bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary safety results of an ongoing phase I/II clinical study of MGN1601, a tumor vaccine comprising allogeneic, gene-modified, and irradiated tumor cells in combination with an immunomodulator in patients with metastatic renal cell carcinoma (ASET study).
Authors: Tschaika M. , Weikert S. , Gruenwald V. , Schmidt-Wolf I. , Schroff M. , Wittig B. , Schmidt M.
Published: February 2017

392

Background: MGN1601 is a cell-based RCC tumor vaccine MGN1601 consisting of two active pharmaceutical ingredients: genetically modified allogeneic (human) cells transfected with four different MIDGE vectors encoding IL-7, GM-CSF, CD80 and CD154 and a synthetic DNA-based immunomodulator dSLIM-30L1, a TLR-9 agonist. The vaccine is being developed for treatment of patients with advanced RCC. Its prophylactic and therapeutic anti-tumor activity has been shown in several in-vivo models. A good safety profile of MGN1601 was shown in a wide program of acute and chronic toxicity studies. Based on these promising data, this phase 1/2 study was started in patients with advanced RCC.

Methods: This multicentric open clinical study for the assessment of safety and efficacy of MGN1601 in patients with advanced RCC was initiated in October 2010. A total of 24 patients have to be recruited into the study. The treatment consists of 8 MGN1601 treatments administered as follows: the first 3 treatments are administered on a weekly basis, and the consecutive 5 treatments on a bi-weekly basis. The treatment dose contains 107 transfected tumor cells and 5 mg dSLIM per administration, which has been proven to be safe with a high safety margin in repeated toxicity studies. The efficacy and safety of the study treatment will be evaluated based on extensive immunological tests, radiological assessment, safety laboratory results and assessments of the quality of life. Here, the first safety data are presented.

[Table: see text]
Brain metastasis in metastatic renal cell carcinoma: Predictive factors of occurrence and survival with or without antiangiogenic therapy.
Authors: Vanhuyse M. , Penel N. , Caty A. , Fumagalli I. , Alt M. , Zini L. , Adenis A.
Published: February 2017

394

Background: We analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in advanced RCC treated with or without antiangiogenic agents (AAA).

Methods: Data from all consecutive metastatic RCC patients (pts) treated in the Northern France Cancer Center (Centre Oscar Lambret, Lille) between 1995 and 2008 were reviewed. Eligible pts had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. Bellini duct and neuroendocrine carcinoma and sarcoma were excluded. AAA were sorafenib, sunitinib, bevacizumab, temsirolimus, and everolimus. Characteristics of the two groups, treated with or without AAA, were compared with a Fisher exact test. Impact of AAA on overall survival (OS) and BM-free survival (BMFS) was explored by Kaplan-Meier method and adjusted to confounders parameters in a Cox model.

Results: A total of 199 pts with advanced RCC were identified, 51 treated with AAA and 148 treated without AAA. The median follow-up duration was 40 months. BM occurred in 35 pts. As expected in this retrospective analysis, characteristics between AAA treated and non AAA treated groups were unbalanced for 11 parameters including age, Motzer prognostic factors, performance status and favoring better prognostic factors in the AAA treated group. The median overall survival was 24 months. Overall survival was higher in patients with AAA versus patients without AAA (31 versus 18 months, hazard ratio (HR) 0.67 [0.45–0.97], p=0.038). The AAA were not associated with better BMFS (HR=0.58 [0.26–1.30], p=0.187). The alkaline phosphatase was an independent prognostic factor for BM (p=0.05). In multivariate cox model, AAA treatment improved the OS (adjusted HR 0.60 [0.38–0.94] but not the BMFS (adjusted HR 0.53 [0.22–1.32].

Conclusions: In this retrospective single center study, elevated alkaline phosphatase is a predictive factor for brain metastasis in metastatic RCC. AAA significantly improved overall survival in advanced RCC without any significant impact on brain-metastasis-free survival.

No significant financial relationships to disclose.
Cost comparison of laparoscopic partial nephrectomy and robot-assisted laparoscopic partial nephrectomy.
Authors: O'Malley R. L. , Kowalik T. , Hayn M. H. , Collins T. B. , Kim H. L. , Schwaab T.
Published: February 2017

402

Background: Although nephron-sparing surgery is the standard of care for the treatment of small renal masses, partial nephrectomy (PN) remains under-utilized. A potential reason for the discrepancy is the desire for minimally invasive surgical approaches but limitation of the advanced laparoscopic techniques needed to perform PN. Robot-assisted surgery has eased the transition to minimally invasive prostate surgery and may also do so for PN, although some believe costs may be prohibitive. The purpose of this investigation was to quantify the cost of robot-assisted PN (RAPN) compared to laparoscopic PN (LPN).

Methods: An institutional renal tumor database was used to identify consecutive patients with normal renal function who underwent RAPN for a localized renal mass by a single surgeon who had performed < 25 previously. The 35 RAPN patients were compared to the last 35 similar patients who underwent LPN by a surgeon who had performed > 150 previous LPNs. Surgical outcomes were compared. Because room time, length of stay and Cxs were similar, cost was compared based only on the total operating room charges (ORC). Total ORC included surgeon and anesthesia fees, as well as labor and supply costs. The depreciation of the robot was included in the ORC as a higher per unit time charge than for LPN. Data on charges were available for the first 29 RAPN patients which were then compared to the last 29 LPN patients.

Results: Dates of operation ranged from October 2008 to July 2009 for LPN and January 2010 to August 2010 for RAPN. Patient and tumor characteristics were similar between groups, except tumor size, which was larger in the RAPN group (3.6 ± 1.8 cm vs. 2.7 ± 0.9 cm, p = 0.007). Cxs, surgical and oncologic outcomes were similar. Mean ORC (IQR) for the LPN group was $28,606 (4,796) and for the RAPN group was $30,874 (20,389) representing a difference of $2,269. If you subtract an additional $858 for the average yearly inflation rate (3%), the difference is $1,411.

Conclusions: RAPN is a safe option with perioperative outcomes similar to those of LPN performed by an experienced surgeon. A cost difference of $2,269 per procedure as estimated using ORC may decrease as the experience of the operating room staff and surgeon increase.

No significant financial relationships to disclose.
Use of genetic instability to predict biochemical recurrence in intermediate-risk prostate cancer.
Authors: Bristow R. G. , Ishkanian A. S. , Malloff C. , Milosevic M. , Pintilie M. , van der Kwast T. , Lam W.
Published: February 2017

42

Background: Biomarkers of local and systemic recurrence are needed to individualize patient risk categories and better define treatment. We hypothesized that genomic instability, as measured by percent genome alteration (PGA), can predict for biochemical failure in intermediate- risk prostate cancer.

Methods: High-resolution array comparative genomic hybridization (arrayCGH) was used to identify PGA in frozen biopsies from 120 intermediate-risk prostate cancer patients. Our cohort included 39 T1c tumors, 78 T2 tumors and 2 T3 tumors. The Gleason score was 6 in 32 tumors, 7 in 82 tumors and 8–9 in 6 tumors. PSA ranged from 2.1–33 (median 8.0). Patients were treated with intensity-modulated radiotherapy (IMRT) with doses of 75.6–79.8 Gy in 1.8–2Gy fractions, or 60–66 Gy in 3 Gy fractions.. Twenty-five percent of patients also received neoadjuvant-concurrent bicalutamide (150mg po od). Biochemical failure, defined by Phoenix criteria or the initiation of salvage therapy, was observed in 35 patients after median follow-up of 5.4 years (range 0.9–8.8).

Results: Array CGH showed variable PGA ranging from <1% to 35% (median 6.7%). PSA and the use of hormonal therapy independently influenced biochemical relapse, and formed a baseline clinical model to which PGA was added. PGA was found to be a strong predictor of biochemical relapse (p<0.0001) independent of the clinical prognostic factors (pre-treatment PSA, Gleason score and T-category). PGA was also found to be associated with unique tumour suppressor and oncogene gene loci clusters involved in genetic stability (e.g. loss of PTEN, p53, RB, NKX3.1, ATM, PARP-1 and gain of c-MYC; validated by in situ FISH).

Conclusions: This is the first report to show genetic instability can independently predict for biochemical recurrence in intermediate-risk prostate cancer. Current studies are associating specific gene loci regions with clinical outcome. Our results could provide a way forward for individualized medicine for non-indolent prostate cancer based on initial daignostic biopsy material. Supported by Prostate Cancer Canada, The Terry Fox Foundation and the Canadian Cancer Society.

No significant financial relationships to disclose.
Association of PTEN loss with outcome of patients (pts) with early high-risk prostate cancer (CaP) treated with adjuvant docetaxel following radical prostatectomy (RP).
Authors: Keizman D. , Zhang Z. , DeMarzo A. , Gurel B. , Lotan T. , Hicks J. , Rosenbaum E. , Antonarakis E. S. , Carducci M. A. , Eisenberger M. A.
Published: February 2017

43

Background: Loss of the PTEN tumor suppressor and subsequent activation of the PI3K pathway is common and has potential clinical and therapeutic value in CaP. We examined the PTEN status of primary tumors in pts who underwent adjuvant docetaxel tx in a prospective clinical trial.

Methods: Of the 77 pts enrolled in a prospective multi-institutional adjuvant docetaxel trial (TAX 2501, J Urol 2007), we prospectively collected 56 primary tumor pathology specimens suitable for analysis of PTEN status by immunoreactivity (IHC) and/or fluorescence in situ hybridisation (FISH) assay. Protocol defined progression included a PSA of ≥ 0.4 ng/mL, radiological/pathological evidence of recurrent disease or death from any cause. Univariate and multivariable analyses based on the Cox proportional hazards regression model were used to analyze the independent association of PTEN and other known prognostic factors with progression free survival (PFS).

Results: PTEN loss was observed in 37/56 pts (66%). Pts with PTEN loss vs detectable PTEN were balanced regarding clinical stage, combined Gleason score, seminal vesicles and surgical margins involvement, and lymph nodes status. Pts with a detectable PTEN had a significantly higher pre-RP PSA (median 14 vs 8.6 ng/mL, p=0.015). 41/56 (73.2%, median followup of 37.5 months, range 10.4 to 44.5) progressed with an overall median PFS of 13 months (mos) (95% CI 9.8–15.8). Independent prognostic factors of progression by multivariate analysis were: seminal vesicles involvement (HR 2.19, p=0.024), combined Gleason score 9–10 (HR 2.46, p=0.027) and PTEN loss (HR 2.36, p=0.037). PFS on pts without PTEN loss (median not reached at a followup time of 37.5 mos, range 10.4–44.5 mos) was significantly longer (log rank test, p = 0.026) compared to those with undetectable PTEN (median PFS 12.9 mos, 95% CI 9.7–15.3).

Conclusions: PTEN loss may be an independent prognostic factor associated with poorer outcome of pts with early high-risk CaP treated with adjuvant docetaxel following RP. These findings may have important prognostic and therapeutic implications in CaP.

No significant financial relationships to disclose.
Variation in UDP glucouronyltransferase (UGT) genes associated with prostate cancer mortality.
Authors: Kohli M. , Mahoney D. W. , Chai H. S. , Hillman D. W. , Rider D. R. , Costello B. A. , Cerhan J. R.
Published: February 2017

44

Background: We investigated the association of germline genetic variation in hormone biosynthesis and metabolism genes with prostate cancer specific mortality in a cohort of advanced prostate cancer patients.

Methods: We successfully genotyped 852 single nucleotide polymorphisms (SNPs) from 97 genes in a cohort of 267 advanced prostate cancer patients at the time of progression to castration recurrence (CRPC) during on-going androgen ablation. Tagging SNPs with minor allele frequency (MAF) of >5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. Medical records were queried for cause of death. The primary endpoint of time to prostate cancer specific mortality (PCSM), was pre-defined as time from development of CRPC to death from prostate cancer progression. Principle components analysis was used for gene-levels tests, and to account for multiple testing, we calculated the false discovery rate (FDR). For SNP level results, hazard ratios (HR) and 95% confidence intervals (CI) were estimated using cox regression.

Results: The median age of the cohort was 72 years at CRPC. 43% had a Gleason score (GS)=8-10, 33% a GS=7, and 24% a GS<7. After a median follow-up of 1.8 years (IQ range: 0.8–3.3 years), 139 patients died, of which 107 were due to prostate cancer progression. In unadjusted gene level analyses, UGT1A7 (p=0.0059; FDR=0.19), UGT1A10 (p=0.0017; FDR=0.17) and UGT1A3 (p=0.0037; FDR=0.18) were associated with PCSM. After adjusting for age and GS, SNPs strongly associated with PCSM are listed in the Table .

Conclusions: Variation in UGT genes involved in hormone metabolism yield prognostic information in CRPC. Further validation is needed to develop these as prognostic biomarkers.

[Table: see text]

No significant financial relationships to disclose.
Caveolin-1 as a biomarker of Src family kinase/Abl inhibition in castrate-resistant prostate cancer.
Authors: Carthon B. C. , Tahir S. , Araujo J. C. , Wen S. , Gallick G. E. , Logothetis C. , Thompson T. C.
Published: February 2017

45

Background: Bone metastases cause significant morbidity in men with castrate-resistant prostate cancer (CRPC). Caveolin-1 (Cav-1), a Src kinase substrate, is overexpressed in primary prostate cancer (PCa) and in PCa bone metastases. In addition, PCa-derived and secreted Cav-1 contributes to malignant progression. We reasoned that Cav-1 may serve as a biomarker of dasatinib (a Src family kinase [SFK]/Abl inhibitor) activity in CRPC patients enrolled in a phase II clinical trial of docetaxel plus dasatinib.

Methods: Levels of prostate-specific antigen (PSA), Cav-1, and markers of bone turnover were measured from baseline and cycle-2, day-1 samples from patients (n = 32) enrolled in this trial. Changes in these markers were stratified by response (responders [R] vs. nonresponders [NR]) and by predominant disease site (lymph node vs. bone). We evaluated Cav-1 expression in human PCa bone metastases samples from trial patients by immunohistochemistry. In parallel, Cav-1 secretion in response to dasatinib treatment was analyzed in PCa cells and osteoblasts.

Results: Serum Cav-1 levels correlated directly with PSA levels in responding patients with node-positive disease (R vs. NR, p = 0.08) but correlated inversely in responding patients with bone-predominant disease (R vs. NR, p = 0.001). Serum from a separate cohort of patients treated with docetaxel only showed no effect on serum Cav-1 levels (R vs. NR, p = 0.85). Levels of Cav-1 were high in the active OBLs in bone specimens with PCa metastases, but not in bone specimens without metastases. Dasatinib treatment led to reduced secretion of Cav-1 in PC-3 and DU145 PCa cells but to increased secretion of Cav-1 in primary mouse osteoblasts or pre-osteoblast MC3T3-E1 cells.

Conclusions: Our results suggest that serum Cav-1 serves as a novel discriminating biomarker for SFK/Abl inhibition in both node-positive and bone-metastatic CRPC. The expression of Cav-1 in OBLs of patients with PCa bone metastases suggests that tumor-associated OBLs are an important source of Cav-1 production in bone marrow. Our data provide evidence that the increase in serum Cav-1 in these patients with bone disease likely occurs through a direct effect of dasatinib on osteoblasts.

No significant financial relationships to disclose.
Use of protein-network modeling of prostate cancer gene signatures to investigate essential pathways in disease recurrence.
Authors: Chen J. L. , Li J. , Stadler W. M. , Lussier Y. A.
Published: February 2017

46

Background: Numerous molecular pathways have been implicated in aggressive prostate cancer. However, it has been difficult to gain an overview of the dominant pathways involved. By analyzing multiple prostate cancer gene signatures of poor prognosis through a protein interaction network, we are able to in an unbiased manner prioritize shared key biological mechanisms.

Methods: We evaluate prostate gene signatures through a previously published Single Protein Analysis of Network (SPAN) methodology to develop a prostate cancer network signature. We assess this signature using a Gene Ontology based information-theoretic metric as well as assess its prognostic ability in an independent clinical dataset. We then examine the interconnectivity of the network signature to develop a phenotype-pathway map that provides an executive summary of critical mechanisms involved in advanced prostate cancer.

Results: Of the 13 prostate cancer signatures that were evaluated, nine gene signatures plus a previously unpublished gene signature met criteria for evaluation. SPAN analysis of these protein interactions resulted in a 42-gene network signature. This network signature had the highest information-theoretic score based on Gene Ontology annotation similarity. Further, the signature identified a statistically significant survival difference (p=0.009) in a cohort of men with prostate cancer in an independent dataset. Additional analysis of the signature generated a phenotype-pathway map that not only recapitulated the centrality of PIK3/NF-κB signaling, but also highlighted less well-established pathways such as the JAK2 kinase activation cascade.

Conclusions: SPAN analysis provides a robust means of abstracting disparate prostate cancer gene expression signatures into clinically useful, prioritized pathways that may ultimately serve as attractive, therapeutic targets.

No significant financial relationships to disclose.
Utility of PCA3 urine assay in Japanese men undergoing prostate biopsy.
Authors: Okihara K. , Ochiai A. , Kamoi K. , Miki T.
Published: February 2017

50

Background: Studies have shown the high specificity of PCA3 urine assay for biopsy detection of prostate cancer in European and American. We determined the diagnostic performance of PCA3 urine test in predicting prostate cancer in Japanese men.

Methods: The study group included 261 men who underwent extended prostate biopsy at our institutions. 79 men of them had repeated biopsy. In all cases, race was Asian. Urine specimens were collected after digital rectal examination. On PROGENSA PCA3 assay, PCA3 score was calculated using PCA3 mRNA copy divided by PSA mRNA copy. PCA3 score was correlated with biopsy outcome and compared with serum PSA and free-total PSA.

Results: 257 urine samples collected were successfully analyzed (i.e., the informative specimen rate was 98%). Biopsy revealed prostate cancer in 104 men (40%). There was no significant relationship between serum PSA and PCA3 score. PCA3 score in prostate cancer was significantly higher than that in negative (median 54.5 vs 17.0, p<0.001). The probability of positive biopsy increased as PCA3 score increased. Using a PCA3 cutoff value of 35.0, sensitivity, specificity and diagnostic accuracy were 65%, 75% and 71%, respectively (p<0.01). Area under the curve (AUC) for PCA3 score was 0.757 and AUC for serum PSA was 0.599 in all men. There was a significant difference in AUC between PCA3 score and serum PSA (p<0.001). In men with serum PSA 4 to 10ng/ml, AUCs of PCA3 score, free-total PSA, and serum PSA were 0.759, 0.681, and 0.542, respectively.

Conclusions: The specificity of PCA3 urine assay was high for detection of prostate cancer in Japanese men. PCA3 urine assay could improve the prediction for prostate cancer and help better decision making for prostate biopsy.

No significant financial relationships to disclose.
Germ-line single nucleotide polymorphism (SNP) predictors of progression-free survival and overall survival in patients with advanced prostate cancer treated with androgen-deprivation therapy (ADT).
Authors: Campbell M. T. , Jung J. , Philips S. , Mohammadi Y. , Carr K. A. , Davis T. L. , Li L. , Sweeney C. , Skaar T. C. , Hahn N. M.
Published: February 2017

51

Background: Significant variation in response duration and overall survival exists among prostate cancer (PCa) patients treated with ADT. Germ-line SNPs affecting function of genes critical to hormone synthesis, transport, metabolism, binding sites, and degradation may contribute to variability in clinical outcomes observed in PCa patients treated with ADT.

Methods: Between 1/07 and 10/08, all PCa patients seen in the Indiana University Simon Cancer Center oncology clinics were approached for recruitment to the Prostate Cancer Genetic Risk Evaluation of SNPs Study (PROGRESS). Participants completed a demographic and clinical questionnaire and provided a peripheral blood sample. Only patients with confirmed ADT initiation dates were included in this analysis. Germ-line DNA was analyzed for SNP genotyping on a 128-SNP chip using a TaqMan OpenArray GT Kit (Applied Biosystems). The chip included genes critical to hormone signaling, transport, and elimination pathways with minor allele frequencies > 5%. Patients were followed for progression-free survival (PFS) and overall survival (OS) endpoints. Univariable analyses were performed to identify significant associations between SNP genotype, clinical parameters, and PFS and OS outcomes.

Results: 107 patients with PCa initiated on ADT enrolled. Demographics included: age (median)–69 yrs, prostate specific antigen (PSA) (median)–28.0 ng/ml, PSA doubling time (median)–4.9 months, biochemical/metastatic–25%/75%, concurrent anti-androgen therapy–44%. No clinical parameters were associated with PFS and OS. Significant SNP associations with PFS and OS are summarized in the Table.

Conclusions: Interpatient differences in hormone pathway germ-line SNPs may contribute to variability in clinical outcomes in patients treated with ADT.

[Table: see text]

[Table: see text]
Use of germ-line single nucleotide polymorphisms (SNPs) in drug transporters (ABCG2/ABCB1) and tubulin (TUBB4) to predict survival in patients with metastatic castrate-resistant prostate cancer (CRPC) receiving docetaxel.
Authors: Hahn N. M. , Jung J. , Philips S. , Patel Y. R. , Carr K. A. , Mohammadi Y. , Magjuka D. , Li L. , Sweeney C. , Skaar T. C.
Published: February 2017

58

Background: Multiple treatment options now exist for metastatic CRPC patients (pts). Germ-line SNPs in docetaxel (D) transport, metabolism, binding site, and degradation genes may contribute to variability in outcomes observed in D treated CRPC pts.

Methods: Between 1/07 and 10/08, all PCa pts seen in the Indiana University Simon Cancer Center oncology clinics were approached for recruitment to the Prostate Cancer Genetic Risk Evaluation of SNPs Study (PROGRESS). Participants completed a demographic and clinical questionnaire and provided a blood sample. Only CRPC pts treated with D were included in this analysis. Germ-line DNA was analyzed for SNP genotyping on a 128-SNP chip using a TaqMan OpenArray GT Kit (Applied Biosystems). The chip included genes critical to D signaling, transport, and elimination with minor allele frequencies > 5%. Pts were followed for progression-free (PFS) and overall survival (OS). Univariable analyses were performed to identify significant associations between SNP genotype, clinical parameters, and PFS and OS outcomes.

Results: 60 pts with metastatic CRPC initiated on D enrolled. Demographics included: age (median) – 69 yrs, ECOG PS 0– 40%, prostate specific antigen (PSA) (median) – 129.9 ng/ml, PSA doubling time (median) – 1.8 months, visceral mets –25%. No clinical parameters were associated with PFS and OS. Significant SNP associations are summarized below.

Conclusions: Differences in germ-line ABCG2, ABCB1, and TUBB4 SNPs may contribute to variation in clinical outcomes in CRPC pts treated with D.

[Table: see text]

[Table: see text]
Role of circulating tumor cells (CTCs) in biochemical recurrence (BR) of prostate cancer.
Authors: Aragon-Ching J. B. , Simmens S. J. , Hendricks F. , Andrawis R. , Frazier H. , Jarrett T. , Patierno S. R. , Siegel R. S.
Published: February 2017

60

Background: CTCs have an established role in the prognosis of metastatic prostate cancer. Little data exists regarding the role of CTCs in BR of prostate cancer. The aim of this study was to determine whether there is a correlation between the number of CTCs in men with BR with varying prostate specific antigen (PSA) and PSA doubling time (PSADT) categories. Secondary endpoints looking at correlation of the CTCs with clinical or laboratory factors (Gleason scores, testosterone, hemoglobin, alkaline phosphatase, BMI, imaging results) will also be assessed.

Methods: BR was defined as patients (pts) who have undergone primary treatment with prostatectomy or radiation or both, with rise to >/= 0.2 from a prior undetectable level for prior prostatectomy or > 2 mg/dl rise from post-nadir radiotherapy. The study was powered to detect a Pearson correlation of .46 with a sample size of 36. Eleven of planned accrual goal of 36 pts were enrolled from May to September 2010. PSADT was obtained and correlated with the CTC values, categorized as PSADT of < 3 months, 3-14.9 months and > 15 months. CTCs were evaluated in 7.5 mL of peripheral blood using the CTC CellSearch test.

Results: The median age for 11 patients was 75 y/o (range: 57-91) with a median PSA of 1.6 ng/mL (range 0.2-6.5) and testosterone levels of 309 ng/dL (range: 31–471). Gleason scores were 8 (n=1), 7 (n=5), 6 (n=2), 5 (n=3). Prostatectomy was the primary treatment in 6 pts, radiotherapy in 5 pts and Cyberknife in 1 pt. Median hemoglobin was 12.43 g/dL, BMI was 26.79 and alkaline phosphatase was 69 IU/L. PSADT varied between 3 to 55 months. All pts accrued had 0 CTC levels. The latter result translates into a 95% confidence interval upper bound of approximately .27 for the proportion of patients in this population who have non-zero CTC levels.

Conclusions: Prostate cancer pts with BR have negative blood CTCs and does not appear to correlate with PSA or PSADT. However, the limited number of patients precludes sufficient interpretation at this time and further accrual is ongoing. The absence of CTC levels in this patient population, if supported through further data collection, could emerge as an important unanticipated finding from this study. Supported by IRG-08-091-01 from ACS to GWU Cancer Institute.

No significant financial relationships to disclose.
High toxicity in patients receiving adjuvant docetaxel plus hormone treatment after radical radiotherapy for high-risk prostate cancer: A preplanned safety report of SPCG 13 trial.
Authors: Kellokumpu-Lehtinen P. , Hjelm-Eriksson M. , Thellenberg-Karlsson C. , Astrom L. , Franzen L. , Marttila T. , Taalikka M. , Ginman C.
Published: February 2017

63

Background: In two randomized trials a survival benefit has been shown for docetaxel (T) in metastatic, hormone refractory prostate cancer PrCa). In order to increase the recurrence-free survival and overall survival with adjuvant treatment we conducted a randomized trial using T in patients (pts) with high risk PrCa after radical radiotherapy (RT).

Methods: Between May 2007 and April 2009 100 pts with PrCa Gleason score (GS) 7 (4+3) and cT2 tumors with PSA >10 to <70 ng/mL or cT2 tumors with GS 8-10 or any cT3 tumors without metastases were randomized between surveillance (S) or six courses of T 75 mg/m2 q21d at the end of RT. Neoadjuvant + adjuvant LHRH-treatment for 9 mo was mandatory. The defined end-point is PSA relapse (ASTRO-RTOG guidelines). The groups were well balanced; mean age 65 vs 66 years, ECOG (0/1, %) 90/10 vs 90/10; time from diagnosis 262 vs 270 days, GS (6-7/8-10, %) 60/40 vs 44/56; tumor stage (T2/T3, %) 26/74 vs 28/72 in groups T vs S, respectively. The mean PSA of the 100 pts at the time of diagnosis was 21.9 ng/mL and the nadir PSA after RT was 0.25 ng/mL. By September 2010 227 out of 378 pts have been randomized to this SPCG 13 trial, NTC 006653848.

Results: During T treatment Grade (G) 3 adverse event (AEs) occurred in 15 pts (30%) and G 4 AEs in 30 pts (60%) mainly due to bone marrow toxicity, which was higher than expected; neutropenia G 3-4 in 72% of the pts. Febrile neutropenia in 24% of the pts, neutropenic infection in 10% the pts and G3 infection without neutropenia in 4% of pts was recorded. Nonhematological G 3 AEs (pts) were rare; anorexia (1), diarrhea (3), fatigue (5), mucositis (1), nausea (1) and pain (1). Other severe SAEs related to T were pulmonary embolism and renal failure. However, only three pts stopped T before 6 cycles were completed due to toxicity. No deaths have occurred. In the S arm only one patient experienced G 3 toxicity (pain) 12 weeks after the randomization.

Conclusions: Adjuvant T chemotherapy after RT has a higher frequency of neutropenia than previous studies on pts with metastatic disease, but very similar to the SPCG 12 trial of adjuvant T after surgery. Otherwise the treatment was quite well tolerated.

[Table: see text]
Evaluation of a prostate brachytherapy technique designed to reduce short- and long-term urinary dysfunction: 5-year results of a multi-institutional comparative cohort study.
Authors: Talcott J. A. , Zietman A. L. , Kaplan I. D. , Clark J. A. , D'Amico A. V.
Published: February 2017

70

Background: To evaluate a novel prostate brachytherapy technique designed to reduce short- and long-term urinary dysfunction by sharply reducing periurethral prostate radiation (XBT), we compared urinary outcomes of XBT patients to those of 2 groups treated with standard technique (SBT) in a prospective 5-year cohort study.

Methods: We surveyed newly diagnosed, untreated patients patients with clinically localized prostate cancer before brachytherapy to gather demographic, clinical and quality of life information, with follow-up at 1, 3, 12, 24, 36, 48 and 60 months after treatment. XBT patients were treated at Brigham and Women's Hospital. SBT was given at Beth Israel-Deaconess or Metrowest Hospital, which used the same technique, or at Massachusetts General Hospital.

Results: Of 263 enrolled patients who completed at least 3-month follow-up, including 73 XBT patients and 190 SBT patients, 99 at 1 site (SBT1) and 91 at the other (SBT2), 167 (63%) had completed 5-year follow-up as of September 2010. XBT patients were younger and reported more baseline urinary obstruction/irritation, but the treatment groups were otherwise similar before treatment. Urinary obstruction/irritation was increased for 24 months. XBT patients reported lower increases which resolved earlier. SBT2 patients initially reported greater urinary dysfunction than SBT1 patients, but the problem resolved after changing technique to better localize the urethra. Urinary incontinence appeared to rise at 60 months after SBT but not XBT. Of patients who reported complete pretreatment urinary control, 33% of SBT vs. 15% of XBT patients reported some incontinence (p=0.08).

Conclusions: Sharply reduced periurethral radiation suppresses post-treatment increases in urinary obstruction/irritation and may reduce long-term urinary incontinence.

No significant financial relationships to disclose.
Percentage of positive biopsy cores to predict distant metastasis of prostate cancer after definitive radiation therapy.
Authors: Huang J. , Kestin L. L. , Vicini F. A. , Williams S. G. , Ye H. , McGrath S. D. , Ghilezan M. , Martinez A.
Published: February 2017

80

Background: To assess the prognostic value of percentage of positive biopsy cores (PPC) and perineural invasion (PNI) in predicting clinical outcome following radiotherapy (RT) for prostate cancer.

Methods: One thousand and fifty-six patients with clinical stage T1-T3 N0 M0 prostate cancer, who had ≥ 4 biopsy cores sampled and complete biopsy core data available, were treated with either adaptive image-guided RT (median 75.6 Gy, n=387), low-dose EBRT (median 66.6 Gy, n=393), or EBRT and high-dose rate brachytherapy boost (n=276) at William Beaumont Hospital (1993-2004). Neoadjuvant and/or adjuvant androgen deprivation (AD) were given to 253 patients (24%). Multivariate cox regression analysis included PPC, gleason score, PSA, T stage, PNI, RT dose, androgen deprivation, and age. Biochemical failure (BF) was scored according to the Phoenix definition. Clinical failure (CF) was defined as any locoregional recurrence (LRR) or distant metastasis (DM). Median follow-up was 7.6 years.

Results: Median cores sampled was 7, median PPC was 33%, and 18% had PNI. On univariate Cox regression, both PPC and PNI were predicators of biochemical failure and clinical failure (all P<0.05). On multivariate Cox regression, PPC, either as continuous or categorical variable, remained an independent predicator of BF, CF, DM, cause-specific survival, and overall survival (all P<0.05). PPC of >50% was associated with significantly higher DM (HR 4.01, 95% CI 1.86-8.61), and its independent predicative value remained significant whether AD was given or not (all P<0.05). Combining ≤50% vs ≥50% PPC with NCCN risk group stratification demonstrated added prognostic value of DM for intermediate-risk (HR 5.44, 95% CI 1.78-16.6) and high-risk groups (HR 4.39, 95% CI 1.70-2.84), with or without AD (all P<0.05). On multivariate Cox regression, PNI was an independent predicator of LRR only (HR 2.51, 95% CI 1.18-5.33).

Conclusions: PPC is an independent and powerful predicator of DM for intermediate- and high-risk prostate cancer, regardless the use of AD. It should be considered for risk stratification and when designing for future trials testing adjuvant treatment after definitive RT for prostate cancer.

No significant financial relationships to disclose.
Brachytherapy as salvage treatment for local nodular recurrence of prostate cancer.
Authors: Kumar A. M. , Traudt K. , Ciezki J. P. , Reddy C. A. , Klein E. A.
Published: February 2017

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Background: Men diagnosed with adenocarcinoma of the prostate treated with radical prostatectomy (RP) have a 10% risk of developing local recurrence within 10 years. While the majority of these recurrences are biochemical failures with no foci of disease, we report on a series of 7 patients who had nodular recurrences in the post-surgical bed and subsequently underwent low-dose rate (LDR) brachytherapy as salvage therapy.

Methods: Patients who were initially treated with RP and subsequently with salvage LDR I-125 brachytherapy for a nodular recurrence were included in this series. All patients failed biochemically within 10 years of RP and received no other adjuvant or salvage treatment by choice. Nodular recurrences were biopsy confirmed adenocarcinoma, and patients had no evidence of nodal or distant metastasis on imaging or bone scan. All patients consented to salvage with LDR brachytherapy. Follow up post-salvage was at least every 6 months with a serial PSA.

Results: Seven patients underwent salvage LDR brachytherapy with median age of 74 (range 63-77) at time of salvage. The median pre-salvage PSA was 4.56. The biopsy Gleason score of the nodular recurrences was 7 or 8. Median volume of nodular recurrence was 16cc, median number of sources was 30, median D90 for nodule was 155.02 Gy, and median rectum V100 was 0.01. Compared to baseline prior to salvage, patients have reported no additional urinary symptoms or sexual side effects from salvage. Patients have been followed for a median of 28 months post-salvage (range 4-48 months) with a median PSA at last follow up of 1.05.

Conclusions: This report presents the first known case series of prostate cancer patients treated with RP who developed local nodular recurrences which were then treated with LDR brachytherapy. For patients who develop a nodular recurrence with no other evidence of distant metastases, LDR brachytherapy offers a novel salvage option.

No significant financial relationships to disclose.
CyberKnife for prostate cancer: Is it cost-effective?
Authors: Parthan A. , Pruttivarasin N. , Taylor D. , Davies D. , Yang G. , Pawar V. , Weinstein M. C.
Published: February 2017

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Background: The study assessed the cost-effectiveness of CyberKnife (CK) compared to surgery and radiation therapy for the treatment of prostate cancer (PC) from a third-party and societal perspective.

Methods: For patients > 65 yrs with localized PC, a Markov model compared treatment with CK, intensity modulated radiation therapy (IMRT), surgery or proton therapy (PT). Following treatment, patients were at risk of long-term toxicity: genitourinary (GU); gastrointestinal (GI); and sexual dysfunction (SD). Long-term toxicity was defined as adverse events >grade 2 on Radiation Therapy Oncology Group scale occurring at least 12 months following treatment. Markov states included all possible combinations of GI, GU, and SD long-term toxicities, no toxicity, and death. During each year patients remained in the same Markov state or died. Costs and utilities were assigned using published sources. Toxicity probabilities were derived using meta-analytical techniques to pool results from multiple studies. It was assumed that long-term disease control would not differ across treatments. The model projected expected lifetime costs and quality adjusted life years (QALYs) for each treatment and incremental cost-effectiveness of CK vs comparators as cost per QALY gained. Costs from societal perspective included lost productivity. Extensive sensitivity analyses were conducted.

Results: Surgery was the least expensive treatment option followed by CK. CK patients had higher expected QALYs (8.11) than other treatment options (7.72- 8.06). From a payer perspective, total lifetime costs were $25,904, $22,295, $38,915, and $58,100 for CK, surgery, IMRT and PT, respectively. Incremental cost per QALY gained for CK versus Surgery was $9,200/QALY. Compared to IMRT and PT, CK was less costly and resulted in higher QALYs (dominance). At a threshold of $50,000/QALY, CK was cost effective in 86%, 79%, and 91% of simulations compared to surgery, IMRT, and PT, respectively. From a societal perspective, CK costs $4,200/QALY compared to surgery and remained dominant vs IMRT and PT. Results were most sensitive to costs of surgery and CK.

Conclusions: Initial CK costs are higher than surgery, but CK patients have better quality of life. CK patients have lower lifetime costs and higher QALYs than IMRT and PT patients.

[Table: see text]
Stereotactic body radiotherapy for treatment of organ-confined prostate cancer: Efficacy and quality of life at 4 years.
Authors: Katz A. J. , Santoro M.
Published: February 2017

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Background: The purpose of this study is to assess the efficacy and toxicity of stereotactic body radiotherapy for organ confined prostate cancer patients.

Methods: Fifty T1cN0M0 prostate carcinoma patients (42 low- and 8 intermediate-risk) received 5 fractions of 7 Gy SBRT with Cyberknife to a total dose of 35 Gy delivered over 5 consecutive days. Mean patient age was 69.5 years and mean pre-treatment PSA was 5.7 ng/mL. All patients received 1500 mg of amifostine intrarectally prior to each SBRT fraction. Patients were treated to the 83%-87% contour line with 5-mm margins added to the gross tumor volume at all borders except for the rectum where a 3-mm margin was added. During treatment, 4 gold fiducial seeds were continuously tracked. Toxicity was assessed using the Radiation Therapy Oncology Group toxicity scale; biochemical failure was assessed by the Phoenix criteria, and quality of life was assessed with the Expanded Prostate Cancer Index Composite Questionnaire (EPIC).

Results: At a median follow-up of 48 months (range, 46-53 months) one biochemical failure has occurred. Three patients died of intercurrent disease. The median PSA at 48 months is 0.10 ng/mL (range, 0.01-3.5 ng/mL). At 42 months, 42 of 47 patients had achieved a PSA of 0.5 ng/mL or less. Toxicity has been minimal with no grade 3+ toxicities. Actuarial 48 month rates for grade 2 urinary and rectal toxicity-free survival were 95.5% and 97.8%, respectively. Mean EPIC bowel and urinary quality of life returned to baseline by 18 months and remain at baseline values at 36 months. Of the 36 patients that were potent prior to treatment 29 (80.5%) maintained potency.

Conclusions: At 48 months median follow-up the promising biochemical control, minimal toxicity and the promising potency preservation rates are highly encouraging.

[Table: see text]
Utilizing metformin as a radiosensitizing agent in the treatment of prostate cancer.
Authors: Klotz L. , Venier N. , Vandersluis A. , Besla R. , Fleshner N. , Pollak M. N. , Venkateswaran V. , Colquhoun A. J.
Published: February 2017

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Background: External beam radiation therapy (EBRT) is a well recognized curative prostate cancer (PCa) treatment modality utilizing ionizing radiation (IR). In addition to mediating DNA damage, IR upregulates several intracellular pro-survival pathways including the insulin- like growth factor (IGR) signaling network. This may contribute to the intrinsic radioresistance exhibited by certain tumors. Diabetic patients with PCa experience poorer outcomes following EBRT than their non-diabetic counterparts. Some attribute this to diabetes-induced chronic hyperinsulinemia with consequent upregulation of pro-survival insulin/IGF signalling. Previous work by our group showed diet-induced hyperinsulinemia to enhance PCa tumor growth in vivo. Metformin, a diabetic treatment, alleviates hyperinsulinemia, and also exhibits anti-neoplastic properties. We postulate that pre-treatment with metformin to correct hyperinsulinemia may protect cells from radiation-mediated pro-survival insulin/IGF signaling. Thus we assessed the radiosensitizing potential of metformin using in vitro and in vivo PCa models.

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

Results: Monotherapy with IR (1-8Gy) or metformin (0.01-10.0mM) caused significant dose-dependent reduction in colony formation rates (p<0.001). Combination treatment further significantly reduced colony formation rates (p<0.03). Preliminary results from our in vivo study show diminished tumor growth in response to combination treatment (p<0.0001), and are currently subject to ongoing statistical analyses.

Conclusions: Our in vitro findings confirm combining metformin with IR significantly reduces PCa cell colony formation rates further than either monotherapy. Recapitulation of these results in vivo would provide justification for translating this work into a phase II clinical trial of metformin as a radiosensitizing agent.

No significant financial relationships to disclose.
Predicting intrafraction displacement of the prostate during a five-fraction radiotherapy regimen: Implications for stereotactic body radiotherapy.
Authors: Quon H. C. , Loblaw D. A. , Cheung P. , Cesta A. , Holden L. , Tang C. I. , Pang G. , Morton G. , Mamedov A. , Deabreu A.
Published: February 2017

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Background: Accurate characterization of prostate displacement during stereotactic body radiotherapy (RT) may help optimize margins to maximize complication and disease-free survival. Also, if individual patients with large intrafraction displacement can be identified, additional interventions can be undertaken.

Methods: Fifty-three men treated on a phase I/II study of extreme hypofractionation were selected for the study. A total dose of 35 Gy in 5 fractions was delivered with intensity modulated radiotherapy (IMRT). Daily image guidance was performed using gold seed fiducials. Position verification was obtained with orthogonal electronic portal images taken immediately before and after each fraction. Prostate shifts were recorded in 3 dimensions.

Results: The mean intrafraction prostate displacements were -0.03 ± 0.61 mm (1SD), 0.21 ± 1.50 mm, and -0.86 ± 1.73 mm in the lateral, superior-inferior, and anterior-posterior directions, respectively. The mean intrafraction displacement during the first two fractions is moderately correlated with the displacement in the remaining 3 fractions, with correlation coefficients of 0.63 and 0.47 in the SI and AP directions, respectively.

Conclusions: The mean intrafraction prostate displacement during a course of extreme hypofractionated radiotherapy is small. A strategy using the first two fractions to predict future displacements >5mm shows promise and warrants further validation.

No significant financial relationships to disclose.
Treating intermediate-risk prostate cancer with hypofractionated external beam radiotherapy alone.
Authors: Dal Pra A. , Faria S. , Cury F. L. , David M. , Duclos M. , Shenouda G. , Souhami L.
Published: February 2017

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Background: A wide range of therapeutic alternatives is available for the treatment of intermediate-risk prostate cancer (IRPC). The use of hypofractionated external beam radiotherapy (HypoRT) in this group of patients appears to be an attractive option. Non-randomized institutional results have provided similar outcomes to conventional fractionation. For health-systems such as we have in Canada, where many patients live far, it significantly shortens treatment duration and impacts favorably in health costs. We report our results using HypoRT alone in IRPC.

Methods: Between October/2002 and July/2009, 82 men with IRPC (T2b-T2c, or PSA 10–20 ng/dL, or GS=7) were treated with HypoRT, without any androgen deprivation. Ultrasound image guidance was used daily to confirm setup. The dose was 66 Gy in 22 daily fractions of 3 Gy (BED=79.4Gy/44) prescribed at the isocenter. PTV was the prostate (+/− 1cm seminal vesicles) with 7-mm margin in all directions. GI and GU toxicity were prospectively assessed every 4–6 months using the CTCAE v3 scoring system. Biochemical failure was defined as nadir PSA + 2 ng/dL.

Results: 60% of patients had Gleason score 7; 43% had stage T2; median initial PSA=9 ng/ml; median age 71 years. With a median follow-up of 43 months (range: 7–89), only three patients (4%) have developed biochemical failure. All three showed metastatic disease few months after biochemical failure. Actuarial biochemical recurrence free survival (bNED) is 95.4%. There was no death related to prostate cancer. Three patients died from other causes without biochemical failure. The 5-year overall survival was 93%. At the last follow up visit, grade ≥ 2 late GI and GU toxicity rates were 2% and 7%, respectively. No grade 4 or 5 has occurred.

Conclusions: Men with IRPC treated with 66Gy/22 fractions and without androgen deprivation have experienced excellent 5-year biochemical control rate with acceptable late toxicity. This regimen is very convenient because the duration of the treatment is half of the time used with conventional fractionation. Whether the addition of short-term androgen deprivation would further improve outcome remains unclear.

No significant financial relationships to disclose.