MP65-09 IMPACT OF PERIOPERATIVE CHEMOTHERAPY ON ...

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May 18, 2015 - decrease in S6 phosphorylation H-score of 12.5% versus a 115% in- crease for ... plus adjuvant chemotherapy, and adjuvant chemotherapy was deliv- ered in 12 (31%), 6 (15%) and 21 (54%) of these patients, respectively.
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CONCLUSIONS: Neoadjuvant GCarbo was associated with improved oncological outcomes and a different recurrence pattern in MIBC patients compared to RC alone. Source of Funding: none

MP65-08 A PHARMACODYNAMIC PHASE 0/I STUDY OF ORAL RAPAMYCIN IN PATIENTS UNDERGOING RADICAL CYSTECTOMY FOR BLADDER CANCER Aashish Kabra*, Essel Marie de Leon, Carolina Livi, Martin Javors, Marlo Nicolas, David Henkes, Dave Sharp, Tyler Curiel, Robert Svatek, San Antonio, TX INTRODUCTION AND OBJECTIVES: Mammalian target of rapamycin (mTOR) inhibitors have demonstrated significant efficacy in bladder cancer in preclinical models. Given discrepancies between preclinical and clinical observations of mTOR inhibition in multiple solid malignancies, we sought to determine pharmacokinetic and pharmacodynamic properties of the mTOR/TORC1 inhibitor rapamycin on bladder tumor tissue in patients undergoing radical cystectomy. METHODS: Patients with muscle-invasive bladder cancer were randomized to receive 3 mg oral rapamycin daily for 4 weeks or no treatment following transurethral resection of bladder tumor (TURBT) and prior to radical cystectomy. Blood and tumor tissue was collected at time of TURBT and cystectomy. The primary outcome measured was the inhibition of phosphorylation of ribosomal S6 protein in cystectomy compared to biopsy specimens. Secondary objectives included measurement of rapamycin blood and tissue levels, concurrent evaluation of pAKT, total AKT, 4EBP-1, and PTEN expression, and safety. S6 phosphorylation was assessed by immunohistochemistry as an indirect measure of S6 kinase activity using a validated antiphospho ribosomal S6 antibody and using an H-score. RESULTS: Twenty patients were accrued including 11 receiving rapamycin and 9 controls. No dose-limiting toxicities were observed. Therapy was discontinued in 1 patient who experienced a cerebrovascular accident which was not attributed to rapamycin. Poor wound healing was observed in 27% of rapamycin-treated patients compared to none of the non-treated patients. Pharmacodynamic studies showed tumor S6 phosphorylation inhibition in 64% of 11 rapamycin-treated patients and 12.5% of 8 evaluable non-treated men with sufficient paired tissue (P¼0.025). Rapamycin-treated patients had a median percentage decrease in S6 phosphorylation H-score of 12.5% versus a 115% increase for controls (P¼0.006). Bladder tissue rapamycin concentrations were 3-fold higher than blood. Phospho-S6 inhibtion correlated strongly with rapamycin blood and tissue levels. No significant effect was observed on pAKT, total AKT or 4EBP-1. Two rapamycin-treated patients with an increase in S6 phosphorylation had elevated pAKT on TURBT. CONCLUSIONS: Rapamycin successfully inhibited bladder cancer S6 phosphorylation and achieved high bladder tissue concentrations. Blood level of 10 ng/mL correspond to tissue levels of 30 ng/g and represent target level to achieve consistent phospho-S6 inhibition. Treatment should not be continued up until surgery due to potential for poor wound healing.

Vol. 193, No. 4S, Supplement, Monday, May 18, 2015

MP65-09 IMPACT OF PERIOPERATIVE CHEMOTHERAPY ON SURVIVAL IN PATIENTS WITH ADVANCED PRIMARY URETHRAL CANCER: RESULTS OF THE INTERNATIONAL COLLABORATION ON PRIMARY URETHRAL CARCINOMA €bingen, Germany; Todd Morgan, Ann Arbor, MI; Georgios Gakis*, Tu €bingen, CA; Kirk Keegan, Harras Zaid, Siamak Daneshmand, Tu Nashville, TN; Jan Hrbacek, Prague, –; Bedeir Ali-El-Dein, Mansoura, €fer, Tu €bingen, Egypt; Rebecca Clayman, Boston, MA; Tilman Todenho Germany; Sigolene Galland, Boston, MA; Kola Olugbade Jr., Ann Arbor, MI; Michael Rink, Hamburg-Eppendorf, Germany; Hans-Martin Fritsche, Maximillian Burger, Regensburg, Germany; Sam Chang, Nashville, TN; Marko Babjuk, Prague, Czech Republic; George Thalmann, Bern, €bingen, Germany; Jason Efstathiou, Switzerland; Arnulf Stenzl, Tu Boston, MA INTRODUCTION AND OBJECTIVES: Primary urethral carcinoma (PUC) is an uncommon but potentially lethal genitourinary malignancy that meets the definition of a “rare cancer,” accounting for well under 1% of all malignancies. In Western countries, the incidence is reported to range between 0.6-1.6 per 1.000.000. Given the rarity of this cancer, there remain critical gaps in our understanding of the optimal management of patients with PUC. In particular, there are no reports we are aware of addressing the timing of perioperative chemotherapy in patients with clinically advanced PUC. In order to evaluate this clinical need, we have assembled a multi-institutional collaborative with the aim of determining the prognostic impact of neoadjuvant and adjuvant treatment in patients undergoing surgery for PUC. METHODS: A contemporary series of 124 patients (86 men, 38 women) were diagnosed with and underwent surgery for PUC in ten referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank testing was used to investigate the impact of perioperative chemo(radio)therapy on relapse-free(RFS) and overall survival (OS). The median follow-up was 21 months (mean: 32 months; IQR: 5-48). RESULTS: Median age at surgery was 64 years (IQR: 58-71). Perioperative chemo(radio)therapy was administered in 39 patients (31%). Neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy plus adjuvant chemotherapy, and adjuvant chemotherapy was delivered in 12 (31%), 6 (15%) and 21 (54%) of these patients, respectively. Receipt of neoadjuvant chemo(radio)therapy was significantly associated with clinically node-positive disease (cNþ; p¼0.033) and lower utilization of cystectomy at surgery (p¼0.015). Only pT3 stage at surgery (p¼0.034/0.030) was a significant predictor of RFS/OS. In the subset of 29 patients (21% of the entire cohort) with stage cT3 and/or cNþ disease, 16 (55%) received perioperative chemo(radio)therapy and 13 surgery alone (45%). The 3-year OS for this locally advanced subset of patients receiving neoadjuvant chemotherapy (N¼5), neoadjuvant chemoradiotherapy plus adjuvant chemotherapy (N¼3), surgery alone (N¼13) or surgery plus adjuvant chemotherapy (N¼8) was 100%, 100%, 50% and 20%, respectively (p¼0.016). CONCLUSIONS: In this series, patients who received neoadjuvant chemotherapy or chemoradiotherapy for locally advanced PUC appeared to demonstrate improved survival compared to those who underwent upfront surgery with or without adjuvant chemotherapy. Source of Funding: None.

Source of Funding: IIMS/CTRC KL2 Scholar in Clinical and Translational Science, Voelcker Fund Young Investigator Award

MP65-10 DELAYED RADICAL CYSTECTOMY IN PATIENTS WITH MUSCLEINVASIVE BLADDER CANCER: A NATIONWIDE ANALYSIS Harman Maxim Bruins*, Katja Aben, Tom Arends, Toine van der Heijden, Fred Witjes, Nijmegen, Netherlands INTRODUCTION AND OBJECTIVES: According to the current EAU muscle-invasive bladder cancer (MIBC) guideline, radical cystectomy (RC) should be performed within 90 days after diagnosing MIBC. We performed a nationwide analysis investigating the adherence to this recommendation. In addition, factors associated with delayed RC (i.e. >90 days) and its impact on survival outcomes were analyzed.