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# A Randomized Feasibility Trial Comparing Surveillance Regimens for Patients with Low and Low-Intermediate Risk Non-Muscle Invasive Bladder Cancer

### BACKGROUND:

Surveillance regimens for non-muscle invasive bladder cancer (NMIBC) are disparate and controlled trials could inform guidelines. The feasibility of randomizing patients to variable frequency surveillance is unknown.

### OBJECTIVES:

To determine patient willingness to randomization to high frequency (HF) versus low frequency (LF) surveillance regimen for NMIBC and compare patient comfort and healthcare costs across regimens.

### METHODS:

A non-blinded, two-arm, randomized-controlled study of patients with low or low-intermediate risk NMIBC was conducted at two institutions where patients were offered randomization to HF vs. LF surveillance following initial tumor resection. The HF group underwent cystoscopy every three months for 2 years, then every 6 months for 2 years, then annually. The LF group underwent cystoscopy at 9 months following the 3-month cystoscopy, then annually. Assuming 75% of patients approached would agree to enrollment, a sample size of n = 35 patients per arm provided a one-sided 95% exact Clopper-Pearson confidence lower-limit of 60%.

### RESULTS:

##### Fig. 4

Cystoscopy surveillance regimen impacts healthcare system expenses more than patient out-of-pocket costs. (A) Average patient out-of-pocket costs for the duration of the surveillance regimen. (B) Average healthcare system costs based on Medicare reimbursement per cystoscopy and cystoscopy frequency in each regimen. (C) Estimated annual economic cost calculated by adding yearly patient out-of-pocket costs and cystoscopy regimen reimbursement costs to healthcare system.

## DISCUSSION

Surveillance regimens in bladder cancer utilize considerable resources. Existing guidelines for surveillance in NMIBC are largely based on expert opinion. Higher levels of evidence, including prospective comparative trials are needed to support these surveillance guidelines. However, patient willingness to participate in randomized trials where patients are delegated to variable surveillance regimens is not clear. This trial compared two surveillance protocols that differed drastically in the frequency of cystoscopy for patients with low and low-intermediate risk NMIBC. While the majority of patients approached agreed to participate, the relatively high rate of patient decline or withdrawal indicates significant barriers to successful completion of a phase III trial, with many patients declining randomization based on preference for more frequent cystoscopy. While our study was not designed to assess a difference in oncologic outcomes, no difference was observed between the HF and LF groups in terms bladder biopsies or disease recurrence. The fact that no patients progressed supports this group of patients as an appropriate population to study surveillance frequency without untoward outcome. Patient-reported quality of life assessments were similar across groups and, as expected, the costs were significantly lower in the LF group compared to the HF group. Collectively, these findings support the current AUA surveillance guidelines for low risk NMIBC, which recommend lower frequency cystoscopies compared to patients with high risk NMIBC.

Out of pocket cost in the setting of NMIBC surveillance is poorly reported. In 2004, 6370 respondents with a diagnosis of any cancer not being treated reported an annual out-of-pocket cost of $1450 [15]. To illustrate the financial burden further, 27% of low-income patient’s earnings went to treatment of cancer. Bladder cancer has had the highest cost for treatment per patient in the U.S. of all cancers, which ranged from$96,000 to $187,000 [2]. The cost of diagnosis and follow up for NMIBC, not including treatment, has been estimated to be$4000 per patient over a 5-year period. Consequently, we predicted that our measured out-of-pocket cost to the patient would also be a sizeable financial burden. Unexpectedly, our results didn’t confirm this. It is unclear why this may be, but as previously stated, the calculated cost didn’t take into account money lost from being away from work. In addition, 23 of the patients were recruited from the Veterans Affairs medical system where there is often transportation provided, no co-pay, and other ancillary services to decrease out-of-pocket expenses for the patient. Lastly, costs could have been underreported by patients.

One prior report compared two different surveillance cystoscopy regimens for patients with papillary NMIBC and randomized 97 patients [8]. Similar to our study, there was no difference between the risk of recurrence or progression between groups. In addition, the number of visits was reduced by 37.5% in the lower frequency group which is less than the 50.1% reduction in the number of visits observed in our trial.

Several patients randomized to the LF group withdrew from our study, due to patient preference for a higher frequency regimen. Future studies could combine reduced frequency surveillance with cost effective measures aimed at providing patients additional reassurance that tumors have not recurred, such as urine-based biomarker testing occurring between surveillance cystoscopies. However, prior studies have shown minimal patient willingness to reduce cystoscopy frequency in lieu of a urine-based recurrence monitoring without a high degree of certainty of urine-based testing sensitivity for tumor detection [13, 14]. Additionally, a nuanced discussion with low and low-intermediate risk patients on the incidence of disease recurrence (∼15%) and lack of association with disease progression (<1%) [16] may lead to additional comfort with reduced surveillance regimens.

The are several methods that can be improved during conduction of a subsequent phase trial. One important metric that was not captured was fear of recurrence, a recently identified outcome in psychosocial cancer research and clinical care [17]. Fear of recurrence imposes a significant burden in patients following definitive treatment and during surveillance of cancer and, therefore, could influence quality of life and cancer outcomes indirectly by impacting surveillance compliance and willingness to participate in trials. Although FACT-BL scores in the emotional domain were similarly low in both HF and LF groups, future studies should more closely investigate disease-related anxiety and fear of recurrence. Also, our study did not directly address patients’ attitudes and desires regarding frequency of surveillance, which would be an important item for further research. Our cost questionnaire recorded easily quantifiable information such as travel distance, but a more comprehensive cost capturing system is recommended in subsequent studies. Finally, this trial addressed extremes of cystoscopy frequency and the patient willingness for participation may be improved with less drastic differences in regimens between treatment groups. Despite these limitations, our study provides critical data needed to develop subsequent trials and suggests that patient quality of life and satisfaction are not substantially different across variable frequency surveillance regimens.

In summary, accrual to a randomized trial comparing variable frequency surveillance regimens is possible but a significant number of patients declined to participate or withdrew after randomization. Frequent surveillance cystoscopy is tolerated by patients and does not result in substantial increase in out-of-pocket costs for patients, supporting use of high frequency surveillance from the patient’s perspective. However, similar biopsy, recurrence, and progression rates between low and high frequency surveillance regimens support the use of lower frequency cystoscopies for patients with low and low-intermediate risk disease from a societal perspective.

## ACKNOWLEDGMENTS

The authors thank the patients and clinical care staff that contributed to this trial.

## FUNDING

RM Reyes - NIH T32GM113896, NIH/NCATS TL1 TR002647, NIA T32 AG 021890. RS Svatek - 8KL2 TR000118, K23, the Mays Family Cancer Center at University of Texas Health San Antonio (P30 CA054174), Roger L. And Laura D. Zeller Charitable Foundation Chair in Urologic Cancer, CDMRP CA170270/P1P2, the Max & Minnie Tomerlin Voelcker Fund.

## AUTHOR CONTRIBUTIONS

RM Reyes: interpretation or analysis of data, writing the article. E Rios: performance of work. S Barney: performance of work, interpretation or analysis of data, writing the article. CM Hugen: performance of work. JE Michalek: performance of work. Y Lotan: performance of work. EM Messing: performance of work. RS Svatek: conception, performance of work, interpretation or analysis of data, writing the article.

## CONFLICT OF INTEREST

RMR, ER, SB, CMH, JEM, EMM declare no potential conflicts of interest. YL serves as a consultant for C2I genomics, Photocure, Astra-Zeneca, Merck, Fergene, Abbvie, Cleveland Diagnostics, Bristol Myers Squibb, Nucleix, Ambu, Seattle Genetics, Hitachi, and Ferring Research, has current research relationships with Cepheid, Pacific Edge, MDxHealth, GenomeDX Biosciences, and Storz, and holds leadership positions with Vessi Medical and CAPs Medical. RSS serves as a consultant for Cold Genesys, Ferring Pharmaceuticals, FKD Therapies, Japanese BCG Laboratories, and Nucleix. None of the above-mentioned relationships are directly relevant to the studies described in this manuscript.