Nonmuscle invasive bladder cancer: a primer on immunotherapy.
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ABSTRACT:
SUBMITTER: Maruf M
PROVIDER: S-EPMC4944546 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Publications
Nonmuscle invasive bladder cancer: a primer on immunotherapy.
Maruf Mahir M Brancato Sam J SJ Agarwal Piyush K PK
Cancer biology & medicine 20160601 2
Intravesical Bacillus Calmette-Guérin (BCG) has long been the gold standard treatment of nonmuscle invasive bladder cancer. Recently, there has been an emergence of novel immunotherapeutic agents, which have shown promise in the treatment of urothelial cell carcinoma. These agents aim to augment, modify, or enhance the immune response. Such strategies include recombinant BCG, monoclonal antibodies, vaccines, gene therapy, and adoptive T-cell therapy. Here, we review the emerging immunotherapeuti ...[more]
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Project description:Purpose of reviewThis article reviews the natural biology of noninvasive bladder cancer and its management strategies while summarizing the most recent advances in the field.Recent findingsNonmuscle invasive bladder cancer (NMIBC) has a tendency to recur and progress. Risk stratification has helped triage patients but improved tools, including biomarkers, are still needed. Enhanced endoscopy with photodynamic imaging, narrow band imaging, optical coherence tomography and confocal laser endomicroscopy show promise for diagnosis, risk stratification and disease monitoring. Attempts at better treatment, especially in refractory high-risk cases, include the addition of intravesical hyperthermia, combination and sequential therapy with existing agents and the use of novel agents such as mycobacterial cell wall extract. New data are emerging regarding the potential role of active surveillance in low-risk patients.SummaryNMIBC represents a variety of disease states and continues to pose management challenges. As our understanding of tumor biology improves and technology advances, achieving better outcomes through individualized care may be possible.
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Project description:Urothelial carcinoma is the most common form of bladder cancer, but pathway changes that occur with stage-wise progression have not been well defined. We used a metabolomics approach to identify potential metabolic pathways uniquely altered in normal urothelium, nonmuscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC). We performed global metabolomic profiling using GC-mass spectrometry (MS) and LC-MS platforms to identify metabolite signatures between normal urothelium and high-grade urothelial carcinoma of different stages. Pathways globally dysregulated in cancer relative to normal urothelium included glucose, tricarboxylic acid (TCA) cycle, lipid, amino acid, and nucleotide pathways. Urothelial carcinoma showed elevated glucose utilization for glycolysis and increased sorbitol pathway intermediates, consistent with Warburg effect. Anaplerosis to sustain energy production suggested by increased late TCA cycle intermediates, amino acids, and dipeptides occurs in bladder cancer. Urothelial carcinoma also shows altered membrane lipid membrane metabolism and differential derivation of nucleic acid components pyrimidine and purine. In stage comparison, MIBC appears to preferentially enhance cyclooxygenase (COX) and lipoxygenase (LOX) signaling, increase heme catabolism, and alter nicotinamide adenine dinucleotide (NAD+) synthesis with a possible influence from associated inflammatory cells. We identify numerous metabolomic alterations in NMIBC and MIBC that likely reflect underlying pathway changes. Differential pathway activity may have value in designing stage-specific novel therapeutics in urothelial carcinoma.
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Project description:We assessed the impact that improved detection of nonmuscle invasive bladder cancer with hexaminolevulinate fluorescence cystoscopy may have on early recurrence rates.This prospective, randomized study enrolled 814 patients suspected of having bladder cancer at increased risk for recurrence. All patients underwent white light cystoscopy and mapping of lesions, followed by transurethral resection of the bladder when indicated. Patients in the fluorescence group also received intravesical hexaminolevulinate solution at least 1 hour before cystoscopy to induce fluorescence of cancerous lesions, and underwent additional inspection with blue light before and after transurethral resection of the bladder. Adjuvant intravesical therapy was based on risk. Followup cystoscopy at 3, 6 and 9 months was conducted with white light.Detection was performed as a within patient comparison in the fluorescence group. In this group 286 patients had at least 1 Ta or T1 tumor (intent to treat). In 47 patients (16%) at least 1 of the tumors was seen only with fluorescence (p = 0.001). During the 9-month followup (intent to treat) there was tumor recurrence in 128 of 271 patients (47%) in the fluorescence group and 157 of 280 (56%) in the white light group (p = 0.026). The relative reduction in recurrence rate was 16%.Hexaminolevulinate fluorescence cystoscopy significantly improves the detection of Ta and T1 lesions and significantly reduces the rate of tumor recurrence at 9 months.
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Project description:BackgroundNonmuscle-invasive bladder cancer (NMIBC) disproportionately affects older adults who often have coexisting chronic conditions such as metabolic syndrome (MetS). Although prior research suggests that MetS is a risk factor for NMIBC, limited data exists on whether MetS is associated with NMIBC recurrence. Our objective was to evaluate the association between MetS and recurrence in older adults treated for NMIBC.MethodsWe identified 1,485 older (age ≥60 years) NMIBC patients (American Joint Committee on Cancer Stage ≤1) from 2community-based health systems. Using data from the health systems' electronic medical record, MetS was defined as the presence of three of the following: diagnosis codes indicating hypertension, hyperlipidemia, diabetes, or body mass index >30. Follow up time was determined by date of the last follow up in the tumor registry and censored at 10 years. Cox proportional hazards regression of time to recurrence that accounts for the competing risk of death included adjustment for age, sex, smoking status, health system, NMIBC stage/grade, tumor size, and number of specimens with cancer.ResultsOverall, 341 patients (23%) met MetS criteria. Median follow up was 5.9 years and 582 patients (39.2%) died. Patients with MetS were more frequently male (84.2%), and mostly current/former smokers (82.6%). By 10 years, 34.1% of the cohort had experienced a recurrence. After accounting for the competing risk of death, there was no association between MetS and time to recurrence (adjusted hazard ratio, 0.88, 95% confidence interval 0.70-1.11, P = 0.28). Patients without MetS had more 0a/low grade recurrences (49.1% vs. 41.4%), though differences were not significant.ConclusionWe found no association between MetS and risk of NMIBC recurrence in this large, multisite cohort of older adults with NMIBC. In order to design personalized care for older NMIBC patients, future research is needed to evaluate associations between common chronic conditions and a variety of oncologic outcomes.
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Project description:PurposePrior reports suggest that renin-angiotensin system inhibition may decrease nonmuscle invasive bladder cancer recurrence. We evaluated whether angiotensin converting enzyme inhibitor or angiotensin receptor blocker treatment at initial surgery was associated with decreased recurrence or progression in patients with nonmuscle invasive bladder cancer.Materials and methodsUsing an institutional bladder cancer database we identified 340 patients with data available on initial transurethral resection of bladder tumor. Progression was defined as an increase to stage T2. Cox proportional hazards models were used to evaluate associations with recurrence-free and progression-free survival.ResultsMedian patient age was 69.6 years. During a median followup of 3 years (IQR 1.3-6.1) 200 patients (59%) had recurrence and 14 (4.1%) had stage progression. Of those patients 143 were receiving angiotensin converting enzyme inhibitor/angiotensin receptor blockers at the time of the first transurethral resection. On univariate analysis factors associated with improved recurrence-free survival included carcinoma in situ (p = 0.040), bacillus Calmette-Guérin therapy (p = 0.003) and angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (p = 0.009). Multivariate analysis demonstrated that patients treated with bacillus Calmette-Guérin therapy (HR 0.68, 95% CI 0.47-0.87, p = 0.002) or angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (HR 0.61, 95% CI 0.45-0.84, p = 0.005) were less likely to experience tumor recurrence. The 5-year recurrence-free survival rate was 45.6% for patients treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers and 28.1% in those not treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers (p = 0.009). Subgroup analysis was performed to evaluate nonmuscle invasive bladder cancer pathology (Ta, T1 and carcinoma in situ) in 85 patients on bacillus Calmette-Guérin therapy alone and in 52 in whom it was combined with angiotensin converting enzyme inhibitor/angiotensin receptor blocker. Multivariate analysis revealed that patients treated with bacillus Calmette-Guérin alone (HR 2.19, 95% CI 1.01-4.77, p = 0.04) showed worse recurrence-free survival compared to patients treated with bacillus Calmette-Guérin and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (stage Ta HR 0.45, 95% CI 0.21-0.98, p = 0.04).ConclusionsPharmacological inhibition of the renin-angiotensin system is associated with improved outcomes in patients with bladder cancer. Renin-angiotensin system inhibitor administration in nonmuscle invasive bladder cancer cases should be studied in a prospective randomized trial.
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Project description:ObjectivesNew targets and approaches are under investigation for the treatment of nonmuscle invasive bladder cancer (NMIBC). Preclinical data suggest cyclooxygenase-2 (COX-2) as a promising target. Celecoxib, a COX-2 selective inhibitor, inhibits tumor development and enhances survival, both in vitro and in vivo models of bladder cancer. Therefore, we conducted a pilot study of celecoxib to prevent recurrence in patients with intermediate risk NMIBC.MethodsTreatment with celecoxib was administered orally for 12 months and compared with a contemporary series of patients treated with intravesical mitomycin C (MMC), given weekly for 4 weeks and then monthly for 11 months. Primary endpoints were time to first recurrence and adverse events.ResultsFrom 2003 through 2006, 58 patients were treated with celecoxib and compared with 66 patients receiving MMC. After a median follow up of 75 months, 49 patients were disease free, including 23 (34.85%) in the MMC group and 26 (44.8%) in the celecoxib group. Median disease-free interval was 67 months [95% confidence interval (CI) 35.8 to NA] versus 41 months (95% CI 27.1-67.1; log-rank p = 0.25) for patients treated with MMC and celecoxib, respectively. In the multivariate analysis, treatment was not found to be an independent predictor for recurrence [hazard ratio (HR) 0.76, 95% CI 0.47-1.22, p = 0.25). Overall, 45 AEs were recorded in 35/124 patients. There were no differences between the two groups.ConclusionsOur data support a clinical benefit of celecoxib and encourage future trials in which COX-2 inhibitors may be tested in selected patients with NMIBC.
| S-EPMC4647141 | biostudies-literature