Search

Objectives: To compare clinical outcomes with programmed-death ligand-1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation therapy (RT) prior to developing metastatic disease., Patients and Methods: We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate [ORR], progression-free survival [PFS], overall survival [OS]) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first-line and second-line or greater [second-plus line]). Logistic regression was used to compare ORR, while Kaplan-Meier analysis and Cox regression were used for PFS and OS. Multivariable models were adjusted for known prognostic factors., Results: We included 562 patients (first-line: 342 and second-plus line: 220). There was no difference in outcomes based on prior locoregional treatment among those treated with first-line ICIs. In the second-plus-line setting, prior RS was associated with higher ORR (adjusted odds ratio 2.61, 95% confidence interval [CI]1.19-5.74]), longer OS (adjusted hazard ratio [aHR] 0.61, 95% CI 0.42-0.88) and PFS (aHR 0.63, 95% CI 0.45-0.89) vs no prior RS. This association remained significant when type of prior locoregional treatment (RS and RT) was modelled separately., Conclusion: Prior RS before developing advanced disease was associated with better outcomes in patients with aUC treated with ICIs in the second-plus-line but not in the first-line setting. While further validation is needed, our findings could have implications for prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include the study's retrospective nature, lack of randomization, and possible selection and confounding biases., (© 2022 BJU International.)

Objectives: To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint inhibitors (ICIs)., Patients and Methods: We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni- and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line)., Results: Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.43-1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio [aHR] 0.93, 95% CI 0.73-1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81-1.27). Patients with mixed-histology UTUC had a significantly lower ORR and shorter PFS vs mixed-histology LTUC (aOR 0.20, 95% CI 0.05-0.91 and aHR 1.66, 95% CI 1.06-2.59), respectively)., Conclusion: Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed-histology UTUC had a lower ORR and shorter PFS compared to mixed-histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy., (© 2021 The Authors BJU International © 2021 BJU International Published by John Wiley & Sons Ltd.)

Objective: To examine the incidence of perioperative complications after radical cystectomy (RC) and assess their impact on 90-day postoperative mortality during the index stay and upon readmission., Patients and Methods: A total of 57 553 patients with bladder cancer (unweighted cohort: 9137 patients) treated with RC, at 360 hospitals in the USA between 2005 and 2013 within the Premier Healthcare Database, were used for analysis. The 90-day perioperative mortality was the primary outcome. Multivariable regression was used to predict the probability of mortality; models were adjusted for patient, hospital, and surgical characteristics., Results: An increase in the number of complications resulted in an increasing predicted probability of mortality, with a precipitous increase if patients had four or more complications compared to one complication during hospitalisation following RC (index stay; 1.0-9.7%, P < 0.001) and during readmission (2.0-13.1%, P < 0.001). A readmission complication nearly doubled the predicted probability of postoperative mortality as compared to an initial complication (3.9% vs 7.4%, P < 0.001). During the initial hospitalisation cardiac- (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.9-5.1), pulmonary- (OR 4.8, 95% CI 2.8-8.4), and renal-related (OR 3.6, 95% CI 2-6.7) complications had the most significant impact on the odds of mortality across categories examined., Conclusions: The number and nature of complications have a distinct impact on mortality after RC. As complications increase there is an associated increase in perioperative mortality., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Objectives: To assess treatment patterns and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy or antiandrogen therapy., Patients and Methods: Patients initiating first-line antiandrogen therapy (abiraterone, enzalutamide) or chemotherapy (taxane) between October 2012 and September 2014 were retrospectively identified in the US Veterans Health Administration database. The impact of antiandrogen therapy vs chemotherapy on overall survival (OS) and time to discontinuation was assessed using Cox proportional hazard models, adjusting for prior androgen deprivation therapy (ADT) duration and available prognostic factors., Results: Overall, 1445 patients were evaluable, of whom 1108 received antiandrogen therapy and 337 received chemotherapy (docetaxel). On multivariable analysis and propensity score analysis, the OS times for antiandrogen therapy vs chemotherapy were not significantly different (hazard ratio [HR] 1.041, 95% confidence interval (CI) 0.853-1.270, P = 0.694, and HR 1.047, 95% CI 0.861-1.273, P = 0.644, respectively). Time to discontinuation was shorter for chemotherapy vs antiandrogen therapy (HR 2.339, 95% CI 1.969-2.779; P < 0.001). Prior ADT duration above the median was associated with longer OS (HR 0.566, 95% CI 0.464-0.690; P < 0.001) and time to discontinuation (HR 0.831, 95% CI 0.699-0.988; P = 0.036) in the antiandrogen therapy cohort and not the chemotherapy cohort, while prior ADT duration below the median was associated with higher prostate specific antigen (PSA) response rate in the chemotherapy vs antiandrogen therapy cohort (61.5% vs 51.1%; P = 0.024). The treatment-free interval after discontinuation was longer after first-line chemotherapy vs antiandrogen therapy (mean 53 vs 39 days; P = 0.030)., Conclusion: After adjusting for key prognostic factors in this large mCRPC dataset, the OS was similar for first-line chemotherapy vs antiandrogen therapy despite shorter time to discontinuation with chemotherapy and longer treatment-free interval after first-line chemotherapy. These hypothesis-generating data also suggest that duration of prior ADT may assist in the selection of patients for chemotherapy vs antiandrogen therapy., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Objective: To study the subsequent therapy and disease outcomes of patients with advanced urothelial carcinoma (UC) after discontinuation of programmed death-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors., Patients and Methods: We performed a retrospective analysis to examine outcomes and systemic therapy administration after PD-1/PD-L1 inhibitor therapy in patients with advanced UC. Data on demographics and therapy administered were collected from the institutions involved in the study. Univariable Cox regression analyses were performed to examine the clinical factors potentially associated with overall survival (OS) after PD-1/PD-L1 inhibitor therapy., Results: Data from 62 patients were available from four institutions, with capture of subsequent therapy and outcomes after checkpoint inhibitor immunotherapy. The median patient age was 65.5 years and 51 patients (82.3%) were male. The median (range) duration of PD-1/PD-L1 inhibitor therapy in 55 patients for whom these data were available was 64 (7-669) days. Of these, 22 patients (35.5%) received post-PD-1/PD-L1 inhibitor therapy through a variety of different chemotherapy regimens (n = 16), chemobiological combination (n = 1), biological agents (n = 4) and immunotherapy (n = 1). The median (range) time from last PD-1/PD-L1 inhibitor therapy to subsequent therapy was 58 (14-242) days. The median OS of all patients after completion of PD-1/PD-L1 inhibitor therapy was 149 days (95% confidence interval [CI]: 75-359). Among those who received some post-PD-1/PD-L1 inhibitor therapy, the median OS was 182 days (95% CI: 121-372), and the median time to progression was 124 days (95% CI: 61-273) from the start of post-PD-1/PD-L1 therapy. Among these 22 patients, the only significant baseline prognostic factor associated with OS was performance status., Conclusions: In this dataset, 35.5% of patients with advanced UC received systemic therapy after salvage therapy with PD-1/PD-L1 inhibitors. Outcomes after subsequent therapy appear similar to those historically observed in patients who had not received prior PD-1/PD-L1 inhibitor therapy. Further study of patients receiving post-PD-1/PD-L1 inhibitor therapy is warranted to identify factors associated with outcomes and potentially synergistic sequences., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

For several years, docetaxel was the only treatment shown to improve survival of patients with metastatic castration-resistant prostate cancer (mCRPC). There are now several novel agents available, although chemotherapy with docetaxel and cabazitaxel continues to play an important role. However, the increasing number of available agents will inevitably affect the timing of chemotherapy and therefore it may be important to offer this approach before declining performance status renders patients ineligible for chemotherapy. Patient selection is also important to optimise treatment benefit. The role of predictive biomarkers has assumed greater importance due to the development of multiple agents and resistance to available agents. In addition, the optimal sequence of treatments remains undefined and requires further study in order to maximize long-term outcomes. We provide an overview of the clinical data supporting the role of chemotherapy in the treatment of mCRPC and the emerging role in metastatic castration-sensitive prostate cancer. We review the key issues in the management of patients including selection of patients for chemotherapy, when to start chemotherapy, and how best to sequence treatments to maximise outcomes. In addition, we briefly summarise the promising new chemotherapeutic agents in development in the context of emerging therapies., (© 2014 The Authors BJU International © 2014 BJU International Published by John Wiley & Sons Ltd.)

Objective: To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons., Results: An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review., Conclusions: Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints., (© 2013 The Authors. BJU International © 2013 BJU International.)

Objective: To study the impact of the prognostic factors liver metastasis (LM), anaemia (haemoglobin [Hb] <10 g/dL), Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥1 and time from previous chemotherapy (TFPC) on the activity of second-line therapy for advanced urothelial carcinoma (UC)., Patients and Methods: Twelve phase II trials evaluating second-line chemotherapy and/or biological characteristics (n = 748) in patients with progressive disease were pooled. Progression-free survival (PFS) was defined as tumour progression or death from any cause. The PFS rate at 6 months (PFS6) was defined from the date of registration and calculated using the Kaplan-Meier method. Response rate (RR) was defined using Response Evaluation Criteria in Solid Tumours (RECIST) 1.0. A nomogram predicting PFS6 was constructed using the rms software package in R (http://www.r-project.org)., Results: Data regarding progression, anaemia, LM, ECOG-PS and TFPC were available from 570 patients in nine phase II trials. The overall median PFS was 2.7 months, PFS6 was 22.2% (95% confidence interval 18.8-25.9) and the RR was 17.5% (95% CI: 14.5-20.9%). For every unit increase in risk group, the hazard of progression in 6 months increased by 41% and the odds of response decreased by 48%. A nomogram was constructed to predict PFS6 on an individual patient level. The model was internally validated and was shown to have acceptable calibration performance., Conclusions: The RR and PFS6 vary as a function of baseline prognostic factors in patients receiving second-line therapy for advanced UC. A nomogram incorporating prognostic factors facilitates the evaluation of outcomes across phase II trials enrolling heterogeneous populations and helps select suitable agents for phase III testing., (© 2013 The Authors. BJU International © 2013 BJU International.)

Objective: To determine the outcomes of patients with final pathological stage T1N0 disease after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) and to determine whether lymphovascular invasion (LVI) is an independent predictor of prognosis in these patients., Patients and Methods: Records of 958 consecutive patients who underwent RC at three academic centres were reviewed. A total of 101 patients with negative lymph nodes and with final stage (the higher of the pre-RC clinical/transurethral resection [TUR] and post-RC pathological stages) T1 UCB were identified. The median (range) follow-up was 38 (0.4-177) months and the median (range) number of nodes examined was 19 (9-80)., Results: Overall, 12/101 (11.9%) patients experienced cancer recurrence and 7/101 (6.9%) died from their cancer. The 3-year recurrence-free survival probability (SD) was 0.89 (0.04) and 3-year cancer-specific survival probability (SD) was 0.96 (0.02). Six of 101 (6%) patients had LVI, of whom four experienced disease recurrence and three died from bladder cancer. All recurrences and deaths occurred in patients who had either LVI and/or concomitant carcinoma in situ. On multivariable analysis, LVI (hazard ratio [HR] 4.9, P = 0.01) and higher pathological stage (HR 8.5, P = 0.04) predicted cancer recurrence and LVI (HR 6.7, P = 0.01) predicted cancer-specific survival., Conclusions: LVI helps identify patients with final pathological T1N0 UCB who are at significantly increased risk of bladder cancer recurrence and death. These patients should be considered for close monitoring after cystectomy., (© 2012 BJU International.)

Unlabelled: What's known on the subject? and What does the study add? Metastatic or locally advanced squamous cell carcinoma of the penis (SCCP) is generally incurable, but it can be palliated with systemic chemotherapy. Two retrospective studies, involving <10 patients each, showed that cisplatin plus continuous infusion of 5-fluorouracil (5-FU) may be effective and well tolerated. Cisplatin, methotrexate and bleomycin, cisplatin and irinotecan and taxanes can also play an important role for patients with locally advanced/metastatic SCCP. Finally, anti-EGFR therapy may also be effective in advanced SCCP. Although cisplatin plus continuous infusion of 5-FU is widely used in clinical practice for palliation of SCCP, toxicity and efficacy data regarding this schedule include a total of 14 patients with SCCP, treated more than two decades ago. In our retrospective study, cisplatin plus continuous infusion of 5-FU was used for palliative purposes in a homogenous sample of 25 patients with SCCP. Partial responses and stable disease were observed in 8 (32%) and 10 (40%) patients, respectively, with a median progression-free survival of 20 weeks. Neutropenia was the most important grade 3-4 side effect observed, occurring in 20% of patients. These data provide confirmation that such a combination regimen is moderately effective and well tolerated in patients with SCCP., Objective: • To investigate the activity and toxicity of 5-fluorouracil (5-FU) as a first-line treatment in metastatic squamous cell carcinoma of the penis (SCCP)., Methods: • The medical records of 78 patients with SCCP treated between January 2000 and June 2011 at the four participating centres were reviewed. • Data regarding patients treated with first-line 5-FU were extracted. • Patients were included in the study if radiological reports were available for determination of response and progression-free survival (PFS) according to response evaluation criteria in solid tumours (RECIST) 1.1., Results: • Between January 2000 and June 2011, 25 patients were treated with i.v. cisplatin on day 1 followed by 5-FU as a continuous 24-h infusion for 4 days every 3 weeks until disease progression or unacceptable toxicity. Partial responses and stable disease were observed in eight (32%) and 10 (40%) patients, respectively, with a disease control rate of 72%. • Severe neutropenia was the most important grade 3-4 side effect observed, occurring in 20% of patients. • The median (interquartile range [IQR]) PFS was 20 (11-20) weeks and the median (IQR) overall survival (OS) was 8 (7-12) months., Conclusion: • 5-FU is associated with a moderate response rate and is well tolerated in patients with metastatic SCCP., (© 2012 BJU INTERNATIONAL.)

Unlabelled: What's known on the subject? and What does the study add? Serum C-reactive protein (C-reactive protein) is emerging as a potential novel prognostic factor in metastatic castration-resistant prostate cancer (mCRPC). In the present study, a prospective trial was investigated retrospectively and a significant prognostic impact for C-reactive protein that was independent of multiple published prognostic models was identified in men receiving docetaxel-based chemotherapy for mCRPC. Prospective validation is warranted., Objective: • Given the recent emergence of C-reactive protein levels as a novel prognostic factor in men with metastatic castration-resistant prostate cancer (mCRPC), we sought to evaluate the independent prognostic ability of C-reactive protein in the context of published prognostic nomograms, risk grouping and disease state models in men receiving docetaxel-based chemotherapy for mCRPC., Patients and Methods: • A large randomized phase II trial (CS-205) of mCRPC patients who received docetaxel-prednisone + AT-101 (Bcl-2 inhibitor) or docetaxel-prednisone + placebo was analyzed retrospectively (n= 220). • Overall survival (OS), progression-free survival (PFS) and measures of discriminatory ability were assessed in a hypothesis-generating analysis using Cox regression and concordance probabilities. • Patients from both treatment groups were combined for this analysis because no significant differences in outcomes were observed. • Because some factors used in nomograms were not collected or defined differently, risk was estimated based on slightly modified versions of nomograms., Results: • C-reactive protein was independently prognostic for OS and PFS (P ≤ 0.002) after adjusting for all modeled risk estimates and classifiers. • C-reactive protein showed a concordance probability of 0.65 for both OS and PFS. • A 10-factor modified prognostic model based on the TAX327 trial had the greatest observed discrimination ability for OS and PFS (concordance probability = 0.623 and 0.603, respectively) among the modified nomograms or classifiers. • Adding the TAX327 model risk estimates to C-reactive protein did not substantially increase discrimination ability over C-reactive protein alone., Conclusions: • Current prognostic classifications provide modest discrimination of outcomes in mCRPC receiving docetaxel-based chemotherapy, highlighting the need for improved risk-based models. • Baseline C-reactive protein appears to be an useful, independent prognostic factor and prospective external validation is warranted., (© 2012 BJU INTERNATIONAL.)

Objective: • To stratify risk of pathological (p) T2N0 urothelial carcinoma of the bladder after radical cystectomy (RC) based on pathological factors to facilitate the development of adjuvant therapy trials for high-risk patients., Patients and Methods: • The study comprised 707 patients from a database of patients with pT2N0 urothelial carcinoma of the bladder who had undergone RC and not received perioperative chemotherapy. • The effect of residual pT-stage at RC, age, grade, lymphovascular invasion and number of lymph nodes removed on recurrence-free survival was evaluated using Cox regression analyses. A weighted prognostic model was devised with significant variables., Results: • The median follow up was 60.9 months. In multivariable analyses, residual disease at RC (pT2a: hazard ratio (HR) 1.740, P = 0.03; for pT2b: HR 3.075, P < 0.001; both compared with

Neoadjuvant cisplatin-based combined chemotherapy is an established standard for muscle-invasive bladder cancer and pathological complete remission is an excellent intermediate surrogate endpoint for survival. Phase III trials are ongoing to elucidate the role of neoadjuvant combined androgen deprivation and docetaxel-based chemotherapy for localized high-risk prostate cancer. Neoadjuvant therapy with biological agents targeting angiogenesis preceding cytoreductive nephrectomy for metastatic renal cell carcinoma is a novel approach, although ongoing randomized trials are validating this paradigm and attempting to establish the timing and necessity of cytoreductive nephrectomy. Neoadjuvant trials provide a window of opportunity to evaluate and screen novel agents for biological activity by using brief therapy preceding surgery and provide a rationale to further develop the most promising agents in larger trials. The neoadjuvant therapy approach followed by surgery is acceptable and feasible with a wide array of agents in urological cancers and provides a paradigm for evaluating the activity, mechanism of action and resistance to new treatments. Urological cancers are initially characterized by localized presentation in the vast majority of cases, coupled with a substantial risk of distant relapses following surgical resection. Therefore, the paradigm of neoadjuvant therapy preceding surgery may expedite the development of novel systemic agents and improve outcomes.

Conventional first-line platinum-based combination chemotherapy with gemcitabine/cisplatin and standard or dose-dense methotrexate, vinblastine, doxorubicin and cisplatin yields high response rates but suboptimal long-term outcomes for advanced urothelial cancer. Salvage therapy is an unmet need, with disappointing outcomes. The emergence of novel biological agents offers the promise of improved outcomes. Neoadjuvant therapy preceding cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biological agents are reviewed.

Conventional front-line platinum-based combination chemotherapy yields high response rates but suboptimal long-term outcomes for advanced urothelial cancer. Salvage therapy is an unmet need, with disappointing outcomes. The profusion of novel biological agents offers the promise of improved outcomes. Neoadjuvant therapy before cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biologic agents are reviewed.