bluuebunny/crossref_metadata_2025 huggingface dataset:
Updated analysis of HERBIS-1: A phase ll study of trastuzumab (T-mab) in combination with tri-weekly S-1 plus CDDP in HER2-positive advanced gastric cancer.
Authors: Gamoh Makio , Sugimoto Naotoshi , Miwa Hiroto , Tsuda Masahiro , Nishina Shinichi , Okuda Hiroyuki , Imamura Hiroshi , Matsuyama Jin , Shimokawa Toshio , Sakai Daisuke , Kurokawa Yukinori , Komatsu Yoshito , Tsujinaka Toshimasa , Ishioka Chikashi , Furukawa Hiroshi
Published: February 2017

98

Background: The HERBIS study demonstrated the promising antitumor activity and manageable toxicities of S-1 plus cisplatin and T-mab (SPT) regimen in patients (pts) with HER2-positive advanced gastric cancer (AGC) (Sugimoto et al. ASCO GI 2012, Abstract 70). We report the updated time-to event analysis. Methods: Main eligibility criteria were gastric or esophagogastric junction adenocarcinoma, HER2-positive, unresectable or recurrent, measurable lesion, no history of chemotherapy or radiotherapy, ECOG PS of 0-1 and adequate organ function. Pts received S-1(80-120mg / day) on days 1-14, cisplatin 60 mg/m2on day 1 and T-mab 8 mg/ kg on day 1 (6 mg/ kg from 2nd course) repeated every 3 weeks until disease progression. Primary endpoint was response rate (RR) and secondary endpoints were overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF) and adverse events. The planned sample size was 50 pts. Results: A total of 56 pts were enrolled from July 2011 to May 2012. Two pts were ineligible and one patient did not receive any treatment. Therefore, the efficacy and safety analyses were conducted in the full analysis set of 53 pts. The confirmed response rate was 67.9% (95% CI: 53.7-80.1), and the disease control rate was 94.3% (95% CI: 84.3-98.9). Median OS was 16.0 months (95% CI: 13.3 - NaN), median PFS was 7.8 months (95% CI: 6.0 – 8.8) and median TTF was 5.7 months (95% CI: 4.2 - 7.1), respectively at the median follow-up time of 13.5 months. The main grade 3/4 adverse events were leukopenia 8%, neutropenia 36%, anemia 15%, increased creatinine 6%, hypoalbuminemia 9%, anorexia 23%, diarrhea 8% and vomiting 6%. Conclusions: SPT have promising antitumor activity and manageable toxicities in pts with HER2-positive AGC. Clinical trial information: UMIN000005739.
Effect of adjuvant and salvage radiotherapy after radical prostatectomy on urinary continence.
Authors: Adam Meike , Lanwehr Dominik , Wenzel Philipp , Graefen Markus , Michl Uwe , Huland Hartwig , Tennstedt Pierre , Becker Andreas , Schwarz Rudolf , Schlomm Thorsten
Published: February 2017

100

Background: The clinical value of adjuvant (aRT) or salvage radiation (sRT) for patient treated with radical prostatectomy (RP) is currently controversially debated. In this study, we assessed the impact of aRT and sRT on long-term urinary continence. Methods: Overall, 15,901 patients who underwent RP in our center between 1992 and 2012 were analyzed. aRT within the first 6 months was performed in 734 (2.9%) patients, and sRT after 6 months in 1405 (8.8%) patients (median time 21.6 months), respectively. Continence rates were assessed annually after RP using a self-administrated questionnaire. Median follow-up was 48.4 months. Continence was defined as the use of no pads or one safety pad. Incontinence was categorized by the number of used pads. The impact of additional radiation therapy on continence results was analyzed by logistic regression analyses, the chi2-likelyhood test and propensity score matching. Results: In multivariate logistic regression analysis, adjusted for age, prostate volume, extend of nerve-sparing, year of surgery, the event of additive RT (OR=1.2, p=0.17) was not statistically relevant correlated with the long-term continence status whereas all other variables significantly correlated with urinary incontinence (p<0.01, each). The lacking correlation of RT and continence remained in a second logistic regression model, adjusted for tumor features (pT, pN, Gleason, PSA, margin-status). The timing of RT (aRT vs. sRT) was not statistically relevant correlated with the long-term continence status (OR=1.7, p=0.09; OR=1.2, p=0.5) In addition, a comparison of all patients received aRT with a propensity score based matched cohort of RP only patients (corrected for age, prostate volume, extend of nerve-sparing and year of surgery) revealed no statistical significant impact of RT on continence (p>0.05). In 248 patients, the continence status was available pre and post RT, again not showing a negative impact of RT (p>0.05). Conclusions: Additive radiation therapy after radical prostatectomy does not negatively affect urinary continence.
Comparison of FRAX score to bone mineral density for estimating fracture risk in patients with CRPC on androgen-deprivation therapy (ADT).
Authors: Bienz Marc Nicolas , James Herbert , Aleksic Ilija , Pieczonka Christopher Michael , Albala David , Iannotta Peter , Alom Modar , Mariados Neil , Mouraviev Vladimir , Saad Fred
Published: February 2017

101

Background: A FRAX algorithm has been elaborated to estimate the ten-year hip fracture risk associated with this under-diagnosed condition. We aim to evaluate the fracture risk of patients who would otherwise be left untreated by the conventional T-score. Methods: Clinical data from 613 PCa patients undergoing ADT was collected from our AMP large urology group. Fracture risk was assessed using the country specific (USA) Fracture Risk Assessment Tool (FRAX). Also, a subset of patients (n=94) had received Dual-energy X-ray Absorptiometry (DXA). We compared the proportion of patients suitable for treatment according to the threshold of the FRAX fracture risk calculated with the BMD (>3%) and the T-score (<-2.5). Results: According to the FRAX algorithm (without BMD), 61.6% of our cohort require treatment. The FRAX score (with BMD) identified 46.8% of patients who had DXA suitable for treatment, in contrast to 19.1% by the T-score alone. Correlations were calculated between the various methods (Table). Conclusions: Our results demonstrate that many patients unidentified for treatment by the conventional T-score are at significant risk for fracture according to the FRAX algorithm with BMD. When calculated without the BMD, an even greater proportion of patients is found to be at risk and suitable for treatment. [Table: see text]
One-step ultrasound-based high dose rate (HDR) prostate brachytherapy with dose escalation to the dominant intra-prostatic lesion.
Authors: Crook Juanita M. , Ots Ana , Parker Brent , Schmid Matt , Batchelar Deidre , Araujo Cynthia , Hilts Michelle , Bachand Francois
Published: February 2017

106

Background: To demonstrate feasibility of using high dose rate (HDR) brachytherapy to deliver 25% higher than prescription dose to the dominant intra-prostatic lesion (DIL) as defined on multi-parametric MRI for intermediate and high risk prostate cancer. Methods: Twenty six patients with predominantly unilateral disease consented to a University Ethics-approved phase II study of selective dose escalation. HDR brachytherapy was performed in weeks 1 and 3 of treatment, each delivering one fraction of 10 Gy to the whole prostate. External beam consisted of 46Gy/23 fractions starting 3 days after the first HDR fraction.T2 FSE images were obtained using 1.5T endorectal MRI in transverse, sagittal and coronal planes followed by Dynamic Contrast Enhancement after injection of gadolinium. Apparent Diffusion Coefficient maps were calculated. The DIL was contoured on the MRI and, following image registration, transposed to the preoperative TRUS performed in the treatment position. Intra-operative TRUS with source-delivery catheters in place was fused to the pre-op TRUS with the transposed DIL. The DIL was included in dose optimization criteria. Results: Twenty five of 26 patients had a visible DIL. Mean prostate percentage receiving the prescription dose (V100) was 98.2% (SD:1.1). Mean dose to 90% of the DIL (D90) was 13.2 Gy (SD: 1.7). DIL mean volume was 2.9 cc (SD:1.8) representing 9.5% (SD: 7.6) of the prostate volume. Coverage of the DIL was excellent with a median of 97% receiving the planned escalation of 25%. Established dose constraints to rectum and urethra were respected in all cases. The factor that limited DIL coverage was proximity to organs at risk. Peri-urethral location of the DIL limited coverage in five cases and two had a posterior DIL such that dose to the rectum limited escalation. However, these seven cases still achieved a mean DIL D90 of 12.2 Gy. Conclusions: Dose manipulation using US-planned HDR brachytherapy is readily achievable within the practice setting of a community cancer center. Dose escalation to the DIL to a mean of 132% of the prescribed dose for selected intermediate and high risk prostate cancer patients is feasible while respecting critical organ constraints. Further escalation is planned. Clinical trial information: NCT01605097.
Androgen receptor independent acquired mechanisms of resistance to enzalutamide in castration-resistant prostate cancer.
Authors: Szmulewitz Russell Zelig , Kregel Steve , Isikbay Masis , Cai Yi , Chen James Lin , Vander Griend Donald J
Published: February 2017

129

Background: Enzalutamide (MDV3100) is a second generation androgen receptor (AR) antagonist with potent activity in the treatment of castration resistant prostate cancer (CRPC). However, most patients develop resistance and progression of disease; thus there is a critical need to identify novel targetable pathways mechanistically linked to this resistance. Methods: A panel of four prostate cancer cell lines (LAPC-4, LNCaP, VCaP, and CWRR1) was created each with a different AR status that are resistant to MDV3100 by culturing cells long-term less than 6 months in the drug at pharmacologic levels. The MDV3100 resistant (MDV-R) lines were assayed for proliferation, viability, resistance to docetaxel, and tumor take of subcutaneous xenografts. AR expression and ligand binding domain (LBD) DNA sequences were analyzed. Gene expression microarray comparison of resistant and non-resistant parental cell lines was performed. Prostate-specific antigen (PSA) and testosterone levels were analyzed from conditioned media. Results: Cell lines demonstrated heterogeneous growth characteristics.In vivo studies depicted increased or unaltered tumor take and growth in castrate athymic mice. In some cell lines growth was increased in vitro when drug was withdrawn; yet this growth was inhibited by physiological testosterone levels, both in vitro and in vivo. MDV-R cells remained sensitive to docetaxel in vitro and had increased levels of ARmRNA. However, total AR protein levels were lower or unchanged than the parental lines, with evidence for increased truncated forms of AR. The AR LBD acquired no new mutations. Secreted PSA was lower in all but one MDV-R line. Gene expression analyses demonstrated strong upregulation of IGFBP3 in all MDV-R cells. Pathway analysis implicated increased IGF and JAK/STAT signaling whereas mammalian target of rapamycin (mTOR) signaling was decreased. Conclusions: Although AR-mediated pathways contribute to enzalutamide resistance, a broader approach across several cell lines suggests that there may be even a greater contribution from pleiotropic, non-AR mediated mechanisms. Such mechanisms may include IGF signaling, JAK/STAT signaling and modulation of mTOR.
Identification of biologic and inflammatory markers for predicting clinical responses to sipuleucel-T in CRPC.
Authors: Hepgur Mehmet Faith , Dorff Tanya B. , Brining Lucy , Cai Jie , Pinski Jacek K. , Reed Mary , Luther Michael , Chan Betty , Quinn David I.
Published: February 2017

134

Background: Sip-T prolongs OS in asymptomatic or minimally symptomatic CRPC. We prospectively evaluated biomarkers in men receiving Sip-T to identify predictors of SDP and OS. Methods: Circulating tumor cells (CTC), PSA, prostatic acid phosphatase (PAP), albumin (Alb), hemoglobin (Hb), serum alkaline phosphatase (SAP), LDH, C-reactive protein (CRP) and β2-microglobulin (β2m) were evaluated in a reference lab. SipT product parameters, CD54, CD54 upregulation (UPREG) and total nucleated cells (TNC) were measured by Dendreon. Survival was evaluated using Kaplan-Meier estimates; univariate Cox regression was used to investigate the effect of biomarkers on SDP and OS using 2-sided tests and corrected for multiple comparisons. Results: 92 men who received Sip-T were included. Median age was 69 (48-90). The median follow-up was 14 (1.3 –34.7) mos, and 33% of men had died. 21 men developed SDP at a median of 5.7 (1-19) mos. Univariate analyses of biomarkers and product parameters are shown in the table. In multivariate analysis independent risks factors were LDH (p=.04) and β2m (p=.004) for SDP; LDH (p=.04), PSA (p=.012), age (p=.012) and UPREG (p=.006) for OS. Conclusions: CTC, CRP, LDH are associated with outcomes after Sip-T, similar to findings with hormone or cytotoxic therapy. Correlation of improved OS with low PSA and higher Hgb, albumin and Sip-T immune parameters supports the hypothesis that SipT is more effective with low disease burden. Prediction of early disease progression by β2m and LDH warrants further study. [Table: see text]
Urinary function after image-guided intensity modulated radiation therapy (IG-IMRT) of localized prostate cancer.
Authors: Obedian Edward , Zimberg Shawn H. , Kapoor Deepak A. , Olsson Carl A.
Published: February 2017

141

Background: Men choosing treatment for prostate cancer risk potential urinary dysfunction or incontinence. The purpose of this study was to determine the effect of high dose image-guided intensity modulated radiation therapy (IG-IMRT) on urine control and function in such men. Methods: Between March 31, 2008 and September 28, 2012, 3,602 men received high dose IG-IMRT for localized prostate cancer with sufficient data for review, including baseline and minimum 11 month follow-up evaluation of urine control and function. The latter were determined by a urinary continence grading questionnaire and the International Prostate Symptom Score (IPSS). These questionnaires were completed by all men prior to radiation (baseline) and at every follow up visit. The continence questionnaire separated patients as G0: no incontinence, G1: minimal incontinence not requiring pads, G2: incontinence requiring pads, and G3: incontinence interfering with daily life activities. Men with IPSS scores of 0 to 7 were deemed mildly, 8 to 19 moderately, and 20 to 35 severely symptomatic. Typical therapy was 8100 cGy delivered to the prostate in 45 fractions. Pelvic lymph nodes were treated in 13% (458) of the cases. Results: At baseline, incontinence grading in our 3,602 men was G0 in 3,086 (86%), G1 in 479 (13%) and G2/3 in 37 (1%) and IPSS was 0-7 in 2092 (58%), 8 to 19 in 1,276 (35%) and 20 or more in 233 (6.5%). After IG-IMRT, 2,635 (85%) of baseline GO men remained continent, 408 (13%) developed G1 incontinence and 43 (1.1%) developed G2/3 incontinence. Of 479 baseline G1 incontinent men, 259 (54%) improved to G0. Of 37 baseline G2/G3 incontinent men, 21 (57%) improved to G0/1 incontinence. In 2,092 mildly symptomatic men by IPSS (average 3.5 at baseline), there was a rise to 5.4 but 1,619 (77%) remained mildly symptomatic. In the 1,276 moderately symptomatic men at baseline the average IPSS (12) decreased to 9.8 at last follow up (p<0.001). Similarly, in the 233 severely symptomatic men at baseline the average IPSS (24) dropped to 13 at last follow up (p<0.001). Conclusions: Urinary incontinence following high dose IG-IMRT for prostate cancer is rare. IG-IMRT seems to improve some men with baseline urinary incontinence and higher IPSS scores. High dose IG-IMRT remains a good treatment option for localized prostate cancer.
PSA patterns during off-time treatment period in patients undergoing intermittent androgen deprivation: Is PSA doubling time reliable in every case?
Authors: Sanchez-Salas Rafael , Prapotnich Dominique , Ingels Alexandre , Olivier Fabien , Fhima Mehdi , Descamps Patrick , Stephane David , Secin Fernando P. , Barret Eric , Galiano Marc , Rozet Francois , Cathelineau Xavier
Published: February 2017

150

Background: Indicators such as prostate-specific antigen (PSA) nadir after the first on-treatment period (ONTP), off-phase interval duration and PSA doubling time (PSADT) were interpreted as potentially predictive, regarding outcomes of intermittent androgen deprivation (IAD). From actual PSA measurement data recorded on patients undergoing IAD during their off-treatment period (OFTP), we conducted a systematic analysis aimed at screening indicators and finely assessing their relevance as predictive candidates. Methods: Between 1992 and 2012, 727 patients with PC were selected for IAD at our institution. Three hundred ten patients had biochemical recurrence (BCR) after local treatment, 172 showed metastatic disease. ONTP consisted of three-month dose injections of gonadatropin-releasing hormone (GnRH) agonist combined with daily oral androgen receptor antagonist. OFTP was indicated when PSA was less than 4 ng/ml. Criteria for resumption of hormonal therapy were PSA more than 20 ng/ml or clinical symptoms. We tested two basic patterns of PSA behavior-exponential and power law (a<1) and combinations of them, on 597 patients with at least one completed OFTP based on four visits or more (population of the study). Results: We identified 597 patients with a total of 1,573 OFTPs. Median follow-up was 12,2 months (3,0-132,6). Median age at initiation was 76,7 (56,7 to 88,5); 811 OFTPs (51,6%) fitted with a pure exponential (r=0,01), whereas the other part (48,4%) followed more complex patterns (power law or two-steps or linear pattern). Mean cancer specific survival duration was 77,4 months (13,5 to 179,8). 5- and 10-year PC survival rate were respectively of 89,3% and 65,2% (CI 95%). Conclusions: Some OFTPs do not present an exponential pattern behavior: logarithmic calculation of PSADT is not suitable. PSADT determination should be adapted to the nature of the OFTP pattern. Through identification and analysis of the different types of OFTP, it is expected to improve the forecast of clinical outcomes.
Does adjuvant treatment affect survival in patients with positive lymph nodes at radical prostatectomy?
Authors: Harris Catherine R. , Cary Clint , Cowan Janet E. , Cooperberg Matthew R. , Carroll Peter
Published: February 2017

157

Background: Men who are found to have positive LN at the time of RP are at risk for worse prognosis and outcomes. Our purpose is to determine whether RT after RP has a greater survival benefit than ADT alone or surgery alone in these men. Methods: This study cohort consisted of men who had RP at the University of California, San Francisco. Men with positive pelvic LN were stratified by type of adjuvant therapy: ADT, RT with or without ADT, or RP only. T-test and chi-square were used to compare clinical and pathologic characteristics. Biochemical recurrence-free, metastatic recurrence-free, and disease-specific survival were assessed with the Kaplan-Meier method, log-rank test, and Cox proportional hazards regression. Biochemical recurrence was defined as two consecutive prostate-specific antigen values >=0.2ng/mL. Results: Of the 1,600 men had pelvic LN dissection at time of RP, 105 had positive LN. Mean age was 61 (SD 7). Median number of LN dissected was 14 (IQR 10-21) for pN1 patients versus nine (5 to 15) for pN0, p<0.01. Median percentage of positive LN was 11% (IQR 7-17). Men with positive LN had higher clinical risk and worse pathologic grade, positive margin rates, and T-stage compared to men without positive LN, all p<0.01. Recurrence-free survival was 55% for pN1 versus 81% for pN1 at 5 years, log-rank p<0.01. Following positive LN dissection at RP, 29 men received ADT monotherapy, 43 men received RT (+/- ADT), and 33 had not yet undergone treatment after RP during a median follow up of 28 months (IQR 6 to 70). Rates of seminal vesicle invasion by treatment group were 52% for ADT, 65% for RT (+/- ADT), and 35% for RP only, p=0.03. Men who underwent ADT alone, RT (+/- ADT), and RP only had few outcome events to date and similar rates of MFS (97% versus 93% versus 92%, p=0.76) and DSS (96% vs. 100% vs. 100%, p=0.32) at 3 years. Cox regression adjusted for surgical CAPRA score also showed that MFS and DSS did not differ between ADT alone, RT (+/- ADT), and RP only groups. Conclusions: Men with positive LN at the time of RP have aggressive clinical and pathologic features. Nevertheless, metastatic recurrence-free and prostate cancer-specific survival rates 3 years after surgery remain good. Although no additional survival benefit to post-RP RT was seen in this cohort of men with limited follow up, further follow up is ongoing.
The enzymology of the selective CYP17 lyase inhibitor, VT-464, and its effects in castration-resistant prostate cancer (CRPC) models.
Authors: Moore William R. , Maity Sankar N. , Eisner Joel Robert , Garvey Edward P. , Hoekstra William J. , Titus Mark Anton , Logothetis Christopher , Araujo John C. , Efstathiou Eleni , Schotzinger Robert J.
Published: February 2017

158

Background: CRPC typically responds to anti-androgen therapy but resistance is common. CYP17 inhibitors that block lyase (L) and not hydroxylase (H), do not require prednisone, and may delay tumor resistance are needed. VT-464 is an oral, non-steroidal inhibitor of CYP17 L in clinical development for CRPC. The present studies characterized: 1) the kinetic mechanism of VT-464 inhibition of h-CYP17 L and H, and 2) VT-464 effects compared to abiraterone acetate (AA) in CRPC models. Methods: CYP17 Enzyme Assays: r-h-CYP17 inhibition studies were conducted using substrates pregnenolone (for H) or 17-a-hydroxypregnenolone (for L). Product rates (17-a-hydroxypregnenolone (H) and DHEA (L)) were assessed by LC/MS/MS. Data were fit to inhibition models using SigmaPlot 11.2. In vitro CRPC studies: VT-464 and AA effects on AR transcription (luciferase) and PSA and NKX3.1 gene expression (QRT-PCR) were compared in C4-2B cells. Mouse xenograft model: Effects of oral VT-464 or AA on tumor growth and tumoral steroids (T, DHT, P) were compared in the MDA-PCa-133 castrate mouse model. Results: VT-464 was a reversible uncompetitive inhibitor of CYP17 L (Ki = 84 nM, K’i=200 nM) and a competitive inhibitor of H (Ki = 620 nM). VT-464 CYP17 L/H selectivity was 7.4 at low [S] but selectivity increased with increasing [S]. VT-464 L/H selectivity was 60-x greater than AA. In C4-2B cells VT-464 and AA inhibited AR transactivation but VT-464 suppressed PSA and NKX3.1 more potently than AA. In the xenograft model, VT-464 decreased tumor volume as effectively as AA. VT-464 more potently decreased T and DHT, while AA increased P. Conclusions: VT-464 demonstrated much greater CYP17 L selectivity than AA and equivalent or superior activity in several CRPC models. Less tumor resistance may arise from treatment with the CYP17 lyase-selective inhibitor VT-464 than with AA, since it more effectively blocked androgen biosynthesis, did not cause an accumulation of progesterone, and should not require co-administration of prednisone.
The effect of prostate brachytherapy technique on quality of life outcomes: 5-year outcomes of a prospective cohort study.
Authors: Talcott James Austin , Clark Jack A. , Manola Judith , Kaplan Irving D. , Zietman Anthony L. , D'Amico Anthony Victor
Published: February 2017

166

Background: Brachytherapy (BT) is widely used to treat clinically localized prostate cancer, but techniques vary and may affect patient outcomes. Methods: We prospectively studied three Boston-area patient cohorts who received different BT techniques: MRI guided, target volume avoids transition zone (MRBT) and two cohorts using standard imaging and planning techniques (USBT1 and USBT2). We surveyed patients pretreatment and at intervals after, using the validated PCSI scales for urinary incontinence (incont), obstruction/irritation (obstir) bowel problems, sexual dysfunction and the effect of incont on their lives (incontQOL). Based on early results showing increased acute urinary toxicity, USBT2 providers adopted an element of USBT1 technique. We report final 5-year follow-up. Results: Of 286 eligible patients, 73 MRBT patients and 190 USBT patients (99 USBT1 and 91 USBT2 patients) completed at least 3-month surveys. Patient differed by age (median: MRBT 65.3 years vs. USBT 68.3 p=0.005, USBT2 65.3 vs. USBT1 68.3 p=0.004) and education (MRBT 8%≤high school vs. USBT 23%, p<0.001) but other demographic and clinical variables were similar. MRBT patients had more pretreatment obstir symptoms and better sexual function pretreatment. USBT2 patients had greater increases in acute (3-month) obstir (28.8 vs. 20.0, p=0.01) and incont (12.2 vs. 7.1, p=0.01) than USBT1 but not bowel or sexual dysfunction, and all outcomes were similar at 5 years. Changing USBT2 technique eliminated the acute urinary differences. Compared to MRBT, USBT patients had greater increases in acute urinary morbidity (obstir 28.8 vs. 20.0, p=0.01; incont 9.6 vs. 2.2, p=0.002; incontQOL 10.2 vs. 2.4, p=0.0002) and long-term incontinence (incont 7.5 vs. 3.3, p=0.05; incontQOL 5.6 vs. 1.2, p=0.01). Other outcomes did not differ. Conclusions: QOL outcomes vary by BT technique. Measuring QOL may provide useful information for patients choosing treatment and providers assessing their technique. Clinical trial information: NCT00681694.
Prostatectomy at high- versus low-volume centers: A decision analysis.
Authors: Barzi Afsaneh , Klein Eric A. , Dorff Tanya B. , Quinn David I. , Sadeghi Sarmad
Published: February 2017

175

Background: Greater experience improves the oncological outcomes of radical prostatectomy (RP) for prostate cancer; however, it is not clear whether referring patients to a high volume center (HVC) for RP is cost effective. This study aims to investigate this question. Methods: We assumed status quo wherein 50% of RPs occur at an HVC and the other 50% occur in less experienced hands (scenario one or “referent scenario”). We then modeled increasing the share of RPs at an HVC by 10% increments (scenarios two, three, and four). Assuming that a lower probability of prostate-specific antigen recurrence (PSAR) is the only advantage of more experienced surgeons, the savings that would result from fewer recurrences, avoidance of salvage radiation therapy (SRT) and management of fewer men with metastatic cancer were calculated. A breakeven analysis using incremental referral costs and a cost effectiveness analysis (CEA), adding the incremental effectiveness measured in years in the no evidence disease (NED) state and the expected difference in overall survival (OS), were performed to determine the breakeven point and the range of the maximum referral costs to an HVC. Results: At five years 8.2% of patients will experience PSAR in the referent scenario versus 6.9% in scenario four. More patients would have PSAR in a low-volume center (LVC) setting after RP. Assuming 37% of these patients would receive SRT and those who will develop metastatic disease will receive treatment, this incremental cost discounted at 3% is $265, $456, and $609 per RP for scenario four at 5, 10, and 15 years, respectively. These figures will be $177, $309, and $415 and $86, $152, and $205 at 5, 10, and 15 years for scenarios three and two, repectively. Breakeven analysis shows that over 15 years, savings from referring patients to an HVC would offset up to $2,000 per RP in initial referral costs. This figure remains stable for scenarios two, three, and four. CEA shows that the range for maximum costs of referral assuming a willingness to pay of $50,000 per year are $4,300 to $23,700 at 15 years of follow up. Lower PSAR rates for LVCs, or using the lower SRT or treatment of metastasis costs result in smaller values for breakeven referral costs. Conclusions: Performing RPs at an HVC is associated with significant savings that offset the initial referral costs and may be cost effective beyond the breakeven point.
The effect of prior abiraterone (Abi) use on the activity of enzalutamide (Enza) in men with mCRPC.
Authors: Cheng Heather H. , Nadal Rosa , Gulati Roman , Azad Arun , Twardowski Przemyslaw , Vaishampayan Ulka N. , Agarwal Neeraj , Heath Elisabeth I. , Pal Sumanta Kumar , Rehman Hibba-tul , Leiter Amanda , Batten Julia Anne , Montgomery Robert B. , Galsky Matt D. , Chi Kim N. , Antonarakis Emmanuel S. , Yu Evan Y.
Published: February 2017

18

Background: Enzalutamide (Enza) and abiraterone (Abi) are next generation hormonal agents for metastatic castration resistant prostate cancer (mCRPC). Whether these agents can be effectively sequenced is not yet well understood. Results of retrospective analyses of Abi after prior Enza have demonstrated modest responses of brief duration, suggesting common resistance pathways. Here, we retrospectively analyze response to Enza with or without prior Abi treatment. Methods: We retrospectively reviewed 195 patients from seven academic centers treated with Enza between January 2009 and August 2013. Data were collected on disease characteristics, prior therapies, and prostate-specific antigen (PSA) values at baseline and while on treatment. Logistic regression was used to evaluate association between 30% or greater PSA decline on Enza and either prior Abi treatment or 30% or greater PSA decline on prior Abi after accounting for potential confounders. Results: One hudred eighty three patients had non-missing PSA starting and nadir values on Enza, with starting PSA median 102.0 (range 1.1–5007.0) ng/mL. Overall, 42% (76 of 183) of Enza-treated patients achieved a 30% or greater PSA decline, with 39% (58 of 150) response among prior Abi-treated patients and 55% (18 of 33) response among Abi-naïve patients. Of 79 patients who lacked significant response to prior Abi, 30% (25 of 79) achieved a 30% or greater PSA decline and 19% (15 of 79) achieved a 50% or greater PSA decline with subsequent Enza. Odds of achieving a 30% or greater PSA response on Enza was 2.3 times higher for Abi-naïve patients versus prior Abi-treated patients (95% CI 1.0–5.5, P=0.06) and 1.9 times higher for Abi-responders vs Abi-non-responders (95% CI 1.0–3.7, P=0.06) after adjusting for prior docetaxel and concurrent steroid use. Conclusions: In this multi-center retrospective study, 39% of patients achieved a 30% or greater PSA decline with Enza after prior Abi treatment. While the activity of Enza appears to be blunted in the post-Abi setting, PSA declines still occur in a meaningful proportion of patients. Notably, 30% of patients without significant response to prior Abi responded to subsequent treatment with Enza, suggesting a subset of men with distinct biological resistance pathways. Data will be updated at the time of presentation.
Diagnostic value of biparametric MRI as an adjunct to PSA-based detection of prostate cancer.
Authors: Rais-Bahrami Soroush , Siddiqui Minhaj , Vourganti Srinivas , Turkbey Baris , Rastinehad Ardeshir , Stamatakis Lambros , Truong Hong , Walton-Diaz Annerleim , Hoang Anthony N. , Nix Jeffrey , Merino Maria , Wood Bradford J. , Simon Richard , Choyke Peter L. , Pinto Peter A.
Published: February 2017

193

Background: To determine the diagnostic yield of analyzing a fast, cost-conscious biparametric (T2 and diffusion-weighted) MRI (B-MRI) for prostate cancer (PCa) detection as an adjunct to to standard digital rectal exam (DRE) and prostate specific antigen (PSA)-based screening. Methods: Review of patients who were enrolled in a trial to undergo MP-MRI and MR/US fusion-guided prostate biopsy at our institution identified 143 men who underwent MP-MRI in addition to standard DRE and PSA-based PCa screening prior to any other prior prostate biopsy sessions. Patient demographics, DRE staging, PSA, PSA density (PSAD), and B-MRI findings were assessed for association with PCa detection on biopsy. Results: Men with detected PCa tended to be older, with higher PSA, higher PSAD, and increased number of screen positive lesions (#SPL) on B-MRI. B-MRI performed well for the detection of PCa with an area under the curve (AUC) of 0.80 (compared to 0.66 and 0.74 for PSA and PSAD). We derived PSA and MRI-based combined screening formulas for detection of PCa with optimized thresholds. (1) for PSA and B-MRI: PSA + 6 x (#SPL) > 14 and (2) for PSAD and B-MRI: 14 x (PSAD) + (#SPL) > 4.25. Area under the curve for equations 1 and 2 were 0.83 and 0.87 and overall accuracy of PCa detection was 79% in both models. Furthermore, the model integrating PSA with #SPL on B-MRI, was much more efficient at maximally identifying men with Gleason 7 or higher disease compared to PSA-screening alone. Use of model combining PSAD and MRI, the number of bGS 7 or higher cancers that were missed was minimized. Overall, combined use of PSA or PSAD coupled with B-MRI #SPL improved the true positive yield of identifying men with bGS 7 or higher while minimizing the false positive number of men identified as “screen-positive,” but with no cancer on biopsy. Conclusions: Number of positive lesions on B-MRI outperforms PSA alone in detecting PCa, supporting the use of this limited, non-contrast MRI as a potential adjunct tool in PCa screening. Furthermore, this imaging criteria coupled as an adjunct with PSA and PSAD, provides even more accuracy in detecting clinically-significant PCa.
Epigenetic profiling of prostate cancer tissue to identify men with high-risk disease.
Authors: Van Neste Leander , Falk Jeffrey , Lee Ming-Chou , Bigley Joseph , Van Criekinge Wim , Crawford E. David
Published: February 2017

197

Background: Prostate cancer (PCa) prognosis and aggressiveness are guided by Gleason Scores (GS). Moreover, biopsied prostate tissue might not be representative of the actual disease. Epigenetics could provide a quantitative method for confirming or upgrading disease status obtained by GS, providing additional information with regard to aggressiveness. Methods: Eighty-four prostatectomy samples from PCa patients with GS6 (n=6), GS3+4 (n=41), GS4+3 (n=26) and GS greater than or equal to 8 (n=11) were epigenetically profiled, for GSTP1, APC, RASSF1, RARB, and GAL3 methylation, using methylation-specific PCR. Unsupervised hierarchical clustering, based on Ward’s method, was performed to discover an association between DNA-methylation patterns and GS. Methylation ratios were scaled across all samples by calculating, per gene, a Z-score. Results: Hierarchical clustering analysis resulted in three distinct clusters. One cluster with a relative, general depletion of methylation, a second cluster with high methylation levels for most genes, particularly for RARB, and a third cluster exhibiting intermediate methylation signals and lower, but distinct, RARB methylation. Kendall’s rank correlation tau indicated a significant positive correlation between GS and methylation levels of all five genes, with tau ranging from 0.010 to 0.376 (all p values<0.05). Methylation levels of all five genes were significantly lower in the samples with GS less than or equal to 3+4 versus those with GS greater than or equal to 4+3 (all p values<0.05). Clustering showed that 100% of the GS6 and 80% of the GS3+4 patient’ samples were associated with low methylation signals. In contrast, 81% and 82% of the GS4+3, and GS greater than or equal to 8 samples respectively, fell into the category with intermediate to high methylation levels. Conclusions: Methylation levels of all genes correlated with GS and were significantly lower in patient' samples with GS6 and GS7 (3+4) compared to GS7 (4+3) and GS greater than or equal to 8. This study shows that epigenetic profiling of selected genes has prognostic value and may help to identify patients with aggressive PCa.
CK- and small nuclear size circulating tumor cell (CTCs) phenotypes in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ferraldeschi Roberta , McDaniel Andrew , Krupa Rachel , Louw Jessica , Tucker Eric , Bales Natalee , Marrinucci Dena , Riisnaes Ruth , Mateo Joaquin , Dittamore Ryan , De Bono Johann Sebastian , Tomlins Scott A. , Attard Gerhardt
Published: February 2017

209

Background: Circulating tumor cell (CTCs) are traditionally defined as EpCAM/CK+ cells, CD45-, and morphologically distinct. However, recent evidence suggests that other populations of CTC candidates exist including cells that are EpCAM/CK- or smaller in size than traditional CTCs. CTC positive selection techniques that isolate CTCs based on size, density, or EpCam positivity may miss subpopulations. We aimed to molecularly characterize novel CTC candidates utilizing the Epic Sciences platform, which performs no physical selection. Methods: Blood from 10 healthy volunteers (HV) and 39 patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) were collected and shipped to Epic Sciences, where all nucleated cells were plated onto glass slides and subjected to immunofluorescence (IF) staining and CTC identification by fluorescent scanners and algorithms. Traditional CTCs were identified as CK+CD45- cells with intact DAPI nuclei and after pathologist review of their morphology. Candidate CK- CTC populations were identified as CK-CD45- that were morphologically malignant. Small nuclear size candidate CTCs were identified as CK+CD45- cells with diameters similar to or smaller than that of a typical white blood cells (WBCs). All candidate CTC were evaluated with prostate cancer relevant biomarkers, including androgen receptor (AR) by IF and PTEN loss and ERG rearrangements by FISH. Results: Thrity eight out of 39 pts had one or more traditional CTCs/mL and 36 out of 39 pts had one or more CK- CTCs/mL of blood. Eight out of 39 samples had more than 10 CK- CTCs/mL. Fifteen out of 39 samples had evidence of small nuclear size CTCs at varying incidences and sizes of cells. We observed PCa biomarkers including high AR expression, PTEN deletion, and ERG rearrangements in both CK- and small nuclear size CTCs. These features were not observed in over 1,000 WBCs evaluated and HV. Conclusions: Candidate CTC that are CK-CD45- and/or with a small nucleus are identified on the Epic Sciences platform in blood from mCRPC pts. Studies are ongoing to determine their clinical relevance.
Physician referral patterns among men with advanced prostate cancer.
Authors: Yong Candice , Onukwugha Ebere , Mullins C. Daniel , Abdulhalim Abdulla M. , Qian Yi , Arellano Jorge , Balakumaran Arun , Liede Alexander , Hussain Arif
Published: February 2017

211

Background: Among men diagnosed with localized prostate cancer (PC), the type of specialist visited has been shown to influence the type of treatment regimen prescribed. There is limited data on referral patterns among men diagnosed with advanced PC. The objective of this study was to characterize referral patterns across physician types who treat men with stage IV nonmetastatic (M0) and metastatic (M1) PC. Methods: Using the linked US SEER (Surveillance, Epidemiology, and End Results) and Medicare database, we identified men aged 66 or older who were diagnosed with incident stage IV M0 or M1 PC between 2000 and 2007. We evaluated patterns of the first and second type of physicians visited after diagnosis of PC for men with visits to the following physician types: urologist, medical oncologist (medonc), radiation oncologist (radonc), or primary care physician (PCP). Results were stratified by M0 and M1 disease. Results: We identified 9,826 men with stage IV PC (median age=77 years). Of these 9,826 men, 8,736 (89%) visited at least two physician types (93% among men with M0 and 87% among men with M1). Across the physician types of interest, 94% of men initially visited a urologist (52%) or PCP (42%). Among men who visited a urologist first, most were referred to a PCP, while smaller percentages were referred to a medonc or radonc (Table). Among men who saw a PCP first, most were referred to a urologist next; smaller proportions were referred to a medonc or radonc. Men with M1 PC had more referrals to medonc and fewer referrals to radonc than men with M0 PC. Conclusions: In this analysis of nearly 10,000 men aged 66 or older with stage IV PC in the US, most men initially visited a urologist or PCP regardless of whether or not they had distant metastasis. Based on the patterns observed, the most frequent referral pattern occurred between urologists and PCPs. More referrals to a medonc were evident if the men had M1 disease. [Table: see text]
Pain palliation as an oncology label indication: Lessons learned in custirsen phase III development.
Authors: Beer Tomasz M. , Hotte Sebastien J. , De Bono Johann Sebastian , Beuzeboc Philippe , Gabrail Nashat Y. , Cain Daniel , Jacobs Cindy , Fizazi Karim
Published: February 2017

222

Background: Durable pain palliation (dPP) in metastatic castrate-resistant prostate cancer (mCRPC) is a measure of clinical benefit suitable for a label indication. A randomized, double-blind, placebo-controlled, phase III study developed with FDA under a Special Protocol Assessment (SPA) compared custirsen/taxane (cust/tax) to placebo/taxane (plac/tax) as second-line chemotherapy for patients (pts) with mCRPC with disease progression during or after first-line docetaxel. Primary efficacy was 12-week or more dPP. Other endpoints included overall survival (OS), serious adverse events (AEs), and ≥Gr 3 AEs. Methods: Patients were randomized (1:1) to second-line taxane (docetaxel retreatment or cabazitaxel; based on prior docetaxel response, progression) + 640 mg custirsen or placebo. Eligible pts had to have baseline stable pain on consistent opioid-analgesic regimen. With a one-sided alpha of 0.025, power of 90%, and estimated difference in proportion of 25% vs. 10% dPP, the trial required 292 pts. Results: Trial was activated at a total of 62 sites and was stopped after 20 months (mo) with only 35 pts screened/14 pts enrolled. Requirements for baseline stable pain/analgesic use proved too restrictive to complete enrollment. Demographics were comparable. Prior response to first-line docetaxel occurred in 93% pts. Disease progression after first-line docetaxel based on bone scan (n=10) or prostate-specific antigen (n=4); median time from end of first-line to progression one mo. Treatment of a median thre cycles plac/tax arm compared to six cycles cust/tax arm. Three pts achieved dPP (n=1 [14%] plac/tax; n=2 [29%] cust/tax). Median OS (95% CI) was 7.8 (3.2, 11.5) mo plac/tax vs. 11.8 (9.8, 15.7) mo cust/tax. AEs greater than or equal to Gr 3 reported for two pts or more included: back pain (0 plac/tax; 2 cust/tax), hyperesthesia (0,2), asthenia (2,1). Serious AEs reported for nine subjects (4,5). Only serious AE reported in more than 1 pt was hyperesthesia, leading to study discontinuation (0, 2). Conclusions: Enrollment was not feasible due to restrictive trial criteria of stable baseline pain/consistent analgesia, which were too difficult to achieve. Thus, a survival based study has been launched and is recruiting, with monitoring of pain/analgesic use. Pragmatic criteria for oncology pain studies are needed. Clinical trial information: NCT01083615.
Dehydroepiandrosterone metabolism in fresh human prostate: A feasibility study.
Authors: Ercole Cesar E. , Chang Kai-Hsiung , AboAli Ghada , Magi-Galluzzi Cristina , Stephenson Andrew J. , Klein Eric A. , Sharifi Nima
Published: February 2017

225

Background: Understanding adrenal androgen metabolism in the prostate provides the opportunity to better define mechanisms of resistance for patients with prostate cancer. This is especially important with men who have a recurrence after their initial treatment (e.g., surgery or radiation) and are subsequently treated with androgen deprivation therapy by chemical or surgical castration. Unfortunately, these patients tend to progress to castrate resistant prostate cancer. With the contribution of adrenal androgens in mind, we sought to determine the feasibility of characterizing the metabolites of dehydroepiandrosterone (DHEA) in the human prostate. Methods: With institutional review board approval, tissue procurement occurred via the Department of Pathology at the Cleveland Clinic. We obtained prostate tissue from patients immediately after radical prostatectomy. The tissue was processed in culture withserum free medium in triplicate and was treated with tritiated-DHEA ([3H]-DHEA; 100 nM, 300,000–600,000cpm; PerkinElmer). Media was collected at specific time intervals (6, 24, 48, and 72 hours). Once all the time points were collected, they were treated with a β-glucuronidase and steroids were extracted. These samples were processed and analyzed with high-performance liquid chromatography (HPLC) and a radioactivity detector for comparison with known standards (DHEA, androstenedione, 5α-androstanedione, testosterone, and dihydrotestosterone). Results: Evaluation of the HPLC tracings showed metabolism of [3H]-DHEA to downstream androgen products and correlated with standard peaks. These tracings were reproducible and consistent with each sample’s triplicate and from specimen to specimen. Conclusions: It is feasible to consistently determine the products of DHEA metabolism in fresh prostate tissues. By obtaining a better understanding of how androgen metabolites are formed we can dissect how response and resistance to hormonal therapy are regulated.
Primary care physician (PCP) referral patterns for prostate cancer (PC) patients: Web-based survey.
Authors: Sunkara Rajitha , Lele Uday , Soyano Aixa , Kozyreva Olga
Published: February 2017

228

Background: Prostate cancer (PC) is the most common cancer and second most common cause of cancer related death in men. The therapeutic options for PC patients are rapidly expanding making treatment decisions more complex. For patients with high-risk PC, significant body of evidence demonstrates that multidisciplinary approach improves outcome. PCP has a major role in early detection, provision of counseling, appropriate referral and management of metabolic side effects (SE) of androgen deprivation therapy (ADT). We conducted a survey among PCP’s to understand their referral patterns. Methods: We emailed a 10 question web based survey to around 300 practicing PCP’s in the Boston area. Of them, 56 responded. We analyzed the responses using independent t test for demographics and ANOVA for years of experience of the individual physician. Additional multivariate analysis was done using all independent variables together. Results: 30.3% of the physicians never feel the need to refer a newly diagnosed prostate cancer patient to a medical oncologist (MO). 60.8% of the PCP’s anticipate that urologist should refer the patients to a MO. Only 9% of PCP’s feel responsible for managing the SE of ADT. 46.4% anticipate urologist and 44.6 % anticipate oncologist to manage the SE of ADT. Female physicians appear to be more comfortable in providing counseling to the newly diagnosed PC patients than the male physicians (P=0.001). Male physicians and US medical graduates tend to refer to the MO most often than the female physicians and foreign medical graduates (P=0.013 and p=0.015 respectively). On multivariate analysis US medical graduates with higher years of experience are more comfortable providing the counseling and discussion of newer treatment options for a newly diagnosed PC (p=0.011 and 0.016 respectively). Overall 44.6% are not aware of newer treatment options for castration resistant PC. Conclusions: In the era of expanding armamentarium of treatments for PC, our results indicate the need to increase the awareness of PCP’s regarding the available treatments and emphasize the importance of multidisciplinary approach to better serve the PC patients with appropriate and timely referrals.