Long‐term outcomes of outpatient laser ablation for recurrent non‐muscle invasive bladder cancer: A retrospective cohort study

Abstract Objectives The objective of this study is to determine the long‐term efficacy and safety of office‐based Holmium:YAG laser ablation for the treatment of recurrent non‐muscle‐invasive bladder cancer (NMIBC). Methods We retrospectively reviewed the medical records of all consecutive patients who underwent office‐based laser ablation for recurrent bladder cancer between 2008 and 2016. The following data were collected: original histology, date of original histology, date of laser ablation, number of repeat laser ablation procedures required, date of tumor recurrence or progression, number of general anesthesia procedures (transurethral resection or cystodiathermy) required after first laser ablation, and number and severity of complications. Kaplan–Meier survival curves were produced for recurrence‐free survival, progression‐free survival, and overall survival. Results A total of 97 patients, with an average age of 84 (62–98) years and an average Charlson Comorbidity Index of 6.9 (4–13), were included. The median follow‐up was 61 (2–150) months. Fifty‐five (56.7%) patients presented with tumor recurrence, and the median recurrence‐free survival time was 1.69 years (95% CI 1.20–2.25). Only 9 (9.3%) patients had evidence of tumor progression to a higher grade or stage, 8 (89%) of which initially had low‐grade tumors; however, no patient progressed to muscle‐invasive disease. The median progression‐free survival time was 5.70 years (95% CI 4.10–7.60), and the median overall survival time was 7.60 years (95% CI 4.90–8.70). No patient required emergency inpatient admission after laser ablation. Conclusion Office‐based Holmium:YAG laser ablation offers a safe and effective alternative method for treating low‐volume, low‐grade recurrent NMIBC, especially in elderly patients with significant co‐morbidity, while avoiding general anesthesia and inpatient admission.


| INTRODUCTION
Non-muscle-invasive bladder cancer (NMIBC) is the most prevalent form of bladder cancer, accounting for 70-75% of cases at presentation. 1 According to the European Association of Urology (EAU) guidelines, NMIBC can be stratified into low, intermediate, or high-risk depending on grade, stage, tumor size, number of tumors, presence of carcinoma-in-situ (CIS), and prior recurrence rate. 1 While high-grade tumors have a high risk of progression to muscle-invasive disease, patients with low-grade tumors are at extremely low risk of progression or cancer-specific mortality. 2,3 Surveillance and treatment protocols are therefore based upon this stratification, with a less intense approach for low-risk tumors.
Low-grade tumors account for approximately 50% of NIMBC, and although the rate of progression and cancer-specific mortality is low, the long-term rate of recurrence is relatively high at 46-62%, especially if large or multifocal. 4 The aim of managing low-grade tumors is to therefore minimize recurrence rates, prolong the time to recurrence, reduce patient inconvenience, and minimize healthcare costs, without compromising oncological control. 5 The most common approach for treating recurrent NMIBC is transurethral resection of the bladder tumor (TURBT) or cysto-diathermy under general or regional anesthesia. However, less burdensome and less invasive options have been recommended for the management of low-grade recurrences, including office-based laser ablation or diathermy and surveillance. 6,7 TURBT carries risks of perioperative morbidity and mortality, especially in the elderly and comorbid population of patients with bladder cancer. Furthermore, repeat TURBT procedures result in considerable healthcare costs; hence, bladder cancer is currently the most expensive cancer to treat, from diagnosis to death. 8 Office-based laser ablation aims to treat recurrences and therefore reduce the need for repeated inpatient procedures. This technique has been shown to reduce the cost of managing NMIBC by almost a third when compared to TURBT in the operating room without compromising oncological control in the short term. 9 However, the long-term efficacy of laser ablation for recurrent NMIBC is not widely reported. This study aims to report the longterm effectiveness of office-based laser ablation of recurrent NMIBC in terms of recurrence rate, time to recurrence, and progression.

| MATERIAL AND METHODS
This is a retrospective study of all consecutive patients who underwent office-based laser ablation with a flexible cystoscope for NMIBC at a single center between 2008 and 2016, focusing on long-term follow-up. The following patients were included: patients with recurrent NMIBC (solitary or multiple, tumor size <2 cm) who had a primary histology of Ta-T1 and G1-G3 and patients over the age of 60 years.
All patients in the present series were high risk for general anesthesia (GA). The exclusion criteria were diagnosis of muscle-invasive bladder cancer (MIBC), large (>2 cm) tumors at time of recurrence, and those with primary CIS. Electronic records were searched and the following Comorbidity Index was reported for each patient, and this was used to calculate an estimated 10-year survival score for patients in this cohort. 10

| Procedure
All patients were treated in an outpatient setting with a 30 W Holmium:YAG laser. A single-dose of intramuscular gentamicin was given 30 min prior to the procedure; no analgesia was required preor post-procedure. The procedure itself was carried out in an aseptic manner. Prior to cystoscopy, 11 ml of Instillagel ® (Farco-Pharma GmbH, Cologne, Germany) was administered. Thereafter, a 16.5-F flexible video cystoscope was used to assess the location of all tumors. Enhanced cystoscopic techniques (e.g., narrow band imaging and blue light cystoscopy) were not used. A Holmium:YAG laser was then used to ablate any recurrent tumors, with a 365-or 200-nm fiber at 0.6-0.8Js energy and rates of 10-15 Hz. Normal saline solution was used as irrigation fluid. Biopsies of papillary recurrences were not usually taken, but in those that had suspicious flat lesions, a biopsy and urine cytology were taken. In those with a history of CIS undergoing surveillance, urine cytology was taken in addition to the surveillance cystoscopy. Patients were asked to void before discharge. No patients were given immediate intravesical therapy following the procedure. Complications were assessed immediately after the procedure and then through notes review at 30 days. All patients underwent initial follow-up 3 months after laser ablation, with subsequent cystoscopic follow-up based on the EAU guideline recommendations depending on their risk stratification. 1 Patient tolerability with the procedure has been published by our group previously and so was not repeated in this study. 9

| Statistical analysis
Kaplan-Meier survival curves from the time of first laser ablation were produced for recurrence-free survival, progression-free survival, and overall survival. Five and ten-year survival estimates were also produced with 95% confidence intervals (CI). Logistic regression analysis was carried out with NMIBC grade (low/high) as the exposure variable to calculate age-and sex-adjusted odds ratios for risk of recurrence and progression; low-grade NMIBC was used as the reference. Pearson's chi-squared test was carried out to calculate the association between NMIBC grade and both recurrence and progression.

| Progression
Nine (9.3%) patients with a mean age of 82.67 AE 6.28 had tumor progression to a higher grade or stage, which included eight (88.8%) patients with initially low-grade tumors and one (11.1%) patient with a high-grade tumor ( Table 2). With regard to histology, six (6.2%) patients with G1 Ta progressed to low-grade G2 Ta, one (1.0%) patient with G1 Ta progressed to G3 Ta, one (1.0%) with G2 Ta progressed to G3 Ta, and one (1.0%) patient with G3 Ta progressed to G3 T1 (Table 2). Importantly, no patients progressed to muscle-invasive or metastatic disease.

| Complications and mortality
The average Charlson Comorbidity Index score was 6 F I G U R E 1 Kaplan-Meier curves for recurrence-free, progression-free, and overall survival estimates at 5 and 10 years ablation. 11,12 This is also similar to the 57.8% recurrence rate reported in the only other long-term study of laser ablation at a follow-up time of 69.8 months ablation. 11,12 The majority (76.3%) of patients in the present study had low-grade histology, and patients with G2 Ta had the highest overall recurrence rate of 64.4%, followed by G1 Ta with a recurrence rate of 62.5%; 9.3% progressed to a higher grade or stage, but no patients progressed to muscle-invasive or metastatic disease, and this may be related to strict patient selection for this procedure. Few studies have assessed progression rates after laser ablation for NMIBC, but where reported, the rates of progression to muscleinvasive disease range from 6% to 9% in a population with a similar proportion of high grade or T1 tumors to the present study. 11,13 Recent recommendations from the International Bladder Cancer Group state that patients with recurrent low-grade Ta tumors be managed with a less intensive approach than repeated transurethral resection in the operating room. 5 Evidence from the present study demonstrates that treatment with laser ablation can achieve this aim without compromising oncological outcomes in appropriately-selected patients. Interestingly, we found no association between grade of tumor and recurrence or progression rates, but this is likely due to the relatively small sample size of those with high-grade tumors and those that progressed. However, this also highlights the fact that appropriate patient selection is important when offering this minimally invasive treatment, and we preferentially offer TURBT to those with high-grade tumors unless the patient is unfit for GA or the aim of treatment is palliative. This approach of risk-adapted management has been increasingly supported, with the aim of avoiding overtreatment of those with low-grade Ta recurrences, but ensuring more intensive management for those with high-grade tumors. 14 Currently, transurethral resection of the bladder tumor (TURBT) is the gold standard procedure for recurrent NMIBC; however, this treatment is associated with side effects and complications, such as bleeding, obturator nerve reflex, and bladder perforation. 15  cost-effective in different healthcare systems. 6,9,16,17 Furthermore, the use of this laser in an office-based setting has the added benefit of not requiring GA. General anesthesia can have severe adverse effects on the elderly population, including postoperative delirium and cognitive dysfunction, both of which can delay rehabilitation and contribute to increased morbidity and mortality. 18 Office-based laser ablation is therefore a safer treatment option for elderly patients with multiple comorbidities, those on anticoagulation, or those who are unsuitable for GA. In the present study, the Charlson Comorbidity Index was used to assess the average estimated survival rate for this cohort based on pre-existing comorbidities. This study population was elderly and comorbid, with a mean age of 83.6 and an average Charlson Comorbidity Index of 6.93. Putting this into context, the estimated 10-year survival of a patient with a Charlson Comorbidity Index of 7 leads to a predicted 10-year survival of 0%. 10 Outpatient-based laser ablation is therefore a good alternative to TURBT to reduce recurrence rates in this comorbid group, with minimal morbidity.
There are several limitations to report regarding this long-term study. This was a retrospective study without a comparator group, and only select patients underwent treatment with laser ablation.
There was heterogeneity in terms of histological subtypes included which could affect the recurrence rates reported, and we did not report outcomes based on tumor size, number, or prior treatment with intravesical therapy. Furthermore, we did not have data on site of recurrence following laser ablation which would be interesting in assessing the efficacy of laser ablation. Biopsies were not taken at the time of laser ablation, and so this may affect the outcome data in terms of upstaging. However, there is evidence that a skilled urologist can accurately identify low-grade, non-invasive recurrent papillary bladder tumors without the need for biopsy and can be treated with fulguration alone. 19 We did not have data on immediate postprocedure haematuria or UTI rates, and no qualitative data, such as patient satisfaction, tolerability, pain, and quality of life, were recorded; however, as discussed earlier, our group has previously reported these aspects. 9 However, this study provides evidence for the long-term efficacy and safety of this minimally invasive treatment and will prove valuable in counseling suitable patients with low-grade recurrent NMIBC in an attempt to minimize the morbidity and cost of long-term management.

| CONCLUSION
We have shown that office-based Holmium:YAG laser ablation is an oncologically safe method of managing recurrent low-grade nonmuscle-invasive bladder cancer in the long-term, with no patients progressing to muscle-invasive disease. Furthermore, the procedure is T A B L E 3 Recurrence-free, progression-free and overall survival estimates at 5 and 10 years safe, and no significant complications were seen in this elderly and comorbid population. The procedure is optimal for those with lowgrade Ta recurrences, and patient selection is important in ensuring satisfactory oncological outcomes. The long-term efficacy reported in this study will prove valuable in counseling patients who may be appropriate for this treatment.