A phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer. Pharmacokinetic Study of Intravesical Gemcitabine in Carcinoma in situ of the Bladder Refractory to Bacillus Calmette-Guérin Therapy Paclitaxel-hyaluronic acid for intravesical therapy of bacillus Calmette-Guérin refractory carcinoma in situ of the bladder: results of a phase I study. SWOG S0353: Phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guérin. A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157 Efficacy and Safety of Blue Light Flexible Cystoscopy with Hexaminolevulinate in the Surveillance of Bladder Cancer: A Phase III, Comparative, Multicenter Study A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin. Is gemcitabine an option in BCG-refractory nonmuscle-invasive bladder cancer? A single-arm prospective trial Is everything all right if nothing seems wrong? A simple method of assessing the diagnostic value of endoscopic procedures when a gold standard is absent. A Phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCGrefractory and BCG-intolerant patients Efficacy of Mycobacterium Phlei Cell Wall-Nucleic Acid Complex (MCNA) in BCG-Unresponsive Patients Activity of endovesical gemcitabine in BCG-refractory bladder cancer patients: a translational study Phase 1b Trial to Evaluate Tissue Response to a Second Dose of Intravesical Recombinant Adenoviral Interferon α2b Formulated in Syn3 for Failures of Bacillus Calmette–Guerin (BCG) Therapy in Nonmuscle Invasive Bladder Cancer Sunitinib in BCG-refractory non-muscle-invasive transitional cell carcinoma of the bladder. Key Steps in Conducting Systematic Reviews for Underpinning Clinical Practice Guidelines: Methodology of the European Association of Urology. Gemcitabine versus bacille Calmette‐Guérin after initial bacille Calmette‐Guérin failure in non‐muscle‐invasive bladder cancer A pilot clinical trial of intravesical mitomycin-C and external deep pelvic hyperthermia for non-muscle-invasive bladder cancer Intravesical Gemcitabine in BCG-Refractory T1G3 Transitional Cell Carcinoma of the Bladder: A Pilot Study Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure. Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guérin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer. Prospective analysis of sensitivity and specificity of urinary cytology and other urinary biomarkers for bladder cancer. Photodynamic therapy using porfimer sodium as an alternative to cystectomy in patients with refractory transitional cell carcinoma in situ of the bladder. Bladder Photofrin Study Group. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. Phase I trial of intravesical gemcitabine in bacillus Calmette-Guérin-refractory transitional-cell carcinoma of the bladder. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. Oral bropirimine immunotherapy of bladder carcinoma in situ after prior intravesical bacille Calmette-Guérin. Radiofrequency-induced Thermo-chemotherapy Effect Versus a Second Course of Bacillus Calmette-Guérin or Institutional Standard in Patients with Recurrence of Non-muscle-invasive Bladder Cancer Following Induction or Maintenance Bacillus Calmette-Guérin Therapy (HYMN): A Phase III, Open-label, Random ElectroMotive drug administration (EMDA) of Mitomycin C as first-line salvage therapy in high risk “BCG failure” non muscle invasive bladder cancer: 3 years follow-up outcomes Phase I trial of intravesical recombinant adenovirus mediated interferon-α2b formulated in Syn3 for Bacillus Calmette-Guérin failures in nonmuscle invasive bladder cancer.
PURPOSE Up to 50 % of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence . Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary . Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use . Nanoparticle albumin-bound paclitaxel ( Abraxane ® , ABI-007 ) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy . Thus , we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel . MATERIAL S AND METHODS Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta , T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior st and ard intravesical regimen failed . Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved . The primary end point was dose limiting toxicity and the secondary end point was response rate . RESULTS A total of 18 patients were enrolled in the study . One patient demonstrated measurable systemic absorption after 1 infusion . Grade 1 local toxicities were experienced by 10 ( 56 % ) patients with dysuria being the most common , and no grade 2 , 3 or 4 drug related local toxicities were encountered . Of the 18 patients 5 ( 28 % ) had no evidence of disease at posttreatment evaluation . CONCLUSIONS Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge . A larger phase II study has begun to formally evaluate the activity of this regimen Introduction : Gemcitabine , a chemotherapeutic agent , has been shown to be active against transitional cell cancer of the bladder . The aim of the study was to determine the pharmacokinetic profile of gemcitabine , administered intravesically in patients with carcinoma in situ(CIS ) . Material and Methods : Nine patients with CIS refractory to intravesical bacillus Calmette-Guérin ( BCG ) therapy were enrolled .  Gemcitabine was given in 50 ml 0.9 % NaCl by catheterization and held in the bladder for 1 h , once weekly for 6 consecutive weeks . The pharmacokinetics for gemcitabine metabolites were performed in plasma and serum . Dose levels were : 1,000 , 1,250 , and 1,500 mg . Clinical evaluation was repeated 4 weeks after therapy and thereafter every 6 months . Results : Grade -1 neutropenia was observed only in 1 patient . Grade -1 urinary frequency and hematuria were observed in 1 and 3 patients , respectively . No grade 2–4 toxicity or clinical ly relevant myelosuppression were observed .  Gemcitabine  was detectable in serum , but with an irrelevant pharmacological effect , in only 1 patient treated with 1,500 mg of gemcitabine . With regard to activity , after 6 instillations of this drug , 4 complete responses were observed . Conclusion : Intravesical gemcitabine is well tolerated and safe . No systemic absorption with a clinical or pharmacological effect was detected and only slightly irritative bladder symptoms were observed . These results warrant further investigation in phase-II trials PURPOSE Carcinoma in situ represents high grade anaplasia of the bladder mucosa . Intravesical immunotherapy with bacillus Calmette-Guérin is the gold st and ard treatment for patients with carcinoma in situ . Patients with carcinoma in situ refractory to bacillus Calmette-Guérin are c and i date s for major surgery such as radical cystectomy . We identified the maximum tolerated dose and the recommended dose , and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guérin . MATERIAL S AND METHODS A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guérin were enrolled in a phase I , open label , single institution study . A minimum of 3 eligible patients were included per dose level . Paclitaxel-hyaluronic acid solution ( ONCOFID-P-B ™ ) was administered for 6 consecutive weeks . The primary objective was to identify the maximum tolerated dose and the recommended dose . As secondary objectives the safety profile of ONCOFID-P-B , the pharmacokinetic profile after each instillation and the tumor response were also evaluated . RESULTS No dose limiting toxicity occurred at any drug level evaluated . The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation . A total of 11 adverse events were reported by 7 patients and 9 ( 60 % ) showed complete treatment response . CONCLUSIONS Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guérin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge . Finally , satisfactory response rates were observed PURPOSE Prior phase II studies of intravesical gemcitabine have shown it to be active and well tolerated , but durable responses in patients with nonmuscle invasive bladder cancer who have experienced recurrence after bacillus Calmette-Guérin treatment are uncommon . We performed a multi-institutional phase II study within the SWOG ( Southwest Oncology Group ) cooperative group to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting . MATERIAL S AND METHODS Eligible patients had recurrent nonmuscle invasive bladder cancer , stage Tis ( carcinoma in situ ) , T1 , Ta high grade or multifocal Ta low grade after at least 2 prior courses of bacillus Calmette-Guérin . Patients were treated with 2 gm gemcitabine in 100 cc normal saline intravesically weekly × 6 and then monthly to 12 months . Cystoscopy and cytology were performed every 3 months , with biopsy at 3 months and then as clinical ly indicated . Initial complete response was defined as negative cystoscopy , cytology and biopsy at 3 months . RESULTS A total of 58 patients were enrolled in the study and 47 were evaluable for response . Median patient age was 70 years ( range 50 to 88 ) . Of the evaluable patients 42 ( 89 % ) had high risk disease , including high grade Ta in 12 ( 26 % ) , high grade T1 in 2 ( 4 % ) and carcinoma in situ in 28 ( 60 % ) with or without papillary lesions . At the initial 3-month evaluation 47 % of patients were free of disease . At 1 year disease had not recurred in 28 % of the 47 patients , all except 2 from the high risk group , and at 2 years disease had not recurred in 21 % . CONCLUSIONS Intravesical gemcitabine has activity in high risk nonmuscle invasive bladder cancer and offers an option for patients with recurrence after bacillus Calmette-Guérin who are not suitable for cystectomy . However , less than 30 % of patients had a durable response at 12 months even with maintenance therapy Purpose : To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant , molecularly enriched non – muscle-invasive urothelial carcinoma of the bladder ( NMIUC ) population . Experimental Design : A multi-site pilot phase II trial was conducted . Key eligibility criteria included the following : Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC ( > 2 prior intravesical regimens ) with increased phosphorylated FGFR3 ( pFGFR3 ) expression by central ly analyzed immunohistochemistry ( IHC+ ) or FGFR3 mutations ( Mut+ ) assessed in a CLIA-licensed laboratory . Patients received oral dovitinib 500 mg daily ( 5 days on/2 days off ) . The primary endpoint was 6-month TURBT-confirmed complete response ( CR ) rate . Results : Between 11/2013 and 10/2014 , 13 patients enrolled ( 10 IHC+ Mut− , 3 IHC+ Mut+ ) . Accrual ended prematurely due to cessation of dovitinib clinical development . Demographics included the following : median age 70 years ; 85 % male ; carcinoma in situ ( CIS ; 3 patients ) , Ta/T1 ( 8 patients ) , and Ta/T1 + CIS ( 2 patients ) ; median prior regimens 3 . Toxicity was frequent with all patients experiencing at least one grade 3–4 event . Six-month CR rate was 8 % ( 0 % in IHC+ Mut− ; 33 % in IHC+ Mut+ ) . The primary endpoint was not met . Pharmacodynamically active ( 94–5,812 nmol/L ) dovitinib concentrations in urothelial tissue were observed in all evaluable patients . Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment . Conclusions : Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition . These results support systemic administration as a viable approach to clinical trials in patients with NMIUC . Long-term dovitinib administration was not feasible due to frequent toxicity . Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma . Clin Cancer Res ; 23(12 ) ; 3003–11 . © 2016 AACR Purpose : We compared blue light flexible cystoscopy with white light flexible cystoscopy for the detection of  bladder cancer during surveillance . Material s and Methods : Patients at high risk for recurrence received hexaminolevulinate intravesically before white light flexible cystoscopy and r and omization to blue light flexible cystoscopy . All suspicious lesions were documented . Patients with suspicious lesions were referred to the operating room for repeat white and blue light cystoscopy . All suspected lesions were biopsied or resected and specimens were examined by an independent pathology consensus panel . The primary study end point was the proportion of patients with histologically confirmed malignancy detected only with blue light flexible cystoscopy . Additional end points were the false‐positive rate , carcinoma in situ detection and additional tumors detected only with blue light cystoscopy . Results : Following surveillance 103 of the 304 patients were referred , including 63 with confirmed malignancy , of whom 26 had carcinoma in situ . In 13 of the 63 patients ( 20.6 % , 95 % CI 11.5–32.7 ) recurrence was seen only with blue light flexible cystoscopy ( p < 0.0001 ) . Five of these cases were confirmed as carcinoma in situ . Operating room examination confirmed carcinoma in situ in 26 of 63 patients ( 41 % ) , which was detected only with blue light cystoscopy in 9 of the 26 ( 34.6 % , 95 % CI 17.2–55.7 , p < 0.0001 ) . Blue light cystoscopy identified additional malignant lesions in 29 of the 63 patients ( 46 % ) . The false‐positive rate was 9.1 % for white and blue light cystoscopy . None of the 12 adverse events during surveillance were serious . Conclusions : Office based blue light flexible cystoscopy significantly improves the detection of patients with recurrent bladder cancer  and it is safe when used for surveillance . Blue light cystoscopy in the operating room significantly improves the detection of carcinoma in situ and detects lesions that are missed with white light cystoscopy PURPOSE A phase II study was performed to assess the efficacy and tolerability of intravesical oportuzumab monatox in patients with urothelial carcinoma in situ of the bladder . Bacillus Calmette-Guérin treatment had previously failed in all patients . MATERIAL S AND METHODS A total of 46 patients received 1 induction cycle of 6 ( cohort 1 ) or 12 ( cohort 2 ) weekly intravesical oportuzumab monatox ( VB4 - 845 ) instillations of 30 mg , followed by up to 3 maintenance cycles of 3 weekly administrations every 3 months . RESULTS A complete response to oportuzumab monatox was seen in 9 of 22 patients ( 41 % ) in cohort 1 and 9 of 23 ( 39 % ) in cohort 2 at the 3-month evaluation . A total of 20 patients ( 44 % ) achieved a complete response . Two other patients without carcinoma in situ who achieved a complete response were not included in the study due to the development of noninvasive papillary ( Ta ) disease . Median time to recurrence in patients who achieved a complete response was 274 and 408 days in cohorts 1 and 2 , respectively . Overall 7 patients ( 16 % ) remained disease-free . Post- study assessment demonstrated that these patients were still disease-free at last followup ( 18 to 25 months ) . The most common adverse events were mild to moderate reversible bladder symptoms . CONCLUSIONS Oportuzumab monatox was effective and well tolerated in patients with bacillus Calmette-Guérin refractory carcinoma in situ of the bladder . These results demonstrate the clinical benefit of oportuzumab monatox and support its continued development for the second line treatment of nonmuscle invasive bladder cancer The objective of this study was to evaluate intravesical gemcitabine in high-risk nonmuscle-invasive bladder cancer ( NMIBC ) refractory to bacillus Calmette-Guérin ( BCG ) . This was a prospect i ve multicentre single-arm trial . Eligible patients were those with high-risk NMIBC refractory to BCG therapy , for which radical cystectomy was indicated but not conducted because of patient refusal or in eligibility . Patients received intravesical gemcitabine twice weekly at a dose of 2000 mg/50 ml for 6 weeks , and then weekly for 3 weeks at 3 , 6 , and 12 months . Outcome measures were recurrence rate , time to first recurrence , progression rate and complications .  Twenty patients were enrolled and included in the analysis . Median follow-up was 15.2 months . Fifty-five percent ( 11 patients ) developed disease recurrence . Mean time to the first recurrence was 3.5 months and 45 % ( five patients ) of recurring patients had disease progression . Overall , treatment was well tolerated . Urinary symptoms represented the primary adverse events . The role of gemcitabine used as second-line treatment in high-risk BCG-refractory NMIBC patients who refused or were unsuitable for radical cystectomy remains to be defined . Further clinical research in this area is needed PURPOSE We demonstrate a simple yet comprehensive method to evaluate the sensitivity of endoscopic procedures when no gold st and ard is available . MATERIAL S AND METHODS In 208 consecutive patients with superficial bladder cancer 328 endoscopies were performed to compare the sensitivity of white light and 5-aminolevulinic acid induced fluorescence endoscopy . Both procedures were performed during the same session . RESULTS The maximum interval of observable sensitivity for 5-aminolevulinic acid induced fluorescence endoscopy ranged between 78 and 97.5 % , and the best estimate for sensitivity based on realistic assumptions was 93.4 % ( 95 % confidence intervals 90 to 97.3 ) . The best sensitivity estimate for white light endoscopy was 46.7 % ( 95 % confidence intervals 39.4 to 54.3 , maximum range 47.2 to 53 % ) . CONCLUSIONS This method to determine the maximum possible range of sensitivity estimates for endoscopic procedures without a gold st and ard is easily applied . Depending on the assumptions a range of reasonable scenarios can be constructed and the corresponding sensitivities can be reported . This approach gives fast and valid results , and could further indicate the diagnostic superiority of 5-aminolevulinic acid induced fluorescence compared to white light endoscopy Purpose A Phase I dose-escalation study was performed to determine the maximum tolerated dose ( MTD ) of the immunotoxin VB4 - 845 in patients with nonmuscle-invasive bladder cancer ( NMIBC ) refractory to or intolerant of bacillus Calmette – Guerin ( BCG ) . Secondary objectives included evaluation of the safety , tolerability , pharmacokinetics , immunogenicity , and efficacy of VB4 - 845 . Patients and methods Sixty-four patients with Grade 2 or 3 , stage Ta or T1 transitional cell carcinoma or in situ carcinoma , either refractory to or intolerant of BCG therapy , were enrolled . Treatment was administered in ascending dose cohorts ranging from 0.1 to 30.16 mg . After receiving weekly instillations of VB4 - 845 to the bladder via catheter for 6 consecutive weeks , patients were followed for 4–6 weeks post-therapy and assessed at week 12 . Results An MTD was not determined , as a dose-limiting toxicity was not identified over the dose range tested . VB4 - 845 therapy was safe and well tolerated with most adverse events reported as mild ; as a result , no patients were removed from the study in response to toxicity . By the end of the study , the majority of patients had developed antibodies to the exotoxin portion of VB4 - 845 . A complete response was achieved in 39 % of patients at the 12-week time point . Conclusions VB4 - 845 dosed on a weekly basis for 6 weeks was very well tolerated at all dose levels . Although an MTD was not determined at the doses administered , VB4 - 845 showed evidence of an antitumor effect that warrants further clinical investigation for the treatment of NMIBC in this patient population Background : We have previously reported the results of a prospect i ve multi-institutional study on the efficacy of MCNA in patients who recurred after intravesical BCG treatment [ 1 ] . Since that publication , a new st and ardized definition for BCG-unresponsiveness has been established [ 2 ] . Objective : We re-analyzed the oncologic outcomes following intravesical MCNA in patients classified as BCG-unresponsive according to the new definition . Methods : For this analysis , we focused on the enrolled patients who satisfied the requirements for BCG Unresponsiveness : i.e. adequate BCG treatment ( at least 5/6 induction and 2/3 maintenance instillations ) and high grade tumor within 6 months of prior BCG . Treatment course included 6 weekly intravesical instillations of 8 mg MCNA followed by 3 weekly instillations at months 3 , 6 , 12 , 18 , and 24 . Followup assessment s included cystoscopy , urine cytology and biopsy . Patients absent of high grade disease confirmed by central review of biopsy were deemed disease-free . Results : Of the 129 patients enrolled , 94 ( 68 CIS with/without papillary tumors , 26 papillary only tumors ) fit the criteria for the new BCG Unresponsive definition . Overall , disease free survival ( DFS ) for all BCG unresponsive patients was 48.9 % ( 95 % CI 38.0–59.0 % ) at 6 months , 34.8 % ( 95 % CI 24.7–45 % ) at 1 year and 28.3 % ( 15.7–34.3 % ) at 2 years post induction . In the group with papillary tumors , DFS measured at months 6 , 12 , and 24 were : 61.2 % ( 38.2–77.8 % ) , 61.2(38.2–77.8 % ) , and 50.1 % ( 27.5–69 % ) . In the CIS-containing group , the corresponding DFS were : 44.8 % ( 32.3–56.4 % ) , 26.5 % ( 16.3–37.9 % ) , and 16.6 % ( 8.6–26.9 % ) , respectively . Conclusions : For patients who are BCG Unresponsive , MCNA has the potential to render 26.5 % of patients with CIS and 61.2 % of patients with papillary tumors disease-free for at least 1 year with an intact bladder . The higher efficacy noted in the true BCG-unresponsive cohort than was previously reported with all-comers emphasizes the importance of having clearly defined criteria for clinical trials investigating new intravesical therapies after BCG failure Intravesical gemcitabine ( Gem ) has shown promising activity against transitional cell carcinomas ( TCC ) of the bladder , with moderate urinary toxicity and low systemic absorption . The present phase II study evaluated the activity of biweekly intravesical treatment with Gem using a scheme directly derived from in vitro pre clinical studies . Patients with Bacille Calmette-Guérin ( BCG ) -refractory Ta G3 , T1 G1 - 3 TCC underwent  transurethral bladder resection  and then intravesical instillation with 2000 mg Gem diluted in 50 ml saline solution on days 1 and 3 for 6 consecutive weeks . Thirty-eight ( 95 % ) of the 40 patients showed persistent negative post-treatment cystoscopy and cytology 6 months after Gem treatment , while the remaining 2 patients relapsed at 5 and 6 months . At a median follow-up of 28 months , recurrences had occurred in 14 patients . Among these , four had downstaged ( T ) disease , three had a lower grade ( G ) lesion and three had a reduction in both T and G. Urinary and systemic toxicity was very low , with no alterations in biochemical profiles . In conclusion , biweekly instillation of Gem proved active in BCG-refractory Ta G3 , T1 G1 - 3 TCC . Our results highlight the importance of pre clinical studies using in vitro systems that adequately reproduce the conditions of intravesical clinical treatment to define the best therapeutic schedule Background A phase 1b trial was conducted to evaluate the duration of interferon-alpha ( IFNα ) production after intravesical administration of recombinant adenovirus-mediated interferon α2b ( Ad-IFN ) formulated with the excipient Syn3 . The primary aim was to determine whether a second instillation 3 days after initial treatment produced prolonged urinary IFN production . Methods The study enrolled seven patients who experienced recurrent non-muscle invasive bladder cancer after bacillus Calmette – Guerin therapy .  Each treatment consisted of intravesical instillation of SCH721015 ( Syn3 ) and Ad-IFN at a concentration of 3 × 1011 particles/mL to a total volume of 75 mL given on days 1 and 4 . The patients were followed for 12 weeks , during which the magnitude and duration of gene transfer were determined by urine INFα levels . Drug efficacy was determined by cystoscopy and biopsy , and patients who had no recurrence at 12 weeks were eligible for a second course of treatment . Results Seven patients were treated with an initial course ( instillation on days 1 and 4 ) . Two of the patients had a complete response at 12 weeks and received a second course of treatment . One patient remained without evidence of recurrence after a second course ( total 24 weeks ) . One patient experienced a non-treatment-associated adverse event . Despite a transient rise in IFNα levels , sustained production was not demonstrated . Conclusion Previously , Ad-IFNα intravesical therapy has shown promising drug efficacy . A prior phase 1 trial with a single instillation compared similarly with the current study , suggesting that a second instillation is not necessary to achieve sufficient urinary IFNα levels 262 Background : Treatment options for pts with BCG-refractory NMITCC are limited and there is no established role for systemic chemotherapy in this setting . While cystectomy remains the gold st and ard , the vast majority of pts are unable or unwilling to have surgery . Sunitinib is an oral tyrosine kinase inhibitor of VEGFR-2 , PDGFR , KIT and FLT3 with demonstrated antitumor activity in advanced TCC . To determine the clinical and biologic effects of sunitinib in BCG-refractory NMITCC pts a prospect i ve phase II study was conducted . METHODS Pts with biopsy proven BCG- refractory NMITCC received three 28-day cycles of continuous sunitinib ( 37.5 mg PO ) . Subsequently , pts underwent cystoscopic evaluation . If no tumor was found , pts continued with st and ard cystoscopic surveillance . A single stage design was employed to test the hypothesis of a 25 % improvement in the 12-month CR rate over the 20 % CR historically observed in this setting . Overall response rate ( ORR ) , disease-free recurrence ( DFR ) and safety were recorded . Exploratory endpoints included treatment effect on CTCs , type-1 response and immunosuppressive Treg cells . RESULTS To date 17 of a planned 31 pts are enrolled . Median age is 72 years ( range , 54 - 82 ) ; 94 % of pts were ECOG 0 ; 6 pts had received additional intravesical therapy other than BCG . Fourteen pts have already completed 3 cycles of treatment and 13 pts had at least once cystoscopic assessment . Among these , 8 pts ( 62 % ) were NED in their first cystoscopic evaluation . Most common treatment-related toxicity observed in both studies included fatigue , HTN , stomatitis , PPE , diarrhea and thrombocytopenia . Treatment with sunitinib also result ed in a sustained increase ( compared to pre-treatment ) in CD3 + and CD4 + IFN-g producing T-cells ( p < 0.07 ) . In addition there was a significant decrease in CD33 + MDSC following 2 and 3 cycles of therapy ( p < 0.04 ) . There was also a significant decrease in T regulatory cells following 2 cycles of therapy ( p = 0.04 ) ; however it was not maintained during cycle 3 ( p = 0.36 ) . CONCLUSIONS Sunitinib has modest clinical activity in pts with BCG-refractory NMITCC . Early immune studies also denote the ability of sunitinib to restore the balance of type-1 and type-2 immune response in bladder cancer . [ Table : see text ] CONTEXT The findings of systematic review s ( SRs ) and meta-analyses ( MAs ) are used for clinical decision making . The European Association of Urology has committed increasing re sources into the development of high quality clinical guidelines based on such SRs and MAs . OBJECTIVE In this paper , we have summarised the process of conducting SRs for underpinning clinical practice guidelines under the auspices of the European Association of Urology Guidelines Office . EVIDENCE ACQUISITION The process involves explicit methods and the findings should be reproducible . When conducting a SR , the essential first step is to formulate a clear and answerable research question . An extensive literature search lays the foundation for evidence synthesis . Data are extracted independently by two review ers and any disagreements are resolved by discussion or arbitration by a third review er . EVIDENCE SYNTHESIS In SRs , data for particular outcomes in individual r and omised controlled trials may be combined statistically in a meta- analysis to increase power when the studies are similar enough . Biases in studies included in a SR/MA can lead to either an over estimation or an under estimation of true intervention effect size , result ing in heterogeneity in outcome between studies . A number of different tools are available such as Cochrane Risk of Bias assessment tool for r and omised controlled trials . In circumstances where there is too much heterogeneity , or when a review has included nonr and omised comparative studies , it is more appropriate to conduct a narrative synthesis . The GRADE tool for assessing quality of evidence strives to be a structured and transparent system , which can be applied to all evidence , regardless of quality . A SR not only identifies , evaluates , and summarises the best available evidence , but also the gaps to be targeted by future studies . CONCLUSIONS SRs and MAs are integral in developing sound clinical practice guidelines and recommendations . PATIENT SUMMARY Clinical practice guidelines should be evidence based , and systematic review s and meta-analyses are essential in their production . We have discussed the key steps of conducting systematic review s and meta-analyses in this paper The efficacy of intravesical gemcitabine was evaluated compared with repeated administration of bacille Calmette‐Guérin ( BCG ) after BCG failure in high‐risk , non‐muscle‐invasive bladder cancer ( BC ) Abstract Purpose : This paper aims to evaluate the safety and heating efficiency of external deep pelvic hyperthermia combined with intravesical mitomycin C ( MMC ) as a novel therapy for non-muscle-invasive bladder cancer ( NMIBC ) . Material s and methods : We enrolled subjects with bacillus Calmette-Guérin ( BCG ) refractory NMIBC to an early phase clinical trial of external deep pelvic hyperthermia ( using a BSD-2000 device ) combined with MMC . Bladders were heated to 42 ° C for 1 h during intravesical MMC treatment . Treatments were given weekly for 6 weeks , then monthly for 4 months . Heating parameters , treatment toxicity , and clinical outcomes were systematic ally measured . Results : Fifteen patients were enrolled on the clinical trial . Median age was 66 years and 87 % were male . Median European Organisation for Research and Treatment of Cancer ( EORTC ) recurrence and progression scores were 6 and 8 , respectively . The full treatment course was attained in 73 % of subjects . Effective bladder heating was possible in all but one patient who could not tolerate the supine position due to lung disease . Adverse events were all minor ( grade 2 or less ) and no systemic toxicity was observed . The most common adverse effects were Foley catheter pain ( 40 % ) , abdominal discomfort ( 33 % ) , chemical cystitis symptoms ( 27 % ) , and abdominal skin swelling ( 27 % ) . With a median follow-up of 3.18 years , 67 % experienced another bladder cancer recurrence ( none were muscle invasive ) and 13 % experienced an upper tract recurrence . Conclusions : External deep pelvic hyperthermia using the BSD-2000 device is a safe and reproducible method of heating the bladder in patients undergoing intravesical MMC . The efficacy of this treatment modality should be explored further in clinical trials Objective : The aim of this pilot study is to analyze the safety and short-term efficacy of gemcitabine ( GEM ) as salvage intravesical therapy in a very selected population of bacille Calmette-Guérin (BCG)-resistant T1G3 patients . Methods : 9 recurrent BCG-refractory pT1G3 patients , unsuitable for radical treatment , were treated with GEM , and compared with 10 pT1G3 patients previously treated with at least two courses of transurethral resection plus BGC , with further conservative endovesical BCG administration . Results : Both intravesical administrations of GEM and BCG were generally well tolerated : no severe adverse events were reported . Of the 9 patients treated with GEM , 3 were recurrence-free after 13 , 17 and 21 months and 7 kept an intact bladder , with an overall survival rate of 9 of 9 . Among 10 patients treated with BCG instillation , 1 was recurrence-free after 27 months and 6 kept their bladders , with a survival rate of 8 of 10 . Conclusions : Our experience confirms the high risk of tumor recurrence and progression of BCG-refractory pT1G3 transitional cell carcinoma . In this case , further BCG courses seem to be unsuitable , result ing in a high risk of tumor progression and mortality . The use of GEM in BCG-refractory pT1G3 patients has to be considered experimental until multicentric r and omized studies with adequate follow-up are able to confirm the preliminary results of this pilot study PURPOSE Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10 % and 30 % . Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes . Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation . We now report the results of a phase II trial to assess efficacy . MATERIAL S AND METHODS This study was an investigator initiated , single center , single arm , phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis , T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Guérin failed . Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations .  Efficacy was evaluated with cystoscopy , biopsy , cytology and imaging . If complete response was achieved , patients were treated with full dose monthly maintenance treatments for 6 months . RESULTS A total of 28 patients were enrolled in the study . Of these patients 10 ( 35.7 % ) exhibited a complete response after initial treatment . At 1 year all of these responses remained durable after maintenance therapy . At a mean followup of 21 months ( range 5 to 47 ) 19 of 28 ( 67.8 % ) patients retained their bladders without progression or distant metastases . A single patient had progression to muscle invasive disease at radical cystectomy . Treatment related adverse events were noted in 9 of 28 ( 32.1 % ) patients and were limited to grade 1 or 2 . CONCLUSIONS Intravesical nab-paclitaxel has minimal toxicity and a 35.7 % response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Guérin failure . Complete response remained durable at 1 year followup in this heavily pretreated patient population Purpose Many patients with high-risk non-muscle-invasive bladder cancer ( NMIBC ) are either refractory to bacillus Calmette-Guerin ( BCG ) treatment or may experience disease relapse . We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 ( rAd-IFNα/Syn3 ) , a replication-deficient recombinant adenovirus gene transfer vector , for patients with high- grade ( HG ) BCG-refractory or relapsed NMIBC . Methods In this open-label , multicenter ( n = 13 ) , parallel-arm , phase II study ( Clinical Trials.gov identifier : NCT01687244 ) , 43 patients with HG BCG-refractory or relapsed NMIBC  received intravesical rAd-IFNα/Syn3 ( r and omly assigned 1:1 to 1 × 1011 viral particles (vp)/mL or 3 × 1011 vp/mL ) . Patients who responded at months 3 , 6 , and 9 were retreated at months 4 , 7 , and 10 . The primary end point was 12-month HG recurrence-free survival ( RFS ) . All patients who received at least one dose were included in efficacy and safety analyses . Results Forty patients  received rAd-IFNα/Syn3 ( 1 × 1011 vp/mL , n = 21 ; 3 × 1011 vp/mL , n = 19 ) between November 5 , 2012 , and April 8 , 2015 . Fourteen patients ( 35.0 % ; 90 % CI , 22.6 % to 49.2 % ) remained free of HG recurrence 12 months after initial treatment . Comparable 12-month HG RFS was noted for both doses . Of these 14 patients , two experienced recurrence at 21 and 28 months , respectively , after treatment initiation , and one died as a result of an upper tract tumor at 17 months without a recurrence . rAd-IFNα/Syn3 was well tolerated ; no grade four or five adverse events ( AEs ) occurred , and no patient discontinued treatment because of an adverse event . The most frequently reported drug-related AEs were micturition urgency ( n = 16 ; 40 % ) , dysuria ( n = 16 ; 40 % ) , fatigue ( n = 13 ; 32.5 % ) , pollakiuria ( n = 11 ; 28 % ) , and hematuria and nocturia ( n = 10 each ; 25 % ) . Conclusion rAd-IFNα/Syn3 was well tolerated . It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy OBJECTIVES Evaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ ( CIS ) of the bladder based on up date d phase III pivotal trial efficacy data together with efficacy and safety data from a supportive phase II/III study . MATERIAL S AND METHODS In 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 r and omized 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 up date d information based on US Food and Drug Administration review . Safety assessment s in A9303 included local bladder adverse events ( LBAEs ) and other adverse events ( AEs ) . RESULTS Eighty 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 . CONCLUSIONS Two 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 ) BACKGROUND Both bacillus Calmette-Guérin ( BCG ) and interferon-alpha ( IFN-alpha ) express activity against superficial bladder cancer . The results of a national multicenter phase II trial of a combination of these 2 agents used in a wide range of patients are reported . MATERIAL S AND METHODS Patients previously having BCG failure received IFN-alpha ( 50 million units ) plus reduced dose BCG , while patients naïve to BCG received the same IFN-alpha dose with st and ard dose BCG . All patients who were relapse free received an additional 3 series of 3-week reduced dose BCG plus IFN-alpha treatments at 3 , 9 , and 15 months after completing induction . Any relapse during the 3-month evaluation was counted as a failure of therapy for Kaplan-Meier analysis . Multivariate analysis was performed to identify factors associated with recurrence . RESULTS Of 1,007 valuable patients , 59 % and 45 % of patients naïve to BCG and those having BCG failure , respectively , remained disease free at 24-month median follow-up . Stage T1 , tumor size>5 cm , prior BCG failure more than once , and multifocality were all statistically significant risk factors for recurrence . CONCLUSIONS Although BCG plus IFN-alpha can be effectively applied to both patients naïve to BCG and those having BCG failure , certain patient and tumor characteristics influence durable response INTRODUCTION Although urinary cytology ( C ) is the most widely used noninvasive test for the detection and surveillance of bladder cancer ( BC ) , it has poor sensitivity especially for low- grade tumors . We prospect ively tested the performance of urine markers on patients with BC using C and 4 commercially available urinary marker tests : Hemoglobin Dipstick ( H ) , BTA Stat ( B ) , NMP22 BladderChek ( N ) , and ImmunoCyt ( I ) . METHODS Urinary sample s from 109 consecutive patients with BC were prospect ively collected . All sample s were tested using conventional C and available biomarkers . Prior and subsequent surgical specimen reports were examined , and sensitivity and specificity were calculated for each . Collected variables included patient demographics , date of urinary collection , type of specimen ( voided , washing , or catheterized ) , surgical pathology , recurrence , and follow-up . RESULTS Sensitivity values for each marker were as follows : C , 48 % ( 16 % for low- grade tumors and 84 % for high- grade [ HG ] tumors ) ; B , 61 % ( 36 % and 91 % ) ; H , 51 % ( 38 % and 66 % ) ; N , 58 % ( 25 % and 92 % ) ; and I , 62 % ( 47 % and 83 % ) . Specificity results for each marker were as follows : C , 86 % ; B , 78 % ; H , 58 % ; N , 85 % ; and I , 79 % . On multivariate analysis , higher stage ( C and N ) and HG disease ( C , H , B , N , and I ) were independent prognostic factors for improved test performance . When urinary markers were combined with C , sensitivity/specificity values for HG disease were as follows : C+H , 85%/57 % ; C+B , 91%/78 % ; C+N , 94%/84 % ; and C+I , 90%/78 % . CONCLUSIONS Based on these data , C seems to yield the highest specificity and N the highest sensitivity for HG tumors . The combination " C+N " seems to be the better approach to improve the sensitivity for HG tumors compared with single markers and other combinations PURPOSE Photodynamic therapy combines a photosensitizer , such as porfimer sodium ( Photofrin ) , with red laser light ( 630 nm . ) to destroy cancer cells . Investigators have reported the effectiveness of photodynamic therapy in the treatment of patients with recurrent superficial bladder cancer . We assess the safety and efficacy of 1 or 2 photodynamic treatments using porfimer sodium and controlled uniform laser light ( 630 nm . ) as an alternative to cystectomy in patients with refractory vesical carcinoma in situ of the bladder . MATERIAL S AND METHODS A total of 36 patients with carcinoma in situ were treated with whole bladder photodynamic therapy as an alternative to cystectomy . In all patients at least 1 course of bacillus Calmette-Guerin ( BCG ) had failed . Each patient received a single whole bladder photodynamic therapy treatment , consisting of 2 mg./kg . porfimer sodium intravenously followed 40 to 50 hours later by intravesical red light ( 630 nm . ) at 15 J./cm.2 . Post-photodynamic therapy evaluations included weekly telephone contact to assess acute adverse reactions , and assessment of efficacy and bladder toxicity at 3 months and quarterly thereafter . RESULTS At initial clinical evaluation at 3 months 58 % of the patients had a complete response as indicated by negative cystoscopy , bladder biopsy and urine cytology but in 42 % treatment failed . At a mean followup of 12 months ( range 9 to 48 ) 10 of the 21 complete responders had recurrence for an overall durable response rate of 31 % . Fourteen patients subsequently underwent cystectomy for persistent carcinoma in situ ( 12 ) and carcinoma in situ recurrence ( 2 ) . Of the 36 patients 7 experienced bladder contracture . CONCLUSIONS The initial results are encouraging for a single whole bladder photodynamic treatment of patients in whom prior intravesical therapy for carcinoma in situ has failed . While followup is short , porfimer sodium photodynamic therapy appears potentially promising as an alternative to cystectomy in patients with refractory carcinoma in situ 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 r and omly 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 c and i date for intrabladder therapy in patients with refractory transitional cancer PURPOSE The aim of this phase I study was to determine the safety and toxicity profile of gemcitabine administered as an intravesical agent in patients with transitional-cell carcinoma ( TCC ) of the bladder . PATIENTS AND METHODS Patients with superficial bladder cancer refractory to intravesical bacillus Calmette-Guérin ( BCG ) therapy and refusing a cystectomy were considered eligible for the trial . Gemcitabine was given in the bladder for 1 hour twice weekly in 100 mL sodium chloride for a total of six treatments . After a 1-week break , a second course of six treatments over 3 weeks was given , followed by response assessment . Four dose levels were explored : 500 mg , 1,000 mg , 1,500 mg , and 2,000 mg . RESULTS Eighteen patients completed therapy : three at 500 mg , six at 1,000 mg , three at 1,500 mg , and six at 2,000 mg . No grade 3 or 4 toxicity was observed at 500 mg . At 1,000 mg , three patients developed hematuria and one had a skin reaction resembling grade 3 h and -foot syndrome . Three patients at 1,500 mg had no grade 3 or 4 toxicity . Of six patients at 2,000 mg , one had grade 3 thrombocytopenia and neutropenia without infection . Seven patients had a complete response ( negative cytology and posttreatment biopsy ) , and four patients had a mixed response ( negative bladder biopsy but positive cytology ) . CONCLUSION Gemcitabine has substantial activity as an intravesical agent in BCG-refractory TCC and warrants further investigation . Therapy given twice weekly was associated with minimal bladder irritation and tolerable myelosuppression . The recommended phase II dose for twice-weekly therapy is 2,000 mg PURPOSE We assessed the safety , pharmacokinetics and anticancer activity of intravesical CG0070 , a cancer selective , replication competent adenovirus , for the treatment of nonmuscle invasive bladder cancer . MATERIAL S AND METHODS A total of 35 patients received single or multiple ( every 28 days × 3 or weekly × 6 ) intravesical infusions of CG0070  at 1 of 4 dose levels ( 1 × 10(12 ) , 3 × 10(12 ) , 1 × 10(13 ) or 3 × 10(13 ) viral particles ) . Response to treatment was based on cystoscopic assessment and biopsy or urine cytology . Urine and plasma CG0070 , and granulocyte-monocyte colony-stimulating factor were measured in all patients . A subset of 18 patients was assessed for retinoblastoma phosphorylation status . RESULTS Grade 1 - 2 bladder toxicities were the most common adverse events observed . A maximum tolerated dose was not reached . High levels of granulocyte-monocyte colony-stimulating factor were detected in urine after administration in all patients . Virus replication was suggested based on an increase in urine CG0070 genomes between days 2 and 5 in 58.3 % of tested patients ( 7 of 12 ) . The complete response rate and median duration of the complete response across cohorts was 48.6 % and 10.4 months , respectively . In the multidose cohorts the complete response rate for the combined groups ( every 28 days and weekly × 6 ) was 63.6 % ( 14 of 22 patients ) . In an exploratory , retrospective assessment patients with borderline or high retinoblastoma phosphorylation who received the multidose schedules had an 81.8 % complete response rate ( 9 of 11 ) . CONCLUSIONS Intravesical CG0070 was associated with a tolerable safety profile and antibladder cancer activity . Granulocyte-monocyte colony-stimulating factor transgene expression and CG0070 replication were also suggested OBJECTIVES Bropirimine is an oral immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ ( CIS ) in both the bladder and upper urinary tract . Activity also has been documented in patients after prior therapy with bacille Calmette-Guérin ( BCG ) . To more accurately estimate bropirimine 's efficacy in BCG-resistant bladder CIS , a Phase II trial was performed . A separate analysis was performed in additional patients intolerant of BCG toxicity . METHODS Patients received bropirimine 3.0 g/day by mouth for 3 consecutive days , weekly , for up to 1 year . Bladder biopsies and cytologic examination were performed quarterly . Complete response ( CR ) required negative biopsy and cytology results . RESULTS Twenty-one of 86 patients entered were not evaluable .  CR was seen in 21 ( 32 % ; 95th percentile confidence interval [ CI ] , 21 % to 44 % ) of 65 evaluable patients , including 14 ( 30 % , CI 17 % to 43 % ) of 47 BCG-resistant , and 7 ( 39 % , CI 16 % to 61 % ) of 18 BCG-intolerant patients . Overall , by intent-to-treat analysis , CR was thus seen in 21 ( 24 % ) of 86 subjects . Most BCG-resistant patients were failures to BCG without relapse , and had received 12 to 36 ( median 12 ) BCG treatments ; intolerant patients had received 4 to 11 treatments ( median 6 ) . Response duration ranged from 65 to 810 days , with median not yet reached ( but greater than 12 months ) . Thirteen ( 15 % ) of 86 stopped bropirimine due to toxicity . Progression to invasive or metastatic disease during or immediately after therapy was documented in only 4 patients ( 6 % ) , all nonresponders . CONCLUSIONS Bropirimine may be an alternative to cystectomy for some patients with bladder CIS who have failed or have not tolerated BCG . Further evaluation to improve responses and durability is warranted BACKGROUND There is no effective intravesical second-line therapy for non-muscle-invasive bladder cancer ( NMIBC ) when bacillus Calmette-Guérin ( BCG ) fails . OBJECTIVE To compare disease-free survival time ( DFS ) between radiofrequency-induced thermo-chemotherapy effect ( RITE ) and institutional st and ard second-line therapy ( control ) in NMIBC patients with recurrence following induction/maintenance BCG . DESIGN , SETTING S , AND PARTICIPANTS Open-label , phase III r and omised controlled trial accrued across 14 centres between May 2010 and July 2013 ( HYMN [ Clinical Trials.gov : NCT01094964 ] ) . INTERVENTION Patients were r and omly assigned ( 1:1 ) to RITE ( 60min , 40 mg mitomycin-C , 42±2 ° C ) or control following stratification for carcinoma in situ ( CIS ) status ( present/absent ) , therapy history ( failure of previous induction/maintenance BCG ) , and treatment centre . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcome measures were DFS and complete response ( CR ) at 3 mo for the CIS at r and omisation subgroup . Analysis was based on intention-to-treat . RESULTS AND LIMITATIONS A total of 104 patients were r and omised ( 48 RITE : 56 control ) . Median follow-up for the 31 patients without a DFS event was 36 mo . There was no significant difference in DFS between treatment arms ( hazard ratio [ HR ] 1.33 , 95 % confidence interval [ CI ] 0.84 - 2.10 , p=0.23 ) or in 3-mo CR rate in CIS patients ( n=71 ; RITE : 30 % vs control : 47 % , p=0.15 ) . There was no significant difference in DFS between treatment arms in non-CIS patients ( n=33 ; RITE : 53 % vs control : 24 % at 24 mo , HR 0.50 , 95 % CI 0.22 - 1.17 , p=0.11 ) . DFS was significantly lower in RITE than in control in CIS with/without papillary patients ( n=71 ; HR 2.06 , 95 % CI 1.17 - 3.62 , p=0.01 ; treatment-subgroup interaction p=0.007 ) . Disease progression was observed in four patients in each treatment arm . Adverse events and health-related quality of life between treatment arms were comparable . CONCLUSIONS DFS was similar between RITE and control . RITE may be a second-line therapy for non-CIS recurrence following BCG failure ; however , confirmatory trials are needed . RITE patients with CIS with/without papillary had lower DFS than control . HYMN highlights the importance of the control arm when evaluating novel therapies . PATIENT SUMMARY This study did not show a difference in bladder cancer outcomes between microwave-heated chemotherapy and st and ard of care treatment . Papillary bladder lesions may benefit from microwave-heated chemotherapy treatment ; however , more research is needed . Both treatments are similarly well tolerated Background In case of high grade non-muscle invasive bladder cancer ( HG-NMIBC ) , intravesical BCG represents the first-line treatment ; despite the “ gold ” st and ard therapy , up to 50 % of patients relapse , needing radical cystectomy . Hence , alternative therapeutic strategies have been developed . The aim of the study was to evaluate a first-line salvage treatment with EMDA ® -MMC in patients with HGNMIBC unresponsive to BCG . Methods We carried out a prospect i ve , single-center , single-arm Phase II study in order to evaluate the efficacy ( in terms of recurrence and progression ) and the safety of the EMDA ® -MMC treatment in 26 ( 21 male , 5 female ) consecutive patients with “ BCG refractory ” HGNMIBC on a 3 years follow-up .  EMDA ® -MMC treatment consisted of 40 mg of MMC diluted in 100 ml of sterile water retained in the bladder for 30 min with 20 mA pulsed electric current . EMDA ® -MMC regimen consisted of an induction course of 6 weekly instillations followed by a maintenance course of 6 monthly instillations . Follow-up was performed with systematic mapping biopsies of the bladder ( with sampling in the prostatic urethra for men ) , voiding and washing urinary cytology , radiological study of the upper urinary tract . We performed Survival Kaplan-Meier curves and Log-rank test in order to analyze high grade disease-free survival . Results At the end of follow-up , 16 patients ( 61.5 % ) preserved their native bladder ; 10 patients ( 38.4 % ) underwent radical cystectomy , in 6 patients ( 23.1 % ) for recurrent HGNMIBC and in 4 patients ( 15.4 % ) for progression to muscle-invasive disease . At the end of follow-up , stratifying patients based on TNM classification ( TaG3 , T1G3 , Cis , TaT1G3 + Cis ) , disease-free rates were 75 , 71.4 , 50 and 25 % , respectively ; survival curves showed statistically significant differences ( p value < 0.05).Regarding toxicity , we reported severe adverse systemic event of hypersensitivity to the MMC in 3 patients ( 11.5 % ) , and local side effects in 6 patients ( 26.1 % ) . Conclusions In the field of alternative strategies to radical cystectomy , the EMDA ® -MMC could be considered safe and effective in high-risk NMIBC unresponsive to BCG , as a “ bladder sparing ” therapy in selected patients . Multicenter studies with a larger number of patients and a longer follow-up might confirm our preliminary results .Trial registration EudraCT2017 - 002585 - 43 . 17 June 2017 ( retrospectively registered ) PURPOSE A phase I trial of intravesical recombinant adenovirus mediated interferon-α2b gene therapy ( rAd-IFNα ) formulated with the excipient SCH Syn3 was conducted in patients with nonmuscle invasive bladder cancer who had disease recurrence after treatment with bacillus Calmette-Guérin . The primary objective was to determine the safety of rAd-IFNα/Syn3 . Secondary end points were demonstrated effective rAd-IFNα gene expression and preliminary evidence of clinical activity at 3 months . MATERIAL S AND METHODS A total of 17 patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin treatment were enrolled in the study . A single treatment of rAd-IFNα ( 3 × 10(9 ) to 3 × 10(11 ) particles per ml ) formulated with the excipient Syn3 was administered . Patient safety was evaluated for 12 or more weeks . Efficacy of gene transfer was determined by urine IFNα protein concentrations . Preliminary drug efficacy was determined at 3 months . RESULTS Intravesical rAd-IFNα/Syn3 was well tolerated as no dose limiting toxicity was encountered . Urgency was the most common adverse event and all cases were grade 1 or 2 . rAd-IFNα  DNA was not detected in the blood . However , transient low serum IFNα and Syn3 levels were measured . High and prolonged dose related urine IFNα levels were achieved with the initial treatment . Of the 14 patients treated at doses of 10(10 ) or more particles per ml with detectable urine IFNα , 6 ( 43 % ) experienced a complete response at 3 months and 2 remained disease-free at 29.0 and 39.2 months , respectively . CONCLUSIONS Intravesical rAd-IFNα/Syn3 was well tolerated with no dose limiting toxicity encountered . Dose dependent urinary IFNα concentrations confirmed efficient gene transfer and expression . Intravesical rAd-IFNα/Syn3 demonstrated clinical activity in nonmuscle invasive bladder cancer recurring after bacillus Calmette-Guérin
CONTEXT There is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer ( NMIBC ) .
Owing to the current lack of effective agents that can be used as a control , the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ ( CIS ) , using complete response rate ( CRR ) and duration of response as the primary endpoints to support marketing applications .
Despite the ensuing growth of clinical trials in this space , no consensus exists on a clinical ly relevant benchmark for CRR .
OBJECTIVE To eluci date the CRR and recurrence-free rate ( RFR ) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results .