Intravesical gemcitabine as bladder‐preserving treatment for BCG unresponsive non‐muscle‐invasive bladder cancer. Results from a single‐arm, open‐label study

Abstract Background There is an unmet alternative medical therapy for BCG unresponsive patients. Objective To report efficacy of intravesical gemcitabine in NMIBC patients, who failed a previous course of BCG, or intolerant, and unwilling to undergo radical cystectomy (RC). Material and methods This is an open‐label, single‐arm study, which enrolled patients showing a failure or were intolerant to BCG and unwilling to undergo the RC. Intravesical gemcitabine was administered once a week for six consecutive weeks and once a month for 12 months. The primary outcome was DFS defined as the lack of a tumor on cystoscopy and negative urine cytology. Secondary endpoint was safety defined according a grading of side effects. OS, PFS, and DFS were described with Kaplan–Meier method at 12 and 24 months. Results and limitations Overall 36 patients were enrolled. The median follow‐up was 27 months. The DFS was 68.75% at the end of induction phase and 44.44% and 31.66% at 12 and 24 months of, respectively. The PFS was 43.75%. The OS and CSS were 77.9% (95% CI 58.78%‐88.92%) and 80.68% (95% CI 61.49%‐90.96%), respectively. There was no life threatening event or treatment‐related death (grade 4 or 5). The most common mild and moderate adverse events reported were urinary symptoms (LUTS) and fatigue (G1‐G2). Conclusion Patients who presented an unresponsive‐BCG recurrent NMIBC and unwilling to receive a RC, could benefit from intravesical gemcitabine as salvage organ‐sparing treatment.


| INTRODUC TI ON
Bladder cancer (BC) is a common neoplasm of the urinary tract. It is the ninth most common malignancy worldwide and the fourth most common cancer in males being nearly three/four times more common in men compared in women. 1 The disease remains confined to the layers above the muscularis propria in approximately 75%-85% of patients, and it is defined as non-muscle-invasive BC (NMIBC).
High grade NMIBC and carcinoma in situ (CIS) are high-risk conditions for progression to muscle invasive BC (MIBC). In the absence of any adjuvant treatment, up to the 90% may recur after transurethral resection (TURBT) and about half of patients' progress to MIBC. 2 The recommended treatment of high risk NMIBC is a six weekly induction course with intravesical instillations of bacillus Calmette-Guérin (BCG) followed by maintenance courses. 3 BCG fails in up to 50% of patients and it may be associated with local or systemic adverse events in approximately 70% of them. 4 Approximately 5% to 9% of patients abandon the treatment due to adverse events not completing all the planned BCG courses. 4 Recently supplies of BCG continued to dwindle leading to a world-wide shortage, which limits the access to the treatment. 5 Radical cystectomy (RC) is the recommended standard-of-care treatment for BCG unresponsive or intolerant patients, although a relevant morbidity is reported, regardless of "open" vs "robotic" approaches. 6,7 Furthermore a substantial proportion of patients are either unfit for or unwilling to undergo surgery. Thus, there is a rising need for bladder-sparing alternatives. In the last decade several new agents, which can be delivered more safely and efficiently to the bladder, have been investigating. 3,8 Unfortunately, development of new drugs in this disease space has been hampered by the heterogeneity in patient population, poor definition of disease status, uncontrolled studies, and consensus on outcome definition. There is an unmet clinical need for effective bladder-sparing agents to treat recurrent NMIBC not responsive to BCG.
Regimens containing gemcitabine are used systemically to treat MIBC and advanced urothelial cancer. 9,10 Sporadic evidence suggested that courses of intravesical gemcitabine could be safe and cost/effective for BCG unresponsive NMIBC, but most of those studies were limited by small number of patients and short-term follow-up. 11,12 Here, we report our experience with intravesical gemcitabine in NMIBC patients, who failed a previous course of BCG and unwilling to undergo RC.

| MATERIAL AND ME THODS
This is an open-label, single-arm study, approved by our Institutional Review Board and local Ethical Committee (n.1313_codice_ICH-007_V1.00), which enrolled patients showing a failure or were intolerant to BCG and unwilling to undergo the recommended standard-of-care RC. Patients were deemed to be unresponsive to BCG if they presented a recurrent NMIBC (confirmed CIS, pT1, or pTa multifocal high grade) 3 months after an induction cycle or during the maintenance treatment. BCG intolerant patients were considered all them who dropped out due to a serious adverse event requiring the discontinuation of BCG therapy. 13 All patients were informed about the disease course after BCG failure, guideline indications, and potential bladder-preserving treatments. Patients, who refused RC, were offered a salvage intravesical gemcitabine therapy. After a shared and informed discussion, they signed the informed consent. Exclusion criteria were: incomplete pathological data, severe cardiovascular diseases within the last 6 months, MIBC, concomitant cancer of the upper urinary tract, previous immunotherapy or chemotherapy. Severe acute or chronic medical or psychiatric condition that might increase the risk of not attending the treatment and follow-ups, and interfere with the interpretation of study results, were considered exclusion criteria.
Gemcitabine (2000 mg in 50 mL) was administered once a week for six consecutive weeks in the intensive phase. Patients were asked to retain the drug in the bladder for 120′. Patients who achieved a disease-free survival (DFS), defined as the lack of a tumor on cystoscopy evaluation with mandate/for-cause biopsy and negative urine cytology, entered the maintenance phase of the study, during which gemcitabine is further administered once a month for 12 months.

| Statistical analysis
Data were described as numbers and percentages, if categorical, or mean and standard deviation, if continuous. Overall Survival (OS) time was calculated from the date of TURB to the date of death or last contact date. PFS time and DFS time were calculated from the date of TURB to first progression or recurrence date, respectively, or last contact date. OS, PFS, and DFS were described with Kaplan-Meier method. Survival at 12 and 24 months were also described as percentage and 95% confidence interval (CI). All analyses were made with Stata 15.

| RE SULTS
From February 2012 to October 2018, 36 patients were included in the study. Demography of enrolled patients is reported in Table 1 Figure 4 showed the K-M curve for PFS. We cannot find a strictly statistical difference when patients were stratified according to DFS or not at the end of induction (P = .098).
Patients generally tolerated intravesical gemcitabine well; Table 2 summarizes side effects due to the drug. According to CTCAE, there was no life threatening event or treatment-related death (grade 4 or 5).
The most common mild and moderate adverse events reported were urinary symptoms (LUTS) in 14 cases and fatigue in 12 (G1-G2).
Three patients experienced CTCAE grade 3: gross hematuria, severe bladder pain, and severe pelvic pain in one female subject that required discontinuation of the therapy.
Ten patients who failed the gemcitabine salvage treatment underwent RC: one due to recurrent nonprogressive NMIBC and nine for progression to MIBC or extravesical lesions. Two patients who presented a progression to metastatic disease received chemotherapy and they did not undergo RC.

| D ISCUSS I ON
We found that salvage intravesical gemcitabine, for a selected unresponsive BCG population, achieved an overall DFS at 12 and Although guidelines recommend RC for BCG failure, it remains is a surgical procedure with significant morbidity and mortality rates, as well as dramatic lifestyle changes. 16 Given the risk of progression and the critical need to balance the safety of RC with bladder preservation, the treatment of those patients is a personal decision, better if it is made through a shared decision. Under such prospective, it appears that there may be a window of opportunity to explore second line salvage intravesical therapies. Several treatments, alternatives to RC have being tested in patients with persistent or recurrent NMIBC or CIS after BCG therapy, but unfortunately, there exists no data-driven efficacy benchmark for salvage bladder-sparing therapy. 15 Food and Drug Administration has approved valrubicin as the only agents for BCG unresponsive patients, but clinical results were disappointed with a complete response rate of 13% after 12 months. 17 Gemcitabine-based chemotherapy has been used for treating MIBC 9,10 and intravesically for high risk NMIBC. Porena   plus MMC has also been investigated with an initial report of 50% DFS at 18 months follow-up. 22 A SWOG study evaluated, as single-agent, intravesical gemcitabine and found RFS rates of 28% at 1 year and 21% at 2 years post-therapy. 23 Notably, this study was conducted in patients with two previous BCG failures and utilized a 6 weeks induction course, followed by monthly maintenance for 12 months. Sternberg et al used two courses of intravesical gemcitabine (2000 mg instilled in 100 mL saline) twice weekly for 3 weeks with courses separated by a week of rest for a total of 12 instillations. 24  treated with bladder-sparing therapy than patients with pure CIS. 15 Unfortunately, we did not perform any sub-analysis of those populations. Furthermore, we did not use any stratification of risk by using biomarkers or molecular characterization. 28  Finally, no assessment of quality of life was performed in our population, although it might represent an important outcome. 30

| CON CLUS ION
Intravesical gemcitabine seems to represent a useful treatment for patients unresponsive or intolerant to BCG, unwilling to undergo the recommended standard-of-care RC. In order to support the evidence we reported, randomized clinical trials, with larger sample size and extended follow-up, remain mandatory to determine the optimal gemcitabine regimen.

ACK N OWLED G M ENT
We would like to thank Nadia Lo Iacono for her valuable technical support.

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest to report.