Therapy For Invasive Bladder Cancer Research Articles

Efficacy and Safety of Bladder Preservation Therapy in Combination with Atezolizumab and Radiation Therapy (BPT-ART) for Invasive Bladder Cancer: Interim Analysis from a Multicenter, Open-label, Prospective Phase 2 Trial

To evaluate the safety and pathological complete response (pCR) rate of radiotherapy with atezolizumab as bladder-preserving therapy for invasive bladder cancer. A multicenter, phase II study was conducted with clinically T2-3 or very high-risk T1 bladder cancer patients who were poor candidates for or refused radical cystectomy. Here, we report our interim analysis of pCR as a key secondary endpoint ahead of the progression-free survival rate primary endpoint. Radiotherapy (41.4 Gy to the small pelvic field and 16.2 Gy to the whole bladder) was given plus 1200 mg intravenous atezolizumab every 3 weeks. After 24 treatment weeks, response was assessed after transurethral resection and tumor programmed cell death ligand-1(PD-L1) expression was assessed using tumor-infiltrating immune cell scores. Forty-five patients enrolled from January 2019 to May 2021 were analyzed. The most common clinical T stage was T2 (73.3%), followed by T1 (15.6%) and T3 (11.1%). Most tumors were solitary (77.8%), small (<3 cm) (57.8%), and without concurrent carcinoma in situ (88.9%). Thirty-eight patients (84.4%) achieved pCR. High pCR rates were achieved in older patients (90.9%) and in patients with high PD-L1-expressing tumors (95.8% vs. 71.4%). Adverse events (AEs) occurred in 93.3% of patients, with diarrhea being the most common (55.6%), followed by frequent urination (42.2%) and dysuria (20.0%). The frequency of grade 3 AEs was 13.3% while no grade 4 AEs were observed. Combination therapy with radiotherapy and atezolizumab provides high pCR rates and acceptable toxicity, indicating it could be a promising option for bladder preservation therapy.

Impact of Maximal Transurethral Resection on Pathological Outcomes at Cystectomy in a Large, Multi-institutional Cohort.

While the presence of residual disease at the time of radical cystectomy for bladder cancer is an established prognostic indicator, controversy remains regarding the importance of maximal transurethral resection prior to neoadjuvant chemotherapy. We characterized the influence of maximal transurethral resection on pathological and survival outcomes using a large, multi-institutional cohort. We identified 785 patients from a multi-institutional cohort undergoing radical cystectomy for muscle-invasive bladder cancer after neoadjuvant chemotherapy. We employed bivariate comparisons and stratified multivariable models to quantify the effect of maximal transurethral resection on pathological findings at cystectomy and survival. Of 785 patients, 579 (74%) underwent maximal transurethral resection. Incomplete transurethral resection was more frequent in patients with more advanced clinical tumor (cT) and nodal (cN) stage (P < .001 and P < .01, respectively), with more advanced ypT stage at cystectomy and higher rates of positive surgical margins (P < .01 and P < .05, respectively). In multivariable models, maximal transurethral resection was associated with downstaging at cystectomy (adjusted odds ratio 1.6, 95% CI 1.1-2.5). In Cox proportional hazards analysis, maximal transurethral resection was not associated with overall survival (adjusted HR 0.8, 95% CI 0.6-1.1). In patients undergoing transurethral resection for muscle-invasive bladder cancer prior to neoadjuvant chemotherapy, maximal resection may improve pathological response at cystectomy. However, the ultimate effects on long-term survival and oncologic outcomes warrant further investigation.

1740P Bladder preservation therapy in combination with atezolizumab and radiation therapy for invasive bladder cancer (BPT-ART): An open-label, single-arm, multicenter, phase II trial

Radical cystectomy (RC) is standard care for patients with muscle invasive bladder cancer (BC) or highest-risk non-muscle invasive BC. However, optimal care for bladder preservation or intolerance to RC remains uncertain. Atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor with synergistic antitumor activity along with radiation therapy (RT), is a promising treatment.

Bladder preservation therapy in combination with atezolizumab and radiation therapy for invasive bladder cancer (BPT-ART) – A study protocol for an open-label, phase II, multicenter study

Radical cystectomy (RC) is recommended for muscle-invasive bladder cancer (MIBC) or highest-risk non-muscle-invasive bladder cancer (NMIBC). Trimodal therapy (TMT) is the most favorable strategy among bladder preservation therapies (BPT) for patients who are ineligible for or refuse RC. However, referrals for TMT, especially following chemotherapy, are limited by the patient's condition. Therefore, new BPT approaches are needed. Atezolizumab inhibits programmed death-ligand 1, is well-tolerated in patient populations heavily dominated by renal insufficiency, and is expected to have synergistic anti-tumor effects in combination with radiation therapy (RT). Therefore, we have conducted this open-label phase II multicenter study to evaluate the efficacy and safety of RT in combination with atezolizumab for T2-3 MIBC and highest-risk T1 NMIBC patients. This study was initiated in January 2019, and we aimed to enroll a total of 45 patients. The study is registered in the Japan Registry of Clinical Trials (Identifier: RCT2031180060).

1219 - Possible molecular targeted therapy for invasive bladder cancer: Sonic hedgehog signaling inhibitor, cyclopamine

1219 - Possible molecular targeted therapy for invasive bladder cancer: Sonic hedgehog signaling inhibitor, cyclopamine

MEG3, as a Competing Endogenous RNA, Binds with miR-27a to Promote PHLPP2 Protein Translation and Impairs Bladder Cancer Invasion

Muscle-invasive and metastatic bladder cancer have an extremely poor 5-year survival rate of 5%. In comparison, all other bladder cancers (BCs) have a 5-year survival rate of 77%. This striking contrast indicates that one of the therapeutic kernels for bladder cancer is to elucidate the molecular mechanisms underlying its invasiveness and metastasis. In the current study, we demonstrated that maternally expressed gene 3 (MEG3) is significantly downregulated in human invasive bladder cancers in comparison to non-invasive bladder cancers, and that ectopic expression of MEG3 dramatically inhibits the invasiveness of human bladder cancer cells. Consistently, ectopic expression of MEG3 also attenuates metastatic ability of T24T cells, a cell line derived from T24 cells, in the lungs of nude mice. Our mechanistic studies reveal that MEG3, as a ceRNA, inhibits the invasiveness of human bladder cancer cells via negative regulation of c-Myc by competing with PHLPP2 mRNA for miR-27a. These findings not only provide a novel insight into understanding the mechanisms behind the MEG3 inhibition of bladder cancer cell invasion, but also reveal the potential for use of MEG3 as a tool for the prevention and therapy of invasive bladder cancer.

Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-Sparing Trimodality Therapy for Muscle-Invasive Bladder Cancer

BackgroundBladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. ObjectiveTo evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT. Design, setting, and participantsWe used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBC patients treated with TMT at a single institution. We observed 60 overall survival events at 5yr, and median follow-up time for patients without an event was 5.0yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed. Outcome measurements and statistical analysisMolecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC. Results and limitationsGene expression profiling of TMT cases identified luminal (N=40), luminal-infiltrated (N=26), basal (N=54), and claudin-low (N=16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14–0.65], p=0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p=0.006), but not in the TMT cohort. This study is limited by its retrospective nature. ConclusionsHigher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response. Patient summaryWe used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer.

Concurrent radiotherapy and panitumumab after lymph node dissection and induction chemotherapy for invasive bladder cancer

PurposeIn this prospective study we evaluated safety and efficacy of concurrent radiotherapy and panitumumab following neoadjuvant/induction chemotherapy (ICT) and pelvic lymph node dissection (PLND) as a bladder preserving therapy for invasive bladder cancer (BC). Materials & MethodsPatients with cT1-4N0-2M0 bladder cancer were treated with PLND and 4 cycles of platinum-based ICT, followed by a six-and-half-week schedule of weekly panitumumab (2.5 mg/kg) and concurrent radiotherapy to the bladder (33x2 Gy)(RT/P). As primary objective, RT/P toxicity was compared to a historical control toxicity rate for concurrent cisplatin/radiotherapy (<35% of patients with Grade 3-5 toxicity). A sample size of 31 patients was estimated. Secondary end-points included complete remission (CR) at 3 months follow-up, bladder preservation rate, EGFR expression and RAS mutational status. ResultsThirty-eight patients were initially included, of whom 34 were staged cN0. After PLND, 7 (21%) patients were upstaged to pN+. Thirty-one out of 38 patients started RT/P. During RT/P, 5 patients (16%, 95% Confidence Interval, 95%CI 0-31%) experienced systemic or local grade 3-4 toxicity. Four patients did not complete treatment due to adverse events. CR was achieved in 29/31 patients (94%, 95%CI 83-100%). With a median follow-up of 34 months, 4 patients had a local recurrence for which 3 patients (10%) underwent salvage cystectomy. Two tumors had an EGFR- or RAS-mutation while 84% had positive EGFR expression. ConclusionsRT/P following ICT and PLND has a non-inferior safety profile to the historical profile of concurrent cisplatin/radiotherapy. The high CR and bladder preservation rates are promising and warrant further study.

OUTCOME OF BLADDER PRESERVATION USING LOW DOSE CHEMORADIATION THERAPY IN PATIENTS WITH LOCALLY INVASIVE BLADDER CANCER

(Purpose) We investigated the outcome of selective organ preservation in invasive bladder cancer using chemoradiation therapy. (Patients and method) We examined locally invasive bladder cancer in 60 patients (51 men, 9 women; mean age at treatment 66.1 years) who underwent chemoradiation therapy for bladder preservation in the Department of Urology at Sumitomo Hospital between 2000 and 2015. The clinical stage was T1, T2, T3 and T4 in 4, 24, 17, 4 patients. Our protocol includes transurethral resection of the bladder tumor (TURBT) and 46 Gy radiation (2 Gy/fraction) to the bladder with concurrent cisplatin chemotherapy (20 mg/body/day, 10 days, intravenously). The initial evaluation included urine cytology and transurethral bladder biopsy. If patients developed superficial residual or recurrent cancer, they were treated with TURBT and/or intravesical Bacillus Calmette-Guerin (BCG), while patients with invasive residual or recurrent cancer were advised to undergo a salvage cystectomy. The mean follow-up was 55 months. (Results) The first assessment after the chemoradiation therapy showed that the complete remission rate for evaluable cases was 72% (38/53) and bladder preservation was achieved in 56 patients (93%). The 1-, 3-, and 5-year overall survival rate was 95, 86, and 78%, respectively. The 1-, 3-, and 5-year cancer-specific survival rate was 97, 90, and 85%, respectively. The 5-year patient survival rate with an intact bladder was 68%. Hydronephrosis and cisplatin dose (<200 mg) were independent adverse factors of overall survival in a Cox model (HR 4.5 and 4.1, respectively). (Conclusions) Chemoradiation therapy for invasive bladder cancer can achieve similar survival rate to those in patients treated with radical cystectomy, and enable the majority of patients to preserve the bladder.

Outcomes and Tolerability of Selective Bladder Preservation by Combined Modality Therapy for Invasive Bladder Cancer in Elderly Patients

The median age of patients diagnosed with muscle invasive bladder cancer (MIBC) in the United States is 73 years old, and only about half of those over 70 receive potentially curative therapy (radical cystectomy, chemoradiation, definitive radiation), suggesting a large proportion of the elderly are undertreated. To address this unmet clinical need, we examined the outcomes and tolerability of bladder-sparing trimodality therapy (TMT) in elderly patients 75 years or older. We retrospectively analyzed 475 patients with cT2-T4a disease treated at our institution between 1986 and 2013 on or per protocol. Patients underwent induction chemoradiation (CRT) after maximal transurethral resection of bladder tumor (TURBT), in most cases with cisplatin-based concurrent chemotherapy. Patients achieving a complete response (CR) received consolidation CRT. Those with less than a CR or an invasive recurrence were recommended to undergo salvage cystectomy. For comparison of elderly patients (defined as 75 years or older) with younger patients, propensity score matching was performed based on T-stage, presence of hydronephrosis, completion of TURBT, and use of neoadjuvant chemotherapy. Disease-specific survival (DSS) was evaluated using Kaplan-Meier method. Multivariate analyses were performed using a Cox proportional hazards regression model. Median age was 67 years (range 27-94), and 112 patients (23.6%) were 75 years or older. Median follow-up was 7.2 years for surviving patients. In a propensity score matching analysis of 101 elderly and 101 younger patients, DSS at 5 and 10 years for the elderly was 61.2% and 47.3%, compared to 68.6% and 61.0% for younger patients (P = 0.20). CR to induction CRT was 72.3% in the elderly, compared to 80.2% in the younger cohort (P = 0.25). 23.8% of elderly and 29.7% of younger patients underwent a salvage radical cystectomy (P = 0.43). Elderly patients, in comparison to younger patients, had similar rates of ED visits during treatment (8.9% vs 6.9%, P = 0.80) and unplanned treatment breaks for any cause (20.8% vs. 17.8%, P = 0.72), but had a nonsignificant increase in hospital admissions for any cause (16.8% vs. 9.9%, P = 0.21) and early discontinuation of therapy due to toxicities (6.9% vs. 3.0%, P = 0.33). On multivariate analysis, T3/T4 disease, incomplete response to CRT, ED visits during treatment, and early treatment discontinuation were significantly associated with worse DSS in elderly patients. In elderly patients with MIBC, outcomes and tolerability of bladder-sparing TMT using cisplatin-based CRT are comparable to that of younger patients. Clinicians should not deny patients potentially curative therapies based on age alone, although further investigation is warranted.

Targeting IL-5Rα with antibody-conjugates reveals a strategy for imaging and therapy for invasive bladder cancer

ABSTRACTDespite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor-specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor α-subunit (IL-5Rα) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Rα as a target for antibody-conjugates to better manage patients with MIBC. Patients were recruited and their tumors were processed for IL-5Rα immunohistochemical analysis. NOD/SCID mice were also heterotopically implanted with the human MIBC HT-1376 and HT-B9 cell lines and established xenografts immunohistochemically evaluated for IL-5Rα and compared against patient tumors. Using the mAb A14, an antibody-drug conjugate (ADC) and a radiolabeled immunoconjugate (RIC) were developed by conjugating to vinblastine and to the positron emitter copper-64 (64Cu), respectively. As a proof-of-concept for ADC and RIC efficacy, in vitro cytotoxicity and in vivo positron emission tomography (PET) imaging in tumor-bearing mice were performed, respectively. In addition, as rapid internalization and accumulation are important components for effective antibody-conjugates, we evaluated these aspects in response to IL-5 and 64Cu-A14 treatments. Our findings suggest that although IL-5Rα protein expression is preferentially increased in MIBC, it is rapid IL-5Rα-mediated internalization allowing vinblastine-A14 to have cytotoxic activity and 64Cu-A14 to detect MIBC tumors in vivo. This is the first report to elucidate the potential of IL-5Rα as an attractive MIBC target for antibody-conjugate applications.

Outcomes and tolerability of selective bladder preservation by combined modality therapy for invasive bladder cancer in elderly patients.

316 Background: The median age of patients diagnosed with muscle invasive bladder cancer (MIBC) in the US is 72 years old, and only about half of those over 70 years receive potentially curative therapy (radical cystectomy, chemoradiation, definitive radiation), suggesting a large proportion of patients are undertreated. To address this unmet need, we examined the outcomes and tolerability of chemoradiation (chemoRT) in the elderly. Methods: We conducted an analysis of 455 patients with cT2-T4a disease treated at our institution between 1986 and 2013. Patients underwent induction chemoRT (40Gy) after transurethral resection of bladder tumor (TURBT). Patients achieving a complete response (CR) received consolidation chemoRT to a total goal dose of 64-65Gy. Those with less than a CR or an invasive recurrence were recommended to undergo salvage cystectomy. Elderly was defined as 75 years or older. For comparison with younger patients, propensity score matching was performed based on sex, T-stage, hydronephrosis, completion of TURBT, and decade of treatment. Disease-specific survival (DSS) was evaluated using Kaplan-Meier method. Results: Median age was 66 years (range 27-94). One hundred and one patients (22%) were 75 years or older. Median follow-up was 7.4 years for surviving patients. In a propensity score matched pair analysis of 84 elderly and 84 younger patients, DSS at 5 and 10 years for the elderly was 64.8% and 51%, compared to 71.7% and 62.0% for younger patients (p = 0.28). Elderly patients, compared to the younger patients, had similar rates of ED visits during treatment (10% vs 12%, p = 0.76), hospital admissions for any cause (17% vs. 14%, p = 0.8), unplanned treatment breaks for any cause (24% vs. 12%, p = 0.16), and discontinuation of therapy due to toxicities (6% vs 7%, p = 1.0). Conclusions: In elderly patients with MIBC, outcomes and tolerability of bladder-sparing chemoRT are comparable to that of younger patients. Clinicians should not deny patients potentially curative therapies based on age alone, although further investigation is warranted.

Systemic Therapy for Invasive Bladder Cancer: The Value Proposition.

Neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy followed by definitive local treatment should be the treatment of choice for otherwise healthy and robust patients with T2b–T4 invasive bladder cancer.

Trimodal therapy for invasive bladder cancer: is it really equal to radical cystectomy?

Trimodal therapy (TMT) is considered the most effective bladder-sparing approach for muscle-invasive urothelial carcinoma of the bladder (MIBC) and an alternative to radical cystectomy. The purpose of this article was to review and summarize the current knowledge on the equivalence of TMT and radical cystectomy based on the recent literature. TMT consists of a maximal transuretral resection of the bladder, followed by a concurrent radiotherapy and chemotherapy, limiting salvage radical cystectomy to nonresponder tumors or muscle-invasive recurrence. In large population studies, less than 6% of the patients with nonmetastatic MIBC receive a chemoradiation therapy and this rate is stable. A growing body of evidence exists that TMT provides good oncologic outcomes with low morbidity when compared with radical cystectomy. TMT requires, however, a close follow-up because of the high risk of local recurrence and salvage radical cystectomy in up to 30% of the patients. Salvage radical cystectomy can be performed with adequate results but does not offer the same opportunity of reconstruction and functional outcomes than primary radical cystectomy. Although radical cystectomy is still the treatment of reference for most of the patients with localized MIBC, TMT represents a reasonable alternative in highly selected patients. Any firm conclusion on the equivalence or superiority of one treatment to the other is still limited by the lack of randomized controlled trials and the heterogeneity of the available literature. Future studies and multidisciplinary approach are mandatory to optimize the patient selection and regimen of TMT.

Activation of cyclic AMP/PKA pathway inhibits bladder cancer cell invasion by targeting MAP4-dependent microtubule dynamics

ObjectiveWith the notorious reputation of the vicious invasion, the bladder cancer is the most common malignant tumor of the urinary system. Inhibiting invasion through microtubule dynamics interruption has emerged as an important treatment of bladder cancer. Here we investigated the role of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway in human bladder cancer cells invasion. Materials and methodsWith or without the treatment of various cAMP elevators, we assessed invasive and migrated capabilities of T24 and UM-UC-3, two high-grade invasive bladder cancer cell lines, using matrigel transwell inserts assay and scratch wound healing assay. The microtubule (MT) dynamics were examined by immunofluorescence and immunoblotting. Microtubule-Associated Protein 4 (MAP4) was silenced to investigate its role in tumor invasion. We also analyzed gene expression of MAP4 in 34 patients with bladder cancer using immunohistochemical staining assay. The interaction between PKA and MAP4 was examined by co-immunoprecipitation. ResultsWe used cAMP elevators and small interfering RNA of MAP4 here, found that both of them can potently inhibit the invasion and the migration of bladder cancer cells by disrupting microtubule (MT) cytoskeleton. Consistently, the bladder cancer grade is positively correlated with the protein level of MAP4. Furthermore, we found that cAMP/PKA signaling can disrupt MT cytoskeleton by the phosphorylation of MAP4. ConclusionOur results indicated that the cAMP/PKA signaling pathway might inhibit bladder cancer cell invasion by targeting MAP4-dependent microtubule dynamics, which could be exploited for the therapy of invasive bladder cancer.

Combining mTOR Inhibition with Radiation Improves Antitumor Activity in Bladder Cancer Cells In Vitro and In Vivo: A Novel Strategy for Treatment

PurposeRadiation therapy for invasive bladder cancer allows for organ preservation but toxicity and local control remain problematic. As such, improving efficacy of treatment requires radiosensitization of tumor cells. The aim of study is to investigate if the mammalian Target of Rapamycin (mTOR), a downstream kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT survival pathway, may be a target for radiation sensitization.Experimental DesignClonogenic assays were performed using 6 bladder cancer cell lines (UM-UC3, UM-UC5, UM-UC6, KU7, 253J-BV, and 253-JP) in order to examine the effects of ionizing radiation (IR) alone and in combination with RAD001, an mTOR inhibitor. Cell cycle analysis was performed using flow cytometry. In vivo, athymic mice were subcutaneously injected with 2 bladder cancer cell lines. Treatment response with RAD001 (1.5 mg/kg, daily), fractionated IR (total 9Gy = 3Gy×3), and combination of RAD001 and IR was followed over 4 weeks. Tumor weight was measured at experimental endpoint.ResultsClonogenic assays revealed that in all bladder cell lines tested, an additive effect was observed in the combined treatment when compared to either treatment alone. Our data indicates that this effect is due to arrest in both G1 and G2 phases of cell cycle when treatments are combined. Furthermore, our data show that this arrest is primarily regulated by changes in levels of cyclin D1, p27 and p21 following treatments. In vivo, a significant decrease in tumor weight was observed in the combined treatment compared to either treatment alone or control.ConclusionsAltering cell cycle by inhibiting the mTOR signaling pathway in combination with radiation have favorable outcomes and is a promising therapeutic modality for bladder cancer.

Surveillance strategies after definitive therapy of invasive bladder cancer

Following definitive therapy for muscle invasive bladder cancer, patients remain at risk for local and distant recurrence. Additionally, recurrences can result from formation of new tumours elsewhere in the urinary tract. We review patterns of recurrence and the prognosis associated with recurrence. Optimal surveillance strategies are discussed.

1418 THE RISK OF TUMOR-RELATED COMPLICATIONS IN PATIENTS WITH ILEAL-NEOBLADDERS

You have accessJournal of UrologyUrinary Diversion: Bladder Reconstruction, Augmentation, Substitution, Diversion (II)1 Apr 20131418 THE RISK OF TUMOR-RELATED COMPLICATIONS IN PATIENTS WITH ILEAL-NEOBLADDERS Bjoern Volkmer, Karen Czeloth, Regina Stredele, and Richard Hautmann Bjoern VolkmerBjoern Volkmer Kassel, Germany More articles by this author , Karen CzelothKaren Czeloth Kassel, Germany More articles by this author , Regina StredeleRegina Stredele Kassel, Germany More articles by this author , and Richard HautmannRichard Hautmann Ulm, Germany More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2772AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Radical cystectomy is a standard therapy for invasive bladder cancer. The choice of urinary diversion is often affected by the surgeons' fear of tumor complications. Since an ileal neobladder is the form of urinary diversion that is located exactly at the former tumor site, it is important to evaluate the real extent of this risk in a neobladder population. METHODS This study is based on the cystectomy series of the University of Ulm 01/86 - 12/08 and of the Kassel General Hospital 01/00 - 12/08. We included all patients with a cystectomy performed for urothelial bladder cancer. The tumor stage was non-organ confined (at least pT3a), or lymph-node positive or metastatic (M1). We excluded those cases with age > 75y and those with macroscopic residual tumor in the true pelvis (R2). We obtained a complete follow-up until 12/08. The mean follow-up was 35 months. RESULTS We included 540 patients (Ulm: 471, Kassel: 69). The 5- and 10-year overall survival was 27.6% and 16.2%, respectively. 284 patients had an ileal neobladder (NBL), 256 other forms of urinary diversion (OTH). The rates of lymph-node metastases and distant metastases were: NBL: 63% and 6%, OTH: 56% and 13%. After 10 years the overall survival was better in the NBL group for pT3b-4b pN0/1 tumors (28.6% vs. 17.6%) and for pN2-3 or M1 tumors (8.0% vs. 3.7%).The rate of local recurrence was 17.3% in the NBL-group, but only 18/49 patients developed tumor-related neobladder complications (6.3% of all neobladder patients in this group): hydronephrosis (n=8), subneovesical obstruction (n=4), hematuria (n=4), neovesico-intestinal fistula (n=5). In all cases the storage function of the neobladder could be maintained. No neobladder was removed. In the cases with a fistula, the affected intestinal segment was bypassed. In subneovesical obstruction, a TUR-BT was successfull in 2, chemotherapy in 1 case. 1 patient had an undiversion to a continent pouch. CONCLUSIONS Patients with ileal neobladders were younger, had a lower comorbidity and better tumor stages than patients with other forms of urinary diversion. The risk of tumor-related neobladder complications remained low and could be handled with preservation of the neobladder in almost all cases. Ileal neobladders can be safely offered to patients even with advanced tumor stages, as long as there is no residual tumor visible in the true pelvis at the end of cystectomy. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e580-e581 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bjoern Volkmer Kassel, Germany More articles by this author Karen Czeloth Kassel, Germany More articles by this author Regina Stredele Kassel, Germany More articles by this author Richard Hautmann Ulm, Germany More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

IJU this issue

Is inflammation related to any diseases? I asked this question when I read the Review and Original Articles in this issue. Carcinogenesis as a result of inflammation has been noted in stomach cancer in relation to Helicobacter pylori, liver cancer as a result of hepatitis virus, and, in the urological field, squamous bladder cancer linked to schistosomiasis. The Review Article by Nakai and Nonomura (Osaka, Japan) described the inflammation in normal prostate and prostate cancer tissues in relation to the initiation of prostate cancer. Proliferative inflammatory atrophy (PIA) is known to be associated with acute or chronic inflammation in the peripheral zone where prostate cancer predominantly develops. PIA might link inflammation and cancer. In an epidemiological view, a fat-rich diet is a risk factor of prostate cancer. Grilled meats produce heterocyclic amine and polycyclic aromatic hydrocarbons. These compounds induce inflammation of prostate tissues. Xenobiotics have received attention because of their estrogenic effects that might cause hypospadias and other congenital abnormalities. The role of estrogen in the initiation and the progression of prostate cancer will be further investigated. Does inflammation accelerate cancer progression? Patients with advanced cancer are associated with high fever and/or inflammatory reactions. Is inflammation the cause or the result of cancer progression? C-reactive protein (CRP) is widely used as a biomarker to monitor whole-body inflammation. Saito and Kihara (Tokyo, Japan) reviewed the role of CRP in urological cancers. CRP is a valuable prognosis factor that can be used in ordinary practice. CRP is generally produced by hepatocytes through the stimulation of cytokines including interleukin (IL)-6 and IL-1β. These cytokines play an important role, because they work as autocrine and/or paracrine growth factors in the cancer microenvironment. Therefore, CRP is not the cause of cancer progression, but the result of cytokines produced by cancer or immunological cells. Then, how are theses cytokines produced? For example, IL-6 is induced by the activation of transcription factors including NF-κB. However, the mechanism underlying NF-κB activation is diverse. Further investigation should be focused on why the inflammatory reaction is common in predicting the poor prognosis of all malignancies. A cancer microenvironment composed of cancer and mesenchymal cells can be conceived as an inflammatory environment where hematological cells target or help cancer cells. Choi et al. (Ansan, Korea) have shown CD74 expression in the microenvironment. CD74 is part of a receptor complex for macrophage migration inhibitory factor (MIF). They found that CD74 expression is increased in high-grade invasive bladder cancer. This implicates the immunological escape of cancer cells. Indeed, CD74 expression was correlated with the absence of tumor-infiltrating inflammatory cells and the presence of tumor-associated inflammatory cells. Milatuzumab is a humanized anti-CD74 antibody being evaluated for hematological malignancies. This study might have opened the gate for molecular-targeted therapy for invasive bladder cancer where no such agents are available at present. How do we treat inflammation? The answer depends on the disease that induced inflammation. Interstitial cystitis (IC) is a refractory inflammatory disease, the cause of which is unknown. Wada et al. (Hokkaido, Japan) have shown the effect of intrathecal administration of E-series prostaglandin 1 (EP1) receptor antagonist in a cyclophosphamide-induced cystitis rat model. EP-1 receptor antagonist is promising for future therapy. Another treatment strategy for IC comes from focusing on the defective urothelial lining in the bladder. The pathogenesis of IC involves the mucin glycosaminoglycan layer of the urothelium. Hyaluronic acid (HA) is a relevant component. Lai et al. (Taipei, Taiwan) showed the result of a comparative randomized trial to determine the optimization of the regimens, namely, four weekly intravesical instillations of 40 mg of HA followed by monthly instillations or 12 intravesical instillations every 2 weeks. Both groups had no differences in showing a significant improvement in symptom scores and Quality of Life Index. None declared.

Abstract 1452: mTOR inhibition radiosensitizes bladder cancer tumor cells in vitro and in vivo: A novel strategy for treatment

Abstract Background: Radiation therapy for invasive bladder cancer allows for organ preservation but systemic toxicity and local control remain problematic. As such, there is a need to increase radiosensitization of tumor cells to improve efficacy. The aim of this study was to investigate if mTOR (mammalian target of rapamycin), a downstream kinase of the PI3K/Akt survival pathway, may be a target for combined bladder cancer therapy. Methods: Clonogenic assays were performed using 6 bladder cancer cell lines in order to address the effects of ionizing radiation (IR) on growth, when tested alone and in combination with RAD001, a potent mTOR inhibitor. Cell cycle analysis was performed using flow cytometry. In the in vivo study, nude mice were subcutaneously injected with KU7 and 253J-BV cells. Treatment with RAD001 (1.5 mg/kg, daily), fractionated IR (total 9 Gy), and the combination of RAD001 and IR was followed over 4 weeks. Tumor growth kinetics was measured and tumor weight at the experimental endpoint. Results: In vitro, a significant decrease in colony formation was observed in the combined treatment when compared to RAD001 or radiation alone (p&amp;lt;0.05) in all cell lines. A G0/G1 as well as a significant increase in G2 arrest was observed in the combined treatment compared to either treatment alone. Changes in the levels of Cyclin D1, p27 and p21 correlated with the observed changes in the cell cycle. Moreover, IR rapidly activated AKT whereas RAD001 effectively inhibited the mTOR downstream signaling as shown by the inhibition of the phosphorylation of S6. Furthermore, autophagy was induced following the treatment with RAD001 and in combination as indicated by the conversion of LC3-I to LC3-II, a protein marker for autophagy. Our in vivo data confirmed our in vitro data, wherein a significant decrease in tumor weight was observed in the combined treatment arm (90% decrease, p&amp;lt;0.001) compared to either treatment alone (60% decrease for RAD001, p&amp;lt;0.05; 77% decrease for IR, p&amp;lt;0.05). These findings point to additive and possibly synergistic beneficial effects of the combined on bladder cancer. Conclusions: The inhibition of mTOR signaling appears promising as a therapeutic modality for bladder cancer, especially in the context of combination with radiation therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1452. doi:1538-7445.AM2012-1452