Trimodality Bladder Preservation Therapy Research Articles

Abstract IA013: Current state of the art: Bladder-preserving trimodality therapy for muscle-invasive bladder cancer

Abstract Many muscle-invasive bladder cancer (MIBC) patients are not getting curative treatment, there remains an undertreated/underserved population and a huge unmet need. Some are not good surgical candidates and others decline a radical cystectomy given concerns regarding its morbidity. Trimodality therapy (TMT), comprising of a maximal transurethral resection of bladder tumor (TURBT) followed by chemoradiation (with salvage cystectomy reserved for those that incur a muscle-invasive recurrence), has emerged as a viable bladder-preserving alternative to radical cystectomy for selected patients. In clinically-matched cohorts, survival is comparable to radical cystectomy in the modern era. More than 85% of contemporary patients keep their own native bladder and long-term quality of life after bladder preservation is good. Salvage cystectomy is feasible and can be curative for those with MIBC recurrences. TMT is now supported by numerous clinical guidelines, including NCCN (category 1 recommendation for stage II and IIIA). There are opportunities to continue to optimize clinical staging of disease (e.g. MRI), delivery of RT (e.g. image guidance, adaptive delivery, dose escalation, hypofractionation, field design) and systemic therapies (e.g. concurrent, neoadjuvant and adjuvant, including possibly immunotherapy) to improve outcomes. Ongoing trials (such as SWOG/NRG 1806 which recently closed to accrual) will inform the addition of immunotherapy to TMT. Validation of biomarkers in independent cohorts and in prospective trials is necessary to further guide bladder preservation therapy for MIBC and for personalized treatment selection. Ultimately, MIBC patients should be seen in a multidisciplinary environment where informed decision making by the patient is key. Citation Format: Jason A. Efstathiou. Current state of the art: Bladder-preserving trimodality therapy for muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA013.

Bladder-Preserving Trimodality Therapy With Capecitabine

IntroductionMany patients with muscle-invasive bladder cancer are poor candidates for radical cystectomy or trimodality therapy with maximal transurethral resection of bladder tumor (TURBT) and chemoradiotherapy with cisplatin or mitomycin C. Given the benefit of chemotherapy in bladder-preserving therapy, less-intense concurrent chemotherapy regimens are needed. This study reports on efficacy and toxicity for patients treated with trimodality therapy using single-agent concurrent capecitabine. Materials and MethodsPatients deemed ineligible for radical cystectomy or standard chemoradiotherapy by a multidisciplinary tumor board and patients who refused cystectomy were included. Following TURBT, patients received twice-daily capecitabine (goal dose 825 mg/m2) concurrent with radiotherapy to the bladder +/˗ pelvis depending on nodal staging and patient risk factors. Toxicity was evaluated prospectively in weekly on-treatment visits and follow-up visits by the treating physicians. Descriptive statistics are provided. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival were estimated using the Kaplan-Meier method. ResultsTwenty-seven consecutive patients met criteria for inclusion from 2013 to 2023. The median age was 79 with 9 patients staged cT3-4a and 7 staged cN1-3. The rate of complete response in the bladder and pelvis was 93%. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival at 2 years were estimated as 81%, 65%, 91%, 75%, and 92%, respectively. There were 2 bladder recurrences, both noninvasive. There were 7 grade 3 acute hematologic or metabolic events but no other grade 3+ toxicities. ConclusionMaximal TURBT followed by radiotherapy with concurrent capecitabine offers a high rate of bladder control and low rates of acute and late toxicity.

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.

Impact of selection bias on outcomes in veterans with muscle-invasive bladder cancer receiving bladder preserving trimodality therapy.

462 Background: Retrospective studies using large registries comparing outcomes between radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) to trimodality therapy (TMT), which includes transurethral resection of bladder tumor followed by chemoradiation, often cannot distinguish whether patients receiving TMT were eligible for cystectomy but declined or simply ineligible for cystectomy. The objective of this study was to compare survival outcomes of patients with MIBC receiving TMT stratified by whether they were cystectomy-eligible to patients receiving RC +/- NAC. Methods: We used the national Veterans Affairs’ (VA) database to identify patients diagnosed between 2000-2017 with urothelial histology, MIBC (T2-4a/N0-3/M0) who underwent RC or TMT. Overall survival (OS) was evaluated with multivariable Cox proportional hazards model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. We conducted a chart review of clinical notes to ascertain if patients were eligible for cystectomy. Results: Overall 2306 Veterans with MIBC were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 107 (4.6%) with TMT eligible for RC, and 221 (9.4%) with TMT ineligible for RC. Median follow up time was 4.7 years. Patients receiving RC were on average 10 years younger, had higher creatinine clearance, and fewer comorbidities than those receiving TMT. Cystectomy-eligible TMT patients had higher creatinine clearance and fewer comorbidities than those ineligible for cystectomy. On multivariable analysis, compared to RC-NAC, TMT in cystectomy-eligible patients was associated with similar OS (hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.76 - 1.28; p = 0.93) and BCSM (HR 1.02; 95% CI 0.71-1.47; p = 0.91). Compared to RC-NAC, TMT in cystectomy-ineligible patients was associated with inferior OS (HR 1.39; 95% CI 1.13 - 1.71; p = 0.002) and BCSM (HR 1.61; 95% CI 1.23 - 2.10; p &lt; 0.001). Conclusions: There is a significant selection bias among patients with MIBC receiving TMT. Cystectomy-eligible patients receiving TMT likely have similar survival outcomes as those receiving RC. Comparisons between RC and TMT in large registry data that lack information regarding eligibility for cystectomy in the TMT arm may be unreliable.

NRG Oncology/RTOG 0926: Phase II Protocol for Patients With Stage T1 Bladder Cancer to Evaluate Selective Bladder Preserving Treatment by Radiation Therapy Concurrent With Radiosensitizing Chemotherapy Following a Thorough Transurethral Surgical Re-Staging

NRG Oncology/RTOG 0926: Phase II Protocol for Patients With Stage T1 Bladder Cancer to Evaluate Selective Bladder Preserving Treatment by Radiation Therapy Concurrent With Radiosensitizing Chemotherapy Following a Thorough Transurethral Surgical Re-Staging

Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial.

4504 Background: Trimodality bladder preservation therapy (TMT) is a standard treatment option for clinically localized MIBC with curative intent. Pembro has shown activity in MIBC in the neoadjuvant setting and may combine well with TMT to improve outcomes. This trial evaluated the safety and efficacy of pembro added to TMT in MIBC. Methods: This multicenter phase 2 trial included pts with cT2 – T4aN0M0 MIBC who declined or were ineligible for cystectomy (RC), ECOG PS 0/1, eGFR &gt; 30 cc/min, and no contraindications to pelvic RT or pembro. No perioperative chemotx for MIBC was permitted. Pts received pembro 200 mg x 1 followed 2-3 weeks by maximal TURBT and then whole bladder RT (52 Gy/20 fx; IMRT preferred) with twice wkly gem 27 mg/m2 and pembro Q3 wks x 3 treatments. 12 wks post-RT, CT/MR AP, TUR of tumor bed and cytology were performed to document response. Up to 6 pts were enrolled to a safety cohort (SC) followed by 48 pts in efficacy cohort (EC). The primary endpt is 2-yr bladder-intact disease-free survival (BIDFS: first of MIBC or regional nodal recurrence, distant metastases, or death) assessed by serial cysto/cytology and CT/MRI. EC had 85% power to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate (RTOG Pooled analysis; Mak JCO 2014). Key secondary endpts were safety, 12 wks CR rate, metastases-free survival and overall survival. Tumor tissue was collected at study entry, maximal TURBT and post-treatment TUR of tumor bed with serial PBMCs for correlative analyses. Results: From 5/2016 to 10/2020, 54 pts (6 SC, 48 EC; 72% M) enrolled at 5 centers; Median age 67 (65-89) for SC and 74 (51-97) for EC. C-stage (74% cT2, 22% cT3, and 4% cT4). 39 (72%) declined RC. All 6 pts in SC and 42/48 (88%) of EC pts completed all study therapy; 1/48 (2%), 2/48 (4%), and 4/48 (8%) discontinued RT/Gem, Gem or Pembro, respectively, most often due to toxicity. As of 1/2021 (median F/U 40.9 mos (38.6-50.8) SC and 11.7 mos (0.6 – 32.2) EC), no recurrences in SC, and 12/48 EC pts had any recurrence (6 NMIBC, 0 MIBC, 2 regional and 4 distant). The estimated 1 yr BIDFS rate is 77% (95% CI: 0.60-0.87). 12 wks CR rate was 100% in SC and 83% for EC (1 PR, 3 NR, 1 Progression, 11 NE; 2 still on active study). In the EC, 35% of pts had a Gr ≥3 TEAE (Gr 3 events included UTI 8%, diarrhea 4%, colitis 4%, bladder pain/obstruction 4%, neutropenia 2%, thrombocytopenia 2%). Notable Pembro Gr ≥3 TRAE included 3 pts (6%) Gr 3 GI toxicity and 1 pt Gr 4 colonic perforation. 1 patient died due to fungemia, unrelated to study therapy. Conclusions: Pembro added to hypofractionated RT and twice weekly gem was well-tolerated with promising efficacy in this early analysis. Pembro-related toxicity was consistent with prior monotherapy trials. Selected correlative analyses from serially collected blood and tissue specimens will be presented. Clinical trial information: NCT02621151.

Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer

Purpose To evaluate trimodal conservative treatment as an alternative to radical surgery for urothelial muscle-invasive bladder cancer (MIBC). Patients and methods This retrospective study reported the carcinologic and functional results of patients (pts) presenting a cT2/T3 N0M0 operable MIBC and fit for surgery, treated by a conservative strategy. Treatment consisted of a transurethral resection (TURB) followed by concomitant bi-fractionated split-course radiochemotherapy (RCT) with 5FU-Cisplatine. A control cystoscopy was performed six weeks after the induction RCT (eq45Gy) with systematic biopsies. Patients with complete histologic response achieved RCT protocol. Salvage surgery was proposed to pts with persistent tumor. Results 313 pts (83% cT2 and 17% cT3) treated between 1988 and 2013 were included, with a median follow-up of 59 months and 67-year mean age. After the induction RCT, the histologic response rate was 83%. After five years, overall, disease-free, and functional bladder-intact survival rates were respectively 69%, 61%, and 69%, significantly better for pts in complete response after induction RCT. Late urinary and digestive toxicities were limited, with respective rates of 4% and 1.5% of grade 3 toxicity. Conclusion Trimodal strategy with RCT after TURB showed interesting functional and oncologic results and should be considered as an alternative to surgery in well-selected pts.

Endoclips as novel fiducial markers in trimodality bladder-preserving therapy of muscle-invasive bladder carcinoma: feasibility and patient outcomes.

ABSTRACTHypothesis:Endoclip can be used as fiducial marker in urology.Objective:To assess the feasibility, cost effectiveness and reliability of endoclips as novel fiducial markers in precision radiotherapy, as part of a trimodality bladder-preserving treatment (TBPT) of muscle-invasive bladder carcinoma.Materials and Methods:This retrospective study was performed at Weifang People's Hospital (Weifang, China) from January 2015 to June 2018. A total of 15 patients underwent TBPT. Endoclips were applied to healthy edges of the resected bladder wall as novel fiducial markers. Radio-sensitizing chemotherapy and routine precision radiotherapy were given. The number and position of the endoclips during radiotherapy sessions were monitored. Complications and tumor recurrence were analyzed.Results:The mean age (±standard deviation) of the patients was 67±10 years (range 46-79). There were 3 females and 12 males. Forty-nine endoclips were applied in all patients (3.3±0.8). The tumor was completely visibly resected in all patients. The number of endoclips remained the same through the planned last radiotherapy session (3.3±0.8), i.e., none were lost. All endoclips were removed after the last radiotherapy session. The average number of follow-up months was 38.9±13.2 (range 11-52). There were no procedure-related complications at discharge or follow-up. At one-year, overall recurrence-free survival was 93.3%. Two patients had recurrences at 18 months and 10 months after TBPT, respectively, and salvage radical cystectomy was performed with no further recurrences. Another patient died due to metastasis 9 months after the completion of therapy.Conclusions:Endoclips are reliable, safe and cost-effective as novel fiducial markers in precision-radiotherapy post-TBPT.

NEXT: A phase II, open-label study of nivolumab adjuvant to chemoradiation in patients (pts) with localized muscle invasive bladder cancer.

TPS605 Background: In pts with localized muscle invasive bladder cancer (MIBC), trimodality bladder preserving therapy (TMT), with transurethral resection of bladder tumor, radio-sensitizing chemotherapy and definitive radiation, has up to a 50% risk of local and systemic relapse during the 2-year post treatment phase. We hypothesize that by inhibiting immune checkpoints, chemo-radiation induced tumor specific immune response will be enhanced both locally and abscopally, resulting in better failure-free survival (FFS). In the NEXT trial, we evaluate the efficacy of nivolumab after completion of the TMT in this setting. Methods: Pts with localized MIBC who have completed standard TMT are eligible. Pts receive nivolumab 480 mg intravenously every 4 weeks for up to 12 doses. Treatment with nivolumab begins within 90 days of completion of TMT. Subjects undergo surveillance cystoscopic and scan based assessments on study. Archived tumor tissue at baseline and at relapse is obtained for correlative studies. The primary endpoint is 2-year FFS. Secondary endpoints include FFS at 2 years in patients with intact bladder, rate of radical cystectomy (RC), cystoscopic local control, distant FFS in patients with intact bladder and those that undergo RC, overall survival, toxicity and quality of life. Exploratory endpoints include to characterize changes in immune cell subsets that can be correlated with clinical outcome and to assess the correlation of response to PD-L1 expression in pretreatment tumor tissue in the study subjects. The planned sample size for this single arm, open label trial is 28 pts. Kaplan-Meier methods will be used to plot survival endpoints and cystoscopic local control rates. Exact binomial methods will be used to provide 6 months, 1-year and 2-year estimates for these endpoints. The sample size justification is based on the maximum width of a two-sided 95% binomial confidence interval for 2 year FFS. With 28 evaluable subjects, a 95% exact binomial confidence interval, estimated using the method of Clopper-Pearson, will extend no more than 20% from the observed FFS. Clinical trial information: NCT03171025.

Impact of Facility Radiation Patient Volume on Overall Survival in Patients with Muscle Invasive Bladder Cancer Undergoing Trimodality Bladder Preservation Therapy

Impact of Facility Radiation Patient Volume on Overall Survival in Patients with Muscle Invasive Bladder Cancer Undergoing Trimodality Bladder Preservation Therapy

Nuclear Factor-κB Overexpression is Correlated with Poor Outcomes after Multimodality Bladder-Preserving Therapy in Patients with Muscle-Invasive Bladder Cancer

The aim of this study was to investigate prognostic molecular targets for selecting patients with muscle-invasive bladder cancer undergoing bladder-preserving therapy. Pretreatment biopsy samples from patients with muscle-invasive bladder cancer receiving trimodality bladder-preserving therapy were analyzed for expression levels of p53, p16, human epidermal growth factor receptor-2 (Her-2), epidermal growth factor receptor (EGFR), nuclear factor-kappa B (NFκB; p65), E-cadherin, matrix metalloproteinase-9 (MMP9), meiotic recombination 11 homolog (MRE11), programmed death-1 ligand (PD-L1), and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemical (IHC) staining. The correlations between these molecular markers with local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and overall survival (OS) were explored. Biopsy samples from 41 out of 60 patients were evaluated using IHC. Univariate analysis revealed that the high expression of NFκB is associated with significantly worse LPFS, DMFS, and OS, and low expression of p16 is associated with significantly lower LPFS. Upon further multivariate analysis including sex, age, stage, and selected unfavorable factors in the model, NFκB and p16 independently remained significant. The investigational in vitro study demonstrated that irradiation induces up-regulation of NFκB signaling. Irradiated bladder cancer cells showed increased invasion capability and clonogenic survival; inhibition of NFκB signaling by an NFκB inhibitor, SC75741, or RNA interference reversed the observed increases. NFκB expression (p65) is associated with prognostic significance for both LPFS and DMFS in patients treated with bladder-preserving therapy, with consistent impact on cell viability of bladder cancer cells. NFκB may be a putative molecular target to help with outcome stratification.

Impact of facility patient volume on overall survival in patients with muscle invasive bladder cancer undergoing trimodality bladder preservation therapy.

e16039 Background: There is an association between higher hospital and urologist case volume and improved survival outcomes for patients with bladder cancer. Limited data on facility volume and outcomes exists following trimodality bladder preservation with TURBT followed definitive chemoradiation (CRT). Methods: The National Cancer Database was queried for patients from 2004-2013 with urothelial bladder cancer (cT2-4aN0M0) receiving definitive CRT after TURBT. High-volume bladder preservation case volume (BPCV) was defined as facilities in the &gt; 70th percentile of trimodality bladder preservation cases per ten years examined. We compared OS between high- and low-BPCV using Cox proportional hazard models. CRT was defined as &gt; = 5040cGy pelvic RT with chemotherapy given within 21 days. Propensity matching was performed to match high- and low-volume centers. Results: A total of 666 treatment facilities treating 1,635 patients with bladder preservation were identified with a median follow-up of 26 months (range 2-136 months). A 70th percentile cutoff identified 497 patients that received treatment at 64 high-volume facilities. Median OS of patients treated at high BPCV centers was 37.0 months (95% CI, 27.9-33.6) versus 32.3 months (95% CI, 27.3-46.7) for patients treated at low BPCV centers (P = 0.004). High BPCV facilities were independently associated with a decreased hazard of death (HR, 0.86, 95% CI, 0.75-0.98; P = 0.031). When BPCV was analyzed as a continuous variable, an increasing number of bladder preservation cases per institute was also independently associated with improved OS (HR: 0.98, 95% CI, 0.97-0.99; P = 0.044). In the propensity score matched cohort, median OS of patients treated at high BPCV was 36.1 months (95% CI, 26.5-45.8) versus 28.1 months (95% CI, 23.9-32.3) for patients treated at a low BPCV facility (P = 0.016). Conclusions: In this observational cohort, treatment at a high BPCV facility was associated with improved OS. Causal factors for this finding may include greater institutional expertise in multidisciplinary bladder cancer care and potential advantages in treatment technology.

Trimodality Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer: Mansoura Experience

Background & objective: Bladder preservation therapy (BPT) using a trimodality approach represents an alternative option to cystectomy inmuscle-invasive bladder cancer (MIBC) patients, also a treatment option in non-cystectomy candidates. The objective of this study was to evaluate BPT using a trimodality approach composed of maximum TURBT, neoadjuvant chemotherapy, followed by chemoradiotherapy, regarding the overall survival (OS), progression free survival (PFS), locoregional progression free survival (LPFS) and treatment toxicity. Patients & methods: This prospective study involved 47 patients with pathologically proven MIBC (T2-T4a N0M0). The study involved muscle invasive bladder cancer patients who refused or were not cystectomycandidates. Patients enrolled received neoadjuvant 3cycles of Gemcitabine/Cisplatin, each cycle was every 21 days. Gemcitabine at 1000mg/m² on days 1&8 and cisplatin at 70mg/m² on day1, followed by Concurrent chemordiotherapy with cisplatin weekly (40mg/m2). Radiation therapy included the whole bladder by 3D conformal planning to a dose of 64Gy/32Fxs. Results: Of the 47 patients, 25 (53.2%) patients expressed complete response (CR), while 22(46.8%) patients had incomplete response. The 4-year OS, PFS, and LPFS rates were 48%, 38%, and 42%, respectively. Acute genitourinary (GU) toxicity of Grade 1 and 2 occurs in 54% and 24%of patients, respectively, while acute gastrointestinal (GI) toxicity (colic &diarrhea) of Grade 1 and 2 occurs in 27.7% and 10.6 %of patients, respectively. Conclusion: For MIBC patients who are non-cystectomy candidates, or who are motivated to maintain their bladders, trimodality bladder preservation therapy (BPT) can be considered as an effective alternative to radical cystectomy.

Comparative Effectiveness of Bladder-Preserving Tri-Modality Therapy versus Radical Cystectomy for Muscle-Invasive Bladder Cancer

Radical cystectomy (RC) has historically been considered the standard of care for muscle-invasive bladder cancer (MIBC). An alternative is trimodality therapy (TMT), a bladder-sparing approach that often achieves preservation of the native bladder. There are limited randomized data comparing these guideline-recommended approaches but, in appropriately selected patients, both are thought to have similar survival outcomes with different morbidity profiles. We therefore aim to compare the effectiveness of TMT and RC using decision-analytic modeling. We simulated the lifetime outcomes in 67-year-old patients with American Joint Committee on Cancer clinical Stage T2-T4aN0M0 MIBC. Competing treatment strategies were tri-modality therapy versus radical cystectomy +/- neoadjuvant chemotherapy. We used a Markov model to determine the incremental effectiveness in quality-adjusted life years (QALYs). Model probabilities and utilities were extracted from the literature. The effectiveness of each strategy was reported and sensitivity analyses were performed. For all MIBC patients, TMT was the most effective strategy with an incremental gain of 1.13 QALYs over RC (8.37 versus 7.24 QALYs, respectively). One-way sensitivity analyses demonstrated the model was most sensitive to the quality of life (QOL) parameters (i.e., the utilities) for RC and TMT; TMT was more effective than RC irrespective of the RC utility (the 95% confidence interval of the RC parameter demonstrated an incremental gain with TMT from 0.01to 4.77 QALYs). The model was relatively less sensitive to the probability of death for either strategy. Probabilistic sensitivity analysis demonstrated that TMT was more effective than RC for 75% of model iterations. When limiting the RC strategy to those with favorable, low-risk (clinical T2) MIBC, TMT remained the most effective strategy with an incremental gain of 0.61 QALYs over RC. Treatment of MIBC with organ-sparing TMT in appropriately selected patients may result in a gain of QALYs relative to RC. Further prospective investigation into the QOL implications of these treatment modalities is warranted.Abstract SU_22_2212; Table 1Effectiveness of RC compared to TMT.StrategyEV (LYs)IVEV (QALYs)IVTMT9.51-8.37-RC, all patients8.890.627.241.13RC, low-risk cohort9.340.177.760.61Abbreviations: EV = expected value; LY = life years; IV = incremental value; QALY = quality-adjusted life years. Open table in a new tab

Bladder Preserving Trimodality Therapy for Muscle-Invasive Bladder Cancer.

Here, we will review and summarize the current status and emerging data supporting the use of trimodality therapy as an alternative to cystectomy for patients with muscle-invasive bladder cancer. There are no randomized-controlled data comparing radical cystectomy with bladder preserving trimodality therapy available for comparison. However, observational data suggests acceptable bladder preservation and functional outcomes in patients receiving bladder preserving trimodality therapy as well as similar oncologic outcomes in select patients compared to radical cystectomy. Future trials are focusing on new techniques and novel therapeutics in patients with bladder cancer. Bladder preserving trimodality therapy results in satisfactory quality of life and comparable disease outcomes for select patients with muscle-invasive urothelial carcinoma of the bladder compared to cystectomy.

Comparative effectiveness of bladder-preserving tri-modality therapy versus radical cystectomy for muscle-invasive bladder cancer.

418 Background: Radical cystectomy (RC) has historically been considered the standard of care for muscle invasive bladder cancer (MIBC). An alternative is tri-modality therapy (TMT), a bladder-sparing approach that often achieves preservation of the native bladder. There are limited randomized data comparing these guideline-recommended approaches but, in appropriately selected patients, both are thought to have similar survival outcomes with different morbidity profiles. Therefore this study compared the effectiveness of TMT and RC using decision-analytic modeling with the primary endpoint of quality-adjusted life years (QALYs). Methods: We developed a Markov model simulating the lifetime outcomes for 67-year-old patients after definitive treatment for American Joint Committee on Cancer clinical Stage T2-T4aN0M0 MIBC using two strategies: TMT or RC +/- neoadjuvant chemotherapy (NAC). Probabilities and utilities were extracted from the literature to determine the incremental effectiveness in QALYs. Sensitivity analyses were performed. Results: TMT was the most effective strategy with an incremental gain of 1.13 QALYs over RC (8.37 versus 7.24 QALYs, respectively; Table). One-way sensitivity analyses demonstrated the model was most sensitive to the quality of life (QoL) parameters (i.e. the utilities) for RC and TMT; TMT was more effective than RC irrespective of the RC utility (the 95% confidence interval of the RC parameter demonstrated an incremental gain with TMT of 0.01 to 4.77 QALYs). The model was relatively less sensitive to the probability of death for either strategy. Probabilistic sensitivity analysis demonstrated that TMT was more effective than RC for 75% of model iterations. Conclusions: Treatment of MIBC with organ-sparing TMT in appropriately-selected patients may result in a gain of over 1 QALY relative to RC. Further prospective investigation into the QoL implications of these treatment modalities is warranted. [Table: see text]

Association of treatment facility case volume with survival in patients undergoing radiotherapy/chemoradiotherapy for muscle-invasive bladder cancer: An analysis of the National Cancer Database.

295 Background: Excellent outcomes with bladder-preserving trimodality therapy have been demonstrated at centers with expertise and high-volume. Some argue that these results may not be replicated at other centers with lower case volumes. We analyzed the National Cancer Database to determine if treatment at a high-volume facility is associated with improved overall survival (OS) for patients undergoing radiotherapy (RT) or chemoradiotherapy (CRT) for non-metastatic muscle-invasive bladder cancer (MIBC). Methods: Patients with cT2-4 N0-3 M0 transitional cell MIBC treated with RT or CRT were selected. The case volume variable was derived by calculating a count of patient records by each facility using the entire database of 439,188 patients. Multivariate analysis (MVA) was performed using the Cox proportional hazards model, which was used to assess the association of case volume with OS while controlling for clinicodemographic and treatment factors associated with OS on univariate analysis, including clustering of patients within their treatment facility type. Results: 872 patients treated with radiotherapy from 2008-2012 at 452 unique facilities were identified. 502 (58%) patients received RT, and 370 (42%) patients received CRT. The median case volume at each unique facility was 376 cases with an interquartile range of 235 – 579 cases. In the entire radiotherapy cohort, MVA controlling for patient case load, age, sex, education, T Stage, N Stage, cumulative radiotherapy dose, Charlson-Deyo comorbidity score, and geographic location, demonstrated that treatment at a facility with a higher case volume was associated with improved OS. For every 250 patient increase in facility case volume, the hazard of death at any given time for patients receiving radiotherapy decreased by 7% (HR = 0.93, 95% CI: 0.87 – 0.98, p = .01). Conclusions: To the authors’ knowledge, this is the first analysis demonstrating an association between treatment facility case volume and OS in the treatment of MIBC patients with RT or CRT. Consideration should be given to referring patients to high volume facilities for treatment of MIBC.

Long-term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience

BackgroundTri-modality therapy (TMT) is a recognized treatment strategy for selected patients with muscle-invasive bladder cancer (MIBC). ObjectiveReport long-term outcomes of patients with MIBC treated by TMT. Design, setting, and participantsFour hundred and seventy-five patients with cT2–T4a MIBC were enrolled on protocols or treated as per protocol at the Massachusetts General Hospital between 1986 and 2013. InterventionPatients underwent transurethral resection of bladder tumor followed by concurrent radiation and chemotherapy. Patients with less than a complete response (CR) to chemoradiation or with an invasive recurrence were recommended to undergo salvage radical cystectomy. Outcome measurements and statistical analysisDisease-specific survival (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results and limitationsMedian follow-up for surviving patients was 7.21 yr. Five- and 10-yr DSS rates were 66% and 59%, respectively. Five- and 10-yr OS rates were 57% and 39%, respectively. The risk of salvage cystectomy at 5 yr was 29%. In multivariate analyses, T2 disease (OS hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.44–0.75, DSS HR: 0.51, 95% CI: 0.36–0.73), CR to chemoradiation (OS HR: 0.61, 95% CI: 0.46–0.81, DSS HR: 0.49, 95% CI: 0.34–0.71), and presence of tumor-associated carcinoma in situ (OS HR: 1.56, 95% CI: 1.17–2.08, DSS HR: 1.50, 95% CI: 1.03–2.17) were significant predictors for OS and DSS. When evaluating our cohort over treatment eras, rates of CR improved from 66% to 88% and 5-yr DSS improved from 60% to 84% during the eras of 1986–1995 to 2005–2013, while the 5-yr risk of salvage radical cystectomy rate decreased from 42% to 16%. ConclusionsThese data demonstrate high rates of CR and bladder preservation in patients receiving TMT, and confirm DSS rates similar to modern cystectomy series. Contemporary results are particularly encouraging, and therefore TMT should be discussed and offered as a treatment option for selected patients. Patient summaryTri-modality therapy is an alternative to radical cystectomy for patients with muscle-invasive bladder cancer, and is associated with comparable long-term survival and high rates of bladder preservation.

Patterns of Bladder Preservation TherapyUtilization for Muscle-Invasive Bladder Cancer.

Background: Trimodality bladder preservation therapy (BPT) in muscle invasive bladder cancer (MIBC) includes a maximal transurethral resection followed by concurrent chemoradiotherapy as an alternative to radical cystectomy (RC) in appropriately selected patients, or as a treatment option in non-cystectomy candidates. Several chemotherapy regimens can be used in BPT, but little is known about current practice patterns.Objective: To describe utilization patterns of BPT and associated survival outcomes in MIBC.Methods: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3,024 consecutive patients from 29 international academic centers from 2005 to 2013. Patients with clinical T2-T4aN0M0 urothelial cancer of the bladder were included.Results: 265 patients received BPT. Compared with the 1,447 patients who received RC, BPT patients were older, had poorer performance status, and had more comorbidities (p < 0.01 for all). Median overall survival (OS) was similar for patients treated with curative radiation doses in BPT and patients treated with RC (41 vs 46 months, p = 0.33, respectively). 45% of BPT patients received concurrent chemotherapy with radiation. The most common regimens included cisplatin alone (23%), carboplatin alone (22%), gemcitabine alone (10%), paclitaxel alone (9%), and 5-FU+mitomycin (5%). There were no significant differences in survival among chemotherapy regimens. Only 10 patients (4% of BPT patients) underwent salvage cystectomy.Conclusions: In clinical practice, BPT patients have similar survival to RC patients when treated with curative radiotherapy doses. Choice of concurrent chemotherapy regimen varied widely with no clear standard. Salvage cystectomy is rarely performed. Continued research is needed on the comparative effectiveness among BPT and RC, and among chemotherapy regimens in BPT.

Patterns of chemotherapy administration in bladder preservation therapy (BPT) for muscle-invasive bladder cancer (MIBC).

4536Background: Trimodality BPT in MIBC includes a maximal transurethral resection followed by concurrent chemoradiotherapy as an alternative to cystectomy in appropriately selected patients, or as...