients undergoing an average of 1.8 interval cystoscopies between treatments (range of 1–5). Importantly, the authors described a tumor growth rate of 1.77 mm per month, with a progression rate of 6.7%. Gofrit and colleagues28 described the active surveillance of 38 tumors in 28 patients, with surveillance halted for tumor size (9 patients), increased number (19 patients), or hematuria. All tumors were Ta on TUR. The authors noted that if the initial tumor was smaller than 5 mm, the growth rate was significantly less than if the tumor was >5 mm. Pruthi and colleagues29 described the expectant management of 22 patients with low-grade bladder tumors. Over 25 months, 8 patients had no growth of identified tumors; 9 patients had minimal growth, and 5 patients had moderate growth. Sixty-eight percent of patients required no intervention; 14% required office cystodiathermy, and 18% required TUR. Only 9% of patients had progression, half (1 patient) of whom had stage progression. Thus, watchful waiting may be a strategy to consider in patients with significant

comorbidities, on blood thinning agents, and having small tumors of