Locally Advanced Bladder Cancer Research Articles

MP56-07 IMPACT OF SMOKING, CUMULATIVE EXPOSURE AND CESSATION ON ONCOLOGIC OUTCOMES AFTER RADICAL CYSTECTOMY AND ADJUVANT CHEMOTHERAPY FOR LOCALLY-ADVANCED BLADDER CANCER: A MULTICENTER STUDY

MP56-07 IMPACT OF SMOKING, CUMULATIVE EXPOSURE AND CESSATION ON ONCOLOGIC OUTCOMES AFTER RADICAL CYSTECTOMY AND ADJUVANT CHEMOTHERAPY FOR LOCALLY-ADVANCED BLADDER CANCER: A MULTICENTER STUDY

Adjuvant Chemotherapy Plus Radiotherapy versus Chemotherapy Alone for Locally Advanced Bladder Cancer after Radical Cystectomy

BACKGROUND: Survival with locally advanced bladder cancer (LABC) following radical cystectomy (RC) remains poor. Although adjuvant chemotherapy (AC) is standard of care, one small, randomized trial has suggested a potential survival benefit when combined with post-operative radiotherapy (PORT). OBJECTIVE: We examined the association of AC + PORT with overall survival (OS) in patients with LABC after RC. METHODS: Using a prior phase 2 trial to inform design, we conducted observational analyses to emulate a hypothetical target trial of patients aged 18–79 years with pT3-4 Nany M0 or pTany N1-3 M0 urothelial bladder carcinoma following RC who were treated with AC (multiagent chemotherapy within 3 months of RC) with or without PORT (≥45 Gy to the pelvis) from 2006–2015 in the NCDB. Patients who received preoperative chemotherapy or radiotherapy were excluded. The associations of treatment with OS were evaluated using multivariable Cox regression. RESULTS: 1,684 patients were included, with 66 receiving AC + PORT and 1,618 AC alone. Compared to patients treated with AC alone, those treated with AC + PORT were more likely to have pT4 disease (52% vs 26%; p < 0.01), positive surgical margins (44% vs 17%; p < 0.01), and be treated at a non-academic facility (75% vs 53%; p < 0.01). Crude 5-year OS was 19% for AC + PORT versus 36% for AC alone (p = 0.01). Adjusted 5-year OS was 33% for AC + PORT versus 36% for AC alone (p = 0.49). After adjusting for baseline characteristics including pathologic features, AC + PORT was not associated with improved OS compared to AC alone (HR 1.11; 95% CI 0.82–1.51). CONCLUSIONS: Although infrequently utilized, the addition of radiotherapy to AC is not associated with improved OS in LABC. These results highlight the need for prospective trials to better define the potential benefits from PORT with regard to symptomatic progression and oncologic outcomes.

Adjuvant chemotherapy in patients with locally advanced bladder cancer after neoadjuvant chemotherapy and radical cystectomy: a systematic review and pooled analysis.

BackgroundNeoadjuvant chemotherapy (NAC) could ameliorate the stage of locally advanced bladder cancer (LABC) which is defined in pT3/T4 and/or pN+, improve overall survival (OS) before radical cystectomy (RC). However, for LABC, the decision to use adjuvant chemotherapy (AC) after NAC and RC is still controversial.MethodsWe performed a comprehensive search of the PubMed, Embase, and Cochrane Library databases for literature that reported prognosis after using AC following NAC and RC. Cumulative analyses of hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were performed. We performed all analyses by Review Manager software, version 5.3, and Stata 15.0.ResultsSix retrospective cohort studies were included, involving 4,346 patients. Pooled analysis results showed that using AC after NAC and RC can improve OS (HR =0.83, 95% CI: 0.74–0.94, P=0.002; I2 =0%) and cancer-specific survival (CSS) (HR =0.56, 95% CI: 0.32–0.99, P=0.04; I2 =0%) but cannot extend recurrence-free survival (RFS) (HR =0.52, 95% CI: 0.27–1.01, P=0.05; I2 =53%) for LABC patients.ConclusionsThis pooled analysis shows that AC after NAC and RC can improve the prognosis for patients with LABC.

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

515 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 chemo or decline it. Adjuvant radiotherapy (RT) is an alternative (or complementary) adjuvant therapy, but is rarely performed, with most of these patients being observed. In a prospective trial, we compared RT vs adjuvant chemo & hypothesized that RT can achieve comparable disease-free survival (DFS). Methods: A randomized phase III trial at the National Cancer Institute (Cairo) compared adjuvant RT (standard of care in Egypt) vs. chemo+RT after RC for LABC. A 3rd arm, adjuvant chemo, was added later (gemcitabine/cisplatin x 4). Herein, we report results of RT vs adjuvant chemo. Patients ≤70 y/o with ≥1 of the following (pT3b/T4a, grade 3 or pN+) with negative margins after RC were eligible. RT was delivered with 3-D conformal RT to the pelvis (45 Gy in 1.5 Gy BID). Routine follow-up & pelvic CT q 6 months were performed. Post hoc non-inferiority exploratory analysis was performed. Results: 123 were enrolled (78 RT/45 chemo). 51% had urothelial carcinoma; 49% had squamous cell carcinoma. The arms were well-balanced except for gender (p=0.06). Two-year outcomes & overall adjusted hazard ratios (HR) for RT vs chemo were 54% vs 47% for DFS [HR 0.65(95%CI 0.35-1.19, p=0.16]; 92% vs 69% for local-regional recurrence-free survival [HR 0.28(95%CI 0.10-0.82), p=0.02]; 75% vs 79% for distant metastasis-free survival [HR 2.39(95%CI 0.94-6.09), p=0.07]; 61% vs 60% for overall survival [HR 0.94(95%CI 0.52-1.69), p=0.83]. In the urothelial cohort, there were no differences in DFS or OS. Late grade ≥3 GI toxicity was observed in 6 RT patients (8%) & 1 chemo patient (2%). Based on our data, there is a >90% probability that the true difference in 2-year DFS is <10%, the prespecified non-inferiority margin. Conclusions: This prospective study demonstrates that adjuvant RT has superior local control vs adjuvant chemo with no statistically significant differences in DFS or OS. Results suggest that RT can be an option for patients with LABC after RC where an alternative to chemo is desired by the patient or physician. Clinical trial information: NCT01734798.

Prospective trial of adjuvant therapy after radical cystectomy for locally advanced bladder cancer: Analysis of the squamous cell carcinoma subgroup.

524 Background: The role of adjuvant therapy after radical cystectomy (RC) is not well-defined for squamous cell carcinoma (SqCC) of the bladder. Several studies suggest limited efficacy for chemo while adjuvant RT improved disease-free survival (DFS) vs. observation in a previous trial. In this study, we report a post-hoc subgroup analysis of SqCC to compare adjuvant therapies. We hypothesized that adjuvant RT would improve DFS vs. chemo for locally advanced bladder cancer (LABC) (≥pT3N0-N+). Methods: A randomized phase III trial was opened to compare adjuvant RT vs. sandwich chemo+RT after RC for LABC at the NCI in Cairo. A 3rd arm, adjuvant chemo, was added later. Bladder cancer patients ≤70 y/o with ≥1 of the following (pT3b/pT4a, grade 3, or pN+) with negative margins after RC were eligible. RT was delivered to the pelvis with 3D conformal RT (45Gy in 1.5Gy BID). Chemo+RT included 2 cycles of gemcitabine/cisplatin before & after RT. Chemo alone included gem/cis x 4. Primary & secondary endpoints were DFS and overall survival (OS). Results: 198 patients were enrolled. 82 (41%) had SqCC & 77 had ≥pT3N0-N+ disease and were analyzed (34 RT, 27 chemo+RT, & 16 chemo). Median age was 53. Median F/U was 20 months (1-127 months). The RT vs chemo arms were well-balanced except for number of nodes removed (mean 12 vs. 9, p=0.05). On univariable analysis, RT was not significantly associated with DFS [HR 0.56 (95%CI 0.26-1.21), p=0.14]. On multivariable analysis, only pN+ was significant. 2-yr DFS was 60% for RT & 43% for chemo (log-rank p=0.13). OS was improved with RT (2-yr OS 71% vs. 43%, p=0.04). There was one death during treatment (chemo-related). There was no significant difference in DFS or OS for RT vs. chemo+RT with 2-yr DFS of 59% & 55% (p=0.65) & 2-yr OS of 67% & 74% (p=0.16). Conclusions: On post-hoc analysis, RT for locally advanced bladder SqCC was associated with significantly improved OS vs. adjuvant chemo. We hypothesize that the inferior OS with chemo was due to increased toxicity & limited efficacy. There was no difference in outcomes for RT vs. chemo+RT. Adjuvant RT should be a standard option for ≥pT3 SqCC of the bladder after RC. Alternative chemo agents for SqCC should be explored. Clinical trial information: NCT01734798.

Effectiveness of postoperative radiotherapy after radical cystectomy for locally advanced bladder cancer.

BackgroundLocal‐regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity/mortality. Postoperative radiotherapy (PORT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of PORT would improve OS in LABC in a large nationwide oncology database.MethodsWe identified ≥ pT3pN0‐3M0 LABC patients in the National Cancer Database diagnosed 2004‐2014 who underwent RC ± PORT. OS was calculated using Kaplan‐Meier and Cox proportional hazards regression modeling was used to identify predictors of OS. Propensity matching was performed to match RC patients who received PORT vs those who did not.Results15,124 RC patients were identified with 512 (3.3%) receiving PORT. Median OS was 20.0 months (95% CI, 18.2‐21.8) for PORT vs 20.8 months (95% CI, 20.3‐21.3) for no PORT (P = 0.178). In multivariable analysis, PORT was independently associated with improved OS: hazard ratio 0.87 (95% CI, 0.78‐0.97); P = 0.008. A one‐to‐three propensity match yielded 1,858 patients (24.9% receiving PORT and 75.1% without). In the propensity‐matched cohort, median OS was 19.8 months (95% CI, 18.0‐21.6) for PORT vs 16.9 months (95% CI, 15.6‐18.1) for no PORT (P = 0.030). In the propensity‐matched cohort of urothelial carcinoma patients (N = 1,460), PORT was associated with improved OS for pT4, pN+, and positive margins (P < 0.01 all).ConclusionIn this observational cohort, PORT was associated with improved OS in LABC. While the data should be interpreted cautiously, these results lend support to the use of PORT in selected patients with LABC, regardless of histology. Prospective trials of PORT are warranted.

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

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 &amp; 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 &amp; 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 &amp; 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%) &amp; 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.

Randomized phase III trial of adjuvant sequential chemotherapy plus radiotherapy versus adjuvant radiotherapy alone for locally advanced bladder cancer after radical cystectomy: Urothelial carcinoma subgroup analysis.

351 Background: The role of post-operative chemotherapy after radical cystectomy (RC) is not well-defined. While some retrospective studies have shown a benefit, trials have been under-powered. In a phase III Egyptian trial, we evaluated the benefit of adjuvant chemo in locally advanced bladder cancer (LABC) patients treated with post-operative radiotherapy (PORT). In this study, we report a post-hoc subgroup analysis of patients with urothelial histology. We hypothesized that the addition of adjuvant chemo would improve disease-free survival (DFS) compared to PORT alone for LABC. Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC &amp; accrued from 2002–2008 at the NCI in Cairo. Bladder cancer pts ≤70 with at least one of the following factors (≥pT3b, grade 3, positive nodes) with negative margins after RC plus pelvic node dissection were eligible. RT was delivered using 3-D conformal RT to the pelvis to 45Gy in 1.5Gy BID. Chemo+PORT included 2 cycles of gemcitabine/cisplatin before &amp; after RT. The primary endpoint was DFS. Secondary endpoints included overall survival (OS) &amp; late GI toxicity. Results: 153 pts were enrolled. 53% had urothelial carcinoma (41 chemo+PORT &amp; 40 PORT). In the urothelial cohort, the arms were well-balanced. Median age was 55. Median follow-up was 21 months for chemo+PORT (range 4-127) &amp; 15 months for PORT (range 5-70). There were 2 local failures for PORT &amp; none for chemo+PORT. Two-year DFS for chemo+PORT vs. PORT was 62% (95% CI 53-71%) &amp; 48% (95% CI 39-58%), log-rank p=0.031. Two-year OS was 71% (95% CI 63-80%) &amp; 51% (95% CI 40-61%), log-rank p=0.048. On multivariable analysis, chemo+PORT was a significant predictor of improved DFS (HR 0.42 95% CI 0.21-0.85, p=0.016) and OS (HR 0.45, 95% CI 0.21-0.96, p=0.039). In the entire cohort, late grade ≥3 GI toxicity was observed in 5 chemo+PORT patients (7%) &amp; 6 PORT patients (8%). Conclusions: The addition of adjuvant chemo to PORT improved DFS &amp; OS for LABC after RC with acceptable late GI toxicity. The results suggest a role for adjuvant therapies to address both local &amp; distant disease. Clinical trial information: 01734798.

The Role of Adjuvant Radiation Therapy in Locally Advanced Bladder Cancer.

Background:The standard of care for locally advanced bladder cancer (LABC) is neoadjuvant chemotherapy followed by cystectomy. However, the role of adjuvant therapy for locally advanced bladder cancer is unclear.Objective:The purpose of this study was to evaluate the outcomes of adjuvant radiation therapy (RT) for patients with LABC, and to determine which risk factors best predict for patients who may best benefit from adjuvant RT.Methods:The National Cancer Data Base (NCDB) was queried (2004– 2013) for patients with newly-diagnosed pT3-4N0-3M0 urothelial carcinoma of the bladder that received neoadjuvant chemotherapy and cystectomy. Patients were divided into two groups based on the adjuvant therapy they received: RT or observation. Statistics included multivariable logistic regression to determine factors predictive of receiving adjuvant RT, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS.Results:Altogether, 1,646 patients met inclusion criteria; 59 (3.6%) patients received adjuvant RT, while 1,587 (96.4%) were observed. Patients treated with adjuvant RT were more likely to be female, have positive surgical margins, and receive treatment at a non-academic facility. There was no difference in median overall survival (OS) between patients treated with RT when compared to patients observed (17.7 months vs. 23.5 months; p = 0.085). However, an improvement in median OS with the use of adjuvant RT was observed among patients with positive surgical margins (20.3 months vs. 13.1 months; p = 0.032). On multivariate analysis, advancing age, pT4 stage, positive N stage, positive margins, and lower socioeconomic status were associated with worse OS.Conclusions:In the largest study to date evaluating efficacy of adjuvant radiotherapy in patients with locally advanced bladder cancer, use of RT was not associated with OS in all patients, while RT was associated with improvemed OS among patients with positive surgical margins. Prospective studies are recommended to confirm these findings.

Effectiveness of adjuvant radiotherapy after radical cystectomy for locally advanced bladder cancer.

484 Background: Local-regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemo and is associated with high morbidity/mortality. Adjuvant radiotherapy (adjRT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of adjRT would improve OS in LABC in a large multi-institutional cohort. Methods: We identified ≥pT3 pN0-3, M0 LABC pts in the NCDB diagnosed in 2004 – 2013 who underwent RC +/- adjRT. AdjRT cohort included pts treated to ≥40Gy to the pelvis within 1 yr of diagnosis. Propensity matching was performed to match RC pts who received adjRT vs. those who did not. OS was calculated using Kaplan-Meier. Factors significant on univariate analysis were entered into Cox proportional hazards regression model to identify predictors of OS. Results: 15,246 RC pts were identified, with 450 (3.0%) receiving adjRT. Median OS was 23.0 mo (95% CI, 22.4-23.6) for RC vs. 19.7 mo (95% CI, 17.7-21.7) for adjRT [Log-rank P = 0.002; Wilcoxon P = 0.862]. Propensity score matching on demographic, clinical, &amp; treatment variables yielded 742 pts (371 in each group). In the matched cohort, OS was 17.1 mo [95%CI, 14.5 - 19.6] for RC vs. 20.1 mo [95% CI, 17.8– 22.5] for adjRT [Log-rank P = 0.044]. On MVA in the matched cohort, factors predictive of OS were sex, pT stage, pN+ status, surgical margin status, number of nodes removed, adjRT, &amp; chemo (p &lt; 0.01 for all). On MVA of subgroups, adjRT was associated with significantly improved OS in pts with positive margins [HR 0.55 (95% CI, 0.43 – 0.71), P &lt; 0.001], pN+ disease [HR 0.62 (95% CI, 0.49 – 0.79), P &lt; 0.001], &amp; pT4 disease [HR 0.68 (95% CI, 0.55 – 0.85), P = 0.001]. In MVA of pts with urothelial carcinoma (N = 578), adjRT remained associated with improved OS in pts with positive margins [HR 0.57 (95% CI, 0.43 – 0.76), P &lt; 0.001], pN+ disease [HR 0.65 (95% CI, 0.50 – 0.86), P = 0.002], &amp; pT4 disease [HR 0.68 (95% CI, 0.54 – 0.85), P = 0.001]. Conclusions: In this observational study, adjRT was associated with improved OS in LABC. While the data should be interpreted cautiously, these results lend support to the use of adjRT in selected pts with LABC, regardless of histology. Prospective trials of adjRT are warranted.

The role of adjuvant chemotherapy in locally advanced bladder cancer

Purpose: The standard of care for locally advanced bladder cancer (LABC) is neoadjuvant chemotherapy followed by cystectomy. However, the role of adjuvant therapy is unclear. The purpose of this study was to evaluate the outcomes of adjuvant chemotherapy for patients with LABC following neoadjuvant chemotherapy and cystectomy, and to determine whether select patients may benefit from adjuvant chemotherapy.Methods: The National Cancer Data Base (NCDB) was queried (2004–2013) for patients with newly diagnosed pT3-4N0-3M0 bladder cancer that received neoadjuvant chemotherapy and cystectomy. Patients were divided into two groups based on the adjuvant therapy they received: chemotherapy alone or observation. Statistics included multivariable logistic regression to determine factors predictive of receiving adjuvant chemotherapy, Kaplan–Meier analysis to evaluate overall survival (OS) and Cox proportional hazards modeling to determine variables associated with OS.Results: Altogether, 2592 patients met inclusion criteria; 901 (34.8%) patients received adjuvant chemotherapy, while 1691 (65.2%) were observed. Patients treated with adjuvant chemotherapy were more likely to have positive margins were younger and more likely to receive treatment at a nonacademic facility. There was no difference in median OS between patients treated with or without adjuvant chemotherapy (22.6 vs. 21.1 months; p = .267). However, a longer median OS was observed with the use of adjuvant chemotherapy was observed among patients with N2–3 disease (17.5 vs. 14.4 months; p = .005) and positive surgical margins (16.7 vs. 12.2 months; p = .025). On multivariate analysis, advancing age, pT4 stage, positive N stage, positive margins and lower socioeconomic status were associated with worse OS.Conclusions: In the largest study to date evaluating efficacy of adjuvant chemotherapy, while no difference in OS was observed for adjuvant chemotherapy in all patients, a longer OS was observed among patients with N2–3 disease or with positive surgical margins. Prospective studies are recommended to further evaluate these findings.

Adjuvant Sandwich Chemotherapy Plus Radiotherapy vs Adjuvant Chemotherapy Alone for Locally Advanced Bladder Cancer After Radical Cystectomy

Locoregional failure for patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity and mortality. Adjuvant radiotherapy (RT) can decrease locoregional failure but has not been studied in the chemotherapy era. To investigate if adjuvant sequential RT plus chemotherapy can improve locoregional recurrence-free survival (LRFS) compared with adjuvant chemotherapy alone. A randomized phase 3 trial was opened to compare adjuvant RT vs sequential chemotherapy plus RT after RC for LABC, but a third arm was added later as a randomized phase 2 trial to compare chemotherapy plus RT vs adjuvant chemotherapy alone, an emerging standard. The intent-to-treat phase 2 trial reported herein enrolled patients from December 2002 to July 2008. Data were analyzed from August 3, 2015, to January 6, 2016. Routine follow-up and surveillance pelvic computed tomographic (CT) scans every 6 months during the first 2 years were performed. The setting was an academic center. Patients with bladder cancer 70 years or younger having 1 or more risk factors (≥pT3b, grade 3, or positive nodes) with negative margins after radical cystectomy plus pelvic lymph node dissection were eligible. Patients had Eastern Cooperative Oncology Group performance status of 0 to 2, no evidence of distant metastases on CT scan of the abdomen and pelvis or on chest imaging, and adequate renal, hepatic, and hematologic function. Ninety-one percent (109 of 120) had ≥ pT3 disease. Chemotherapy plus RT included 2 cycles of gemcitabine (1000 mg/m2 intravenously on days 1, 8, and 15) and cisplatin (70 mg/m2 intravenously on day 2) before and after RT to 4500 cGy in 150 cGy twice-daily fractions over 3 weeks using 3-dimensional conformal techniques. Chemotherapy alone included 4 cycles of gemcitabine and cisplatin. Locoregional recurrence-free survival. The chemotherapy plus RT arm accrued 75 patients, and the chemotherapy-alone arm accrued 45 patients, with a weighted randomization to speed accrual. Fifty-three percent (64 of 120) had urothelial carcinoma, and 46.7% (56 of 120) had squamous cell carcinoma or other. The arms were balanced except for age (median, 52 vs 55 years; P = .04) and tumor size (mean, 4.9 vs 5.8 cm; P < .01), both favoring chemotherapy plus RT. Two-year outcomes and overall adjusted hazard ratios (HRs) for chemotherapy plus RT vs chemotherapy alone were 96% vs 69% (HR, 0.08; 95% CI, 0.02-0.39; P < .01) for LRFS, 68% vs 56% (HR, 0.53; 95% CI, 0.27-1.06; P = .07) for disease-free survival, and 71% vs 60% (HR, 0.61; 95% CI, 0.33-1.11; P = .11) for overall survival (OS). Five patients (7%) had RT-associated late grade 3 gastrointestinal tract adverse effects in the chemotherapy plus RT arm. Adjuvant chemotherapy plus RT was reasonably well tolerated and was associated with significant improvements in LRFS and marginal improvements in disease-free survival vs chemotherapy alone in LABC. The addition of adjuvant RT should be considered for LABC. This regimen warrants further study in phase 3 trials. clinicaltrials.gov Identifier: NCT01734798.

MP21-13 DOES QUALITY OF CARE IMPACT OUTCOMES IN PATIENTS WITH LOCALLY ADVANCED BLADDER CANCER AFTER ROBOT-ASSISTED RADICAL CYSTECTOMY?

You have accessJournal of UrologyBladder Cancer: Invasive I1 Apr 2017MP21-13 DOES QUALITY OF CARE IMPACT OUTCOMES IN PATIENTS WITH LOCALLY ADVANCED BLADDER CANCER AFTER ROBOT-ASSISTED RADICAL CYSTECTOMY? Youssef Ahmed, Ahmed Hussein, Paul May, Basel Ahmed, Amir Khan, John Binkowski, Justen Kozlowski, and Khurshid Guru Youssef AhmedYoussef Ahmed More articles by this author , Ahmed HusseinAhmed Hussein More articles by this author , Paul MayPaul May More articles by this author , Basel AhmedBasel Ahmed More articles by this author , Amir KhanAmir Khan More articles by this author , John BinkowskiJohn Binkowski More articles by this author , Justen KozlowskiJusten Kozlowski More articles by this author , and Khurshid GuruKhurshid Guru More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3275AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Lack of tactile feedback and potential higher risk of positive margins may advocate against the use of Robot-assisted Radical Cystectomy (RARC) for Locally advanced disease (LAD). We evaluated the quality of RARC in patients with LAD and compared it to organ-confined disease (OCD) METHODS Retrospective review of 421 consecutive RARCs between 2005 and 2015 was performed. Patients with LAD (>=pT3 and/or N+) were compared with OCD (<=pT2/N0). Validated Quality Cystectomy Score (QCS) based on 4 sets of quality metrics was used to compare surgical performance in both groups: [I- Preoperative (Administration of Neoadjuvant Chemotherapy); II- Operative (Overall operative time (< 6.5 hours) and estimated blood loss less <500 ml); III- Pathologic (Negative Soft Tissue Surgical Margins and Lymph Node Yield>20); and IV- Peri-operative (No high grade complications, Readmission or Mortality within 30-d)]. Star Scores were assigned according to the number of criteria achieved. Kaplan Meier method was used to compute recurrence free (RFS), cancer-specific (CSS) and overall survival (OS) rates. Cox proportional hazards model were fit to evaluate predictors of survival. RESULTS 52% had LAD. They had fewer neobladders (3% vs 12%, p<0.001), received adjuvant chemotherapy more frequently (34% vs 4%, p<0.001), and experienced higher mortality within 90 d of RARC (8% vs 1%, p=0.001). LAD patients showed more positive surgical margins (18% vs 2%, p<0.001) and developed recurrences more frequently (41% vs 13%, p<0.001). There was no significant difference in complications or readmissions. Patients with OCD exhibited better 3-year RFS, DSS and OS (85% vs 47%, 96% vs 65% and 81% vs 28%, respectively) (Figure 1). 91% of OCD patients achieved >=3 stars in comparison to 81% in LAD (Table 1). For OCD, patients who achieved star score of 3 or 4 remained stable (approximately 90%), while for LAD, it improved from 72% to 93% between 2005 and 2015. CONCLUSIONS Despite receiving comparable quality of surgical care, patients with LAD exhibited worse RFS, DSS and OS. © 2017FiguresReferencesRelatedDetailsCited byHautmann R (2018) Declining Use of Orthotopic Reconstruction Worldwide—What Went Wrong?Journal of Urology, VOL. 199, NO. 4, (900-903), Online publication date: 1-Apr-2018. Volume 197Issue 4SApril 2017Page: e252 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Youssef Ahmed More articles by this author Ahmed Hussein More articles by this author Paul May More articles by this author Basel Ahmed More articles by this author Amir Khan More articles by this author John Binkowski More articles by this author Justen Kozlowski More articles by this author Khurshid Guru More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Is paclitaxel, cisplatin, and gemcitabine (PCG) feasible as neoadjuvant therapy for locally advanced bladder cancer (LABC)?

e15510 Background: Neoadjuvant therapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) improves survival in LABC. PCG has proven to be an alternative with high response rate in metastatic disease and recent evidences demonstrates it as an option in adjuvant context. However its role in neoadjuvant scenario is still uncertain. Our objective is to evaluate time free of recurrence(TFR) and overall pathologic response in pts with LABC who underwent neoadjuvant PCG. Methods: This is a retrospective cohort study which compares patients(pts) who received neoadjuvant PCG with pts who were submitted to cistectomy alone. TFR was estimated by Kaplan-Meier, log-rank test used to evaluate prognosis factors and Chi square test was used to compares variables. The pathologic specimens were examined by independent pathologists. We considered complete pathologic response (cPR) cases that pathologic staging was T0 or T1 with no nodal involvement. Results: Neoadjuvant therapy with PCG was administered in 16 ...

Randomized phase III study of adjuvant versus progression-triggered treatment with gemcitabine (G) after radical cystectomy (RC) for locally advanced bladder cancer (LABC) in patients not suitable for cisplatin-based chemotherapy (CBC) (AUO-trial AB22/00).

250 Background: Cisplatin-based chemotherapy (CBC) has been widely used in trials of adjuvant therapy for LABC after RC. A high proportion of patients are unfit for CBC after RC for LABC. We therefore performed a prospective randomized phase III trial on G-monotherapy administered as adjuvant therapy (G-adj) vs in case of progression (G-prog) in pts not suitable for CBC. Methods: Between 7/2000 and 12/2008 120 of 178 planned pts with LABC unfit for CBC were randomized between 6 adjuvant cycles of G (q3w) starting within 12 wks after RC and G in case of disease progression. The primary endpoint of the trial was progression-free survival (PFS). Secondary endpoints included cancer-specific (CSS) and overall survival (OS) as well as treatment related toxicity. Results: The trial of 178 planned pts was closed early due to slow accrual. Of 120 randomized pts from 29 centers 114 were eligible for analysis. Median age of 81 male and 33 female pts was 72 (45-82) years. Lymph-node positive disease was found in 52/114 (47%) of pts at the time of surgery. The intention-to-treat analysis demonstrated a 10% difference in PFS after 3 years 50% (G-adj) vs 40% (G-prog) with a median PFS of 23 mo (G-adj) vs 17 mo (G-prog). The difference in PFS was not statistically significant (nss) (p= 0.335; HR 1.375, 95%CI 0.719 - 2.627). CSS at 3ys: 56% (G-adj) vs 50% (G-prog) with a median CSS of 49 mo (G-adj) vs 38 mo (G-prog). The difference in CSS was nss (p= 0.622; HR 1.166, 95%CI 0.632 - 2.149). OS at 3ys: 49% (G-adj) vs 48% (G-prog) with a median OS of 32 mo (G-adj) vs 31 mo (G-prog). The difference in OS was nss (p= 0.426; HR 1.225, 95%CI 0.743 - 2.018). Treatment with G was usually well tolerated, with less than 15% grade 3/4 toxicities..There was one treatment related death in the G-adj arm. Conclusions: The study-hypothesis of a 15% difference in PFS after 3 years in favor of G-adj vs G-prog could not be confirmed. Nevertheless a marked difference in survival in favor of G-adj was shown by Kaplan-Meier plots regarding PFS, CSS and OS within the first 24 months after RC. Clinical trial information: NCT00146276.

885 - The Efficacy of Gemcitabine-Based Chemoradiotherapy for the Definitive Treatment of Locally-Advanced Bladder Cancer

ABSTRACT Aim The aim of the present study was to investigate the efficacy and the tolerability of gemcitabine-based chemoradiotherapy (CRT) for the definitive treatment of locally-advanced bladder cancer. Methods Patients with the diagnosis of locally-advanced, transitional cell bladder cancer, who had been treated with gemcitabine-based CRT at the Radiation Oncology department of the Uludag University between January 2005 and January 2009, were enrolled in this retrospective analysis. After maximal transurethral resection of tumor, three-dimensional radiotherapy (RT) was administered at an initial dose of 45 Gy to the primary tumor site plus regional lymphatics followed by a 20 Gy boost to the whole bladder with additional 2 cm margins (1.8 Gy daily fractions, five days a week). All patients received weekly gemcitabine at a dose of 350 mg/m2 on Mondays during the course of RT. Response evaluations were performed every three months by systoscopic examinations and appropriate radiologic studies. Results A total of 20 patients were entered into the study. There were 18 male and 2 female with a median age of 72 (range: 40–78). The median disease-free survival was 35,0 ± 8,2 months (95% CI: 18,7–51,2), and the median overall survival was 37,0 ± 4,4 (95% CI: 28,3–45,7). Acute treatment-related grade ¾ hematologic toxicities were seen in 4 patients (20%). Although 3 patients (15%) exhibited grade ½ gastrointestinal toxicities, there were no grade ¾ non-hematologic toxicities. Conclusion Gemcitabine-based definitive CRT seems to be effective and tolerable treatment option for the treatment of locally-advanced bladder cancer. Disclosure All authors have declared no conflicts of interest.

Randomized Phase III Trial of Radical Radiotherapy with Concurrent Carbogen and Nicotinamide in Locally-advanced Bladder Cancer

A pilot study in advanced bladder cancer of accelerated radiotherapy with concurrent carbogen and nicotinamide (RT+CN) suggested a therapeutic advantage relative to radiotherapy alone (RT). Subsequently, between 2000 and 2006, 333 patients have been recruited into a Phase-III randomized trial comparing RT+CN (n = 168) with RT (n = 165).

BRCA1 mRNA expression in patients (p) with bladder cancer treated with neoadjuvant cisplatin-based chemotherapy

5021 Background: In p with locally-advanced bladder cancer, neoadjuvant chemotherapy followed by cystectomy improves survival compared to surgery alone, especially in p attaining a pathological response (pT0–1N0M0). However, at present no clinical markers are available to predict response to chemotherapy in bladder cancer. BRCA1 mRNA expression has been associated with chemosensitivity and survival in lung and ovarian cancer p (Taron et al. 2004; Quinn et al. 2007) and could be a useful predictive marker in bladder cancer as well. Methods: We analyzed BRCA1 mRNA expression by quantitative PCR in tumor biopsies obtained by transurethral resection from 51 p with locally-advanced bladder cancer. 44 p were clinically staged as cT3–4N0M0, 5 p had regional lymph nodes (cTxN+), and 2 p had distant lymph nodes. 35 p received cisplatin, methotrexate plus vinblastine; 16 p were treated with gemcitabine plus cisplatin. Results: After a median of 3 cycles of chemotherapy, cystectomy was performed in 49 p (96%). A significant pathological response (pT0 or T1) was attained in 25 p (50%). A close correlation was found between BRCA1 levels and pathological response. 21 p (65%) with low/intermediate BRCA1 levels but only 4 p (26%) with high BRCA levels obtained a pathological response (P=0.01). Median disease-free survival (DFS) was 120 months (m) in 17 p with low BRCA1 levels, 184 m in 17 p with intermediate BRCA1 levels, and only 14 m in 17 p with high BRCA1 levels (P=0.02). In the multivariate analysis of DFS, only BRCA1 levels and lymphatic invasion emerged as independent prognostic markers (table). Conclusions: Low levels of BRCA1 can predict response to neoadjuvant cisplatin-based chemotherapy and longer DFS in p with bladder cancer. Clinical trials of customized chemotherapy based on BRCA1 levels are warranted. The prognostic role of BRCA1 in p with bladder cancer merits further investigation. Hazard Ratio 95% CI p BRCA1 mRNA levels Low 1 (ref.) Intermediate 1.16 0.4–3.36 0.77 High 3.1 1.15–8.40 0.02 Lymphatic invasion Yes 7.8 2.54–23.90 <0.0001 No 1 (ref.) No significant financial relationships to disclose.

Significance of Cancer Involvement at the Ureteral Margin Detected on Routine Frozen Section Analysis during Radical Cystectomy

Introduction: We investigated the clinical significance of preoperatively-unsuspected ureteral involvement of cancer detected on intraoperative frozen section analysis of ureteral margins during radical cystectomy. Patients and Methods: We performed a retrospective study of 115 patients who received radical cystectomy for locally-advanced but node-negative transitional cell carcinoma of the bladder between 1995 and 2002 by reviewing their records. Results: Of 115 total patients, 5 (4.3%) demonstrated carcinoma in situ at the ureteral margin with 2 of 5 having a positive margin on final pathologic analysis. Meanwhile, only 3 of 115 total patients (2.6%) later showed upper urinary tract recurrence at a median interval of 30 months after cystectomy. And all 3 patients had intramural or juxtavesical ureter involvement of disease (p = 0.006), while not demonstrating carcinoma in situ in ureteral margins resected during cystectomy. On multivariate analysis, only the stage and grade of bladder cancer along with pathologic feature of vascular invasion were observed to be independent prognostic predictors of disease-specific survival. Conclusions: Cancer involvement of the distal ureteral margin detected through intraoperative frozen section analysis may not be a significant factor regarding upper tract recurrence and survival of patients with locally-advanced bladder cancer after radical cystectomy. Upper tract recurrence may be more prone to occur in patients with cancer involvement at the intramural or juxtavesical ureter.

Expression of Multidrug Resistance Proteins P-Glycoprotein, Multidrug Resistance Protein 1, Breast Cancer Resistance Protein and Lung Resistance Related Protein in Locally Advanced Bladder Cancer Treated With Neoadjuvant Chemotherapy: Biological and Clinical Implications

Resistance to chemotherapy is a major obstacle to overcome in the conservative treatment of patients with locally advanced bladder cancer (LABC). We investigated the predictive value of the response to neoadjuvant chemotherapy (NACT) and prognosis of the expression of multidrug resistance (MDR) related proteins, P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP) and lung resistance related protein/major vault protein (LRP/MVP) in LABC. Using immunohistochemistry we studied the expression of MDR proteins in tumors from 83 patients with LABC treated with NACT using a bladder sparing approach. Expression was related to the response to NACT, bladder preservation and prognosis. P-gp, MRP1, BCRP and LRP/MVP were expressed at high levels in 53%, 59%, 28% and 70% of cases, respectively. P-gp expression correlated with shorter progression-free survival (p = 0.04) but not with overall survival. Surprisingly MRP1 expression correlated with a higher response (p = 0.005) and a higher probability of bladder preservation following NACT (p = 0.001). BCRP did not show any prognostic impact. High LRP/MVP expression was significantly associated with a worse response to NACT and a decreased probability of bladder preservation (p = 0.035). Our data suggest that MRP1 and LRP/MVP may be useful in combination with other clinicopathological prognostic factors for selecting patients with LABC to be candidates for bladder preservation after NACT. A large prospective study is warranted to confirm the prognostic value of these MDR proteins.