Gene expression as a predictive marker of outcome for high-risk transitional-cell carcinoma (TCC) of the bladder in patients (pts) randomized to adjuvant chemotherapy with cisplatin-gemcitabine (PG) or observation (OBS) after radical cystectomy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15502-15502
Author(s):  
C. F. Pollera ◽  
G. Pessina ◽  
F. Nelli ◽  
A. Felici ◽  
L. Moscetti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Adjuvant Chemotherapy ◽  
Mrna Expression ◽  
Radical Cystectomy ◽  
Expression Level ◽  
Phase Iii ◽  
Mrna Levels ◽  
Muscle Invasive

15502 Background: A randomized phase III trial comparing PG vs OBS in muscle-invasive TTC of the bladder is currently ongoing. ERCC1 and RRM1 genes are involved in the nucleotide excision repair pathways, and their up-regulation by tumor has been clearly related to resistance of cisplatin and gemcitabine, respectively. Preliminary correlations in patients with bladder cancer randomized to PG were already presented (Proc ASCO 2005, Abstract No: 4589). In the present study, we have examined the predictive value of ERCC1 and RRM1 as markers of tumor progression, as well as their potential correlation with other known prognostic factors also in patients randomized to OBS. Methods: Thirty-nine paraffin-embedded TTC samples of a subset of patients entered the trial were collected. The characteristics were: pT2 23%, pT3 54%, pT4a 23%, pN1–2 46%; G3–4 98%; M/F 10%/90%, median age: 65 years (range 53–74); PG/OBS: 49%/51%. Analysis consisted of real time RT-PCR quantification of mRNA levels of ERCC1 and RRM1. Results: After a median follow-up of 25 months (range 12–51), 17 patients relapsed and 10 deceased. A good correlation was found between mRNA expression levels of both genes. Three-year disease-free survival (DFS) was 74% vs 33% for patients with low and high ERCC1 expression (p=0.03), and 64% vs 22% for those with low and high RRM1 expression (p=0.26), respectively. Comparable result in favour of patients showing lower ERCC1 mRNA levels was found in both groups of patients randomized to PG or obs. Multivariate analysis demonstrated that only the presence of N1–2 and low expression level of ERCC1 were significant prognostic factor for better DFS (HR 4.358, 2.775 and p value = 0.006 and 0.046, respectively). Conclusions: Determination of ERCC1 mRNA expression level in muscle-invasive bladder cancer can make a contribution as an independent predictor of DFS after radical cystectomy. It’s still unclear if quantification of ERCC1 gene expression level could interact with adjuvant chemotherapy. Longer follow-up will help to address this issue (Supported by CNR-MIUR grants 02.00447, 03.00387-ST97). No significant financial relationships to disclose.

scholarly journals Nucleotide Oligomerization Domain-like receptor 4 (NLR4) Gene Expression and Interleukin 1-β (IL 1-β) Level in Urine Samples Before and After Intravesical BCG Therapy For Treatment of Bladder Cancer

2021 ◽  
Vol 22 (6) ◽  
pp. 1141-1154
Author(s):  
Ahmed Samar Abd Elmoaty Eissa ◽  
Ossama Rasslan ◽  
Lamia Fouad ◽  
Fahim Hisham Abdelmajeed ◽  
Amira Esmail Abdel-Hamid
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Fold Increase ◽  
Urine Samples ◽  
Expression Level ◽  
Muscle Invasive Bladder Cancer ◽  
Bcg Therapy ◽  
Muscle Invasive ◽  
Surgical Sample

Bladder cancer is the 7th most commonly diagnosed cancer in males worldwide and the 11th when both genders are considered. Seventy five per cent of bladder cancer cases are non-muscle invasive bladder cancer (NMIBC). Bacillus Calmette–Gu rin (BCG) immunotherapy remains the standard intravesical agent for NMIBC. The exact mechanism by which BCG prevents recurrence is unknown. The aim of this study was to evaluate NLR4 gene expression and IL-1β as possible prognostic indicators for NMIBC recurrence and BCG treatment failure, and to detect the difference in their levels among muscle invasive bladder cancer (MIBC) and NMIBC that may aid in primary differentiation between cases. This study was conducted in 30 patients who had NMIBC and 17 patients who had MIBC. Urine samples were obtained in sterile cups before operation. From NMIBC cases, four more samples were obtained as mentioned below. Evaluation of NLR4 gene expression was performed in pre-surgical sample for MIBC and in 4 samples for NMIBC: pre-surgical sample, sample collected 4 hours after the 3rd dose of BCG instillation, and samples collected during follow up (3 and 6 months post-surgically). There was statistical significant increase in NLRP4 expression levels in NMIBC (CT=0.87±1.48) compared to MIBC (CT=2.82±2.07). As far as we searched, no published results were found regarding comparative gene expression levels between NMIBC and MIBC cases. Gene expression in recurrent cases was higher in pre-surgical urine samples than in non-recurrent cases. The expression level further increased up to 21 fold than the pre-surgical level in the sample taken after injection of the 3rd dose of BCG. This level decreased distinctly to become 1-fold increase over pre-surgical level at the 3rd month follow up then to only 0.9-fold at the 6th month. In non- recurrent cases, gene expression level started pre-surgically in much lower levels than those encountered in recurrent cases. There were 11-fold increase in expression level after 3rd dose of BCG instillation and then decreased to be 5.6 folds higher in the sample taken at 3rd month follow up than in presurgical samples. Gene expression further decreased to become 4.1 fold higher in samples taken at 6 month follow up than the pre-surgical levels. IL-1β levels were estimated for NMIBC and MIBC cases in urine samples pre-surgically and during BCG therapy in case of NMIBC before and 4 hours after the 3rd dose and during 3rd month follow-up of those cases for searching its possible use of for primary differentiation between NMIBC and MIBC, and also as a prognostic factor for possible recurrence in case of NMIBC cases. The level of IL-1β was generally higher in pre-surgical samples (0.62±0.12 pg/ml) when compared to its level before the 3rd dose of BCG induction therapy (0.53±0.13 pg/ml). Its level was distinctly higher four hours after administration of the 3rd dose BCG (1.96±0.62 pg/ml) than both previous levels. Levels decreased bellow pre-surgical level at 3rd month follow up (0.57±0.099 pg/ml). The levels of IL-1β estimated in samples collected four hours after the 3rd dose BCG was higher in cases that showed recurrence later on than non-recurrent cases. The levels decreased in both cases and became higher in non-recurrent cases (0.64±0.05 pg/ml) than in cases already developed recurrence at the 3rd month diagnosed during follow-up (0.45±0.05 pg/ml). To conclude, on following NLRP4 gene expression and IL-1β levels during BCG administration among recurrent and non-recurrent cases of thirty NMIBC cases, there was a significant statistical difference in both levels for the samples collected after the third dose BCG, being higher in patients who showed subsequent recurrence at the 3rd and 6th month of follow-up. If these preliminary reported findings will be confirmed in upcoming larger cohort’s studies, it could be promising in prognosis of such cases, with the possibility of early manipulation of individualized treatment schedule, keeping patients most probably prone to encounter recurrence safe from possible side effects of BCG therapy. The assessment of NLRP4 expression and IL-1β levels could help predict failure of BCG therapy, playing an appreciable role in early deciding radical surgery. When comparing NLRP4 expression and IL-1β levels between MIBC and NMIBC cases, increased values were noted among non-invasive ones. This finding may serve as a possible diagnostic tool, which represents a challenging issue. Hence, cut-off values for gene expression and cytokine level are to be specified.

Adjuvant chemotherapy (AC) for muscle-invasive bladder cancer: A pooled analysis from phase III studies

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 4664-4664
Author(s):  
E. M. Ruggeri ◽  
D. Giannarelli ◽  
E. Bria ◽  
P. Carlini ◽  
A. Felici ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Adjuvant Chemotherapy ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive ◽  
Phase Iii Studies

Effect of detecting asymptomatic recurrence after radical cystectomy on prognosis in patients with muscle invasive bladder cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 428-428
Author(s):  
Shingo Hatakeyama ◽  
Ayumu Kusaka ◽  
Hirotake Kodama ◽  
Noriko Tokui ◽  
Hayato Yamamoto ◽  
...  
Keyword(s):  
Overall Survival ◽  
Bladder Cancer ◽  
Regression Analysis ◽  
Radical Cystectomy ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Asymptomatic Group ◽  
Symptomatic Group ◽  
Muscle Invasive

428 Background: The prognostic benefit of oncological follow-up to detect asymptomatic recurrence after radical cystectomy (RC) remains unclear. We aimed to assess whether routine follow-up to detect asymptomatic recurrence after RC improves patient survival. Methods: We retrospectively analyzed 581 RC cases for muscle invasive bladder cancer at four hospitals between May 1996 and February 2017. All patients had regular follow-up examinations with urine cytology, blood biochemical tests, and computed tomography after RC. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of recurrence (asymptomatic group vs. symptomatic group) was estimated using the Kaplan–Meier method with the log–rank test. Cox proportional hazards regression analysis via inverse probability of treatment weighting (IPTW) was used to evaluate the impact of the mode of diagnosing recurrence on survival. Results: Of the 581 patients, 175 experienced relapse. Among those, 12 without adequate data were excluded. Of the remaining 163 patients, 76 (47%) were asymptomatic and 87 (53%) were symptomatic at the time of diagnosis. The most common recurrence site and symptom were lymph nodes (47%) and pain (53%), respectively. Time of overall survival after RC and from recurrence to death were significantly longer in the asymptomatic group than symptomatic group. A multivariate Cox regression analysis using IPTW showed that in the patients with symptomatic recurrence was an independent risk factor for overall survival after RC and survival from recurrence to death. Conclusions: Routine oncological follow-up for detection of asymptomatic recurrence contributes to a better prognosis after RC.

Randomized trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4507-4507 ◽  
Author(s):  
Mohamed S. Zaghloul ◽  
John Paul Christodouleas ◽  
Tarek Zaghloul ◽  
Andrew Smith ◽  
Ahmed Abdalla ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bladder Cancer ◽  
Adjuvant Chemotherapy ◽  
Radical Cystectomy ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Adjuvant Radiation ◽  
Advanced Bladder Cancer ◽  
Grade 3

4507 Background: Some chemotherapy-naïve patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) are sufficiently de-conditioned that they are not candidates for adjuvant chemotherapy or decline it, even though such treatment may be warranted. There is no clear alternative adjuvant therapy for these patients, who are usually observed. In this study, we compare post-op radiotherapy (PORT) vs. adjuvant chemotherapy in a randomized clinical trial. We hypothesized that PORT can achieve comparable disease-free survival (DFS). Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC & accrued from 2002–2008 at the NCI in Cairo. In 2007, a third arm comparing adjuvant chemo was added. Herein, we report the results of PORT vs. adjuvant chemo. Patients ≤70 y/o with ≥1 of the following factors (≥pT3b/T4a, grade 3, or positive nodes) with negative margins after RC + pelvic node dissection were eligible. Routine follow-up & pelvic CT q6 months were performed. PORT included 3D conformal pelvic RT (45Gy/1.5Gy BID). Chemo included gemcitabine/cisplatin x 4. Post-hoc non-inferiority exploratory analysis was performed. Results: The PORT arm accrued 78; the chemo arm accrued 45. 51% had urothelial carcinoma; 49% had squamous cell carcinoma/other. The two arms were well-balanced except for gender (p = 0.06). Two-year outcomes & overall adjusted hazard ratios (HR) for PORT vs. chemo alone were 54% vs. 47% (HR 0.65(95%CI 0.35-1.19, p = 0.16) for DFS; 92% vs. 69% (HR 0.28(95%CI 0.10-0.82), p = 0.02 for LRFS; 75% vs. 79% (HR 2.39(95%CI 0.94-6.09), p = 0.07) for DMFS; 61% vs. 60% (HR 0.94(95%CI 0.52-1.69), p = 0.83) for OS. Late grade ≥3 GI toxicity was observed in 6 PORT patients (8%) & 1 chemo patient (2%). Based on our data, there is a greater than 90% probability that the true difference in 2 yr DFS is less than 10%, the pre-specified non-inferiority margin. Conclusions: This randomized study demonstrates superior local control with PORT vs. adjuvant chemo with no significant differences in DFS, DMFS or OS. Results suggest that PORT could be an option for patients with LABC after RC who are medically unfit for adjuvant chemo or who decline it. Clinical trial information: NCT01734798.

scholarly journals Selective organ preservation with neo-adjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder

2015 ◽  
Vol 112 (10) ◽  
pp. 1626-1635 ◽  
Author(s):  
S Hafeez ◽  
A Horwich ◽  
O Omar ◽  
K Mohammed ◽  
A Thompson ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Adjuvant Chemotherapy ◽  
Organ Preservation ◽  
Bladder Tumour ◽  
Poor Responders ◽  
Bladder Preservation ◽  
Platinum Based Chemotherapy ◽  
Neo Adjuvant Chemotherapy ◽  
Muscle Invasive

Abstract Background: Radiotherapy for muscle invasive bladder cancer (MIBC) aims to offer organ preservation without oncological compromise. Neo-adjuvant chemotherapy provides survival advantage; response may guide patient selection for bladder preservation and identify those most likely to have favourable result with radiotherapy. Methods: Ninety-four successive patients with T2-T4aN0M0 bladder cancer treated between January 2000 and June 2011 were analysed at the Royal Marsden Hospital. Patients received platinum-based chemotherapy following transurethral resection of bladder tumour; repeat cystoscopy (±biopsy) was performed to guide subsequent management. Responders were treated with radiotherapy. Poor responders were recommended radical cystectomy. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan–Meier method; univariate and multivariate analyses were performed using the Cox proportional hazard regression model. Results: Response assessment was performed in 89 patients. Seventy-eight (88%) demonstrated response; 53 (60%) achieved complete response (CR); 74 responders had radiotherapy; 4 opted for cystectomy. Eleven (12%) demonstrated poor response, 10 received cystectomy. Median survival for CR was 90 months (95% CI 64.7, 115.9) compared with 16 months (95% CI 5.4, 27.4; P<0.001) poor responders. On multivariate analysis, only response was associated with significantly improved PFS, OS and DSS. After a median follow-up of 39 months (range 4–127 months), 14 patients (16%) required salvage cystectomy (8 for non-muscle invasive disease, 5 for invasive recurrence, 1 for radiotherapy related toxicity). In all, 82% had an intact bladder at last follow-up after radiotherapy; 67% had an intact bladder at last follow-up or death. Our study is limited by its retrospective nature. Conclusions: Response to neo-adjuvant chemotherapy is a favourable prognostic indicator and can be used to select patients for radiotherapy allowing bladder preservation in >80% of the selected patients.

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