Course Of Intravesical Therapy Research Articles

Impact of intravesical Bacillus Calmette-Guérin and chemotherapy on the bladder microbiome in patients with non-muscle invasive bladder cancer.

Intravesical therapy (IVT), including Bacillus Calmette-Guérin (BCG), is the standard of care for high grade (HG) non-muscle invasive bladder cancer (NMIBC). Despite the use of IVT, many patients recur after treatment. The bladder microbiome and its role in disease processes has recently risen to prominence. We aim to characterize changes that occur in the bladder microbiome over the course of intravesical therapy and assess whether these changes correlate with outcomes in patients with NMIBC. Patients with NMIBC undergoing induction BCG or intravesical therapy were prospectively enrolled from January 2019 to March 2020. Patients with clinical T2 or greater pathology or active urinary tract infection at enrollment were excluded. Twenty-nine patients had catheterized (bladder) urine samples collected prior to induction intravesical therapy and prior to each IVT instillation. Twenty-seven received BCG while 2 received intravesical gemcitabine. Bacteria were identified using 16S ribosomal RNA gene sequencing. Bladder microbiome changes were evaluated and differences between patients who recurred and patients who did not recur after IVT were investigated. Across the 29 patients analyzed, bacterial richness decreased significantly following intravesical therapy (Richness, P=0.01). Evenness and overall diversity did not change significantly (Pielou, P=0.62; Shannon, P=0.13). Patients who experienced recurrence had a higher relative abundance of Aerococcus in their urine (P<0.01), while those who did not recur had significantly more Ureaplasma (P=0.01) and Escherichia/Shigella species (P=0.05). Patients with decreased levels of alpha diversity were more likely to fall within the non-recurrence cohort. IVT for NMIBC appears to change the urinary microbiome by decreasing richness while not altering evenness or overall diversity. The presence of Aerococcus species may be predictive of a poor cancer response to IVT, while the presence of Ureaplasma and Escherichia/Shigella may predict a favorable response to IVT. Further studies are warranted to elucidate and confirm the significance of changes in the bladder microbiome.

The experience of UK patients with bladder cancer during the COVID-19 pandemic: a survey-based snapshot.

The COVID-19 pandemic has placed unprecedented strain on healthcare systems worldwide with the requirement to treat large influxes of infected patients, many of whom require respiratory support. Healthcare systems have had to redirect resources and redeploy staff away from routine diagnostic, treatment and follow-up services. The UK's National Health Service (NHS) is no different and cancer services have undergone significant disruption to create the emergency capacity to tackle the pandemic. As a charity that endeavours to support bladder cancer (BC) patients and improve outcomes, Action Bladder Cancer UK (ABCUK, Tetbury, UK) designed and administered an online survey to investigate the prevalence of such disruption.

MP73-08 INTRAVESICAL GEMCITABINE AND DOCETAXOL IN HEAVILY PRE-TREATED PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC)

You have accessJournal of UrologyBladder Cancer: Non-invasive IV (MP73)1 Apr 2020MP73-08 INTRAVESICAL GEMCITABINE AND DOCETAXOL IN HEAVILY PRE-TREATED PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) Adele Caruso*, Roshan Ravishankar, Keith VanArsdalen, and Stanley Malkowicz Adele Caruso*Adele Caruso* More articles by this author , Roshan RavishankarRoshan Ravishankar More articles by this author , Keith VanArsdalenKeith VanArsdalen More articles by this author , and Stanley MalkowiczStanley Malkowicz More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000959.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Therapeutic options are limited for BCG resistant/ refractory NMIBC patients who are unfit or refuse radical cystectomy. Combination chemotherapy is not regularly used due to additive toxicity. The non-desiccant properties of Gemcitabine allow for combined therapy not previously employed. Docetaxol as a single agent demonstrates significant activity with acceptable toxicity. The objective of this study was to evaluate combination intravesical chemotherapy for its initial response and therapeutic durability in those patients heavily pre-treated with BCG. METHODS: Patients who had failed or were intolerant to BCG therapy were offered combination intravesical therapy per the following regimen 1000 mg of GEM in 100 cc’s of saline instilled for two hours followed by bladder emptying and reinstallation of 37.5 mg DOC in 50 mls saline. This was done weekly for 6 weeks. At twelve weeks patients underwent cystoscopy with full bladder mapping and cytology. Cystoscopy was performed every 3 months for one year and at 3 months or 6 months thereafter. Further biopsiy or resection was performed for positive cytology, distinct recurrent tumor or suspicious areas on cystoscopy. Failure was defined as positive cytology, tumor recurrence or distant failure. RESULTS: Between 12/2015 and 6/2019, thirty patients were recruited. 26 are eligible for evaluation and had a mean of 3.2 prior induction courses of intravesical therapy. There were 20 men and 6 women with a mean age of 77 (range 68-94). Twenty four of 26 patients demonstrated an initial negative evaluation. 16/26 patients recurred during this time period with a mean disease free interval of 12.45 months (range 3-34 months). Ten patients are NED for a mean of 9.6 months (range 3-15 months) 11 failures were local (2 muscle invasive progression), 4 cytology only, 1 pelvic lymph node progression. The regimen was well tolerated per patient complaints and AUA voiding scores. CONCLUSIONS: Sequential, combination Gemcitabine and Docetaxol intravesical chemotherapy is an active regimen in BCG pretreated patients who are unfit or unwilling to undergo cystectomy. A near universal initial response with a complete response maintained for over one year in responders suggests a role for maintenance therapy and supports continued study of this intravesical regimen. Source of Funding: NONE © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1124-e1124 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Adele Caruso* More articles by this author Roshan Ravishankar More articles by this author Keith VanArsdalen More articles by this author Stanley Malkowicz More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract CT047: Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous Pembrolizumab in high grade nonmuscle invasive bladder cancer

Abstract PURPOSE: A phase I trial of intravesical bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab was conducted in patients with high grade non-muscle invasive bladder cancer who had persistent or recurrent disease after failing treatment with at least 2 courses of intravesical therapy (one of which had to contain BCG) or BCG followed by maintenance BCG. The primary objective was to determine the safety of this combination. Secondary end points included response to treatment at 19 weeks (end of treatment) and 3 months post treatment. MATERIALS AND METHODS: A total of 9 patients with recurrent/persistent high-grade non-muscle invasive bladder cancer after at least two courses of intravesical therapy or one course of BCG treatment followed by one course of maintenance BCG were enrolled in the study. Six doses of pembrolizumab were given every 3 weeks over 16 weeks given concurrently with 6 weekly doses of BCG beginning at week 7. Patient safety was evaluated during and for 30 days following pembrolizumab treatment. Preliminary combination efficacy was determined at 19 weeks using cystoscopy. Bladder biopsy was performed in patients with suspicious lesions. RESULTS: The combination of BCG and pembrolizumab was well tolerated at both 100mg and 200mg fixed doses. Fatigue and cystitis-type symptoms (burning, spasm, urgency, sensitivity, and frequency) were the most common adverse events and all cases were either grade 1 or 2. Two patients died during the trial period. One patient died due to progression of low grade upper urinary tract transitional cell carcinoma. The other patient died after cystectomy (for progressive disease) due to causes unrelated to the trial treatment. Of the 9 patients treated, 6 (78%) had no evidence of disease in the bladder and 1 had a mixed response (progression in the upper urinary tract only) at 19 weeks (end of treatment) while 5 (56%) remained disease-free at the 3 month follow up. CONCLUSIONS: The combination of BCG and pembrolizumab was well tolerated with subjects exhibiting the expected adverse effects associated with the use of both medications. Intravesical BCG and pembrolizumab may have clinical activity in non-muscle invasive bladder cancer recurring after repeated intravesical therapy. .A phase III trial is now open and enrolling in the United States and other countries (NCT03711032). Citation Format: Shaheen Alanee, Ahmed El Zawahry, Sherjeel Sana, Kevin McVary, Kathy Robinson, Krishna A. Rao. Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous Pembrolizumab in high grade nonmuscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT047.

An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non–muscle-invasive bladder cancer: Interim results

ObjectivesCG0070 is a replication-competent oncolytic adenovirus that targets bladder tumor cells through their defective retinoblastoma pathway. Prior reports of intravesical CG0070 have shown promising activity in patients with high-grade non–muscle invasive bladder cancer (NMIBC) who previously did not respond to bacillus Calmette-Guérin (BCG). However, limited accrual has hindered analysis of efficacy, particularly for pathologic subsets. We evaluated interim results of a phase II trial for intravesical CG0070 in patients with BCG-unresponsive NMIBC who refused cystectomy. Patients and methodsAt interim analysis (April 2017), 45 patients with residual high-grade Ta, T1, or carcinoma-in-situ (CIS) ± Ta/T1 had evaluable 6-month follow-up in this phase II single-arm multicenter trial (NCT02365818). All patients received at least 2 prior courses of intravesical therapy for CIS, with at least 1 being a course of BCG. Patients had either failed BCG induction therapy within 6 months or had been successfully treated with BCG with subsequent recurrence. Complete response (CR) at 6 months was defined as absence of disease on cytology, cystoscopy, and random biopsies. ResultsOf 45 patients, there were 24 pure CIS, 8 CIS + Ta, 4 CIS + T1, 6 Ta, 3 T1. Overall 6-month CR (95% CI) was 47% (32%–62%). Considering 6-month CR for pathologic subsets, pure CIS was 58% (37%–78%), CIS ± Ta/T1 50% (33%–67%), and pure Ta/T1 33% (8%–70%). At 6 months, the single patient that progressed to muscle-invasive disease had Ta and T1 tumors at baseline. No patients with pure T1 had 6-month CR. Treatment–related adverse events (AEs) at 6 months were most commonly urinary bladder spasms (36%), hematuria (28%), dysuria (25%), and urgency (22%). Immunologic treatment–related AEs included flu-like symptoms (12%) and fatigue (6%). Grade III treatment–related AEs included dysuria (3%) and hypotension (1.5%). There were no Grade IV/V treatment–related AEs. ConclusionsThis phase II study demonstrates that intravesical CG0070 yielded an overall 47% CR rate at 6 months for all patients and 50% for patients with CIS, with an acceptable level of toxicity for patients with high-risk BCG-unresponsive NMIBC. There is a particularly strong response and limited progression in patients with pure CIS.

When the Gold Standard Proves to Be Fool's Gold—Blue-light Cystoscopy in a Case of High-risk Non–muscle-invasive Bladder Cancer

A 75-year-old man was referred for a second opinion on the management of bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC). He was initially diagnosed with NMIBC 2 years before his referral to our institution upon workup for painless gross hematuria. His initial biopsy demonstrated multifocal carcinoma in situ (CIS), and he subsequently underwent an induction course of intravesical therapy with bacillus Calmette-Guérin. He tolerated the therapy well, and he underwent a post-BCG bladder biopsy, which unfortunately demonstrated persistent CIS. He then underwent a second induction course of intravesical BCG plus interferon-α2b. Post-therapy bladder biopsy was repeated and demonstrated no evidence of urothelial carcinoma. He started maintenance intravesical BCG and underwent vigilant periodic cystoscopic surveillance. He remained disease free for approximately 18 months, but was found to have a velvety erythematous patch on the right lateral wall of his bladder on his next surveillance cystoscopy. Site-directed bladder biopsies and resection of the aforementioned lesion were performed; the pathology was consistent with a single focus of CIS, which prompted the referral to our institution.

MP26-11 THE TIMING OF RADICAL CYSTECTOMY FOR BCG FAILURE: COMPARISON OF OUTCOMES AND RISK FACTORS FOR PROGNOSIS

You have accessJournal of UrologyBladder Cancer: Non-invasive I1 Apr 2015MP26-11 THE TIMING OF RADICAL CYSTECTOMY FOR BCG FAILURE: COMPARISON OF OUTCOMES AND RISK FACTORS FOR PROGNOSIS Christopher Haas, LaMont Barlow, G. Joel DeCastro, and James McKiernan Christopher HaasChristopher Haas More articles by this author , LaMont BarlowLaMont Barlow More articles by this author , G. Joel DeCastroG. Joel DeCastro More articles by this author , and James McKiernanJames McKiernan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1133AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Radical cystectomy (RC) is the first-line treatment after BCG failure. However, many patients initially refuse surgery and pursue salvage intravesical therapy (IVT). The aims of this study are to compare the pathologic and survival outcomes of patients who receive RC soon after BCG failure with those who receive additional salvage IVT prior to undergoing RC for non-muscle-invasive bladder cancer (NMIBC) and identify risk factors of prognosis for the entire cohort. METHODS A single-institutional database was reviewed for patients who underwent RC for persistent NMIBC after at least 1 BCG induction course from 1990 to 2012. Multivariable logistic regression analysis assessed risk factors for upstaging to muscle invasion on final pathology. Kaplan Meier curves and multivariable cox regression analyses identified predictors of OS and CSS. RESULTS 117 patients were identified who had RC for intermediate to high risk NMIBC treated with at least one induction course of BCG. The cohort was separated into 2 groups: Group 1 (n = 61) was comprised of patients treated only with BCG +/- IFN; group 2 (n = 56) received at least one additional salvage IVT after BCG. Mean courses of IVT for groups 1 and 2 were 1.4 (range 1-2) and 3.4 (range 2-6), respectively. Group 1 had 13 (21.3%) patients with muscle invasion on RC pathology while group 2 had 11 (19.6%). In the total cohort, significant risk factors for muscle invasion on multivariable analysis were the percent frequency of TURBTs with HG T1 in individual patients (OR 1.03, p < 0.001), the percent frequency of TURBTs with CIS (OR 1.02, p = 0.047) and age (OR 1.07, p = 0.033). On Kaplan Meier analysis, there was no difference in OS and CSS between groups 1 and 2. Controlling for percent frequency of TURBTs with HG T1 and CIS, age, presence of LVI, and prostatic urethra involvement on cox regression, group 2 did not have a significantly worse risk of dying after RC (OR 1.4, p = 0.32); only age (OR 1.06, p = 0.01) and LVI (OR 2.8, p = 0.02) achieved significance. While being in group 1 or 2 did not significantly predict ureteral or urethral involvement, higher frequency of CIS on TURBTs increased the risk of ureteral or urethral involvement (OR 1.35, p = 0.03), which was in turn a feature associated with worsened OS and CSS and on Kaplan Meier analysis (p = 0.003 and p = 0.01, respectively). CONCLUSIONS There was no statistically significant difference in pathologic or oncologic outcomes amongst earlier RC versus additional salvage IVT prior to RC. Appropriately selected candidates for salvage IVT appear to have equivalent outcomes should they remain with NMIBC prior to RC. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e297-e298 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Haas More articles by this author LaMont Barlow More articles by this author G. Joel DeCastro More articles by this author James McKiernan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD17-09 DECADE-LONG EXPERIENCE WITH INTRAVESICAL DOCETAXEL IN THE MANAGEMENT OF NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC) REFRACTORY TO BCG THERAPY

You have accessJournal of UrologyBladder Cancer: Non-invasive II1 Apr 2015PD17-09 DECADE-LONG EXPERIENCE WITH INTRAVESICAL DOCETAXEL IN THE MANAGEMENT OF NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC) REFRACTORY TO BCG THERAPY LaMont Barlow, Danny Lascano, James McKiernan, and Mitchell Benson LaMont BarlowLaMont Barlow More articles by this author , Danny LascanoDanny Lascano More articles by this author , James McKiernanJames McKiernan More articles by this author , and Mitchell BensonMitchell Benson More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.666AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Since completing the phase I clinical trial in 2005, intravesical docetaxel has demonstrated significant activity in patients with recurrent NMIBC after BCG therapy. We now present our cumulative experience in the largest cohort of intravesical taxane therapy ever reported. METHODS Patients who received salvage intravesical docetaxel for BCG-refractory NMIBC between 2003 and 2014 were identified, including 18 patients treated during the original phase I trial. All patients were treated with 6 weekly instillations of intravesical docetaxel. Patients in the latter portion of the study period with a complete response to induction treatment were given single-dose monthly maintenance treatments starting at month 3 for a total of up to 12 months of docetaxel therapy. Recurrence was defined as either a positive biopsy or positive urine cytology. Recurrence-free survival, disease-specific survival, and overall survival were determined using Kaplan-Meier analyses. RESULTS 68 patients have been treated, including 25 patients with T1 disease, 18 patients with Ta disease, and 25 patients with Tis prior to docetaxel therapy. 40/68 patients (59%) had at least two prior induction courses of intravesical therapy. The median age was 72 (range: 38-90); median follow-up was 45.6 months (range: 3-137 months). 41/68 patients (60%) had a complete initial response after induction therapy. 27/41 patients with a complete initial response received additional monthly maintenance treatments. Median time to recurrence in initial responders treated with and without docetaxel maintenance was 39.3 and 19.0 months, respectively. 1 and 3-year recurrence-free survival rates for the entire cohort were 42% and 27%, respectively. 49/68 patients (72%) kept their bladders during follow-up, and 19/68 patients (28%) underwent radical cystectomy. In this high-risk group, 5-year disease-specific survival (DSS) and overall survival (OS) rates for the entire cohort were 84% and 71%, respectively; 5-year DSS and OS rates for patients undergoing cystectomy were both 83%. CONCLUSIONS After over a decade of experience, salvage intravesical docetaxel continues to demonstrate a very high response rate with durability that appears to surpasses other salvage intravesical therapies. This agent, when used in a combined induction and maintenance regimen, is a powerful tool in the management of recurrent NMIBC after BCG therapy. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e384 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information LaMont Barlow More articles by this author Danny Lascano More articles by this author James McKiernan More articles by this author Mitchell Benson More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Salvage Combination Intravesical Immunotherapy With Bacillus Calmette-Guérin and Interferon-α2B: Impact on Recurrence, Progression, and Survival

Background: The population of patients with bladder cancer who have recurrence following an initial instillation of Bacillus Calmette-Guérin (BCG) is critical to study, as treatment delay with repeated courses of intravesical therapy may yield poor prognosis in patients with disease progression. Objective: To evaluate our institution's experience with use of BCG alone and in combination with interferon (INF)-α2B in regard to the rates of bladder cancer recurrence, disease progression, need for eventual cystectomy, and survival in patients with initial BCG failure. Study Design: We identified a combined series of 139 patients who had undergone intravesical instillations of BCG alone (n = 114) or in combination with INF-α2B (n = 25) performed at Brigham and Women's Hospital, Boston, between 2002 and 2007. All patients previously received an initial 6-week course of BCG therapy and subsequently had BCG failure on follow-up cystoscopy. Study outcome measures included: time to cancer recurrence in patients, progression of disease, eventual cystectomy, and patient mortality. Results: At a median follow-up of 64.7 months from initial BCG administration, 84% of patients treated with BCG + INF-α2B had disease recurrence. The average time to recurrence was < 1 year, and 63% of patients had recurrence on the first post-treatment biopsy. Among patients with a positive first biopsy, 52% had disease progression on initial surveillance. Overall, disease progression was seen in 48% of patients receiving BCG + INF-α2B therapy, and 28% of all patients eventually underwent radical cystectomy. All outcomes occurred more frequently in patients undergoing combination intravesical therapy compared with patients given BCG monotherapy. Conclusions: Patients with bladder cancer undergoing salvage intravesical BCG + INF-α2B at our institution had a > 50% chance of disease recurrence and progression, and > 25% of patients eventually proceeded to radical cystectomy. Randomized trials are needed to clarify the issues present in our findings and to determine the appropriate role for concomitant INF therapy in patients when BCG monotherapy has failed.

Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin

ObjectivesEvaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)–refractory carcinoma in situ (CIS) of the bladder based on updated phase III pivotal trial efficacy data together with efficacy and safety data from a supportive phase II/III study. Materials and MethodsIn a phase II/III open-label study (A9303), BCG refractory/intolerant adults with CIS (≥1 previous course of BCG or could not complete a BCG course owing to toxicity or contraindication) were randomized to receive 6 or 9 weekly intravesical valrubicin (800 mg) instillations. In the pivotal phase III open-label study, BCG-refractory/recurrent adults with CIS (≥2 previous courses of intravesical therapy, including ≥1 BCG course) received 6 weekly intravesical valrubicin (800 mg) instillations. Patients with muscle-invasive disease were excluded. Patients underwent a primary disease evaluation (PDE) at 3 months (∼6 weeks after last dose) that included cytoscopy, biopsy, and cytology. Disease recurrence was monitored at 3-month intervals. Complete response (CR) was defined as no evidence of disease at the PDE (month 3) and follow-up (month 6). Efficacy data from the pivotal trial reflect updated information based on US Food and Drug Administration review. Safety assessments in A9303 included local bladder adverse events (LBAEs) and other adverse events (AEs). ResultsEighty patients enrolled and 78 completed treatment and underwent the PDE in study A9303; in the pivotal trial, the respective numbers were 90 and 87 patients. In study A9303, 39% of patients had received ≥2 previous courses of BCG and 11% had received ≥3 courses vs. 70% and 28%, respectively, in the pivotal trial. In both studies, the CR rate was 18%. In A9303, LBAEs were the most common AEs, reported by 86% of patients during treatment and 45% during follow-up; most treatment-related LBAEs were mild to moderate. 2 serious AEs in 1 patient (azotemia/reflux nephropathy) were judged as definitely or possibly treatment related; none of the patient deaths were judged to be related to valrubicin. ConclusionsTwo trials of valrubicin in patients with CIS demonstrate a consistent degree of efficacy in highly pretreated patients (pivotal trial; BCG-refractory patients) and those with fewer previous therapies (A9303; BCG-refractory/intolerant patients).

Factors Affecting Valrubicin Response in Patients with Bacillus Calmette-Guérin–Refractory Bladder Carcinoma in Situ

Objective: Patients with bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the bladder are candidates for intravesical (IVe) valrubicin. This post-hoc analysis of data from the pivotal phase 3, prospective, open-label study of valrubicin evaluated the effects of patient characteristics and past treatments on the response to valrubicin. Methods: Enrolled patients had non-muscle-invasive CIS with or without concurrent papillary disease stage Ta and/or T1 for which papillary tumors had been resected before treatment, and had previously received ≥ 2 courses of IVe therapy (≥ 1 BCG course). Patients received a course of valrubicin, which consisted of 6 weekly IVe treatments of valrubicin (800 mg). Complete response was defined as no evidence of disease by urine cytology, cystoscopy, and biopsy at 3 and 6 months posttreatment. Patient characteristics, baseline urinary symptoms, and number and type of previous treatment courses and instillations were compared for complete versus nonresponders (including partial responders) to valrubicin. Results: Ninety patients enrolled; 87 patients with positive biopsy at initiation completed a valrubicin course and underwent the 3-month assessment. Five had missing data at 6 months. Of the remaining 82 patients, 18 demonstrated a complete response; 64 demonstrated partial or no response. For complete responders versus partial or nonresponders, differences in patient characteristics, baseline urinary symptoms, and number of previous courses or instillations of BCG or other types of treatment were not significant (P < 0.05). More complete responders had evidence of inflammation before or during valrubicin treatment (P = 0.005 vs nonresponders). Conclusions: In these patients with BCG-refractory CIS, complete responders to valrubicin did not differ significantly from partial or nonresponders in the number of prior courses or instillations. The results suggest that therapy with valrubicin may be considered in appropriate candidates who have not responded to prior therapies. Cystectomy should be reconsidered when valrubicin treatment fails.

Urovysion™ testing can lead to early identification of intravesical therapy failure in patients with high risk non-muscle invasive bladder cancer

In this study, we investigated the ability of UroVysion to assess response to intravesical therapy in patients with high risk superficial bladder tumors. We performed a retrospective review of patients undergoing intravesical therapy for high risk superficial bladder tumors. Urine specimens were collected for UroVysion analysis before and immediately after a course of intravesical therapy. Cytology and cystoscopy were performed six weeks after treatment, using either a positive cytology or visible abnormality on cystoscopy as a prompt for biopsy. The operating characteristics of the UroVysion test were then determined. 41 patients were identified in whom 47 cycles of induction and 41 cycles of maintenance intravesical therapy were given during the study period. This yielded a total of 88 treatment and evaluation cycles. Median follow-up was 9 months per induction (range 1-21 months) and 13 months per patient (range 1-25 months). A total of 133 urine samples were collected for UroVysionTM of which 40 were positive. Based upon standard clinical evaluation, 41 biopsies were performed which detected 20 recurrences. UroVysionTM testing performed immediately upon completion of therapy for the 41 patients undergoing biopsy yielded a sensitivity, specificity, and accuracy of 85%, 61%, and 71%. The use of UroVysionTM following intravesical therapy for high-risk superficial bladder tumors helps to identify patients at high risk of refractory or recurrent disease who should undergo immediate biopsy under anesthesia.

Understanding bladder cancer death

To the authors' knowledge, the extent to which death from bladder cancer is attributable to tumor biology or physician practice patterns is unknown. For this reason, the relative importance of broadening indications for aggressive therapy has unclear implications. Patients whose deaths were caused directly by bladder cancer were identified using institutional (n = 126 patients) and administrative (n = 6326 patients) data sources. By using implicit review (clinical data, 2001-2005) and explicit algorithms (Surveillance, Epidemiology, and End Results [SEER]-Medicare, 1992-2002), the authors estimated the proportion of potentially avoidable deaths from bladder cancer. After an implicit review of clinical data, 40 of 126 deaths (31.7%) were classified as potentially avoidable. Compared with those patients who were deemed unsalvageable, these patients generally presented with nonmuscle-invasive disease (80% vs 25.6%; P < .001), received multiple courses of intravesical therapy (32.5% vs 1.2%; P < .001), and had a more protracted course from diagnosis to aggressive treatment (median, 23 months vs 2 months; P < .001). An explicit review of claims data indicated that between 31.6% and 46.8% of the 6326 bladder cancer deaths identified in the SEER-Medicare data potentially were avoidable, depending on the survivorship threshold chosen. Patients whose deaths potentially were avoidable more commonly presented with nonmuscle-invasive disease (66.7% vs 24.7%; P < .0001) and lower grade disease (35.1% vs 15.1%; P < .0001). The greatest inroads into reducing death from bladder cancer likely hinge on earlier detection or improvement of systemic therapies. However, changing physician practice may translate into nontrivial reductions in bladder cancer mortality.

The increasing use of intravesical therapies for stage T1 bladder cancer coincides with decreasing survival after cystectomy: Lambert EH, Pierorazio PM, Olsson CA, Benson MC, McKiernan JM, Poon S, Department of Urology, Columbia University Medical Center, New York, NY.

Objective Intravesical therapy (IVT), chemo, and immunotherapy, have made conservative, bladder-sparing strategies a viable option for managing patients with high grade T1 bladder cancer. However, many of these patients will have recurrence and occasionally progression, questioning delayed intervention. This study examines the patterns of use of IVT in high-grade T1 bladder cancer and the subsequent impact on survival for patients ultimately proceeding to radical cystectomy (RC). Patients and Methods Between 1990 and 2005, 104 patients were identified with T1 high-grade transitional cell carcinoma (TCC) who underwent RC. Patients were divided into two groups; those having RC before 1998 (median year of surgery) and those after 1998. Trends in time from diagnosis to RC, courses of IVT, recurrence, and pathological stage were analyzed using two sample t-tests with 95% confidence intervals. Kaplan-Meier analysis was used to determine the disease-free and overall survival rates. Results Before 1998, 28 of 38 patients (74%) proceeded directly to RC with no IVT, vs. 20 of 47 (43%) after 1998 (P = 0.004). The mean number of IVT courses per patient was 0.53 before 1998 and 1.2 afterward (P = 0.016). Patients who had RC before 1998 had a 69.7% disease-free survival at 5 years, vs. 39.6% for those after 1998 (P = 0.05). Conclusions In the past 15 years, our experience indicates that patients having RC for T1 high-grade TCC after 1998 were more likely to receive IVT. These same patients had a worsening disease-free survival. In very few other cancers has disease-free survival decreased over time. We postulate that the decrease in survival might be related to an increased use of IVT.

The increasing use of intravesical therapies for stage T1 bladder cancer coincides with decreasing survival after cystectomy

Intravesical therapy (IVT), chemo and immunotherapy, has made conservative, bladder-sparing strategies a viable option for managing patients with high grade T1 bladder cancer. However, many of these patients will have recurrence and occasionally progression, questioning delayed intervention. This study examines the patterns of use of IVT in high-grade T1 bladder cancer and the subsequent impact on survival for patients ultimately proceeding to radical cystectomy (RC). Between 1990 and 2005, 104 patients were identified with T1 high-grade transitional cell carcinoma (TCC) and who underwent RC. Patients were divided into two groups; those having RC before 1998 (median year of surgery) and those after 1998. Trends in time from diagnosis to RC, courses of IVT, recurrence and pathological stage were analysed using two-sample t-tests with 95% confidence intervals. Kaplan-Meier analysis was used to determine the disease-free and overall survival rates. Before 1998, 28 of 38 patients (74%) proceeded directly to RC with no IVT, vs 20 of 47 (43%) after 1998 (P = 0.004). The mean number of IVT courses per patient was 0.53 before 1998 and 1.2 afterward (P = 0.016). Patients who had RC before 1998 had a 69.7% disease-free survival at 5 years, vs 39.6% for those after 1998 (P = 0.05). In the past 15 years, our experience indicates that patients having RC for T1 high-grade TCC after 1998 were more likely to receive IVT. These same patients had a worsening disease-free survival. In very few other cancers has disease-free survival decreased over time. We postulate that the decrease in survival might be related to an increased use of IVT.

The optimum timing of radical cystectomy for patients with recurrent high‐risk superficial bladder tumour

To establish the optimum time of radical cystectomy (RC) for patients with recurrent high-risk superficial bladder tumours after the failure of intravesical therapy. Among 318 patients with transitional cell carcinoma treated with RC and with no neoadjuvant therapy, there were 46 with clinical stage Ta, T1 or Tis refractory to transurethral resection associated with intravesical therapy. These patients had at least one of: (i) high-risk superficial bladder tumours after failure of two consecutive induction courses of intravesical therapy; (ii) superficial bladder tumours with prostatic stromal invasion; (iii) superficial bladder tumours with mucosa/ducts involvement after failure of one course of intravesical therapy; (iv) uncontrolled superficial tumours with transurethral resection associated or not with intravesical therapy. Progression and cause-specific survival of these patients were compared to those with muscle-invasive tumours. Univariate and multivariate analyses of predictive factors for cause-specific survival were also used in patients with superficial tumours. The incidence of significant prognostic factors was compared in both superficial and muscle-invasive tumours, as were the progression pattern and survival. The progression-free and cause-specific survival of patients with superficial tumours was 54% and 67%, respectively, with no significant difference from those with muscle-invasive tumours. In multivariate analysis, positive lymph-nodes and prostatic stromal invasion were significant and independent variables for survival. The incidence of positive lymph nodes was 15% vs 30% (P < 0.05) and of stromal invasion was 32% vs 1.5% (P < 0.001) in patients with superficial and muscle-invasive tumours, respectively. Accounting for the progression pattern in patients with superficial tumours, extravesical urothelial recurrence prevailed over local or distant recurrences (30% vs 15%), whereas in patients with muscle-invasive tumours the opposite occurred (5% vs 33%, respectively). The cause-specific survival of patients with superficial tumour and prostatic stromal invasion was one of three, and in those who developed extravesical urothelial recurrence was 28.5%. In patients with recurrent high-risk superficial bladder cancer after intravesical therapy, our criteria for RC were inappropriate, and patients had a survival rate similar to those with muscle-invasive tumours. RC might have been used too late, as there was a high incidence of prostatic stromal invasion and extravesical urothelial recurrence after RC. Both events seem to be responsible of the low cause-specific survival. Predictive factors for progression are needed to indicate early RC in patients with recurrent high-risk superficial tumours. From a previous analysis the pathological pattern of the clinical lack of response (T1, G3, bladder carcinoma in situ and prostate involvement) to intravesical therapy evaluated at 3 months might be important for predicting progression, and an early RC at that time might be useful.

Risk of continued intravesical therapy and delayed cystectomy in BCG-refractory superficial bladder cancer: an investigational approach

Objectives. To assess the risk of continued intravesical therapy and delayed cystectomy in the management of superficial bladder cancer refractory to bacillus Calmette-Guérin (BCG) therapy. Methods. We retrospectively reviewed the medical records of 24 patients who underwent an experimental intravesical treatment with BCG plus interferon alpha-2b or valrubicin for transitional cell carcinoma of the bladder. All patients had Stage Tis and/or T1 transitional cell carcinoma and had failed multiple prior courses of intravesical therapy, including at least one course of BCG. Results. Patients were followed up for a median of 28.5 months (range 6 to 48). One patient died of unrelated disease. All other patients were alive at last follow-up. Fourteen patients with preserved bladder were continuing cystoscopic surveillance: four had no recurrence, five had recurrence limited to the mucosa (Ta or Tis) and became free of disease after an additional course of intravesical therapy, and five had recurrent Ta or Tis or positive cytologic findings. The remaining 9 patients underwent radical cystectomy. All pathologic specimens showed no evidence of progression to muscle-invasive disease. Tis of the resected ureters in 6 and involvement of the prostate in 4 of the 9 patients (three in the urethral ducts and glands and one in the prostatic stroma) were noted. Conclusions. A select group of patients with BCG-refractory transitional cell carcinoma and a poor surgical risk for cystectomy may benefit from continued intravesical therapy without a significant risk of progression. However, a cautious approach to this treatment modality is recommended, and very close follow-up is necessary to detect bladder recurrences and involvement of the upper tract and prostatic urethra.

EFFICACY AND SAFETY OF VALRUBICIN FOR THE TREATMENT OF BACILLUS CALMETTE-GUERIN REFRACTORY CARCINOMA IN SITU OF THE BLADDER

We assess the efficacy and safety of intravesical valrubicin for the treatment of carcinoma in situ in patients with failure or recurrence after bacillus Calmette-Guerin (BCG) and who otherwise would have undergone cystectomy. Total anthracycline recovery in urine samples obtained within 24 hours of valrubicin administration was assessed in a subset of patients. A total of 90 patients with recurrent carcinoma in situ after failed multiple prior courses of intravesical therapy, including at least 1 course of BCG, participated in this open label, noncomparative study. Each patient received 6 weekly instillations of 800 mg. intravesical valrubicin. Disease evaluations were made at baseline and 3-month intervals following treatment. Evaluations included cystoscopy with biopsy and urine cytology. Toxicity was noted throughout treatment and followup. No evidence of disease recurrence for 6 months or greater was considered a complete response. Of 90 patients 19 (21%) had a complete response, including 7 who remained disease-free at the last evaluation, with a median followup of 30 months. Additionally, 14 patients who did not meet the strict protocol definition of complete response had superficial Ta disease only. Median time to failure and/or last followup for complete responders was greater than 18 months. Recurrence has been noted in 79 patients to date, including only 2 with clinically advanced disease (stage T2). Of these 79 patients 44 (56%, 4 responders and 40 nonresponders) underwent radical cystectomy. Of the 41 patients with known pathological stage 6 (15%) had stage pT3 or greater at cystectomy. Four patients died of bladder cancer during the median followup of 30 months, none of whom was a complete responder or underwent cystectomy following valrubicin. The main side effects of valrubicin therapy were reversible local bladder symptoms. Valrubicin was effective and well tolerated in patients with carcinoma in situ of the bladder refractory to BCG therapy. Delaying cystectomy while attempting salvage therapy with valrubicin does not pose an undue risk to most patients.

EFFICACY AND SAFETY OF VALRUBICIN FOR THE TREATMENT OF BACILLUS CALMETTE-GUERIN REFRACTORY CARCINOMA IN SITU OF THE BLADDER

Purpose: We assess the efficacy and safety of intravesical valrubicin for the treatment of carcinoma in situ in patients with failure or recurrence after bacillus Calmette-Guerin (BCG) and who othe...

Phase I trial of photo dynamic therapy in the treatment of recurrent superficial transitional cell carcinoma of the bladder

Objectives A Phase I trial of photodynamic therapy (PDT) in the treatment of superficial transitional cell carcinoma (TCC) of the bladder was performed. Methods Twenty patients with recurrent superficial TCC of the bladder after receiving a mean of 2.6 (range 1 to 6) courses of intravesical therapy were treated with PDT. The photosensitizer Photofrin II dose was 1.5 or 2.0 mg/kg. A 630-nm intravesical red laser was used to activate the photosensitizer 2 days after administration of Photofrin II. A 0.01 % intralipid solution was used as a bladder-filling medium to scatter light and achieve more homogeneous light distribution. Light doses from 5.1 to 25.6 J/cm 2 (total dosage 1500 to 5032 J) were used to illuminate the bladder. Results Twenty patients underwent 21 treatments with PDT. Complications included asymptomatic reflux in 4 patients. One other patient, treated at the highest total light dose, experienced bladder contraction and fibrosis. Nine patients (45%) had no tumor evident at cystoscopy, on random biopsies, or in urinary cytology at the 3-month evaluation after treatment. Four patients remained without recurrent disease for 23 to 56 months. Sixteen of 20 (80%) patients experienced recurrence, and 8 of the 16 underwent cystectomy. Conclusions An intravenous photosensitizer dose of 1.5 mg/kg Photofrin II followed by light energy in the range of 13 J/cm 2 (total light dose 2500 to 3250 J) was defined as a safe treatment parameter and resulted in tumor responses. With present technologies, administration of PDT requires careful dosimetry.