bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical recurrence post-biochemical failure of prostate cancer.
Authors: Reddy C. A. , Ciezki J. P. , Klein E. A.
Published: February 2017

195

Background: The purpose of this study is to evaluate the role of salvage therapy (STx) after biochemical failure (bF) for prostate cancer (CaP) and to determine what factors are associated with the development of clinical recurrence (cR).

Methods: From 1996-2009, 7,585 patients (pts) with CaP were treated with prostatectomy (RP), brachytherapy (PI), or external beam radiotherapy (RT). For RP patients (pts), bF was defined as a postoperative PSA >0.3 and for PI and RT pts the Phoenix definition was used. bF was documented in 927 pts. cR was defined as any image-based or pathological diagnosis of disease recurrence after bF. Cox proportional hazards regression was used to examine if the use of STx after bF, the time of bF, along with disease characteristics were associated with cR after bF.

Results: The median follow-up after bF was 31months (mo; range: 0-131). Thirty percent of pts had a cR after bF, and the 5-year rate of cR free survival was 58%. STx within 1 year after bF (early) was given to 46% of pts, STx more than 1 year after bF (late) was given to 11% of pts, and 43% of pts did not receive STx. On univariate analysis, factors found to be significantly associated (p-value <0.05) with cR were a short interval between initial treatment and bF (bFTime), no use of STx, early initiation of STx, biopsy Gleason Score (bGS), clinical stage, older age at bF, the use of PI or RT, and increased frequency of PSA follow-up after bF (PSAfreq). In multivariable analysis, bFTime, no use of STx, early initiation of STx, bGS, the use of PI or RT, and PSAfreq remained significant. To better evaluate the effect the timing of initiation of STx had on the development of cR, a second analysis was preformed, limited to the 529 pts who did receive STx after bF. In multivariable analysis, early use of STx remained significant for cR (HR=2.09, 95%CI=1.24- 3.51). As a continuous variable, in a second multivariable analysis, delayed use of STx resulted in a reduced risk of developing cR (HR=0.98, 95%CI=0.96-1.00).

Conclusions: This study suggests that while the use of STx after bF reduces the risk of subsequently developing cR, early use of STx after bF is not beneficial. Other factors such as the time interval between initial treatment and bF need to be evaluated when determining when to initiate STx after bF.

No significant financial relationships to disclose.
Racial disparities in stage IV prostate cancer outcomes in the Veterans Affairs hospital system.
Authors: Al-Howaidi I. , Shatat L. , Tashi T. , Gonsalves W. , Silberstein P. T. , Subbiah S.
Published: February 2017

199

Background: Epidemiological studies have demonstrated that African-American (AA) men with prostate cancer have lower overall survival and cancer-specific survival rates than Caucasian (CA) men with prostate cancer. We aim to assess whether racial disparities exist for prostate cancer within an equal access health care system like the Veterans Affairs (VA) hospitals.

Methods: A retrospective analysis of AA and CA with metastatic prostate adenocarcinoma diagnosed between 1995 to 2007 via the Veterans Affairs Central Cancer Registry was conducted. Age, Race and type of treatment received were studied with respect to overall survival by using log-rank and Kaplan-Meier analysis.

Results: A total of 8,195 patients with advanced prostate cancer were analyzed, majority of them where CA (66.32%), 30.8% were AA and 2.8% belonged to other races. The median survival for AA was 2.71 years, 2.88 years in CA and 4.02 years in other races (P value <0.0001). Subgroup analysis based on treatment modality used showed the following median survival rates in years: No treatment (CA: 1.73, AA: 1.39, other races: 3.79, P<0.816), Hormonal therapy alone (CA: 2.51,AA: 2.45, Others:3.72, P<0.022), Radiation therapy alone (CA: 2.2, AA: 2.7, Others: 2.26, P<0.832), combined hormone and radiation therapy (CA: 2.71, AA: 2.31, Others: 6.64, P<0.029). However when CA and AA survival were compared excluding other races there was no statistically significant difference in survival irrespective of type of therapy received.

Conclusions: In advanced prostate cancer, AA and CA have uniformly poor prognosis. Type of therapy received did not influence the survival of both races. The numbers for other races is too small to make a definitive conclusion regarding their prognosis.

No significant financial relationships to disclose.
Influence of body mass index (BMI) on PSA kinetics in castrate-resistant prostate cancer (CRPC).
Authors: Teo M. , Mayer N. J. , Khan N. , Sweeney J. P. , O'Reilly S. , Power D. G.
Published: February 2017

209

Background: Understanding of the role of host energetics in cancer outcomes has been increasing in recent years. In early stage prostate cancer trials obesity is associated with worse outcome. Its effect on treatment response and survival in advanced disease is largely unexplored. We sought to explore the relationship between BMI, the most validated measure of obesity, and biochemical response as well as overall survival in patients receiving first-line chemotherapy.

Methods: We reviewed a prospectively-maintained institutional database identifying patients who received docetaxel (D) for CRPC. Demographics and PSA levels during treatment were extracted. Pts were divided into 2 BMI groups (> and < 30 kg/m2). We calculated biochemical responses as per historically validated surrogates: PSA decrease > 30% at 3months; overall decrease > 50%; time to PSA nadir and PSA half-life after 4 cycles, for each group. Results were compared with unpaired t-test and chi-square test.

Results: 33 pts were identified between June ‘04 and Sept ‘10, 16 pts with BMI > 30 (hBMI) (range 30.1-34.2) and 17 with BMI < 30 (nBMI) (21.5-29.6). Median age for the entire cohort was 67.9 yrs (47.7-79.8), median Gleason score 8, median cycles of D received was 6 (3-20) with median duration of 3.7 months (1.4-8.7), p>0.05. Baseline PSA was 89.1 ng/ml (0.34-417) and 259.2 (16.1-1,589) for hBMI and nBMI respectively, p = 0.023. For hBMI group, only 56.3% (9/16) of patients demonstrated biochemical response, compared with 88.2% (15/17) in nBMI group(p = 0.039). Of the biochemical responders, 6/16 (38%) of hBMI and 9/7 (53%) of nBMI achieved >50% fall in PSA (p = 0.743) while 8/16 (50%) patients in hBMI group and 10/17 (59%) in nBMI group had a PSA drop >30% at 3 months (p = 0.61); Median time to PSA nadir was 3.4 months (0.7-4.9) and 2.7 (0.7-7.5), and median PSA half life was 56.4 days (16-138) and 46.1 days (16-302) for hBMI and nBMI groups, respectively, p > 0.05.

Conclusions: Obese patients with CRPC have lower pre-D PSA levels. However, they also experience a lower rate of biochemical response to therapy. PSA kinetics in biochemical responders do not appear to be influenced by BMI. Survival data will be presented.

No significant financial relationships to disclose.
Clinicopathologic findings in Jamaican men with prostate cancer.
Authors: Kampel L. J. , Tse K. , Joseph M.
Published: February 2017

214

Background: Jamaican men appear to have higher age adjusted incidence rates (302/100K) than African Americans (250/100K) and Caucasians (182/100K). The purpose of this study is to examine the clinicopathologic findings in Jamaican born men presenting to Memorial Sloan-Kettering Cancer Center over a five-year period.

Methods: We reviewed the records of 150 Jamaican-born men seen at MSKCC for prostate cancer between 2003 and 2008. Age at diagnosis, highest pretreatment PSA levels, Gleason scores, and clinical stage were tabulated. Pathologic T and N stage was included for patients undergoing prostatectomy.

Results: 23 patients were excluded because the diagnosis of prostate cancer was not confirmed. The mean age at diagnosis was 59 years (37-77). The median PSA was 8 ng/mL (1-7,400 ng/mL). The distribution of Gleason scores was Gleason 6: 51 patients (40%), Gleason 7: 57 patients (45%), and Gleason 8-10: 19 patients (15%). 92% (75/81) of the men had organ confined disease by (cT1-2) by DRE. Of 46 men who had prostatectomy, 31 (67%) had organ confined disease (p T2) and 84% (37/44) were node negative.

Conclusions: Without a comparison cohort, no firm conclusions can be drawn. But, Jamaican born men presenting to MSKCC for treatment of prostate cancer do not seem to have unusually adverse pretreatment characteristics or more advanced pathological findings at prostatectomy. Our results may be affected by referral bias in favor of patients with lower risk disease. Further research is needed to determine if Jamaican men with prostate cancer present with more advanced stage or higher grade disease than men in the general population.

No significant financial relationships to disclose.
EGFR, TS, and ERCC1 expression in penile squamous cancer (PSC).
Authors: Dorff T. B. , Schwartz R. , Ma Y. , Cai J. , Bulbul A. , Skinner E. C. , Quinn D. I. , Danenberg K. , Schuckman A.
Published: February 2017

219

Background: PSC is an aggressive disease with devastating consequences. While near-universal EGFR overexpression has been documented, little is known about its clinical implications, and the potential role of KRAS mutations has not been described. In other tumor types, ERCC1 and TS expression are associated with response to platinum and 5FU chemotherapy, but have not yet been evaluated in PSC.

Methods: After IRB approval, 28 PSC patients treated at LAC-USC were identified with tumor specimens available. Testing for EGFR, TS, and ERCC1 expression relative to internal standard gene was performed by real-time RT-PCR and correlated with clinical features.

Results: The median age was 45 (30-78). There were 2 Black, 1 Asian, 1 White, and 15 Hispanic men; 9 had unspecified race. T stages included 4 Tis, 6 T1, 17 T2, and 9 T3; 11 men had lymph node (LN) involvement. No KRAS mutations were identified. EGFR had the highest relative expression (median 4.65, range 1.6-44.2), followed by TS (median 1.69, range 0.49-4.69); ERCC1 overexpression was rare (median 0.54, range 0.21-1.29). Higher EGFR expression was significantly associated with poor differentiation (median 12.5 compared to 3.6 for moderate/well differentiated tumors) on continuous (p=0.03 by Mann Whitney) and cut-point analysis using >7 (two- sided p=0.03 by Fisher's exact test) but did not correlate with stage. Stage > T2 showed a trend toward higher risk of LN involvement (p=0.06 by chi square). There was no correlation between differentiation and stage, and no significant correlation for ERCC1 or TS with grade or stage.

Conclusions: EGFR overexpression is common in PSC and correlates with tumor grade but not stage, suggesting it may be important for disease progression. The absence of KRAS mutations may portend responsiveness to EGFR- targeted therapy based on experience in other tumors. Low ERCC1 as an association with platinum response will be explored in an expanded cohort.

No significant financial relationships to disclose.
Utilizing metformin to enhance the efficacy of androgen-deprivation therapy in the treatment of prostate cancer.
Authors: Klotz L. , Venier N. , Vandersluis A. , Besla R. , Fleshner N. , Pollak M. N. , Venkateswaran V. , Colquhoun A. J.
Published: February 2017

22

Background: Prostate cancer (PCa) incidence varies by geographic location, with developed countries exhibiting higher levels of disease. Some attribute this to the “Westernized lifestyle” of high energy diets and limited physical activity with consequent obesity. Obesity and related diseases like diabetes, cause hyperinsulinemia, which upregulates pro-survival insulin/insulin-like growth factor signalling. Previous work shows diet-induced hyperinsulinemia enhances PCa tumor growth in vivo. Metformin, a diabetic treatment, reduces hyperinsulinemia, and also exhibits anti-neoplastic properties. We assessed the potential benefit of combining a standard PCa treatment (bicalutamide) with metformin in vitro and in vivo.

Methods: The effect of bicalutamide and/or metformin on colony formation rates was assessed in LNCaP, PC3, DU145 and PC3AR2 PCa cell lines using clonogenic assay. Western blot and cell cycle analyses were used to elucidate mechanisms of interaction between the drugs. The combination treatment regimen was assessed in vivo using a murine xenograft model.

Results: Micromolar bicalutamide or millimolar metformin caused significant dose-dependent reduction in colony formation rates (p<0.001). Combination treatment further significantly reduced colony formation rates (p<0.005). Differing mechanisms of interaction occurred in AR positive and negative cell lines. Following combination treatment LNCaP cells exhibited altered cell proliferation (decreased PCNA) and perturbed cell cycle kinetics (G1/S arrest). PC3 cells showed evidence of enhanced apoptosis (increased BAX, decreased caspase 3, phospho-Akt). Preliminary in vivo results show significantly diminished tumor growth following combination treatment (p<0.0001).

Conclusions: Combining bicalutamide and metformin significantly reduces PCa cell colony formation rates further than either monotherapy. In AR positive cells this effect is mediated by reducing cell proliferation rates, whereas in AR negative cells combination treatment promotes apoptosis. This combination drug regimen may potentially improve prostate-cancer specific survival via the direct anti-neoplastic properties outlined.

[Table: see text]
Chemotherapy for squamous cell carcinoma of the penis: An 8-year, single-institution experience.
Authors: Kularatne B. Y. , Ayres B. E. , Mukherji D. , Watkin N. , Lam W. , Perry M. , Pickering L. M.
Published: February 2017

222

Background: Penile cancer is a rare malignancy affecting approximately 400 men per year in the United Kingdom. There are relatively limited data regarding the role of chemotherapy, although it may be considered in the adjuvant setting for high-risk disease and for palliation of metastatic disease.

Methods: Patients treated with chemotherapy between June 2002 and March 2010 were identified from our prospectively maintained institutional database. Regimens were recorded and toxicity documented according to the Common Toxicity Criteria version 4.0. Response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 until 2009 and then version 1.1.

Results: Twenty patients received chemotherapy either for adjuvant treatment (n=6) or for metastatic disease (n=14). Median age was 59 (range 33-80). Different regimens were used over the time period. In the adjuvant setting 4-6 cycles of chemotherapy were planned and all patients received cisplatin in combination with 5-FU or capecitabine. Five (83%) completed planned treatment with no grade 3 or 4 toxicities. One patient stopped after 2 cycles due to deteriorating renal function. Patients remained disease free at up to 22 months follow-up. In the metastatic setting, 10 patients received cisplatin and capecitabine, 1 cisplatin and 5-FU and 1 carboplatin and capecitabine. Of these 12 patients, 2 (17%) had partial response as their best response, 4 (33%) had stable disease (SD) and 6 (50%) had progressive disease (PD). Three patients (25%) experienced pulmonary embolism, 1 of whom died. Two (17%) developed grade 3 neutropenia. One patient received carboplatin, methotrexate and bleomycin with PD after 3 cycles and developed grade 3 neutropenia, stomatitis, and diarrhea. One patient received 3 cycles of paclitaxel, ifosfamide, and cisplatin with SD and no grade 3 or 4 toxicities.

Conclusions: Combination chemotherapy can be delivered with acceptable toxicity in the adjuvant setting. In the metastatic setting response rates were disappointing and treatments were associated with greater toxicity. New treatments are urgently required to improve outcomes in this difficult malignancy.

[Table: see text]
Long-term survival and competing causes of death in men with stage I seminoma.
Authors: Beard C. , Chen M. , Arvold N. D. , Nguyen P. L. , Ng A. K. , Hoffman K. E.
Published: February 2017

226

Background: To better understand the impact of RT on mortality, we analyzed long-term survival and patterns of excess mortality in men with stage I seminoma.

Methods: 9,045 men with stage I seminoma were identified in the Surveillance Epidemiology and End Results database. Time to testicular-cancer mortality (TCM), death from second malignancy (SM), cardiovascular mortality (CVM) or suicide (SUIC) and all-cause mortality (ACM) were calculated. Survival estimates were calculated using the Kaplan-Meier method. Gender- and age-adjusted standardized mortality ratios (SMR) were calculated using U.S. population data. Cox and Fine and Gray multivariable analysis were used to evaluate the effect of RT on mortality outcomes.

Results: 7,025 men (78%) received RT. After a median follow-up of 11.7 years, 869 men (9.6%) had died: sixty-five from TCM, 279 from SM, 169 from CVM and 37 from SUIC. 10-year rates of ACM and TCM were 4.24% and 0.52% among men who received RT and 7.14% and 1.22% among men who did not. Compared to the adjusted general population, men with seminoma had increased risk of ACM (SMR 1.12; 95% confidence interval [CI] 1.12-1.28), SM (SMR 1.78; 95% CI 1.58-2.00) and SUIC (SMR 1.40; 95% CI 1.02-1.94) and decreased risk of CVM (SMR 0.73; 95% CI 0.62-0.84). Rates of ACM, SM and SUIC (SMR, all p < 0.05) were increased whether RT was used or not. Men who received RT were less likely to die (adjusted hazard ratio [AHR] 0.76; 95% CI 0.65-0.89; p < 0.001) and had a lower risk of TCM (AHR 0.39; 95% CI 0.24-0.65; p < 0.001). There was no difference in CVM between men who did and did not receive RT (AHR 0.89; 95% CI 0.60-1.15; p = 0.230) and a numerical increase in SM in men who received RT as compared to others (AHR 1.25; 95% CI 0.90-1.72; p=0.180).

Conclusions: Compared to the general population, men with a history of stage I seminoma had increased risks of all-cause mortality, death from second malignancies, and suicide. Our data suggest that 15 years after diagnosis, men who did receive RT may be more likely to die from a second malignancy than men who did not. Although not receiving RT was associated with higher testicular-cancer mortality, the results may reflect decreased access to care or follow-up as active surveillance protocols were not common during the study era.

No significant financial relationships to disclose.
Adjuvant radiation therapy for early-stage seminoma: Proton-photon comparison and second cancer risk.
Authors: Efstathiou J. A. , Paly J. J. , Lu H. , Athar B. S. , Niemierko A. , Bekelman J. E. , Coen J. , Shipley W. U. , Zietman A. L. , Paganetti H.
Published: February 2017

228

Background: Seminoma constitutes the majority of testicular cancers and 75% percent of patients present with localized disease. Given that seminoma remains the most curable solid tumor, concerns of toxicity including late sequelae such as excess malignancies have given pause to the use of conventional adjuvant radiation therapy (RT) following orchiectomy for early-stage seminoma. As a result of the unique physical dose deposition characteristics of protons to avoid normal tissue, we evaluated both photon and proton beam therapy (PBT) treatment plans for para-aortic irradiation to assess dose distributions to organs at-risk and model rates of second cancers.

Methods: Ten patients with stage I seminoma treated with conventional adjuvant para-aortic AP-PA photon RT to 25.5 Gy between 2004-2009 at Massachusetts General Hospital had PBT plans generated (AP-PA and PA alone). The dose differences to critical organs, as modeled by Equivalent Uniform Dose (EUD), were examined. The risks of second primary malignancies were calculated using validated methods and compared both to each other and to baseline population risks.

Results: PBT plans were superior to photons in limiting dose to organs at-risk. The volume of whole body normal tissue spared 0.1 Gy was 9.0L and 7.8L for PA and AP-PA protons, respectively, compared to photons. The volume spared 1Gy was 5.0L and 3.8L for PA and AP-PA protons, respectively; while the volume spared 10Gy was 1.3L and 0.85L, respectively. PBT decreased the EUD by 46% (8.2 Gy) and 64% (10.2 Gy) to the stomach and large bowel, respectively (p<0.01), presumably translating into lower levels of nausea and fatigue. Notably, PBT was found to avert 612 excess second cancers among a population of 10,000 men diagnosed at age 35 and surviving to age 75 (p<0.01).

Conclusions: In this comparative dosimetric and modeling study, the use of protons provided a favorable dose distribution with an ability to limit unnecessary exposure to critical normal structures in the treatment of stage I seminoma patients. It is expected that this will translate into decreased acute toxicity and reduced risk of second cancers, for which prospective studies are warranted.

No significant financial relationships to disclose.
Surveillance for stage I testicular seminoma at a single institution in Japan: Retrospective analysis of prognostic factors for relapse.
Authors: Kakimoto K. , Takeda K. , Yoshida T. , Nakayama M. , Arai Y. , Nishimura K.
Published: February 2017

234

Background: Treatment options for clinical stage I seminoma include adjuvant radiotherapy (RT) as well as surveillance and adjuvant chemotherapy (CT). Data available from the surveillance, adjuvant RT and adjuvant CT series suggest that all treatment strategies achieve a complete cure in almost 100% of the patients with stage I testicular seminoma. The success of surveillance of patients with stage I nonseminomatous germ cell tumors and the establishment of curative CT for advanced disease have led to re-examination of the standard treatment approach. We report the results of a retrospective analysis of the prognostic factors for stage I testicular seminoma.

Methods: We retrospectively reviewed the survey of 87 patients with stage I testicular seminoma who were admitted in an institution between January 1982 and January 2009. We examined if the following tumor characteristics could possibly predict the relapse: age at diagnosis, tumor size, pathological T (pT) stage, elevation of beta-hCG level and/or LDH level, invasion of the rete testis, vascular invasion and lymphatic invasion. The cause-specific survival rate was calculated using the Kaplan-Meier method.

Results: During a median follow-up of 8.1 years (range, 1.2-25.7 years), 13 (14.9%) relapses were observed, with an actuarial 5-year relapse-free rate (RFR) of 87.9%. The univariate analysis showed that the following characteristics were not predictive of relapse: age at diagnosis (RFR: 89% [<36 years] vs. 88% [≥36 years]), tumor size (RFR: 90% [<5.6 cm(median)] vs. 85% [≥5.6 cm]), pT stage (RFR: 91% [pT = 1] vs. 84% [pT = 2 and pT = 3]), elevation of beta-hCG level (RFR: 89% [normal] vs. 87% [elevated]), invasion of the rete testis (RFR:90% [absent] vs. 80% [present]), vascular invasion (RFR:86% [absent] vs. 87% [present]), and lymphatic invasion (RFR: 88% [absent] vs. 87% [present]). The overall 5-year survival rate was 97%.

Conclusions: Prognostic factors for relapse could not be identified in this retrospective analysis of the patients admitted in a single institution. To identify the prognostic factors for risk-adapted treatment for stage I testicular seminoma, we need to study a large sample population in Japan.

No significant financial relationships to disclose.
Defining molecular determinants of sensitivity to EGFR inhibition in urothelial carinoma.
Authors: Kim W. Y. , Hadzic T. , Heathcote S. A. , Gammons D. T. , Rathmell K. , Whang Y. E. , Godley P. A. , Nielsen M. E. , Wallen E. , Pruthi R.
Published: February 2017

268

Background: Activation of EGFR in cancer patients has been shown to correlate with tumor proliferation, angiogenesis, and metastasis. EGFR inhibition has been shown to be clinically beneficial in several solid tumors and appears to be a tractable therapeutic target. EGFR is over-expressed in bladder cancer and a phase II trial of neoadjuvant erlotinib in patients with muscle invasive bladder cancer suggests possible clinical activity. We therefore hypothesized that we could define molecular correlates to predict response to EGFR inhibition.

Methods: Correlative tumor samples derived from a phase II trial of neoadjuvant erlotinib in muscle invasive urothelial carcinoma of the bladder were analyzed to define molecular determinants of response to EGFR inhibition. The effect of silencing a candidate molecular predictor of resistance to EGFR inhibition, HRAS, was assessed by changes in the IC50 of T24 cells (harbor mutant HRAS) expressing short hairpin RNAs to HRAS or a control shRNA.

Results: Analysis of the gene expression profiles of TURB-T (pretreatment) samples show that tumors from non-pT0 patients had significantly elevated levels of HRAS relative to tumors from pT0 patients. Furthermore, knock-down of HRAS in T24 cells enhanced the sensitivity of these cells to erlotinib.

Conclusions: Elevated HRAS expression is correlated with a lack of response to erlotinib in vivo and silencing of HRAS in T24 cells results in enhanced sensitivity to erlotinib in vitro. Further molecular analyses are ongoing.

No significant financial relationships to disclose.
Perioperative morbidity and mortality in patients treated by radical cystectomy: A multi-institutional retrospective study.
Authors: Takada N. , Abe T. , Maruyama S. , Sazawa A. , Shinohara N. , Seki T. , Togashi M. , Nonomura K. ,   Hokkaido Urothelial Research Cancer Group
Published: February 2017

270

Background: It is well known that radical cystectomy is associated with comparatively high perioperative morbidity and mortality. In the present study, we collected data of perioperative outcomes from Hokkaido University Graduate School of Medicine and our teaching hospitals and assessed the complications and death rate within 90 days after radical cystectomy.

Methods: We collected clinical data of 970 patients undergoing radical cystectomy for nonmetastatic bladder cancer in 21 institutions between 1999 and 2009. We then assessed 90-day complications and death after radical cystectomy. The complications were classified according to the modified Clavien classification. Over 40 variables were included in the analysis, including age, ASA score, BMI, comorbidity, neoadjuvant chemotherapy, clinical stage, type of urinary diversion, operative time, estimated blood loss, transfusion, and hospital stay. Statistical analysis was performed utilizing Student's t-tests, chi-square tests, and logistic regression analysis.

Results: The median patient age was 70 (range, 25-91) years old. 62.5% of patients had an ASA score≥2. Regarding the urinary diversion, ileal conduit was performed in 523 (53.6%) patients, neobladder in 178 (18.4%), ureterocutaneostomy in 255 (26.3%). Median operative time was 399 (range, 100-927) minutes. Median hospital stay was 39 (0-364) days. Regarding the complications, 660 (68%) patients experienced at least one complication and death rate within 90 days after surgery was 1.34% (n=13), respectively. Of the complications, 34.1% was classified as grade 1, 41.5% as grade 2, 20.1% as grade 3, 1.1% as grade 4, 1.2% as grade 5. Multivariate analysis identified age≥70 (odds ratio 1.41), urinary diversion utilizing intestine (OR 1.58) and operative time ≥ 400 (OR 1.54) were independent risk factors.

Conclusions: Death rate was 1.34%, which was compatible to reports form western high- volume centers. About two-thirds of the patients experienced at least one complication, although they were mostly classified as grade 2 or less. Age, urinary diversion, and operative time were significant risk factors for perioperative complications after radical cystectomy.

No significant financial relationships to disclose.
Phase II study of a polyethoxylated castor oil–free, polymeric micelle formulation of paclitaxel for patients with advanced urothelial cancer previously treated with gemcitabine and platinum.
Authors: Lee J. , Park S. , Lim H. , Kwon J. , Kim G. , Song C. , Hong J. , Kim C. , Ahn H. , Ahn J.
Published: February 2017

272

Background: Paclitaxel-loaded polymeric micelle (Genexol-PM; G-PM) is a novel polyethoxylated castor oil (Cremophor EL [CrEL])-free formulation of paclitaxel. This multicenter phase II study was designed to evaluate the efficacy and safety of the G-PM monotherapy for the treatment of gemcitabine- and cisplatin-refractory advanced urothelial cancer.

Methods: Patients with advanced urothelial cancer received G-PM 240 mg/m2 intravenously over 3 hours every 3 weeks without premedication as salvage chemotherapy after failure to gemcitabine and cisplatin combination chemotherapy. Intrapatient dose escalation of G-PM to 300 mg/m2 was carried out from the second cycle if the prespecified toxicities were not observed after the first cycle.

Results: Thirty-seven patients were enrolled in this study. Platinum-free interval was less than 6 months in 72% of patients and 64% of patients were categorized into intermediate or poor prognostic group. Overall response rate was 19% including one complete response. When response occurs it is long lasting with a median response duration of 7.8 months (range 1.5∼19.3+). The median progression-free survival was 2.7 months (95% CI, 09-4.6) with a median overall survival of 5.7 months (95% CI, 3.1-8.3). The most common major grade 3-4 non-hematologic toxicity was peripheral neuropathy (sensory type 5.6% and motor type 8.3%) followed by infection (5.6%). Grade 3 or worse hematologic toxicities were observed in only one patient.

Conclusions: G-PM showed modest activity with favorable toxicity profiles when used as salvage therapy after gemcitabine-cisplatin failure in advanced urothelial cancer.

No significant financial relationships to disclose.
Gemcitabine/cisplatin in patients with advanced bladder and impaired renal function: A retrospective analysis.
Authors: Morales R. , Serrano C. , Bellmunt J. , Mellado B. , Guix M. , Gallen M. , Font A. , Suarez C. , Valverde C. M. , Carles J.
Published: February 2017

274

Background: A four-weekly regimen of gemcitabine and cisplatin (GEMCIS) has similar activity and is less toxic than MVAC in advanced bladder cancer. However, full-dose cisplatin in unfit patients with impaired renal function is contraindicated and other carboplatin-based schedules have been developed. We have previously reported the feasibility of GEMCIS in a biweekly schedule in unfit patients with renal impairment. Here we report a multicenter retrospective study of this biweekly regimen in patients with impaired renal function.

Methods: Between January 2004 and October 2009, 40 patients with locally advanced nonsurgically resectable or metastatic bladder cancer and impaired renal function were included. Treatment consisted of gemcitabine 2500 mg/m2 on day 1 and cisplatin 35 mg/m2 on day 1, every 14 days.

Results: Median age of the patients was 73 years (range: 51-82 years). Median IK was 80% (range: 60-100%). Mean creatinine clearance was 49 ml/min (range:37-59 ml/min). Eight patients had previously received chemotherapy with gemcitabine and/or platinum based therapy. Metastatic localizations were: 17 lymph nodes, 10 pulmonary, 10 bone, 7 liver, 12 pelvic and 1 central nervous system. The median number of cycles/patient was 6 (1-13). Out of 36 patients evaluable for response, there was one complete response, 14 partial responses (ORR: 42%; 95% CI 27-58%), 11 stabilizations and 10 progressive diseases. Hematologic toxicities were grade 1 anaemia in 15 patients, grade 2 in 8; grade 3 in 2; grade 3 neutropenia in 5 patients and grade 4 in 1 patient; grade 3 plaquetopenia in 3 patients. Nonhematologic toxicities were grade 1-2 vomiting in 2 patients. Two patients showed a grade 2 hepatic toxicity. Worsening of the renal function was observed in two patients. Alopecia grade 1-2 was seen in three patients. There was one toxic death related to metabolic acidosis.The median progression-free survival is 15 weeks. The median OS from first cycle of GEMCIS is 35 weeks and 1-year OS is 43% (St error 9%).

Conclusions: A two-weekly schedule of gemcitabine plus cisplatin is feasible, active, and generally well tolerated in an outpatient setting in unfit patients with poor renal reserve.

No significant financial relationships to disclose.
Effect of signet-ring cell carcinoma histology on bladder cancer outcome.
Authors: Wang J. , Wang F. , Enke C. A.
Published: February 2017

275

Background: Signet-ring cell carcinoma (SRCC) of the urinary bladder is a rare entity. Recent case series of the condition showed inconsistent results. We used a population-based data set to compare the cancer specific survival of patients with signet-ring cell carcinoma vs. transitional cell carcinoma (TCC) of the urinary bladder.

Methods: Signet-ring cell carcinoma of the urinary bladder and transitional carcinoma of the urinary bladder were identified in the Surveillance, Epidemiology and End Results program (2001 to 2004). Demographic and pathological characteristics at diagnosis were compared. Differences in cancer specific survival were compared with univariate and multivariate Cox regression analysis.

Results: A total of 103 SRCC cases were present in the database from 2001 to 2004. In that time 14,648 cases TCC cases were diagnosed. SRCC was more common in younger than in older patients (p <0.001); more commonly presented with high grade histology (p <0.001) and advanced stage disease (p <0.001). The 3-year cancer specific survival rate was 67.0% and 33.2% for TCC and SRCC, respectively. On multivariate analysis there was an increased mortality risk in patients with SRCC vs TCC (HR 1.42, 95% CI 1.03–1.97, p <0.001). When only high grade cases of SRCC and TCC were compared, the risk was still worse in SRCC (HR 1.430, 95% CI 1.035–1.976, 0.03). When only local stage of SRCC and TCC were compared, the risk was worse in SRCC (HR 4.294, 95% CI 1.035–17.825, 0.045). Limited to patient who underwent cystectomy only, the difference in cancer specific survival disappeared (HR 1.289, 95% CI 0.771–2.155, 0.33).

Conclusions: Even after adjusting for demographic, pathological and treatment factors, cancer specific survival is significantly worse in patients with SRCC than TCC. Further research into the biology of this rare tumor is required to explain these results.

No significant financial relationships to disclose.
Gene expression profile of circulating tumor cells (CTCs) in clear cell metastatic renal cell carcinoma (mRCC).
Authors: Iacovelli R. , Nicolazzo C. , Petracca A. , Risi E. , Cortesi E.
Published: February 2017

302

Background: The presence of circulating tumor cells (CTCs) is described in 50% of patients affected by mRCC. The detection of CTC seems to be correlated with advanced tumor stage and more aggressive tumor phenotype. In some other solid tumors, such as breast, colorectal and prostate cancer, a growing body of evidence is emerging about the molecular portrait of these cells, whose nature is still largely unknown. The lack of information about CTCs characterization in RCC strongly hampers their application into the clinical practice. Aim of the study was to trace a gene expression profile of CTCs in mRCC patients.

Methods: 18 metastatic clear cell mRCC patients were enrolled in the study. All patients provided informed consent. CTCs were isolated from 10cc of peripheral blood by CELLection Dynabeads coated with the monoclonal antibody towards the human Epithelial Cell Adhesion Molecule (EpCam). CELLection Epithelial Enrich is designed to optimally enrich bead-free, viable epithelial tumor cells. Tumor cells were eluted, subjected to RNA extraction and cDNA synthesis. PCR was then performed to investigate the expression of cytokeratin 8 (CK8) and vimentin as markers of clear cell RCC, multidrug resistance (MDR1), multidrug resistance related proteins 1–5–7 (MRP 1, MRP5, MRP 7) as drug resistance markers.

Results: According with standard CTCs definition (CK+/CD45-), we found their presence in 9/18 samples (50%). Out of them, vimentin was found in 2/9 (22%), MDR1 in 3/9 (33%), MRP1 in 1/9 (11%), MRP5 in 6/9 (66%) and MRP7 in 9/9 (100%).

Conclusions: To our knowledge this is the first attempt to describe a gene expression portrait in CTCs from clear cell mRCC. Of note is that vimentin, classically used as diagnostic marker for clear cell RCC is often lost in CTCs. This seems to further confirm the discrepancy between CTCs and primary tumor phenotype, already demonstrated in breast cancer. The expression profile of genes involved in multidrug resistance in CTCs seems to reflect the well known drug resistance observed in RCC. How these biological information obtainable from a gene expression profile performed on CTCs in clear cell mRCC may be translated into the clinic is currently under investigation.

No significant financial relationships to disclose.
TORAVA trial: Lessons from this trial in the two control arms, sunitinib and bevacizumab in combination with interferon.
Authors: Escudier B. J. , Perol D. , Ferlay C. , Gravis G. , Chevreau C. , Delva R. , Bay J. , Geoffrois L. , Blanc E. , Negrier S.
Published: February 2017

315

Background: The TORAVA trial, reported at ASCO 2010, was a randomized phase II study aimed to determine the efficacy and safety of temsirolimus and bevacizumab combination. Both efficacy and safety were demonstrated as insufficient. Interestingly, 2 control arms were used in this study, sunitinib (arm B) or bevacizumab and a-interferon (arm C). Both PFS and RR were higher in arm C than arm B (16.8 mths and 39% vs. 8.6 mths and 23.8%). Post-hoc analysis were thus performed to determine the predictive factors for better efficacy.

Methods: Overall, 171 pts were randomized in this study, 42 in arm B and 41 in arm C. The study was stratified on PS only, 0–1 vs 2. These 83 pts were analyzed regarding baseline characteristics, and dose reduction.

Results: Some important differences were detected in the 2 arms, in favor of arm C: DFI>12mths (29 vs. 39%), good MSKCC risk (31 vs. 39%), Fuhrman grade 1–2 (32 vs. 38%), liver metastases (19 vs. 14.6%), high LDH (17.1 vs. 7.9%). Interestingly, pts who had dose reduction of interferon (27/41 pts) had a longer PFS than those who did not reduced the dose. Updated analyses will be presented.

Conclusions: Small randomized trials such as randomized phase II trials are not guaranteed to balance predictive/ prognostic factors across treatment arms. Before interpreting RR and PFS in mRCC, careful analysis of pt characteristics should be performed. However, this study will probably help to determine a population more likely to benefit from bevacizumab-interferon combination.

[Table: see text]
Effect of everolimus therapy on skeletal muscle wasting in patients with metastatic renal cell carcinoma (mRCC): Results from a placebo-controlled study.
Authors: Albiges L. , Antoun S. , Martin L. , Merad M. , Loriot Y. , Baracos V. , Escudier B. J.
Published: February 2017

319

Background: We have previously reported that sorafenib induces muscle wasting in mRCC (Antoun, JCO 2010). As everolimus exerts its antineoplastic through inhibition of the mammalian target of rapamycin (mTOR), a key element of intracellular signalling of protein synthesis in skeletal muscle, we hypothesized that muscle wasting would be also an important side effect of everolimus therapy.

Methods: All patients with mRCC enrolled in RECORD 1 (everolimus (E) or placebo (P) post TKI failure) in IGR (n=40) were analyzed for this study. Patients were eligible if at least 2 CT scans were available. CT image analysis, which has high precision and specificity for evaluation of specific muscles, was used to define change in total skeletal muscle. The third lumbar vertebra (L3) was chosen as a landmark. Images were analyzed using Slice-O-Matic software V4.3 (Tomovision). Tissue Hounsfield unit thresholds were employed: −29 to +150 for skeletal muscle. Subsequently, tissue cross-sectional areas (cm2) were computed.

Results: 35 patients (83% male, median age 60y) were evaluable, 10 on P and 25 on E. In addition, 9 patients initially on P could cross to E (as per protocol) and were analyzed both on P and on E. Median durations of treatment were 79 and 263 days respectively on P and E. Placebo patients had stable body weight, with no significant mean gain or loss of muscle. By contrast, patients on E lost body weight over time: −2.5±3.6 kg by 83 d (p=0.02), −4.9±5.7 (p=0.005) by 167 d and –5.0±7.6 kg (p=0.02) by 286 d. E patients progressively lost skeletal muscle compared .with baseline from −2.5±5.9% at 83d (p=0.06), to −4.0±7.5% at 167d (p=0.03) and −4.8±6.8% at 263d (p=0.01). Interstingly, the 9 patients who had maintained body weight (+2.0 kg) and muscle (+2.7%) whilst on placebo, and crossed to E, promptly lost weight (−4.8 kg, p<0.03) and skeletal muscle (−5.3%) (about 1.5 kg of muscle) when crossed to E.

Conclusions: Body weight and muscle wasting are induced by everolimus in mRCC, and are not related to progressive disease. These changes increase over time. Relation between these changes and outcome will be presented at the meeting.

[Table: see text]
Use of comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys to investigate the role of nonmodifiable factors in determining ultimate renal function.
Authors: Lane B. R. , Russo P. , Uzzo R. , Hernandez A. V. , Boorjian S. A. , Thompson R. H. , Fergany A. F. , Love T. , Campbell S.
Published: February 2017

321

Background: Factors that determine renal function after partial nephrectomy (PN) are not well defined, including the impact of cold vs. warm ischemia and the relative importance of modifiable and non-modifiable factors. We studied these determinants in a large cohort of patients with a solitary functioning kidney undergoing PN.

Methods: In 1980–2009, 660 PN were performed at 4 centers for tumor in a solitary-functioning kidney under cold (n=300) or warm (n=360) ischemia. Data were collected in IRB-approved registries; follow- up averaged 4.5 years. Pre- and postoperative glomerular filtration rates (GFR) were estimated via CKD-EPI equation.

Results: At 3 months after PN, median GFR decreased by equivalent amounts with cold or warm ischemia (21% vs. 22%, respectively, p=0.7) although median cold ischemic times were much longer (45 vs. 22 min. respectively, p<0.001). In multivariable analyses, increasing age, larger tumor size, lower preoperative GFR, and longer ischemia time were associated with decreased postoperative GFR (p<0.05). When percentage of parenchyma spared was incorporated into the analysis, this factor and preoperative GFR proved to be the primary determinants of ultimate renal function, and duration of ischemia lost statistical significance.

Conclusions: This non-randomized comparative study suggests that long-term renal function after PN is determined primarily by the quantity and quality of renal parenchyma that can be preserved. Within the relatively strict parameters of conventional practice, i.e. predominantly short ischemic intervals and liberal use of hypothermia, ischemia time was not an independent predictor of ultimate renal function after PN. Nevertheless, type and duration of ischemia remain the most important modifiable factors during PN, and mandate further study.

[Table: see text]
Predictors of long-term survival in patients with metastatic renal cell carcinoma in the cytokine era: An analysis of 473 patients treated between 1995 and 2005.
Authors: Shinohara N. , Maruyama S. , Abe T. , Sazawa A. , Nonomura K. ,   Hokkaido Immunotherapy Research Group
Published: February 2017

335

Background: Based on the clinical data in Japanese renal cell carcinoma (RCC) patients who underwent cytokine therapy (Naito et al, Eur Urol 2010), the overall survival (OS) of these patients has been considered to be better than that of Caucasian patients. We identified long-term survivors among a cohort of 473 metastatic RCC patients, and explored clinical predictors of OS in these patients.

Methods: Between 1995 and 2005, 473 patients with metastatic RCC were the subjects of this retrospective analysis. Three hundred sixty-one (76%) patients received IFN-α and no patient did molecular-targeted drugs. The patients with survival times of greater than 5 years after the development of metastases were identified as long-term survivors. Multiple logistic regression analysis was performed to evaluate the impact of clinical variables potentially influencing OS.

Results: Median OS for all patients was 22.3 months (95%CI 18.7-27.6), the estimated 5-year survival rate was 27.4% (95% CI 22.9-31.9). Sixty-eight patients (14.4%) among 473 patients were identified as long-term survivors. Twenty-six (38%) had metastases at diagnosis of kidney cancer, 3 (4%) and 11 (16%) had liver mets and bone mets, respectively. According to MSKCC risk classification, 19 (28%), 28 (41%), and 6 (9%) were classified as favorable, intermediate, and poor risk, respectively. All patients had undergone prior nephrectomy, and 40 (59%) underwent metastatectomy. Multiple logistic regression analysis from all patients identified metastatectomy (HR 5.0; 95%CI 2.7-9.5) and MSKCC risk group (HR 3.7; 95%CI 1.5-9.1) as adverse prognostic factors for long-term OS.

Conclusions: Selected patients with metastatic RCC who can undergo metastatectomy have a good opportunity for long-term survival, especially those with favorable or intermediate risk classified by MSKCC risk classification.

No significant financial relationships to disclose.
Hematologic toxicities in renal cell carcinoma and other malignancies treated with bevacizumab: A meta-analysis of clinical trials.
Authors: Fontes Jardim D. L. , Je Y. , Schutz F. A. , Choueiri T. K.
Published: February 2017

336

Background: Bevacizumab is a humanized monoclonal antibody directed against the VEGF ligand. Clinical trials with this drug mainly included patients with renal cell cancer (in combination with interferon-alpha) and several other solid tumors (in combination with cytotoxic chemotherapy). Although hematologic toxicities are not among the main concerns associated with the addition of bevacizumab, discontinuation of therapy or dose reductions due to these toxicities have been reported. We performed a meta-analysis to determine the incidence and risk of hematologic toxicities associated with bevacizumab use.

Methods: The databases of Medline were searched for articles from 1966 to September 2010. Abstracts presented at the American Society of Clinical Oncology meetings were also searched. Eligible studies include randomized trials with bevacizumab, and adequate safety data profile reporting anemia, neutropenia, febrile neutropenia, or thrombocytopenia. Statistical analyses were conducted to calculate the summary incidence, RR, and 95% confidence intervals (CI).

Results: A total of 15,239 patients were included in the analysis. The incidence of bevacizumab-associated all-grade anemia, neutropenia and thrombocytopenia were 19.4%, 22.3%, and 14.5%, respectively. The incidences of high-grade events were 3.94%, 18.4% and 3.38%, respectively. Febrile neutropenia was present in 3.75% of patients. Bevacizumab was associated with a decreased risk of high-grade anemia (RR=0.73; 95% CI 0.60-0.89; p=0.002), and increased risks of high-grade neutropenia (RR=1.08; 95% CI 1.02-1.13; p=0.005) and febrile neutropenia (RR=1.31; 95% CI 1.08-1.58; p=0.006), as compared to the non-bevacizumab containing arms. Stratified analysis by the dose of bevacizumab (2.5mg/wk vs. 5mg/wk) demonstrated similar risks.

Conclusions: Concurrent use of bevacizumab with chemotherapy or immunotherapy is associated with a lower risk of high-grade anemia and an increased risk of high-grade neutropenia and febrile neutropenia.

[Table: see text]