Multi-institutional analysis of sequential intravesical gemcitabine and mitomycin C chemotherapy for non–muscle invasive bladder cancer

ObjectiveApart from cystectomy, few treatment options exist for the management of bacillus Calmette-Guerin refractory non–muscle invasive bladder cancer (NMIBC). We report a multi-institutional experience with sequential intravesical combination chemotherapy using gemcitabine and mitomycin C (MMC) for NMIBC in the treatment of high-risk patients.MethodsWe performed a retrospective review of patients who received 6 weekly treatments with sequential intravesical gemcitabine (1 g) and MMC (40 mg) chemotherapy for NMIBC. Gemcitabine was administered first and retained for 90 minutes and then drained. MMC was then administered directly after and retained for an additional 90 minutes. Forty-seven patients received treatment from 3 academic tertiary referral centers between 2000 and 2010.ResultsForty-seven patients (median age 70, range 32–85; 36 males, 11 females) who previously failed a median of 2 intravesical treatments were reviewed. Complete response, 1-year, and 2-year recurrence-free survival rates for all patients were 68%, 48%, and 38%, respectively. Median recurrence-free survival for all patients was 9 months (range 1–80). Fourteen of 47 patients (30%) remained free of recurrence with a median time to follow-up of 26 months (range 6–80 mo). Ten patients required cystectomy.ConclusionSequential intravesical combination chemotherapy using gemcitabine and MMC appears to be a useful treatment for patients with high-grade NMIBC as well as those with prior bacillus Calmette-Guerin failure. Further prospective studies are warranted.     

Current clinical trials in non–muscle invasive bladder cancer

Background

The treatment options for non–muscle invasive bladder cancer (NMIBC) remain limited. Bacillus Calmette-Guerin (BCG) was the last major breakthrough in bladder cancer therapy almost 4 decades ago. There have been improvements in the understanding of immune therapies and cancer biology, leading to the development of novel agents. This has led to many clinical trials that are currently underway to find the next generation of therapies for NMIBC.

Role of immunotherapy in bacillus Calmette–Guérin-unresponsive non–muscle invasive bladder cancer

Intravesical instillation of live attenuated bacillus Calmette–Guérin (BCG) is the gold standard for patients with intermediate- and high-risk non–muscle-invasive bladder cancer (NMIBC). BCG-failures include a heterogenous population of patients who share a designation of disease recurrence or progression following BCG and include patients with complete unresponsiveness to BCG, patients who respond initially but develop relapse and, in some cases, patients who are intolerant to BCG due to side effects. Given the efficacy and relatively rapid approval of several monoclonal antibodies against PD-L1 or PD-1 for advanced and metastatic bladder cancer, the role of these checkpoint inhibitors in BCG-relapsing disease at various disease stages is under consideration. Data supporting a role for immune checkpoint inhibitors is largely theoretical with limited supportive data from animal models and from clinical evidence of increased PD-L1 expression in BCG-unresponsive tumors. Current trials in BCG-unresponsive disease are underway and expected to provide insight regarding these concepts.     

Histological variants of non–muscle invasive bladder cancer: Survival outcomes of radical cystectomy vs. bladder preservation therapy

BackgroundTo compare the overall survival (OS) outcomes of non–muscle invasive bladder cancer (NMIBC) patients with variant histology who underwent radical cystectomy (RC) vs. bladder preservation therapy (BPT).MethodsWe investigated the National Cancer Database for NMIBC patients with variant histological features. Patients diagnosed with micropapillary, sarcomatoid, neuroendocrine, squamous, and glandular variants were identified. Inverse probability weighting (IPW)-adjusted Kaplan Meier survival curves and Cox proportional hazard models were utilized to compare OS in the setting of RC versus BPT.ResultsA total of 8,920 (2.7%) NMIBC patients presented with variant histology, of whom 2,450 (27.5%) underwent RC, while 6,470 (72.5%) had BPT. When compared with BPT, patients who underwent RC had significantly higher 5-year OS rates for sarcomatoid (31.9% vs. 23.3%, P < 0.001) neuroendocrine (31% vs. 21.7%, P < 0.001), glandular (44% vs. 41%, P = 0.04) and squamous variants (39.7% vs 19.9%, P < 0.001). This OS benefit was not observed with micropapillary variant (43.9% vs. 53.2% P = 0.14). IPW-adjusted log-rank analysis identified RC as an independent predictor of OS for patients with sarcomatoid (hazards ratio [HR] 0.78, confidence interval [CI] 0.71–0.85, P < 0.001), squamous (HR 0.56, CI 0.53–0.59, P < 0.001), and neuroendocrine variants (HR 0.83, CI 0.76–0.91, P < 0.001), but not for micropapillary variant (HR 1.45, CI 1.24–1.7, P < 0.001).ConclusionsAmong NMIBC patients presenting with variant histologies, RC was associated with better OS for sarcomatoid, squamous, glandular, and neuroendocrine variants when compared to BPT. This OS survival benefit was not observed in patients with micropapillary variant suggesting a potential role for bladder preservation in such population.     

An immediate,single intravesical instillation of mitomycin C is of benefit in patients with non–muscle-invasive bladder cancer irrespective of prognostic risk groups

Background

In a recent meta-analysis, subgroups of patients were defined that may not benefit from a single, immediate instillation with chemotherapy. This led to a change in the European Association of Urology bladder cancer guidelines. In a previous paper, our group confirmed the efficacy of an immediate instillation of mitomycin C (MMC). However, prognostic groups in that study differ from those in the meta-analysis. Therefore, we performed a reanalysis using contemporary risk groups.

Midterm follow-up (3 years) confirms and extends short-term results of intravesical gemcitabine as bladder-preserving treatment for non–muscle-invasive bladder cancer after BCG failure

BackgroundThere is a high demand for bladder sparing therapies in patients who do not respond to bacillus Calmette-Guérin (BCG).ObjectiveTo report the mid-term results of intravesical gemcitabine in non–muscle-invasive bladder cancer (NMIBC) patients, who failed BCG and who were unwilling to undergo radical cystectomy (RC).Material & methodsThis is an extended confirmatory open-label, single-arm study, which enrolled consecutive patients who failed BCG or were BCG intolerant and unwilling to undergo the RC (histologically confirmed Tis (CIS), T1 high grade or multifocal Ta high grade of the urinary bladder). Intravesical gemcitabine was administered once a week for 6 consecutive weeks and once a month for 12 months. The primary outcome was disease-free survival (DFS) defined as the lack of tumor on cystoscopy and negative urine cytology. The secondary endpoint was safety, defined according a grading of side effects. overall survival, progression-free survival and DFS were described with Kaplan-Meier method at 12, 24, and 36 months.Results and limitationsOverall 46 patients were enrolled. The mean follow-up was 40 months. The DFS was 69.05% at the end of induction phase and 32.69% at 36 months. The progression-free survival at 36 months was 65.38%. The overall survival and cancer specific survival were 66.97% (95% confidence interval 47.25%–80.70%) and 78.71% (95% confidence interval 59.16%–89.66%), 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 (lower urinary tract symptoms) and fatigue (G1-G2).ConclusionIntravesical gemcitabine seemed to represent a valid and safe alternative at 3 years follow-up for patients who failed BCG and were unwilling to undergo RC.     

Impact of bladder neck involvement on progression in patients with primary non–muscle invasive bladder cancer: A prospective validation study

PurposeOur previous retrospective study reported that bladder neck involvement (BNI), as well as tumor grade and stage, was a significant risk factor for progression in primary non–muscle invasive bladder cancer (NMIBC). We prospectively validated BNI as a significant predictor for progression using a new cohort of patients with primary NMIBC.Patients and methodsA total of 297 new Japanese patients who underwent transurethral resection and were pathologically diagnosed with Ta or T1 urothelial carcinoma were enrolled in this prospective study. Clinicopathologic data were collected at study entry. Multivariate Cox proportional hazards regression models were performed to identify the independent predictors for progression. A predictive scoring model for progression was developed using the regression coefficients (RCs) from the final multivariate model. The predictive ability of the model was assessed using Harrell's c-index.ResultsWith a median follow-up of 37 months, 16 patients (5.4%) progressed. Progression probability at 1 and 5 years were 1.5% and 8.0%, respectively. Multivariate analysis revealed that histologic grade 3 (hazard ratio [HR] 9.45, P = 0.0004, RC 2.25), pathologic T1 stage (HR 6.91, P = 0.0014, RC 1.93), and BNI (HR 11.75, P = 0.0009, RC 2.46) were all independent predictors of progression. When all 3 variables were scored as 1 point and the patients were divided into 3 groups, progression rates were clearly discriminated (P<0.0001). The c-index was 0.80.ConclusionsThis prospective validation study has shown that BNI is a significant prognostic factor for progression in primary NMIBC. The scoring model including BNI enables the physician to classify patients with primary NMIBC into 3 groups with clearly different progression rates.     

Impact of age on outcomes of patients with non–muscle-invasive bladder cancer treated with immediate postoperative instillation of mitomycin C

Objectives

To evaluate whether age affects the clinical benefit afforded by immediate postoperative intravesical instillation of mitomycin C in a contemporary cohort of patients with NMIBC.

The predictive value of GSTT1 polymorphisms in predicting the early response to induction BCG therapy in patients with non–muscle invasive bladder cancer

IntroductionWe evaluated the predictive value of glutathione S transferase mu (GSTM1) and theta (GSTT1) polymorphisms in early response to bacillus Calmette-Guérin (BCG) induction therapy in patients with primary non–muscle invasive bladder cancer.MethodsGSTM1 and GSTT1 polymorphisms were analyzed by multiplex polymerase chain reaction using blood genomic DNA from 135 patients with primary non–muscle invasive bladder cancer who were being treated with a single induction course of BCG. BCG nonresponsiveness (early BCG failure) was defined as a tumor recurrence or progression within 12 months after BCG induction therapy. The predictive value of GST polymorphisms was evaluated by Kaplan-Meier analysis and multivariate logistic regression models.ResultsPatients carrying a GSTT1-positive genotype demonstrated a higher likelihood of early BCG failure regardless of cigarette smoking. After stratification based on the tumor stage and grade, the high-risk group (T1G3) with a GSTT1-positive genotype showed a 14-fold higher risk of early BCG failure compared with those with a GSTT1-null genotype. In a combined analysis of 2 genes, the GSTT1-positive/GSTM1-null genotype had a higher risk of BCG nonresponsiveness compared with the GSTT1-null/GSTM1-null genotype (odds ratio = 4.17, 95% CI: 1.54–11.26). By multivariate logistic regression analysis, the GSTT1-positive genotype was an independent predictor of early BCG failure (odds ratio = 3.67, 95% CI: 1.61–8.38). Kaplan-Meier estimates revealed a significant difference in disease-free survival depending on the GSTT1 genotype (log rank test, P = 0.038).ConclusionsThe results of this study suggest that the GSTT1-positive genotype is an independent predictor of early BCG failure. These results can help determine whether patients would benefit from adjuvant BCG treatment or may require more aggressive alternative therapies.     

Predictors of adequate lymph node dissection in patients with non–muscle invasive bladder cancer undergoing radical cystectomy and effect on survival

IntroductionRadical cystectomy (RC) is the standard of care for refractory high-risk non-muscle invasive bladder cancer (NMIBC). We aim to identify predictors of adequate lymph node dissection (LND) in a cohort of NMIBC patients undergoing RC, as well as its impact on clinical outcomes.MethodsThe National Cancer Database was queried for patients who underwent RC for urothelial cell carcinoma for clinical stage Tis/a/1 N0M0 disease between 2004 and 2013. Patients were stratified by LND: none, inadequate (<10) or adequate (≥10 nodes). Factors associated with LND were analyzed. Inverse-probability weighted propensity score matching was used to assess the impact of adequate LND on overall survival.ResultsThe final cohort of 3,226 patients had a median follow-up of 39.0 months, had a mean age of 65.3 years, was 70% male, and was 81% Caucasian. Overall, 16.6% received no LND, 28.5% inadequate LND, and 55.0% adequate LND. Treatment at an academic facility, Charlson-Deyo Comorbidity score of 1, and later year of treatment were significantly associated with adequate LND. Overall survival was significantly higher with adequate LND compared to a matched-cohort of inadequate LND patients (68.7% vs. 60.6% at 5 years, P < 0.01).ConclusionsNearly half of NMIBC patients undergoing RC do not receive an adequate LND, despite an association with increased overall survival. Treatment at an academic facility was associated with increased likelihood of adequate LND. Initiatives to improve adequate LND in this population may be warranted.     

Monopolar vs. bipolar transurethral resection for non–muscle invasive bladder carcinoma: A post-hoc analysis from a randomized controlled trial

Purpose

Traditionally, transurethral resection of bladder tumors (TURB) is performed using monopolar technique. Bipolar resection has been postulated to reduce complications. In this study we compare safety and efficacy between monopolar TURB (mTURB) and bipolar TURB (bTURB) for patients with primary non-muscle invasive bladder cancer (NMIBC).

Considerations on the use of urine markers in the management of patients with low-/intermediate-risk non–muscle invasive bladder cancer

ObjectivesMany molecular assays for bladder cancer diagnosis and surveillance have been developed over the past several decades. However, none of these markers have been routinely implemented into clinical decision making. Beyond their potential for screening high-risk populations, urine markers likely have the greatest potential in the follow-up of patients with non–muscle invasive bladder cancer (NMIBC).MethodsHere, we discuss the current options and limitations of the use of urine markers for patient surveillance, focusing on patients with low-/intermediate-risk NMIBC.ResultsAs these patients have a very low risk of tumor progression, the primary goal of surveillance is detection of recurrent disease. Although urine cytology seems to be limited to detection of few patients who would develop high-grade tumors, we conclude that the use of markers with high sensitivity for low-grade disease for patient follow-up has the potential to decrease the frequency of urethrocystoscopy without compromising patient prognosis. Because a single marker may not have sufficient sensitivity for detection of low-grade tumors, different scenarios, e.g., multitesting and reflex or sequential approaches, are discussed.ConclusionsThere is consensus that currently available markers have the potential to support clinical decision making in follow-up of patients with low-/intermediate-risk NMIBC. In light of our analysis, further additional randomized controlled studies to effectively assess the clinical usefulness of modern urine markers are required.     

Neutrophil-to-lymphocyte ratio predicts progression and recurrence of non–muscle-invasive bladder cancer

ObjectiveNeutrophil-to-lymphocyte ratio (NLR) predicts advanced stage disease and decreased survival in patients undergoing radical cystectomy for urothelial carcinoma of the bladder. The predictive value of NLR in non–muscle-invasive bladder cancer (NMIBC) has not been well studied. We aimed to evaluate whether NLR predicted disease recurrence and progression in NMIBC.Materials and methodsThe medical records of 122 consecutive, newly diagnosed, patients with NMIBC treated with transurethral tumor resection, between the years 2003 and 2010, were reviewed. Patients with hematological malignancies (n = 4) and without preoperative NLR (n = 11) were excluded. Cutoff points for NLR were tested separately for recurrence and progression using the standardized cutoff-finder algorithm. Univariate and multivariate Cox regression analyses were used to evaluate the association between NLR and disease recurrence and progression.ResultsThe study cohort comprised 91 men and 16 women at a median age of 68 years. The median NLR was 2.85 (interquartile range: 2–3.9). In total, 68 patients (64%) had an NLR>2.41. Patients with NLR>2.41 were more often men (P = 0.02) and had T1 category tumors (P = 0.034). Analyzed as a continuous variable, higher NLR showed a weak positive association with high tumor grade (R = 0.21, P = 0.028).The median follow-up for patients without disease recurrence was 40 months (interquartile range: 23–51). The estimated 3-year progression-free survival rate in patients with an NLR>2.41 was 61%, compared with 84% in patients with an NLR≤2.41 (P = 0.004). On multivariate analysis, an NLR>2.41 (hazard ratio [HR] = 3.52; 95% CI: 1.33–9.33; P = 0.012) and high-risk tumors compared with low-intermediate-risk tumors (HR = 4.83; 95% CI: 1.31–17.77; P = 0.018), as defined by the European Organization for Research and Treatment of Cancer risk tables, were associated with disease progression. An NLR>2.43 (HR = 1.75; 95% CI: 1.05–2.92; P = 0.032) and treatment with intravesical instillations (HR = 0.49; 95% CI: 0.28–0.85; P = 0.011) were associated with disease recurrence on multivariate analysis.ConclusionsNLR is an independent predictor of disease progression and recurrence in patients with NMIBC without hematological malignancies. Prospective studies are required to validate the role of NLR as a prognostic marker in NMIBC.     

A prospective comparative study to assess the efficacy and tolerability of 2 different doses of intravesical bacillus Calmette-Guerin (BCG) in patients with non–muscle-invasive bladder cancer

BackgroundBacillus Calmette-Guerin (BCG) is widely used as an immunotherapeutic agent and recommended in management of non–muscle-invasive bladder cancer (NMIBC). There is no consensus on the optimal dose of the BCG. However, dose reduction has been assessed to decrease the side effects following instillation of BCG. This study compared the efficacy and safety of 80 and 120 mg doses of Sii Onco BCG (Moscow I, Russian strain) in patients with NMIBC.MethodsPatients with histologically confirmed, completely resected solitary or multiple Ta or T1 (with or without carcinoma in situ), grade 1 to 3 urothelial carcinoma of the bladder were included. After transurethral resection of the tumor, repeated intravesical instillations with Sii Onco BCG (80 or 120 mg) were administered, following the induction and 3 weekly maintenance schedule (at 3, 6, 9, 15, 21, 27, and 33 months). Recurrence and progression of the tumor were monitored at scheduled time intervals using cystoscopy.ResultsA total of 104 eligible patients were enrolled to receive 80 mg (n = 51) dose or 120 mg dose (n = 53) of Sii Onco BCG. On completion of 3 years follow-up, recurrence-free survival rate of 84.31% and 86.79% and progression-free survival rate of 84.31% and 94.34% were observed for 80 and 120 mg groups, respectively; difference being statistically nonsignificant.ConclusionBoth, 80 and 120 mg doses of Sii Onco BCG are effective and safe for prophylaxis and management of NMIBC.     

Incidence and location of lymph node metastases in patients undergoing radical cystectomy for clinical non–muscle invasive bladder cancer: Results from a prospective lymph node mapping study

ObjectivesThe objective of this study is to investigate the incidence and location of lymph node metastases (LNMs) in patients undergoing radical cystectomy (RC) and lymph node dissection (LND) for clinical non–muscle invasive bladder cancer (NMIBC).Methods and materialsProspectively collected data of 637 patients who underwent RC and ‘superextended’ LND with intent-to-cure for urothelial carcinoma of the bladder between 2002 and 2008 were examined. Inclusion criteria were (a) clinical stage Ta, Tis-only, or T1, (b) muscle presence at diagnostic transurethral resection in clinical T1 patients, (c) no prior diagnosis of≥T2 disease, (d) no neoadjuvant therapy, and (e) lymphatic tissue sample submitted from all 13 predesignated locations. Lymph node mapping was performed in all patients to determine the location of metastatic lymph nodes. Median follow-up time was 4.7 years. Recurrence-free survival and overall survival were reported.ResultsA total of 114 patients were included of whom 9 patients (7.9%) had LNM. Stratified by clinical stage, LNM was present in 6/67 (9.0%) patients with cT1, 3/25 (12.0%) patients with cTis-only, and none of the 22 patients with cTa. Of the 9 node-positive patients (33.3%), 3 had LNM proximal to the aortic bifurcation. No skip metastases were found. After RC, 27 patients (23.7%) were upstaged to muscle invasive disease; of whom 16.7% had cT1, 2.6% had cTa, and 4.4% had cTis-only. Of the remaining 87 patients with pathologic NMIBC, 1 patient (1.1%) had LNM, limited to the true pelvis. Five-year RFS was 82.3%, 81.5%, and 62.0% in patients with pathologic NMIBC, clinical NMIBC, and pathologic muscle invasive bladder cancer, respectively.ConclusionsRoutine LND is important in patients with cT1 and cTis-only bladder cancer, but may have limited value in patients with cTa. LNM beyond the boundaries of a standard LND occurred in up to one-third of node-positive patients. In the absence of skip metastases, however, performing a standard LND would correctly identify all node-positive patients. Whether removal of LNM proximal to the common iliac vessels provides a survival benefit remains to be evaluated in future prospective studies.