Advanced UC Research Articles

Cisplatin-Based First-Line Therapy for Advanced Urothelial Carcinoma After Previous Perioperative Cisplatin-Based Therapy

BackgroundOutcomes 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 MethodsData 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). ResultsData 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. ConclusionLonger 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.

812PD - Mature Survival (Os) Data of a Randomised International Phase Ii Trial (Jasint1): Vinflunine (Vfl)-Gemcitabine (Gem) Vs. Vfl-Cbdca in Cddp-Unfit Patients (Pts) with Advanced Urothelial Carcinoma (Uc)

ABSTRACT Aim: There is no standard 1st line chemotherapy (CT) for advanced or metastatic UC in pts unfit for a CDDP-based regimen. VFL, an EMA approved agent in the post-platinum setting has shown to be safe in pts with renal impairment. The study aimed to assess the benefit/risk ratio of 2 VFL-based CT regimens in UC. Methods: Pts with a creatinine clearance (CrCl) Results: 69 pts (34 arm A, 35 arm B) were enrolled over 18 months: at the median (med) follow-up of 25.9 mo 74% pts had died. Pts characteristics were similar in both groups: med age 70 yrs; PS 0 / 1 in 42% / 58%; primary sites: 52% bladder and 46% upper tract; visceral mets 49%, med CrCl 46mL/min. Med number of cycles was 5 (A) and 4 (B). More haematological G3/4 adverse events (AE) were reported in arm B: neutropenia in 68% (vs 38%) and febrile neutropenia in 14% (vs 3%) of pts. Main non-haematological G3/4 AE were fatigue (21.7%), infection (7.2%), and constipation (4.3%) without major difference between arms. DCR was 77% in both groups; ORR was 44.1% vs 28.6%, med PFS 5.9 vs 6.1 mo and med OS 14.0 vs 12.8 mo in arms A and B, respectively. Cause of death: progression in 90%, 1 drug-related AE (B), other reasons in 8%. Further anticancer drugs: 59% (A) and 51% (B); CBDCA, GEM and paclitaxel in 23%, 29% and 30%, respectively, with more taxanes in arm A (35%) and more GEM in arm B (37%). Conclusions: Both VFL doublets are feasible with a similar DCR. However, a higher ORR and OS, while showing less haematological toxicity, favour VFL-GEM which warrants further clinical study. Disclosure: M. De Santis: Advisory board: Laboratoire Pierre Fabre Corporate-sponsored research: Laboratoire Pierre Fabre Consultancy: Laboratoire Pierre Fabre; C. Lucas: Pierre Fabre employee; J. Bellmunt: Advisory board member of Laboratoires Pierre Fabre; K. Legrand and R. Fougeray: Laboratoires Pierre Fabre employee; S. Culine: Advisory board member and consultancies for Laboratoires Pierre Fabre. All other authors have declared no conflicts of interest.

865P - The Significance of Complete Response (Cr) in Patients Receiving Salvage Therapy for Advanced Urothelial Carcinoma (Uc)

ABSTRACT Aim: Molecular interrogation of tumors showing CR with salvage therapy for UC may provide insights regarding biology, as suggested by the discovery of TSC1 mutations in those with durable CR on everolimus. We hypothesized that CR with salvage therapy is robustly associated with long term outcomes, and may represent an intermediate endpoint and identify tumors warranting molecular interrogation. Methods: Phase II trials of salvage chemotherapy and/or biologic agent therapy were utilized. Data on CR or PR (partial response) as best response by RECIST were required in addition to previously recognized prognostic factors: time from prior chemotherapy (TFPC), hemoglobin (Hb), performance status (PS) and liver metastasis (LM) status. Cox proportional hazards regression was used to evaluate the association of CR and other response parameters with overall survival (OS) and progression free survival (PFS). Trial was a stratification factor. Results: 789 of 814 patients enrolled in 14 phase II trials evaluating chemotherapeutic, biologic or chemobiologic regimens were evaluable with all required data available. The overall median PFS and OS were 2.7 (95% CI: 2.5-2.8) and 6.8 (95% CI: 6.2-7.1) months, respectively. CR and partial response (PR) were seen in 14 (1.8%) and 109 (13.8%) patients. Median (95% CI) 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 Conclusions: CR occurred in a small minority (1.8%) of patients receiving salvage therapy for advanced UC. CR warrants validation as an intermediate endpoint and may help select tumors for molecular interrogation, given the robust association with durable PFS and OS. Disclosure: R. Fougeray: Employee of Pierre Fabre, but not relevant to subject matter of abstract. All other authors have declared no conflicts of interest.

867P - Outcomes with Cisplatin-Based First-Line Therapy for Advanced Urothelial Carcinoma (Uc) Following Previous Perioperative Cisplatin-Based Therapy

ABSTRACT Aim: Outcomes with cisplatin-based first-line therapy for advanced UC following previous perioperative cisplatin-based chemotherapy are unclear. We conducted a retrospective study to evaluate outcomes and identify a threshold of time from prior cisplatin-based perioperative chemotherapy (TFPC) when repeating cisplatin-based chemotherapy may not be justified. Methods: Data were collected for patients who received cisplatin-based first-line therapy for advanced UC following previous perioperative cisplatin-based therapy. The Kaplan-Meier method was used to estimate survival. Cox proportional hazards models were used to investigate the prognostic ability of variables on overall survival (OS). The multivariable model included patients with complete data for the all factors (visceral metastasis, ECOG performance status [PS], TFPC, anemia, leukocytosis, albumin). All tests and confidence intervals were two-sided and at p = 0.05 level of significance. Results: Individual level data for 40 patients from 8 institutions were obtained. The study included 33 men (77.5%), the median age was 61 years (range 41 to 71), the majority received gemcitabine plus cisplatin (N = 25, 62.5%) and the median number of cycles was 4 (range 1-8). The median OS was 70 weeks (95% CI: 48.0-81.0). Multivariable Cox regression analysis results showed an independent prognostic impact on OS for PS >0 vs. 0 (HR 4.34 [1.52-12.36], p = 0.006) and TFPC ≥1.5 years vs. Conclusions: Longer TFPC ≥1.5 years and ECOG-PS = 0 were independently prognostic for better survival with cisplatin-based first-line chemotherapy for advanced UC following prior perioperative cisplatin-based chemotherapy. The present analysis supports employing >1 year from prior perioperative cisplatin-based chemotherapy to re-challenge with cisplatin-based first-line chemotherapy for metastatic disease. Disclosure: All authors have declared no conflicts of interest.

Molecular Profiling of Infiltrating Urothelial Carcinoma of Bladder and Nonbladder Origin

BackgroundInfiltrating UC represents the second most common genitourinary malignancy. Advanced UC has a poor prognosis and new treatments are needed. Molecular profiling of UC might identify biomarkers associated with targeted therapies or chemotherapeutics, providing physicians with new treatment options. Materials and MethodsFive hundred thirty-seven cases of locally advanced or metastatic UC of the bladder, 74 nonbladder, and 55 nonurothelial bladder cancers were profiled using mutation analysis, in situ hybridization, and immunohistochemistry assays for biomarkers predictive of therapy response. ResultsMolecular profiling of UC showed high overexpression of topoisomerase 2α, common phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha and/or phosophatase and tensin homolog (PTEN) alterations in nonbladder (27%) and bladder UC (21%), and rare gene mutations across subtypes. Compared with nonbladder, bladder UC consistently exhibited more frequent abnormal protein expression, including HER2 (10% vs. 3%; P = .04), tyrosine protein c-Kit receptor kinases (11% vs. 5%), c-Met proto-oncogene, receptor tyrosine kinases (25% vs. 8%), androgen receptor (16% vs. 6%), O(6)-methylguanine-methyltransferase (63% vs. 43%), ribonucleotide reductase M1 (32% vs. 11%), Serum protein acidic and rich in cysteine (SPARC) (69% vs. 33%), and topoisomerase 1 (63% vs. 39%). Bladder UC also exhibited increased amplification of HER2 (12% vs. 2%; P = .06). ConclusionComprehensive molecular profiling of UC identified a large number of biomarkers aberrations that might direct treatment in conventional chemotherapies and targeted therapies, not currently recommended in this population. As a group, bladder UC exhibited higher levels of actionable biomarkers, suggesting that UC from different primary sites and non-UC are driven by different molecular pathways. These differences could have clinical implications resulting in different treatment regimens depending on the site of origin of UC.

Postchemotherapy Lymphadenectomy in Patients With Metastatic Urothelial Carcinoma: Long-Term Efficacy and Implications for Trial Design

BackgroundThe contribution of postchemotherapy pelvic (PLND) or retroperitoneal lymphadenectomy (RPLND) on survival in patients with advanced and metastatic UC is still unclear. Patients and MethodsBetween September 1986 and May 2012, 157 patients with locally advanced or metastatic UC received first-line chemotherapy consisting of mMVAC (modified methotrexate, vinblastine, doxorubicin, and cisplatin), according to our policy. Patients with subdiaphragmatic nodal disease and/or local recurrence only and who experienced at least stable disease (SD) were selected. Fifty-nine patients were identified, 28 of whom underwent surgery, 31 started consolidation chemotherapy with or without radiotherapy or observation. The prognostic effect of candidate factors on survival was evaluated using Cox proportional hazard regression models. ResultsA total of 14 PLND and 14 RPLND patients were identified after they had achieved a complete response (CR; n = 7) or a partial response (PR) and SD (n = 21). Median follow-up was 88 months (interquartile range, 24-211 months). Median PFS was 18 (95% confidence interval [CI], 11-not estimated) and 11 (95% CI, 5-19) months, respectively, in favor of the surgical cohort and curves were statistically different (log-rank test, P = .009). In multivariate analysis, postchemotherapy surgery was significantly prognostic for PFS and OS and response to chemotherapy (PR and SD vs. CR) was prognostic for PFS and trended to significance for OS. A model including these 2 factors showed bootstrap-corrected Harrel C statistics for PFS and OS of 0.65 and 0.68, respectively. ConclusionIn well selected patients with UC like those who achieved a clinical benefit with chemotherapy and had nodal metastatic disease, there was a survival advantage in removal of disease residuals.

695 SEQUENTIAL CHEMOTHERAPY WITH GEMCITABINE PLUS CARBOPLATIN, FOLLOWED BY ADDITIONAL DOCETAXEL FOR AGED PATIENTS WITH ADVANCED UPPER-TRACT UROTHELIAL CANCER

You have accessJournal of UrologyUrothelial Cancer: upper Tract Tumors (I)1 Apr 2013695 SEQUENTIAL CHEMOTHERAPY WITH GEMCITABINE PLUS CARBOPLATIN, FOLLOWED BY ADDITIONAL DOCETAXEL FOR AGED PATIENTS WITH ADVANCED UPPER-TRACT UROTHELIAL CANCER Takahiro Yoneyama, Kazuhisa Hagiwara, Takuma Narita, Masaaki Oikawa, Naoki Sugiyama, Yuuichirou Suzuki, Hayato Yamamoto, Akiko Okamoto, Yuuki Tobisawa, Tohru Yoneyama, Atsushi Imai, Kazuyuki Mori, Shingo Hatakeyama, Yasuhiro Hashimoto, Takuya Koie, and Chikara Ohyama Takahiro YoneyamaTakahiro Yoneyama Hirosaki, Japan More articles by this author , Kazuhisa HagiwaraKazuhisa Hagiwara Hirosaki, Japan More articles by this author , Takuma NaritaTakuma Narita Hirosaki, Japan More articles by this author , Masaaki OikawaMasaaki Oikawa Hirosaki, Japan More articles by this author , Naoki SugiyamaNaoki Sugiyama Hirosaki, Japan More articles by this author , Yuuichirou SuzukiYuuichirou Suzuki Hirosaki, Japan More articles by this author , Hayato YamamotoHayato Yamamoto Hirosaki, Japan More articles by this author , Akiko OkamotoAkiko Okamoto Hirosaki, Japan More articles by this author , Yuuki TobisawaYuuki Tobisawa Hirosaki, Japan More articles by this author , Tohru YoneyamaTohru Yoneyama Hirosaki, Japan More articles by this author , Atsushi ImaiAtsushi Imai Hirosaki, Japan More articles by this author , Kazuyuki MoriKazuyuki Mori Hirosaki, Japan More articles by this author , Shingo HatakeyamaShingo Hatakeyama Hirosaki, Japan More articles by this author , Yasuhiro HashimotoYasuhiro Hashimoto Hirosaki, Japan More articles by this author , Takuya KoieTakuya Koie Hirosaki, Japan More articles by this author , and Chikara OhyamaChikara Ohyama Hirosaki, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.251AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Gemcitabine+cisplatin may be a promising regimen for advanced upper-tract UC as well as for advanced bladder cancer. However, cisplatin is proved to be too toxic for the patients with impaired renal function and aged patients. Cisplatin often unfits for those patients. We retrospectively evaluated the effectiveness and adverse events (AEs) of a sequential chemotherapy with gemcitabine+carboplatin(GCarbo) followed by GCcarbo+ docetaxel (GCD) for advanced upper-tract UC. METHODS 44 patients with advanced upper-tract urothelial cancer (30 men and 14 women) with the age of 65 years or older were enrolled. They were treated at our clinic between September 2004 and December 2011. Mean age was 73.0 (65–89), and mean creatinine clearance was 47.9 (11.6–99.2) ml/minute. Mean observation period was 17.9 (3–63.4) months. The patients received 2 courses of GCarbo consisted of 800mg/m2 gemcitabine on days 1, 8, and 15 and carboplatin (AUC 4) on day 2. If this regimen was effective, another 2 courses of GCcarbo was performed. If this regimen did not induce any tumor size reduction, we switched to 2 courses of GCD (70mg/m2) treatment as second-line treatment. RESULTS GCarbo regimen yielded 1 cases (2.2%) of CR, 20 (45.5%) of PR, and the mean duration of response of 8.1(3–50) months. GCD treatment was administered in 10 cases, and yielded one (10.0%) PR and a duration of response was 7.0 months. The median survival period was 14.0 months with GCcarbo/GCD regimens. As for ARs with GCcarbo regimen, there were 23 (52.2%) of G3/4 blood toxicity and 5 (11.4%) of G3/4 urticaria. In GCD regimen, there were 10 (100%) of blood toxicity and 6 (60.0%) of gastrointestinal AEs. There was no G3/4 renal toxicity in both regimens. CONCLUSIONS Although the present study is small and preliminary, the present sequential chemotherapy is safe and active for advanced upper-tract urothelial cancer of the patients 65 years or older. GCarbo regimen achieved relatively high response rate (47.7%) in advanced upper-tract urothelial cancer . The median overall survival of 14.0 months is acceptable when average age of 73.0 year for the subjects is took into consideration. However, GCD had limited effectiveness for non-responder of GCarbo. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e285-e286 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takahiro Yoneyama Hirosaki, Japan More articles by this author Kazuhisa Hagiwara Hirosaki, Japan More articles by this author Takuma Narita Hirosaki, Japan More articles by this author Masaaki Oikawa Hirosaki, Japan More articles by this author Naoki Sugiyama Hirosaki, Japan More articles by this author Yuuichirou Suzuki Hirosaki, Japan More articles by this author Hayato Yamamoto Hirosaki, Japan More articles by this author Akiko Okamoto Hirosaki, Japan More articles by this author Yuuki Tobisawa Hirosaki, Japan More articles by this author Tohru Yoneyama Hirosaki, Japan More articles by this author Atsushi Imai Hirosaki, Japan More articles by this author Kazuyuki Mori Hirosaki, Japan More articles by this author Shingo Hatakeyama Hirosaki, Japan More articles by this author Yasuhiro Hashimoto Hirosaki, Japan More articles by this author Takuya Koie Hirosaki, Japan More articles by this author Chikara Ohyama Hirosaki, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

External validation of prognostic models for overall survival (OS) in patients (pts) with advanced cancer (UC) treated with cisplatin-based chemotherapy.

4592 Background: The most commonly used model predicting OS for UC pts treated with cisplatin-based chemotherapy is based on 2-variables (visceral metastases and performance status), developed at MSKCC in 1999, and validated in a phase III study (DeSantis JCO 2011). A prognostic model of OS for advanced UC pts based on 4 variables (visceral metastases, albumin, performance status, and hemoglobin) was developed using 308 pts from MSKCC (ASCO 2007 abstr 5055). We report the discriminative ability of the 4- and 2- variable models for advanced UC pts using an independent dataset from CALGB 90102. Methods: The analysis was performed using an external multi-institutional dataset from CALGB 90102. The primary measurement of predictive discrimination was Harrell’s c-index which was computed with 95% confidence interval (CI). To assess whether there was a statistically significant difference in discrimination between the two models, the U statistic was used to test whether the predictions of the 4-variable model in all possible pairs were more concordant with actual observations than the 2-variable model in the same pairs. Results: CALGB 90102 included 74 UC pts (58 males, 16 females), median age 64 years, treated with cisplatin, gemcitabine and gefitinib, enrolled from 7/02 to 4/05 with a median follow-up of 72.5 months. Visceral metastases were present in 64% (bone, 18%, liver, 31%, lung, 43%), median KPS 90%. The MSKCC 2-variable risk group distribution was 30% =0, 65%= 1 and 5%=2. The median OS =12.7 months (95% CI=10.4-20.5) with 68 deaths observed. When applied to the CALGB cohort, the predictive accuracy for the 4- and 2-variable models were 0.63 (95 CI= 0.56- 0.69) and 0.58 (95% CI= 0.52-0.65), respectively. There was a statistically significant difference in discrimination between the two models (p =0.019), with superiority of the 4-variable model compared to the 2-variable model. Conclusions: A 4-variable prognostic nomogram for survival in pts with advanced UC was superior to a 2-variable risk-group model. The 4-variable prognostic model may replace the widely used 2-variable model and can be used in the design and conduct of future phase II and III trials in advanced UC.

Paclitaxel gemcitabine (P-G) for patients (pts) with advanced urothelial cancer (UC) age &gt; 70 years (yrs): SWOG 0028.

4569 Background: Pts age ≥ 70 yrs are under-represented in cancer trials. Primary aim: to assess feasibility of enrolling pts age ≥ 70 yrs with advanced UC to phase II trial of P-G with PK and PD sampling. Secondary aims: assess toxicity, response, feasibility of self-report measures of comorbidity, depression and functional status, and study of genetic polymorphisms. Methods: Key eligibility included: histologic confirmation; age ≥70 yrs, or < 60 yrs; previously untreated advanced, measurable or evaluable UC; standard biochemical and hematologic parameters; Zubrod performance status 0-2; agreement to undergo PK and PD tests; written informed consent. Pts treated with P 175mg/m2 day1 (d1) and G 1000mg/m2 d1&8, with standard anti-emetic Rx, repeat q21 days, 6 cycles. Pts completed Medical Conditions Questionnaire, Instrumental Activities of Daily Living Form, and the Feelings Questionnaire. Nurses assessed same issues. Toxicity assessed via standard SWOG parameters. PK and gene polymorphisms for P and G me...

ULTRAFINE GRAINED AND NANOSTRUCTURED MATERIALS FOR ADVANCED ENERGY APPLICATIONS

The understanding of nanoscale interactions of nuclear materials will help to mastering the complex behavior of actinides and of fission products, and the interfacial behavior of fuel-cladding under extreme conditions. Ultrafine grained and nanostructured engineering materials are also suggested as protective armors on the plasma-facing first wall of D-T fusion power plants. We review the constitution and preparation by arc-melting and ball milling of ultrafine grained materials for the advanced nuclear reactor fuels UC, UC-W, UN, UN- Mo , and UN-W. We report also the preparation of the first wall armour materials nano-W, nano W-Y alloys, nano-graphite, and nano- B4C by high energy ball milling and their characterization by metallography, XRD, DSC and HRTEM.