NOS3 895G>T and CBR3 730G>A Are Associated with Recurrence Risk in Non-Muscle-Invasive Bladder Cancer with Intravesical Instillations of THP

Chemotherapy ◽  
2018 ◽  
Vol 63 (4) ◽  
pp. 191-197 ◽  
Author(s):  
Qidong Zhou ◽  
Weihong Ding ◽  
Yingjie Weng ◽  
Guanxiong Ding ◽  
Guowei Xia ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Recurrence ◽  
Recurrence Risk ◽  
Invasive Bladder Cancer ◽  
Rank Test ◽  
Muscle Invasive Bladder Cancer ◽  
European Organization ◽  
Muscle Invasive ◽  
Intravesical Instillations

Objectives: To analyze the correlation between pharmacogenomic biomarkers and the efficacy of pirarubicin (THP, also named 4’-O-tetrahydropyranyl-adriamycin) and to explore potential associations of individual genetic backgrounds with the clinical outcomes of non-muscle-invasive bladder cancer (NMIBC) patients. Methods: Between July 2003 and June 2011, a total of 91 patients were treated with transurethral resection (TUR) of the bladder tumor and were histopathologically confirmed to have NMIBC. Patients received an immediate instillation and maintenance therapy with THP. All patients underwent follow-up for recurrence. We genotyped 13 single nucleotide polymorphisms (SNPs) from blood and saliva DNA samples of all patients. Results: The associations of patients’ genotypes with tumor recurrence risks were analyzed by survival analysis. A total of 16 (17.6%) of the 91 patients with NMIBC had tumor recurrences with a median follow-up of 17 months (range, 2–83 months). We confirmed the effect of the European Organization for Research and Treatment of Cancer (EORTC) risk score for predicting tumor recurrence (p = 0.002, log-rank test). We adjusted for the EORTC score and found that 2 SNPs, NOS3 895G>T (rs1799983) (p = 0.02, HR = 4.32, 95% CI, 1.30–14.39, GT+TT vs. GG) and CBR3 730G>A (rs1056892) (p = 0.04, HR = 2.57, 95% CI, 1.07–6.18, GA+AA vs. GG), were significantly associated with a higher recurrence risk after TUR and instillations of THP in NMIBC patients. Conclusions: Our results suggest that NOS3 895G>T and CBR3 730G>A are genetic markers that can be used to predict tumor recurrence in NMIBC patients receiving intravesical instillations of THP. The effects of those 2 SNPs are independent of the EORTC scores. Further studies with larger sample sizes and longer follow-ups are needed to confirm our results.

Oncotherad immunotherapy elicits promising responses in Bacillus Calmette-Guérin-unresponsive non–muscle invasive bladder cancer: Results from phase I/ II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17048-e17048
Author(s):  
João Carlos Cardoso Alonso ◽  
Ianny Brum Reis ◽  
Juliana Mattoso Gonçalves ◽  
Bianca Ribeiro de Souza Sasaki ◽  
Adriano Angelo Cintra ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Adverse Events ◽  
Phase I ◽  
Tumor Recurrence ◽  
Disease Recurrence ◽  
Invasive Bladder Cancer ◽  
Bacillus Calmette Guerin ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

e17048 Background: Standard treatment for high-grade non-muscle-invasive bladder cancer (HGNMIBC) is transurethral resection of the bladder tumor followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. Up to 40% of patients with HGNMIBC will fail intravesical BCG therapy. A promising therapeutic perspective is represented by OncoTherad immunotherapy. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein developed by University of Campinas/Brazil that exhibits antitumor properties. The aims of this study were to evaluate the efficacy and safety of OncoTherad immunotherapy for BCG-refractory or relapsed HGNMIBC. Methods: We conducted a prospective, single-center (Municipal Hospital of Paulinia, São Paulo, Brazil), single-arm phase I/ II study of OncoTherad immunotherapy in 29 (18 male, 11 female) patients with BCG-unresponsive HGNMIBC (≥ 1 previous course of BCG intravesical therapy). The schedule was initiated with weekly intravesical (120 mg/mL) and intramuscular (25 mg/mL) OncoTherad treatment for 6 weeks, followed by one every other week application for 3 months and, one monthly application until the end of the treatment (24 months). Follow-up was performed with systematic mapping biopsies of the bladder, cystoscopy and ultrasound. The primary endpoint was pathological complete response (pCR) and recurrence-free survival (RFS). The recurrence was defined as histology proven tumor recurrence (any grade) and monitored at 3-month intervals. Secondary endpoints were time to disease recurrence and safety response. Results: The median age of the 29 patients was 64 years (range 34-94). At baseline pTis, pTaG2-3, pT1G2-3 occurred in 10%, 59% and 31% of patients respectively. OncoTherad treatment showed pCR rates (95% CI) of 100% at 3, 6 and 9 months, 89,6% (26/29) at 12 months and, 89,6% (26/29) at 24 months. A 24-months RFS rate in all patients was 79,3%. Also, the median time to disease recurrence for patients was 459 days (15,3 months; 95% CI) at 24-months follow-up. 95% of adverse events were Grade 1 or 2. The most commonly reported treatment-related adverse events were dysuria (51,7%), cystitis (34,5%), pruritus (44,8%), rash (27,6%), arthralgia (27,6%) and fatigue (27,6%). Conclusions: In conclusion, OncoTherad seems a safe and effective treatment option for BCG-unresponsive HGNMIBC patients and may provide benefit for preventing tumor recurrence. Clinical trial information: RBR-6swqd2.

Single-arm phase I/II study of the safety and efficacy of OncoTherad immunomodulator in patients BCG-refractory or relapsed non-muscle invasive bladder cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16000-e16000
Author(s):  
Wagner José Fávaro ◽  
Sonia Regina Iantas ◽  
Juliana Mattoso Gonçalves ◽  
Eduardo Augusto Rabelo Socca ◽  
Nelson Duran ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Tumor Recurrence ◽  
Invasive Bladder Cancer ◽  
Intravesical Therapy ◽  
Urinary Cytology ◽  
Effective Treatment Option ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

e16000 Background: There is no effective intravesical second-line therapy for high-grade non-muscle-invasive bladder cancer (HGNMIBC) when Bacillus Calmette-Guerin (BCG) fails. In this scenario, a new perspective is represented by OncoTherad immunomodulator. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein, developed by University of Campinas/ Brazil, which exhibits antitumor properties. The aims of the study were to evaluate the efficacy and safety of OncoTherad immunomodulator for BCG-refractory or relapsed HGNMIBC. Methods: We carried out a prospective, single-center (Municipal Hospital of Paulinia, São Paulo, Brazil), single-arm phase I/II study in 15 (10 male, 5 female) consecutive patients with HGNMIBC-refractory or relapsed (≥ 1 previous course of BCG intravesical therapy). Patients with muscle-invasive disease were excluded. OncoTherad regimen consisted of an induction course of 6 weekly intravesical instillations followed by a maintenance course of 1 monthly instillation until completing 1 year of treatment. Follow-up was performed with systematic mapping biopsies of the bladder, cystoscopy, ultrasound and urinary cytology. The primary endpoint was recurrence-free survival (RFS) rate, and secondary endpoint was safety response. The recurrence was defined as histology proven tumor recurrence (any grade), and monitored at 3-month intervals. Results: The median age and follow-up were 71 years and 14.0 months, respectively. A 14-months RFS rate in all patients was 86.7%. Only 2 patients (13.3%) showed recurrence during follow-up, however these patients showed incipient malignant lesions (downstaging of pT1G3 to pTaG1). Regarding toxicity, we reported moderate adverse systemic event of hypersensitivity to OncoTherad in 2 patients (13.3%), and minimal local side effects (dysuria and cystitis)in 6 patients (40.0%). Conclusions: In conclusion, OncoTherad seems a safe and effective treatment option for BCG-refractory or relapsed HGNMIBC patients and may provide benefit for preventing tumor recurrence. We report a RFS rate of 86.7% (14.0 months), potentially avoiding or postponing the need for radical surgery in these patients. Clinical trial information: CAAE: 93619718.7.0000.5404.

scholarly journals Clinical Evaluation of Patients with Mixed Low-and-High Grade Non-muscle Invasive Bladder Cancer with EORTC Risk Scores

2020 ◽  
Author(s):  
Tianjie Lan ◽  
Yuhong Li ◽  
Yi Lu ◽  
Chuanfeng Liu ◽  
Gaoteng Lin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Invasive Bladder Cancer ◽  
Risk Scores ◽  
Rank Test ◽  
High Grade ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Log Rank Test ◽  
Muscle Invasive

Abstract Background: To evaluate the recurrence and progression rate of patients with mixed low-and-high grade (MG) non-muscle invasive bladder cancer (NMIBC), and compare these outcomes with the European Cancer Research and Treatment Organization (EORTC) prognostic risk scores.Methods: A retrospective analysis was performed based on the data from 68 MG NMIBC patients undergoing transurethral resection of bladder treatment (TUR-BT) from October 2013 to November 2018 in our hospital. The patients received intravesical treatment, and the follow-up protocols, including cystoscopy, ultrasound and urinary cytology, for the mean follow-up period of 33±10.7 months. The patients were divided into 4 groups according to the EORTC risk scores, and the recurrence rate and progression scores of tumors in each group were calculated and compared with the estimated rates based on EORTC risk scores. The log-rank test and multivariable analysis were used to analyze the possible differences between the risk groups and to identify independent prognostic factors.Results: Among the 68 patients, averagely 67.6 years (32-86 years), 42 patients were of Stage Ta and 26 were of Stage T1; the tumor recurrence was noted in 15 patients (22.1%), 11 as LG (low grade) and 4 as HG (high grade); and tumor progression in 4 patients (5.9%), 2 stages of progression. The Kaplan-Meier curve showed a real recurrence-free survival (RFS) difference rates between Group 1-4 and Group 5-9 (P=0.0362<0.05, log-rank test); while for Group 0, Group 2-6 and Group 7-13, the real progression-free survival (PFS) was statistically different (P=0.0077<0.01, log-rank test)． Conclusions: The pathology and clinical behavior of MG are “benign” prior to LG even if the patients did not receive overly aggressive intravesical instillations. The EORTC risk scores can be applied to the short-term prognostic assessment of recurrence and progression risk in MG patients of the cohort. However, the value and applicability of long-term prognosis assessment are to be confirmed in further studies in the future.

scholarly journals Non-maintenance intravesical Bacillus Calmette–Guérin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Makito Miyake ◽  
◽  
Kota Iida ◽  
Nobutaka Nishimura ◽  
Tatsuki Miyamoto ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Propensity Score ◽  
Invasive Bladder Cancer ◽  
Rank Test ◽  
Bacillus Calmette Guerin ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Landmark Analyses ◽  
Muscle Invasive ◽  
Group B

Abstract Background To explore possible solutions to overcome chronic Bacillus Calmette–Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG). Methods This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000–2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven−/eight-dose iBCG (Group C), 60 (2.2%) received seven−/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan–Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed. Results RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts. Conclusions Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.

A prospective observational study on oral administration of Ellagic Acid and Annona Muricata in patients affected by non-muscle invasive bladder cancer not undergoing maintenance after 6-week intravesical prophylaxis

2021 ◽  
pp. 039156032110222
Author(s):  
Vincenzo Serretta ◽  
Ettore De Berardinis ◽  
Alchiede Simonato ◽  
Alessio Guarneri ◽  
Nino Dispensa ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Oral Administration ◽  
Ellagic Acid ◽  
Invasive Bladder Cancer ◽  
Prophylactic Effect ◽  
Annona Muricata ◽  
Muscle Invasive Bladder Cancer ◽  
Number Of Patients ◽  
Muscle Invasive

Introduction: BCG and MMC shortage and Covid-19 pandemic, more recently, limit accessibility to maintenance regimen in intravesical prophylaxis against recurrence of non-muscle invasive bladder cancer (NMIBC). Ellagic acid (EA) and Annona muricata (AM) exert antitumor activity against different human tumours. An observational prospective study on the prophylactic effect of oral administration of EA+AM in patients avoiding maintenance regimen is presented. Materials and methods: Patients affected by NMIBC and not undergoing maintenance after a 6-week course of intravesical prophylaxis with MMC or BCG were entered. Tis and very high-risk tumours were excluded. After informed consent, the patients were subdivided in relation to the oral assumption or not of EA (100 mg) plus AM (100 mg), daily for 6 months. All patients were submitted to 3-month cytology and cystoscopy. Results: 162 (90%) of 180 entered patients are evaluable, 90 and 72 receiving or not EA+AM. No difference emerged in patients’ characteristics between the two groups. BCG was given in 86 (54%) and chemotherapy in 74 (46%) patients. The recurrence free rate at 3, 6 and 12 months in patients assuming or not EA was 96.5% versus 84.6% ( p = 0.003), 85.4% versus 64.8% ( p = 0.005) and 74.2% versus 60.6% ( p = 0.246), respectively. The recurrence free survival at 12 months in patients assuming or not EA was 63.0% versus 34.5% ( p < 0.0001). Discussion and conclusions: Our study suffers several limits: not randomized trial although prospective, limited number of patients and short follow-up, nevertheless it shows the prophylactic effect of oral EA+AM in absence of maintenance after intravesical chemotherapy or immunotherapy induction.

scholarly journals Effectivity of intravescical thermo-chemotherapy prophylaxis for patients with high recurrence and progression risk for non-muscle invasive bladder cancer

2017 ◽  
Vol 89 (2) ◽  
pp. 102 ◽  
Author(s):  
Ali Serdar Gözen ◽  
Paolo Umari ◽  
Walter Scheitlin ◽  
Fuat Ernis Su ◽  
Yigit Akin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Recurrent Disease ◽  
Bladder Wall ◽  
Invasive Bladder Cancer ◽  
Outpatient Basis ◽  
High Grade ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Background&amp;Aim: High grade non-muscle invasive bladder cancer (NMIBC) is common in urological practice. Most of these cancers are or become refractory to intravesical immunotherapy and chemotherapy. Here we evaluated the efficacy of combined local bladder hyperthermia and intravesical mitomycin-C (MMC) instillation in patients with high-risk recurrent NMIBC. Materials and methods: Between February 2014 and December 2015, 18 patients with high risk NMIBC were enrolled. Patients were treated in an outpatient basis with 6 weekly induction sessions followed by monthly maintenance sessions with intravesical MMC in local hyperthermia with bladder wall thermo-chemotherapy (BWT) system (PelvixTT system, Elmedical Ltd., Hod Hasharon, Israel). The follow-up regimen included cystoscopy after the induction cycle and thereafter with regular intervals. Time to disease recurrence was defined as time from the first intravesical treatment to endoscopic or histological documentation of a new bladder tumour. Adverse events were recorded according to CTC 4.0 (Common Toxicity Criteria) score system. Results: Mean age was 72 (32-87) years. 10 patients had multifocal disease, 9 had CIS, 6 had recurrent disease and 2 had highly recurrent disease (&gt; 3 recurrences in a 24 months period). 6 patients underwent previous intravesical chemotherapy with MMC. The average number of maintenance sessions per patient was 7.6. After a mean follow-up of 433 days, 15 patients (83.3%) were recurrence-free. 3 patients had tumour recurrence after a mean period of 248 days without progression. Side effects were limited to grade 1 in 2 patients and grade 2 in 1 patient. Conclusions: BWT seems to be feasible and safe in high grade NMIBC. More studies are needed to identify the subgroup of patients who may benefit more from this treatment.

scholarly journals Comparison of the EORTC and CUETO prognostic models in non-muscle-invasive bladder cancer

2018 ◽  
Vol 14 (2) ◽  
pp. 162-170
Author(s):  
A. D. Kaprin ◽  
O. I. Apolikhin ◽  
B. Ya. Alekseev ◽  
D. A. Roshchin ◽  
A. A. Kachmazov ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Treatment Strategy ◽  
Scoring Systems ◽  
Prognostic Models ◽  
Invasive Bladder Cancer ◽  
Molecular Characteristics ◽  
Muscle Invasive Bladder Cancer ◽  
European Organization ◽  
Genetic Characteristics ◽  
Muscle Invasive

Bladder cancer is one of the most common malignant diseases involving the urinary system. Accurate prediction of the disease course and outcome is crucial for choosing an appropriate treatment strategy in these patients. Currently, there are several prognostic models for predicting non-muscle invasive bladder cancer outcomes. The scoring systems developed by the European Organization for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) are the most widely used prognostic models for bladder cancer. Despite the undeniable merits of these scales, they need to be supplemented. Since the prognostic score has a direct impact on the treatment strategy, intensity and costs of postoperative follow-up, and outcome, its accuracy should be higher than it is now. Identifying the additional parameters that would increase the robustness of these models is one of the major challenges for researchers.The molecular and genetic characteristics of the tumor, that can be estimated after the first surgery, are probably the best candidates for this role. The main limitation of these prognostic models lies in the fact that they assess only morphological properties of the tumor, while the most important molecular characteristics are neglected. These scoring systems do not evaluate clinical factors, concomitant diseases, and iatrogenic complications occurring during the treatment of relapses. The assessment of molecular mechanisms and clinical characteristics underlying the development of non-muscle-invasive bladder cancer as well as identification of key molecular markers, that could complement the currently existing risk assessment models, are the most important goals for researchers dealing with bladder cancer. It will significantly improve predictive capabilities of these models, ensuring the choice of an optimal treatment strategy.

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