Mitomycin C Instillation Research Articles

EP230 - A Closed Loop Audit for Peri-Operative Outcomes Comparing Laparoscopic and Robotic-Assisted Nephroureterectomy for Upper Tract Transitional Cell Carcinoma

Abstract Introduction Transitional cell carcinoma (TCC) of the upper urinary tract (localised high-risk disease) is treated with a radical nephroureterectomy (RNU). Evidence shows laparoscopic and robotic-assisted RNU have similar oncological outcomes to open RNU, but improved peri-operative outcomes, namely length of stay (LOS) and time to mitomycin C (MMC) – given to reduce bladder recurrence. Standard The European Association of Urology (EAU) Guidelines suggest MMC instillation should occur 2-10 days after RNU. Aim To determine if this standard was being met in a single tertiary centre following laparoscopic RNU, and if the expansion of the robotics service has improved this and other peri-operative outcomes. Methods Retrospective data was collected from patient notes and collated in an excel spreadsheet for descriptive statistical analysis. Results The first loop analysed laparoscopic procedures (n = 36). The average LOS was 5 days (SD = 3.7±) and the average time to MMC was 14 days (SD = 6.7±). Bladder recurrence occurred in 41% (n = 14) of this cohort, over an average follow up time of 30.6 months. The second loop analysed robotic-assisted procedures (n = 33). The average LOS was 4 days (SD = 2.23±) and the average time to MMC was 2 days (SD = 0.57±). Bladder recurrence occurred in 30% (n = 8) of this cohort, over an average follow up time of 13 months. Conclusion Both procedures are safe and effective with satisfactory oncological outcomes. By expanding the robotics service, the average LOS and time to MMC decreased. Disease recurrence was higher in the laparoscopic cohort, but the follow-up period was longer.

A Novel Approach to Intraluminal Mitomycin C Instillation for Treatment of High Grade Nonmuscle Invasive Upper Tract Urothelial Carcinoma

Abstract Introduction and Objective: We present a novel technique for intrapelvicalyceal mitomycin C (MMC) instillation mixed with a contrast agent for treatment of high-grade nonmuscle invasive upper tract urothelial carcinoma in patients in whom nephroureterectomy would render them dialysis-dependent. Methods: After incomplete endoscopic resection, the patient underwent 3 intrapelvicalyceal instillations of MMC mixed with iopamidol, each 2 weeks apart. Results: Treatment has had a durable response for over 2 years after treatment. Conclusions: Intraluminal MMC mixed with iopamidol is an approach which helps to avoid pyelovenous backflow and provides visual confirmation that the drug is in adequate contact with the tumor.

MP08-14 LONG TERM OUTCOMES OF REPEATED MITOMYCIN C INSTILLATION IN LOW RISK AND INTERMEDIATE RISK NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS

You have accessJournal of UrologyCME1 Apr 2023MP08-14 LONG TERM OUTCOMES OF REPEATED MITOMYCIN C INSTILLATION IN LOW RISK AND INTERMEDIATE RISK NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS Pietro Scilipoti, Mattia Longoni, Mario de Angelis, Chiara Re, Giuseppe Rosiello, Alessandro Bertini, Giulio Avesani, Donato Cannoletta, Giorgio Gandaglia, Umberto Capitanio, Andrea Salonia, Francesco Montorsi, Alberto Briganti, and Marco Moschini Pietro ScilipotiPietro Scilipoti More articles by this author , Mattia LongoniMattia Longoni More articles by this author , Mario de AngelisMario de Angelis More articles by this author , Chiara ReChiara Re More articles by this author , Giuseppe RosielloGiuseppe Rosiello More articles by this author , Alessandro BertiniAlessandro Bertini More articles by this author , Giulio AvesaniGiulio Avesani More articles by this author , Donato CannolettaDonato Cannoletta More articles by this author , Giorgio GandagliaGiorgio Gandaglia More articles by this author , Umberto CapitanioUmberto Capitanio More articles by this author , Andrea SaloniaAndrea Salonia More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , and Marco MoschiniMarco Moschini More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The use of repeated Mitomycin C (MMC) instillation in low- (LR) and intermediate-risk (IR) Non-Muscle Invasive Bladder Cancer (NMIBC) is still a matter of discussion among the urological community. The aim of the current study was to analyze long term outcomes of maintenance regimen of repeated MMC instillations in LR and IR patients. METHODS: We identified 228 patients diagnosed with NMBIC after transurethral resection of bladder tumor (TURBT) that underwent MMC instillations between 2013 and 2022 at a tertiary referral center. All patients felt within the criteria for LR or IR class according to European Association of Urology Guidelines. Recurrence-free survival (RFS) was analyzed and compared with Cox-derived univariate Kaplan-Meier (KM). A Multivariable Cox-regression analyses (MVA) assessed the impact of MMC maintenance regimen on RFS (covariates: T stage, grade, multifocality, early instillation). Subgroup analysis evaluated the effect of MMC instillations number on RFS in patients who received maintenance. RESULTS: Overall, 89 (39%) and 139 (61%) patients were diagnosed with LR and IR NMIBC, respectively. Low grade lesions were found in 88% (n=200) of cases. Pathological Ta tumors were 93% (n=211) and multifocality was present in 107 cases (47%). Median age at diagnosis and follow-up time were 71 (IQR 62-77) and 44 months (IQR 28-63), respectively. Early instillation was performed in only 21 patients (9.2%). Recurrence occurred in 57 patients (25%). All patients underwent MMC induction with 89% rate of 6-instillations cycle completion; 118 patients (51%) underwent maintenance instillations with a median number of instillations equal to 9.5 (6-11). Overall, RFS at 5 years follow-up was 69.6% [62.7, 77.2]. Patients who did or did not receive MMC maintenance had a 5-years RFS of 73.4% vs 65.2%. At MVA, MMC maintenance and number of instillations did not significantly correlate with a better RFS. CONCLUSIONS: Our study showed that MMC maintenance instillations do not reduce the risk of recurrence in LR and IR NIMBC patients who received MMC induction. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e99 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pietro Scilipoti More articles by this author Mattia Longoni More articles by this author Mario de Angelis More articles by this author Chiara Re More articles by this author Giuseppe Rosiello More articles by this author Alessandro Bertini More articles by this author Giulio Avesani More articles by this author Donato Cannoletta More articles by this author Giorgio Gandaglia More articles by this author Umberto Capitanio More articles by this author Andrea Salonia More articles by this author Francesco Montorsi More articles by this author Alberto Briganti More articles by this author Marco Moschini More articles by this author Expand All Advertisement PDF downloadLoading ...

Randomized phase III clinical trial of neoadjuvant intravesical mitomycin C (MMC) treatment in patients with primary treatment-naïve non-muscle invasive bladder cancer (NMIBC).

TPS578 Background: Approximately 75-85% of vesical urothelial carcinomas are non-muscle invasive bladder cancers (NMIBC). The primary treatment is transurethral resection (TUR) followed by adjuvant intravesical therapies with immunotherapy (BCG) and/or chemotherapy agents (i.e. mitomycin C - MMC). Unfortunately, the response to intravesical treatments is variable and incomplete and there is a un-met clinical need to improve its efficacy for reducing the recurrence rate and progression to muscle invasive BC (MIBC). Recently, has been showed that MMC induces immunogenic cell death (ICD), determining the expression of specific damage signals, like HMGB1 molecule, that favors the phagocytosis of dying tumor cells, the activation of innate immune cells and the presentation of tumor antigens to T lymphocytes [1]. The identification of ICD as a novel immune-related mechanism of action of MMC could provide opportunities to optimize bladder cancer management by proposing the use of MMC in a “neoadjuvant” setting. The aim of current clinical trial is to test the hypothesis that the neoadjuvant instillation of MMC in patients with NMIBC may reduce the recurrence rate and/or progression to MIBC. Methods: This is a prospective phase III randomized clinical trial in patients with primary treatment-naïve NMIBC recruiting since March 2022 (EudraCT 2021-003751-42_studio ICH-013-MMC). Patients are randomized 1:1 to neo-adjuvant MMC or standard of care. Patients enrolled in the neo-MMC group receive two intravesical instillations of MMC (40 mg/40 ml saline) in the 2 weeks before (days: -14 and -7) the scheduled TUR (day: 0). After TUR, as for clinical practice, both controls and neoMMC subjects, undergo adjuvant treatment, if required, based on the histological evaluation of the tumor and following EAU/PMID: 33040478 guidelines. The primary endpoint of the study is to evaluate the efficacy of MMC neoadjuvant treatment in reducing the recurrence rate of BC calculated as the proportion of patients who achieve a complete response (no evidence of BC after 3, 6, 12 and 24 mo.). The secondary clinical endpoint will be the analysis of the rate of grade and stage progression to MIBC in case of recurrence and the correlation with specific biomarker (i.e. expression of HMGB1). Consider that the primary aim of the study is to see a reduction of relapse, leading to an HR of 0.6, estimating on the control group a 30% relapse free at 12 months. With equal-sized group, a two-sided significance level test (α =0.05) with power 80% power (β=0.2), and assume that recruitment was to be terminated after 12 months, with a 2-year follow up, the required sample size is approximate 160 patient, 80 in each group (control / neoMMC).

Hyperthermic Mitomycin C in Intermediate-risk Non–muscle-invasive Bladder Cancer: Results of the HIVEC-1 Trial

BackgroundOptimising therapeutic strategies of intermediate-risk non–muscle-invasive bladder cancer (IR-NMIBC) is needed. ObjectiveTo compare recurrence-free survival (RFS) with adjuvant intravesical mitomycin C (MMC) at normothermia or hyperthermia using the COMBAT bladder recirculation system at 43 °C for 30 and 60 min. Design, setting, and participantsA prospective open-label, phase 3 randomised controlled trial (HIVEC-1) accrued across 13 centres between 2014 and 2020 in Spain. After complete transurethral resection of the bladder and immediate postoperative MMC instillation, patients with IR-NMIBC were randomised (1:1:1) to four weekly followed by three monthly 40-mg MMC instillations at normothermia (control; n = 106), 43 °C for 30 min (n = 107), or 43 °C for 60 min (n = 106) were investigated. Therapeutic compliance was defined as four or more instillations. Outcome measurements and statistical analysisThe primary outcome was RFS at 24 mo in the intention-to-treat (ITT) and per-protocol (PP) populations. The secondary outcomes included progression-free survival at 24 mo, safety outcome measures, and changes in health-related quality of life. Log-rank, Fisher, χ2, and analysis of variance tests were used. Results and limitationsThe ITT 24-mo RFS was 77% for control, 82% for 43 °C-30 min, and 80% for 43 °C–60 min (p = 0.6). The PP 24-mo RFS was 77% for control, 83% for 43 °C–30 min, and 80% for 43 °C-60 min (p = 0.59). Six patients progressed to muscle-invasive disease in the ITT population (four in the control, 43 °C–30 min, and 43 °C–60 min groups each) and four in the PP population (all controls). Serious adverse events occurred in 26 patients (8.1%), and we were unable to demonstrate a difference between groups (p = 0.5). Adverse events, mainly dysuria and spasms, occurred in 124 patients (33% in control, 35% in 43 °C–30 min, and 48% in 43 °C–60 min; p = 0.05). The total International Prostate Symptom Score worsened by 1.2 ± 7.3 points, similarly across groups (p = 0.29). The Functional Assessment of Cancer Therapy—Bladder domains and indexes showed no significant change. ConclusionsFour-month adjuvant hyperthermic MMC using the COMBAT system for 30 and 60 min in IR-NMIBC is well tolerated, but we did not find it to be superior to normothermic MMC at 24 mo. Patient summaryWe were unable to demonstrate the effectiveness of hyperthermia using the COMBAT system in intermediate-risk non–muscle-invasive bladder cancer. Further evaluation of long-term recurrence and progression, and maintenance regimens appears mandatory.

The clinical efficacy and safety of equipment-assisted intravesical instillation of mitomycin C after transurethral resection of bladder tumour in patients with nonmuscular invasive bladder cancer: A meta-analysis.

This review and meta-analysis aimed to systematically evaluate the clinical efficacy and safety of equipment-assisted intravesical instillation of mitomycin C (MMC) in patients with nonmuscular invasive bladder cancer (NMIBC) after transurethral resection of bladder tumour (TURBT). The Embase, PubMed, CNKI, CBM, WANGFANG, VIP, Cochrane Library, and Clinicaltrial.com databases were searched for articles published before April 2022. The experimental group was treated with intravesical instillation of MMC assisted by equipment, including radiofrequency-induced thermochemotherapy, conductive thermochemical therapy, electromotive drug administration, or locoregional hyperthermia. The control group was treated with simple MMC perfusion. The outcomes of interest in the meta-analysis were recurrence, progression, side-effects, gross haematuria, and bladder irritation. A total of 15 studies that enrolled 1,190 patients were included in the meta-analysis. Compared to that of the control group, device-assisted intravesical instillation of MMC significantly reduced both tumour recurrence (odds ratio [OR] = 0.32, 95% confidence interval [CI] [0.24, 0.42], P <0.00001) and progression (OR = 0.29, 95% CI [0.12, 0.67], P = 0.004). There were no significant differences between the two groups in terms of safety (OR = 1.21, 95% CI [0.66,2.21], P = 0.54), bladder irritation (OR = 1.06, 95% CI [0.72,1.55], P = 0.78), or gross haematuria (OR = 1.11, 95% CI [0.64,1.94], P = 0.72). Equipment-assisted intravesical instillation of MMC significantly reduced the recurrence and progression of patients with NMIBC who underwent TURBT and improved their quality of life. Given the significant heterogeneity in research quality and sample size among earlier studies, more prospective, multicentre, large sample randomized controlled trials are needed to supplement and verify this in the future.

Mitomycin C allergy after passive and device-assisted hyperthermia for non-muscle invasive bladder cancer treatment: A retrospective cohort from a high-volume center.

Mitomycin C (MMC) is one of the most frequently utilized intravesical chemotherapy drugs for the management of non-muscle-invasive bladder cancer (NMIBC). Allergic reactions (Type 4 delayed hypersensitivity) are seldomly reported in the literature but not so infrequent in daily practice, its incidence has been increasing with the use of device-assisted hyperthermia. This study aims to identify the incidence, risk factors, and clinical characteristics of patients with allergic reactions to MMC. Single-center retrospective cohort from June 2014 to August 2018. Patients with intermediate or high-risk NMIBC were included. Patients received passive MMC (4 weekly and eleven monthly instillations of 40mg of MMC) or Chemohyperthermia (CHT) with MMC (6 weekly and 6-monthly instillations, heated at 43°C [+/- 0.5°C] using Combat BRS). We included 258 patients (MMC = 157, CHT = 101) and found 7 (4.4%) suspected and 4 confirmed (2.4%) allergies in the passive MMC group and 11 suspected (10.9%) and 7 confirmed (6.9%) in the CHT group. The mean number of instillations received before developing the allergy was 6 in the passive MMC and 5 in the CHT group. Seven out of 18 suspected allergy cases were pseudo-allergic reactions with negative allergy tests. Early postoperative MMC instillation was associated with an increased risk of allergy (OR 2.47 [CI 1.39-4.36], P = 0.001), while neither history of atopy nor history of other medications allergy was found to increase the risk. MMC allergy risk is increased with the use of device-assisted hyperthermia with an incidence of 2.4% for passive MMC and 6.9% for CHT. History of prior allergies does not seem to increase the risk of developing MMC allergy. In this series 38% of suspected cases were found to be pseudo-allergic reactions, highlighting the need to confirm the diagnosis before definitively stopping the treatment.

Trial-based Cost-effectiveness Analysis of an Immediate Postoperative Mitomycin C Instillation in Patients with Non–muscle-invasive Bladder Cancer

BackgroundBladder cancer imposes a significant public health burden on the European Union. There is a need for cost-effective treatment and follow-up regimens. ObjectiveTo assess the cost-effectiveness of immediate mitomycin C (MMC) instillation within 1 d after surgery compared to delayed MMC instillation within 2 wk after surgery with further adjuvant treatment, depending on the patient’s risk group. Design, setting, and participantsThis economic evaluation was based on a randomized controlled trial among 2243 Dutch patients with non-muscle-invasive bladder cancer (NMIBC) patients from a health care perspective over a 3-yr time period. Outcome measurements and statistical analysisThe treatment effect was measured as time to recurrence and recurrence-free survival. Missing effect data were imputed with multiple imputation. Health care utilization and related costs were estimated on the basis of treatment protocols for NMIBC patients in the Netherlands. Statistical uncertainty was estimated using bootstrapping and is graphically presented using cost-effectiveness planes and cost-effectiveness acceptability curves. Results and limitationsTime to recurrence was significantly longer for immediate MMC instillation (27.31 mo) than for delayed MMC instillation (24.97 mo), with an adjusted mean difference of 2.21 mo (95% confidence interval [CI] 1.58–2.84). The proportion of patients with recurrence-free survival was significantly higher after immediate MMC instillation (0.65) than after delayed MMC instillation (0.56), with an adjusted mean difference of 0.08 (95% CI 0.06–0.11). Total mean health care costs per patient were significantly lower for immediate MMC instillation (€22959) than for delayed MMC instillation (€24624), with an adjusted mean difference of −€1350 (95% CI −€1799 to −€900). The study is limited by the retrospective estimation of costs. ConclusionsThis trial-based cost-effectiveness analysis shows that from a health care perspective, immediate MMC instillation is more effective and less expensive compared to delayed MMC instillation. Patient summaryWe assessed the cost-effectiveness of immediate bladder instillation of mitomycin C after surgery to reduce the risk of recurrence after removal of the bladder tumor as compared to delayed instillation in a large Dutch population of patients with non–muscle-invasive bladder cancer. We found that immediate instillation was more effective and less expensive than delayed instillation. We conclude that immediate mitomycin C instillation is a cost-effective treatment for non–muscle-invasive bladder cancer.

Intraoperative Mitomycin C Bladder Instillation During Radical Nephroureterectomy Is Feasible and Safe

BackgroundBladder recurrence after radical treatment of upper urinary tract urothelial cancer (UTUC) is frequent, and patients are required to undergo surveillance cystoscopies following surgery. The use of intravesical adjuvant chemotherapy is an accepted method to prevent bladder recurrence, but the timing of this method is not standardized and the concept of intraoperative use is unexplored. ObjectiveThe objective of the study is to examine the feasibility and safety of intraoperative intravesical mitomycin C (MMC) instillation using a closed-circuit system following bladder cuff excision and bladder closure. Design, setting, and participantsAll patients who underwent radical nephroureterectomy (RNU) for UTUC at the Department of Urology of Zealand University Hospital, Roskilde, Denmark from 2017 to 2020 were identified. Patient complications within 30 d and data regarding oncological outcome were registered. Outcome measurements and statistical ana lysisClavien-Dindo grade for complications and descriptive statistics were used. ResultsDuring the study period, 64 patients underwent RNU. Of these patients, 49 received bladder instillation of MMC during RNU. Complications were observed in 11 patients (21.4%), where four patients (8.2%) had Clavien-Dindo complication grade (CD) I, four patients (8.2%) had CD II, one patient (2%) had CD III, and one patient (2%) had CD IIIa. None of the complications were suspected to be related to MMC. Five of the 15 patients (33%) who did not receive MMC experienced complications. There were no significant differences in complication rates between patients who received MMC and those who did not. Study limitations include a small sample size and a single-center study. ConclusionsIntraoperative vesical instillation of MMC is feasible and was, in the present study, not associated with an increased complication rate. Patient summaryBladder recurrence after radical treatment of upper urinary tract cancer is frequent. The present study findings indicate that intraoperative bladder irrigation with the chemotherapeutic mitomycin C during surgery does not lead to excessive complications and could be a method to reduce the risk of bladder recurrence.

TP7.2.3 The effect of immediate versus early instillation of mitomycin C after transurethral resection of bladder cancer: Is timing everything?

Abstract Introduction and Aims Almost three quarters of patients diagnosed with bladder cancer have non-muscle invasive disease. The European Association of Urology (EAU) guidelines recommend the use of intravesical instillation of Mitomycin C (MMC) to reduce the rate of recurrence. Methods A retrospective cohort analysis was carried out of all patients who underwent a TURBT between January 2016 and January 2019 in our Trust. A comparison of recurrence outcomes was investigated between patients who had immediate instillation of MMC (within 1 hours post-TURBT) versus early instillation (within 24 hours post-TURBT). Recurrence was assessed at 3 months cystoscopy and at 1 year follow-up. Results 201 patients were included. 100 underwent immediate MMC instillation (75% male, 25% female); 101 early instillation (72% male, 28% female). There was 11% recurrence (immediate) versus 13% (early) in instillation groups at 3 months. At first year, recurrence was seen in 12% (immediate) versus 14% (early) groups. Of these recurrences, there was an upstaging of tumour in 27% (immediate) versus 31% (early) at the 3 monthly follow-up and 25% (immediate) versus 28% (early) at the 1st year. The mean period of post-operative stay following initial TURBT was 0.8 days in the immediate versus 1.1 days in the early instillation groups. Conclusion Although no statistical differences were seen in this study, the results appear to favour immediate instillation of MMC after TURBT with respect to reduction in recurrence and upstaging rates. Post-operative length of stay in hospital was also shorter in patients who had an immediate MMC instillation.

Intravesical mitomycin C (MMC) and MMC + cytosine arabinoside for non-muscle-invasive bladder cancer: a randomised clinical trial.

ObjectivesTo compare the urinary pH, recurrence‐free survival (RFS), and safety of adjuvant intravesical therapy in patients with non‐muscle‐invasive bladder cancer (NMIBC) receiving mitomycin C (MMC) therapy and MMC + cytosine arabinoside (Ara‐C) therapy.Patients and MethodsA total of 165 patients with NMIBC from six hospitals were randomly allocated to two groups: weekly instillation of MMC + Ara‐C (30 mg/30 mL + 200 mg/10 mL) for 6 weeks and the same instillation schedule of MMC (30 mg/40 mL). The primary outcome was RFS, and secondary outcomes were urinary pH and toxicity in the two groups.ResultsA total of 81 and 87 patients were randomised into the MMC and MMC + Ara‐C groups, respectively. Overall, the RFS in the MMC + Ara‐C group was significantly longer (P = 0.018) than that in the MMC group. A similar significant difference was detected in patients with intermediate‐risk NMIBC, but not in those with high‐risk NMIBC. The mean (SD) urinary pH was significantly higher in the MMC + Ara‐C group than in the MMC group, at 6.56 (0.61) vs 5.78 (0.64) (P < 0.001), and the frequency of a urinary pH of >7.0 in the MMC and MMC + Ara‐C groups was 6.3% and 26.7%, respectively (P < 0.001). Multivariate analysis models including clinicopathological features and second transurethral resection demonstrated that increased urinary pH was associated with better outcomes (hazard ratio 0.18, 95% confidential interval 0.18–0.038; P < 0.001). In all, there were 14 and 10 adverse events in the MMC and MMC + Ara‐C groups, respectively, without a significant difference (P = 0.113).ConclusionsOur randomised clinical trial suggested that intravesical therapy with MMC and Ara‐C is useful and safe for patients with intermediate‐risk NMIBC. Increase in urinary pH with Ara‐C is speculated as a mechanism for increased anti‐cancer effects.

Post-Transurethral Resection of Bladder Tumor Bladder Perforation Resulting in Mitomycin C Extravasation, Pudendal Neuralgia, and Ureterohydronephrosis

Background: Mitomycin C (MMC) extravasation after transurethral resection of bladder tumor (TURBT) is a rare and highly morbid complication. Management of these cases may require a multidisciplinary approach with strategies ranging from conservative management to surgical intervention. Case Presentation: We present a 48-year-old woman who received a TURBT for a 5 mm bladder tumor. Procedure was uneventful and no bladder perforation was noticed. A single dose of instillation of MMC was performed after surgery resulting in extravasation, consequent ipsilateral pudendal neuralgia, and ureterohydronephrosis. Treatment included a second TURBT, Double-J stent placement, and multiple pain management schemes. After 8 months the patient had complete resolution of pain and ureterohydronephrosis. Conclusion: Perioperative chemotherapy is the standard of care in low-risk bladder cancer. Extravasation of MMC, although rare, can produce severe complications, sometimes irreversible. Other treatment options, such as gemcitabine, are less frequently used despite being less irritant and having similar efficacy. Further studies are needed to compare single-dose instillation regimens.

Safety and feasibility of early single-dose mitomycin C bladder instillation after robot-assisted radical nephroureterectomy.

To assess the safety and feasibility of early single-dose mitomycin C (MMC) bladder instillation after robot-assisted radical nephroureterectomy (RARNU) at a tertiary kidney cancer centre. RARNU with bladder cuff excision and subsequent MMC bladder instillation to reduce recurrence risk is the 'gold standard' for high-risk upper urinary tract urothelial carcinoma (UUTUC). We adapted a RARNU technique with precise distal ureteric dissection, bladder cuff excision and watertight bladder closure. We retrospectively reviewed all patients undergoing RARNU for UUTUC at our centre performed as a standardised transperitoneal procedure comprising of: bladder cuff excision, two-layer watertight closure and intraoperative bladder leak test; without re-docking/re-positioning of the robotic surgical system. Patient demographics, the timing of MMC instillation, adverse events (surgical and potentially MMC-related) and length of stay (LOS) were assessed according to the Clavien-Dindo classification. A total of 69 patients underwent a RARNU with instillation of MMC. The median (interquartile range [IQR]) age was 70(62-78) years. The median (IQR) day of MMC instillation was 2(1-3)days and the median (IQR) LOS was 2(2-4)days, with urethral catheter removal on day of discharge in all cases. Only Grade I Clavien-Dindo complications occurred in seven patients (10%); five had ileus, one a wound infection and one a self-limiting delirium, all managed conservatively. No adverse events potentially related to MMC instillation were noted within 30days postoperatively. The use of intravesical MMC instillation given in the immediate postoperative period appears feasible and safe in patients undergoing RARNU with intraoperative confirmation of a water-tight closure ensuring early catheter-free discharge, with no significant adverse events. The potential reduction in intravesical recurrence in patients receiving early MMC needs to be assessed with longitudinal follow-up studies.

Editorial comment on: The role of continuous saline bladder irrigation after transurethral resection in patients with high-grade non-muscle-invasive bladder cancer

In this randomized study by Onishi et al. [1] the use of a single immediate instillation of Mitomycin-C (SI) is compared to continuous saline bladder irrigation (CSBI) after transurethral resection...

Re: Value of an Immediate Intravesical Instillation of Mitomycin C in Patients with Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Randomised Study in 2243 patients

Abstract Background The efficacy of an immediate single chemotherapy instillation after transurethral resection of a bladder tumour (TURBT) in patients with non–muscle-invasive bladder cancer (NMIBC) remains a topic of debate. Evidence is even more scarce when an immediate instillation is followed by adjuvant instillations. Objective To compare the effect of a mitomycin C (MMC) instillation within 24h to an instillation 2 wk after TURBT in patients with NMIBC with or without adjuvant instillations. Design, Setting, and participants Between 1998 and 2003, 2844 NMIBC patients were randomised for immediate versus delayed MMC instillation after TURBT. Patients were categorised in low-risk (LOR), intermediate-risk (IMR), and high-risk (HIR) groups. Total numbers of instillations in these groups were 1, 9, and 15, respectively. Outcome measurements and statistical analysis Primary end point was 3-yr recurrence risk for the IMR and HIR groups and 5-yr risk for the LOR group. Secondary outcomes were time to recurrence and incidence of adverse events. Analyses were performed with the log-rank test, Cox-regression, and χ 2 test in SPSS. Results and limitations A total of 2243 patients were eligible on an intention-to-treat basis. Recurrence risks were 43% and 46% in the LOR group (5-yr follow-up, p =0.11), 20% and 32% in the IMR group (3-yr follow-up, p =0.037), and 28% and 35% in the HIR group (3-yr follow-up, p =0.007), for an immediate and a delayed instillation, respectively. For all patients, the recurrence risk was 27% (95% confidence interval [CI], 24–30) in the immediate and 36% (95% CI, 33–39) in the delayed instillation group ( p p p =0.08). The risk groups in our study differ slightly from the current guidelines, which is a limitation of our study. Conclusions An immediate, single instillation after TURBT reduces the recurrence risk in NMIBC patients, independent of the number of adjuvant installations. Patient summary A single instillation of chemotherapy after the resection of non–muscle-invasive bladder cancer reduces the recurrence risk, even if patients are treated with an adjuvant schedule of instillations.

MP83-19 MITOMYCIN C (MMC) PLUS BACILLUS CALMETTE E GUERÌN (BCG) SEQUENTIAL THERAPY FOR RECURRENT NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC)

You have accessJournal of UrologyBladder Cancer: Non-invasive II1 Apr 2018MP83-19 MITOMYCIN C (MMC) PLUS BACILLUS CALMETTE E GUERÌN (BCG) SEQUENTIAL THERAPY FOR RECURRENT NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) Mauro Ragonese, Luca Di Gianfrancesco, Niccolò Lenci, Salvatore Marco Recupero, Giuseppe Palermo, and Marco Racioppi Mauro RagoneseMauro Ragonese More articles by this author , Luca Di GianfrancescoLuca Di Gianfrancesco More articles by this author , Niccolò LenciNiccolò Lenci More articles by this author , Salvatore Marco RecuperoSalvatore Marco Recupero More articles by this author , Giuseppe PalermoGiuseppe Palermo More articles by this author , and Marco RacioppiMarco Racioppi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2767AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES BCG therapy represents the gold standard treatment in high grade NMIBC to prevent recurrence and reduce the risk of progression. In patients who do not respond to BCG the gold standard is radical cystectomy. For patients not suitable or not willing to undergo radical surgery there are some bladder preservation strategies: a second BCG induction therapy and chemo-immunotherapy with BCG and MMC are among these options. METHODS We retrospectively evaluated data from 200 patients treated in our Department for a recurrent high grade NMIBC. All the patients were not suitable for surgery or they do not want to undergo radical surgery and were treated with different endovesical regimen. A group of 120 patients (Group 1) was treated with a schedule of combined therapy with 4 weekly instillations of MMC followed by 4 weekly instillations of BCG and a second group of 80 patients (Group 2) was treated with a second induction therapy of BCG. Patients with a complete response after induction were treated with maintenance therapy. We evaluated the complete response after the induction cycle and after a median follow up of 18 months and we compared the rate of side effects evaluated with the Common Terminology Criteria for Adverse Events (CTCAE) RESULTS Complete response after the first evaluation at three months was similar for the two groups, 67.5 % (81 patients) in group 1 and 63.7 % (51 patients) in group 2 without a statistically significant difference. At the median follow-up of 18 months a recurrent disease was present in 76 patients (38 %), 37 (46.2 %) from group 2 and 39 (37.5%) from group 1 (p < 0.01). 7 patients (6%) in group 1 and 6 patients (7.5 %) in group 2 had a progression to muscle-invasive disease. The regimen was well tolerated with low treatment toxicity, only Grade 1 and Grade 2 events were reported and the overall rate of complications was 25 % in group 1 and 11.2 % in group 2 (p < 0.01). No severe adverse events (Grade 3, 4 or 5) were reported and all the patients with a response after the induction complete the maintenance therapy. CONCLUSIONS Recurrent NMIBC is a great challenge for urologist in particular in patients not suitable for radical cystectomy. Sequential therapy and repeat BCG therapy are among these options and our preliminary findings indicate a better efficacy for the combination treatment. Further prospective randomized trials are needed to find out if this regimen could really become a valid alternative for these patients. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1123-e1124 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Mauro Ragonese More articles by this author Luca Di Gianfrancesco More articles by this author Niccolò Lenci More articles by this author Salvatore Marco Recupero More articles by this author Giuseppe Palermo More articles by this author Marco Racioppi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Intravesical radiofrequency induced hyperthermia enhances mitomycin C accumulation in tumour tissue

Introduction: Non-muscle invasive bladder cancer (NMIBC) is a highly recurrent disease with potential progression to muscle invasive disease despite the standard bladder instillations with mitomycin C (MMC) or Bacille Calmette–Guérin immunotherapy. Therefore, alternatives such as radiofrequency-induced chemohyperthermia (RF-CHT) with MMC are being investigated. The mechanism explaining the efficacy of RF-CHT is only partly understood. We examined whether RF-CHT results in higher MMC tissue concentrations as compared to cold MMC instillation.Patients and methods: Prior to a planned transurethral resection of bladder tumour (TURBT), patients with stage Ta NMIBC were allocated to either (1) cold MMC instillation or (2) RF-CHT. After MMC instillation, three biopsies were taken of both normal and tumour tissue. Biopsies were snap-frozen and MMC tissue concentrations were analysed using ultra-performance liquid chromatography.Results: Eleven patients were included of which six received RF-CHT. Ten patients had TaG2-LG/HG papillary tumours at pathology. One patient in the RF-CHT group appeared to be free of malignancy and was excluded from the analysis as no tumour biopsies were available. The median MMC concentration in tumour tissue was higher in the RF-CHT group (median 665.00 ng/g vs. 63.75 ng/g, U = 51.0, p = 0.018). Moreover, in both techniques the MMC concentration was lower in normal tissue compared to tumour tissue. Tissue MMC concentration measurements varied substantially within, and between, different patients from the same group.Conclusion: Intravesical RF-CHT results in higher tumour MMC concentrations vs. cold MMC instillation which contributes to its superior efficacy.

Value of an Immediate Intravesical Instillation of Mitomycin C in Patients with Non–muscle-invasive Bladder Cancer: A Prospective Multicentre Randomised Study in 2243 patients

BackgroundThe efficacy of an immediate single chemotherapy instillation after transurethral resection of a bladder tumour (TURBT) in patients with non–muscle-invasive bladder cancer (NMIBC) remains a topic of debate. Evidence is even more scarce when an immediate instillation is followed by adjuvant instillations. ObjectiveTo compare the effect of a mitomycin C (MMC) instillation within 24h to an instillation 2 wk after TURBT in patients with NMIBC with or without adjuvant instillations. Design, Setting, and participantsBetween 1998 and 2003, 2844 NMIBC patients were randomised for immediate versus delayed MMC instillation after TURBT. Patients were categorised in low-risk (LOR), intermediate-risk (IMR), and high-risk (HIR) groups. Total numbers of instillations in these groups were 1, 9, and 15, respectively. Outcome measurements and statistical analysisPrimary end point was 3-yr recurrence risk for the IMR and HIR groups and 5-yr risk for the LOR group. Secondary outcomes were time to recurrence and incidence of adverse events. Analyses were performed with the log-rank test, Cox-regression, and χ2 test in SPSS. Results and limitationsA total of 2243 patients were eligible on an intention-to-treat basis. Recurrence risks were 43% and 46% in the LOR group (5-yr follow-up, p=0.11), 20% and 32% in the IMR group (3-yr follow-up, p=0.037), and 28% and 35% in the HIR group (3-yr follow-up, p=0.007), for an immediate and a delayed instillation, respectively. For all patients, the recurrence risk was 27% (95% confidence interval [CI], 24–30) in the immediate and 36% (95% CI, 33–39) in the delayed instillation group (p<0.001) with a 27% reduction in relative recurrence risk (hazard ratio: 0.73, 95% CI, 0.63–0.85, p<0.001). The incidence of adverse events did not differ significantly between treatment groups (immediate instillation 25%, delayed instillation 22%, p=0.08). The risk groups in our study differ slightly from the current guidelines, which is a limitation of our study. ConclusionsAn immediate, single instillation after TURBT reduces the recurrence risk in NMIBC patients, independent of the number of adjuvant installations. Patient summaryA single instillation of chemotherapy after the resection of non–muscle-invasive bladder cancer reduces the recurrence risk, even if patients are treated with an adjuvant schedule of instillations.

Systematic Review and Cumulative Analysis of the Combination of Mitomycin C plus Bacillus Calmette-Gu\xe9rin (BCG) for Non\u2013Muscle-Invasive Bladder Cancer

This systematic review and cumulative analysis aimed to explore the efficacy and safety of the combination of intravesical mitomycin C (MMC) plus bacillus Calmette-Guerin (BCG) for non-muscle-invasive bladder cancer (NMIBC) patients. A comprehensive literature search using Pubmed, Embase, Medline, Cochrane Library, CBM, CNKI and VIP databases was performed to identify studies applying intravesical MMC plus BCG therapy on NMIBC patients up to June 2016. Summarized unadjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the efficacy and safety of the combination therapy. A total of 25 studies containing 2749 NMIBC patients were included in this systematic review. Compared with BCG monotherapy, the combination therapy could significantly reduce the tumor recurrence rate (OR = 0.64, 95% CI: 0.44–0.94, P = 0.02) and cancer-specific mortality (OR = 0.54, 95% CI: 0.34–0.87, P = 0.01), without more toxicities (OR = 0.58, 95% CI: 0.17–1.94, P = 0.37). The combination therapy could also lead to significant lower tumor recurrence rate than MMC monotherapy (OR = 0.41, 95% CI: 0.24–0.69, P = 0.0009). Our study indicates that the combination of MMC plus BCG instillation is an effective and safe adjuvant treatment for NMIBC patients.

Characterization of a human anti-tumoral NK cell population expanded after BCG treatment of leukocytes

ABSTRACTImmunotherapy, via intra-vesical instillations of BCG, is the therapy of choice for patients with high-risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, is believed to induce a local immune response that eliminates these tumors, but the detailed mechanisms of action of this therapy are not well understood. Here, we have studied the phenotype and function of the responding lymphocyte populations as well as the spectrum of cytokines and chemokines produced in an in vitro model of human peripheral blood mononuclear cells (PBMCs) co-cultured with BCG. Natural killer (NK) cell activation was a prominent feature of this immune response and we have studied the expansion of this lymphocyte population in detail. We show that, after BCG stimulation, CD56dim NK cells proliferate, upregulate CD56, but maintain the expression of CD16 and the ability to mediate ADCC. CD56bright NK cells also contribute to this expansion by increasing CD16 and KIR expression. These unconventional CD56bright cells efficiently degranulated against bladder cancer cells and the expansion of this population required the release of soluble factors by other immune cells in the context of BCG. Consistent with these in vitro data, a small, but significant increase in the intensity of CD16 expression was noted in peripheral blood CD56bright cells from bladder cancer patients undergoing BCG therapy, that was not observed in patients treated with mitomycin-C instillations. These observations suggest that activation of NK cells may be an important component of the anti-tumoral immune response triggered by BCG therapy in bladder cancer.