differences in the recurrence pattern after neoadjuvant chemotherapy ...

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metastasis included variant histology (OR ¼ 2.06; p ¼ 0.026) and extravesical disease (OR ¼ 2.76; p ¼ 0.002). Patients with an ICT > 85 days had a higher risk of node metastasis though this was not significant. CONCLUSIONS: Patients can undergo RC anytime between 2.5 - 12 weeks after NAC with no difference in risk of surgical complications or nodal metastasis. Source of Funding: n/a

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months (IQR 8, 54). On Cox regression analysis, OS was associated with male gender, pN0, negative surgical margins and cisplatin therapy. CONCLUSIONS: Complete pathological nodal response can be achieved in a significant proportion of cN1-3 patients receiving induction chemotherapy. The best outcomes are observed in those receiving cisplatin regimens who have negative RC margins and complete nodal response (pN0).

MP65-06 A MULTI-INSTITUTIONAL ANALYSIS OF OUTCOMES IN PATIENTS WITH CLINICALLY NODE POSITIVE UROTHELIAL BLADDER CANCER TREATED WITH INDUCTION CHEMOTHERAPY AND RADICAL CYSTECTOMY Kamran Zargar-Shoshtari*, Tampa, FL; Homayoun Zargar, Vancouver, Canada; Adrian S. Fairey, Los Angeles, CA; Laura S. Mertens, Amsterdam, Netherlands; Colin P. Dinney, Houston, TX; Maria C. Mir, Cleveland, OH; Laura-Maria Krabbe, Dallas, TX; Michael S. Cookson, Oklahoma, OK; Niels-Erik Jacobsen, Edmonton, Canada; Nilay Gandhi, Baltimore, MD; Joshua Griffin, Kansas City, KS; Jeffrey S. Montgomery, Ann Arbor, MI; Nikhil Vasdev, Newcastle Upon Tyne, United Kingdom; Evan Y. Yu, Seattle, WA; Evanguelos Xylinas, New York, NY; Nicholas J. Campain, Exeter, United Kingdom; Wassim Kassouf, Montreal, Canada; Marc A. Dall’Era, Sacramento, CA; Jo-An Seah, Toronto, Canada; Pranav Sharma, Tampa, FL; Cesar E. Ercole, Cleveland, OH; Simon Horenblas, Amsterdam, Netherlands; Srikala S. Sridhar, Toronto, Canada; John S. McGrath, Jonathan Aning, Exeter, United Kingdom; Shahrokh F. Shariat, Vienna, Austria; Jonathan L. Wright, Seattle, WA; Andrew C. Thorpe, Newcastle Upon Tyne, United Kingdom; Todd M. Morgan, Ann Arbor, MI; Jeff M. Holzbeierlein, Kansas City, KS; Trinity J. Bivalacqua, Baltimore, MD; Scott North, Edmonton, Canada; Daniel A. Barocas, Nashville, TN; Yair Lotan, Dallas, TX; Jorge A. Garcia, Andrew J. Stephenson, Cleveland, OH; Jay B. Shah, Houston, TX; Bas W. van Rhijn, Amsterdam, Netherlands; Siamak Daneshmand, Los Angeles, CA; Philippe E. Spiess, Tampa, FL; Peter Black, Vancouver, Canada INTRODUCTION AND OBJECTIVES: Selected bladder cancer patients with pelvic lymphadenopathy (cN1-3) are treated with induction chemotherapy followed by radical cystectomy (RC). However, there is little data on clinical outcomes in these patients. We aimed to assess pathological and survival outcomes in cN1-3 patients treated with induction chemotherapy and RC. METHODS: Data was collected on patients from 19 North American and European centers with clinical stage T1N1-3M0/T2T4aN0-3M0 urothelial carcinoma who received chemotherapy followed by RC between 2000 and 2013. The outcomes in the cN1-N3 group were assessed in this study. Chemotherapy regimens were methotrexate/ vinblastine/ doxorubicin/ cisplatin (MVAC), gemcitabine/cisplatin (GC) or “other” non-cisplatin combinations. The primary endpoints were complete (pCR, pT0N0) and partial (pPR, pT1N0) response rates and overall survival (OS) was a secondary endpoint. Logistic regression and Cox proportional hazard ratios were used for multivariate analysis of factors predicting pCR, pPR and OS. RESULTS: Of 1618 patients in the database, 304 (18.8%) had clinical evidence of lymph node involvement (cN1-N3) and formed the study population. MVAC was used in 128 (42.1%), GC in 132 (43.4%) and other regimens in 44 patients. The pN0 rate was 48% (cN1:55.6%, cN2:39.2%, cN3:38.5%, p¼0.034). The pCR and pPR rates for the entire cohort were 14.5% and 26.6% respectively. In a multivariate analysis of factors predicting pCR, there was a trend favoring male gender (OR: 2.311 [95% CI: 0.916-5.832], p¼0.076) and cisplatin regimens (OR: 2.528 [CI: 0.948-6.743], p¼0.064). In a similar analysis, cisplatin chemotherapy was the only significant predictor of pPR (OR: 2.165 [CI: 1.008-4.651], p¼0.048). The estimated median OS time for the cohort was 22

Source of Funding: none

MP65-07 DIFFERENCES IN THE RECURRENCE PATTERN AFTER NEOADJUVANT CHEMOTHERAPY COMPARED TO SURGERY ALONE IN PATIENTS WITH MUSCLE-INVASIVE BLADDER CANCER Hiromichi Iwamura*, Takuya Koie, Hayato Yamamoto, Atsushi Imai, Shingo Hatakeyama, Takahiro Yoneyama, Yasuhiro Hashimoto, Tohru Yoneyama, Yuki Tobisawa, Chikara Ohyama, Hirosaki, Japan INTRODUCTION AND OBJECTIVES: In patients with muscleinvasive bladder cancer (MIBC), neoadjuvant chemotherapy confers a survival benefit compared to radical cystectomy (RC) alone. Recurrence is observed in many cases and is the most common cause of death in MIBC patients. However, the rate and pattern of recurrence after neoadjuvant chemotherapy in MIBC patients remains unclear. METHODS: We retrospectively reviewed the charts of 348 consecutive patients who underwent RC and bilateral pelvic node dissection (PLND) between May 1994 and July 2012. Our study focused on patients with MIBC who had histologically confirmed stage T2eT4a urothelial carcinoma of the bladder without lymph node or distant metastasis. Accordingly, 265 patients were included in this analysis, of whom, 130 received neoadjuvant chemotherapy (NAC) and 135 underwent RC alone. Propensity score matching was used to adjust for potential selection biases associated with treatment type. Recurrence was defined as local recurrence and distant metastasis, according to site. RESULTS: Propensity score matching analysis identified 130 matched pairs from the 2 groups. For the neoadjuvant gemcitabine and carboplatin (GCarbo) and RC alone groups, the 5-year overall survival rates were 89.2% and 51.4%, respectively (P < 0.0001) and the recurrence-free survival rates were 85.4% and 57.0%, respectively (P < 0.0001). However, the total number of local recurrences was markedly lower in the neoadjuvant GCarbo group than in the RC alone group.

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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.

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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.