bluuebunny/crossref_metadata_2025 huggingface dataset:
Familial clustering of prostate cancer (Pca) cases in a nonselected south European population (sEp).
Authors: Gil-Bazo Ignacio , Castanon Eduardo , Fusco Juan Pablo , Martin Patricia , Zubiri Leire , Ceniceros Lucia , Legaspi Jairo , Gil-Aldea Isabel
Published: February 2017

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Background: Universal Pca screening programs (SP) are controversial. The selection of high-risk subjects might improve the efficiency of early SP. A positive family history (FH) of Pca increases its relative risk and also increases with multiple affected relatives. Pca FH is associated with earlier onset and aggressive behavior. Therefore, in this subpopulation SP would have clear advantages. This is the first study to investigate the incidence of familial Pca conducted in a sEp. Methods: Overall, 365 cancer patients (pts) of Spanish (n=342) or Portuguese (n=23) origin diagnosed at a single institution were included in the analysis. A non-selected cohort of 182 (173 with known FH) consecutive males (cases) diagnosed with Pca was studied for FH of any type of cancer including Pca. Another cohort of 183 (174 with known FH) males (controls) with similar demographic characteristics and diagnosed with other cancer types different from Pca was also studied for FH of cancer. We investigated whether Pca pts in a sEp show a higher incidence of familial Pca aggregation than subjects affected by other solid tumors. Results: Among Pca pts with a positive FH for Pca, 30.2% showed their father as the only Pca relative, 22.6% one or more brothers, 15% one or more uncles, 13.3% their father and one or more brothers, 9.4% their grandfather and 9.5% showed other combinations. Regarding the number of relatives affected, in our Pca cohort 1 relative was the most frequent finding with 41/53 pts (77.1%), 2 in 4 cases (7.6%), 3 in 3 subjects (5.8%) and 4 or more relatives in 5 cases (9.5%). We studied the overall incidence of any type of family cancer among cases and controls. No differences were found between groups (64.7% vs 67.8%; p=0.664). However, in our cohort of Pca cases, 53/173 pts (30.6%) had a FH of Pca in first or second degree whereas, among cancer control pts only 18/174 pts (10.34%) showed a Pca FH (p=0.001). Conclusions: We present the first estimation of Pca FH in a non-selected sEp with Pca. 30% of Pca cases showed a positive FH for Pca, being that incidence significantly higher (threefold) compared to cancer pts from a different origin. Therefore, the usefulness of directed SP for subjects with positive FH of Pca should be prospectively evaluated.
Phase I clinical study of cabazitaxel plus prednisolone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in a Japanese population.
Authors: Takahashi Shunji , Mukai Hirofumi , Uemura Hirotsugu , Uemura Hiroji , Kosaka Takeo , Nishiyama Hiroyuki , Suzuki Kazuhiro , Kakehi Yoshiyuki , Okihara Koji , Namiki Shunichi , Ogawa Osamu , Kato Masashi , Nakai Yasutomo , Ohno Keiji ,   TED11576 Investigators
Published: February 2017

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Background: Cabazitaxel (CBZ), a novel taxoid agent, promotes tubulin assembly and stabilizes microtubules, as docetaxel (DTX). CBZ had antitumor activity in DTX-resistant tumor models in vitro. We assessed dose-limiting toxicities (DLTs), safety and efficacy of CBZ in patients (pts) with mCRPC with prior DTX treatment. Methods: This was an open-label, dose escalation study of CBZ every 3 weeks, with daily prednisolone. Two CBZ dose levels (20 or 25 mg/m2) were set in the dose escalation cohort to determine the maximum tolerated dose (MTD). Pts in the expansion cohort received the MTD. DLTs were evaluated at cycle 1 and were defined as follows: Grade (Gr) 4 neutropenia > 7 days, Gr 4 thrombocytopenia, Gr 4 febrile neutropenia (FN), or Gr 3/4 non-hematological toxicities. Gr 3/4 neutropenia was prospectively studied based on occurrence of Gr 3/4 neutropenia during prior DTX treatment. Results: A total of 48 pts received CBZ (median age 66.1 years; ECOG PS: 0, 34 pts; 1, 14 pts; median cumulative DTX dose 753 mg/m2). None of the evaluable pts in the dose escalation cohort experienced a DLT. All pts had at least one Gr 3/4 adverse event (AE). Frequent Gr 3/4 AEs at 25 mg/m2 were neutropenia (44 pts, 100%) and FN (24 pts, 54.5%). G-CSF prophylaxis was not allowed at cycle 1 and was only used in 10% of cycles from cycle 2 onward. Neutropenia occurrence during prior DTX treatment did not affect neutropenia or FN incidence during CBZ treatment. No pt discontinued CBZ due to neutropenia or FN and no toxic death was reported. In total, 12/41 pts (29.3%) had a PSA response, and 2/12 evaluable pts had a partial response as the best overall response. Conclusions: The safety profile of CBZ in Japanese pts was generally consistent with that reported in previous studies. The cumulative dose of prior DTX was higher and use of G-CSF prophylaxis less frequent than in previous studies, which may have contributed to the increased incidence of neutropenia and FN in Japanese pts. The majority of neutropenia and FN events were manageable and did not lead to treatment discontinuation. In terms of safety and efficacy, CBZ has a favourable risk–benefit profile in Japanese pts with mCRPC following prior DTX therapy. Clinical trial information: NCT01324583.
Regional analysis of a cohort compassionate-use program (CUP) and early access program (EAP) with cabazitaxel (Cbz) plus prednisone (P; Cbz + P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (D).
Authors: Malik Zafar , di Lorenzo Giuseppe , Bracarda Sergio , Ardavanis Alexandros , Basaran Mert , Parente Phillip , de Schultz Wito , Saad Fred , van Oort Inge , Gerritsen Winald R. , Antón Aparicio Luis M. , Matus Geoffrey , Hitier Simon , Heidenreich Axel , Bahl Amit
Published: February 2017

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Background: Cbz is an established second-line treatment for pts with mCRPC, having demonstrated an overall survival benefit (with P) vs mitoxantrone with P in the Phase III TROPIC trial. The global CUP (CABAZ_C_05005) and EAP (NCT01254279) (both funded by Sanofi) aimed to provide access to Cbz + P before commercial availability and to document safety in a real-world population. We present a regional analysis of interim data from the CUP and EAP. Methods: Expected total enrolment is 1,450 pts. Pts received Cbz 25 mg/m2 IV Q3W + P 10 mg QD until disease progression (PD), death, unacceptable toxicity or physician/pt decision. Granulocyte colony-stimulating factor (G-CSF) was administered per ASCO guidelines. The cut-off date for this analysis was 30 May 2012. Results: Globally, 1,301 pts have been included from eight regions (Eastern Europe [EE], Western Europe [WE], Northern Europe [NE] and Southern Europe [SE]; Asia [As]; Canada [Ca]; Latin America [LA]; and Australia [Aus]). Key data by region are shown in the Table. Median age varied from 65 years (Ca) to 70 years (Aus, LA, SE). In pts who progressed after last D line, time from last D dose to last PD ranged from 2.3 months (EE, LA) to 6.6 months (Ca). G-CSF use (therapeutic or prophylactic) at Cycle 1 varied widely between regions, from 23% (WE) to 79% (As). Between 11% (LA) and 30% (NE) of patients received ≥10 cycles of Cbz. Conclusions: In this extensive, real-world CUP/EAP cohort of mCRPC pts, substantial regional variation was observed for baseline and on-treatment parameters, including time from last D dose to last PD and G-CSF use. The low proportion of patients receiving ≥10 cycles in LA, Ca and WE may result from a limit of 10 cycles of therapy in some centers. Clinical trial information: NCT01254279. [Table: see text]
Immune impact induced by PSA-tricom, a therapeutic vaccine for prostate cancer.
Authors: Madan Ravi Amrit , Tsang Kwong Yok , Jochems Caroline , Marte Jennifer L. , Tucker Jo A , Hodge James W. , Singh Harpreet , Surolia Ira , O'Sullivan Coyne Geraldine Helen , Liewehr David J. , Steinberg Seth M. , Heery Christopher Ryan , Schlom Jeffrey , Gulley James L.
Published: February 2017

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Background: PSA-TRICOM is a vector-based therapeutic cancer vaccine designed to generate a targeted anti-tumor immune response against prostate-specific antigen (PSA)–expressing tumor cells. Early clinical trials have evaluated the immunologic impact of this vaccine and demonstrated promising clinical activity. PSA-TRICOM is being evaluated in a phase III trial in metastatic castration resistant prostate cancer (mCRPC). Methods: We recently conducted a broad overview of both published and new data which analyzed the immune responses to PSA-TRICOM. Immune responses included ELISPOT for antigen-specific immune response and flow-cytometry analysis of peripheral immune cells. Results: 104 patients (pts) with prostate cancer were tested for T-cell responses and 59 out of 104 (57%) demonstrated a greater than or equal to 2-fold increase in PSA-specific T cells 4 weeks after vaccine. The responders had a median 5-fold increase relative to pre-vaccine levels. For most pts PSA-specific immune responses (likely memory cells) seen 28 days following the most recent vaccine are quantitatively similar to levels of circulating influenza-specific T cells in the same pts. In addition, 19 out of 28 pts (68%) evaluated demonstrated immune responses to tumor-associated antigens not present in the vaccine (antigen spreading). Since PSA-TRICOM is designed to generate a cellular (TH1 immune response), it is not surprising that 2 out of 349 pts (<1.0%) demonstrated evidence of PSA antibody induction following vaccine. This suggests that post-vaccine PSA kinetics were not affected by PSA antibodies. Conclusions: PSA-TRICOM has demonstrated the ability to generate immune responses. Despite these findings, it is important to note that systemic immune response to PSA may underestimate the true therapeutic immune response since it does not measure cells that trafficked to tumor or antigen spreading. Furthermore, while the entire PSA gene is the vaccine, only one epitope of PSA is specifically evaluated in the T-cell responses. Further immune analysis continues in an ongoing phase III of PSA-TRICOM in mCRPC (NCT01322490), accruing worldwide, and two trials combining PSA-TRICOM with enzalutamide (biochemical recurrence/ NCT01875250 and mCRPC/ NCT01867333) currently accruing at NCI. Clinical trial information: multiple trials.
Looking to possible predictive factors of primary resistance to abiraterone acetate (AA) and enzalutamide (ENZ) in pretreated patients (pts) with castration-resistant prostate cancer (CRPC).
Authors: Caffo Orazio , Veccia Antonello , Maines Francesca , Bonetta Alberto , Spizzo Gilbert , Galligioni Enzo
Published: February 2017

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Background: Abiraterone acetate (AA) and enzalutamide (ENZ) are new generation hormonal agents (NHA) which demonstrated a survival gain in patients (pts) with castration-resistant prostate cancer (CRPC) pre-treated with docetaxel. Although all patients eventually became resistant to these NHAs, some of them show primary resistance, defined as an early progression within the first 3 months, which leads to an early treatment interruption. In the present analysis we have tried to identify which factor, if any, may predict primary resistance to AA and ENZ. Methods: We evaluated a consecutive series of 57 pts, treated in our hospital in two successive named patient programs conducted in our hospital to allow pre-treated CRPC patients to receive NHAs before their approval in Italy: 26 received AA (1,000 mg po + prednisone 10 mg po daily) and 31 ENZ (160 mg po daily). For each pt we have recorded the pre- and post-NHA clinical history, the treatment details and outcomes. We have also assessed the ability of a series of 24 selected clinical factors to predict NHAs resistance, through a logistic regression analysis. Continuous variables were categorized by quartiles and chosen for the initial model after a univariate chi-square analysis. Results: Among the 24 factors, the presence of pain at baseline, high baseline lactate dehydrogenase levels and prostate-specific antigen (PSA) levels after one month of treatment were predictive of primary NHA resistance at the univariate analysis. However, only PSA levels were confirmed at the multivariate analysis [exp(beta) 0.115; p = 0.007], as patients failing to achieve a 50% or more reduction in baseline PSA levels, were more likely to show primary NHA resistance (48% vs. 15%). Conclusions: Our results suggest that PSA trend may represent a simple and rapid method of identifying patients with primary resistance to NHAs, so patients failing to achieve a 50% or more reduction within the first month of treatment should undergo intensive investigations, to verify whether they have primary resistance to NHAs. These data should be confirmed in a larger patient population.
Incidence of patient-reported urinary incontinence after stereotactic body radiation therapy for clinically localized prostate cancer.
Authors: Chen Leonard N. , Woo Jennifer Ai-Lian , Bhagat Aditi , Moures Rudy A. , Kim Joy S. , Yung Thomas M. , Collins Brian Timothy , Suy Simeng , Lynch John H. , Dritschilo Anatoly , Collins Sean P.
Published: February 2017

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Background: Urinary incontinence (UI) following prostate radiotherapy is a rare toxicity that adversely affects a patient’s quality of life. The potential for hypofractionated radiotherapy to increase the risk of UI was investigated. This study sought to evaluate the incidence and severity of UI following stereotactic body radiation therapy (SBRT) for prostate cancer. Methods: Between February 2008 and August 2011, 216 men with clinically localized prostate cancer were treated definitively with SBRT at Georgetown University Hospital. Patients were treated to 35 to 36.25Gy in five fractions delivered with the CyberKnife (Accuray). UI was defined as self-reported involuntary urine loss and was assessed via the UI domain of the Expanded Prostate Index Composite (EPIC)-26 at baseline and at months 1, 3, 6, 9, 12, 18, and 24. EPIC scores range from 0 to 100 with lower values representing worsening incontinence. The minimally important difference (MID) was defined as a change of one-half standard deviation from the baseline. Results: The median age was 66 with a median prostate volume of 38 cc. The median follow-up was 3.2 years. Baseline UI was common with 22.0%, 26.2%, and 3.3% of patients reporting leaking, dribbling and pad usage, respectively. At two year post treatment, 31.1%, 34.7%, and 7.1% of patients reported some degree of incontinence based on leaking, dribbling and pad usage, respectively. Average EPIC UI domain scores showed a slow decline over the first two years following treatment. At two year post treatment, the median decreased from a baseline of 92.1 to 88.0. This change was statistically (p < 0.001) but not clinically significant (MID=6.7). The proportion of men feeling that their UI was a moderate to big problem increased from 1% at baseline to 6% at two years post treatment. Conclusions: SBRT for clinically localized prostate cancer was well tolerated with UI rates comparable to conventionally fractionated radiotherapy and brachytherapy. Greater than 90% of men who were pad-free prior to treatment remained pad-free two years following treatment. Less than 10% of men felt posttreatment UI was a moderate to big problem.
Real-world corticosteroid utilization in prostate cancer patients treated with two new oral agents.
Authors: Lafeuille Marie-Helene , Grittner Amanda M. , Lefebvre Patrick , Ellis Lorie , McKenzie R. Scott
Published: February 2017

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Background: Two oral agents have recently been approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC): abiraterone acetate (AA) combined with prednisone (P) for treatment of patients with mCRPC and enzalutamide (ENZ) for patients with mCRPC previously treated with docetaxel. Although corticosteroid (CS) co-administration is not required in ENZ prescribing information, 48% of ENZ-treated patients receive CS according to a large phase III clinical trial. To date, real world CS utilization patterns in AA- and ENZ-treated patients has not been reported. Methods: ProMetis Lx administrative claims data covering multiple health plans were used to identify patients with ≥1 PC diagnosis (ICD-9 185, V10.46) during ≥6 months of claims activity before the first AA or ENZ claim (index date). The proportion of patients receiving CS (identified by NDC codes) during AA or ENZ treatment (observation period-defined as first to end of last AA or ENZ prescription) was reported using descriptive statistics. Additionally, dosing and medication possession ratio (MPR) were calculated for the subset of patients receiving P. Results: A total of 3,228 AA-treated and 675 ENZ-treated PC patients were identified. Baseline comorbidities patterns were similar between treatment groups for hypertension (AA 55%, ENZ 56%), diabetes (25% both groups), and cardiovascular disease (28% both groups). The mean (SD) observation period for AA-treated patients was 142 (133) days and for ENZ-treated patients was 74 (46) days. CS use, P dose and P MPR are described in the following table. Conclusions: CS use was common in PC patients prior to and during treatment with AA and ENZ. While this data set may underreport CS use, patterns of CS use are consistent with clinical trial data. Further research based on data with longer follow-up and additional observational datasets is warranted. [Table: see text]
The management of adenocarcinoma of the prostate in rural Georgia: A population-based analysis.
Authors: Hall William A. , Nickleach Dana , Switchenko Jeffrey M. , Lipscomb Joseph , Goodman Michael , Ward Kevin C. , Gillespie Theresa Wicklin
Published: February 2017

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Background: The management of adenocarcinoma of the prostate (ACP) in minority populations and in the rural setting remains understudied. We conducted a population-based analysis exploring the management of ACP in rural Georgia. Methods: All cases of ACP diagnosed from 2001 to 2003 in a rural, 33-county, Southwest Georgia region were included. Data were obtained for all patients through direct medical record abstraction. Patient characteristics were described and associated with three specific outcomes: receipt of therapy, initiation of planned therapy, and completion of radiation therapy (RT) when initiated. Results: One thousand eighty seven patients were available for the analysis; median patient age was 69, and 44% of the patients were African American (AA). A total of 804 patients underwent a course of definitive therapy or elected to pursue regular active surveillance (AS). Of the patients 8.9% underwent radical prostatectomy (RP) alone, 3.1% RP and external beam radiation therapy (EBRT), 30.2 % EBRT alone, 10.8% brachytherapy (BT) alone, and 44.5% combination EBRT and BT; 2.5 % of patients underwent AS. Hormone therapy (HT) was used in 43.8% of all patients available for analysis. In a multivariable analysis conducted for the entire patient cohort, not being married (OR 0.60, 95% CI 0.42-0.85, p=0.004), lack of insurance (OR 0.32, 95% CI 0.16-0.61, p=0.008), and older age (OR 0.93, 95% CI 0.91-0.95, p<0.001) were all independently associated with not receiving definitive therapy. Race was not significantly related to receipt of definitive therapy. The full course of EBRT was successfully completed as planned in 98.4% of patients. Conclusions: Amongst those patients undergoing therapy for ACP in rural Georgia, a combination of BT and EBRT was the most common treatment modality. In contrast to recent studies, we found that race was not a significant predictor of receipt of care in Southwest Georgia. In this rural setting, EBRT was associated with extremely high rates of treatment completion. Despite the geographic and socioeconomic challenges associated with rural residency, our population-based study demonstrates that EBRT is a common treatment modality, with high patient compliance, even when used in a rural setting.
ODM-201 and the CNS: A clinical perspective.
Authors: Shore Neal D. , Bono Petri , Massard Christophe , Snapir Amir , Sarapohja Toni , Fizazi Karim
Published: February 2017

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Background: ODM-201 is a potent, new generation androgen receptor inhibitor with activity in preclinical in vivo and in vitro studies. ODM-201 shows negligible penetration into the rat brain at pharmacological doses. In the phase I/II study with 134 patients with progressive castration-resistant prostate cancer (CRPC) (the ARADES study) patients with a history, or risk, of a seizure were not excluded. We reviewed the ARADES safety database to assess potential seizure or seizure-related adverse events (AEs). Methods: The following AE terminology was reviewed: seizure, syncope, presyncope, loss of consciousness, depressed level of consciousness, encephalopathy, and transient ischemic attack, hallucinations, vasovagal syndrome, falls and fall-related injuries, nonpathologic fractures, urinary or fecal incontinence, tonic-clonic activity, abnormal EEGs. We further reviewed medical histories and use of anti-seizure medications, as well as medications that could lower the seizure threshold and identified any seizure or seizure like condition as an AE. Results: Twenty one percent of the patients had concomitant medications indicated for epilepsy or other seizure-related disorders. Twelve patients had one or more of the above listed AE. None of the patients experienced seizures or related disorders while receiving ODM-201; one seizure event was reported to occur 27 days after stopping treatment. There were five fall events, one syncope, one presyncope, and four urinary incontinence cases - all interpreted by the investigators as not related to ODM-201 treatment and not leading to treatment discontinuation. Careful evaluation of these cases suggested that these events were unlikely to be related to seizure. Conclusions: ODM-201 has negligible brain entrance in nonclinical models. Treatment with ODM-201 was not linked with CNS-related events in patients in this trial. These preliminary findings suggest minimal CNS safety concerns. Clinical trial information: NTC01317641, NTC01429064.
The effect of cell cycle progression (CCP) score on treatment decisions in prostate cancer: Results of an ongoing registry trial.
Authors: Kar Ashok J. , Scholz Mark Creamer , Fegan Jeffrey E. , Crawford E. David , Scardino Peter T. , Kaldate Rajesh R. , Brawer Michael K.
Published: February 2017

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Background: Improved prognostic markers that provide individual patient risk stratification are a pressing need in prostate cancer. The CCP signature test (Prolaris, Myriad Genetic Laboratories, Inc.) is a novel prognostic assay that has been validated in multiple cohorts and provides accurate risk of prostate cancer-specific disease progression and disease specific mortality risk when combined with standard clinicopathologic parameters. This study evaluated clinicians’ judgment regarding the clinical utility of the CCP test in a prospective registry. Methods: Clinicians ordering the CCP signature test commercially were asked to complete a survey regarding their treatment recommendations before and after they received the CCP test result. In addition, clinicians were asked how influential the CCP test result was in making therapeutic decisions on a 5 point scale (0=None, 5=Very High). Results: Currently, 368 patients have been enrolled and 47 clinicians have completed surveys on the influence of the CCP signature test in 58 cases. In five additional surveys, the therapeutic decision was undecided pre-test, post-test or both. In 77% of cases [95% CI: 65%-86%], there was a change recorded between the therapy initially planned and the therapy actually selected. The table shows the change in intended therapeutic burden from pre-CCP test to post-CCP test. In 30 of 58 cases [52%; 95% CI 39%-64%], clinicians indicated they would reduce the intended therapeutic burden post-CCP test. The CCP signature test influenced treatment selection to a ‘High’ or ‘Very High’ degree in 37 men (62%) and had “Low” or “No” influence in only 3% of cases. Conclusions: Based on the judgment of ordering physicians, the CCP score appears to add meaningful new information to risk assessment for localized prostate cancer patients. Test results led to major changes in treatment decisions with a significant increase in conservative management options, including active surveillance or watchful waiting. [Table: see text]
Biochemical outcome of small volume or insignificant prostate cancer treated with radical prostatectomy.
Authors: Hashimoto Yasuhiro , Okamoto Akiko , Imai Atsushi , Yamamoto Hayato , Hatakeyama Shingo , Yoneyama Takahiro , Koie Takuya , Ohyama Chikara
Published: February 2017

279

Background: We examined biochemical outcome of small volume prostate cancers (<0.5 cc, SVCa), and insignificant prostate cancers (<0.5 cc and Gleason scores <7, InsigCa) treated with radical prostatectomy. Methods: Between April 2000 and May 2011, 609 patients with prostate cancer were treated with radical prostatectomy in Hirosaki University Graduate School of Medicine. Of these, 237 were excluded from analysis because of pre-operative adjuvant treatment. The remaining 372 patients were eligible in the present study. Along with the routine pathological assessment, tumor volume (TV) was assessed in all patients. Biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) levels of greater than 0.2ng/ml. Results: The median age was 68 (48 to 78) and median pre-treatment PSA was 7.50 ng/ml.Average follow up period was 45.9 month. Mean tumor volume (TV) was 2.16 cc. We investigated 372 patients and found SVCa (<0.5 cc) in 60 patients (16.3%), and InsigCa in 14 patients (3.7%). The five year BCR-free survival rate for TV greater than or equal to 0.5 group and SVCa was 67.3% and 87.1% respectively. A significant difference was seen in the log-rank test between the two groups ( p=0.008). We could not identify BCR in InsigCa patients. Conclusions: Despite the limited number of cases, in our study InsigCa were clinically insignificant but in SVCa group 12.9% patients developed PSA failure after radical prostatectomy. SVCa is not identical to InsigCa. Therefore new biomarker is needed to examine what the prognostic relevance is of SVCa.
The prevalence of vasomotor and psychological symptoms in prostate cancer patients receiving hormonal therapy: Results from a single-institution experience.
Authors: Challapalli Amarnath , Saleem Waqar , Gjafa Ernese , Laniado Marc , Stanbridge Bente , Hellawell Giles , Mangar Stephen
Published: February 2017

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Background: Hormonal therapy is an important therapeutic modality in both early and metastatic prostate cancer. Whilst the long term effects of androgen deprivation (AD) have been extensively studied, little attention has focussed on assessing short-term vasomotor and psychological effects and the resulting impact of quality of life (QoL) in prostate cancer, relying on data mainly extrapolated from breast cancer patients. This prospective study sought to assess these effects and identify any predictive factors. Methods: Data from 200 consecutive prostate cancer patients were collected from January 2010 to August 2013. A self-reported questionnaire was employed to objectively assess a variety of vasomotor and psychological symptoms, graded from 1 no toxicity, 2 mild, 3 moderate to 4 severe toxicity. Other parameters including height, weight, Body Surface Area (BSA), Body Mass Index (BMI), duration and type of hormonal therapy were also recorded. Results: 181 patients were fully evaluable, with a median age of 75 (IQR 70.5-80). 166 received an LHRH analogue,11 maximum androgen blockade, and 4 received anti-androgens only. 33 (18.2%) of patients reported no toxicity, with 76 (42%), 55 (30%) and 17 (9.4%) experiencing mild, moderate and severe (debilitating) symptoms respectively. The commonest debilitating symptoms were vasomotor: drenching sweats (82%), and hot flashes (82%), which usually coexisted, and less commonly psychological: sleep disturbances (18%) and tiredness (12%). Age (median: 77 vs. 74 yrs), weight (median: 79.8 vs. 84.4), and BMI (median: 26.6 vs. 28.3) significantly predicted between those with grade 1/2 and grade 3/4 symptoms, (p=0.0007, 0.02, 0.02). A non-significant trend was observed with increasing duration of hormonal treatment and toxicity (median: 5, 7, 9.5 and 12 months for Grade 1-4, respectively, p=0.07). Conclusions: The short term side-effect profile of hormonal therapy for prostate cancer is generally favourable, though debilitating predominantly vasomotor symptoms can occur in a significant minority of cases. Increasing age, weight, and BMI may be predictive of toxicity.
Somatic genomic alterations in urothelial cancer: Results of the Cancer Genome Atlas (TCGA) bladder cancer (BC) analysis.
Authors: Rosenberg Jonathan E. , Kim Jaegil , Cherniack Andrew , Sougnez Carrie , Meyerson Matthew , Getz Gad , Weinstein John N. , Lerner Seth P. , Kwiatkowski David J. ,   The Cancer Genome Atlas Research Network Bladder Cancer Project
Published: February 2017

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Background: We report here an integrated analysis of mutation and somatic copy number alterations (SCNAs) in 131 BCs to provide a comprehensive landscape of molecular alterations. Methods: Exon capture, whole exome sequencing (WES), and SNP arrays were performed on 131 MIBCs with no prior chemotherapy treatment, analyzed using the Cancer Genome Atlas Firehose Pipeline, and validated using orthogonal methods. Significantly mutated genes (SMGs) were determined by MutSig v1.5. Recurrent SCNAs were identified via GISTIC 2.0. Consensus non-negative matrix factorization (CNMF) was used to identify SCNA and SMG clusters. Results: 32 genes showed statistically significant levels of recurrent somatic mutation. Known druggable SMGs included FGFR3 (12%), PIK3CA (20%), TSC1 (8%), and ERBB3 (11%). CDKN1A (14%), ERCC2 (12%), RXRA (9%), ELF3 (8%), KLF5 (8%), FOXQ1 (5%), RHOB (5%), PAIP1 (5%), and BTG2 (5%) were not previously reported as SMGs in any other TCGA cancer type. Truncating mutations in 4 SMGs involved in epigenetic regulation (MLL2, ARID1A, KDM6A, and EP300) were significantly enriched. Clustering of both SMGs and focal SNCAs in 125 samples identified three distinct groups. Group A is highly enriched in focal SCNAs in several genes, as well as mutations in MLL2. Group B is enriched in papillary histology, loss of CDKN2A, and alterations in FGFR3. Group C has TP53 mutations, enrichment with RB1 mutations, and amplifications of E2F3 and CCNE1. There were no statistically significant associations between smoking status and the mutational spectrum, frequency of mutation in any SMG, focal SCNAs, or CNMF subtype. Conclusions: Analyses identified potential therapeutic targets in 69% of BCs, including 42% with targets in the PI3K/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Clustering reveals 3 groups with differences in pattern of genomic alteration suggesting the possibility of different pathogenic mechanisms of BC development. Epigenetic regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date, suggesting the future possibility of targeted therapy for chromatin abnormalities.
Quality of transurethral resection in patients with bladder cancer: A process-outcomes link.
Authors: Ballon-Landa Eric Christian , Chamie Karim , Bassett Jeffrey C. , Daskivich Timothy J. , Leventhal Meryl , Deapen Dennis , Litwin Mark S.
Published: February 2017

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Background: Detrusor muscle at diagnostic transurethral resection of a bladder tumor (TURBT) is often used as a surrogate of resection quality. We examined whether surgical and pathologic quality at the time of initial resection was associated with improved cancer-specific survival among subjects diagnosed with non-muscle-invasive bladder cancer. Methods: We retrospectively reviewed the operative and pathology reports of all individuals ≥18 years of age within the Los Angeles SEER registry, with an incident diagnosis of urothelial non-muscle-invasive bladder cancer between 2004-2005. We recorded patient age, gender, race, marital status, socioeconomic status, insurance type, institution type, surgeon and pathologist volume, tumor stage and grade, detrusor muscle presence/mention, and vital status. After adjusting for confounding using competing-risks regression analysis, we determined whether surgical and pathologic quality was associated with cancer-specific survival. Results: We identified 1,865 patients, 335 urologists, and 278 pathologists. Muscle was reported as present in 972 (52.1%), reported as absent in 564 (30.2%), and was not mentioned in 329 (17.7%) of the initial pathology reports. The incidence of detrusor muscle sampling did not differ according to grade or stage. However, bladder cancer death was more likely with higher stage disease (Tis: HR=5.00, 95% CI 2.38-10.50; T1: HR=5.44, 95% CI 3.00-9.88) and lower quality staging (muscle absent: HR=1.50, CI 1.00-2.27; muscle not mentioned: HR=2.01, CI 1.14-3.56). This pattern was enhanced among those with high-grade disease. For this group, the 5-year cancer-specific mortality was 8.0%, 13.0%, and 21.5% when muscle was present, absent, or not mentioned, respectively. Conclusions: Nearly half of all diagnostic TURBTs do not include muscle. This omission is associated with increased mortality, particularly in high-grade disease—yet few of these patients undergo treatment to correct this error. Because urologists cannot discern between high- or low-grade disease, we contend that all patients with bladder cancer should undergo endoscopic resection with detrusor muscle sampling (and appropriate pathology reporting) at diagnosis.
Outcomes in patients with p0 versus PCIS on final cystectomy pathology.
Authors: Golla Vishnukamal , Kamat Ashish M. , Dinney Colin P. N. , Grossman H. Barton , Shah Jay Bakul
Published: February 2017

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Background: For patients with superficial bladder cancer, the presence of Carcinoma in situ (CIS) is known to increase the risk of subsequent upper tract recurrence. In this study, we focused on patients with no residual invasive carcinoma at cystectomy to determine if those patients with pCIS only on final pathology have worse outcomes than patients with p0 bladders. Methods: We performed a retrospective review of our institutional cystectomy database to identify patients with no residual invasive carcinoma on final pathology (p0 or pCIS only). Chi squared test was used to analyze categorical variables and recurrence rates and the Kaplan-Maier method was used to assess the impact of surgical pathology on recurrence-free survival and overall survival over time. Results: Of the 1,897 cystectomy patients in our institutional database, 630 had no residual invasive carcinoma and had complete follow up data. Of these, 285 had stage p0 and 345 had stage pCIS. Local recurrence, upper tract recurrence, and distant recurrence rates were similar between the two groups (p> 0.05 for all). Disease-specific and overall survival rates were also similar for the two groups. In the subset of patients that had received neoadjuvant chemotherapy, there were also no differences in recurrence and survival rates between the p0 and the pCIS groups. Conclusions: The presence of CIS alone in the cystectomy specimen does not increase risk of upper tract recurrence, distant recurrence, or worsened survival compared to patients with p0 bladder pathology. To note there was no financial funding for this study.
Quantification and molecular profiling of circulating tumor cells (CTCs) in urothelial cancer (UC) before and during systemic treatment: Implications across the clinical stages.
Authors: Necchi Andrea , Fina Emanuela , Giannatempo Patrizia , Colecchia Maurizio , Iacona Chiara , Farè Elena , Raggi Daniele , Nicolai Nicola , Salvioni Roberto , Gianni Alessandro M. , Mariani Luigi , Daidone Maria Grazia , Cappelletti Vera
Published: February 2017

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Background: CTCs from patients (pts) at different clinical stages were analyzed by a never explored experimental approach based on a combination of two techniques. Provision of this information may contribute to optimize tailored therapies. Methods: 3 cohorts were analyzed: pts with muscle-invasive bladder cancer receiving neoadjuvant (NA) sorafenib + chemotherapy (CT) (NCT01222676), and metastatic (M1) pts receiving 1st-line MVAC, and 2nd-line (M2) anti-TGFβ receptor ALK1 PF-03446962 (NCT01620970). 5 ml of whole blood were filtered by ScreenCell Cyto devices and CTC status was assessed with centralized scoring by referral pathologists. Additional 5 ml of whole blood were processed by immunomagnetic beads (AdnaTestSelect kit) and the expression level of a panel of markers (including EPCAM and MUC1) was studied using RT-multiplex PCR. The objective was the association with clinical response/relapse. Results: From 07/2012 to 08/2013, 48 pts (17 NA, 17 M1, and 14 M2) were enrolled. Rates of baseline CTC+ were: 91, 77, 75% (ScreenCell), and 36, 41, 69% with AdnaTest, respectively. NA setting: from baseline to post-CT, all pts had a stepwise reduction of CTC count/5 ml blood by ScreenCell (median baseline of 15 [0-40] to 0 [0-3]). Increase in circulating EPCAM±MUC1 levels by CTC was seen in accordance with the 3 disease progressions (PD). M1 setting: Pts who relapsed had a median of 25 CTC/5 ml (IQR: 12-47) at the end of CT, while all the others had levels <10. EPCAM profile was concordant in all cases (median 1.10 vs 0.42 ng/µl). Despite classified as partial/complete responders by RECIST criteria, 5/7 cases with >6 month follow-up displayed an increase in EPCAM levels and CTC number which anticipated a relapse. M2 setting: increase in CTC signals from baseline to +2 months was observed in 8/9 evaluable cases by AdnaTest and 4/5 evaluable cases by ScreenCell, in accordance with PD. Conclusions: This combined technique showed a promising ability to anticipate the detection of clinical relapse, although it still needs a larger sample size. Refining molecular characterization will help designing informed clinical trials.
The efficacy of EORTC risk tables in Japanese patients with non-muscle invasive bladder cancer.
Authors: Muto Satoru , Ieda Takeshi , Sugiura Syou-ichiro , Nakajima Akiko , Horiuchi Akira , Shimizu Fumitaka , Inoue Masahiro , Noma Yasuo , Kitamura Kousuke , Saito Keisuke , Isotani Shuji , Ide Hisamitsu , Yamaguchi Raizo , Horie Shigeo
Published: February 2017

331

Background: To predict recurrence and progression of non-muscle invasive bladder cancer (NMIBC), EORTC risk tables are widely used worldwide. EORTC risk tables were, however, developed on the basis of individual data from 2,596 NMIBC patients included in seven special European Organization for Research and Treatment of Cancer trials. Therefore, it is not clear the efficacy of these risk tables in clinical practice, especially in Japan. I will report the recurrence and progression rate on the basis of EORTC risk tables in Japanese NMIBC patients. Methods: A retrospective analysis of 619 patients with NMIBC treated between January 1998 and 2012 was performed. Patients were divided into three groups on the basis of EORTC risk tables. We compared recurrence- and progression-free survival rates between groups. Recurrence- and progression-free survival was estimated using the Kaplan-Meier method. Results: We evaluated the clinical outcome of 1,032 TUR-Bt. The recurrence rate is 32.3% in low risk group (n=31), 44.5% in intermediate risk group (n=757), and 49.4% in high risk group (n=85). The median recurrence free survival time is 87 months in low risk group, 35 months in intermediate risk group, and 25 months in high risk group. Although there are significant differences in recurrence free survival time between low risk group and intermediate risk group (p=0.0351), there are no significant differences between intermediate risk group and high risk group (p=0.1871). On the other hand, the progression rate is 1.6% in low risk group (n=128), 5.8% in intermediate risk group (n=451), and 18.0% in high risk group (n=294). The median progression free survival time is 176 months in low risk group, 131 months in intermediate risk group, and 109 months in high risk group. There are significant differences in progression free survival time between low risk group and intermediate risk group (p=0.0138), and between intermediate risk group and high risk group (p=<0.0001). Conclusions: There is an urgent need to establish the standard of recurrence risk classification in Japan.
Intravesical ethiodized oil injection technique for image-guided radiation therapy for bladder cancer.
Authors: Baumgarten Adam S. , Emtage Justin B. , Wilder Richard , Biagioli Matthew C. , Gupta Shilpa , Spiess Philippe E.
Published: February 2017

337

Background: Bladder sparing trimodality therapy consisting of maximal TURBT, radiation, and chemotherapy offers a feasible and effective option to patients with muscle invasive bladder cancer that are unwilling to undergo cystectomy. The shape and position of the bladder change significantly during radiation therapy, and it is possible to miss the tumor bed when a radiation boost is delivered to only part of the bladder. This study describes the technique of injecting ethiodized oil in the submucosa of the urinary bladder wall as a novel modality to improve localization of muscle invasive bladder tumors prior to image-guided radiation therapy (IGRT). Methods: Eight patients underwent submucosal ethiodized oil injections at the time of transurethral bladder tumor re-resection. A rigid cystoscope with a working port was used to inject ethiodized oil into bladder submucosa circumferentially around the tumor bed (2-3 mm from margin of resection). Roughly 20-30 injections were used to demarcate the tumor bed for external beam radiation therapy, which was used as part of a bladder sparing approach. All patients were diagnosed with clinically localized, high-grade, muscle invasive carcinoma and were deemed nonsurgical candidates or were unwilling to undergo radical cystectomy. Results: 5 of the 8 patients underwent IGRT at our institution. 95% of ethiodized oil injections were visible on treatment planning CT scans and kV portal images throughout the 7-week course of IGRT. In 2 of 5 patients, the tumor bed based upon ethiodized oil extended outside a planning target volume that would have been treated with radiation therapy based upon cystoscopy reports and computed tomography scans without ethiodized oil. There were no adverse events or treatment-related toxicities secondary to ethiodized oil injection. Conclusions: Intravesical ethiodized oil injection is an easy-to-perform technique that is safe and effective. Ethiodized oil serves as a fiducial marker that improves tumor bed localization for radiation therapy, thereby reducing the likelihood of missing the tumor.
The performance of targeted magnetic resonance imaging/ultrasound fusion biopsy versus random 12-core biopsy for prediction of total prostate cancer tumor volume.
Authors: Okoro Chinonyerem , Rais-Bahrami Soroush , George Arvin , Walton-Diaz Annerleim , Siddiqui Minhaj , Shakir Nabeel , Rothwax Jason , Raskolnikov Dima , Stamatakis Lambros , Su Daniel , Turkbey Baris , Choyke Peter L. , Wood Bradford J. , Merino Maria , Pinto Peter A.
Published: February 2017

34

Background: Tumor quantification with percent core and/or core length involvement is a parameter used to determine burden of disease for patients with prostate cancer (PCa). However, controversy exists regarding tumor quantification in random 12-core biopsies due to discrepancies in lesion targeting and overall needle core lengths obtained. Targeted MRI/US fusion biopsy allows for more optimal lesion targeting and interpretation of this parameter. We aim to correlate highest percentage core involvement and corresponding tumor length for both targeted fusion and random 12-core biopsies with total tumor volume. Methods: Patients who underwent multiparametric MRI (MP-MRI) with targeted MRI/US fusion biopsy at our institution between 2007 and 2012 were reviewed. Those that met Johns Hopkins criteria for active surveillance (AS) based on outside 12−core biopsy were then identified. MRI tumor volumes were calculated in fusion biopsy positive lesions and correlated with the highest percentage core involvement and corresponding tumor length for both targeted fusion biopsy and 12-core biopsy. Bivariate analysis was used to determine the empirical relationship between these variables. Results: Six hundred ninety six patients had MP-MRI with MRI/US fusion biopsy, 109 of which met Johns Hopkins criteria for AS upon entry and 47 of these patients had fusion biopsy confirmed PCa. Mean age was 61 and mean PSA was 5.6ng/ml. For highest percentage core involvement, targeted biopsy showed a positive correlation (r=0.57) whereas 12-core biopsy showed a poor correlation (r=0.016) with the total tumor volume (p<0.0001 and p=0.91 respectively). Similarly, for tumor length of the highest percentage core, targeted biopsy showed a positive correlation (r=0.6) whereas 12-core biopsy showed a poor correlation (r=0.01) with the total tumor volume (p<0.0001 and p=0.94 respectively). Conclusions: Highest percentage core involvement and corresponding tumor length on targeted MRI/US fusion biopsy positively correlate with total tumor volume. Targeted biopsy better predicts overall burden of disease and can aid in risk stratification of patients seeking AS.
Impact of number of lines of prior chemotherapy in patients (pts) with advanced urothelial carcinoma (UC) receiving salvage therapy.
Authors: Sonpavde Guru , Bellmunt Joaquim , Rosenberg Jonathan E. , Bajorin Dean F. , Regazzi Ashley Marie , Choueiri Toni K. , Qu Angela Q. , Niegisch Guenter , Albers Peter , Necchi Andrea , di Lorenzo Giuseppe , Fougeray Ronan , Wong Yu-Ning , Sridhar Srikala S. , Ko Yoo-Joung , Milowsky Matthew I. , Galsky Matt D. , Pond Gregory Russell
Published: February 2017

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Background: The prognostic impact of number of lines of prior chemotherapy and prior perioperative chemotherapy on survival results in salvage trials for advanced UC is unknown. Methods: We pooled 10 prospective phase II trials of salvage therapy for advanced UC with data on the number of prior lines of therapy in addition to known prognostic factors: TFPC (time from prior chemotherapy), Hb (hemoglobin), PS (performance status), and LM (liver metastasis) status. Cox proportional hazards regression was used to evaluate the association of number of prior lines with overall survival (OS) and progression-free survival (PFS). Trial was included as a stratification factor. Sub-analysis examined the impact of prior perioperative chemotherapy. Results: Of 731 pts, data for all factors was available for 711. The overall median PFS and OS were 2.7 and 6.8 months, respectively. Trials evaluated vinflunine (N=151), docetaxel +/- vandetanib (N=147), paclitaxel-gemcitabine (N=83), sunitinib (N=77), nab-paclitaxel (N=48), volasertib (N=46), everolimus (N=45), pazopanib (N=43), cetuximab +/-paclitaxel (N=39) and paclitaxel-cyclophosphamide (N=32). The number of prior lines of therapy were 1 in 559 (78.6%), 2 in 111 (15.6%), 3 in 29 (4.1%), 4 in 10 (1.4%) and 5 in 2 (0.3%) pts. Prior perioperative chemotherapy was given to 277 (39.1%) and chemotherapy for metastatic disease to 454 (64.1%) pts. While TFPC, Hb, PS and LM were significantly associated with OS and PFS on multivariate analyses, the number of prior lines was not associated with OS (HR 0.99 [95% CI: 0.86-1.14]) or PFS (0.92 [0.80-1.05]). Prior peri-operative chemotherapy was a favorable factor for both OS and PFS on univariable but not multivariable analysis. Conclusions: The number of prior lines of therapy and prior perioperative chemotherapy were not independently prognostic for OS or PFS in UC pts receiving salvage therapy, although the data are limited by few pts with >2 prior regimens. We infer that interpretation of OS and PFS results in salvage therapy trials will not be affected by inclusion of pts with ≥ 2 prior regimens including perioperative and/or metastatic disease treatment. These data need external validation.