Key points

Introduction

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.

Introduction

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, and over 380,000 incident bladder tumors were identified annually worldwide in 2008, including 73,000 tumors in the United States. 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. 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). The overall rate of recurrence for nonmuscle invasive bladder cancer is 48%, with a range of 31% to 78% at 5 years, ranging from low to high risk. 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. 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 stage (T1) occurred in 5% of cases. Progression was heralded by conversion from negative to positive cytology in 71% of cases (12/17). Risk factors for progression include >1 tumor (2-fold increase), recurrence at 3-month cystoscopy, prior recurrence rate of >1 recurrence per year, and size of tumor >3 cm. No patients with PUNLMP or papillomas progressed. Thus, low-grade 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. 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. The majority of the cost for bladder cancer is hospital-based transurethral resection of a bladder tumor (TURBT), estimated to be responsible for 71% of the cost of bladder cancer in the United Kingdom. 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. 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. 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 cost-effective than perioperative intravesical chemotherapy instillation.

Identification of patients for office-based 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 colleagues 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%. 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/ ). 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 office-based 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. In a larger study of over 500 patients, only 5% of tumors were inaccurately categorized as noninvasive by flexible cystoscopy. 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. 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. 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 patients, with 30% of patients requiring repeat treatment. In a prospective study of 267 patients carefully selected (as per the Donat criteria), office-based fulguration was the only intervention required in 60% of patients, 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. At 15 weeks, 59% of patients had no recurrence, and only 6% of patients had recurrence at the site of treatment. Wedderburn and colleagues 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 colleagues 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 colleagues 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 colleagues 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 <0.5 cm.

Frequency and timing of follow-up and tumor surveillance

No prospective randomized trials have demonstrated sufficient level of evidence to support a specific surveillance protocol for the management of noninvasive bladder tumors. The goals of surveillance would be to minimize the cost and psychological burden of surveillance, tempered by prudent follow-up to prevent growth of tumors necessitating inpatient TUR. From watchful waiting studies, it has been noted that small tumors (<5 mm) may be observed for almost 10 months without intervention. Yet, to prevent an operative TUR, one could argue that repeated cystodiathermy may be prudent at decreased intervals. Thus, cystoscopic tumor surveillance (from the National Comprehensive Cancer Network [NCCN] 2013) is recommended at 3 months and then subsequently at increasing intervals. The European Association of Urology (EAU) recommends a cystoscopy at 3 months, then 9 months, then yearly for 5 years for low-risk tumors. Many urologists manage low-risk tumors similar to higher-risk tumors and perform cystoscopy every 3 months for the first 2 years, every 6 months for 2 years after, and yearly thereafter. Clearly this is an area of future clinical research to determine the appropriate follow-up interval for low-grade tumors to minimize cost and intervention but not increase risk of bulky recurrence.

Voided biomarkers for surveillance

The use of prognostic biomarkers could potentially play a critical role in the management of patients with low-grade bladder cancer. Invasive procedures, such as cystoscopy, could potentially be avoided if a biomarker reliably had a high negative predictive value. There are several biomarkers approved for surveillance by the US Food and Drug Administration. Voided cytology has a long-documented role in the identification of high-grade bladder cancer and can be used to identify patients who require further intervention. The sensitivity ranges from 13% to 75% (median 35%); specificity ranges from 75% to 95% (median 94%). Although a positive cytology is a predictor of high-grade bladder cancer, atypical and suspicious cytologies are more troubling to the urologist without a clear indication for intervention. Limitations of cytology include interobserver variability and artifact associated with fixation. NMP22 is a point-of-care test with a sensitivity ranging from 47% to 100% (median 54%), and a specificity ranging from 55% to 98% (median 78%). The Urovysn fluorescence in-situ hybridization (FISH) has a sensitivity of 70% to 86% (median79%) and a specificity ranging from 66% to 93% (median 70%). BTAstat is a point-of-care marker that can be tested at home by the patient, with a sensitivity of 29% to 74%(median 58%) and specificity of 56% to 86% (median 73%). There are currently no markers that reliably outperform cystoscopy for detection of a bladder cancer recurrence, or have been demonstrated to be more accurate in prospective trials. In a study of patients undergoing cystoscopic surveillance for bladder cancer, 75% described anxiety related to missing cancer from voided markers and desired a test with 95% sensitivity to identify a bladder recurrence to forgo cystoscopy.