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In the phase 3 CLEAR trial, lenvatinib plus pembrolizumab (L + P) showed superior efficacy versus sunitinib in treatment-naïve patients with advanced renal cell carcinoma (aRCC). The combination treatment was associated with a robust objective response rate of 71%. Here we report tumor responses for patients in the L + P arm in CLEAR, with median follow-up of ∼4 yr at the final prespecified overall survival (OS) analysis. Tumor responses were assessed by independent review using Response Evaluation Criteria in Solid Tumors v1.1. Patients with a complete response (CR; n = 65), partial response (PR) with maximum tumor shrinkage ≥75% (near-CR; n = 59), or PR with maximum tumor shrinkage <75% (other PR; n = 129), were characterized in terms of their baseline characteristics. The median duration of response was 43.7 mo (95% confidence interval [CI] 39.2-not estimable) for the CR group, 30.5 mo (95% CI 22.4-not estimable) for the near-CR group, and 17.2 mo (95% CI 12.5-21.4) for the other PR group. The 36-mo OS rates were consistently high in the CR (97%), near-CR (86%), and other PR (62%) groups. Robust objective response rates were observed across International Metastatic RCC Database Consortium favorable-risk (69%, 95% CI 60-78%), intermediate-risk (73%, 95% CI 67-79%), and poor-risk (70%, 95% CI 54-85%) subgroups. The robust response to L + P supports this combination as a standard-of-care first-line treatment for patients with aRCC. PATIENT SUMMARY: The CLEAR trial enrolled patients with advanced kidney cancer who had not previously received any treatment for their cancer. Here we report results for tumor shrinkage observed in the group that received lenvatinib plus pembrolizumab combination treatment during the trial. Shrinkage of target tumors with this combination was long-lasting and was observed in patients irrespective of their disease severity. This trial is registered on ClinicalTrials.gov as NCT02811861., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Interim results from IMvigor010 showed an overall survival (OS) benefit for adjuvant atezolizumab (anti-PD-L1) versus observation in patients with circulating tumor DNA (ctDNA)-positive muscle-invasive urothelial carcinoma (MIUC)., Objective: To report updated OS and safety by ctDNA status., Design, Setting, and Participants: This ad hoc analysis from a global, open-label, randomized, phase 3 trial (NCT02450331) included intention-to-treat (ITT) population with evaluable cycle 1 day 1 (C1D1) ctDNA samples., Intervention: Atezolizumab (1200 mg every 3 wk) or observation for ≤1 yr., Outcome Measurements and Statistical Analysis: OS, relapse rates, and safety by ctDNA status were assessed., Results and Limitations: Among 581 of 809 ITT patients included, 214 (37%) were ctDNA positive. Atezolizumab did not improve OS versus observation in ITT patients (hazard ratio [HR] 0.91 [95% confidence interval {CI} 0.73-1.13]; median follow-up 46.8 mo [interquartile range, 36.1-53.6]). In the observation arm, ctDNA positivity versus negativity was associated with shorter OS (HR 6.3 [95% CI 4.3-9.3]). The ctDNA positivity identified patients with an OS benefit favoring atezolizumab versus observation (HR 0.59 [95% CI 0.42-0.83]). A greater reduction in ctDNA levels with atezolizumab (C3D1) was associated with longer OS (100% clearance, 60.0 mo [95% CI 35.5-not estimable]; 50-99% reduction, 34.3 mo [95% CI 15.2-not estimable]; <50% reduction, 19.9 mo [95% CI 16.4-32.2]). The ctDNA positivity at C1D1 + C3D1 was associated with relapse with greater sensitivity than C1D1 alone (68% vs 57%). Adverse events were more frequent with atezolizumab than with observation, regardless of ctDNA status. A study limitation was its exploratory design., Conclusions: Evidence suggests that ctDNA positivity in MIUC predicts a benefit with atezolizumab. An in-progress prospective study will further evaluate these findings., Patient Summary: Among patients with urothelial cancer after surgery, survival was poorer if tumor-derived DNA was detected in their bloodstream; these patients' survival was longer with atezolizumab versus observation. Bloodstream tumor-derived DNA may identify patients who benefit from atezolizumab., (Copyright © 2023. Published by Elsevier B.V.)

Background: Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC)., Objective: To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC., Design, Setting, and Participants: Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening., Intervention: Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily., Outcome Measurements and Statistical Analysis: The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS)., Results and Limitations: Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range [IQR], 65-76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22-47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval [CI], 4.0-6.5) and median OS was 14 mo (95% CI, 10.4-18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3-5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design., Conclusions: Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC., Patient Summary: Pembrolizumab plus olaparib showed antitumor activity and expected safety in patients with metastatic castration-resistant prostate cancer., (Copyright © 2022 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Apalutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS), overall survival (OS), and time to prostate-specific antigen (PSA) progression in the placebo-controlled SPARTAN study of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC)., Objective: To assess the relationships between PSA kinetics, outcomes, and molecular subtypes in SPARTAN., Design, Setting, and Participants: The authors conducted a post hoc analysis of nmCRPC patients randomized to receive apalutamide (n = 806) or placebo (n = 401) plus ADT and a subset stratified by molecular classifiers., Intervention: Apalutamide 240 mg/d., Outcome Measurements and Statistical Analysis: The association between PSA kinetics and MFS, OS, time to PSA progression, and molecular subtypes was evaluated using the landmark analysis and Kaplan-Meier methods., Results and Limitations: By 3 mo, PSA decreased in most apalutamide-treated patients and increased in most placebo-treated patients. After apalutamide, the median time to PSA nadir, confirmed ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml were 7.4, 1.0, 1.9, and 2.8 mo, respectively. By 6 mo, 90%, 57%, and 32% of apalutamide patients had ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml, respectively, while only 1.5% of placebo patients experienced ≥50% PSA reduction. PSA reductions were observed within 3 mo and up to 12 mo of apalutamide treatment, and were similar across molecular subtypes. Deep PSA responses (≥90% PSA reduction or PSA ≤0.2 ng/ml) at landmark 6-mo apalutamide treatment were significantly associated with improved time to PSA progression (hazard ratio {HR} [95% confidence interval {CI}] 0.25 [0.18-0.33] or 0.13 [0.08-0.21]), MFS (0.41 [0.29-0.57] or 0.3 [0.19-0.47]), and OS (0.45 [0.35-0.59] or 0.26 [0.18-0.38]; p < 0.001 for all)., Conclusions: Apalutamide plus ADT produced rapid, deep, and durable PSA responses by 6-mo treatment regardless of assessed molecular prognostic markers. An early PSA response with apalutamide was associated with clinical benefits, supporting prognostic value of PSA monitoring., Patient Summary: In this report, we describe how prostate-specific antigen (PSA) levels relate to outcomes in patients with nonmetastatic castration-resistant prostate cancer treated with apalutamide plus androgen deprivation therapy (ADT). We found that treatment with apalutamide plus ADT resulted in rapid, deep, and durable PSA responses in the majority of patients, including those with high-risk molecular subtypes, which were associated with improved survival., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The CARMENA trial in patients with metastatic renal cell carcinoma (mRCC) demonstrated that treatment with sunitinib alone was noninferior to cytoreductive nephrectomy (CN) followed by sunitinib (nephrectomy⬜sunitinib)., Objective: The objective of this study was to provide updated overall survival (OS) outcomes of CARMENA and assess whether some subgroups may still benefit from upfront CN., Design, Setting, and Participants: CARMENA was a phase III trial in 450 patients with mRCC enrolled from 2009 to 2017., Intervention: Patients in the intention-to-treat population received nephrectomy⬜sunitinib (standard of care [SOC]; n = 226) or sunitinib alone (n = 224)., Outcome Measurements and Statistical Analysis: Primary endpoint was OS, assessed using an updated data cut-off (October 2018; median OS event-free follow-up, 36.6 mo). Patients were reclassified by risk using International Metastatic RCC Database Consortium (IMDC) criteria., Results and Limitations: Sunitinib alone was noninferior to nephrectomy⬜sunitinib (hazard ratio [HR], 0.97; 95% confidence interval, 0.79⬜1.19; p = 0.8) and demonstrated longer median OS (19.8 mo vs 15.6 mo, respectively). For patients with two or more IMDC risk factors, OS was significantly longer with sunitinib alone than with nephrectomy⬜sunitinib (31.2 mo vs 17.6 mo, respectively; HR, 0.65; p = 0.03). For patients with one IMDC risk factor, OS was longer for nephrectomy⬜sunitinib versus sunitinib alone although not significantly (31.4 mo vs 25.2 mo; HR, 1.30; p = 0.2). The post hoc nature of the subgroup analyses may limit their interpretation., Conclusions: Sunitinib alone was noninferior compared with nephrectomy⬜sunitinib, suggesting that CN should not be considered SOC in patients with mRCC requiring systemic treatment. Certain subgroups, including patients with one IMDC risk factor, may still benefit from upfront CN., Patient Summary: We assessed the survival of patients with metastatic kidney cancer in a clinical trial. Patients treated with sunitinib on its own had the same survival as patients who had surgery before sunitinib treatment. We conclude that surgery may not be necessary for some patients with metastatic kidney cancer., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Primary tumour response may impact therapeutic strategies in metastatic renal cell carcinoma (mRCC) but remains unknown in the era of immune checkpoint inhibitors. We aimed to describe the response of the primary tumour in patients who did not undergo upfront cytoreductive nephrectomy (uCN) and were treated with nivolumab in the GETUG-AFU-26 NIVOREN phase 2 trial. Primary tumour response was prospectively assessed, as well as the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Among 720 patients, 111 did not undergo uCN, mainly patients with intermediate (45%) and poor (49%) International mRCC Database Consortium (IMDC) risk. In the 111 patients, nivolumab was used in the second line for 63% of patients and the third line or more for 37%, with an ORR of 16% (95% confidence interval [CI] 1025%); with a median follow-up of 24.5 mo (95% CI 21.6-27.1), median PFS was 2.7 mo (95% CI 2.5-4.0) and median OS was 15.9 mo (95% CI 9.5-19.8). A total of 67 patients had an evaluable primary renal lesion, four of whom (6%) experienced shrinkage of more than 30%. Overall, patients who did not undergo uCN had adverse baseline characteristics and nivolumab activity against the primary tumour was limited. PATIENT SUMMARY: In this report, we observed that nivolumab was associated with a limited response of the primary tumour in previously treated patients with metastatic kidney cancer., (Copyright © 2021. Published by Elsevier B.V.)

Background: Better blood tests to elucidate the behaviour of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed to drive therapeutic decisions. Plasma cell-free DNA (cfDNA) comprises normal and circulating tumour DNA (ctDNA). Low-pass whole-genome sequencing (lpWGS) of ctDNA can provide information on mCRPC behaviour., Objective: To validate and clinically qualify plasma lpWGS for mCRPC., Design, Setting, and Participants: Plasma lpWGS data were obtained for mCRPC patients consenting to optional substudies of two prospective phase 3 trials (FIRSTANA and PROSELICA). In FIRSTANA, chemotherapy-naïve patients were randomised to treatment with docetaxel (75 mg/m 2 ) or cabazitaxel (20 or 25 mg/m 2 ). In PROSELICA, patients previously treated with docetaxel were randomised to 20 or 25 mg/m 2 cabazitaxel. lpWGS data were generated from 540 samples from 188 mCRPC patients acquired at four different time points (screening, cycle 1, cycle 4, and end of study). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: lpWGS data for ctDNA were evaluated for prognostic, response, and tumour genomic measures. Associations with response and survival data were determined for tumour fraction. Genomic biomarkers including large-scale transition (LST) scores were explored in the context of prior treatments., Results and Limitations: Plasma tumour fraction was prognostic for overall survival in univariable and stratified multivariable analyses (hazard ratio 1.75, 95% confidence interval 1.08-2.85; p = 0.024) and offered added value compared to existing biomarkers (C index 0.722 vs 0.709; p = 0.021). Longitudinal changes were associated with drug response. PROSELICA samples were enriched for LSTs (p = 0.029) indicating genomic instability, and this enrichment was associated with prior abiraterone and enzalutamide treatment but not taxane or radiation therapy. Higher LSTs were correlated with losses of RB1/RNASEH2B, independent of BRCA2 loss., Conclusions: Plasma lpWGS of ctDNA describes CRPC behaviour, providing prognostic and response data of clinical relevance. The added prognostic value of the ctDNA fraction over established biomarkers should be studied further., Patient Summary: We studied tumour DNA in blood samples from patients with prostate cancer. We found that levels of tumour DNA in blood were indicative of disease prognosis, and that changes after treatment could be detected. We also observed a "genetic scar" in the results that was associated with certain previous treatments. This test allows an assessment of tumour activity that can complement existing tests, offer insights into drug response, and detect clinically relevant genetic changes., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The phase 3 SPARTAN study evaluated apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and prostate-specific antigen doubling time of ≤10 mo. At primary analysis, apalutamide improved median metastasis-free survival (MFS) by 2 yr and overall survival (OS) data were immature., Objective: We report the prespecified event-driven final analysis for OS., Design, Setting, and Participants: A total of 1207 patients with nmCRPC (diagnosed by conventional imaging) were randomised 2:1 to apalutamide (240mg/d) or placebo, plus on-going androgen deprivation therapy. After MFS was met and the study was unblinded, 76 (19%) patients still receiving placebo crossed over to apalutamide., Outcome Measurements and Statistical Analysis: OS and time to cytotoxic chemotherapy (TTChemo) were analysed by group-sequential testing with O'Brien-Fleming-type alpha spending function., Results and Limitations: At median 52-mo follow-up, 428 deaths had occurred. The median treatment duration was 32.9 mo for apalutamide group and 11.5 mo for placebo group. Median OS was markedly longer with apalutamide versus placebo, reaching prespecified statistical significance (73.9 vs 59.9 mo, hazard ratio [HR]: 0.78 [95% confidence interval {CI}, 0.64-0.96]; p=0.016). Apalutamide also lengthened TTChemo versus placebo (HR: 0.63 [95% CI, 0.49-0.81]; p=0.0002). Discontinuation rates in apalutamide and placebo groups due to progressive disease were 43% and 74%, and due to adverse events 15% and 8.4%, respectively. Subsequent life-prolonging therapy was received by 371 (46%) patients in the apalutamide arm and by 338 (84%) patients in the placebo arm including 59 patients who received apalutamide after crossover. Safety was consistent with previous reports; when adverse events were adjusted for treatment exposure, rash had the greatest difference of incidence between the apalutamide and placebo groups., Conclusions: Extension of OS with apalutamide compared with placebo conferred impactful benefit in patients with nmCRPC. There was a 22% reduction in the hazard of death in the apalutamide group despite 19% crossover (placebo to apalutamide) and higher rates of subsequent therapy in the placebo group., Patient Summary: With data presented herein, all primary and secondary study end points of SPARTAN were met; findings demonstrate the value of apalutamide as a treatment option for nonmetastatic castration-resistant prostate cancer., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment., Objective: To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy., Design, Setting, and Participants: Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m 2 ) or cabazitaxel (20 or 25mg/m 2 ) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m 2 ) as second-line chemotherapy (PROSELICA)., Outcome Measurements and Statistical Analysis: Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies., Results and Limitations: In 2502 samples, baseline log 10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR]=1.54; 95% confidence interval [CI]: 1.15-2.08; p=0.004), and shorter OS on taxane therapy (HR=1.53; 95% CI: 1.18-1.97; p=0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log 10 cfDNA concentrations during the first four cycles of treatment (per cycle -0.03; 95% CI: -0.044 to -0.009; p=0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA., Conclusions: We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes., Patient Summary: In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3-9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D., Objective: To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT])., Design, Setting, and Participants: Data were accessed from two independent phase III trials of ADT alone or ADT+D-GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized., Outcome Measurements and Statistical Analysis: The primary end point was OS., Results and Limitations: Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials., Conclusions: There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients., Patient Summary: Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Androgen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC., Objective: To investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC., Design, Setting, and Participants: Retrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC., Outcome Measurements and Statistical Analysis: For the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance., Results and Limitations: Overall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel (p=0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6-7.7) and 4.1 mo (95% confidence interval: 1.3-4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel (p=0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3-4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups., Conclusions: Docetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients., Patient Summary: Rechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Prostate cancer is the most frequent male cancer. Since the median age of diagnosis is 66 yr, many patients require both geriatric and urologic evaluation if treatment is to be tailored to individual circumstances including comorbidities and frailty., Objective: To update the 2014 International Society of Geriatric Oncology (SIOG) guidelines on prostate cancer in men aged >70 yr. The update includes new material on health status evaluation and the treatment of localised, advanced, and castrate-resistant disease., Data Acquisition: A multidisciplinary SIOG task force reviewed pertinent articles published during 2013-2016 using search terms relevant to prostate cancer, the elderly, geriatric evaluation, local treatments, and castration-refractory/resistant disease. Each member of the group proposed modifications to the previous guidelines. These were collated and circulated. The final manuscript reflects the expert consensus., Data Synthesis: Elderly patients should be managed according to their individual health status and not according to age. Fit elderly patients should receive the same treatment as younger patients on the basis of international recommendations. At the initial evaluation, screening for cognitive impairment is mandatory to establish patient competence in making decisions. Initial evaluation of health status should use the validated G8 screening tool. Abnormal scores on the G8 should lead to a simplified geriatric assessment that evaluates comorbid conditions (using the Cumulative Illness Score Rating-Geriatrics scale), dependence (Activities of Daily Living) and nutritional status (via estimation of weight loss). When patients are frail or disabled or have severe comorbidities, a comprehensive geriatric assessment is needed. This may suggest additional geriatric interventions., Conclusions: Advances in geriatric evaluation and treatments for localised and advanced disease are contributing to more appropriate management of elderly patients with prostate cancer. A better understanding of the role of active surveillance for less aggressive disease is also contributing to the individualisation of care., Patient Summary: Many men with prostate cancer are elderly. In the physically fit, treatment should be the same as in younger patients. However, some elderly prostate cancer patients are frail and have other medical problems. Treatment in the individual patient should be based on health status and patient preference., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The role of chemotherapy in metastatic non castrate prostate cancer (mNCPC) is debated. Survival benefits of docetaxel (D) added to androgen-deprivation therapy (ADT) were shown in the CHAARTED trial in patients with metastatic high-volume disease (HVD)., Objective: To assess the impact of metastatic burden and to update overall survival (OS) data of the GETUG-AFU15 study., Design, Setting, and Participants: Randomized phase 3 trial of ADT plus D versus ADT alone in 385 mNCPC patients; median follow-up of 7 yr., Outcome Measurements and Statistical Analysis: Primary end point was OS. Secondary end points were biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS). Retrospective analysis was by tumor volume., Results and Limitations: After a median follow-up of 83.9 mo, median OS in the overall population was 62.1 mo (95% confidence interval [CI], 49.5-73.7) and 48.6 mo (95% CI, 40.9-60.6) for ADT plus D and ADT arms, respectively (hazard ratio [HR]: 0.88 [95% CI, 0.68-1.14]; p=0.3). Median OS in ADT plus D and ADT arms, respectively, was for HVD patients: 39.8 mo (95% CI, 28.0-53.4) versus 35.1 mo (95% CI, 29.9-43.6) (HR: 0.78 [95% CI, 0.56-1.09]; p=0.14), for low-volume disease (LVD) patients; median was not reached (NR; 95% CI, 69.5-NR) and 83.4 mo (95% CI, 61.8-NR) (HR: 1.02 [95% CI, 0.67-1.55]; p=0.9). For upfront metastatic patients, OS was 52.6 mo (95% CI, 43.3-66.8) and 41.5 mo (95% CI, 36.3-54.5), respectively (HR: 0.93 [95% CI, 0.69-1.25]; p=0.6). The bPFS (HR: 0.73 [95% CI, 0.56-0.94]; p=0.014) and rPFS (HR: 0.75 [95% CI, 0.58-0.97]; p=0.030) were significantly longer in the ADT plus D arm. Limitations included the retrospective analysis of metastatic extent and the lack of statistical power to detect a significant difference in subgroups., Conclusions: The post hoc analyses of the GETUG-AFU15 study demonstrated a nonsignificant 20% reduction in the risk of death in the HVD subgroup. Patients with LVD had no survival improvement with early D., Patient Summary: In this study, docetaxel added to castration did not improve survival in patients with metastatic hormone-sensitive prostate cancer, partly due to methodological issues. However, early chemotherapy should be discussed with all patients, given the data of three randomized trials including GETUG-AFU15., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC)., Objective: To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity., Design, Setting, and Participants: Post-hoc exploratory analysis of randomised phase 3 studies examining post-docetaxel (COU-AA-301) or chemotherapy-naïve mCRPC (COU-AA-302) patients receiving AA. The treatment effect on overall survival (OS), radiographic progression-free survival (rPFS), and prostate-specific antigen (PSA) response analysed by quartile duration of prior gonadotropin-releasing hormone agonists (GnRHa) or androgen receptor (AR) antagonist., Intervention: Patients were randomised to AA (1000mg, orally once daily) plus prednisone (5mg, orally twice daily) or placebo plus prednisone. Prior endocrine therapy was GnRHa (COU-AA-301, n=1127 [94%]; COU-AA-302, n=1057 [97%], 45.1 mo or 36.7 mo median duration, respectively) and/or orchiectomy (COU-AA-301, n=78 [7%] COU-AA-302, n=44 [4%]); castrated patients received prior AR antagonists (COU-AA-301, n=1015 [85%]; COU-AA-302, n=1078 [99%], 15.7 mo or 16.1 mo median duration, respectively)., Outcome Measurements and Statistical Analysis: Cox model was used to obtain hazard ratio and associated 95% confidence interval with statistical inference by log rank statistic., Results and Limitations: Clinical benefit with AA was observed for OS, rPFS, and PSA response for nearly all quartiles with GnRHa or AR antagonists in both COU-AA-301 and COU-AA-302. In COU-AA-301, patients with a longer duration of prior endocrine therapy tended to have greater AA OS, rPFS, and PSA response benefit, with lead-time chemotherapy bias potentially impacting COU-AA-301 results. Time to castration resistance was not captured. This analysis is limited as a post-hoc exploratory analysis., Conclusions: In the COU-AA-301 and COU-AA-302 studies, AA produced clinical benefits regardless of prior endocrine therapy duration in patients with mCRPC., Patient Summary: Metastatic castration-resistant prostate cancer patients derived clinical benefits with abiraterone acetate regardless of prior endocrine therapy duration., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The Glass model developed in 2003 uses prognostic factors for noncastrate metastatic prostate cancer (NCMPC) to define subgroups with good, intermediate, and poor prognosis., Objective: To validate NCMPC risk groups in a more recently diagnosed population and to develop a more sensitive prognostic model., Design, Setting, and Participants: NCMPC patients were randomized to receive continuous androgen deprivation therapy (ADT) with or without docetaxel in the GETUG-15 phase 3 trial. Potential prognostic factors were recorded: age, performance status, Gleason score, hemoglobin (Hb), prostate-specific antigen, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), metastatic localization, body mass index, and pain., Outcome Measurements and Statistical Analysis: These factors were used to develop a new prognostic model using a recursive partitioning method. Before analysis, the data were split into learning and validation sets. The outcome was overall survival (OS)., Results and Limitations: For the 385 patients included, those with good (49%), intermediate (29%), and poor (22%) prognosis had median OS of 69.0, 46.5 and 36.6 mo (p=0.001), and 5-yr survival estimates of 60.7%, 39.4%, and 32.1%, respectively (p=0.001). The most discriminatory variables in univariate analysis were ALP, pain intensity, Hb, LDH, and bone metastases. ALP was the strongest prognostic factor in discriminating patients with good or poor prognosis. In the learning set, median OS in patients with normal and abnormal ALP was 69.1 and 33.6 mo, and 5-yr survival estimates were 62.1% and 23.2%, respectively. The hazard ratio for ALP was 3.11 and 3.13 in the learning and validation sets, respectively. The discriminatory ability of ALP (concordance [C] index 0.64, 95% confidence interval [CI] 0.58-0.71) was superior to that of the Glass risk model (C-index 0.59, 95% CI 0.52-0.66). The study limitations include the limited number of patients and low values for the C-index., Conclusion: A new and simple prognostic model was developed for patients with NCMPC, underlying the role of normal or abnormal ALP., Patient Summary: We analyzed clinical and biological factors that could affect overall survival in noncastrate metastatic prostate cancer. We showed that normal or abnormal alkaline phosphatase at baseline might be useful in predicting survival., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies have reported on prognostic factors for castration-resistant prostate cancer (CRPC); however, most of these studies were conducted before docetaxel chemotherapy was approved for CRPC., Objective: To evaluate the prognostic value of multiple parameters in men with bone metastases due to CRPC using a contemporary dataset., Design, Setting, and Participants: The analysis included 1901 patients with metastatic CRPC enrolled in an international, multicenter, randomized, double-blind phase 3 trial conducted between May 2006 and October 2009., Outcome Measures and Statistical Analysis: We developed multivariate validated Cox proportional hazards models and nomograms to estimate 12-mo and 24-mo survival probabilities and median survival time., Results and Limitations: The median (95% confidence interval) overall survival was 20 (18, 21) mo. The final model included 12 of the 15 potential prognostic variables evaluated (concordance index 0.72). Seven bone-related variables were associated with longer survival in the final model: alkaline phosphatase ≤143 U/l (p<0.0001); bone-specific alkaline phosphatase (BSAP) <146 U/l (p<0.0001); corrected urinary N-telopeptide (uNTx) ≤50 nmol/mmol (p=0.0008); mild or no pain (Brief Pain Inventory-Short Form [BPI-SF] score ≤4) (p<0.0001); no previous skeletal-related event (SRE; p=0.0002); longer time from initial diagnosis to first bone metastasis (p<0.0001); and longer time from first bone metastasis to randomization (p<0.0001). Other significant predictors of improved survival included prostate-specific antigen (PSA) level <10 ng/ml (p<0.0001), hemoglobin >128g/l (p<0.0001), absence of visceral metastases (p<0.0001), Eastern Co-operative Oncology Group (ECOG) score ≤1 (p=0.017), and younger age (p=0.008). Nomograms were generated based on the parameters included in the final validated models (with/without uNTx and BSAP). One limitation was that lactate dehydrogenase (LDH) levels, a known prognostic factor, were not available in this study., Conclusions: Bone-related parameters are strong prognostic variables for overall survival in patients with bone metastases from CRPC., Patient Summary: Survival time is variable in patients with bone metastases from prostate cancer. We found that factors related to bone help to predict how long a patient will live., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: We have recently witnessed a rapid increase in the number of effective systemic agents for men with metastatic castration-resistant prostate cancer (CRPC), including novel hormonal therapies (abiraterone acetate and MDV3100), immunotherapies (sipuleucel-T), chemotherapies (cabazitaxel), and bone microenvironment targeting agents (denosumab, radium 223). Given the increasing complexity of treatment decisions for this disease, major research and clinical priorities are (1) finding biomarkers that enable an understanding of the natural history and complex biology of this heterogeneous malignancy, (2) defining predictive biomarkers that identify men most likely to benefit from a given therapy, and (3) identifying biomarkers of early response or progression to optimize outcomes., Objective: In this review, we discuss existing and potential biomarkers in CRPC and how they may currently inform prognosis, aid in treatment selection (predictive value), and relate to survival outcomes (surrogacy)., Evidence Acquisition: PubMed-based literature searches and abstracts through September 2011 provided the basis for this literature review as well as expert opinion., Evidence Synthesis: We address blood and urine-based biomarkers such as prostate-specific antigen, lactate dehydrogenase, total and bone alkaline phosphatase and other bone turnover markers, hemoglobin, and circulating tumor cells in the context of prognosis, prediction, and patient selection for therapy. Given the inherent problems associated with defining progression-free survival in CRPC, the importance of biomarker development and the needed steps are highlighted. We place the discussion of biomarkers within the context of the design/intent of a trial and mechanism of action of a given systemic therapy. We discuss novel biomarker development and the pathway for surrogate or predictive biomarkers to become credentialed as useful tests that inform therapeutic decisions., Conclusions: A greater understanding of biomarkers in CRPC permits a more personalized approach to care that maximizes benefit and minimizes harm and can inform clinical trials tailored to men most likely to derive benefit., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The optimal chemotherapy for patients with advanced transitional cell carcinoma of the urothelium who are not eligible for cisplatin remains to be defined., Objective: To assess the activity of gemcitabine alone (GEM) or in combination with oxaliplatin (GEMOX) in a randomized phase 2 trial., Design, Setting, and Participants: The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors criteria. The sample size was based on a two-stage Fleming design with p0=35% and p1=55%. At the end of the first stage designed to register 20 patients on each treatment arm, the observation of seven or more objective responses would have led to the inclusion of 30 more patients in each arm., Results and Limitations: From July 2004 to March 2009, 44 patients in 10 centers were randomly assigned into the GEM or the GEMOX arm, 22 on each treatment arm. The median age was 76 yr. Seven patients were included for a performance status (PS) of 2 only. The remaining 37 patients had an impaired renal function, 11 of whom also had a PS of 2. The median creatinine clearance was 45 ml/min (range: 30-80 ml/min). The trial was closed after the first part because the GEMOX arm did not reach the targeted objective response rate to proceed further., Conclusions: Oxaliplatin does not add any significant activity (in terms of response rates) compared with gemcitabine alone in patients with advanced transitional cell carcinoma of the urothelium who are ineligible for cisplatin., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: The natural history of renal cell carcinoma (RCC) is highly unpredictable. Small renal masses may be accompanied by metastatic disease. Conversely, patients with locally advanced disease may enjoy long-term disease-free survival., Objective: To review the status of prognostic factors in RCC., Evidence Acquisition: A literature review was performed using the PubMed, MEDLINE, and Cochrane databases for articles published as of February 15, 2010. Electronic articles published ahead of print were also considered. Search was limited to the English language. Search was conducted using the following keywords: renal cell carcinoma, molecular, tissue, markers, blood, urine, progression, prognosis, risk factor, and survival. Studies were selected according to the relevance of the study, the number of patients included, originality, actuality, and clinical applicability of the results., Evidence Synthesis: Four areas of prediction were examined: (1) new RCC diagnostics, (2) RCC grade and stage at diagnosis, (3) disease progression, and (4) disease-specific mortality. All identified reports represented either case series or controlled studies. Although a large number of markers were identified, only a few were validated. Several prognostic factors were integrated in predictive or prognostic models., Conclusions: Several prognostic factors can help discriminate between favourable and unfavourable RCC phenotypes. Of those, several clinical, pathologic, and biologic markers have been tested and validated, and they are used in predictive and prognostic models. Nonetheless, the search continues, especially for informative markers predicting the response to targeted therapies., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Context: Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease., Objective: This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery., Evidence Acquisition: A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed., Evidence Synthesis: Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications., Conclusions: For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting., (Copyright © 2010 European Association of Urology. All rights reserved.)

Background: Several studies suggest a causal relationship between platelet activation and cancer metastasis. Activated platelet microparticles (PMPs) release vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which play a major role in angiogenesis., Objective: We conducted a prospective, nonrandomised, single-centre study in hormone-refractory prostate cancer (HRPC) patients to determine the impact of PMPs on the outcome., Design, Setting, and Participants: Eligible chemonaive and metastatic HRPC patients received docetaxel-based chemotherapy and a low dose of prednisone., Intervention: PMPs in whole blood were quantified before the start of chemotherapy through flow cytometry using an anti-CD41a monoclonal antibody, and plasma VEGF and bFGF were determined with an enzyme-linked immunosorbent assay., Measurements: The primary end point was to evaluate the impact of the PMPs on overall survival (OS). We also studied the statistical interaction between PMPs and platelets and their relationship with OS. The median PMP value was used to sort patients into two groups., Results and Limitations: Data of 43 consecutive HRPC patients treated in a single French centre were analysed. Significant correlations were observed between Eastern Cooperative Oncology Group performance status (ECOG PS), platelets, and PMP level. The median OS was significantly shorter for patients with >6867 PMPs per microl of whole blood than for those with lower values (16.7 vs 26.4 mo, p=0.013). A significant relationship was found between OS and PMPs, whereas a statistical interaction term between PMPs and platelets was significantly associated with OS (p=0.019). No association was found between OS and plasma VEGF and bFGF. In the multivariate analysis, only baseline prostate-specific antigen (PSA) and ECOG PS remained significantly predictive of risk of death., Conclusions: In HRPC patients, PMPs and their interaction with platelets were predictive of outcome. A biologic association between PMPs and the OS of HRPC patients, independent of chemotherapy regimen, should be demonstrated by confirmatory prospective studies.

We present a case series of seven patients with metastatic renal cell carcinoma treated with bevacizumab (10 mg/kg) in combination with sunitinib 25-50 mg as salvage therapy after disease progression under sunitinib monotherapy. Two patients had a partial response, four had stable disease, and one patient had disease progression. After a median follow-up of 17.2 mo, median progression-free survival and overall survival were 8.5 and 15.1 mo, respectively. Two patients experienced exacerbation of their preexisting hypertension; there were no grade 4 toxicities. The bevacizumab-sunitinib combination in sunitinib-refractory patients seems active and has a tolerable toxicity profile.

Background: There are no data on the patterns of care and outcome of very elderly patients with castration-resistant prostate cancer (CRPC) treated with docetaxel., Objective: To assess the routine use of first-line docetaxel-based chemotherapy in CRPC patients aged >75 yr., Design, Setting, and Participants: We reviewed the clinical files of 175 patients aged > or =75 yr with CRPC treated with first-line docetaxel in nine French tertiary care cancer centres from 2000 to 2007., Measurements: Response rate, survival, and adverse events (AE)., Results and Limitations: Median age was 78 yr. Ninety-five patients (54%) received a standard 3-wk regimen (SR), and 80 patients (46%) received an adapted regimen (AR) delivered on a weekly schedule with various times for rest periods. Patients treated with an AR were older (>80 yr) and had poorer performance status (PS; > or =2) than patients treated with the SR. The prostate-specific antigen (PSA) response rates were not significantly different between the standard and adapted treatment groups (71% vs 68%, p=0.79). The median progression-free survival (PFS) was 7.4 mo. The median overall survival (OS) was 15 mo. The incidence of grade 3 or 4 AEs was 46% and was correlated with poor PS and the presence of visceral disease but not with the regimen. Early discontinuation of treatment because of toxicity occurred more frequently in the AR group than in the SR group (30% vs 8.4%, p=0.0005). In multivariate analysis, only PS and the presence of visceral disease were predictors of OS., Conclusions: Docetaxel is active and feasible in elderly patients with good PS. The optimal treatment of frail patients with CRPC remains to be established. Geriatric tools should be used to more accurately detect elderly CRPC patients who are unfit for chemotherapy. Age by itself should not be used as a criterion to deny patients with CRPC a potentially effective chemotherapy.

Objective: To provide a systematic review of the side effects associated with sorafenib, sunitinib, and temsirolimus and to provide an outline of possible preventive or therapeutic measures., Methods: We performed a PubMed-based systematic review of side effects associated with the three agents and relied on product monographs and prescribing information to provide an outline of treatments aimed at reducing these toxicities., Results: Side effects range from <1% to 72%. Grade 3/4 side effects are less common and range from <1% to 13% for sorafenib, <1% to 16% for sunitinib, and 1% to 20% for temsirolimus. Overall, sunitinib causes the most grade 3/4 side effects and sorafenib causes the fewest grade 3/4 side effects, although head-to-head trials are required to compare safety profiles of all three kinase inhibitors. Virtually all side effects can be managed effectively., Conclusion: Prevention, recognition, and prompt management of side effects are of key importance and avoid unnecessary dose reductions, which may undermine treatment efficacy.

Objective: To report our preliminary experience with trastuzumab (Herceptin) in the management of metastatic transitional cell carcinoma of the urinary tract., Patients and Methods: From november 2001 to august 2002, six patients received trastuzumab for metastatic transitional cell carcinoma of the bladder (n=5) or renal pelvic cancer (n=1). Trastuzumab was administered as a first-line therapy in 2 patients, a second-line therapy in 3, and a third-line therapy in 1. Each patient received a weekly intravenous administration of trastuzumab (initial dose of 4 mg/kg, followed by 2mg/kg for other courses). A total of 6 courses was given. In 4 patients, trastuzumab was administered in association with paclitaxel (175 mg/m2) and carboplatin (area under the curve of 6). One patient received the same combination of trastuzumab and paclitaxel, but without carboplatin. The remaining patient received only trastuzumab., Results: The trastuzumab-based regimen achieved partial regression of metastases in all patients. Initial regression of metastases varied between 30% and 80%. The therapy was well tolerated. Treatment-related toxicity was moderate in all patients, except for one who experienced transient grade 4 neutropenia. Five patients died from cancer. The interval between trastuzumab initiation and patient death ranged from 8 to 22 months. The remaining patient was still alive 28 months after trastuzumab initiation., Conclusions: Our preliminary data suggest that trastuzumab-based therapy may be safe and effective in metastatic transitional cell carcinoma of the urinary tract. Prospective trials are needed to further investigate this therapeutic option.

When human glioma cells were incubated for 24 hr in serum-free medium with nanomolar concentrations of 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195), a specific ligand of the peripheral benzodiazepine receptor (PBR), a significant increase in the membrane fluidity of mitochondria isolated from these cells was registered. These effects were not observed with a shorter incubation time (2 hr) of the cells with PK11195 nor in the presence of serum. Other significant associated changes were observed: a significant increase of 16+/-4% of [3H]thymidine incorporation into DNA was detected in cells in the presence of PK11195 in serum-free medium, and an increase of 33+/-5% as compared to controls in nonyl acridine orange uptake, as indicator of mitochondrial mass, was also registered in cells treated with 10 nM PK11195. [3H]PK11195 binding was decreased in cells incubated with PK11195; a 45% decrease compared to controls was obtained. In view of the effect of PBR ligands on DNA synthesis, changes in mitochondrial lipid metabolism through interaction with PBRs might lead to biogenesis of mitochondria to support the increased metabolic requirements for cell division, which is even higher in malignant cells.