bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of additional chemotherapy following failure of currently approved therapies in patients with castration-resistant prostate cancer.
Authors: Campedel Luca , Blanc-Durand Paul , Assoun Sandra , Mateescu Cristian , Roupret Morgan , Bitker marc-Olivier , Vaessen Christophe , Parra Jerome , Comperat Eva , Boostandoost Haide Angele , Malouf Gabriel G. , Spano Jean-PHilippe
Published: March 2017

274

Background: Approved therapies for patients with castration resistant prostate cancer (CRPC) include next generation androgen receptor inhibitors as well as taxanes which are given sequentially. After failure of these drugs, physicians may use additional chemotherapy such as carboplatin, paclitaxel, mitoxantrone and vinorelbine. The clinical benefit of these drugs in this setting remains fully unknown. Methods: A retrospective monocentric study of patients treated for CRPC was performed. Presence of metastasis and visceral involvement at diagnosis and at castration resistance, time between start of hormonotherapy and castration resistance were recorded as well as several clinical and biological parameters at start of CRPC first line. The cohort was divided into two groups according to the use of additional chemotherapies following failure of currently approved therapies. Results: Fourty subjects out of 138 cases (28.9%) fulfilled the inclusion criteria. At diagnosis, median patients age was 68 years (range, 53-86), median Gleason grade was 8 (6-10) and 53% of them harbored distant metastasis. At castration-resistance stage, 93% were metastatic including 27% out of them wihich harbored visceral involvement. Median overall survival (OS) of patients since castration-resistance was 34.9 months (range, 7.4-88.0). The two groups were comparable in terms of age, PSA level, and Gleason grade. Median OS for patients in the additional chemotherapy group (n = 16) was 42.4 months as compared to 37.3 months in the non additional treatment group (n = 24), with no statistical difference (p = 0.961). Main treatments administered consisted of carboplatin (n = 6), paclitaxel (n = 4) and mitoxantrone (n = 4). PSA response rate (decrease > 50%) obtained with use of additional treatment was 12%. Median progression-free survival was 1.9 months (range, 0.7-13.1) and median overall survival was 4.2 months (range, 2.2-17.8). Conclusions: Our retrospective study suggests that additional treatment after standard treatment failure for CRPC is associated with limited benefit. Further studies are needed to clarify the role of new agents therapies in this setting.
Modes of action of low-dose cabazitaxel in combination with the antiangiogenic and antitumoral pigment epithelium-derived factor in prostate cancer.
Authors: Nelius Thomas , Jarvis Courtney , Filleur Stephanie
Published: March 2017

275

Background: Despite the approval of several new agents, taxanes remain the main alternative treatment for castration-refractory metastatic prostate cancer (mCRPC). In a previous work, we have demonstrated that cabazitaxel is more efficient in a low-dose setting than docetaxel in inhibiting the proliferation and inducing apoptosis of CRPC cells in vitro, and delaying tumor growth in vivo. In the present study, we have investigated the efficacy of low-dose cabazitaxel when combined with the anti-angiogenic and anti-tumoral Pigment Epithelium-Derived Factor (PEDF). Methods: CRPC CL1 cells (LNCaP-derivative) that express PEDF or control plasmid were used. Tumor cells were injected s.c. into C.B.17-SCID mice. After two weeks, mice were randomized into groups: 1) Placebo; 2) Docetaxel: 5mg/kg i.p. d4; and 3) Cabazitazel 5-1-0.5-0.1mg/kg i.p. d4, d1-7, d2, and daily. To investigate the molecular mechanisms involved in the anti-tumor effect of the combined treatment, tumor cell migration was measured using the inverted Boyden chamber assay. Tumor cell phagocytosis was also assessed in CL1-RAW264.7 macrophages co-cultures. Results: We showed that while 0.5 and 0.1 mg/kg cabazitaxel did not improve PEDF efficacy on tumor growth, 1mg/kg was extremely toxic, killing 1/2 animals within the first week of treatment. In contrast, we demonstrated that PEDF combined with 5mg/kg cabazitaxel lead to stabilization of the disease. PEDF/cabazitaxel was also found to be drastically more efficient than PEDF/docetaxel in delaying the disease. In vitro, PEDF/cabazitaxel inhibited tumor cell migration at a superior level compared to PEDF/docetaxel. Finally, PEDF/cabazitaxel induced more phagocytosis of the tumor cells by macrophages than PEDF/docetaxel suggesting that the combination may target macrophages within the tumor microenvironment. Conclusions: Our data demonstrated that PEDF with low-dose cabazitaxel could be used as a novel therapeutic combination to treat CRPC. Our results also emphasize on the importance in closely evaluating the cytotoxicity of the combination tested and investigating the role of the tumor microenvironment in the anti-tumor effect.
The natural history, treatment, and survival of 199 patients with sarcomatoid carcinoma of the prostate.
Authors: Biswas Roy Sreeja , Cheney Scott , Brunnhoelzl Daniel , Wang Jue
Published: March 2017

278

Background: Sarcomatoid carcinoma of the prostate (SCP) is a rare and aggressive subtype of prostate cancer. Current data on clinical features, appropriate management and long-term outcomes of SCP are limited. Methods: A systematic review of literature was performed to identify published reports on SCP using keywords “sarcomatoid”, “prostate”, and “carcinosarcoma”. No randomized trials were identified. Four single-center case series and one registry-based study were included in final analysis. Results: In total, 199 patients were included in the review (54 from the SEER registry, 145 from the four case series). SCP occurs more frequently in the late sixth to seventh decade of life (age range: 28-91 years). Many patients with SCP (range, 48%-78%) have a history of prostate adenocarcinoma, with variable time to SPC onset (range, 0.5-20 years). Most tumors are high grade, with locally advanced or distant stage. Urinary obstruction was the most common symptom (50%-92%). Advanced stage was associated with poor prognosis in all reports. Although prostatectomy as part of multimodality treatment likely affected cancer-specific survival in select patients, large variation was observed in prostatectomy and adjuvant therapy rates. No effective systemic chemotherapy was reported. Conclusions: SCP is an aggressive variant of prostate adenocarcinoma. Molecular studies are needed to illuminate their aggressive underlying biology and develop individualized therapeutic approaches. The results of this analysis may help increase awareness of this rare malignancy and serve as a baseline for future clinical studies. [Table: see text]
Intravesical rad-IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guérin (BCG) refractory or relapsed non-muscle invasive bladder cancer: A phase II randomized study.
Authors: Boorjian Stephen A. , Shore Neal D. , Canter Daniel , Ogan Kenneth , Karsh Lawrence Ivan , Downs Tracy , Gomella Leonard G. , Kamat Ashish M. , Lotan Yair , Svatek Robert S. , Bivalacqua Trinity J. , Grubb Robert , Krupski Tracey , Lerner Seth P. , Woods Michael , Inman Brant Allen , Milowsky Matthew I. , Parker Nigel , Sawutz David , Dinney Colin P.N.
Published: March 2017

279

Background: While bacillus Calmette-Guérin (BCG) is the most effective intravesical treatment for reducing recurrence and progression for high-risk non-muscle invasive bladder cancer (NMIBC), many patients are either refractory to treatment or relapse. We assessed the efficacy and safety of rAd-IFNα/Syn 3 (Instiladrin, FKD Finland), a replication deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG refractory or relapsed NMIBC. Methods: In this open-label, US multicenter (n=13), parallel-arm Phase II study (NCT01687244), 43 patients with HG BCG refractory or relapsed NMIBC were randomized 1:1 to receive intravesical rAd-IFNα/Syn3 at 1x1011 or 3x1011viral particles/mL. Patients responding at months 3, 6, and 9 were re-treated at months 4, 7, and 10. Most patients (n=21) had a primary tumor classification of carcinoma in situ (CIS); 9 had both CIS and Ta/T1 disease and 10 had Ta/T1 disease alone. The primary endpoint was 12-month HG recurrence-free survival (RFS). All patients receiving at least one dose were included in efficacy and safety analyses. Results: Forty patients received rAd-IFNα/Syn3 (1 x 1011 vp/mL: n=21; 3 x 1011vp/mL: n=19) between November 2012 and April 2015. Fourteen patients (35.0%; 90% CI 22.6%, 49.2%) remained free of HG tumor recurrence 12 months after initial treatment. Comparable 12 month HG RFS was noted between dosage arms, as well as between patients with refractory and relapsed NMIBC. Interestingly, the 12 month HG recurrence-free survival for patients with Ta/T1-only disease was 50% (5/10). rAd-IFNα/Syn3 was well-tolerated, with no Grade 5 adverse events (AEs), one Grade 4 AE (COPD; unrelated to treatment), and no patient discontinuing treatment due to an adverse event. The most frequently reported AEs were micturition urgency (n=16), dysuria and pollakiuria (n=13 each), fatigue (n=9), and nocturia (n=10). Conclusions: rAd-IFNα/Syn3 was well tolerated and demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who are unable or unwilling to undergo radical cystectomy. A phase III trial utilizing this novel agent is ongoing. Clinical trial information: 01687244.
Temporal trends and factors associated with overuse of neoadjuvant androgen deprivation therapy in low and very low risk prostate cancer.
Authors: Delancey John Oliver , Matulewicz Richard , Schaeffer Edward M.
Published: March 2017

28

Background: Evidence has emerged that androgen deprivation (ADT) use prior to radical prostatectomy or radiation therapy in low risk prostate cancer patients does not provide a survival benefit and may subject patients to adverse side effects and clinical outcomes. We examined trends and factors associated with ADT use prior to definitive therapy in low and very low risk prostate cancer. Methods: We identified men diagnosed with low or very low risk prostate cancer in the National Cancer Database from 2004-2013 who elected definitive treatment with radical prostatectomy (RP), external beam radiation (EBRT) or brachytherapy (BT). Neoadjuvant ADT use was defined as receipt of ADT prior to definitive treatment. Trends in neoadjuvant ADT use were assessed and multivariable logistic regression was used to evaluate associations between treatment, age, race, insurance status and urban/rural status and receipt of neoadjuvant ADT. Results: Of 199,933 patients with low or very low risk prostate cancer, neoadjuvant ADT use decreased from 14.6% in 2004 to 2.7% in 2013 (23.0% to 8.8% for BT, 20.6% to 6.0% for EBRT and 2.3% to 0.5% for RP; each p for trend < 0.001). Controlling for covariates and year, we found increased odds [OR (95% CI)] of neoadjuvant ADT use in patients undergoing BT [12.01 (11.23-12.83)] or EBRT [8.75 (8.16-9.39)], African Americans [1.08 (1.02-1.14)] vs. whites, patients 75 or older [1.93 (1.80-2.06)] and 65-74 [1.52 (1.44-1.60)] vs. less than 65, patients in communities less than 250,000 [1.28 (1.23-1.34)] vs. metropolitan areas and patients with Medicare or Medicaid [1.22 (1.16-1.29)] vs. private insurance. Conclusions: Use of ADT prior to definitive prostate cancer treatment has declined over the past decade. However, patients receiving radiotherapy, African Americans, patients of older age, rural location, and insured by Medicare or Medicaid more frequently received neoadjuvant ADT. Since this treatment is unlikely to provide a survival benefit and may subject patients to adverse side effects or clinical outcomes, strategies to minimize overuse of ADT in low or very low risk patients prior to definitive therapy may help limit overtreatment and its associated harms.
Long-term incidence of venous thromboembolic events following cystectomy: A population-based analysis.
Authors: Wallis Christopher J.D. , Magee Diana , Satkunasivam Raj , Nam Robert
Published: March 2017

288

Background: Cancer and immobility both contribute to the development of venous thromboembolic events (VTE), including pulmonary embolism and deep vein thrombosis. As such, patients undergoing radical cystectomy for bladder cancer are at elevated risk. We sought to assess the long-term incidence of VTE among all patients undergoing radical cystectomy in the province of Ontario. Methods: We conducted a population-based cohort study to examine the incidence of VTE, a composite of pulmonary embolism and deep vein thrombosis, among all patients treated with radical cystectomy for bladder cancer between 2002 and 2014 in Ontario, Canada. We estimated the cumulative incidence of VTE and used Fine and Grey competing risk survival analysis to assess risk factors for VTE while accounting for the risk of any cause mortality. Results: Among 3623 eligible patients, the 10 year cumulative incidence of VTE was 6.68% (Table 1). Among those who experienced VTE, the median time from surgery was 216 days (interquartile range 52-677 days; mean 527 days). However, VTE rates peaked much earlier with a mode of 20 days. Neither preoperative (HR 0.68, 95% CI 0.39-1.18) nor postoperative chemotherapy (HR 1.32, 95% CI 0.95-1.84) were significantly associated with VTE incidence. While patients with a prior history of VTE had increased risk of VTE after cystectomy (HR 5.1, 95% CI 2.2-12.0), age, gender, comorbidity score, rurality, diversion type (continent vs ileal conduit), treatment at an academic institution, or year of treatment were not significantly associated with the risk of VTE. Conclusions: Among patients undergoing cystectomy for bladder cancer, the cumulative incidence of VTE continues to rise long after the date of surgery indicating that previous studies may have underestimated these rates, but the highest rates occur at 20 days after surgery. Chemotherapy does not appear to increase the risk of VTE. [Table: see text]
The positive predictive value of PI-RADS 4 lesions stratified by lesion number in biopsy naïve men.
Authors: Syed Jamil , Javier-desloges Juan , Nguyen Kevin , Sheridan Alison , Levi Angelique , Weinreb Jeffrey , Sprenkle Preston
Published: March 2017

29

Background: To assess the positive predictive value (PPV) of PI-RADS 4 lesions stratified by suspicion for tumor multi-focality. Methods: Between April 2015 and July 2016, 62 biopsy naïve men with at least one PI-RADS 4 lesion underwent mpMRI/US fusion biopsy. Patients were placed into group 1 if they had a single lesion, group 2 if they had an additional PI-RADS 3 or 2 lesion, and group 3 if they had an additional PI-RADS 4 or 5 lesion. Image interpretation was performed prospectively and assessed using PI-RADS version 2. The ANOVA and chi-square tests were used to assess differences between continuous and categorical variables, respectively. Results: Using systematic and targeted biopsy combined, the overall and GS ≥ 7 cancer detection rate for the entire cohort was 80.6% (50/62), and 53.2% (33/62), respectively. There were a total of 88 lesions with 26,14, and 48 lesions in groups 1,2, and 3, respectively. There were no significant differences in mean age, PSA density, race, or lesion location between groups; p = 0.107, p = 0.694, p = 0.511, and p = 0.558, respectively. The PPV for any prostate cancer was 65.4% (17/26), 100% (14/14), and 90% (43/48) for groups 1,2, and 3 respectively (p = 0.005). The PPV for GS ≥ 7 was 42% (11/26), 50% (7/14), and 75% (36/48) for groups 1,2, and 3, respectively (p = 0.001). Conclusions: Our data indicate that the PPV for a PI-RADS category assessment score of 4 may be influenced by tumor multi-focality on imaging. Further assessment with increased sample size will be useful to confirm our initial results.
Epidermal growth factor receptor (EGFR) targeted photoimmunotherapy (PIT) for the treatment of EGFR expressing bladder cancer.
Authors: Railkar Reema , Krane Spencer , Li Q. Quentin , Sanford Thomas , Choyke Peter L. , Kobayashi Hisataka , Agarwal Piyush K.
Published: March 2017

291

Background: There are limited treatment options for patients with non-muscle invasive bladder cancer (NMIBC) who fail intravesical bacillus Calmette-Guerin (BCG). The use of light as a means of therapy for bladder cancer (BC) has a long history but has been hampered by a lack of tumor specificity and toxicity. Monoclonal antibody (mAb)-conjugates represent an emerging therapeutic approach for malignancies that improves upon tumor specificity. The use of a mAb-photo-absorber (PA) conjugate is a more selective method of delivering light therapy and has been termed “photoimmunotherapy” (PIT). In this report, PIT is used to target the epidermal growth factor receptor (EGFR). EGFR is a good tumor-specific target as it is enriched in the basal molecular subtype of BC. In the present study, anti-EGFR antibody panitumumab (pan) was labeled with the PA, IRDye 700Dx (IR700), to create a pan IR700 mAb-PA conjugate which is activated by near-infrared radiation (NIR). Methods: BC tissue microarray (TMA) and BC cell lines were analyzed for expression of EGFR. Mechanism of PIT induced cell death was studied using proliferation assays, transmission electron microscopy (TEM), and production of reactive oxygen species. Finally, the in vivo effect was studied in xenografts. Results: EGFR staining of TMAs showed that while most BCs have expression of EGFR to some degree, squamous cell carcinomas (SCC) have the highest expression of EGFR. Pan IR700 activated by NIR light rapidly killed UMUC-5 cells, a bladder SCC line. Pan alone, pan IR700 without NIR, or NIR alone had no effect on cells. TEM demonstrated that cell death is due to necrosis. Singlet oxygen species contributed towards cell death. NIR-PIT with pan IR700 reduced growth compared to only pan IR700 treated UMUC-5 xenograft tumors. Conclusions: PIT is a new targeted treatment for BC. Our data demonstrate that pan IR700-induced PIT selectively kills EGFR-expressing bladder cancer cells in vitro and in vivo and hence warrants further studies in orthotopic models and in patients. We suspect that EGFR-directed therapy with PIT is a viable strategy for the basal molecular subtype of BC and will be testing this hypothesis in the future.
Effectiveness of adjuvant chemotherapy after radical nephroureterectomy for locally advanced and/or positive regional lymph node upper tract urothelial carcinoma.
Authors: Krasnow Ross Erik , Seisen Thomas , Bellmunt Joaquim , Roupret Morgan , Leow Jeffrey J. , Lipsitz Stuart R. , Vetterlein Malte , Preston Mark A , Hanna Nawar , Kibel Adam S. , Sun Maxine , Choueiri Toni K. , Trinh Quoc-Dien , Chang Steven Lee
Published: March 2017

305

Background: There is limited evidence supporting the use of adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Against this backdrop, we hypothesized that such treatment is associated with an overall survival (OS) benefit in patients with locally advanced and/or positive regional lymph node disease. Methods: Within the National Cancer Data Base (2004-2012), we identified 3,253 individuals who received AC or observation after RNU for pT3/T4 and/or pN+ UTUC. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and Cox regression analyses were used to compare OS of patients in the two treatment groups. Additionally, we performed exploratory analyses of treatment effect according to age, gender, Charlson comorbidity index, pathological stage (pT3/T4N0, pT3/T4Nx and pTanyN+) and surgical margin status. Results: Overall, 762 (23.42%) and 2,491 (76.58%) patients with pT3/T4 and/or pN+ UTUC received AC and observation after RNU, respectively. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for AC vs. observation (47.41 [IQR, 19.88-112.39] vs. 35.78 [IQR, 14.09-99.22] months; P< 0.001). The 5-year IPTW-adjusted rates of OS for AC vs. observation were 43.90% vs. 35.85%, respectively. In IPTW-adjusted Cox regression analysis, AC was associated with a significant OS benefit (HR = 0.77; 95% CI = [0.68-0.88]; P< 0.001). This benefit was consistent across all subgroups examined (all P< 0.05) and no significant heterogeneity of treatment effect was observed (all Pinteraction> 0.05). The 3-month conditional landmark IPTW-adjusted analysis demonstrated little impact of immortal time bias (HR = 0.79; 95% CI = [0.70-0.91]; P = 0.001). Conclusions: We report an OS benefit in patients who received AC vs. observation after RNU for pT3/T4 and/or pN+ UTUC. Although our results are limited by the usual biases related to the observational study design, we believe that the present findings should be considered when advising post-RNU management of advanced UTUC, pending level I evidence.
Results of the GETUG-AFU 19 trial: A randomized phase II study of dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with or without anti-epidermal growth factor receptor (EGF-R) monoclonal antibody panitumumab (PANI) in advanced transitional cell carcinoma (ATCC).
Authors: Culine Stephane , Flechon Aude , Gravis Gwenaelle , Roubaud Guilhem , Loriot Yohann , Joly Florence , Barthelemy Philippe , Assaf Elias , Mahammedi Hakim , Beuzeboc Philippe , Van Hulst Sylvie , Rolland Frederic , Guillot Aline , Gross-Goupil Marine , Kayat David , Tartas Sophie , Deblock Mathilde , Habibian Muriel , Thezenas Simon , Allory Yves
Published: March 2017

307

Background: Frequent overexpression and correlation with stage and survival has been reported with the EGF-R pathway in ATCC. Methods: 93 patients (pts) with locally advanced or metastatic bladder or upper urinary tract (UUT) transitional cell carcinoma were planned with a 1:2 randomisation ratio. Patients with K-Ras or H-Ras mutations were excluded. dd-MVAC included M 30 mg/m2d1, V 3 mg/m2d2, D 30 mg/m2d2 and cisplatin 70 mg/m2d2 (d1 = d14) with G-CSF support. PANI 6 mg/kg was given on d2. The number of pts was determined from the 9-month median progression-free survival (PFS) rate reported with dd-MVAC. Using a one stage Fleming design, the dd-MVAC+PANI combination will be considered to be active if at least 37 patients among 70 do not show tumor progression at 9 months (p0 = 0.50, p1 = 0.70, alpha = 0.08 and beta = 0.03). As basal-like subtype might be related to Anti-EGFR treatment response, the phenotype was determined using a Keratin 5/6 and GATA3 double immunostaining (8 basal like among 58 cases tested). Results: From September 2010 to November 2015, 96 patients (bladder 68, UUT 21, both 8) received dd-MVAC (33) or dd-MVAC+PANI (63). No significant difference was observed among baseline characteristics and prognostic factors. The median number of cycles was 6 (1-6) in both arms. At least one grade > 2 toxicity was observed in 79% and 76% of patients in the dd-MVAC and PANI arms, respectively. More dermatological adverse events were observed in the PANI arm. Objective responses were reported in 23 (70%) pts in the dd-MVAC arm and 30 pts (48%) in the PANI arm. With a median follow-up of 27 months, PFS was 6.8 months and 5.7 months in the dd-MVAC and PANI arms respectively; OS was 20.2 months and 12.5 months in the dd-MVAC and PANI arms, respectively. No association was observed between PFS and basal-like feature for patients treated by MVAC+PANI. Molecular subtyping is in progress to confirm this observation at mRNA level. Conclusions: When combined with dd-MVAC, PANI does not seem to improve efficacy in pts with ATCC. Clinical trial information: NCT02818725.
A model for predicting focal ablation candidates in patients with prostate cancer based on MRI and biopsy criteria.
Authors: Calio Brian P. , Sidana Abhinav , Sugano Dordaneh , Gaur Sonia , Jain Amit L , Maruf Mahir , Valera Vladimir , Merino Maria J , Turkbey Baris , Choyke Peter L. , Wood Bradford J. , Pinto Peter A.
Published: March 2017

31

Background: To determine the accuracy of multiparametric MRI (mpMRI) and fusion biopsy in predicting focal therapy candidates by correlating agreement between patients’ pre-prostatectomy MRI and biopsy findings with whole mount pathology. Methods: Patients who underwent mpMRI and biopsy followed by prostatectomy between 2010-2015 were included in the study. Patients were considered good candidates for focal therapy if they had intermediate risk cancer (max Gleason 3+4 or 4+3 on biopsy) in only one hemisphere of the prostate, and if they had an mpMRI visible lesion(s) on one hemisphere that did not cross midline. Patients were considered poor candidates for focal therapy if they had either low risk cancer (Gleason 6), high risk cancer (Gleason 8, 9 and 10), intermediate risk cancer bilaterally, MRI visible lesions that cross the midline, or contained extracapsular extension or seminal vesicle invasion. Whole mounts of patients considered good candidates were then examined histologically for maximum tumor involvement. Results: 501 patients who underwent prostatectomy between 2010 and 2015 were included in the study, with mean age 60.0 (±10.0) and PSA 6.21 (±6.0). 395 patients were considered poor focal candidates, and 106 were considered good focal candidates. Of these 106, 66 patients had whole mounts available for analysis (14 random biopsy, 52 fusion biopsy). 42/66 (63.6%) patients were confirmed as candidates (6/14 (42.9%) who had random biopsy and 36/52 (68.0%) who had fusion). Candidates failed prediction due to Gleason upgrade in final histopathology in 20/24 (83.3%), and for significant Gleason detection bilaterally in 4/24 (16.7%). Conclusions: Our results suggest that application of mpMRI and biopsy criteria to predict focal therapy candidates may result in undertreatment of a large portion of patients with significant cancer. Results from mpMRI guided targeted biopsy were shown to be a more accurate tool for predicting candidates for focal therapy than results from random biopsy alone. More accurate predictive capability is needed before focal therapy can be widely accepted.
Association of age with utilization of radical cystectomy for high-grade nonmuscle invasive bladder cancer: Results from the National Cancer Database.
Authors: Parker William P. , Zaid Harras B. , Habermann Elizabeth B. , Frank Igor , Thompson Robert Houston , Tollefson Matthew K. , Karnes Jeffrey , Boorjian Stephen A.
Published: March 2017

312

Background: Radical cystectomy (RC) is a preferred option for high−grade non−muscle invasive bladder cancer (HG NMIBC), particularly after failure of intravesical therapy. However, clinicians may be reluctant to offer surgery to older patients with NMIBC given concerns regarding morbidity. We therefore sought to evaluate the association of age with use of RC and clinicopathologic outcomes after RC for HG NMIBC. Methods: The National Cancer Data Base was queried to identify patients diagnosed with HG NMIBC between 2004−2013. Patients were stratified according to age at diagnosis: <60, 61−70, 71−80, >80 years. Multivariable logistic regression was performed to assess the associations of age group with utilization of RC and with pathologic upstaging (pT2−4 or pN+). Overall survival (OS) was evaluated using unadjusted and inverse propensity score weighted (IPTW) Kaplan−Meier methods and compared with the log-rank test. Results: RC was performed in 3,641 (5.7%) of 63,402 patients with HG NMIBC. Utilization of RC remained relatively constant over the study period (4.3%−6.8%; p=0.44). On multivariable analysis, increasing age was inversely associated with RC utilization, with the lowest utilization in those >80 (2.1% rate; OR 0.24; p<0.01). Similar associations of age with RC were observed at high volume centers (> 15 cases/year), academic centers, and for patients with cT1 disease. Among patients who underwent RC, pathologic upstaging was identified in 1,445 (43.6%), and no significant association was noted with age. NMIBC pathologic tumor stage was associated with improved OS compared to progression to pT2−4 or N+ disease at RC for all age groups: median OS improvement not reached in those under 60; 32 months in those 61−70; 55 months in those 71−80; and 34 months in those over 80 (all p<0.01). Similar improvements in survival were noted after IPTW. Conclusions: Older patients are significantly less likely to receive RC for HG NMIBC, despite a similar risk of upstaging and an improved survival when pathologic NMIBC is found at RC. These data support the use of RC for HG NMIBC in well selected patients across age strata.
Association of chemotherapy regimen with venous thromboembolic risk in patients with urothelial tract cancer.
Authors: Ramos Jorge , Holt Sarah , Schade George , Galsky Matt D. , Wright Jonathan L. , Gore John L. , Yu Evan Y.
Published: March 2017

314

Background: Cisplatin chemotherapy (CTX) is associated with increased risk of venous thromboembolism (VTE); however, other agents have also been hypothesized to increase risk. We assessed the association of VTE with different CTX regimens in urothelial tract cancer patients. Methods: We identified > 66 year-old patients diagnosed with urothelial tract cancers (excluding renal pelvis) from the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database from 1998 to 2011. CTX regimens included gemcitabine/cisplatin (GC), methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), or gemcitabine/carboplatin (GCarbo). We calculated VTE rates within 120 days of CTX initiation and compared VTE by CTX regimen with multivariable logistic regression models adjusted for patient and cancer characteristics. Results: Of 5050 identified patients, VTE occurred in 13.1% (660/5050). VTE rates were 15.3% (265/1737) and highest for GC; 8.8% (23/262) and 12.2% (372/3051) of MVAC and GCarbo patients experienced VTE, respectively. Adjusted for patient demographic and cancer-specific variables, MVAC and GCarbo were associated with lower odds of VTE compared with GC (see Table). Conclusions: Compared with GC, MVAC and GCarbo are associated with a decreased rate of VTE. This finding suggests that gemcitabine may add to the increased thrombosis risk from cisplatin. Patients treated with GC should be counseled about this association. Sensitivity analyses to assess VTE risk of different CTX regimens in the perioperative setting will be presented. [Table: see text]
Outcomes and tolerability of selective bladder preservation by combined modality therapy for invasive bladder cancer in elderly patients.
Authors: Miyamoto David Tomoaki , Drumm Michael , Clayman Rebecca Helen , Niemierko Andrzej , Heney Niall M. , Kaufman Donald S. , Zietman Anthony L. , Shipley William U. , Efstathiou Jason A.
Published: March 2017

316

Background: The median age of patients diagnosed with muscle invasive bladder cancer (MIBC) in the US is 72 years old, and only about half of those over 70 years receive potentially curative therapy (radical cystectomy, chemoradiation, definitive radiation), suggesting a large proportion of patients are undertreated. To address this unmet need, we examined the outcomes and tolerability of chemoradiation (chemoRT) in the elderly. Methods: We conducted an analysis of 455 patients with cT2-T4a disease treated at our institution between 1986 and 2013. Patients underwent induction chemoRT (40Gy) after transurethral resection of bladder tumor (TURBT). Patients achieving a complete response (CR) received consolidation chemoRT to a total goal dose of 64-65Gy. Those with less than a CR or an invasive recurrence were recommended to undergo salvage cystectomy. Elderly was defined as 75 years or older. For comparison with younger patients, propensity score matching was performed based on sex, T-stage, hydronephrosis, completion of TURBT, and decade of treatment. Disease-specific survival (DSS) was evaluated using Kaplan-Meier method. Results: Median age was 66 years (range 27-94). One hundred and one patients (22%) were 75 years or older. Median follow-up was 7.4 years for surviving patients. In a propensity score matched pair analysis of 84 elderly and 84 younger patients, DSS at 5 and 10 years for the elderly was 64.8% and 51%, compared to 71.7% and 62.0% for younger patients (p = 0.28). Elderly patients, compared to the younger patients, had similar rates of ED visits during treatment (10% vs 12%, p = 0.76), hospital admissions for any cause (17% vs. 14%, p = 0.8), unplanned treatment breaks for any cause (24% vs. 12%, p = 0.16), and discontinuation of therapy due to toxicities (6% vs 7%, p = 1.0). Conclusions: In elderly patients with MIBC, outcomes and tolerability of bladder-sparing chemoRT are comparable to that of younger patients. Clinicians should not deny patients potentially curative therapies based on age alone, although further investigation is warranted.
Association of presurgery neutrophil-to-lymphocyte ratio with survival outcomes in patients with urothelial carcinoma treated without neoadjuvant chemotherapy and with radical cystectomy.
Authors: Kukreja Janet Baack , Podolnick Jason M , Wang Xuemei , Chen Hsiang-Chun , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Shah Jay Bakul
Published: March 2017

324

Background: There is growing interest in finding inexpensive, easily reproducible biomarkers to predict outcomes in patients with urothelial bladder carcinoma (BC). An elevated preoperative neutrophil-to-lymphocyte Ratio (NLR) has been found to be an independent prognostic factor for decreased survival, predictive of upstaging at radical cystectomy (RC), and predictive of recurrence and progression. This study investigated the utility of the preoperative NLR predicting long-term outcomes in chemotherapy naïve patients undergoing RC for BC at a large tertiary care center. Methods: In a retrospective cohort study, 849 RC patients with BC were identified between 2000 and 2011. NLR data for these patients was obtained within 30 days prior to RC. Univariate CART analysis was used to determine an NLR cutoff point that was significantly associated with both overall survival (OS) and disease specific survival (DSS). OS and DSS were estimated using Kaplan-Meier curves. Results: The median follow-up time among survivors was 7.3 years. 597 (70%) patients died and 252 (30%) were alive at last follow. Using CART analysis, a preoperative NLR cutoff point of 3.19 was identified to have the strongest association with both OS and DSS (p < 0.001). 562 (66%) patients had a preoperative NLR < 3.19 and 475 (34%) had a preoperative NLR ≥ 3.19. The median OS and DSS for patients with preoperative NLR < 3.19 was 5.96 years and 15.64 years, respectively. The median OS and DSS for patients with a NLR ≥ 3.19 was 4.44 years (95% CI: 3.18-4.81 years) and 8.23 years (95% CI: 5.15-11.87 years). DSS Kaplan-Meier curve was significant, p < 0.001. Patients with a NLR < 3.19 had a 5-year OS and DSS of 59% and 77%, respectively. RC patients with a NLR ≥ 3.19 had a 5-year OS and DSS of 43% and 56%. Conclusions: A preoperative NLR ≥ 3.19 is significantly associated with decreased OS and DSS in patients treated with RC for UC. This finding further validates NLR as a biomarker in BC prognosis. NLR can help to determine patients with a poor prognosis who may benefit from more aggressive, adjuvant therapy following RC.
External validation and optimization of international consensus clinical target volumes for adjuvant radiation in bladder cancer.
Authors: Reddy Abhinav V. , Christodouleas John Paul , Wu Tianming , Smith Norm D. , Steinberg Gary D. , Liauw Stanley L.
Published: March 2017

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Background: International Consensus (IC) clinical target volumes (CTVs) have been proposed to standardize radiation field design in the treatment of patients at high risk for local regional failure (LRF) after radical cystectomy. The purpose of this study was to externally validate the IC CTVs in a cohort of post-surgical patients followed for LRF, and identify revisions that might improve its performance. Methods: Of 334 patients with pT3-4 bladder cancer treated with radical cystectomy, 58 (17%) developed LRF, of which 52 had CTs available for review. Images with LRF were exported into a treatment planning system, and IC CTVs were contoured and evaluated for adequacy of coverage of each LRF, with respect to both the patient and each of six pelvic subsites: common iliac (CI), obturator region (OR), external and internal iliac (EI/II), presacral (PS), cystectomy bed (CB), or other pelvic site. Revisions to the IC contours were proposed based on the findings. Results: Of the 52 patients with documented LRF, 13 (25%) patients had LRFs that were outside of the IC CTV involving 17 pelvic subsites: 5 near the CI CTV, 5 near the OR CTV, 1 near the EI/II, and 6 near the CB. The 5 CI failures were located superior to the CTV and the 5 OR failures were located medial to the CTV. Increasing the superior boundary of the CI to a vessel-based definition of the aortic bifurcation, and increasing the medial extension of the OR by an additional 9 mm, decreased the rate of patients with LRF outside of the IC CTV to 7 (13%) patients. Conclusions: “Modified IC CTVs” inclusive of a slight adjustment superiorly for the common iliac region, and medially for the obturator region, may reduce the risk for pelvic failure in patients treated with adjuvant radiation therapy.
The impact of treatment delay from diagnosis to prostatectomy on the biochemical recurrence rate.
Authors: Isharwal Sudhir , Zabell Joseph , Berglund Ryan Kent , Stephenson Andrew J.
Published: March 2017

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Background: In this study, we evaluate the impact of treatment delay on the biochemical recurrence (BCR) rate specifically in patients with NCCN intermediate to high-risk prostate cancer (PCa). Methods: We reviewed our institutional database of patients who underwent radical prostatectomy (RP) between 2004-2014. A validated preoperative nomogram was used to predict the 5-year BCR-free probability. We evaluated the actual risk of BCR (PSA>0.2) stratified by time from diagnosis to treatment controlling for age and preoperative nomogram derived risk of BCR. We did subset analysis in the cohort of NCCN defined intermediate/high-risk categories. Results: A total of 3029 patients met the inclusion criteria. Median age for the entire cohort was 60 years. Median time from diagnosis to treatment was 77 days (IQR 54-110). Median overall follow-up time was 25 months. Group 1 (61.7%) experienced delay of less than 90 days, Group 2 (31.5%) 90-180 days, and Group 3 (6.7%) >180 days. BCR occurred in 9.6%, 9.6%, and 4.9% of patients in Groups 1, 2, and 3 respectively (p=0.08). Out of the entire cohort, 1837 (60.6%) patients had NCCN intermediate or high-risk disease. On cox multivariable analysis, there was no significant difference in risk of BCR stratified by time to RP in the entire cohort as well in the patients with intermediate/high-risk disease (see table). Conclusions: In our cohort of patients, the delay in treatment did not have significant effect on the risk of BCR. While patients with high-risk pathology should receive prompt treatment, our data suggests that patients and urologists have time to obtain genomic or imaging information, seek second opinions or referral for surgery without significantly affecting the BCR. [Table: see text]
Efficacy of mycobacterium phlei cell wall-nucleic acid complex (MCNA) in BCG-unresponsive patients.
Authors: Li Roger , Amrhein John , Cohen Zvi , Champagne Monique , Kamat Ashish M.
Published: March 2017

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Background: Previously, we reported the results of a single-armed, multi-institutional study on the efficacy of MCNA in patients who failed intravesical BCG treatment. Since that publication, a new standardized definition for BCG-unresponsiveness has been established. We re-analyzed the oncologic outcomes following intravesical MCNA in patients classified as BCG-unresponsive according to the new definition. Methods: Patients with recurring high grade NMIBC after intravesical BCG were enrolled. For this analysis, we focused on the patients satisfying the minimum criterion for adequate BCG treatment (5/6 induction and 2/3 maintenance). Treatment course included 6 weekly intravesical instillations of 8mg MCNA followed by 3 weekly instillations at months 3, 6, 12, 18, and 24. Followup assessments included cystoscopy, urine cytology and biopsy. Patients absent of high grade disease confirmed by central review of biopsy were deemed disease-free. Results: Of the 129 patients enrolled, 94 (68 CIS with/without papillary tumors, 26 papillary only tumors) fit the criteria for the new BCG-unresponsive definition. In the group with papillary tumors, DFS measured at months 6, 12, and 24 were 61.2%(38.2-77.8%), 61.2(38.2-77.8%), and 50.1%(27.5-69%). In the CIS-containing group, the corresponding DFS were 44.8%(32.3-56.4%), 26.5%(16.3-37.9%), and 16.6%(8.6-26.9%), respectively. Conclusions: Intravesical MCNA therapy has the potential to offer 26.5% of patients with CIS and 61.2% of patients with papillary tumors a chance to safely preserve their bladder for at least 1 year. The efficacy in BCG-unresponsive patients was higher than that reported with all-comers, suggesting that adequate priming with BCG might be required for further immune-based response.
Neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) for muscle-invasive urothelial bladder cancer (MIUBC): Final results and translational findings of an open-label, single-arm, phase II study.
Authors: Necchi Andrea , Lo Vullo Salvatore , Raggi Daniele , Giannatempo Patrizia , Nicolai Nicola , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Calareso Giuseppina , Togliardi Elena , Colecchia Maurizio , Busico Adele , Perrone Federica , Pennati Marzia , Zaffaroni Nadia , Mariani Luigi , Salvioni Roberto
Published: March 2017

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Background: Despite cisplatin-based chemotherapy (CT) is recommended in MIUBC, an unmet need is to identify new drugs or combinations to improve the outcomes. SGC combination was evaluated in an open-label, single-arm, phase 2 trial (NCT01222676). Methods: After TURB, pts with T2-T4a N0 MIUBC received 4 cycles of cisplatin 70 mg/m2 d1, gemcitabine 1000 mg/m2d1 and 8, q3 wks. Sorafenib 400 mg q12h was administered daily from day 1 until radical cystectomy. In a Simon’s 2-stage design, the primary endpoint was pathologic complete responses (pT0). Residual carcinoma in situ was considered pT0. ITT analysis was applied. Statistical hypothesis assumed H0: ≤0.20 and H1: ≥0.40 (α and β of 5% and 10%). ERCC1 immunohistochemistry (IHC) and next-generation sequencing (NGS) of TURB tissue, and measurement of baseline circulating VEGF levels, were planned. Results: From 04/2011-06/2016, 45 pts were enrolled. 28 pts (62.2%) had macroscopical residual disease after TURB, 17 (37.8%) presented with clinical stage T3-4. pT0 was obtained in 19 pts (42.2%, 95%CI: 27.6-57.9); pT≤1 in 24 (53.3%, 95%CI: 37.9-68.3). After median follow-up of 35 months, median PFS was not reached (IQR: 29.4-NE), like median OS (IQR: 30.3-NE). Pathological response (pT0 vs pT≤1 vs other) predicted for both PFS (p=0.015) and OS (p=0.046). Hematologic (hem) G3-4 adverse events (AE): platelet 28.9%, neutrophils 15.6%, Hb (4.4%). Extra-hem AEs were seen in 9 pts (20%). 24 (53.3%) pts needed S temporary interruption (5 cases discontinuation). Tumor samples were available from 23 pts for ERCC1-IHC, 24 for NGS: ERCC1 IHC expression was associated with non response (pT≥2, p=0.033). ERBB2/ERBB3 mutations were found only in responders (pT≤1, 20%). PIK3CA/AKTmutations (missense, and newly-identified mutations) were more frequent in pT≥2 pts (35.7% vs 20%). Baseline VEGF levels did not predict for PFS/OS. NGS of the remaining pts of the trial is ongoing. Conclusions: SGC combination was active and effective in MIUBC. Translational analyses are providing information to develop combination of CT with new more potent and selective TKIs, possibly in more selected pts. Clinical trial information: NCT01222676.
Nomogram to assess benefit of new over historical agents as salvage therapy for metastatic urothelial carcinoma (mUC) in non-randomized trials: Effect of atezolizumab on 12-month survival.
Authors: Pond Gregory Russell , Sonpavde Guru , Rosenberg Jonathan E. , Choueiri Toni K. , Bellmunt Joaquim , Regazzi Ashley Marie , Mullane Stephanie Anne , Necchi Andrea , Raggi Daniele , Lee Jae-Lyun , Lee Soonil , Simpson Joe , Derleth Christina Louise , Lin Shih-Wen , Bajorin Dean F.
Published: March 2017

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Background: Early surrogate endpoints of benefit in mUC phase 2 salvage therapy trials are necessary to identify promising drugs, particularly for checkpoint inhibitors where response and progression-free survival are inadequate. We developed a nomogram using prognostic variables from phase 2 trials of historical agents to estimate 12 month survival to which observed survival in single arm trials could be compared. Methods: Data were obtained from phase II trials of salvage therapy for mUC for survival and 5 prognostic factors: hemoglobin, performance status, liver metastasis, treatment-free interval and albumin. Patients (pts) were randomly allotted to discovery:validation (DIS:VAL) datasets in a 2:1 ratio. A nomogram was developed for estimating 12-month survival. Calibration plots were constructed in the VAL dataset by plotting estimated vs. observed 12-mo survival and data bootstrapped to assess performance. The nomogram was applied to external nonrandomized salvage therapy data: 1) retrospective pemetrexed data or 2) trials of atezolizumab: PCD4989g and IMvigor210. Results: Data were available from 340 pts receiving sunitinib (n = 77), everolimus (n = 45), docetaxel + vandetanib or placebo (n = 109), pazopanib (n = 42), paclitaxel (n = 36) and docetaxel (n = 31). Calibration and prognostic ability of the model was acceptable (c-index = 0.634, 95% CI = 0.596-0.652). Observed 12-month survival for pts on pemetrexed (n = 127, 23.5% [95% CI: 16.2%-31.7%]) were similar to nomogram-predicted survival (19% [95% CI: 16.5-21.5], P> 0.05), while observed result with atezolizumab (n = 403, 39.0% [95% CI: 34.1-43.9]) exceeded predicted result (24.6% [95% CI: 23.4-25.8], P< 0.001). Conclusions: Atezolizumab was associated with a significantly longer 12-mo survival compared to nomogram-predicted survival while pemetrexed was not. This nomogram incorporates baseline prognostic factors to provide expected 12-mo survival of phase 2 patient cohorts with which to compare observed survival, thereby providing a useful tool to quantify benefit in phase II studies while controlling for the impact of clinical variables.