Purpose The aim of this phase II study was to determine the efficacy of gemcitabine administered as an intravesical agent in patients with bacille Calmette-Guerin (BCG) –refractory transitional cell carcinoma of the bladder. Patients and Methods Patients with superficial bladder cancer refractory or intolerant to intravesical BCG therapy and refusing a cystectomy were considered eligible for the trial. Eligible patients received two courses of intravesical gemcitabine twice weekly at a dose of 2,000 mg/100 mL for 3 consecutive weeks, with each course separated by 1 week of rest. Patients were evaluated for response at 8 weeks, then every 3 months to 1 year. Results Thirty eligible patients were included on study. The median follow-up for all the patients was 19 months (range, 0 to 35 months). Of the 30 patients, 15 (50%; 95% CI, 32% to 68%) achieved a complete response (CR). Twelve patients had tumor recurrence with a median recurrence-free survival time of 3.6 months (95% CI, 2.9 to 11.0 months). Two pat...

Phase I Trial of Intravesical Gemcitabine in Bacillus Calmette-Guérin–Refractory Transitional-Cell Carcinoma of the Bladder

Importance Low-grade non–muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT). Objective To determine whether immediate post-TURBT intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non–muscle-invasive urothelial cancer compared with saline. Design, Setting, and Participants Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non–muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016. Interventions Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT. Main Outcomes and Measures The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause. Results Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90;P Conclusions and Relevance Among patients with suspected low-grade non–muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents. Trial Registration clinicaltrials.gov Identifier:NCT00445601

/pdf/effect-of-intravesical-instillation-of-gemcitabine-vs-saline-4ufls9e8tf.pdf

Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial.

Purpose Approximately 30% to 40% patients with a superficial bladder cancer treated with Bacille Calmette-Guerin (BCG) or epirubicin do not respond; of the initial responders, 35% have a relapse within 5 years. We compare the therapeutic efficacy and toxicity of intravescical infusions of gemcitabine (GEM) with mitomycin (MMC) in patients with a recurrent superficial bladder cancer. Patients and Methods Patients with a history of a previously treated, recurrent Ta-T1, G1-G3 bladder transitional cell carcinoma were enrolled in the study. The patients received a 6-week course of GEM infusions or 4-week course of MMC. In both arms, for the initial responders who remained free of recurrences, maintenance therapy consisted of 10 monthly treatments during the first year. Results A total of 120 patients were enrolled and randomly assigned to either the MMC or GEM treatment arm. At the end of the study, 109 patients (55 in MMC and 54 in GEM) were assessable. The median duration of follow-up was 36 months for either arm. In the GEM arm, 39 (72%) of 54 patients remained free of recurrence versus 33 (61%) of 55 in MMC arm. Among patients with recurrences, 10 in the MMC arm and six in the GEM arm also had a progressive disease by stage. The incidence of chemical cystitis in the MMC arm was statistically higher than in the GEM arm (P .012). Conclusion This study demonstrates that GEM has better efficacy and lower toxicity than MMC; therefore, GEM appears as a logical candidate for intrabladder therapy in patients with refractory transitional cancer. J Clin Oncol 28:543-548. © 2009 by American Society of Clinical Oncology

https://ascopubs.org/doi/pdf/10.1200/jco.2008.20.8199

Randomized Phase III Trial on Gemcitabine Versus Mytomicin in Recurrent Superficial Bladder Cancer: Evaluation of Efficacy and Tolerance

https://urology.jhu.edu/docS/Intravesical_therapy.pdf

Intravesical Pharmacotherapy for Non–Muscle-Invasive Bladder Cancer: A Critical Analysis of Currently Available Drugs, Treatment Schedules, and Long-Term Results

What's known on the subject? and What does the study add?

The standard treatment for non-muscle invasive bladder (NMIBC) is transurethral resection followed by intravesical therapy. Intravesical agents, e.g. bacille Calmette-Guerin (BCG) or mitomycin C (MMC), have activity in delaying and reducing the incidence of tumour recurrence after surgery but have significant side-effects and are not effective in all patients. Clinical data suggests that gemcitabine has activity in this disease in terms of tumour response and is less toxic, and warrants further study.

This systematic review comprehensively presents the available clinical evidence on intravesical gemcitabine for NMIBC. The limited data from randomised trials suggest that gemcitabine may have role in intermediate-risk patients, as an alternative to MMC, and in high-risk, BCG-refractory patients. Data from observational studies indicate that minimal systemic absorption occurs with intravesical administration and that gemcitabine is active in reducing tumour recurrence.

• Intravesical immunotherapy or chemotherapy for non-muscle invasive bladder cancer is a well-established treatment for preventing or delaying tumour recurrence after tumour resection. However, up to 70% of patients may fail and new intravesical agents with improved effectiveness are needed. Gemcitabine is a relatively new anticancer drug that has shown activity against bladder cancer.
• To systematically review the literature on the effectiveness and toxicity of intravesical gemcitabine for non-muscle invasive bladder cancer (NMIBC).
• MEDLINE, EMBASE, CINAHL, the Cochrane database of systematic reviews, LILACS, SCOPUS, BNI, Biomed Central, Web of Science and BIOSIS were searched to identify trials of intravesical gemcitabine for the treatment of NMIBC. Also searched were meeting proceedings, international guidelines and trial registries. Data on authors, study design, patient characteristics, interventions and outcome data relating to tumour recurrence, disease progression, survival and adverse events were extracted from relevant studies.
• Six relevant randomised trials were identified with the number of patients randomised in each trial varying from 30 to 341 (total 704). All trials compared gemcitabine to active controls and varied in the reporting of outcomes.
• The first was a marker lesion study which reported greater tumour response rates when intravesical gemcitabine (2 g) was given as three bi-weekly doses (36%) or six weekly doses (40%) compared with a single dose (9%).
• One study compared a single postoperative instillation of intravesical gemcitabine with a saline placebo in 341 patients and found no significant difference in the rates of tumour recurrence (28% vs 39%, respectively) or recurrence-free survival (hazard ratio 0.95, 95% confidence interval 0.64–1.39, P= 0.77). The rate of progression to invasive disease was greater with gemcitabine (2.4% vs 0.8%).
• A further trial compared gemcitabine with intravesical mitomycin C (MMC) and reported that the rates of recurrence (28% vs 39%) and progression (11% vs 18%) were lower with gemcitabine but did not reach statistical significance. The overall incidence of adverse events was significantly less with gemcitabine (38.8% vs 72.2%, P= 0.02).
• Three trials compared gemcitabine with intravesical bacille Calmette-Guerin (BCG) but a meta-analysis was not possible due to clinical heterogeneity.
• In untreated patients at intermediate risk of recurrence (primary Ta–T1, no carcinoma in situ) one trial showed that gemcitabine and BCG were similar with respective recurrence rates of 25% and 30% (P= 0.92) and overall progression equal. Dysuria (12.5% vs 45%, P < 0.05) and frequency (10% vs 45%, P < 0.001) were significantly less with gemcitabine.
• In a second trial of high-risk patients the recurrence rate was significantly greater with gemcitabine compared with BCG (53.1% vs 28.1%, P= 0.04%) and the time to recurrence significantly shorter with gemcitabine (25.5 vs 39.4 months, P= 0.042).
• Finally, in a third trial of high-risk patients who had failed previous intravesical BCG therapy, gemcitabine was associated with significantly fewer recurrences (52.5% vs 87.5%, P= 0.002) and a longer time to recurrence (3.9 vs 3.1 months, P= 0.9) compared with BCG. Progression rates were similar in both groups (33% vs 37.5%, P= 0.12) with no significant differences in grade 2 or 3 toxicities.
• The data from several observational studies confirm the pharmacology of gemcitabine as an intravesical agent whilst others report the activity of gemcitabine in terms of tumour recurrence. However, these studies are inherently biased and these data should be interpreted appropriately.
• In conclusion a single study suggests that in NMIBC multiple doses of intravesical gemcitabine reduce tumour recurrences to a greater extent than a single dose.
• In contrast, a single dose immediately after surgery is ineffective based on one study. Gemcitabine may be more active than MMC with a lower toxicity profile.
• Compared with intravesical BCG therapy, gemcitabine had similar effects in intermediate-risk patients, less effective in high-risk patients and superior in BCG-refractory patients. However, each randomised trial identified represents a different clinical setting in NMIBC and therefore the evidence base is limited. Consequently these data should be interpreted with caution until further corroborative evidence becomes available.
• Intravesical gemcitabine is a promising drug that may add to the urologist's options in treating patients with NMIBC.

https://bjui-journals.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1464-410X.2011.10880.x

Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review.

Purpose: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer. Patients and Methods: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 2′2′-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy. Results: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 wee...

Intravesical Gemcitabine Therapy for Superficial Transitional Cell Carcinoma of the Bladder: A Phase I and Pharmacokinetic Study

Background: There is an unmet need for an effective local treatment of upper tract urothelial carcinoma (UTUC). Drug delivery to the pyelocaliceal system and pursuant efficacy of intracavitary therapy is limited by urine production that washes the drug away, shortening dwell time and direct contact with the urothelium. Successful endoscopic management is often dictated by lesion size, grade, and focality. A thermo-reversible hydrogel formulation of Mitomycin C (UGN-101, formerly MitoGel) was developed and has demonstrated the safety and feasibility of increased time of the drug in the pyelocaliceal system resulting in chemoablation of tumors. Objectives: To examine the efficacy and safety of UGN-101 used for chemoablation of UTUC. Methods: There were 22 patients approved for compassionate use treatment at 14 institutions. Six-weekly instillations of UGN-101 were administered via ureteral catheter or percutaneous nephrostomy. Ureteroscopy was performed 2–6 weeks following treatment completion for response determination. Adverse events were recorded throughout treatment. Patients were followed up according to the standard of care of each center. 1co-first authors. ∗Correspondence to: Seth P. Lerner, MD, FACS, Scott Department of Urology, Baylor College of Medicine, 7200 Cambridge, Houston, TX 77030, USA. Tel.: +1 713 798 6841; Fax: +1 713 798 5553; E-mail: slerner@bcm.edu. ISSN 2352-3727/19/$35.00 © 2019 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0). 22 N. Kleinmann et al. / Thermo Reversible Hydrogel Delivery for UTUC Results: Median age of the cohort was 75 yrs., with 16 (73%) males. Eighteen patients had low-grade (LG) tumors, 2 highgrade (HG), and 2 had indeterminate grade. Median volume of UGN-101 instilled was 13.5cc with median Mitomycin dosage of 54 mg. Eight patients had complete response (36%) including 44% (8/18) of the patients with low grade tumors. Partial responses were observed in 23% and 28% of LG. Two patients had no response (9%) and 1 did not undergo ureteroscopy. Four patients could not complete 6 weeks due to adverse events (pyelonephritis, acute renal failure, pancytopenia, and unstable cardiac condition); 1 patient was diagnosed with a non-urothelial cancer during treatment; and 1 patient died prior to the third instillation due to suspected pulmonary embolus, determined to be unrelated to treatment with UGN-101. Out of the patients who had a complete response, 3 (37.5%) patients are recurrence free from 18–30 months. A total of 83 adverse events were recorded. Of these, 6 events related to UGN-101 were serious (requiring medical intervention), and 23 events related to UGN-101 were not serious. Conclusions: This compassionate use program of UGN-101 demonstrates proof of concept for chemoablation treatment of UTUC. A single arm Phase III multi-center registration trial to treat patients with low-grade low-volume renal pelvis tumors is open and enrolling patients (NCT02793128).

Thermo reversible hydrogel based delivery of mitomycin C (UGN-101) for treatment of upper tract urothelial carcinoma (UTUC)

Purpose: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer. Patients and Methods: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 22-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy. Results: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 weeks. Low concentrations of gemcitabine ( 1,500 mg, dFdU concentrations increased until 90 to 120 minutes and then declined little, if any. Plasma dFdU concentrations implied absorption of 0.5% to 5.5% of instilled dose. Between 61% and 100% of the gemcitabine dose was accounted for in voided urine. No dFdU was measured in voided urine. Conclusion: Intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising efficacy in treatment of superficial bladder cancer. J Clin Oncol 21:697-703. © 2003 by American Society of Clinical Oncology.

Intravesical G emcitabine T herapy f or S uperficial T ransitional Cell C arcinoma o f t he B ladder: A P hase I a nd Pharmacokinetic S tudy

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Intravesical Gemcitabine Therapy for Superficial Transitional Cell Carcinoma of the Bladder: A Phase I and Pharmacokinetic Study

Thermo reversible hydrogel based delivery of mitomycin C (UGN-101) for treatment of upper tract urothelial carcinoma (UTUC)

Intravesical G emcitabine T herapy f or S uperficial T ransitional Cell C arcinoma o f t he B ladder: A P hase I a nd Pharmacokinetic S tudy