bluuebunny/crossref_metadata_2025 huggingface dataset:
A cohort compassionate-use program with cabazitaxel plus prednisone for patients with metastatic castration-resistant prostate cancer: Interim results.
Authors: Bavbek Sevil E. , Malik Zafar , Di Lorenzo Giuseppe , Scholz Hans-Jorg , van Oort Inge M , Ng Siobhan , Ozguroglu Mustafa , Gerritsen Winald R. , Mueller Stefan , Marttila Timo , Anton-Aparicio Luis M. , Albers Peter , Gschwend Juergen , Bensfia Samira , Ecstein-Fraïssé Evelyne B , Bracarda Sergio , Heidenreich Axel
Published: February 2017

172

Background: In the Phase III TROPIC trial ( NCT00417079 ), cabazitaxel/prednisone (CbzP) improved overall survival compared with mitoxantrone/prednisone in patients (pts) with mCRPC who had progressed on or after prior docetaxel (D) (HR 0.70; P < 0.0001). The survival benefit observed supported the establishment of 2 programs (based on local regulations): a compassionate use (CUP) and an early access program (EAP) ( NCT01254279 ).

Methods: The aims of both programs are to provide drug to pts with mCRPC who may benefit from CbzP prior to commercial availability, and further evaluate CbzP safety profile. Total enrollment for both programs is targeted to be 1,600 pts from 250 centers in Europe, Asia, Latin America and Canada. Eligible pts will receive CbzP (25 mg/m2 Q3W plus oral prednisone 10 mg daily) until disease progression, death, unacceptable toxicity or physician/pt decision.

Results: Baseline characteristics and safety data are available for the first 399 pts. Median age was 68 yrs (range 43–89); 90.2% were ECOG PS 0–1. Median cumulative dose of prior D was 675 mg/m2 (median 9 cycles). For pts whose disease progressed following D, the median time from last dose of D to progression was 4 months; 53.3% of pts experienced disease progression either during or < 3 months after D. 61% of pts had ≥ 2 metastatic sites; the most common were bone (93.2%) and regional lymph nodes (34.4%). A median of 4 cycles of CbzP was administered and 4 pts received ≥ 10 cycles. Median relative dose intensity was 99.2% (range 80.1–104.9). G-CSF was administered to 34.3% of pts in Cycle 1 (6.3% therapeutic, 26.6% prophylactic). Overall, 71.4% of pts experienced adverse events (AEs) (all grades) considered related to study drug. The most common Grade 3–4 AEs included neutropenia 11.3%, febrile neutropenia 6.3%, anemia 2.8%, fatigue 2%, neutropenic sepsis 1.8%, vomiting 1.3% and diarrhea 1%. 8 (2%) treatment-related deaths were reported.

Conclusions: The CUP/EAP programs provide additional safety data for CbzP in a routine clinical practice population of pts with mCRPC. Treatment with CbzP was tolerable, with a manageable toxicity profile consistent with the data reported for the TROPIC trial.
Cardiovascular mortality following short-term androgen deprivation in clinically localized prostate cancer: An analysis of RTOG 94-08.
Authors: Efstathiou Jason Alexander , Paulus Rebecca , Smith Matthew R. , Jones Christopher U. , Leibenhaut Mark H. , Husain Siraj M. , Rotman Marvin , Souhami Luis , Sandler Howard Mark , Shipley William U.
Published: February 2017

18

Background: Androgen deprivation therapy (ADT) is associated with greater risk of diabetes and coronary heart disease in men with prostate cancer but there is significant controversy surrounding its potential impact on cardiovascular mortality especially among men with lower rates of cancer-specific death. We assessed the relationship between ADT and mortality in a large randomized trial of men treated with or without short-course ADT and radiation therapy (RT) for clinically-localized prostate cancer.

Methods: Between 1994-2001, 1979 eligible men (median age 71) with clinically-localized (T1-2, PSA<20) prostate cancer were enrolled on a phase III trial (RTOG 94-08) and randomized to RT and 4 months of neoadjuvant/concurrent ADT or RT alone. Fine-Gray proportional hazards model was used to evaluate the relationship between treatment arm and mortality (disease-specific and cardiovascular). Covariates included PSA, Gleason score, T-stage, age, race, weight, prevalent cardiovascular disease (CVD), diabetes (DM), and hypertension.

Results: After a median follow-up of 8.2 years, use of ADT improved overall and disease-specific survival but there was no ADT-related increase in cardiovascular mortality or non-prostate cancer death. There were a total of 191 cardiovascular-related deaths. At 10-years, cardiovascular mortality for men treated with RT+ADT was 9.8% vs 10.7% for men treated with RT alone. In multivariate analyses, treatment arm was not significantly associated with an increased risk of cardiovascular mortality [adjusted hazard ratio (HR)=0.93, 95% confidence interval (CI) 0.69-1.26, p=0.64]. Traditional cardiac risk factors, including prevalent CVD and DM, were significantly associated with greater cardiovascular mortality. Results were similar when limiting analyses to patient subsets at high risk for cardiovascular mortality and at low risk for disease-specific mortality.

Conclusions: Use of short-course ADT improves overall and disease-specific survival but does not appear to increase cardiovascular mortality in men with clinically-localized prostate cancer. Supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from NCI.
Does low-risk prostate cancer detection change with repeat biopsies?
Authors: Najari Bobby B. , Rink Michael , Hansen Jens , Heuer Roman , Eichelberg Christian , Ahyai Sascha A. , Haese Alexander , Steuber Thomas , Heinzer Hans , Fisch Margit , Kluth Luis A. , Huland Hartwig , Graefen Markus , Scherr Douglas , Shariat Shahrokh F. , Chun Felix K.
Published: February 2017

188

Background: Many patients with a negative prostate biopsy (PBx) but persistent clinical suspicion of prostate cancer (PCa) undergo repeat PBx. Although higher rates of low grade PCa on repeat PBx have been reported, we hypothesize that a considerable risk of clinically significant PCa remains.

Methods: We retrospectively reviewed the data from a cohort of 25,584 patients who underwent one or more PBx at two institutions. To ensure current standards, we only included patients biopsied from 2004 to 2010 with a minimum of ten cores taken. Statistical analysis was performed using SPSS v.17.0.

Results: 6,729 men met the inclusion criteria, 764 (11.4%) of whom underwent a second PBx after negative initial biopsy. Overall, 3669 (54.6%) men were diagnosed with PCa on first PBx whereas 199 (26.0%) had a positive second PBx (p<0.01, Table 1). Cancers detected on the second PBx were more likely to be Gleason 6 than cancers detected on initial PBx (60.8% vs. 46.1%, p<0.01). We further categorized men as having low risk PCa, as defined by PSA <10ng/mL, Gleason sum 6, clinical stage ≤T2a, and ≤2 biopsy cores positive. The proportion of low risk patients was significantly higher in repeat PBx compared to initial PBx (36.2% vs. 23.6%, p<0.01).

Conclusions: Despite having a negative initial PBx, over a quarter of men who underwent a repeat biopsy in our large cohort had PCa detected. Despite the pathologic characteristics being more favorable on repeat PBx, almost two-thirds of these men still had intermediate or high-risk PCa. In conclusion, men in whom there is persistent suspicion for PCa despite a negative PBx should be counseled that repeat biopsies detect a high number of clinically significant PCa.

[Table: see text]
Neuroendocrine prostate cancer (NEPC) after androgen deprivation therapy (ADT): Clinical characteristics.
Authors: Akhtar Naveed Hassan , Beltran Himisha , Afzal Muhammad Zubair , Ecker Caryn , Nanus David M. , Tagawa Scott T.
Published: February 2017

190

Background: NEPC is an aggressive variant of PC that may arise de novo or, more commonly, from existing prostate adenocarcinoma following the use of ADT. With additional agents targeting the AR signaling pathway, NEPC transformation may become more commonly clinically significant.

Methods: With IRB approval, we retrospectively identified 48 metastatic (met) PC patients (pts) who met NEPC (or anaplastic) criteria for trial enrollment: a) PC with >50% immunohistochemical (IHC) staining for NE markers chromogranin (CgA), synaptophysin, or neuron specific enolase (NSE) OR Histological/cytological confirmed adenocarcinoma with clinical progression despite medical/surgical castration and at least one of the following: b) Predominant liver or brain mets c) Serum CgA > 5x upper limit of normal (ULN) or NSE > 2x ULN d) Short interval (<6 months) to development of CRPC following ADT.

Results: Overall 48 pts met the criteria of NEPC. All pts received prior ADT, 54.2% received prior chemotherapy (84.6% docetaxel). The table demonstrates overall and subgroup demographics and survival from time of NEPC diagnosis. One pt with a history of long-term ADT including abiraterone after docetaxel demonstrated complete transformation to small cell phenotype, losing AR, PSA, PSMA, and Erg expression on IHC, only retaining FISH evidence of Erg rearrangement (along with AURKA and MYCN amplifications), confirming prostate origin of his emergent liver and lung metastases.

Conclusions: NEPC arising from prostatic adenocarcinoma is an emerging issue, leading to one of the most lethal forms of PC. As we further refine clinical and molecular diagnostic criteria, therapeutic studies targeting this population warrant further exploration.

[Table: see text]
Biochemical outcomes for patients with intermediate-risk, organ-confined prostate cancer treated with I-125 interstitial brachytherapy monotherapy.
Authors: Tran Anna Thi Huyen , Mandall Paula , Swindell Ric , Hoskin Peter , Bottomley David , Wylie James
Published: February 2017

192

Background: Treatment with low dose rate brachytherapy (LDR-BT) monotherapy is well established for low risk prostate cancer. The routine use of LDR-BT in intermediate risk (IR) is more controversial and is often combined with additional external beam radiotherapy (EBXRT). We report the biochemical outcome of a large cohort of patients with IR disease treated with LDR-BT monotherapy.

Methods: A multi-institutional prospective database identified 615 patients with IR prostate cancer treated with I-125 interstitial BT between 2003–2007. IR was defined using Memorial Sloan-Kettering Cancer Centre (MSKCC) definition of either T2b, or Gleason score (GS) 7 or raised initial PSA (iPSA) 10.1-20ng/ml. Patients receiving additional EBXRT were excluded. Biochemical failure was defined by both ASTRO (3 rises past nadir) and Phoenix criteria (nadir plus 2). Kaplan-Meier methods were used to estimate biochemical no evidence of disease rates (bNED) and univariate analyses used to identify potential prognostic factors.

Results: The median age was 64 years (range 49–82). Forty-three patients had stage T2b, 180 had iPSA 10.1-20 and 392 had GS 7 disease. Only 108 received androgen deprivation therapy (ADT) prior to implant. Median follow up was 5.0 years. The 5-year bNED rates (95% confidence interval) by ASTRO are 85.5% (82.0–88.3%) and for Phoenix 83.7% (80.0–86.7%). Use of ADT, GS 3+4 versus 4+3, and dosimetric indices were not significant prognostic variables. When stratified by risk factor (T2b, GS7 or raised iPSA) raised iPSA correlated to poorer outcome only by Phoenix criteria (by Phoenix p=0.001, by ASTRO p=0.311).

Conclusions: We have demonstrated good biochemical control for IR patients treated with LDR-BT alone. No additional benefit was seen with the use of ADT. We believe LDR-BT alone is an effective treatment option in selected IR prostate cancer patients with comparable outcome to other treatment modalities such as surgery or EBXRT.
Urinary TMPRSS2: Use of ERG and PCA3 to predict tumor volume and Gleason grade in an active surveillance cohort—Results from the Canary/EDRN Prostate Active Surveillance Study.
Authors: Lin Daniel W. , Newcomb Lisa F , Brown Elissa C , Brooks James D , Carroll Peter , Feng Ziding , Gleave Martin E. , Lance Ray , Sanda Martin G. , Thompson Ian Murchie , Wei John , Nelson Peter
Published: February 2017

2

Background: Active surveillance is an increasing alternative for the management of low risk prostate cancer; however, there is a crucial need for better biomarkers to distinguish men with indolent versus aggressive disease. Both PCA3 and TMRPSS2-ERG (T2-ERG) are biomarkers that show promise in that they may be associated with more aggressive disease. This study examines the correlation of these biomarkers with higher volume or grade cancer in an active surveillance cohort.

Methods: Post-DRE urine was collected prospectively as part of the multi-institutional Canary/EDRN Prostate Active Surveillance Study (PASS). PCA3 and T2-ERG levels were analyzed in urine collected from 401 men at study entry. Many of the men had undergone previous biopsies after initial prostate cancer diagnosis, and 20% of the urine specimens were associated with a negative serial biopsy. Biomarker scores were correlated to clinical and pathologic variables, including tumor volume - measured by percent of biopsy core involvement - and Gleason score, using non-parametric and univariate analyses.

Results: Both PCA3 and T2-ERG scores were significantly associated with higher volume disease. For negative repeat biopsy, 1-10%, 11-34%, >34% positive cores, median (95% CI) PCA3 scores were 27 (24-31), 26 (22-33), 40 (29-51), 47 (26-90), p = 0.003 [Kruskal Wallis test (KW)], and median T2-ERG scores were 5 (2-8), 9 (4-14), 21 (14-40), 23 (4-115), p < 0.0001 (KW). Both PCA3 and T2-ERG scores were also significantly associated with presence of higher grade disease. For negative biopsy, Gleason 5 - 6, and Gleason >7, the median PCA3 scores were 27 (24-31), 31 (27-35), 48 (31-92), p = 0.02 (KW), and median T2-ERG scores were 5 (2-8), 14 (9-18), 29 (13-78), p = 0.001 (KW). The odds ratio for a positive biopsy versus a negative biopsy (ref) on modeling was 1.37 (1.04-1.81), p = 0.02 for PCA3 and 1.30 (1.12-1.51), p = 0.0006 for T2-ERG.

Conclusions: Both PCA3 and T2-ERG appear to stratify risk, for men on active surveillance, of having aggressive cancer as defined by tumor volume or Gleason score and may have clinical applicability in selecting men with low volume/low grade disease for active surveillance.
Use of VEGFR1 expression in benign pelvic lymph nodes to predict biochemical recurrence in patients with high-risk prostate cancer.
Authors: Pal Sumanta Kumar , Zhang Wang , Deng Jiehui , Liu Yong , Reckamp Karen L. , Liu Xueli , Nelson Rebecca A. , Wilson Timothy G. , Lau Clayton , Yu Hua , Figlin Robert A.
Published: February 2017

205

Background: High-risk prostate cancer (PCa) is a heterogeneous disease, and biomarkers that accurately predict clinical outcome within this subset are lacking. The pre-metastatic niche (PMN) represents one possible biomarker—this harbinger of future metastasis may be characterized by infiltration of VEGFR1+ cells [Kaplan et al Nature 139:820, 2005]. Given the predilection of PCa to spread to nodal sites, the association between VEGFR1 expression in benign pelvic lymph nodes and clinical outcome was examined.

Methods: The City of Hope Prostate Cancer Registry (COH PCR) was used to identify 46 patients with high-risk PCa (baseline PSA > 20, pT3a-4 disease, or biopsy Gleason 8–10) who had undergone radical prostatectomy and pelvic lymph node dissection (PLND). The COH PCR prospectively collects clinical data associated with patients undergoing prostatectomy at the institution, and warehouses available clinical specimens. Benign tissue specimens derived from PLND were acquired for each patient, and were stained for VEGFR1 expression. VEGFR1+ cell clusters were counted within 8 distinct 40x fields, and the cluster count was averaged.

Results: VEGFR1+ clustering in benign PLND specimens was a significant predictor of biochemical recurrence on multivariate Cox proportional hazards analysis, and outperformed other variables including established prognostic factors such as age, extracapsular spread, seminal vesicle invasion, and the aforementioned high-risk features. Patients with increased VEGFR1+ clustering pelvic lymph node tissue had a shorter interval to biochemical recurrence (HR 0.18, P<0.10).

Conclusions: These preliminary results indicate that increased VEGFR1+ cell clustering in benign nodal tissue may predict poorer clinical outcome in patients with high-risk PCa. VEGFR1+ cells (a purported constituent of the PMN) represents a targetable entity. A randomized, phase II study employing axitinib (VEGFR1 IC50=1 nM) as neoadjuvant therapy in patients with high-risk PCa is nearing initiation at City of Hope ( NCT01385059 ).
Correlation between human epidermal growth factor receptor 2 (HER2) status and central nervous system (CNS) involvement in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Gernone Angela , Pagliarulo Vincenzo , Silvestris Francesco , Pagliarulo Arcangelo
Published: February 2017

210

Background: The incidence of CNS metastasesin prostate cancer is very low. Recent data suggest that HER-2/neu is involved in progression of prostate cancer. Docetaxel-based chemotherapy has provided a survival advantage for mCRPC. The purpose of this retrospective study was to evaluate the relation between HER-2 status and risk of CNS metastases in pts with mCRPC treated with docetaxel.

Methods: From 2003 to 2010, 130 pts with mCRPC were treated with 3wk docetaxel 75 mg/mq. 72/130 pts were retreated with the same regimen on disease progression. 50 out of these 72 pts received second docetaxel retreatment. All pts had bone metastases. Pts underwent total body CT scan before starting docetaxel chemotherapy and every 6 months during treatment. The median age was 66 (41–88), median baseline PSA: 110 ng/ml (range 5–1100), median ECOG Performance Status: 1 (range 0–2). The data on 130 pts, who underwent diagnostic biopsy or potentially curative resection , were reviewed. Tissue blocks from primary prostate cancer tissues were obtained. Grade 3 of the HER-2 by IHC staining was defined as a positive result or gene amplification by FISH. 10 out of these 50 pts receiving second docetaxel retreatment were diagnosed with CNS metastases.

Results: CNS metastases were observed in HER-2 positive pts. 6/10 pts presented parenchymal metastases: 4 pts were asymptomatic, 3 pts underwent metastasectomy and all of them received palliative whole-brain RT. 4/10 pts presented leptomeningeal metastases with neurological symptoms and 2 of them received palliative whole-brain RT. The median time from prostate cancer diagnosis to the date of diagnosis of CNS metastases was 6 years (1–8). The median time from first cycle of docetaxel to the date of diagnosis of CNS metastases was 3 years (1.5–4).

Conclusions: These preliminary data demonstrated that HER-2 expression confers an increased risk of CNS metastases in mCRPC and constitutes a therapeutic challenge. The apparent increase of CNS presentation may be related to the effectiveness of systemic therapy. These informations support the further evaluation of neurological symptoms in long-term docetaxel treated pts.
Balancing efficacy with tolerability: The conversational mechanics of shared decision making in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ellis Lorie , Davidson Brad , DiChiara Matthew , Senbetta Mekre
Published: February 2017

229

Background: Discussions of therapeutic risk or benefit have a different tone in patients facing metastatic cancer. The literature predicts misalignment on therapy selection and communication gaps between patients and physicians. Gaps in assumed reasons for therapy selection may hinder the mCRPC patient’s ability to make fully informed decisions. (Fine, E. et al; J. Palliative Med, 2010, 13(5); 595-603.)

Methods: This IRB-approved, observational, linguistic study describes naturally occurring conversations between mCRPC patients (n=42; 69% African American) and their treating urologist (n=7) or oncologist (n=7) during a normal clinic visit in Summer 2011. Clinic interactions were videotaped without 3rd party observers present. Patients and physicians were interviewed again separately after the clinic visit. All conversations were transcribed and analyzed using standard techniques from anthropology and discourse analysis fields.

Results: At both a lexical and goal-oriented level, several disparities were observed. When discussing treatment options and goals for mCRPC, lexically, words used by physicians differed from those used by patients. This difference was found in physicians’ use of technical language and in language describing goals and results of therapy. Of interest, physicians consistently used vague language to describe therapeutic effect (e.g. “working”), and frequently presented treatment options without presenting treatment risks (e.g. “maybe go to another treatment altogether”). Patients and physicians also differed in the way they framed goals of therapy.

Conclusions: The current research highlights communication gaps between clinicians and mCRPC patients about treatment options and risks. These results suggest that patient decision making may be hindered by a lack of clear understanding of treatment choice implications and poorly defined treatment goals. Treatments with an optimum balance of efficacy and tolerability may present an opportunity to improve this dialogue.
Aggressive phenotype for prostate cancer cells that survive high-dose ionizing radiation.
Authors: Wang Tao , Carraway Robert , Briggs Joshua , Fitzgerald Thomas J
Published: February 2017

236

Background: Radiation therapy (RT) is an important primary treatment for localized prostate cancer (PCa). However, certain patients can relapse and become resistant to RT. To identify the molecular mechanisms underlying RT resistance, we studied human PCa cells that survive fractionated high dose IR in vitro.

Methods: DU145 (DU), a human cell line from PCa metastasized to brain, was exposed to fractionated ionizing radiation (IR) up to 40 Gy. The cancer biology of the surviving cells (DUIR) after 4 month in culture was studied. Cell growth and survival were assessed using cell counting, SRB and clonogenic assay. Invasiveness was measured using Boyden chambers. Caspase activity was determined for apoptosis. Activation of signaling molecules and expression of biomarkers was assessed using Immunoblot. Hormone binding to receptors was assayed using iodinated ligands.

Results: Whereas DU was squamous in shape, DUIR displayed fibroblast-like morphology with long protrusions resembling cells undergoing epithelial-mesenchymal transition (EMT) confirmed by reduced E-cadherin and enhanced vimentin expression. DUIR cells showed higher level of neurotensin receptor 1 (NTR1) and chromogranin B resembling a neuroendocrine (NE) phenotype. DUIR has significantly higher survival than DU when exposed to IR (6–10 Gy) or zinc-directed toxins and grows significantly faster in response to serum or NT at a dose dependent manner. Addition of NTR1 antagonist SR486923 abolished the NT enhanced cell growth. DUIR had increased invasiveness through the matrigel-coated membrane. ERK and PKC, but not AKT, were constitutively active in DUIR. BCL2 level was upregulated in DUIR. NT stimulation reduced apoptosis while SR486923 enhanced apoptosis in DUIR cells upon IR.

Conclusions: PCa cells that survive high dose IR display an aggressive phenotype characterized by NE and EMT features including invasion and resistance to IR/drug induced cell death. These changes could be due to constitutive activation of growth signaling pathways and upregulation of anti-apoptosis/necrosis molecules. Further study may provide insight into the mechanism of cellular resistance to therapy and establish strategies for novel therapeutic applications.
Comparison of second-line treatments in patients with castration-resistant prostate cancer with PSA relapse after or during docetaxel chemotherapy.
Authors: Pfister David J. K. P. , Porres Daniel , Piper Charlotte , Merseburger Axel S. , Klotz Theodor , Heidenreich Axel
Published: February 2017

243

Background: Docetaxel was the first agent with a proven survival benefit and improved quality of life in patients with castration resistant prostate cancer. Recently there are two new agents, Cabazitaxel (Caba) and Abiraterone Acetate (AA) approved for the second-line treatment in case of progressive disease after Docetaxel. We compared the PSA response and complication rate of these three different second-line treatment options: Caba, AA and Docetaxel Re-Challenge (R-Doc).

Methods: The data of 71 patients with progressive disease after/during Docetaxel chemotherapy were analyzed retrospectively. 25 patients with R-Doc, 27 patients with AA and 19 patients with Caba. All patients except two had a PSA-Response or stable disease to primary docetaxel chemotherapy. Mean patient age was 74 years for R-Doc, 71 for AA and 69 for Caba with a mean PSA before initiating treatment of 45 ng/ml, 162ng/ml and 563ng/ml.

Results: PSA response rates (>50% regression) were seen in 14 (56%), 8 (38%) and 6 (32%) patients respectively. PSA stabilization was seen in 7 (28%), 2 (9,5%) and 7 (36,8%) patients. Haematologic complications grade >=3 were seen more frequently in R-Doce (32%) and Caba (42%) compared to AA (4%). Cardiovascular complications >= grade 3 were seen in 30% of the patients with AA whereas none of the patients with R-Doc or Caba had cardiovascular grade 3 or 4 side effects.

Conclusions: With AA, Caba and the possibility of R-Doc there are compareable treatment options with regard to PSA response rates, even if a stable disease can be seen more frequently in Caba and R-Doc. As the drugs have different side effects the first second line treatment should be considered to the patient’s characteristics and comorbidity in the palliative setting. PSA progression free survival and overall survival data are awaited.
A phase II trial of chemotherapy plus hormone therapy as initial treatment of unresectable/metastatic adenocarcinoma of the prostate.
Authors: Amato Robert J. , Jac Jaroslaw , Stepankiw Mika , Ramirez Perla
Published: February 2017

247

Background: Chemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone is present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy could be effective initial treatment for locally advanced or metastatic prostate cancer. This study examined the efficacy and safety of chemohormal therapy approach.

Methods: Patients received medical castration plus an anti-androgen and chemotherapy (nab-paclitaxel, leuprolide, bicalutamide). Patients were followed with PSA levels and radiographic assessments.

Results: Forty-six men (median age) 64.7 years were treated. Fifty-eight percent underwent prior local therapy including prostatectomy (30%), prior radiation (15%), or both (13%). Median baseline PSA was 8.9 ng/ml, and 96% of patients had a Gleason score of ≥7%. At 2 years, 78% of patients experienced tumor regression with a median reduction in PSA level of >90%. Median time to progression was 28.43 months measured by PSA and 34.52 months measured radiographically. Median OS was 62.4 months. The most frequent significant adverse events included grade 3 hypokalemia (17%) and lymphopenia (59%).

Conclusions: Combination chemohormonal therapy for locally advanced and metastatic prostate cancer delayed disease progression and enhanced OS. Information presented will include curves and correlation detailing efficacy and adverse events of various sub-populations.
Impact of race on prostate cancer selection and cause-specific mortality: A SEER database analysis.
Authors: Duarte Catherine , Sarkisian Natasha , Nguyen Paul Linh , Garroutte Eva , Hurwitz Mark D
Published: February 2017

248

Background: The objective of this study was to assess relationships between race, treatment, and cause-specific mortality for prostate cancer.

Methods: The Surveillance, Epidemiology and End Results (SEER) database yielded 328,151 prostate cancer patients diagnosed between 1990–2007 including 5,129 Japanese-American, 50,717 Black-American, and 282,305 White-American men. Japanese-American men were selected as they have the lowest incidence of prostate cancer and best treatment outcomes. Cox proportional-hazards regression analysis was used to assess association of race with prostate-cancer specific mortality before and after adjusting for age, health, and treatment. To assess impact of race on treatment selection, we compared mean incidence of treatment type [external beam radiation therapy (EBRT), brachytherapy, and surgery] by race using one-way ANOVA and post-testing with Bonferroni correction.

Results: Race significantly impacted survival after prostate cancer treatment. Blacks had the highest (HR= 1.198; 95% CI: 1.159 to 1.239, p< .001) and Japanese the lowest (HR= .618; 95% CI: .560 to .682, p< .001) mortality hazard compared to Whites. Tumor grade was the strongest predictor of survival (p< .001). Treatment was also significant: Brachytherapy had the lowest mortality hazard for radiation treatments and surgery was associated with lower mortality hazard compared to no surgery. 37.8%, 44.1%, and 29.1% of Blacks, Whites, and Japanese-Americans underwent surgery (p< .05), 27.3%, 23.8%, and 38.2% of Blacks, Whites, and Japanese-Americans underwent EBRT, (p< .05), and 4.9%, 6.7%, and 4.7% of Blacks, Whites, and Japanese-Americans underwent brachytherapy, with Whites significantly different from the other groups( p<.05).

Conclusions: SEER database analysis revealed race impacts prostate cancer survival. Treatment selection for prostate cancer differs among racial groups and race is associated with differential treatment outcomes. Comparisons between treatments must be viewed with caution as confounding variables likely exist not accounted for in the SEER database. Future research on race, treatment, and socioeconomic impact on cancer-specific mortality is warranted.
Dosimetric comparison of targeted high-dose-rate brachytherapy versus whole gland treatment.
Authors: Chung Melody P , Kayode Oluwatosin , Wang Jason , Park Sang-June , Marks Leonard S. , Demanes D. Jeffrey , Kamrava Mitchell
Published: February 2017

255

Background: To determine potential benefits of focal brachytherapy, we investigated target coverage and magnitude of decreased dose to organs at risk (OARs) with hemigland (HG) compared to whole gland (WG) high dose rate brachytherapy.

Methods: 10 WG implants were used to generate 10 WG and 20 HG (left and right) treatment plans using Inverse Planning Simulation Annealing in Oncentra Masterplan (Nucletron). The same distribution of 17-18 catheters was used for WG and HG plans. The same dose constraints were used for all plans (D90 100-115%, V100 97-100%, V150<35%, Rectum D0.1cc <85%, Bladder D0.1cc < 95%, and Urethra D0.1cc <110%). The HG contour was a modification of the WG contour whereby the urethra divided the prostate into hemiglands. Contours for OARs were identical. HG plans were not actually delivered. The prescription dose was 7.25 Gy x 6. A D90, V100, and V150 were calculated for HG and WG, along with D0.1cc, D1cc, D2cc, and Davg to OARs. We estimated mean difference and 95% confidence intervals for outcome measures. Bonferroni correction was used to adjust for bias due to multiple comparisons. Statistical analyses were conducted using SAS 9.2 (SAS Institute, Cary, NC), with a significance level set at p=0.003.

Results: Compared to WG, HG was associated with a higher D90 (108 vs 112%, p < 0.0001), lower V100 (98.8 vs 97.6%, p = 0.0001), and higher V150 (26.5 vs 33.8%, p = 0.0001). WG therapy resulted in higher tissue doses to OARs. Mean values for the rectum were D0.1cc (76.0 vs 71.2%, p=.0027), D1cc (68.4 vs 59.0%, p<0.0001), D2cc (64.1 vs 53.1%, p<0.0001) and Davg (27.5 vs 20.5%, p<0.0001). Mean values for the bladder were D0.1cc (83.8 vs 82.2%, p=0.0925), D1cc (73.4 vs 64.0%, p<0.0001), D2cc (67.5 vs 55.9%, p<0.0001) and Davg (22.1 vs 16.2%, p<0.0001). Mean values for the urethra were D0.1cc (106.5 vs 97.7, p<0.0001), D1cc (103.1 vs 82.9%, p<0.0001), D2cc (95.2 vs 69.3%, p<0.0001) and Davg (73.5 vs 57.2%, p<0.0001).

Conclusions: The catheter distribution used for WG may not be ideal for HG as a higher D90 and V150 was noted. HG plans decreased Davg to the rectum, bladder, and urethra by a difference of 7.0, 5.9, and 16.3%. Further research is warranted to determine whether further dose reductions can be achieved and are clinically meaningful.
Sociodemographic and clinical characteristics among men with metastatic prostate cancer: An aged-stratified analysis.
Authors: Forlenza Jamie , Senbetta Mekre , Smalarz Amy , Riggs Kimberly
Published: February 2017

256

Background: Data on age-specific comparisons in metastatic prostate cancer (MPC) is limited. This analysis evaluated socio-demographic and clinical characteristics among men with MPC aged <65 years versus ≥65 years.

Methods: Eighty-four US men aged ≥18 years with self-reported MPC completed a cross-sectional survey in January-February 2011 which collected data on socio-demographic and clinical characteristics including treatment history and source of care.

Results: Forty-nine men were aged <65 years; 35 men were ≥65 years. There were no differences (all P>0.05) between groups for marital status (80% of those <65 years and 83% of those ≥65 years were married), race/ethnicity (94% of both groups were white), education (88% of those <65 years and 77% of those ≥65 years had attended college), and annual household income (29% of those <65 years and 31% of those ≥65 years had incomes of $35,000-$54,999). Time since diagnosis differed between groups with 12%, 84%, and 4% of those aged <65 years and 3%, 69%, and 29% of those aged ≥65 years having been diagnosed <1, 1-9, and ≥10 year(s) ago, respectively (P<0.001). Respondents aged <65 years and ≥65 years reported similar experience with chemotherapy (37% in both groups had received chemotherapy), no anemia in last 4 weeks (80% and 83%, respectively), no bone fractures or spinal cord compression in last 4 weeks (90% and 94%, respectively), receiving previous radiation therapy (69% and 66%, respectively), receiving previous surgery (63% and 66%, respectively), and utilizing hormonal treatments previously or currently (86% and 90%, respectively) (all P>0.05). In addition, those <65 years versus ≥65 years did not differ regarding their self-reported source of primary care for prostate cancer (51% and 54% reported receiving their care from oncologists, respectively; 47% and 43% from urologists; 2% and 3% from family physicians/internists).

Conclusions: In this study of men with MPC, those aged <65 years and those ≥65 years reported similar prostate cancer treatment utilization as well as socio-demographic and clinical characteristics with the exception of a difference in time since diagnosis. Further research in larger populations is warranted.
Trends in the adoption of robotic technology in the surgical management of prostate cancer: A population-based analysis.
Authors: Chang Steven Lee , Jiang Wei , Chung Benjamin I.
Published: February 2017

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Background: The adoption of the da Vinci Surgical System (Intuitive Surgical, Inc) for robotic surgery requires a substantial financial investment by hospitals, acquisition of new surgical skills by surgeons, and demand from patients. Although the benefits of this technology have been previously described, the prevalence and adoption rate for the treatment of prostate cancer is not currently known. We performed a population-based analysis to determine how the introduction of robotic technology has altered the surgical management of prostate cancer.

Methods: We analyzed patient-level data from the Prospective Rx Comparative Database (Premier, Inc., Charlotte, NC), which collects data from over 600 non-federal hospitals throughout the United States. We captured all men who underwent a radical prostatectomy between January 1, 2003, and December 31, 2010, based on the International Classification of Disease, 9th edition. Radical prostatectomies utilizing the da Vinci Surgical System were identified by a detailed review of the hospital charge data. Descriptive analysis with univariate and multivariate statistical analyses were performed.

Results: Prior to 2006, <10% of radical prostatectomies were performed with robotic surgery. Beginning in 2006 there was a rapid rise in adoption reaching 56% utilization in 2009 and leveling off in 2010 to 54%. Adjusted analysis demonstrated that the odds of adopting robotic surgery were higher in teaching hospital (odds ratio [OR] 1.45, p<0.001) and hospitals in the Northeast (vs Midwest [OR 2.99, p<0.001]). Smaller hospitals (<200 beds) had a lower likelihood of adopting robotic surgery (OR 0.4, p<0.001). Patient age had no impact on the odds of undergoing robotic radical prostatectomy.

Conclusions: Over past 5 years, there has been widespread adoption of robotic surgery in the management of prostate cancer now with just over half of procedures performed with the da Vinci Surgical System. Our analysis suggests that the adoption of robotic surgery has been determined primarily by the acquisition of this technology by hospitals, which was more common in teaching institutions, larger hospitals, and hospitals in the Northeast.
Randomized phase II trial of maintenance sunitinib versus placebo following response to chemotherapy (CT) for patients (pts) with advanced urothelial carcinoma (UC).
Authors: Grivas Petros , Nanus David M. , Stadler Walter Michael , Daignault Stephanie , Dreicer Robert , Kohli Manish , Petrylak Daniel Peter , Vaughn David J. , Bylow Kathryn A. , Belldegrun Arie S. , Sottnik Joseph L. , Keller Evan T. , Smith David C. , Hussain Maha
Published: February 2017

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Background: UC response to CT is not durable. Angiogenesis may play a role in the progression of UC. We evaluated whether maintenance sunitinib delays progression after response to CT.

Methods: Pts with ECOG PS 0-2, adequate organ function, stable disease, partial or complete response (SD, PR, CR) after 4-6 cycles of CT for advanced UC were randomized to oral sunitinib 50 mg/day, 28 days on, 14 days off (6-week cycle) or placebo. Disease was assessed every 12 wks. At progression, placebo pts were offered open label sunitinib. Primary endpoint: progression rate at 6 months (ms); secondary endpoints: safety, objective response rate, survival, VEGF/sVEGFR2 serum level changes. Using a randomized selection design 42 pts/arm has 90% probability of selecting sunitinib if true reduction in 6-ms progression rate is 15% (from 50% to 35%).

Results: Study was closed early due to slow accrual. 54 pts with median age 69 years, median ECOG PS 1, 70% with bladder primary, 26 with SD, 23 with PR, 5 with CR to CT were randomized to sunitinib (26) or placebo (28). The median number of cycles was 2/arm (sunitinib 0-15, placebo 0-13). The 6-ms progression rate was 81% (95%CI 61-93%), median time-to-progression (TTP) 5 ms (0.3-22.2, 95%CI 2.4-6.3) for sunitinib and 75% (95%CI 55-89%), 2.7 ms (0.8-19.6, 95%CI 2.5-7.4) for placebo. Response rate in pts with SD at enrollment was 9% for sunitinib and 7% for placebo. Most common G3/4 AEs on sunitinib were diarrhea (15.4%/0%), fatigue (15.4%/3.8%), thrombocytopenia (15.4%/7.7%), hypertension (11.5%/0%). 16 placebo pts received sunitinib with best response 1 PR (6.25%), 6 SD (37.5%), 5 PD (31.25%); 4 not response evaluable. Median TTP was 3.4 ms (0.1-22, 95%CI 1.6-5.5). 11 pts had G3/4 AEs, 5 pts discontinued sunitinib due to AEs (4 related, 1 unrelated). Placebo pts had no change in VEGF/sVEGFR2 over time. Sunitinib pts had no change in VEGF but sVEGFR2 significantly decreased after 1 cycle (p<0.0001) and at progression (p=0.0002). VEGF/sVEGFR2 did not correlate with TTP.

Conclusions: Maintenance sunitinib was feasible but did not improve 6-ms progression rate; open label sunitinib had limited activity. sVEGFR-2 decreased on sunitinib.
ATDC as a novel oncogene in bladder cancer.
Authors: Palmbos Phillip Lee , Wang Lidong , Yang Huibin , Detzler Taylor , Ney Gina , Lotan Yair , Wilkerson J E , Kunju Priya , Ljungman Mats , Liebert Monica , Simeone Diane M.
Published: February 2017

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Background: Bladder cancer is a common and deadly disease, but the molecular events leading to its initiation and progression are incompletely understood. We recently identified Ataxia-Telangiectasia Group D Associated (ATDC) as a novel oncogene which drives tumor proliferation and invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we describe the role of ATDC as an oncogene in bladder cancer.

Methods: To further determine the oncogenic role of ATDC, we generated ATDC transgenic (tg) mice in which ATDC expression was driven by a CMV promoter and characterized the resulting tumors.

Results: The dominant phenotype in these mice was the development of both papillary and invasive urothelial carcinomas (9% and 20% respectively, average age of onset 10-12 months of age). Histologically, these tumors were indistinguishable from human urothelial carcinomas. Gene expression profiling of invasive tumors derived from ATDC tg mice demonstrated a marked overlap with gene signatures of human invasive bladder cancers. Analysis of a human bladder cancer tissue microarray (311 samples) showed elevated expression in 70% (173/252) of muscle-invasive carcinomas, whereas normal bladder had no expression. 22% (5/23) of papillary tumors also expressed elevated levels of ATDC. ATDC was the 11th most highly up-regulated gene in bladder cancers represented in the Oncomine gene expression database. ATDC tg mouse bladder tumors demonstrated loss of p53 signaling and down-regulation of PTEN expression, which was determined to be due to ATDC abrogation of p53 function by cytoplasmic sequestration and ATDC-mediated methylation of the PTEN promoter. Furthermore, ATDC knock-down in invasive cancer cell lines resulted in decreased proliferation, invasion and reactivation of p53-mediated signaling and PTEN expression.

Conclusions: ATDC is a novel oncogene that is highly expressed in human bladder cancers and is sufficient to drive the development of invasive bladder tumors in tg mice. The mechanism by which ATDC drives bladder cancer formation involves alterations in p53 and PTEN pathways known to be important in bladder tumorigenesis.
Updated results of a phase I/II trial of intravesical CG0070 in patients with superficial bladder cancer after BCG failure.
Authors: Friedlander Terence W. , Weinberg Vivian K. , Yeung Alex , Burke James , Lamm Donald L. , McKiernan James M. , Nemunaitis John J. , Stephenson Joe , Small Eric Jay , Fong Lawrence , Meng Maxwell V.
Published: February 2017

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Background: Loss of retinoblastoma (Rb) tumor suppressor activity occurs commonly in bladder cancer and leads to upregulation of the E2F-1 transcription factor. CG0070 is a replication competent oncolytic adenovirus genetically modified to express GMCSF under control of the human E2F-1 promoter. Updated results from a phase I/II study of CG0070 in patients with recurrent superficial bladder cancer (T1, Ta, Tcis) after BCG treatment are presented here.

Methods: The V-0046 phase I/II study previously reported the safety and evidence of efficacy of single and multiple doses of intravesical CG0070. Efficacy was determined using quarterly cystoscopy, biopsy, and/or urine cytology. Tumor Rb status was assessed immunohistochemically in 18 tumors.

Results: 35 patients were treated with either a single dose (n=13) of CG0070 ranging from 1x1012 to 3x1013 viral particles (vp) or with weekly x 6 (n=9) or every 4 week x 3 doses (n=13) ranging from 1x1012 to 1x1013 vp per dose. Only one dose limiting toxicity, grade 3 lymphopenia in an every 4 week patient, was observed. The most common adverse events regardless of schedule were flu-like illness, dysuria, hematuria, bladder spasm, and nocturia. Urine GMCSF was detectable in 94% of patients and 58% of patients in the single dose cohort had an increase in CG0070 levels suggesting in-vivo viral replication. The CR rate in the single dose cohort was 23% (3/13), and 64% (14/22) in the multi-dose cohorts. Median follow up for all responders is 9.1 months. Of all responders, 11 recurred with a remission duration ranging from 3.0 - 33.4 months and 6 patients, all in the multiple dose cohorts, remain in remission as of last follow-up with a remission duration ranging from 3.3 – 38.2 months. Phosphorylated (inactive) Rb was detected in 13 of the 18 (72%) patients evaluated. Nine of these 13 patients (70%) had a CR. All patients (5/5, 100%) with known phosphorylated Rb treated in the weekly cohort experienced a CR.

Conclusions: CG0070 was well tolerated with minimal local and systemic toxicities. Complete responses were more frequently observed in the multiple-dose cohorts, including durable CRs in patients with phosphorylated Rb. Further study in Rb inactivated tumors is warranted.
Neoadjuvant gemcitabine plus carboplatin followed by immediate radical cystectomy in patients with muscle-invasive bladder cancer: A propensity score analysis.
Authors: Koie Takuya , Okamoto Teppei , Suzuki Yuichiro , Tobisawa Yuki , Yoneyama Tohru , Mori Kazuyuki , Yamamoto Hayato , Hatakeyama Shingo , Yoneyama Takahiro , Kamimura Noritaka , Ohyama Chikara
Published: February 2017

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Background: Standard neoadjuvant chemotherapy has not yet been established for patients with muscle-invasive bladder cancer. Our pervious phase II trial demonstrated the efficacy and safety of neoadjuvant gemcitabine plus carboplatin (GCarb) chemotherapy followed by immediate radical cystectomy (RC) in patients with muscle-invasive bladder cancer. In the present study, we conducted a propensity score analysis to elucidate clinical significance of the present treatment protocol.

Methods: The cohort of neoadjuvant group consists of 120 patients with muscle-invasive bladder cancer. They received 2 courses of GCarb therapy consisting of 800 mg/m2 gemcitabine on days 1, 8, and 15 and carboplatin with an AUC of 4 on day 2 between March 2005 and June 2011. After the chemotherapy, RC and bilateral pelvic lymph node dissection (PLND) were performed within an interval of 1 month. The cohort of surgery alone group includes 155 patients with muscle-invasive bladder cancer treated with RC and bilateral PLND between May 1994 and December 2004. Propensity score matching was used to adjust for potential selection biases associated with treatment type. The endpoints were overall (OS) and disease-free survival (DFS).

Results: Of the 120 patients who received GCarb and RC, 28 (23.3%) RC specimens showed pT0. Grade 3/4 neutropenia occurred in 40 patients (33.9%) and thrombocytopenia in 23 patients (19.8%). Propensity score-matched analysis indicated 112 matched pairs from both groups. The 5-year OS rate was 91.5% for neoadjuvant GCarb versus 51.3% for surgery alone group (P < 0.0001). The DFS rate was 83.8% for neoadjuvant GCarb versus 53.1% for surgery alone (P < 0.0001). Multivariate analysis revealed that the neoadjuvant GCarb regimen was an extremely strong predictor of the improvement in OS and DFS.

Conclusions: Although the present study is not randomized, neoadjuvant gemcitabine plus carboplatin therapy followed by immediate RC achieved significantly longer OS and DFS comparing to surgery alone. The clinical usefulness of the present treatment for the patient with muscle-invasive bladder cancer should be verified by further trials.