Efficacy of Platinum Rechallenge in Metastatic Urothelial Carcinoma After Previous Platinum-Based Chemotherapy for Metastatic Disease.

BACKGROUND: Fit patients with metastatic urothelial carcinoma (mUC) receive first-line platinum-based combination chemotherapy (fPBC) as standard of care and may receive additional later-line chemotherapy after progression. Our study compares outcomes with subsequent platinum-based chemotherapy (sPBC) versus subsequent non-platinum-based chemotherapy (sNPBC). MATERIALS AND METHODS: Patients from 27 international centers in the Retrospective International Study of Cancers of the Urothelium (RISC) who received fPBC for mUC and at least two cycles of subsequent chemotherapy were included in this study. A multivariable Cox proportional hazards model compared overall survival (OS) and progression-free survival (PFS). RESULTS: One hundred thirty-five patients received sPBC and 161 received sNPBC. Baseline characteristics were similar between groups, except patients who received sPBC had higher baseline hemoglobin, higher disease control rate with fPBC, and longer time since fPBC. OS was superior in the sPBC group (median 7.9 vs 5.5 months) in a model adjusting for comorbidity burden, performance status, liver metastases, number of fPBC cycles received, best response to fPBC, and time since fPBC (hazard ratio, 0.72; 95% confidence interval, 0.53-0.98; p = .035). There was no difference in PFS. More patients in the sPBC group achieved disease control than in the sNPBC group (57.4% vs 44.8%; p = .041). Factors associated with achieving disease control in the sPBC group but not the sNPBC group included longer time since fPBC, achieving disease control with fPBC, and absence of liver metastases. CONCLUSION: After receiving fPBC for mUC, patients who received sPBC had better OS and disease control. This may help inform the choice of subsequent chemotherapy in patients with mUC. IMPLICATIONS FOR PRACTICE: Patients with progressive metastatic urothelial carcinoma after first-line platinum-based combination chemotherapy may now receive immuno-oncology agents, erdafitinib, enfortumab vedotin, or sacituzumab govitecan-hziy; however, those ineligible for these later-line therapies or who progress after receiving them may be considered for subsequent chemotherapy. In this retrospective study of 296 patients, survival outcomes and disease control rates were better in those receiving subsequent platinum-based rechallenge compared with non-platinum-based chemotherapy, suggesting that patients should receive platinum rechallenge if clinically able. Disease control with platinum rechallenge was more likely with prior first-line platinum having achieved disease control, longer time since first-line platinum, and absence of liver metastases.

Optimal pathological response after neoadjuvant chemotherapy for muscle-invasive bladder cancer: results from a global, multicentre collaboration.

OBJECTIVES: To evaluate outcomes of patients achieving a post-treatment pathological stage of

Five-Factor Prognostic Model for Survival of Post-Platinum Patients with Metastatic Urothelial Carcinoma Receiving PD-L1 Inhibitors.

PURPOSE: A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the chemotherapy setting. MATERIALS AND METHODS: Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets. RESULTS: The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.

The Impact of Cisplatin- or Non-Cisplatin-Containing Chemotherapy on Long-Term and Conditional Survival of Patients with Advanced Urinary Tract Cancer.

BACKGROUND: The impact of cisplatin use on long-term survival of unselected patients with advanced urinary tract cancer (aUTC) has not been adequately investigated. We used a multinational database to study long-term survival and the impact of treatment type in unselected patients with aUTC. MATERIALS AND METHODS: A total of 1,333 patients with aUTC (cT4bN0M0, cTanyN+M0, cTanyNanyM+), transitional-cell, squamous, or adenocarcinoma histology who received systemic chemotherapy and had available survival data were selected. Long-term survival was defined as alive at 3 years following initiation of first-line chemotherapy. Conditional overall survival (COS) analysis was employed to study change in prognosis given time survived from initiation of first-line chemotherapy. RESULTS: Median follow-up was 31.7 months. The combination of cisplatin use and cisplatin eligibility accurately predicted long-term survival. Eligible patients treated with cisplatin conferred a 31.6% probability of 3-year survival (95% confidence interval [CI]: 25.1-38.3), and 2-year COS for patients surviving 3 years after initiation of cisplatin-based chemotherapy was 83% (95% CI: 59.7-93.5). The respective probabilities for patients who were ineligible for cisplatin or not treated with cisplatin despite eligibility were 14% (95% CI: 10.8-17.6) and 49.3% (95% CI: 28.2-67.4). Two-year COS remained significantly different between these two groups up to 3 years after chemotherapy initiation. CONCLUSION: Cisplatin-based therapy was associated with the highest likelihood of long-term survival in patients with aUTC and should be used in patients who fulfill the established eligibility criteria. Novel therapies are necessary to increase long-term survival in cisplatin-ineligible patients. IMPLICATIONS FOR PRACTICE: Long-term, disease-free survival is possible in one in four eligible-for-cisplatin patients with advanced urinary tract cancer (aUTC) treated with cisplatin-based combination chemotherapy. Therefore, deviations from eligibility criteria should be avoided. Consolidation surgery should be considered in responders. These data provide benchmarks for the study of novel therapies in aUTC.

Impact of the Number of Cycles of Platinum Based First Line Chemotherapy for Advanced Urothelial Carcinoma.

PURPOSE: We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma. MATERIALS AND METHODS: We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed. RESULTS: Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78-1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied. CONCLUSIONS: Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients.

Radical cystectomy or bladder preservation with radiochemotherapy in elderly patients with muscle-invasive bladder cancer: Retrospective International Study of Cancers of the Urothelial Tract (RISC) Investigators.

BACKGROUND: Radical cystectomy (RC) and radiochemotherapy (RCT) are curative options for muscle-invasive bladder cancer (MIBC). Optimal treatment strategy remains unclear in elderly patients. MATERIAL AND METHODS: Patients aged 80 years old and above with T2-T4aN0-2M0-Mx MIBC were identified in the Retrospective International Study of Cancers of the Urothelial Tract (RISC) database. Patients treated with RC were compared with those treated with RCT. The impact of surgery on overall survival (OS) was assessed using a Cox proportional hazard model. Progression included locoregional and metastatic relapse and was considered a time-dependent variable. RESULTS: Between 1988 and 2015, 92 patients underwent RC and 72 patients had RCT. Median age was 82.5 years (range 80-100) and median follow-up was 2.90 years (range 0.04-11.10). Median OS was 1.99 years (95%CI 1.17-2.76) after RC and 1.97 years (95%CI 1.35-2.64) after RCT (p = .73). Median progression-free survival (PFS) after RC and RCT were 1.25 years (95%CI 0.80-1.75) and 1.52 years (95%CI 1.01-2.04), respectively (p = .54). In multivariate analyses, only disease progression was significantly associated with worse OS (HR = 10.27 (95%CI 6.63-15.91), p < .0001). Treatment modality was not a prognostic factor. CONCLUSIONS: RCT offers survival rates comparable to those observed with RC for patients aged ≥80 years.

Pathological T0 following radical cystectomy with or without neoadjuvant chemotherapy: a useful surrogate.

PURPOSE: Several large, randomized, controlled trials provide evidence that neoadjuvant chemotherapy improves the outcome of radical cystectomy for muscle invasive urothelial bladder cancer. We analyzed the designs, methods and observations of these trials to identify patient subgroups that appeared most likely to benefit. We also identified distinguishing features compared to groups that did not achieve improved outcomes. MATERIALS AND METHODS: We analyzed initial and updated methods and results of the 4 main prospective trials of neoadjuvant chemotherapy (SWOG, Medical Research Council, and Nordic I and II) and subsequent meta-analyses. These series are the basis for advocating neoadjuvant chemotherapy in all patients with muscle invasive urothelial bladder cancer who undergo radical cystectomy. RESULTS: The greatest apparent benefit was seen in patients free of cancer at radical cystectomy (pT0). They had markedly improved overall and disease specific survival compared to patients with residual disease. However, improvements occurred regardless of whether there was down-staging from muscle invasive urothelial bladder cancer to pT0 after transurethral resection alone (controls) or after resection plus neoadjuvant chemotherapy. Thus, the major benefit of chemotherapy appeared to be that more patients achieved pT0. We also explored the study limitations that may have influenced outcomes and considered the potential for overtreatment in patients not likely to benefit from chemotherapy. Finally, we used risk stratification to create a decision tree model for selecting patients for neoadjuvant chemotherapy that could conceivably maximize oncologic outcome and minimize overtreatment. CONCLUSIONS: Patients with pT0 in the 4 main neoadjuvant chemotherapy trials and their subsequent meta-analyses experienced similar survival, far exceeding that in groups that did not achieve pT0. The benefit of neoadjuvant chemotherapy appears to be the larger number of cases than in the transurethral resection only group that were down-staged to pT0, suggesting that variables other than chemotherapy may have influenced outcomes. Therefore, strategies to selectively administer neoadjuvant chemotherapy to certain patients at risk have the potential to maintain improved bladder cancer outcomes while reducing overtreatment and its associated toxicity.

Using Circulating Tumor DNA To Guide Adjuvant Therapy in Bladder Cancer: IMvigor010 and IMvigor011.

Recent data from IMvigor010 impressively demonstrate the potential of circulating tumor DNA (ctDNA) as a prognostic and a predictive biomarker in patients with urothelial carcinoma. Although ctDNA status was prospectively assessed, the published data are only exploratory and require further prospective validation. Results from the IMvigor011 trial are therefore eagerly awaited.

Establishment and Evaluation of Dual HDAC/BET Inhibitors as Therapeutic Options for Germ Cell Tumors and Other Urological Malignancies.

Urological malignancies represent major challenges for clinicians, with annually rising incidences. In addition, cisplatin treatment induced long-term toxicities and the development of therapy resistance emphasize the need for novel therapeutics. In this study, we analyzed the effects of novel histone deacetylase (HDAC) and bromodomain and extraterminal domain-containing (BET) inhibitors to combine them into a potent HDAC-BET-fusion molecule and to understand their molecular mode-of-action. Treatment of (cisplatin-resistant) germ cell tumors (GCT), urothelial, renal, and prostate carcinoma cells with the HDAC, BET, and dual inhibitors decreased cell viability, induced apoptosis, and affected the cell cycle. Furthermore, a dual inhibitor considerably decreased tumor burden in GCT xenograft models. On a molecular level, correlating RNA- to ATAC-sequencing data indicated a considerable induction of gene expression, accompanied by site-specific changes of chromatin accessibility after HDAC inhibitor application. Upregulated genes could be linked to intra- and extra-cellular trafficking, cellular organization, and neuronal processes, including neuroendocrine differentiation. Regarding chromatin accessibility on a global level, an equal distribution of active or repressed DNA accessibility has been detected after HDAC inhibitor treatment, questioning the current understanding of HDAC inhibitor function. In summary, our HDAC, BET, and dual inhibitors represent a new treatment alternative for urological malignancies. Furthermore, we shed light on new molecular and epigenetic mechanisms of the tested epi-drugs, allowing for a better understanding of the underlying modes-of-action and risk assessment for the patient.

Impact of timing of adjuvant chemotherapy following radical cystectomy for bladder cancer on patient survival.

BACKGROUND: Trials of adjuvant chemotherapy following radical cystectomy generally require chemotherapy to start within 90 days postoperatively. However, it is unclear, whether the interval between surgery and start of adjuvant therapy (S-AC-interval) impacts the oncological outcome. METHODS: Using the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) data base, we identified patients who underwent radical cystectomy for muscle invasive bladder cancer and subsequent adjuvant chemotherapy. Univariate analysis of patient characteristics, surgical factors and tumor characteristics regarding their impact on S-AC-interval was performed using Kruskal-Wallis testing and Fisher's exact test. Analysis of progression-free (PFS) and overall survival (OS) (follow-up time beginning with the start date of adjuvant chemotherapy) was analyzed in relation to S-AC-interval (continuous and dichotomous with a cut-off at 90 days) using Kaplan-Meier method and COX regression analysis. RESULTS: We identified 238 eligible patients (83.5% male, mean age: 63.4 years, 76.1% T3/T4, 66.4% pN+, 14.7% R+, 70.6% urothelial carcinoma, 71% cisplatin-based adjuvant chemotherapy). The majority of patients (n = 207, 87%) started chemotherapy within 90 days after surgery. Median S-AC-interval was 57 days (interquartile range 32.8). S-AC-interval did not have consistent association with any patient/tumor characteristics or surgery related factors (type of surgery, urinary diversion). Survival analysis using continuous S-AC-interval revealed a trend toward an impact of S-AC-interval on OS (hazard ratio 1.004, 95% confidence ratio 0.9997-1.0084, P = 0.071). With regards to PFS, that impact was shown to be statistically significant (hazard ratio 1.004, 95% confidence ratio 1.0003-1.0075, P = 0.032). In multivariate analysis, however, S-AC-interval was negated by tumor and patient related factors (pathological T-stage, N-stage, ECOG performance status). Accounting for eligibility criteria defined in some clinical trials, we extended our analysis dividing S-AC-interval in ≤90 and >90 days. Although we could confirm the trend toward better outcome in patients with a shorter S-AC interval in dichotomous analysis, neither differences in OS nor in PFS reached statistical significance (P = 0.438 and P = 0.056). CONCLUSIONS: In a large multi-institutional experience, 87% of patients who received adjuvant chemotherapy received it within the guideline recommended window of 90 days. While it was not possible to determine whether this is the optimal cut-off, early start of adjuvant chemotherapy seems to be reasonable. Regarding prognosis, tumor-related pathological factors abrogated the importance of the S-AC-interval in our analysis.

Lack of Effectiveness of Postchemotherapy Lymphadenectomy in Bladder Cancer Patients with Clinical Evidence of Metastatic Pelvic or Retroperitoneal Lymph Nodes Only: A Propensity Score-based Analysis.

BACKGROUND: Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma. OBJECTIVE: To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic±RP) only, first-line platinum-based chemotherapy given. INTERVENTION: LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation. RESULTS AND LIMITATIONS: Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p=0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p=0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations. CONCLUSIONS: Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials. PATIENT SUMMARY: We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies.

Venous Thromboembolism Risk in Patients With Locoregional Urothelial Tract Tumors.

BACKGROUND: Venous thromboembolism (VTE) is common in cancer patients, but there is limited data on patients with urothelial tract tumors (UTT). We previously identified several associative factors for increased VTE rates in patients with metastatic UTT. In this study, we assessed the frequency, associative factors, and impact on survival of VTE in patients with locoregional UTT. METHODS: Patients with locoregional bladder, upper urinary tract, or urethral cancer were included in this multi-center study from 29 academic institutions. Patients with < cT2, > N1, or M1 disease at diagnosis were excluded. Patients with incomplete clinical staging or miscoded/missing data were excluded. Cumulative, unadjusted VTE incidence was calculated from time of diagnosis of muscle-invasive disease, excluding VTEs diagnosed in the metastatic setting. χ2 statistics tested differences in VTE rates across baseline and treatment-related factors. Significant covariates were incorporated into a multivariate, logistic regression model. Overall survival stratified by VTE was estimated using Kaplan-Meier methods and evaluated using the log-rank test. RESULTS: A total of 1732 patients were eligible. There were 132 (7.6%) VTEs. On multivariate analysis, non-urothelial histology (P < .001), clinical Nx stage (P < .001), cardiovascular disease (P = .01), and renal dysfunction (P = .04) were statistically significant baseline factors associated with VTE. Using surgery alone as reference, surgery with perioperative chemotherapy (P = .04) and radiation with concurrent chemotherapy (P = .04) also were significant. CONCLUSIONS: The VTE incidence of 7.6% in locoregional disease is comparable with our previously reported rate in the metastatic setting (8.2%). Similar to our findings in metastatic UTT, non-urothelial histology, renal dysfunction, and CVD was associated with increased VTE risk.

Venous thromboembolism in metastatic urothelial carcinoma or variant histologies: incidence, associative factors, and effect on survival.

Venous thromboembolism (VTE) is common in cancer patients. However, little is known about VTE risk in metastatic urothelial carcinoma or variant histologies (UC/VH). We sought to characterize the incidence, associative factors, including whether various chemotherapy regimens portend different risk, and impact of VTE on survival in metastatic UC/VH patients. Patients diagnosed with metastatic UC/VH from 2000 to 2013 were included in this multicenter retrospective, international study from 29 academic institutions. Cumulative and 6-month VTE incidence rates were determined. The association of first-line chemotherapy (divided into six groups) and other baseline characteristics on VTE were analyzed. Each chemotherapy treatment group and statistically significant baseline clinical characteristics were assessed in a multivariate, competing-risk regression model. VTE patients were matched to non-VTE patients to determine the impact of VTE on overall survival. In all, 1762 patients were eligible for analysis. There were 144 (8.2%) and 90 (5.1%) events cumulative and within the first 6 months, respectively. VTE rates based on chemotherapy group demonstrated no statistical difference when gemcitabine/cisplatin was used as the comparator. Non-urotheilal histology (SHR: 2.67; 95% CI: 1.72-4.16, P < 0.001), moderate to severe renal dysfunction (SHR: 2.12; 95% CI: 1.26-3.59, P = 0.005), and cardiovascular disease (CVD) or CVD risk factors (SHR: 2.27; 95% CI: 1.49-3.45, P = 0.001) were associated with increased VTE rates. Overall survival was worse in patients with VTE (median 6.0 m vs. 10.2 m, P < 0.001). Thus, in metastatic UC/VH patients, VTE is common and has a negative impact on survival. We identified multiple associated potential risk factors, although different chemotherapy regimens did not alter risk.

Quality of life in patients with cisplatin-resistant urothelial cancer: Typical ailments and effect of paclitaxel-based salvage therapy.

INTRODUCTION: Efficacy of palliative second-line treatment in patients suffering from advanced urothelial cancer (aUC) is limited. Accordingly, careful observation of patient-reported and treatment-related changes of quality of life (QoL) is mandatory. Therefore, we evaluated "typical" ailments and treatment related QoL changes in these patients. PATIENTS AND METHODS: Results of the EORTC QLQ-C30 questionnaire were reviewed in 129 patients included in 2 prospective trials on paclitaxel-based treatment of cisplatin-resistant aUC (gemcitabine/paclitaxel: 102 patients [AB 20/99]; paclitaxel/everolimus: 27 patients [AB 35/09]). Eligible patients had completed EORTC QLQ-C30 questionnaire questionnaire before treatment start and available data on response. Global health status (QL), functional scales (FuSc) and symptom scales (SySc) were compared with published normative data for patients suffering from metastatic/recurrent cancers. Treatment related changes of QoL were evaluated. For statistical evaluation 2-way analysis of variance was used. RESULTS: A total of 87 patients were eligible (63 men and 24 women, median age = 65 [interquartile range: 60-71]y, AB 20/99: 63 patients [72%], AB 35/09: 24 patients [28%]). Compared with metastatic/recurrent cancers normative data, impaired emotional FuSc (-11.6 [95% CI:-21.0 to-2.1] points, P<0.01) and higher pain SySc (+12.9 [CI: 3.7-22.1] points, P<0.001) were the most relevant differences. QL and further FuSc/SySc were comparable. Pain SySc was significantly lower after 3 (-15.8 [CI:-31.4 to-0.7] points, P<0.01] and 4 cycles (-13.6 [CI:-29.2-2.1] points, P<0.05). Further changes of QL, FuSc or SySc during treatment were not observed. QL, FuSc, and SySc at baseline and during treatment did not differ between responders and nonresponders. CONCLUSIONS: Patients with aUC who received additional treatment demonstrated QoL changes similar to persons with other recurrent/metastatic cancers. Special emphasis should be attributed to pain and emotional problems. Despite treatment related side effects, patients did not report impairment of QoL.

Single-agent Taxane Versus Taxane-containing Combination Chemotherapy as Salvage Therapy for Advanced Urothelial Carcinoma.

BACKGROUND: Single-agent taxanes are commonly used as salvage systemic therapy for patients with advanced urothelial carcinoma (UC). OBJECTIVE: To study the impact of combination chemotherapy delivering a taxane plus other chemotherapeutic agents compared with single-agent taxane as salvage therapy. DESIGN, SETTING, AND PARTICIPANTS: Individual patient-level data from phase 2 trials of salvage systemic therapy were used. INTERVENTIONS: Trials evaluating either single agents (paclitaxel or docetaxel) or combination chemotherapy (taxane plus one other chemotherapeutic agent or more) following prior platinum-based therapy were used. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Information regarding the known major baseline prognostic factors was required: time from prior chemotherapy, hemoglobin, performance status, albumin, and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of prognostic factors and combination versus single-agent chemotherapy with overall survival (OS). RESULTS AND LIMITATIONS: Data were available from eight trials including 370 patients; two trials (n=109) evaluated single-agent chemotherapy with docetaxel (n=72) and cremophor-free paclitaxel (n=37), and six trials (n=261) evaluated combination chemotherapy with gemcitabine-paclitaxel (two trials, with n=99 and n=24), paclitaxel-cyclophosphamide (n=32), paclitaxel-ifosfamide-nedaplatin (n=45), docetaxel-ifosfamide-cisplatin (n=26), and paclitaxel-epirubicin (n=35). On multivariable analysis after adjustment for baseline prognostic factors, combination chemotherapy was independently and significantly associated with improved OS (hazard ratio: 0.60; 95% confidence interval, 0.45-0.82; p=0.001). The retrospective design of this analysis and the trial-eligible population were inherent limitations. CONCLUSIONS: Patients enrolled in trials of combination chemotherapy exhibited improved OS compared with patients enrolled in trials of single-agent chemotherapy as salvage therapy for advanced UC. Prospective randomized trials are required to validate a potential role for rational and tolerable combination chemotherapeutic regimens for the salvage therapy of advanced UC. PATIENT SUMMARY: This retrospective study suggests that a combination of chemotherapy agents may extend survival compared with single-agent chemotherapy in selected patients with metastatic urothelial cancer progressing after prior chemotherapy.

Cisplatin- Versus Non-Cisplatin-based First-Line Chemotherapy for Advanced Urothelial Carcinoma Previously Treated With Perioperative Cisplatin.

INTRODUCTION: The optimal choice of first-line chemotherapy for patients with relapse of urothelial carcinoma (UC) after perioperative cisplatin-based chemotherapy (PCBC) is unclear. We investigated the outcomes with cisplatin rechallenge versus a non-cisplatin regimen in patients with recurrent metastatic UC after PCBC in a multicenter retrospective study. PATIENTS AND METHODS: Individual patient-level data were collected for patients who had received various first-line chemotherapy regimens for advanced UC after previous PCBC. Cox proportional hazards models were used to investigate the prognostic ability of the type of perioperative and first-line chemotherapy to independently affect overall survival (OS) and progression-free survival (PFS) after accounting for known prognostic factors. RESULTS: Data were available for 145 patients (12 centers). The mean age was 62 years; the Eastern Cooperative Oncology Group (ECOG) performance status (PS) was > 0 for 42.0% of the patients. Of the 145 patients, 63% had received cisplatin-based first-line chemotherapy. The median time from previous chemotherapy (TFPC) was 6.2 months (range, 1-154 months). The median OS was 22 months (95% confidence interval [CI], 18-27 months), and the median PFS was 6 months (95% CI, 5-7 months). A better ECOG PS and a longer TFPC (> 12 months vs. ≤ 12 months; hazard ratio [HR], 0.32; 95% CI, 0.20-0.52; P < .001) was prognostic for OS and PFS. Cisplatin-based chemotherapy was associated with poor OS (HR, 1.86; 95% CI, 1.13-3.06; P = .015), which appeared to be pronounced in those patients with a TFPC of ≤ 12 months. Retreatment with cisplatin in the first-line setting was associated with worse OS (HR, 3.38; P < .001). CONCLUSION: The results of the present retrospective analysis suggest that for patients who have undergone previous PCBC for UC, rechallenging with cisplatin might confer a poorer OS, especially for those with progression within < 1 year.

Patterns of Bladder Preservation Therapy Utilization 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.

Cisplatin-based first-line therapy for advanced urothelial carcinoma after previous perioperative cisplatin-based therapy.

BACKGROUND: Outcomes with cisplatin-based first-line therapy for advanced UC after previous perioperative cisplatin-based chemotherapy are unclear. In this study we evaluated outcomes with a focus on the effect of time from previous cisplatin-based perioperative chemotherapy. PATIENTS AND METHODS: Data were collected for patients who received cisplatin-based first-line therapy for advanced UC after previous perioperative cisplatin-based therapy. Cox proportional hazards models were used to investigate the prognostic ability of visceral metastasis, ECOG PS, TFPC, anemia, leukocytosis, and albumin on overall survival (OS). RESULTS: Data were available for 41 patients from 8 institutions including 31 men (75.6%). The median age was 61 (range, 41-77) years, most received gemcitabine plus cisplatin (n = 26; 63.4%), and the median number of cycles was 4 (range, 1-8). The median OS was 68 weeks (95% confidence interval [CI], 48.0-81.0). Multivariable Cox regression analysis results showed an independent prognostic effect on OS for PS > 0 versus 0 (hazard ratio [HR], 4.56 [95% CI, 1.66-12.52]; P = .003) and TFPC ≥ 78 weeks versus < 78 weeks (HR, 0.48 [95% CI, 0.21-1.07]; P = .072). The prognostic model for OS was internally validated with c-index = 0.68. Patients with TFPC < 52 weeks, 52 to 104 weeks, and ≥ 104 weeks had median survival of 42, 70, and 162 weeks, respectively. CONCLUSION: Longer TFPC ≥ 78 weeks and ECOG PS = 0 were independently prognostic for better survival with cisplatin-based first-line chemotherapy for advanced UC after previous perioperative cisplatin-based chemotherapy. The data support using TFPC ≥ 52 weeks to rechallenge with cisplatin-based first-line chemotherapy for metastatic disease.

Complete response as an intermediate end point in patients receiving salvage systemic therapy for urothelial carcinoma.

BACKGROUND: The complete remission (CR) rate with salvage systemic therapy for urothelial carcinoma (UC) is unclear, and its value as an intermediate end point and association with survival are unknown. MATERIALS AND METHODS: Data from phase II trials of salvage chemotherapy and/or biologic agents were pooled. Data regarding response, overall survival (OS), progression-free survival (PFS), time from prior chemotherapy, hemoglobin, performance status, and liver metastasis status were collected. Cox proportional hazards regression was used to evaluate the association of CR and other prognostic factors with outcomes. RESULTS: A total of 789 of 818 patients enrolled in 12 phase II trials had evaluable data. CR and partial response were seen in 14 (1.8%) and 109 (13.8%) patients. Median (95% confidence interval) OS for those with a CR was 21.5 (14.2-34.3) months, compared with 6.7 (6.0-7.0) months in those without a CR (P < .001). Median (95% confidence interval) PFS for those with a CR was 15.7 (8.2-27.1) months, compared with 2.6 (2.4-2.8) months for those without a CR (P < .001). Prior cisplatin and time from prior chemotherapy of ≥ 3 months were associated with CR (P < .05). The presence of poor prognostic factors and suboptimal response to prior therapy did not preclude CR. CONCLUSION: CR occurs in 1.8% of patients receiving salvage therapy for advanced UC and is strongly associated with durable OS and PFS. CR warrants validation as an intermediate end point and may help select agents for further investigation and tumors for molecular interrogation.

Six-month progression-free survival as the primary endpoint to evaluate the activity of new agents as second-line therapy for advanced urothelial carcinoma.

OBJECTIVE: Second-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents. METHODS: Ten second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction. RESULTS: In the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R(2) = 0.55, Pearson correlation = 0.66) and individual levels (82%, Қ = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Қ = 0.36), and the trial level association was not statistically significant (R(2) = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Қ = 0.44) appeared stronger than the correlation of response (76%, Қ = 0.17) with OS12 in the external validation dataset. CONCLUSIONS: PFS6 is strongly associated with OS12 and appears more optimal than RR to identify active second-line agents for advanced UC.