Intravesical Instillations Of Mitomycin C Research Articles

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).

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.

Évaluation de l’optimisation des conditions de réalisation des instillations endo-vésicales de mitomycine C dans le traitement des tumeurs de vessie non infiltrant le muscle

The efficacy of intravesical instillation of mitomycin C (MMC) requires alkalinisation and concentration of urine before each instillation. The objective of the study was to assess compliance and effectiveness of urine alkalinazation and fluid restriction protocols in patients treated with intravesical instillations of MMC for TVNIM. Descriptive prospective epidemiological study in all patients consecutively treated with intravesical instillations of MMC for non-muscle invasive bladder cancer (NMIBC). Patients should be advised to drink 2 liters of water from Vichy and to perform fluid restriction the day before the instillations. Before each instillation, a questionnaire on the implementation of these measures was filled, density and pH were determined by urinalysis strips. On 126 questionnaires fulfilled, 117 patients (93%) and 106 patients (84%) reported having made alkalinization and fluid restriction, respectively. Ninety-one of patients (78%) reported having performed alkalinization had a pH greater than or equal to 6.5 and the mean urinary pH was 6.94 vs. 5.94 in patients stating not to have made alkalizing (P=0.0001). No significant differences in urine density according to fluid restriction was found. The observance of the instructions regarding urine alkalinization before MMC instillations was satisfactory and has achieved a sufficiently high urinary pH to prevent degradation of the product in 91% of cases. Conversely, the fluid restriction was not followed closely and has not shown its effectiveness on the concentration of urine.

Prediction of Intravesical Recurrence After Radical Nephroureterectomy: Development of a Clinical Decision-making Tool

BackgroundIntravesical recurrence after radical nephroureterectomy (RNU) is a frequent event requiring intense cystoscopic surveillance. Recently, a prospective randomized clinical trial has shown that a single intravesical postoperative dose of mitomycin C (MMC) reduces the absolute risk of intravesical recurrence after RNU. ObjectiveThe aim of the current study was to identify predictors of intravesical recurrence and to develop a tool to allow a risk-stratified approach supporting patient counseling for cystoscopic surveillance and postoperative intravesical MMC administration. Design, setting, and participantsWe performed a retrospective analysis of 1839 patients with upper tract urothelial carcinoma (UTUC). The data set was split into a development cohort of 1261 patients from North America and a validation cohort of 578 patients from Europe. InterventionsRNU with bladder cuff excision was performed. The surgical approach was open in 1424 patients (77.4%) and laparoscopic in 415 patients (22.6%). Outcome measurements and statistical analysesUnivariable and multivariable Cox regression models addressed time to intravesical recurrence after RNU. We developed a nomogram for prediction of the probability of intravesical recurrence at 3, 6, 9, 12, 18, 24, and 36 mo. Predictive accuracy was quantified using the concordance index. Decision curve analysis was performed to evaluate the clinical benefit associated with the use of our nomograms. Results and limitationsWith a median follow-up of 45 mo, intravesical recurrence occurred in 577 patients (31%). The probability of intravesical recurrence-free survival at 6, 12, 24, and 36 mo was 85%±1%, 78%±1%, 68%±1%, and 47%±2%, respectively. In multivariable Cox regression analysis, advanced age, male gender, ureteral tumor location, laparoscopic surgical technique, endoscopic distal ureteral management, previous bladder cancer, higher tumor stage, concomitant carcinoma in situ, and lymph node involvement were all significantly associated with intravesical recurrence (p values ≤0.04). The nomograms were highly accurate for predicting intravesical recurrence in the external validation cohort (concordance index of 67.8% and 69.0% for the reduced model and the full model, respectively), and calibration plots revealed only minor overestimation beyond 24 mo. If one decided to perform postoperative instillation based on the risk of intravesical recurrence of 15% at 24 mo, one would spare 23% of the patients while not preventing only 0.3% of intravesical recurrences. The lack of information on the stage and grade of the intravesical recurrences is the main limitation of the study. ConclusionsIntravesical recurrence after RNU is a common event in patients with UTUC. We developed nomograms that predict intravesical recurrence after RNU with reasonable accuracy. Such nomograms could improve the clinical decision-making process with regard to cystoscopic surveillance scheduling and postoperative intravesical instillations of MMC after RNU.

Systemic Absorption and Pharmacokinetics of Single-dose Early Intravesical Mitomycin C After Transurethral Resection of Non-muscle-invasive Bladder Cancer

To study the systemic absorption and pharmacokinetics of a single dose of intravesical mitomycin C (MMC) given immediately after transurethral resection of bladder tumor (TURBT). Fourteen patients with primary or recurrent non-muscle-invasive bladder cancer were eligible for a single early intravesical instillation of MMC (40 mg in 50 mL distilled water) administered immediately after TURBT. Blood samples were obtained at baseline and at 20, 40, 60 (time of voiding), 90, 120, and 150 minutes after instillation. Concentrations of the drug were determined by validated high-performance liquid chromatography assay. During TURBT, we counted the number of excursions of the resecting loop required to completely eradicate the tumor, including a portion of the underlying muscular wall. TURBTs were categorized as small and large, defined as requiring ≤6 or >6 full excursions of the resecting loop, respectively. Maximal MMC plasma concentrations were reached 40 minutes after instillation. At 150 minutes, only minimal drug plasma levels were detectable in 4 patients. The highest plasma peak was 49.25 ng/mL. In the first samples, at 20 minutes after instillation, the plasma concentration of MMC was significantly correlated with the extent of TURBT (P = .026). Four patients (28.6%) complained of G1 side effects, 3 after a large TURBT and 1 after a small TURBT, and 1 patient had G2 dysuria after a large TURBT. Low peak blood levels of MMC are observed after a single-dose intravesical instillation immediately after TURBT, with low systemic and local toxicity. The early absorption rate depends on TURBT extension.

1153 EFFECT OF MITOMYCIN C ON LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND ITS RECEPTORS IN BLADDER CANCER CELLS AND IN BLADDERS OF RATS INTRAVESICALLY INSTILLED WITH MITOMYCIN C

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 20101153 EFFECT OF MITOMYCIN C ON LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND ITS RECEPTORS IN BLADDER CANCER CELLS AND IN BLADDERS OF RATS INTRAVESICALLY INSTILLED WITH MITOMYCIN C Avanti Verma, Marcia A. Wheeler, Justin DeGrado, Hristos Z. Kaimakliotis, Adam B. Hittelman, and Robert M. Weiss Avanti VermaAvanti Verma More articles by this author , Marcia A. WheelerMarcia A. Wheeler More articles by this author , Justin DeGradoJustin DeGrado More articles by this author , Hristos Z. KaimakliotisHristos Z. Kaimakliotis More articles by this author , Adam B. HittelmanAdam B. Hittelman More articles by this author , and Robert M. WeissRobert M. Weiss More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.652AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The chemotherapeutics, mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) are effective intravesical treatments for superficial bladder cancer and carcinoma in situ. Intravesical instillation of BCG does not change vascular endothelial growth factor (VEGF) immunoreactivity in bladders from TCC patients and upregulates VEGF receptors in rats. The impact of MMC on expression of the soluble form of VEGF (VEGF-A) and on VEGF receptor-2 (VEGFR-2) which mediates many angiogenic properties of VEGF, has been largely unexamined. We plan to examine the effect of MMC on proliferation and on levels of VEGF-A, VEGF receptor-1 (VEGFR-1) and VEGFR-2 in in vitro and in vivo models. METHODS One day after MMC treatment (6-100 μg/ml), we measured proliferation, and VEGF-A, VEGFR-1 and VEGFR-2 levels in T-24 and RT4 bladder cancer cells. The effect of pretreatment of VEGF siRNA on MMC induced decreases in proliferation was measured. Rats were intravesically instilled with saline or MMC (200 μg/rat). Urinary VEGF levels, and bladder levels of VEGFR-2 protein relative to actin and VEGF, VEGFR-1, and VEGFR-2 mRNA relative to GAPDH mRNA were measured. RESULTS Although MMC treatment inhibited cell proliferation, it did not decrease VEGF protein expression in T-24 and RT4 cells. In fact, in T-24 cells, MMC (6-50 μg/ml) increased VEGF mRNA expression normalized to GAPDH 3-13 fold and increased VEGFR-2 mRNA and protein expression, 2-12 fold and 2-5 fold, respectively. Levels of VEGFR-1 were unchanged. In T-24 cells, MMC (25 μg/ml) reduced proliferation 40 ± 5%, while increasing VEGF mRNA levels 3.4 fold. However, pretreatment of MMC treated cells with VEGF siRNA blocked VEGF mRNA production and potentiated MMC induced reductions in proliferation by an additional 27 ± 4%. Similar results were seen with RT-4 cells. In rats intravesically instilled with MMC, urinary VEGF/creatinine was increased 80% and VEGFR-2 mRNA and protein levels were increased 80% and 150%, respectively, compared to levels in saline instilled rats (n = 4-6). CONCLUSIONS MMC treatment increases levels of VEGF mRNA and VEGFR-2 mRNA and protein in bladder cancer cells. VEGF siRNA potentiates mitomycin inhibitory effects on proliferation in bladder cancer cells. Intravesical Instillation of MMC increases urinary VEGF and bladder VEGFR-2 levels. We speculate that MMC increases the angiogenic potential of both cancer and normal cells. Combining MMC with agents that reduce VEGF levels may be of value in treatment of transitional cell carcinoma of the bladder. New Haven, CT© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e446-e447 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Avanti Verma More articles by this author Marcia A. Wheeler More articles by this author Justin DeGrado More articles by this author Hristos Z. Kaimakliotis More articles by this author Adam B. Hittelman More articles by this author Robert M. Weiss More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Cell Proliferation and DNA Content in Rat Urothelial Lesions after Repeat Intravesical Instillations of Mitomycin C and Bacillus Calmette-Guérin

Aim: To study cell proliferation and DNA content in urothelial lesions identified after repeated intravesical instillations of mitomycin C (MMC) and bacillus Calmette-Guérin (BCG) in normal rat urothelium. Material and Methods: A total of 45 rats were divided into nine equal groups: those intravesically instilled with MMC; those receiving BCG intravesically, and a control group intravesically instilled with a physiological solution of sodium chloride (SF). Animals were killed 1, 4 or 8 weeks after the last intravesical instillation. An immunohistochemical streptavidin-biotin-peroxidase technique was performed to investigate Ki-67 expression and the DNA ploidy status was measured using static cytometry. Results: In urothelium exposed to MMC lesions such as simple hyperplasia, dysplasia, carcinoma in situ(CIS), and squamous cell metaplasia were identified. The proliferation index presented values of 11.73, 22.43 and 31.46% in hyperplasias, dysplasias, and CIS, respectively (p < 0.05). The frequency of abnormal DNA content amongst those animals exhibiting simple hyperplasias 25% were aneuploid, in the dysplasia 85.2% were aneuploid (p = 0.041). CIS were all multiploid, and squamous cell metaplasias were all diploid. Animals treated with BCG and SF presented no urothelial lesions and a diploid DNA content. Conclusions: The aneuploid and multiploid DNA content and proliferation index observed in urothelial lesions identified after repeated intravesical instillations of MMC reflect a high degree of genomic instability in such lesions which in itself may lead to rapid regeneration of new phenotypes.

Intravesical Instillation of Mitomycin-C in 242 Patients with Superficial Bladder Cancer at High Risk of Recurrence: Long-Term Results

Objective: The present study evaluated the long-term results of intravesical mitomycin C (MMC) instillation after transurethral resection (TUR) in 242 consecutive patients with superficial bladder cancer at high risk of recurrence (stage Ta, grade 1–3, or stage T1, grade 1 and 2, primary multiple or recurrent tumor). Materials and Methods: 242 patients were treated with weekly instillations of 40 mg MMC for 8 weeks after TUR. Tumor-free patients then followed a maintenance course with monthly instillations for 3 months. Results: Median follow-up of disease-free patients is 43.5 (range 23–112) months. The incidence of first recurrence is 59.5% (144/242 patients) with a median time to first recurrence of 29 months. 95 patients (39.3%) remained disease-free. Three had disease progression as the first event. The risk of recurrence was significantly higher for multifocal tumors (p = 0.0023, hazard ratio 1.79, 95% CI 1.23–2.59). Overall, patients have been followed for a median time of 57 (range 10–114) months. During this period the recurrence rate was 4.9. Eleven more patients had disease progression. The progression rate is 5.8% (14/242), with a mean time to progression of 34 months. At present 209 patients are alive, 6 have died of bladder cancer, 16 of causes unrelated to the disease and 11 (4.5%) have been lost to follow-up. Thus the crude survival rate is 86.4%, disease-specific mortality 2.5%, and non-disease-specific mortality 6.6%. Conclusions: Patients with multiple tumors seem to benefit the least from MMC instillation. Probably recurrent disease could be better prevented with intravesical bacillus Calmette-Guérin.

Mitomycin-C in superficial bladder cancer. Is long-term maintenance therapy worthwhile after initial treatment?

A total of 72 patients with recurrent superficial transitional cell carcinoma of the bladder (TCC) were treated with 40 mg intravesical instillations of mitomycin-C (MMC) weekly for 10 weeks, followed by monthly maintenance doses. With a mean follow-up period of 41 months, 30 patients (42%) had a complete and sustained response after the initial treatment course, and a further 14 (19%) achieved a complete response on maintenance therapy. Sixteen patients (22%) continued to have recurrent tumours and the remaining 12 (17%) developed recurrent tumours after an initial complete response. Of these, 4 patients with carcinoma in situ (CIS) showed symptomatic improvement, but the histological changes persisted and all of those with tumours > 2 cm in size did not respond. We conclude that maintenance treatment with MMC is beneficial in superficial bladder cancer but is of limited value in the presence of bulky tumours or CIS.

Recurrence of Superficial Bladder Carcinoma after Intravesical Instillation of Mitomycin‐Comparison of Exposure Times

A total of 70 patients were treated with intravesical instillations of Mitomycin-C (MMC) following transurethral resection for superficial bladder carcinoma. In this randomised prospective study the influence of 2 exposure times (0.5 and 1 h) was studied in relation to tumour recurrence, recurrence interval, tumour progression and toxicity. The number of patients with recurrent tumours was significantly lower in the 1-h group. Tumour progression was seen in only 2 patients in each group and all had primary or secondary carcinoma in situ of the bladder or prostatic urethra. Fourteen patients were excluded from further evaluation because of side effects. A longer instillation time over a longer period and a lower dose of MMC are recommended.