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187 Background: In the past decade, several therapies have been approved for mCRPC. However, most pts develop resistance and experience disease progression. Thus, there remains a high unmet need. Atezo (anti–PD-L1) blocks the interaction between PD-L1 and its receptors, PD-1 and B7.1, thereby restoring anti-tumor immunity. Atezo has demonstrated clinical efficacy in many tumor types. Here we report the clinical safety and activity of atezo in pts with mCRPC from a Phase Ia study (PCD4989g; NCT01375842). Methods: Eligible pts previously received enzalutamide and/or sipuleucel-T for mCRPC. Pts also had PSA or radiographic progression prior to enrollment. Atezo 1200mg was administered IV q3w. CT and bone scans were performed q6w for 24w and q12w thereafter (q6w if treatment beyond disease progression). Primary objectives were safety and tolerability; OS was an exploratory objective. mCRPC cohort–specific objectives included PSA response, radiographic progression per PCWG2 criteria, soft tissue response per RECIST v1.1 and immune-related response criteria (irRC). Survival follow-up data was collected ≈ every 3 mo until death or loss to follow-up. Results: The 15 pts in the initial mCRPC cohort were evaluated (clinical cutoff: December 31, 2016). 13 pts (87%) had received ≥ 2 prior lines of therapy for mCRPC. Median survival follow-up was 15.8 mo (range, 2.3-23.0). 9 pts (60%) had a treatment-related AE (TRAE); only 1 pt (7%) experienced a Gr 3 TRAE (hyponatremia). No Gr 4-5 TRAEs were reported. The landmark 12-mo OS rate was 55.6% (95% CI: 27.4, 83.7); median OS was not reached (range, 2.3-23.0 mo). Median PFS was 3.4 mo (95% CI: 2.3, 5.7); the 6-mo PFS rate was 26.7% (95% CI: 4.3, 49.1). 1 pt (9%) had a PR per irRC (irPR); 5 pts (45%) had SD per RECIST v1.1 and irRC. 2 pts (13%) had a ≥ 50% decrease in PSA from baseline. The pt who experienced an irPR had increased CD8 expression and expansion of T-cell clones on study treatment. Conclusions: Atezo was well tolerated and demonstrated long-term disease control in pts with heavily pretreated mCRPC, with a 12-mo OS rate of 55.6%. Preliminary biomarker analyses from the pt who experienced an irPR were suggestive of an activated immune response. Clinical trial information: NCT01375842.

A 57-year-old woman presented to the emergency department at a community hospital with a 2-month history of fatigue and right-sided flank and abdominal pain. Noncontrast CT of the abdomen and pelvis revealed a 9.1 cm right renal mass.Contrast CT of the chest, abdomen and pelvis, MRI of the abdomen and pelvis with gadolinium, radionuclide bone scan, lung nodule biopsy, complete blood count, comprehensive metabolic profile, and measurement of serum lactate dehydrogenase.Stage IV, T3bN0M1 clear cell renal cell carcinoma, with an associated tumor thrombus extending into the vena cava.The patient was treated with neoadjuvant sunitinib, which resulted in a marked response in the primary tumor and metastatic lesions as well as regression of the tumor thrombus well into the renal vein. Thus, laparoscopic radical nephrectomy was feasible and was achieved without hemorrhagic or wound healing complications. One month after surgery, she had evidence of disease progression in the lung and a periaortic lymph node. She was restarted on sunitinib with resultant disease stabilization, but discontinued the drug owing to toxicity. Eight months after cessation of sunitinib, she received a dendritic cell vaccine. She remains alive without evidence of disease progression 2 years after her diagnosis.

Objective: Despite the introduction of newer treatment approaches in metastatic renal cell carcinoma (mRCC), overall survival remains disappointing and further exploration of current chemotherapeutic agents for second or third-line treatment is imperative. We conducted a phase II trial to determine the efficacy and safety of the combination of thalidomide and capecitabine in mRCC. Materials and Methods: We enrolled 13 eligible patients, who had progressive measurable metastatic disease, between May 2003 and January 2005. Treatment consisted of thalidomide 200 mg daily for 21 days per cycle, and capecitabine 1250 mg/m2 twice daily for 14 days per cycle. The primary end point was response rate. Secondary endpoints included overall survival and toxicity assessment. Results: Twelve patients were eligible for statistical analysis. The median age was 59 years, and most patients had an Eastern Cooperative Oncology Group performance status of 0–1 (92%). Nine patients had previous nephrectomy. The median number of administered cycles was 4 (range 2–10). Anemia was the only grade 3 toxicity. Grade 2 toxicities included fatigue, constipation, anemia, hand-foot syndrome, diarrhea, and peripheral neuropathy. Although no radiographic responses were observed, 5 patients (42%) achieved stable disease. Seven patients (58%) experienced disease progression. The median overall survival was 10.2 months. Conclusion: Despite being well tolerated with manageable side effects, the use of thalidomide and capecitabine in patients with mRCC did not significantly impact response or survival.

In 2014, more than 74,000 new cases and 15,000 deaths from bladder cancer were estimated to occur. The most reliable prognostic factors for survival are pathologic stage and histologic grade. Accordingly, a good understanding of the pathologic features of these cancers is essential to guide optimal clinical treatment, which requires a multidisciplinary team of pathologists, urologists, radiation oncologists, and medical oncologists. This review highlights several clinical scenarios in which detailed pathologic evaluation and accurate reporting impact clinical management.

Non-clear cell renal cell carcinomas (RCCs) represent up to 20% of all RCCs. Despite often being clustered as a single entity, these tumors represent a heterogeneous group of diseases with distinct molecular drivers, histologies, and clinical outcomes. Their low incidence and heterogeneity have resulted in a lack of studies that address the optimal strategies for each subtype. This article (the first in a 2-part series) reviews the histology of RCC, whereas the second article reviews current targeted therapies approved for RCC, such as the vascular endothelial growth factor receptor tyrosine kinase inhibitors and the mammalian target of rapamycin inhibitors. Ongoing studies will provide more information regarding the role of these agents in non-clear cell RCC.

Non-clear cell renal cell carcinomas (RCCs) represent a heterogeneous group of diseases with distinct molecular drivers, histologies, and clinical outcomes. Their low incidence and heterogeneity have resulted in a lack of studies that address the optimal strategies for each subtype. This article (the second in a 2-part series) reviews the current targeted therapies approved for RCC, such as the vascular endothelial growth factor receptor tyrosine kinase inhibitors and the mammalian target of rapamycin inhibitors. Ongoing studies will provide more information regarding the role of these agents in non-clear cell RCC. Ultimately, enhanced understanding of genetic triggers and the development of more tailored treatments remain imperative to improve outcomes in non-clear cell RCC.

Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells.To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer.In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013.To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors.In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] for M0 disease and 0.84 [95% CI, 0.67-1.06] for M1 disease; P for interaction = .72).Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.

Patients with mRCC may have variable clinical courses when treated with targeted therapy. The two extremes of the survival spectrum need to be characterized. Analyzing data from a large database (International Metastatic Renal Cell Carcinoma Database Consortium - IMDC) we found that baseline prognostic criteria and absence of PD after first- and second-line targeted therapy may discriminate long-term survival. Background: Targeted therapies improve survival in metastatic renal cell carcinoma (mRCC). However, survival patterns can be divergent, and patients at the 2 extremes of the survival spectrum need to be characterized. Patients and Methods: Data from 2161 patients included in the International mRCC Database Consortium (IMDC) were analyzed. We identified patients on the basis of their duration of survival. Long-term survival (LTS) was defined as overall survival (OS) of � 4 years, and short-term survival (STS) was defined as OS of � 6 months from the start of targeted therapy. Baseline characteristics, including demographic, clinicopathologic, and laboratory data, were compared between LTS and STS. Treatment response by the RECIST criteria was summarized for the 2 survival groups. Results: A total of 152 patients experienced LTS and 218 experienced STS. Adverse clinical and laboratory prognostic factors previously described in the IMDC prognostic model were significantly more frequent in the STS group (P < .0001). In the LTS group, 138 patients (91%) had nonprogressive disease (non-PD) as best response to first-line targeted therapy, and 56 (60%) of 94 patients who received second-line therapy had non-PD. In the STS group, only 51 patients (23%) had non-PD on first-line therapy. None of 21 the patients who received secondline therapy had non-PD as best response. In LTS, the median duration of therapy was 23.6 months (range 0.4 to

Background: Targeted therapies (TTs) have revolutionized metastatic renal cell carcinoma (mRCC) treatment in the past decade, largely replacing immunotherapy including high-dose interleukin-2 (HD IL-2) therapy. We evaluated trends in HD IL-2 use for mRCC in the IT era. Methods: Our cohort comprised a weighted estimate of all patients undergoing HD IL-2 treatment for mRCC from 2004 to 2012 using the Premier Hospital Database. We assessed temporal trends in HD IL-2 use including patient. disease, and hospital characteristics stratified by era (pre-TT uptake: 2004-2006, uptake: 2007-2009, and post-TT uptake: 2010-2012) and fitted multivariable regression models to identify predictors of treatment toxicity and tolerability. Results: An estimated 2,351 patients received HD IL-2 therapy for mRCC in the United States from 2004 to 2012. The use decreased from 2004 to 2008. HD IL-2 therapy became increasingly centralized in teaching hospitals (24% of treatments in 2004 and 89.5% in 2012). Most patients who received HD IL-2 therapy were men, white, younger than 60 years, had lung metastases, and were otherwise healthy. Vasopressors, intensive care unit admission, and hemodialysis were necessary in 53.4%, 33.0%, and 7.1%, respectively. Factors associated with toxicities in multivariable analyses included being unmarried, male sex, and multiple metastatic sites. African Americans and patients with single-site metastases were less likely to receive multiple treatment cycles. Conclusions: HD IL-2 therapy is used infrequently for mRCC in the United States, and its application has diminished with the uptake of TT. Patients are being increasingly treated in teaching hospitals, suggesting a centralization of care and possible barriers to access. A recent slight increase in HD IL-2 therapy use likely reflects recognition of the inability of TT to effect a complete response. (C) 2015 Elsevier Inc. All rights reserved.

The immune checkpoint inhibitors have shown outstanding clinical benefits in many tumor types. While the cytokine interleukin-2 was FDA approved to treat metastatic RCC over twenty years, this therapy is highly toxic and suffers from low response rates. Over the last decade an alternate method of stimulating antitumor T lymphocyte activity has been in clinical development: immune checkpoint inhibition. By blocking the pathways that dampen lymphocyte activity, the immune system can produce impressive antitumor responses which can be potentially durable. Ipilimumab, which blocks cytotoxic T lymphocyte antigen-4 (CTLA-4) activity, was the first immune checkpoint blocking agent to be FDA approved for the treatment of metastatic melanoma. The next generation of immune checkpoint inhibitors block the PD-1/PD-L1 pathway which likely work by re-activating cytotoxic CD8+ T cells. These agents appear to be less toxic than high dose IL-2 or ipilimumab. Here we will review the progress in the field and focus on the early clinical trials for patients with metastatic RCC.

Objectifs Comparer l’efficacite de la therapie trimodale (TTM) vs. cystectomie radicale (CR) pour le traitement des tumeurs de vessie infiltrant le muscle (TVIM) localisees. Methodes Nous avons realise une etude observationnelle a partir de la Nationale Cancer Data Base. Les patients ayant recu un traitement curatif pour une TVIM localisee entre 2003 et 2011 ont ete identifies et inclus dans les groupes TTM et CR. La TTM etait definit comme la realisation d’une resection transuretrale de vessie, suivie d’une radiochimiotherapie concomitante ≥ 59 Gy ou ≥ 39 Gy avec CR de sauvetage. Des courbes de Kaplan-Meier et un modele de Cox avec covariable changeante au cours du temps, ajustes par la probabilite inverse de recevoir la TTM (IPTW) ont ete utilises pour comparer la survie globale entre les 2 groupes de traitement. Resultats Au total, 625 (4,48 %) et 13,313 (95,52 %) patients avec une TVIM localisee ont recu une TTM et CR, respectivement. Les courbes de Kaplan-Meier ( Fig. 1 ) montraient une diminution significative de la survie globale chez les patients ayant recu TTM vs. RC (32,33 vs. 43,53 mois ; p = 0,004). Le taux de survie globale a 5 ans etait de 37,53 % vs. 43,89 %, chez les patients ayant recu le TTM vs. RC, respectivement. L’analyse de Cox montrait que la TTM vs. CR etait associe a une diminution significative de la survie globale (HR = 0,56 ; p p = 0,340), les femmes ( p = 0,604), les patients avec un score de Charlson ≥ 2 ( p = 0,251) et ceux avec une tumeur ≥ cT3 ( p = 0,633). Conclusion Bien que la survie globale soit generalement meilleure apres CR vs. TTM pour le traitement des TVIM localisees, certains sous-groupes de patients pourraient choisir un traitement conservateur sans que cela impacte negativement leur survie.

e16001 Background: Cystectomy and RT are both utilized in the management of MIBC. Elderly pts are more likely to be treated with non-surgical approaches that include RT. Using the SEER database, we evaluated outcomes in elderly pts with MIBC. Methods: Inclusion required pts ≥75 years with MIBC (T2-4, N0-3, M0). Cohorts were based on treatment received: cystectomy; RT; TURBT or no treatment. A propensity score was developed to address differences in treatment allocation according to age, race, sex, T and N stage, tumor location, and year of diagnosis. Propensity-adjusted competing risks analysis compared cancer specific mortality (CSM) between cohorts. Results: We identified 8506 pts with MIBC treated from 2007-2012. Of the 8423 pts with adequate treatment data, 26% had cystectomy (2196), 21% underwent RT (1752), 49% received TURBT alone (4128), 3% (262) received no treatment, and 1% (85) received both RT and cystectomy. Compared to RT, cystectomy cohort had a significantly higher proportion of pts < 80 yrs (49% vs. 25%) and was surgically staged with a higher degree of node + (22% vs. 4%) and ≥T3 disease (58% vs. 17%; all P < 0.001). At median follow-up of 10 mo (0-71), 48% (1061) of cystectomy pts and 61% (1064) of RT pts had died. MIBC was the leading cause of death (31% cystectomy, 39% RT). On propensity adjusted analysis, RT was associated with significantly worse CSM (HR: 1.62; 95% CI: 1.45-1.82) compared to cystectomy. Patients treated with TURBT or no treatment had the worst outcomes (5 year CSM: 71% each). Conclusions: Even in elderly pts with competing morbidities, MIBC accounted for more deaths than other causes. In this SEER cohort, non-surgical approaches involving RT were associated with significantly worse outcomes compared to cystectomy. However, worse performance status, less concurrent chemotherapy use, discrepancies between pathologic and clinical staging, use of lower dose RT, or lack of completion TURBT could not be examined and could have contributed to worse outcomes in the RT cohort. These results highlight the need for aggressive management of fit elderly patients with cystectomy or multimodality BPT.

4585 Background: Adjuvant trials aim to integrate systemic therapy earlier to increase cure rates over surgery alone. Overall survival (OS) is a critical endpoint for these studies but requires long durations to events and significant patient resources. We explored the potential use of disease-free survival (DFS) as an intermediate readout for OS in the adjuvant setting for localized renal cell carcinoma (RCC). Methods: We performed a systematic literature review following the PRISMA guidelines. Inclusion criteria required randomized controlled trials (RCT) for adjuvant systemic therapy in localized RCC, which reported on both DFS and OS. Data on hazard ratio (HR) and 5-year event-free rate from Kaplan-Meier estimates were extracted. We performed a trial level meta-analysis and correlated these estimates for OS and DFS, weighted by the number of DFS events. R-square > 0.7 would indicate a strong correlation and potential for surrogacy. Results: Thirteen RCTs encompassing 6,473 patients treated with various forms of systemic therapy were eligible for the analyses. Minimum follow-up was 40 months. There was a moderate correlation between 5-year DFS and 5-year OS rates (R-square = 0.49, 95% CI:0.15-0.68) and between treatment effects as measured by DFS and OS hazard ratios (R-square = 0.44, 95% CI:0.00-0.69). Conclusions: Across trials of adjuvant systemic therapy for localized RCC, we observed a moderate correlation between 5-year DFS and OS rates and between treatment effects (HRs) on these endpoints. Further granularity may be achieved using individual patient data to assess different and earlier time points for surrogacy than are commonly reported. [Table: see text]

5042 Background: Ra-223, a targeted alpha therapy, prolonged survival with good safety in metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 ALSYMPCA trial. REASSURE will evaluate Ra-223 short- and long-term safety in routine clinical practice settings. This is the first planned interim analysis (median 7 mo observation). Methods: This global, prospective, single-arm, observational study enrolled pts with mCRPC with bone metastases (mets) for whom Ra-223 therapy was planned. Follow-up will continue up to 7 years after last Ra-223 dose. Results: 1106 pts (437 N. America, 665 Europe, 4 not recorded) enrolled from 2 Sep 2014 to 22 Sep 2016. Baseline data are available from 583 pts receiving 1st- (1L), 2nd- (2L), or ≥3rd-line (≥3L) Ra-223 for mCRPC(Table). The majority of pts (n=369, 63%) completed 5–6 doses (1L, 70%; 2L, 64%; ≥3L, 49%); median 6 doses (1L,6; 2L, 6; ≥3L, 4). Treatment-emergent drug-related AEs occurred in 215 pts (37%). Post-treatment grade 3/4 thrombocytopenia occurred in 14 pts (2.4%) and anemia in 45 (7.7%). Conclusions: In routine clinical practice, Ra-223 was associated with no short-term safety concerns and appeared to be used in pts with less advanced mCRPC than in ALSYMPCA. The majority of pts on 1L/2L Ra-223 therapy received 5–6 doses. Ra-223 was often used with abiraterone or enzalutamide, but not chemotherapy. The next interim analysis in 2019 will report long-term safety and outcomes on all pts. Clinical trial information: NCT02141438. [Table: see text]

TPS4596 Background: The anti-PD-1 antibody nivolumab (nivo) improves overall survival (OS) in metastatic treatment refractory RCC and is generally tolerable. In 2017, there is no standard adjuvant therapy proven to increase OS over surgery alone in non-metastatic (M0) disease. Mouse solid tumor models have revealed an OS benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivo in RCC patients (pts) have shown preliminary feasibility and safety with no surgical delays or complications. The PROSPER RCC trial will examine if the addition of perioperative nivo to radical or partial nephrectomy can improve clinical outcomes in pts with locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in M0 RCC, we propose a three-pronged, multidisciplinary approach of presurgical priming with nivo followed by resection and adjuvant PD-1 blockade. Methods: Tumorbiopsy prior to randomization is mandatory to ensure the correct diagnosis and will permit unparalleled correlative science in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. 766 pts with clinical stage ≥T2 or any node positive M0 RCC of any histology will be enrolled. The study arm will receive nivo 240mg IV for 2 doses prior to surgery followed by nivo adjuvantly for 9 months (q2 wks x 3 mo followed by q4 wks x 6 mo). The control arm will undergo the current standard of care: surgical resection followed by observation. Pts are stratified by clinical T stage, node positivity, and histology. There is 84.2% power to detect a 14.4% absolute increase in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 yrs (HR 0.70). The study is also powered to detect a significant OS benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the significance of the baseline immune milieu and changes after neoadjuvant priming and to identify predictive gene expression patterns. Additional collaborations are welcomed.

459 Background: OS is a critical endpoint for adjuvant RCC trials testing the benefit of early systemic therapy to increase cure rates, but requires long duration and significant patient resources. We explored the potential use of DFS as a surrogate for OS when assessing the efficacy of adjuvant therapy in localized RCC. Methods: We performed a systematic literature review following the PRISMA statement. Inclusion criteria required randomized controlled trials (RCT) for adjuvant systemic therapy in localized RCC, which reported on both DFS and OS. DFS was defined from randomization or nephrectomy (R/N) to the first evidence of clinical recurrence (loco-regional or distant) or death from any cause. OS was defined from R/N to death from any cause. We extracted data on hazard ratio (HR) and 5-year event free rate from Kaplan Meier estimates. We performed a meta-analysis and correlated these estimates for OS and DFS, weighted by number of DFS events. R-square >0.7 would indicate a strong correlation and potential surrogacy. Results: Of the more than 315 studies screened, 10 studies investigating various forms of cytokine and vaccine immunotherapy and angiogenesis inhibitors (e.g., sunitinib, sorafenib, thalidomide) between 1987 and 2016 were eligible for the analyses. The total enrolled patients were 5,497, with median follow-up ranging 3 to 10 years. Conclusions: Across trials of adjuvant systemic therapy for localized RCC, we observed a moderate correlation between 5 yr DFS and OS rate and between treatment effects (HRs) on these endpoints. Future meta-analyses of more mature trials in the era of modern adjuvant targeted therapy are needed to evaluate the surrogacy of intermediate endpoints. Further granularity may be achieved using individual patient data to assess different and earlier time points for surrogacy than are commonly reported. [Table: see text]

137 Background: Prior work from SWOG 9346 revealed that PSA ≤ 0.2 ng/dL at 7 months (mo) is prognostic for longer OS with ADT alone. We sought to evaluate if this optimal decline remained predictive of better OS when D was added to ADT for initial mHSPC treatment. Methods: We performed a landmark survival analysis at 7 mo using the E3805 database (NCT00309985). Inclusion required at least 7 mo of followup and PSA levels at 7 mo from ADT initiation. Survival was defined from ADT start or randomization to death. SWOG 9346 PSA nadirs of ≤ 0.2, > 0.2-4 and > 4 were used as classifiers. Results: 719 patients were eligible for analysis: 358 treated with ADT plus D and 361 with ADT alone. Median follow-up was 23.1 mo. On multivariable analysis (MVA), achieving a PSA ≤ 0.2 at 7 mo was more likely if the patient received D and had lower volume disease, prior local therapy, and lower baseline PSAs (all p ≤ 0.01). Across all patients, median OS was significantly longer if PSA at 7 mo reached ≤ 0.2 compared to > 4 (p < 0.0001) (Table). On MVA, PSA ≤ 0.2 at 7 mo and low volume disease were prognostic of longer OS (all p < 0.01). On ADT, 28.8% achieved a PSA ≤ 0.2 at 7 mo vs. 45.3% on ADT+D. Patients on ADT alone who achieved a PSA nadir ≤ 0.2 had the best survival. These patients were more likely to have low volume disease (56.7%) compared to the ADT + D pts (46.3%). Conclusions: Achieving PSA ≤ 0.2 at 7 mo remains prognostic for longer OS with ADT for mHSPC, whether administered alone or with D. Adding D to ADT increased the likelihood of a lower PSA and improved survival. Partial support and drug supply by Sanofi. Clinical trial information: NCT00309985. [Table: see text]

221 Background: Recent reports have shown that patients (pts) with low volume (LV) mHSPC and those who relapse after prior local therapy (PLT) have median overall survival (OS) longer than 5 years with androgen deprivation therapy (ADT) alone. Using data from our prospectively collected hospital-based database, we aimed to detail the outcomes of pts with mHSPC by combining PLT or de novo (DN) and LV or high volume (HV) of disease. Methods: A cohort of mHSPCpts treated with ADT between 1990 and 2013 was identified in the Dana-Farber Cancer Institute IRB approved database and categorized as DN or PLT and HV or LV, at time of ADT start. HV was defined as visceral metastases and/or ≥ 4 bone metastases (BM) with at least 1 BM beyond the pelvis and axis. The analysis endpoints included OS, defined as time from ADT start to death from all causes. Kaplan-Meier method estimated the time to events distribution with median (95% CI). Cox proportional hazards model evaluated patient and disease volume groups on disease outcomes and provided estimates of hazard ratio (95% CI) for the comparison by groups. Results: Of the 354 pts included and classified as LV or HV, 202 (57%) had PLT, while 152 (43%) presented with DN metastases. The distributions of the 4 groups are 38% (PLT/LV), 19% (PLT/HV), 14% (DN/LV) and 29% (DN/HV). Compared to pts in PLT/LV group, those in the other 3 cohorts had a significantly higher risk of death. In particular, a statistically significant gradient in OS was noted (Trend test P < 0.001) within the groups in favor of PLT, primarily, and LV, secondarily. Conclusions: Consistent with the results seen in clinical trials, our hospital database informs us that disease volume and history of PLT define 4 distinct subgroups with different outcomes. This classification can be routinely used for counseling pts and future clinical trial design including oligometastatic disease. [Table: see text]

467 Background: Nivolumab, a monoclonal antibody against PD-1, has been shown to improve survival for pts with mRCC. The current standard of care is to administer treatment on a continuous basis until progression or toxicity. Outcomes of pts who experience a response to treatment and then discontinue therapy for irAEs have not been fully characterized. The purpose of this analysis was to evaluate outcomes of responders to PD-1/PD-L1 targeted therapy (TT) who discontinue treatment for irAEs. Methods: We identified pts with mRCC having experienced a response to PD-1/PD-L1 TT, which was subsequently discontinued for an irAE. Clinical characteristics, response, and survival data were collected. Results: We identified 9 mRCC pts who were treated with a PD-1/PD-L1 inhibitor, experienced a response to therapy, and subsequently discontinued treatment for an irAE. 8 had clear cell histology and 1 had translocation RCC. 7 pts were treatment naive. 2 pts had International mRCC Database Consortium favorable risk, 4 intermediate risk, and 3 poor risk disease. 44% (n = 4) of pts received PD-1/PD-L1 monotherapy and the overall median duration of therapy was 5 months (mos) (range 4-15). There was 1 complete response, 7 partial responses, and 1 stable disease (17% shrinkage). Treatment was discontinued for the following irAEs: arthritis, uveitis, arthropathy, hypophysitis, myositis, blepharitis, hepatitis, rash, pericarditis, and amylase and lipase elevations. After PD-1/PD-L1 treatment discontinuation, 4 (44%) pts remained progression free with a median time off therapy of 20 mos (range 10-44) and median time on therapy of 9 mos (range 4-15). 5 (56%) pts progressed within 6 mos (range 2-6) of treatment discontinuation and median time on therapy was 4 mos (range 3-10). Conclusions: We demonstrate that some pts can have persistent clinical benefit after discontinuation of PD-1/PD-L1 TT for irAEs. Larger studies are warranted to evaluate the need for continuous drug dosing in all pts, identify pts in which continuous dosing is not required, and evaluate long-term outcomes in this population.

477 Background: PD-1 blockade with nivolumab has demonstrated efficacy in mccRCC patients who have failed prior therapy; however, durable benefit is observed only in a subset of patients. Correlative studies have demonstrated that tumor PD-L1 expression alone fails to reliably identify patients likely to benefit. Therefore, the development of more robust predictive markers is warranted. Methods: We studied 20 mccRCC patients treated with nivolumab (n=17) or atezolizumab (n=3) with distinct clinical outcomes: 8 pts who experienced durable clinical benefit (DCB) for ≥ 12 months and 12 pts with limited clinical benefit (LCB) for ≤ 6 months from start of therapy. Expression of PD-L1 and PD-L2 on tumor cells and density of tumor infiltrating CD8+ T cells and Foxp3+ cells were evaluated by immunohistochemistry. Percentages of tumor infiltrating CD8+T cells expressing the immune-inhibitory molecules PD-1, TIM-3, or LAG-3 either alone or in combination were determined by multiplex immunofluorescence, using the Inform algorithm (Perkin Elmer). The association between clinical benefit (CB) and biomarker expression was assessed using Fisher exact test. Results: Baseline patient characteristics were similar in the DCB and LCB groups. When analyzed separately, tumor cell expression of PD-L1 or PD-L2 showed no association with CB. However, when positivity was defined as expression of either or both PD-L1(≥ 1% cutoff) and PD-L2 (≥ 5% cutoff), a significant association with CB was found (7/8 DCB vs 4/11 LCB, p = 0.04). A low percentage of tumor infiltrating CD8+PD-1+ T cells co-expressing either or both TIM-3 and LAG-3 (75thpercentile cutoff) was also significantly associated with CB (8/8 DCB vs 7/12 LCB, p = 0.05). Conclusions: Our results suggest that expression of a PD-1 ligand on tumor cells (PD-L1 and/or PD-L2), and a low percentage of severely exhausted T cells, i.e. CD8+PD-1+ T-cells co-expressing the immune-inhibitory receptors TIM-3 and/or LAG-3, might represent valuable predictive biomarkers for response to PD-1 blockade in mccRCC. Independent validation in a larger patient cohort is ongoing.

332 Background: Prior studies have reported that variant histology is associated with poor outcomes in NMIBC. We utilized the Surveillance, Epidemiology and End Results (SEER) database to compare disease specific survival (DSS) and mortality (DSM) among the different variant histologies and urothelial carcinoma (UC). Methods: Patients diagnosed with NMIBC (Ta, Tis, T1) between 2004 and 2012 were eligible for analysis. Patients were separated into cohorts based on histology: UC and variant histology which included micro-papillary variant (MPV), neuroendocrine (NEC), squamous (SCC), adenocarcinoma (AC) and other variants (e.g., lymphoepithelial, giant cell, undifferentiated/anaplastic, sarcomatoid). Univariate and multivariable Cox proportional hazard analysis was used to evaluate the impact of variant histology on DSM after adjusting for other covariates. DSS was estimated amongst the different histologic and treatment groups using the Kaplan-Meier method and compared using Log-rank test. Results: We identified 111,756 patients, who were predominantly Caucasian (90%) and older than 70 years (57.5%; n=64,314). Variant histology accounted for 1.2% (n=1354) of cases. AC and SCC were the most common variant subtypes (26.4%; n=357 and 25.6%; n=347 respectively) followed by NEC (11.2%; n=151) and MPV (7.1%; n=96). On multivariable analysis adjusting for age, sex, race, T-stage, histologic grade and number of primary tumors, all variant subgroups except MPV were associated with increased DSM compared to UC (p

Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting.Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC.In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P = .77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P = .48).Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice.

Ligands for inhibitory immune receptors on T cells may be constitutively expressed on tumor cells or host cells in tumor microenvironment as a consequence of adaptive immunity. Programmed death 1 (PD-1) is 1 such receptor on T cells, which functions as a negative regulator of T cell activity. Tumors that up-regulate programmed death ligand 1 (PD-L1) (B7-H1) may abrogate the host's effector T cell antitumor response. Higher tumoral PD-L1 expression has been linked with inferior clinical outcomes. Multiple cancers including renal cell cancers (RCCs) and melanomas have relatively high levels of PD-L1 on the cell surface. Early evaluations of antibodies that block the interaction of PD-1 and PD-L1 have shown efficacy and a favorable tolerability profile with notable inflammatory toxicities that are generally manageable. Upward of 30% of RCC patients and 50% of melanoma patients achieve objective responses. Durable responses can occur, even in some patients who have discontinued treatment. The developing investigation of PD-1/PD-L1 pathway-blocking agents in RCC and melanoma will likely alter our approaches to the treatment of these 2 deadly diseases.

Chemoradiotherapy is often administered for locally advanced penile squamous cell carcinoma (PSCC), an orphan malignancy, but outcomes with this approach are unclear. This retrospective analysis of 26 patients reports outcomes with concurrent chemoradiotherapy for locally advanced and advanced PSCC. The study highlights dismal outcomes with chemoradiotherapy and suggests the need for better understanding of tumor biology and evaluation of novel systemic agents. Background: Outcomes with concurrent chemoradiotherapy for penile squamous cell carcinoma (PSCC) are unclear, and only anecdotal reports have been published. This study was a retrospective analysis of patients who received concurrent chemotherapy and radiotherapy for PSCC. Patients and Methods: Individual patient-level data were obtained from 5 institutions for outcomes with concurrent chemoradiotherapy for PSCC. Descriptive statistics were calculated, and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic effect of candidate factors on progression-free survival (PFS) and overall survival (OS). Results: A total of 26 men were evaluable. The mean age was 60.3 years. The clinical stage was

Chemokines and cytokines have been implicated in progression to castration-resistant prostate cancer (CRPC).Retrospective data were accessed from 122 men with serum samples drawn at a median of 0.5 months after starting ADT for metastatic prostate cancer. MCP-1, IL-1-β, IL-2, IL-8, IL-6, and TNF-α levels were measured by multiplex electrochemiluminescence assays. A multivariable Cox model assessed the association of time to CRPC and overall survival by the protein levels and adjusted for clinical variables (age and prostate specific antigen (PSA) levels at start of ADT, race, ECOG status, and extent of metastases). Associations were reported as hazard ratio (HR) with 95% confidence interval (CI).Median follow-up and overall survival were 44 and 42.2 months, respectively. ECOG performance status (≥1 vs. 0) was negatively associated with overall survival [HR = 2.8 (1.1-7.0), P = 0.03], and PSA nadir 0.2 was predictive of longer time to development of CRPC [HR = 0.3 (0.2-0.5), P 0.0001]. The HR for time to CRPC by protein above the median was 1.4 (95% CI: 0.9, 2.2, P = 0.13) for IL-8; 1.3 (95% CI: 0.8, 2, P = 0.18) for TNF-α; 1.0 (95% CI: 0.7, 1.6, P = 0.95) for MCP-1. The HR for median overall survival for protein levels above the median was: 1.9 (95% CI: 1.0, 3.5, P = 0.04) for IL-8; 2.0 (95% CI: 1.1, 3.5, P = 0.02) for TNF-α; 1.7 (95% CI: 1.7, 3.0, P = 0.08) for MCP-1. There was no association with IL-1-β, IL-2, or IL-6.Higher levels of inflammation-associated cytokines correlate with poorer prostate cancer outcomes and may guide strategies to improve prostate cancer therapy.

The International Metastatic Renal-Cell Carcinoma Database Consortium model offers prognostic information for patients with metastatic renal-cell carcinoma. We tested the accuracy of the model in an external population and compared it with other prognostic models.We included patients with metastatic renal-cell carcinoma who were treated with first-line VEGF-targeted treatment at 13 international cancer centres and who were registered in the Consortium's database but had not contributed to the initial development of the Consortium Database model. The primary endpoint was overall survival. We compared the Database Consortium model with the Cleveland Clinic Foundation (CCF) model, the International Kidney Cancer Working Group (IKCWG) model, the French model, and the Memorial Sloan-Kettering Cancer Center (MSKCC) model by concordance indices and other measures of model fit.Overall, 1028 patients were included in this study, of whom 849 had complete data to assess the Database Consortium model. Median overall survival was 18·8 months (95% 17·6-21·4). The predefined Database Consortium risk factors (anaemia, thrombocytosis, neutrophilia, hypercalcaemia, Karnofsky performance status80%, and1 year from diagnosis to treatment) were independent predictors of poor overall survival in the external validation set (hazard ratios ranged between 1·27 and 2·08, concordance index 0·71, 95% CI 0·68-0·73). When patients were segregated into three risk categories, median overall survival was 43·2 months (95% CI 31·4-50·1) in the favourable risk group (no risk factors; 157 patients), 22·5 months (18·7-25·1) in the intermediate risk group (one to two risk factors; 440 patients), and 7·8 months (6·5-9·7) in the poor risk group (three or more risk factors; 252 patients; p0·0001; concordance index 0·664, 95% CI 0·639-0·689). 672 patients had complete data to test all five models. The concordance index of the CCF model was 0·662 (95% CI 0·636-0·687), of the French model 0·640 (0·614-0·665), of the IKCWG model 0·668 (0·645-0·692), and of the MSKCC model 0·657 (0·632-0·682). The reported versus predicted number of deaths at 2 years was most similar in the Database Consortium model compared with the other models.The Database Consortium model is now externally validated and can be applied to stratify patients by risk in clinical trials and to counsel patients about prognosis.None.

e16026Background: The available prognostic models (PM) for OS of pts with mUC were derived from clinical trial populations of cisplatin (cis)-treated pts. We sought to validate and improve these PM...

4536Background: Trimodality BPT in MIBC includes a maximal transurethral resection followed by concurrent chemoradiotherapy as an alternative to cystectomy in appropriately selected patients, or as...

e16509Background: Inhibition of the androgen receptor (AR) may de-repress c-Met, which could play a role in progression to CRPC, metastasis, and therapeutic resistance. Preclinical work has shown t...

Purpose The objective of this study was to prospectively evaluate various quantitative metrics on FDG PET/CT for monitoring sunitinib therapy and predicting prognosis in patients with metastatic renal cell cancer (mRCC). Methods Seventeen patients (mean age: 59.0 ± 11.6) prospectively underwent a baseline FDG PET/CT and interim PET/CT after 2 cycles (12 weeks) of sunitinib therapy. We measured the highest maximum standardized uptake value (SUVmax) of all identified lesions (highest SUVmax), sum of SUVmax with maximum six lesions (sum of SUVmax), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) from baseline PET/CT and interim PET/CT, and the % decrease in highest SUVmax of lesion (%Δ highest SUVmax), the % decrease in sum of SUVmax, the % decrease in TLG (%ΔTLG) and the % decrease in MTV (%ΔMTV) between baseline and interim PET/CT, and the imaging results were validated by clinical follow-up at 12 months after completion of therapy for progression free survival (PFS). Results At 12 month follow-up, 6/17 (35.3%) patients achieved PFS, while 11/17 (64.7%) patients were deemed to have progression of disease or recurrence within the previous 12 months. At baseline, PET/CT demonstrated metabolically active cancer in all cases. Using baseline PET/CT alone, all of the quantitative imaging metrics were predictive of PFS. Using interim PET/CT, the %Δ highest SUVmax, %Δ sum of SUVmax, and %ΔTLG were also predictive of PFS. Otherwise, interim PET/CT showed no significant difference between the two survival groups regardless of the quantitative metric utilized including MTV and TLG. Conclusions Quantitative metabolic measurements on baseline PET/CT appears to be predictive of PFS at 12 months post-therapy in patients scheduled to undergo sunitinib therapy for mRCC. Change between baseline and interim PET/CT also appeared to have prognostic value but otherwise interim PET/CT after 12 weeks of sunitinib did not appear to be predictive of PFS.

494 Background: Re-irradiation (re-RT) with external beam RT following prior pelvic RT has not been reported, given both an absence of guidelines and concerns for toxicity. We sought to characterize bladder and bowel toxicities among patients treated with high-dose palliative re-RT for genitourinary secondary malignant neoplasms (SMN) or local recurrence (LR) following prior RT for pelvic cancer and to assess the response to re-RT with regard to palliation of symptoms. Methods: With IRB approval, the records of 28 consecutive patients with advanced pelvic malignancies given palliative re-RT between 2008-2014 were retrospectively analyzed. Descriptive analyses focused on toxicities and symptom control; responses were evaluated by two independent observers. Results: The cohort contained 27 males and 1 female. Initial cancers included 19 prostate, 4 ureteral, 2 bladder, 2 rectal and 1 penile carcinoma and 1 large cell lymphoma. Median initial RT dose was 63.5 Gy (range, 30-75.6 Gy; 8 unknown). The median time between initial RT and re-RT was 9.5 years (range, 0.2-32 years). At re-RT, there were 16 LRs and 12 SMNs including 14 bladder, 11 prostate, 3 ureteral and 1 penile cancers. Indications for re-RT were most commonly pain and bleeding. Given the severity of symptoms and bulk of disease at the time of re-RT, hypofractionated higher-dose RT was given. Median re-RT dose was 50 Gy (range, 27.5-66 Gy). For patients who received < 60 Gy, the median daily re-RT dose was 250 cGy. Re-RT was well-tolerated; there were no grade 2-4 toxicities. After treatment, 24 patients (92%) had complete resolution of their symptoms. Relief was durable in 67% of patients. Median overall survival was 5.8 months (range, 0.3-38.9 months) and 89% of patients were followed until death. Median follow-up was 5.2 months (range, 0.23-30.2 months). Conclusions: This institutional series suggests that moderate- to high-dose re-RT with median cumulative doses ≥ 100 Gy may achieve successful palliation of pelvic symptoms without undue toxicity in patients previously treated with high-dose RT. These results require validation in a larger prospective cohort.

422 Background: VTE is common in cancer patients, but there is limited data in patients with UTT. We previously demonstrated that non-urothelial histology, cardiovascular disease (CVD) or CVD risk factors or renal dysfunction increased VTE risk in metastatic UTT. In this study, we assessed the frequency and risk factors for VTE in localized disease. Methods: Data was collected via an electronic data capture platform from 29 centers. Patients diagnosed with < cT2, > N1, or M1 disease at diagnosis were excluded. Patients without a date of diagnosis, last follow up, or VTE data were excluded. Cumulative, unadjusted VTE incidence was calculated from time of diagnosis, excluding VTEs diagnosed in the metastatic setting. Chi-squared analyses were used to assess differences in VTE rates for various patient, therapy, and tumor-related factors. Significant covariates were incorporated into a multivariate, logistic regression model. Results: 1131 patients were eligible for analysis. Perioperative chemotherapy was utilized in 46.9% (530/1131) of patients. 70.8% (801/1131) underwent definitive surgical intervention. There were 64 VTEs (cumulative incidence 5.7%). Treatment with chemotherapy (p = 0.609) or surgery (p = 0.886) did not increase VTE risk. In the univariate analysis, non-urothelial histology (p = 0.025), CVD or CVD risk factors (p = 0.004), renal dysfunction (p = 0.023), and radiation to the primary tumor (p = 0.048) were statistically significant factors. Multivariate analysis demonstrated that non-urothelial histology and CVD or CVD risk factors were associated with increased VTE risk (table). Conclusions: The VTE incidence of 5.7% in localized disease is lower than our previously reported rate in the metastatic setting (8.2%). Consistent with our findings in metastatic UTT, non-urothelial histology and CVD or CVD risk factors increase VTE risk in localized disease. Additional analyses to control for baseline demographics in patients treated with surgery and chemotherapy will be performed. [Table: see text]

196 Background: Statins compete with DHEAS for influx through the transporter SLCO2B1 and may prolong time to progression (TTP) on androgen deprivation therapy (ADT). The androgen biosynthesis inhibitor, AA, may also undergo SLCO-mediated transport. We hypothesized that statins may compete with AA for influx by SLCO2B1, which could negatively impact drug efficacy. Methods: We queried our institutional clinical database for patients treated with AA for CRPC. Data on statin use including on-therapy dates were retrospectively collected from the medical record. Time on AA was used as a surrogate for TTP. Duration of AA was defined as the time from AA initiation to time to when AA was discontinued or censored on the last known alive date. The association between statin use and AA duration was estimated using the Kaplan-Meier method. Multivariable Cox regression adjusted for known prognostic factors (e.g, prior docetaxel (D) or enzalutamide (E) use, and sites of metastases (mets) specifically bone or lymph node versus liver or other viscera. Results: Of the 224 patients eligible for analysis, the majority (96%) had metastatic disease at time of AA initiation. 26% had prior D and 7% E. Nearly half were statin users (41%). The median duration on AA was 10.7 months (mo) with a trend to longer duration in statin users: 14.2 vs. 9.2 mo (HR 0.79, 95% CI: 0.57-1.09, p = 0.14). Prior D and E was significantly associated with shorter AA duration while site of mets and age were not. Adjusting for prior use of D, E, and site of mets did not alter the relationship between statin use and AA duration (p = 0.18, HR 0.81, 0.58-1.11). Conclusions: Contrary to our initial hypothesis, there was a trend to longer AA duration in statin users. Given our prior work demonstrating a 10 mo prolonged TTP on ADT in men concurrently taking statins (adjusted HR 0.83), and in vitro findings of inhibition of DHEAS uptake by statins, we postulate that there could be an additive effect of statins and AA by blocking DHEAS uptake. Alternatively, statins may inhibit hepatic AA uptake prolonging drug exposure and increasing effectiveness. Ongoing analyses are evaluating the impact of SLCO SNPs on AA efficacy.

368 Background: Effective treatment of MIBC requires a multidisciplinary (multiD) approach including surgical, radiation, and chemotherapeutic modalities, which are further supported by pathology, radiology, nursing, social work, nutrition, pharmacy, and psychologic expertise. As surgical and bladder preservation approaches have not been directly compared, practice patterns are heterogeneous. Our primary objective was to catalogue the different styles of multiD approaches or lack thereof in the management of MIBC. Secondary objectives were to assess physician interest, capture examples of successful approaches, and describe barriers to implementation. Methods: We conducted an international online survey regarding the type of multiD approach and available resources used by clinicians managing MIBC. We collaborated with the Bladder Cancer Advocacy Network and the Genitourinary Medical Oncologists of Canada to reach a wide variety of academic and community practices. Results: Of the 101 clinicians surveyed, most practiced at NCI designated comprehensive cancer centers (46%) or Canadian academic institutions (29%). The median number of cases per month was 5 (0-40).Of the different multiD styles, sequential (separate) visits on different days was the most common (60%) followed by sequential same day (41%), concurrent (one visit with all providers, 23%), and none (5%). However, most preferred a sequential same day (44%) or concurrent (28%) approach. Although most academic practices had some form of multiD approach, reported barriers for implementing the preferred strategy were lack of clinic space (63%), funding (46%), staff (46%), and time (34%). The majority felt a multiD approach enriched their practice. Conclusions: Most surveyed practitioners at academic centers integrate a multiD strategy in the management of MIBC. The major barriers are not attitudinal but rather insufficient resources and time. Thus, most physicians employ a sequential rather than a concurrent approach. Future goals include developing strategies to overcome these obstacles and integrating these results with patient preferences to optimize the management of MIBC patients.

Summary Background The advent of targeted therapies in the past 7 years has extended median survival for metastatic renal-cell carcinoma. This improvement in clinical outcome has created a need for new, more accurate prognostic measures. We assessed the use of conditional survival—a measure that accounts for elapsed time since treatment initiation—for prognostication in patients with metastatic renal-cell carcinoma treated with first-line VEGF-targeted therapies. Methods We obtained data for patients with metastatic renal-cell carcinoma who were treated with a first-line VEGF-targeted therapy between April 7, 2003, and Oct 12, 2010, from our large multi-institutional International mRCC Database Consortium (centres in Canada, the USA, Singapore, Denmark, and South Korea). All histologies, performance statuses, and prognostic risk groups were included. The primary outcome was 2-year conditional survival, defined as the probability of surviving an additional 2 years from a given timepoint since the start of targeted therapy. Secondary analyses included 1-year and 3-year conditional survival, along with stratification of patients by Heng prognostic risk criteria and Karnofsky performance score, and conditional survival based on length of time on therapy. We used the Kaplan-Meier method and a landmark analysis to calculate conditional survival. Findings In the 1673 patients analysed, median follow-up for alive patients was 20·1 months (IQR 9·0–34·4). We recorded an increase in the 2-year conditional survival probability from 44% (95% CI 41–47) at 0 months to 51% (46–55) at 18 months since beginning targeted therapy. When stratified by the Heng prognostic risk criteria defined at therapy initiation, 2-year conditional survival changed little in the favourable and intermediate groups, but in the poor-risk group, 2-year conditional survival improved from 11% (8–15) at 0 months to 33% (18–48) after 18 months. When conditioned on time on targeted therapy from 0 months to 18 months, 2-year conditional survival improved from 44% (41–47) to 68% (60–75) in the overall population and from 74% (68–79) to 90% (77–96) in the favourable group, 49% (45–53) to 57% (45–67) in the intermediate group, and 11% (8–15) to 73% (43–89) in the poor risk group. Interpretation Conditional survival is a clinically useful prediction measure that adjusts prognosis of patients with metastatic renal-cell carcinoma on the basis of survival since treatment initiation or therapy duration. Conditional survival might be especially relevant to adjust prognosis for poor-risk patients. Funding The Trust Family Fund for Kidney Cancer Research.

A recent increase in the detection of contrast enhancing renal masses 4 cm or smaller suspicious for malignancy has led to the widespread use of nephron sparing options. Limited data exist to help clinicians decide which of these competing nephron sparing therapies is most appropriate. We performed a cost-effectiveness analysis to evaluate the relative clinical and economic merits of commonly available nephron sparing strategies for small renal masses.We developed a decision analytic Markov model estimating the costs and health outcomes of treating a healthy 65-year-old patient with an asymptomatic unilateral small renal mass using competing nephron sparing options of immediate intervention (ie open and laparoscopic partial nephrectomy as well as laparoscopic and percutaneous ablation), active surveillance with possible delayed intervention and nonsurgical management with observation. Benefits were measured in quality adjusted life-years. We used a societal perspective, lifetime horizon and willingness to pay threshold of $50,000 per quality adjusted life-year gained. Model results were assessed with sensitivity analyses.In the base case scenario the least costly option was observation and the optimal option was immediate laparoscopic partial nephrectomy, which had an incremental cost-effectiveness ratio of $36,645 per quality adjusted life-year gained compared to surveillance with possible delayed percutaneous ablation. Results were sensitive to age at diagnosis, health status and tumor size.Immediate laparoscopic partial nephrectomy is the preferred nephron sparing option for healthy patients younger than 74 years old with a small renal mass. Surveillance with possible delayed percutaneous ablation is a cost-effective alternative for patients with advanced age or significant comorbidities. Observation maximizes quality adjusted life-years in patients who are poor surgical candidates or with limited life expectancy (less than 3 years).

To assess whether high ribonucleotide reductase subunit M1 (RRM1) expression in patients with resected, muscle-invasive (T2-4NxM0) urothelial carcinoma (UC) correlated with longer overall survival (OS). RRM1 is the primary cellular target of gemcitabine and previous studies in resected early-stage lung cancer have shown a survival benefit for patients with high expression.In all, 84 radical cystectomy specimens with muscle-invasive UC were identified from existing tissue microarrays. The patients' medical records were retrospectively reviewed to confirm pathology and stage. Specimens were analysed for RRM1 expression using automated quantitative analysis. The median value of RRM1 was established a priori as the threshold for high and low expression.The median age of the patients was 69 years. Stages were nearly equally distributed: 30%, 38%, and 32% for stage II, III, and IV, respectively. Most were high grade (99%) with no nodal involvement (69%). The median (range) OS was 2.0 (0-13.1) years. Tumoral RRM1 levels did not correlate with OS for the entire cohort, but when adjusted for age, high tumoral RRM1 expression in younger patients (aged70 years) correlated with increased survival. Younger patients with high RRM1 expression had a median OS of 10.6 years compared with 1.6 years in older patients (P= 0.001). There was no difference in OS among low RRM1 expressors: 2.3 vs 1.6 years in younger and older patients, respectively (P= 0.22).Our results suggest that high RRM1 expression may be prognostic for improved survival in patients with muscle-invasive UC aged70 years.

Purpose Previous studies suggest that some common medications alter prostate-specific antigen (PSA) levels. It remains unclear whether these reported medication effects are due to clinicodemographic factors or concurrent use of other medications. We investigated the impact of individual and combinations of common medications on PSA in a large cross-sectional study of the United States population. Patients and Methods The study included men ≥ 40 years old without prostate cancer from the 2003 to 2004 and 2005 to 2006 cycles of the National Health and Nutrition Examination Survey (NHANES). Men with recent prostate manipulation, prostatitis, and those on hormone therapy were excluded. Weighted multivariate linear regression was performed on log-transformed total PSA to determine the effect of the 10 most commonly prescribed medication classes, adjusting for potential confounders including demographics, clinical characteristics, physical examination, laboratory studies, and duration of medication use. Results In total, 1,864 men met inclusion criteria. Nonsteroidal anti-inflammatory drug (NSAID; P = .03), statin (P = .01), and thiazide diuretic (P = .025) intake was inversely related to PSA levels. Five years of NSAID, statin, and thiazide diuretic use was associated with PSA levels lower by 6%, 13%, and 26%, respectively. The combination of statins and thiazide diuretics showed the greatest reduction in PSA levels: 36% after 5 years. Concurrent calcium channel blocker use minimizes or negates the inverse relationship of statin use and PSA level. Conclusion We found that men using NSAIDs, statins, and thiazide diuretics have reduced PSA levels by clinically relevant amounts. The impact of regularly consuming these common medications on prostate cancer screening is unknown.

Background: Despite high response rates with front-line platinum-based therapies, 80% of patients with metastatic urothelial cancer progress. Multiple agents and couplets have been investigated, but no standard second-line regimen exists. We conducted a phase II study to evaluate the efficacy and safety of docetaxel and oxaliplatin in metastatic urothelial cancer patients who had received prior platinum therapy. Patients and Methods: Patients with metastatic urothelial cancer, who had disease progression after platinum therapy, were treated with docetaxel 75 mg/m2 and oxaliplatin 85 mg/m2 every 3 weeks until disease progression or intolerable toxicity. Results: Between November 2004 and September 2005, 11 patients were enrolled. All patients had low or intermediate Bajorin risk. The median number of cycles administered was 2 (range 2–8). One patient achieved near complete response. Three patients experienced disease stabilization, resulting in a disease-control rate of 36%. Median overall survival was 7 months. The most common toxicities were fatigue and anemia (50%). Conclusion: Second-line docetaxel and oxaliplatin in metastatic urothelial cancer is safe and tolerable but did not achieve an appreciable response rate.

Agents that inhibit vascular endothelial growth factor (VEGF) are now standard of care for the treatment of advanced renal cell carcinoma (RCC). Two VEGF tyrosine kinase inhibitors (TKIs), sunitinib and sorafenib, are now FDA approved for metastatic RCC. Sunitinib increases overall survival compared to interferon-α in the first line setting, and both improve response and progression-free survival (PFS). A monoclonal antibody against VEGF, bevacizumab, is still investigational but has recently been shown to improve PFS in combination with interferon-α. These and other investigational VEGF inhibitors continue to be actively investigated as monotherapies and in combination with other targeted agents for the treatment of advanced RCC among other cancers. Surrogate biomarkers that accurately predict therapeutic VEGF inhibition and anti-tumor response to these inhibitors would be useful. Preclinical work at our institution revealed that extremely stringent VEGF inhibition in mice resulted in increased hemoglobin and erythropoietin (Epo). This Epo production originated in the liver, not the kidney, implicating endogenous VEGF as a previously unsuspected repressor of hepatic Epo synthesis and suggested that hemoglobin and Epo may be non-invasive markers for VEGF inhibition in vivo. We retrospectively reviewed whether hemoglobin levels increased in patients receiving bevacizumab as monotherapy or in combination with epidermal growth factor receptor (EGFR) or dose-reduced (or eventual dose-reduced) VEGF TKIs for advanced RCC. Twelve patients with advanced RCC were eligible for retrospective review. Demographic data, baseline anemia, initial and treatment hemoglobin levels, response, and confounding factors such as recent chemotherapy, blood transfusions, iron supplementation, or growth factor use were assessed. Correlation between the degree of change in hemoglobin from baseline to peak level and PFS were evaluated. The majority of patients were male and treatment naïve (67%). Fifty percent of patients had bone metastases, and 50% had baseline anemia. Five patients were on concurrent treatment with sunitinib, sorafenib, or erlotinib. Hemoglobin rose on bevacizumab in 11 patients. The median change in hemoglobin was 1.6 g/dL (0–2.7). The median percent rise was 12.3%; 10.9% in the monotherapy cohort and 18.6% in the combination group. For all 12 patients, the median time to initial increase in hemoglobin was 35 days (0–168 days) and 82 days (0–476 days) from baseline level to peak level. Median time to peak hemoglobin (first rise to peak) was 68.5 days (0–308 days). Median duration of hemoglobin rise was defined as the first rise in hemoglobin to the first decline in levels after peak and was 113 days (n=10, range: 28–350 days). The best response was disease stabilization in 8 patients. In the metastatic patients, degree of peak increase correlated with longer PFS: a 5–15% increase yielded a 3.1 month median PFS whereas a greater than 15% increase corresponded to an 8.2 month median PFS. In conclusion, the majority of patients (92%) on bevacizumab monotherapy or in combination with dose-reduced VEGF or full-dose EGFR tyrosine kinase inhibitors experienced an increase in hemoglobin from their pre-treatment baseline suggesting a correlative effect. The combination group was expected to have less of an increase in hemoglobin as sunitinib and sorafenib are known to cause anemia via c-Kit inhibition. We hypothesize that the reduced doses of these agents when used in combination with bevacizumab were inadequate to cause significant anemia but were sufficient to induce more complete VEGF inhibition in these patients. This is the first human study to identify increased hemoglobin as a possible consequence of treatment with VEGF inhibitors. The correlation between degree of increase in hemoglobin and longer PFS suggests that hemoglobin may be useful as a surrogate marker of stringent VEGF inhibition and as a predictive factor for clinical response. This relationship warrants validation in larger cohorts.