bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of neoadjuvant hormone therapy on the permanent 125I-seed brachytherapy for low- or intermediate-risk prostate cancer.
Authors: Tanimoto Ryuta , Bekku Kensuke , Ebara Shin , Araki Motoo , Yanai Hiroyuki , Katayama Norihisa , Nasu Yasutomo , Kumon Hiromi
Published: February 2017

201

Background: To determine whether neoadjuvant hormonal therapy improves the biochemical outcome for men with low or intermediate risk prostate cancer and undergoing permanent brachytherapy.

Methods: From January 2004 to April 2011, 449 patients with low-risk (221 men) or intermediate-risk (228 men) based on NCCN guideline underwent transperineal ultrasonography-guided permanent 125I-seed brachytherapy. Of these patients, 186 received neoadjuvant hormonal therapy (NHT). The median patient age was 67 years. The median follow-up (SD) was 48 (20) months (calculated from the day of implantation). Biochemical disease-free (BDF) survival was defined using Phoenix definition. The clinical variables evaluated for BDF survival included presence of NHT, Gleason score, clinical T-stage and pretreatment PSA.

Results: For all patients, the 1, 3, 5-year actuarial BDF survival rates were 99.2%, 96.2% and 90% without NHT, 100%, 97.2%, 91.0% with NHT (p=0.954). When stratified by risk group, NHT did not improve the outcome for patients at low risk (P = 0.745) or at intermediate risk (P = 0.888). The duration (<= 5 vs >5 months) or combinations (single vs combined androgen blockade) of hormonal therapy were not statistically significant in predicting biochemical recurrence. In a multivariate analysis (shown below), only the Gleason score was a strong predicting factor, while NHT as well as pretreatment PSA, T stage were insignificant.

Conclusions: In patients treated by permanent prostate brachytherapy, NHT did not improve the biochemical outcome for those at low-risk or intermediate-risk features. Furthermore, the duration or combinations of hormonal therapy conferred no additional biochemical advantage.

[Table: see text]
Injection of hyaluronic acid (HA) to better preserve the rectal wall in prostate hypofractionated radiotherapy (HFR).
Authors: Chapet Olivier , Udrescu Corina M , Ruffion Alain , Sotton Marie-Pierre , Devonec Marian , Vincent Marion , Zahra Nabil , Mazzara Christophe , Colombel Marc , Azria David , Jalade Patrice
Published: February 2017

202

Background: Several studies are in favor of an α/β ratio of less than 3Gy for prostate (P) cancer, encouraging HFR. However, the development of such radiation patterns can only be done if the risk of rectal toxicity is well controlled. The objective of the present study was to evaluate the contribution of an injection of HA between the rectum and the P to reduce the risk of rectal toxicity in a HFR approach.

Methods: A phase II study of HFR at 62Gy in 20 fractions (BED = 84Gy; α / β = 1.5Gy) is currently conducted. A transperineal injection of 10cc of HA (NASHA Spacer gel, Q-Med AB, Uppsala, Sweden) is systematically performed, between the rectum and the P, under local anesthesia and under ultrasound guidance. A dosimetric CT scan is performed before (CT1) and after injection (CT2). Patients are treated with a 7 beams IMRT plan, optimized on the CT2. For the first 10 patients included in the study, the same treatment plan was optimized on CT1. The rectum was empty on the 2 CTs and defined from 2cm above the seminal vesicles to 2 cm below the P. The rectal wall was defined by an internal expansion of 5 mm. The volumes of rectum irradiated, with and without HA, were compared on the following dosimetric parameters: maximum dose (D max), dose to 2.5cc (D2.5), 5cc (D5) and 10cc (D10) of rectal wall and volume of rectum receiving 90% (V90), 80% (V80) and 70% (V70) of the prescribed dose of 62Gy. To limit a potential impact of variation of rectal volume between the two CT, all results are given in cc and not in % of volume.

Results: The mean P volume was 52.4cc (30cc - 93.8cc) on the CT1 and 52cc (32.5 - 92.7) on the CT2. The injection of HA reduced the mean D max value to the rectal wall of 4.5Gy (57.5Gy vs 62 Gy). The mean values of V90, V80, and V70 are reduced by 69% (1.9cc vs 6.1cc), 46% (4.5cc vs 8.4cc) and 32% (7.4cc vs 10.9cc). Same way, the average values of D2.5, D5 and D10 are reduced by 6.2 Gy (54.6Gy vs 60.8Gy) 9.3Gy (49.0Gy vs 58.3Gy) and 7.8Gy (39.7Gy vs 47.5Gy).

Conclusions: In this study, the injection of HA limited the doses to the rectal wall. These results suggest that late toxicities could be significantly reduced. A phase II study is underway to assess the rate of late rectal toxicities when a HFR at 62Gy in 20 fractions is combined with an injection of HA.
Does salvage radiation therapy (SRT) change the biology of recurrent prostate cancer (PCa) based on PSA doubling times (PSADT)? Results from the SEARCH database.
Authors: Muller Roberto Lodeiro , Presti Joseph C. , Aronson William J , Terris Martha K. , Kane Christopher J , Amling Christopher L , Freedland Stephen J.
Published: February 2017

203

Background: SRT offers a second opportunity for PCa control after biochemical recurrence in men treated with radical prostatectomy. Although some retrospective data suggest an overall survival benefit, we hypothesized that in men with radio-resistant tumors, SRT may indeed promote transformation to a more aggressive cancer due to radiation-induced mutations. To test this, we used PSADT as a surrogate for cancer aggressiveness and compared PSADT before and after SRT in men who failed SRT.

Methods: Of 288 men who underwent SRT in the Shared Equal Access Regional Cancer Hospital (SEARCH) database since 1988, we detected 78 with SRT failure defined as PSA ≥ 0.2 ng/mL above the post-SRT nadir. Of these, 44 had PSADT available before and after SRT, which was compared using Wilcoxon’s paired test with men serving as their own controls. We also tested predictors of PSADT change using multivariable logistic regression.

Results: There were no differences in PSADT before and after SRT (10.6 vs. 12.2 months; P=0.85). However, in some individual cases large changes were observed. Only seminal vesicle invasion showed a trend towards an association with a shorter post-SRT PSADT relative to the pre-SRT PSADT (P=0.067).

Conclusions: Overall, the PSADT after and before SRT were statistically similar suggesting that after SRT failure, PCa does not emerge with more aggressive biologic features. Further studies are needed to identify predictors and the clinical relevance of individual PSADT changes noted in our study. (Note: Authors R. L. Muller and S. J. Freedland received support from DoD Award Number W81XWH-10-1-0155).
Prostate MRI/ultrasound fusion and biopsy yield.
Authors: Margolis Daniel , Kumar Dinesh , Macairan Maria Luz , Narayanan Ram , Natarajan Shyam , Gandhi Nishant , Shaw Gregory , Marks Leonard S.
Published: February 2017

206

Background: MRI has been shown useful for identifying targets after negative biopsy. We purport to show the advantage of realtime fusion of MRI data with ultrasound for initial or repeat TRUS biopsy compared with sextant biopsy.

Methods: An IRB-approved prospective study of 57 consecutive men with diffusion weighted imaging and dynamic contrast enhanced (DCE) perfusion in addition to T2-weighted imaging on a Siemens Magnetom 3.0 T Trio using an external phased array coil had targets chosen based on decreased T2 signal with abnormally restricted diffusion or abnormal DCE by a uroradiologist with 6 years experience in prostate imaging, followed by ultrasound-guided biopsies using MR/ultrasound fusion software (Artemis, Eigen) in addition to standard 12-core sextant biopsies.

Results: In 56 patients, 101 suspicious areas were identified by MRI; 28 positive targets were found in 22 men, including 19 Gleason 3+3 (68%), 8 Gleason 3+4 (29%), and one with HGPIN (3%). In 28 patients, neither targets nor systematic cores were positive, and in one patient no targets were identified. Positive cores were found in 12 patients only on targets only including 6 Gleason 3+4. One patient was “upstaged;” the target was Gleason 3+4 whereas the positive systematic cores were Gleason 3+3. In 8 patients the Gleason score of systematic and targeted cores was identical, 2 Gleason 3+4 and 6 Gleason 3+3. In 7 patients systematic cores were Gleason 3+3 with negative targets, all less than 4 mm and less than 25 percent of the core. Fisher exact test showed a trend to significance, p = 0.06 for any cancer identified, and p = 0.03 for Gleason 3+4 disease.

Conclusions: The improved accuracy of MRI-TRUS fusion biopsies may be able to replace systematic biopsies, avoiding the discomfort and risks associated, and improve diagnostic yield, and improve confidence for patients with a small amount of low-grade cancer who opt for active surveillance.
TNF-α deficiency as protection against sickness behavior related to external beam radiation of the pelvis in mice.
Authors: Chennupati Sravana K , Siddiqui Faisal A , McDonald Tasha L. , Thomas Charles R. , Hung Arthur , Wood Lisa J
Published: February 2017

208

Background: Prostate cancer patients undergoing localized external beam radiation therapy (EBRT), experience significant fatigue during treatment, which can affect physical functioning and QOL. We hypothesize that cancer treatment related fatigue (CTRF) is the same as sickness behavior caused, in part, by increases in TNF-α. Our previous data demonstrate that pelvic EBRT induces systemic increases in TNF-α and a decline in voluntary wheel running activity (VWRA) , an objective measure of sickness in mice. A specific aim of this study was to determine the requirement of EBRT for TNF-α for the induction of sickness behavior.

Methods: Daily VWRA was monitored in male WT (n=10) and TNF-α−/− (n=10) anesthetized mice undergoing pelvic EBRT at 4.6 Gy/fraction, 5 days per week for 15 fractions for a total dose of 69 Gy [4.6 X 15 = 69, not 70]. Control WT (n=10) and TNF-α−/− (n= 10) mice underwent anesthesia followed by sham EBRT. The effect of treatment on weight and food intake was also determined by calculating change in weight and daily food intake during treatment. A 2 x 2 repeated measure analysis of covariance ANCOVA was used to determine whether there was a significant interaction between treatment group (EBRT or Control) and genotype (WT or TNF-α−/−) on voluntary wheel running activity controlling for baseline differences in this variable. Similarly a 2 x 2 ANOVA was used to determine whether there was a drug x genotype interaction between change in body weight or food intake.

Results: There was a significant effect of EBRT on VWRA (p< 0.001), food intake (p0.002), and weight (p<0.001). We did not however observe a significant interaction between EBRT and genotype in VWRA (p= 0.756), food intake (p=0.654), or weight (p= 0.450).

Conclusions: Targeting TNF-α using specific cytokine blocking agents has been suggested as a potential strategy for preventing or managing EBRT related fatigue. Although our prior data support that localized EBRT to the pelvis may induce TNF-α and sickness behavior in mice, our latest data do not support a direct role for this cytokine in mediating these effects.
Inhibition of 3β-hydroxysteroid dehydrogenase by abiraterone as a rationale for dose escalation in castration-resistant prostate cancer.
Authors: Sharifi Nima , Li Rui , Evaul Kristen , Sharma Kamalesh , Auchus Richard J
Published: February 2017

209

Background: Treatment with abiraterone acetate (abi) increases the survival of men with castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to up-regulation of steroidogenic enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone (DHT), which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. The 1000 mg daily abi dose was selected for the phase III trials despite the absence of dose-limiting toxicities at higher doses. Based on the 3β-hydroxyl, Δ5-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for the intratumoral synthesis of DHT in CRPC, regardless of origins or routes of synthesis.

Methods: We tested if abi inhibits recombinant 3βHSD2 activity in vitro or endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), androgen receptor (AR) nuclear translocation, expression of AR-responsive genes, and LAPC4 xenograft growth in orchiectomized mice supplemented with DHEA.

Results: Abi has a mixed inhibition pattern of 3βHSD2 in vitro, blocks the conversion from DHEA to AD and DHT with an IC50 of < 1 µM in CRPC cell lines, inhibits AR nuclear translocation and expression of TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented mice.

Conclusions: Abi blocks 3βHSD enzymatic activity, synthesis of AD and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at concentrations that are clinically achievable. Variable abi inhibition of 3βHSD might account in part for the heterogeneous clinical response to abi. More importantly, 3βHSD inhibition with abi might be clinically harnessed to reverse resistance to CYP17A1 inhibition at the standard dose by dose-escalation, or simply by administration with food to increase drug exposure.
Use of total illness burden index for prostate cancer (TIBI-CaP) to predict nonprostate cancer morbidity.
Authors: Liss Michael Andre , Osann Kathryn , Moskowitz Ross , Kaplan Adam , Billimek John , Greenfield Sheldon , Dash Atreya
Published: February 2017

215

Background: Comorbidities significantly influence how physicians approach the treatment of prostate cancer and should be evaluated prior to the prostate biopsy. The Total Illness Burden Index for Prostate Cancer (TIBI-CaP) patient questionnaire and Charlson Comorbidity Index (CCI) usually calculated by the physician, may provide information on competing risks but have not been compared prospectively.

Methods: A prospective observational cohort study was performed of 133 participants prior to obtaining a transrectal ultrasound guided prostate biopsy. Eleven patients had incomplete data or missing follow-up; therefore, a total of 122 (92%) patients were retained for a mean of 21 months (range 4 – 31 months). The TIBI-CaP and CCI scores were compared between subgroups defined by non-elective hospital admission, elective surgery, non-prostate malignancy and survival status using t-tests.

Results: Patients averaged 64.5 years at enrollment. One patient died in the study from a metastatic sarcoma. The overall hospital admission rate was 17% (21/122), most commonly from cardiovascular or pulmonary complications. Forty-six men (38%) were diagnosed with cancer on the prostate biopsy. The most common treatments were prostatectomy (39%), active surveillance (26%), or external beam radiation therapy (20%). Twenty-three percent (28/122) had elective surgery and 5% (6/122) were diagnosed with a non-prostate malignancy. Mean TIBI-CaP scores were higher in men who were admitted to the hospital (5.1 vs. 3.5, p=0.03), had elective surgery (4.8 vs. 3.4, p=0.05) or non-prostate cancer (5.5 vs 3.7, p=0.17). No significant differences were observed in CCI scores In stepwise logistic regression, a TIBI-CaP score > 5.0 was associated with 3.5 times higher risk for hospital admission (95% CI: 1.3–10.0, p=0.02).

Conclusions: The patient-reported measure of comorbidity (TIBI-CaP) identified patients at high risk for non-elective hospital admission over at 20 month average follow up period and may aid medical decision making specifically in the prostate biopsy population better than that of the Charlson Comorbidity Index.
Active surveillance for low-risk prostate cancer: Practice across Europe.
Authors: Azmi Aini , Dillon Ruth , Marignol Laure , Borghesi Simona , Dunne Mary , Power Richard , O'Neill Brian
Published: February 2017

217

Background: Active surveillance (AS) is a recognized treatment option for patients with low-risk prostate cancer (PCa). We carried out a web-based survey to evaluate how AS is practiced by European urologists and to review criteria for patient selection, follow up and indications for intervention.

Methods: 2959 potential participants were identified via various European urological association databases and invited via email to complete an online survey consisting of 19 questions. Only urologists practising in an EU country were eligible to participate.

Results: 226 urologists participated in the survey corresponding to a response rate of 8%. None of the 19 questions were answered by all urologists, therefore results exclude the missing data. 220 (97%) urologists offer AS. 48% (n=103/216) and 24% (n=53/216) urologists offer AS within the context of an official protocol or clinical trial respectively. The most used factors in selecting patients are Gleeson score (GS) ≤3+3=6 (n=174/202, 86%) and PSA ≤10ng/ml (n=171/200, 85%). 48% (n=96/201) only include patients with ≤2 cores positive while 18% (n=37/201) include those with <50% positive biopsy cores. 41% urologists (n=82/202) only include patients with a clinical stage ≤T1cN0M0. MRI pelvis is performed as a baseline investigation by only 28% (n=57/200). All responding urologists (n=194) use serial PSA to follow up their patients. 89% (n=172/194) carry out serial DRE while 83% (n=161/194) perform repeated prostate biopsy. Re-biopsy is performed within the first year of AS by 77% of urologists (n=131/171). Only 8% (n=15/193) use serial MRI pelvis to monitor their patients. The follow up intensity also varies widely. GS progression was the most frequently cited trigger for intervention (n=168/192, 87%) followed by PSA doubling time of ≤3 years (n=115/192, 60%).

Conclusions: Several internationally published guidelines on PCa treatment have recommended AS as a therapeutic option for patients with low-risk PCa. However presently there is a lack of consensus on an optimal AS protocol. This survey shows the wide variation in the practice of AS across Europe and highlights the need for patients to be included in clinical trials to enable an evidence-based guideline to be established.
Bowel and bladder toxicity patterns in patients with prostate cancer treated with proton beam versus intensity-modulated radiation therapy.
Authors: Gray Phillip J. , Paly Jonathan J. , Sanda Martin G. , Sandler Howard Mark , Michalski Jeff M. , Talcott James Austin , Coen John , Shipley William U. , Zietman Anthony L. , Bekelman Justin E. , Efstathiou Jason Alexander ,   The PROST-QA Consortium
Published: February 2017

22

Background: Limited data exist comparing contemporary technologies in the treatment of prostate cancer. Proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT) are both accepted ways of delivering high-dose radiation. We evaluated patient-reported quality of life (QOL) outcomes from two modern prospective cohorts treated with either PBT or IMRT.

Methods: QOL data for 153 patients treated with IMRT and collected by the PROST-QA consortium using the Expanded Prostate Cancer Index Composite instrument were compared to data for 95 patients treated on protocol between 2004 and 2008 at the Massachusetts General Hospital with PBT using the Prostate Cancer Symptoms Index instrument. Mean score changes from baseline were compared using the Satterthwaite t-test. Clinically meaningful decline was defined as a score drop exceeding half the standard deviation of the baseline value.

Results: Both cohorts had a similar distribution of Gleason score and baseline PSA though the IMRT cohort was older (median age 69 vs. 64, p<.0001). Treatment dose range was 75.6-79.2 Gy for IMRT and 74-82 CGE for PBT. Neither group received hormonal therapy. By 3 months after treatment there was a significant worsening in the bowel domain for the IMRT but not PBT cohort (15.9 point reduction vs. 1.5, p<.0001) which normalized by 12 months. Post-treatment scores were also lower in the urinary irritation domain (13.8 point reduction vs. 5.5, p<.0001) and in the urinary incontinence domain (7.3 point reduction vs. 1.5, p=.002) for IMRT but were similar by 24 months. All immediate post-treatment score changes in the IMRT but not PBT cohort were clinically meaningful. A steady decline in the sexual function domain was seen in both groups but the difference was not significant.

Conclusions: In this non-randomized comparison using two validated QOL instruments measuring similar domains, PBT appears to be associated with lower gastrointestinal and urinary toxicity early after treatment with similar late outcomes. While subject to selection bias, these preliminary data suggest transient differences in toxicity patterns underscoring the rationale for a randomized controlled trial.
Effects of 6 months of abiraterone acetate (AA) on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Brondfield Samuel Craig , Weinberg Vivian K. , Koepfgen Kathryn M. , Molina Arturo , Ryan Charles J. , Small Eric Jay , Harzstark Andrea Lynne
Published: February 2017

222

Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in patients with mCRPC who have previously been treated with chemotherapy. Androgen deprivation therapy (ADT) has been shown to result in muscle wasting in prostate cancer pts. The effects of AA on progression of muscle and fat wasting have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle mass or adipose mass.

Methods: 10 sequential pts who responded to AA therapy for at least 6 months and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COU-AA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to determine the change in measurements.

Results: At baseline, 7 of 10 pts were overweight or obese (body mass index [BMI] > 25 kg/m2), and none were underweight. Advanced muscle wasting (sarcopenia, previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm2/m2) was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, pts lost an average of 1.9 kg ± 1.9 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass (−0.80 ± 1.71, p = 0.18) and total non-adipose mass (−1.44 ± 3.09, p = 0.17) were not significant. A significant decrease in total adipose mass (−0.61 ± 0.84, p = 0.048) was observed.

Conclusions: Sarcopenia is prevalent in pts with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is ongoing.
Final analysis: A multicenter phase I study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody to human αv integrins, in progressive castrate-resistant prostate cancer with bone metastases after chemotherapy.
Authors: Wirth Manfred , Heidenreich Axel , Gschwend Jürgen E. , Gil Thierry , Zastrow Stefan , Laniado Michael , Zuehlsdorf Michael , Gerloff Joachim , Uhl Wolfgang , Lannert Heinrich
Published: February 2017

231

Background: EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting αv integrins involved in tumor progression.

Methods: The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts). 24 pts (43–80 years) were treated with IV infusions of 250, 500, 1000, or 1500 mg EMD 525797 given over 1 h and received 3 doses (weeks 1, 3, and 5) before response assessment at the end of week 6. Pts without progressive disease could receive further doses every 2 weeks. Dose-limiting toxicities (DLTs) were assessed over the first 6 weeks and safety was monitored until 4 weeks after the last administration of EMD 525797.

Results: Final analysis showed that 13 of 24 pts had a longer exposure time than expected (≥84 d): 7 pts had exposure times ≥126 d, 3 pts ≥280 d and 1 pt received EMD 525797 for 534 d (Table). All pts experienced adverse events (AEs), and in 11 pts AEs were considered related to EMD 525797. 4 pts had generalized pruritus, erythema, or rash and 3 pts experienced fatigue, mucosal inflammation, or peripheral edema, but no pt had administration site reactions. Changes in clinical lab values were consistent with basic disease. No DLTs occurred. EMD 525797 showed a dose-dependent, nonlinear PK profile in line with a target-mediated drug disposition. Pt 1 and 2 of the 500 mg cohort had a marked decrease in prostate specific antigen. Pt 1 also had primary tumor shrinkage and normalization of lymph node size. These pts had long-term anti-integrin treatment (297 and 534 d, respectively). Both patients showed additional pain relief.

Conclusions: EMD 525797 showed clinical activity in mCPRC pts in salvage setting, pain relief, and tumor regression. EMD 525797 is well tolerated without any premedication and did not show clinically relevant dose-related changes in the safety parameters assessed.

[Table: see text]
Three-dimensional ultrasound-based spectroscopic imaging for the detection of prostate cancer.
Authors: Chung Hans T. , Sofrani Ervis , Papanicolau Naum , Sugar Linda , Morton Gerard , Yaffe Martin , Nam Robert , Czarnota Gregory J.
Published: February 2017

234

Background: The objective of this translational research was to investigate the use of real-time novel three-dimension, quantitative ultrasound-based spectroscopic imaging of the prostate as a means of cancer detection.

Methods: Fourteen patients with T2-3 prostate cancer underwent a 6–9 MHz trans-rectal ultrasound scan of the prostate prior to radical prostatectomy. Equally spaced axial ultrasound images (0.5 cm separation) corresponding elasticity and spectroscopy data were collected in each patient. Colour-coded spectroscopic parametric maps of 0-Mhz intercept (0-Mhz), mid-band fit (MBF) and slope of line of best fit (slope) were generated indicating where the disease in the prostate gland is hypothetically located. Quantitative data (% volume of cancer over the prostate gland) were compared to whole-mount radical prostatectomy histopathology maps to determine the sensitivity and accuracy in parametrically delineating prostate cancer.

Results: Representative data indicate spectral changes were associated with the presence of co-incident disease as located on correlative histopathology whole mount sections. Of the 14 patients enrolled, 7 have been analyzed and presented here. The mean % difference between 0-MHz and MBF, with H&E, was 14% (SD 38%) and 21% (SD 24%), respectively. Gross areas of disease were readily visualized in ultrasound parametric maps and corresponded to a maximum 10dB decrease in 0-MHz or MBF. Parametric maps generated from the spectral slope offered no discrimination of disease. There were differences in scatterer size estimates and scatter concentration estimates between putative disease areas and the remaining tissue.

Conclusions: Initial results suggest that there is good correlation between spectroscopic maps with disease on whole-mount specimens. This method may ultimately permit ultrasound-guided targeted biopsies to improve detection rates and non-invasive assessment of disease for radiotherapy planning.
Health care cost in hormone-naive and hormonally pretreated patients with prostate cancer treated with degarelix.
Authors: Wolff Johannes , Tolle Alexander , Gedamke Michael
Published: February 2017

240

Background: Degarelix, is a GnRH-antagonist, which is used in the treatment of prostate cancer since 2009. We performed a non-interventional study (NIS) with prostate cancer (PCA) patients treated routinely with degarelix. This NIS focused on pharmaco-economical data, quality of life as well as efficacy and safety in patients receiving degarelix as first or second line therapy.

Methods: In the interims analysis of this ongoing NIS, data from 279 out of 670 PCA-patients treated with degarelix were included. The included cohort reflects advanced PCA patients (age: 72 years, PSA: 15.8 ng/ml (median values)).Testosterone and PSA values, quality of life and pharmaco-economical data were collected at baseline, 1, 3, 6, 9 and 12 months. Quality of life was assessed by EQ-5D. Pharmaco-economical data included direct costs for physicians, drugs, hospital, emergency treatment and others.

Results: Treatment costs in hormon-naïve patients treated with degarelix were lower than in the hormonally pre-treated patients. Direct costs for six month were 498,- € for hormone naïve patients treated with degarelix in contrast to 1436,- € for hormonally pre-treated patients. As expected there was a marked difference in the PSA-decline between hormone-naïve patients and hormonally pre-treated patients. Hormone-naïve patients experienced a sharp median decrease in PSA by 80.7% (n=116) at month 1. This decline remained stable in 98.7% of the patients after one year. Median PSA reduction was significantly different (p=0.013) between hormone-naïve and pre-treated patients. Furthermore treatment of degarelix improved quality of life by 14% at one year compared to baseline. Testosterone was suppressed to a median of 0.2 ng/ml from month 1 to 12. Safety results mirrored the results of clinical trials.

Conclusions: First-line treatment with degarelix was supported by a marked difference in health care costs between hormone naïve and pre-treated prostate cancer patients, who received degarelix. As expected a pronounced difference in the PSA-decrease in hormone naïve and pre-treated patients was seen. However a distinct quality of life improvement was noted in all patients.
Characteristics of the screen-failure (SF) patient population in an early castrate-resistant prostate cancer vaccine clinical trial: Lessons for future trial design.
Authors: Vaena Daniel A. , Zehr Pamela , Griffith Karen , Brown Erica , Brown James A , Eastman Julie , Lubaroff David
Published: February 2017

241

Background: AdPSA is an investigational replication-deficient adenovirus-based PSA vaccine. A prior phase I trial in patients (pts) with metastatic CRPC showed safety and ability to generate immune responses. We are conducting a phase II trial in early CRPC in our comprehensive cancer center + VA. This study contains an analysis of the SF (post-informed consent) population.

Methods: Patients with CRPC defined as rising PSA despite androgen deprivation therapy are eligible for this trial. Main eligibility criteria requires a bone scan, chest X-ray and abdomen pelvis CT without evidence of metastatic disease (any PSA or PSA doubling time allowed). Pts with metastatic disease are also eligible if they have a PSA doubling time greater than 6 months and a PSA less than 10 and are asymptomatic. Prior antiandrogens or ketoconazole are allowed, provided the PSA is rising. Prior chemotherapy or sipuleucel-T is not allowed.

Results: 38 pts have been consented for the clinical trial, of which 21 pts have proceeded with study therapy. 17 pts were SF for the following reasons: 13 had positive CT and/or bone scans with exclusionary PSA or PSADT values, 1 had declining PSA prior to starting therapy, and for 3 pts initiation of study therapy was contraindicated (second cancer discovered on CT, aggressive pace of progression, and unrelated patient death). Median PSA was 10.2 for SF vs 1.9 ng/mL for treated pts. 6 SF patients had PSA < 5 ng/mL. 26 pts had prior bicalutamide (12 SF, 14 treated group). Prior ketoconazole was rare in both groups. The vast majority of pts who were treated did not have metastatic disease.

Conclusions: In a large academic cancer center, it is challenging but possible to find patients with early non-metastatic CRPC. Higher PSA may predict SF, but several patients with PSA < 5 ng/mL also had metastases on screen. Prior antiandrogen is not a predictor for SF. Since this abstract only relates to patients who consented for the trial, the denominator of cancer center patients with early CRPC (but not eligible) is even larger. This information will help accrual estimates in cancer centers and feasibility assessment of early CRPC studies.
Use of sector analysis of I-125 permanent prostate brachytherapy to evaluate and compare pre- and postimplant dosimetry.
Authors: Mohamed Yoosuf Ahamed Badusha , Workman Geraldine , O'Toole Monica M , Straney Margaret , Verghis Rejina , Napier Eoin , Mitchell Darren M.
Published: February 2017

242

Background: To evaluate 12 sector analysis in the assessment and comparison of pre- and post- implant dosimetric parameters during the development of an I-125 prostate brachytherapy (PPB) service.

Methods: 50 consecutive men being treated with PPB had dose volume analysis in 12 sectors of their pre implant ultrasound (PIUS) and post implant CT (PICT) data using a Variseed 8.0 treatment planning system. PIUS dosimetry was performed 2 weeks prior to implantation and PICT dosimetry 4 weeks post implant. Individual sectors were created by dividing the cranio-caudal prostate length into 3 equal lengths creating prostate base (PB), midgland (PM) and apex (PA). Each of these volumes was then divided into four axial sectors (right and left anterior, right and left posterior). The planning target volume (PTV), dose to 90% of prostate (D90), prostate volume enclosed by 100% (V100), 150% (V150) and 200% (V200) dose were recorded in each sector on PIUS and PICT. Adjacent sectors on PIUS were assessed for dose-volume homogeneity as were adjacent sectors on PICT. Differences in individual sectors on PIUS and PICT were evaluated.

Results: Adjacent sector analysis demonstrated dose homogeneity in all sectors of PIUS and the majority of sectors on PICT. Statistically significant differences between PIUS and PICT were noted in target volume, particularly in PB with PICT >PIUS. When individual sectors on PIUS and PICT were compared, statistically significant differences were noted in the majority of dosimetric parameters. The anterior PB and PM were significantly lower on PICT (p value < 0.001) and significantly higher at the posterior PM and PA (p value < 0.05). These changes were consistent across all analysed parameters. In particular, significant absolute differences in D90 in equivalent sectors on PIUS and PICT were seen.

Conclusions: 12 sector analysis allows rapid assessment of PIUS and PICT dose and volume homogeneity. It offers a scientific method of identifying areas of relative over and under dosing on PICT when compared with PIUS providing both clinicians and physicists with a learning tool to refine dosimetric analysis and highlight sectors where implant quality could be improved.
Variability in prostate volume as determined by MRI versus ultrasound and its impact on treatment recommendations for patients with favorable-risk prostate cancer.
Authors: Murciano-Goroff Yonina R. , Wolfsberger Luciant D. , Parekh Arti , Fennessy Fiona M. , Tuncali Kemal , Orio Peter F. , Niedermayr Thomas , Suh W. Warren , Devlin Phillip M. , Tempany Clare M. , Nguyen Paul Linh
Published: February 2017

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Background: Prostate volume affects whether patients qualify for brachytherapy (desired size ≥20mL and ≤60mL) or active surveillance (desired PSA density ≤0.15). This study examines variability in prostate volume as determined by contoured axial ultrasound slices, ultrasound ellipsoid (HxWxL) calculation, and endorectal coil MRI (erMRI) ellipsoid calculation, and quantifies the impact of this variability on treatment recommendations for men with favorable-risk prostate cancer.

Methods: The study examined 72 patients who presented consecutively for consideration of brachytherapy for favorable-risk prostate cancer who had 3 volume estimates from direct contouring on ultrasound axial slices (2.5mm thickness), the ultrasound ellipsoid method, and the erMRI ellipsoid method.

Results: Average gland size by the contoured ultrasound, ellipsoid ultrasound, and eMRI methods were 34.22, 37.15, and 39.58 mLs, respectively. All pairwise comparisons between methods were significant (all p<0.02). Of the 68 patients who anatomically qualified for brachytherapy on ellipsoid ultrasound measures (size ≥20mL and ≤60mL), 22 (32.35%) did not qualify on eMRI (5 patients <20 mL, 11 patients >60 mL) or contoured ultrasound measures (7 patients <20 mL, 3 patients >60 mL). 40 patients (55.56%) were very low risk (PSA density ≤0.15 ng/dl) as calculated using ellipsoid ultrasound volumes, while 35 (48.61%) and 39 patients (54.17%) were very low risk using contoured ultrasound and eMRI volumes, respectively.

Conclusions: The ultrasound ellipsoid and erMRI ellipsoid methods appeared to overestimate ultrasound contoured volume by an average of 8.56% and 15.65% respectively. 32.35% of those who qualified for brachytherapy based on ellipsoid ultrasound volume would be disqualified based on ultrasound contoured and/or erMRI volume. As treatment recommendations increasingly rely on estimates of prostate size, clinicians must consider method of volume estimation.
Long-term outcomes in patients with muscle-invasive bladder cancer after bladder-preserving combined-modality therapy: A pooled analysis of RTOG 8802, 8903, 9506, 9706, 9906, and 0233.
Authors: Mak Raymond H. , Hunt Daniel , Shipley William U. , Efstathiou Jason Alexander , Tester William J. , Hagan Michael P. , Kaufman Donald S. , Heney Niall M. , Zietman Anthony L.
Published: February 2017

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Background: Multiple prospective RTOG studies have evaluated bladder preserving combined-modality therapy (CMT) including local resection with chemo-radiation for the treatment of muscle invasive bladder cancer (MIBC) reserving cystectomy for salvage. Here we report a pooled analysis of long-term outcomes.

Methods: We performed a pooled analysis of 468 patients (pts) with MIBC enrolled on six RTOG bladder preservation studies, including five Phase II studies: RTOG 8802, 9506, 9706, 9906, and 0233, and one phase III study: 8903. Overall survival (OS) was estimated with the Kaplan-Meier method, and disease specific survival (DSS), local failure (LF) and distant metastasis (DM) were estimated by the cumulative incidence method.

Results: The median age of the pts was 66 (range, 34-93), and the majority had a Zubrod performance status (PS) of 0 (89.1%). The most common tumor histology was transitional cell carcinoma (94.2%). Clinical tumor stage distribution included 60.6% T2, 29.1% T3a, 6.2% T3b, and 3.9% T4a. A complete response to CMT was observed in 72.0% of pts. With a median follow-up of 4.29 years among all pts, and 7.80 years among survivors (n=205), the 5-year and 10-year results were as follows (Table). Examining outcomes by subgroups, higher clinical T-stage (T2 vs. T3/T4) was associated with decreased DSS (5-year DSS: 74% vs. 66%; 10-year DSS: 69% vs. 60%; p=0.05), and OS (5-year OS: 62% vs. 49%; 10-year OS: 41% vs. 30%; p=0.002). On multivariate analysis, after adjusting for age and PS, higher T-stage was associated with decreased DSS (Hazard ratio: 1.65; 95% confidence interval: 1.19-2.27; p=0.002). Among pts with non-transitional cell carcinoma histology (n=29), the 5-year and 10-year DSS was 66% and 60%, respectively, and 5-year and 10-year OS was 41% and 21%.

Conclusions: This pooled analysis of RTOG trials of bladder preserving CMT for MIBC demonstrates long-term OS and DSS comparable to modern immediate cystectomy-based strategies with and without neoadjuvant chemotherapy. CMT can be considered as an alternative to radical cystectomy in selected pts.

[Table: see text]
Prognostic value of SPINK1 expression in bladder cancer after radical cystectomy.
Authors: Rink Michael , Shariat Shahrokh F. , Park Kyung , Volkmer Bjoern , Cha Eugene K. , Robinson Brian D. , Hautmann Richard , Scherr Douglas , Fisch Margit , Rubin Mark A. , Chun Felix K. , Kuefer Rainer , Mosquera Juan Miguel
Published: February 2017

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Background: Serine peptidase inhibitor Kazal type 1 (SPINK1) overexpression has been associated with poor outcomes. In one small study, loss of SPINK1 expression in urothelial carcinoma of the bladder (UCB) was associated with advanced tumor stage. We assessed the expression of SPINK1 in normal urothelium and UCB and analysed the association of SPINK1 with pathological features and clinical outcomes of patients treated with radical cystectomy (RC).

Methods: The study used TMAs containing samples from 438 consecutive UCB patients treated with RC. 62 cases of normal urothelium were included as controls. A monoclonal antibody was used for immunohistochemical SPINK1 staining. SPINK1 expression of UCB was evaluated by two pathologists, blind to clinical outcome. Samples demonstrating less than 50% staining extent and 0 to 1 intensity (scale 0 to 3), were considered to have loss of expression.

Results: SPINK1 expression was noted in umbrella cells of normal urothelium in 32/62 controls (52%). UCB of 254 patients (57.9%) exhibited loss of SPINK1 expression. Loss of SPINK1 expression was significantly associated with advanced pathological stage (p=0.002) and presence of lymph node (LN) metastasis (p=0.04). Within a median follow-up of 130 month (IQR 98.4), loss of SPINK1 expression was associated with an increased risk of disease recurrence (5-year RFS: 52±3 vs. 61±4 months; p=0.02) and cancer-specific mortality (5-year CSS: 59±3 vs. 68±3 months; p=0.03). In multivariable Cox regression analyses that adjusted for the effects of age, gender, tumor stage and grade, concomitant CIS, LN status and adjuvant chemotherapy, SPINK1 was not associated with disease recurrence (p=0.09) or cancer-specific death (p=0.12).

Conclusions: While umbrella cells in normal urothelium commonly expresses SPINK1, more than half of UCB specimen exhibit loss of SPINK1 expression. Loss of SPINK1 expression is strongly correlated with local disease stage and LN metastasis. SPINK1 revealed no independent prognostic value for outcome prognostication, but it is a very promising marker for tumor staging which could be used for tailored follow-up protocols and possibly as a target for therapy as it has similarities with epidermal growth factor.
Contribution of C-reactive protein to predicting overall survival in patients with advanced urothelial carcinoma: Development of a nomogram and evaluation by decision curve analysis.
Authors: Ishioka Junichiro , Saito Kazutaka , Sakura Mizuaki , Yokoyama Minato , Matsuoka Yoh , Numao Noboru , Koga Fumitaka , Masuda Hitoshi , Kihara Kazunori
Published: February 2017

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Background: To accurately estimate the individual survival of patients with advanced urothelial carcinoma (UC), the application of prediction models such as nomograms has been warranted in clinical use. We therefore constructed a nomogram which included C-reactive protein (CRP) as a novel biomarker in order to increase its predictive accuracy. Furthermore, the clinical usefulness of this nomogram was evaluated by decision curve analysis which incorporated the negative consequences of each decision to generate a net benefit (Vickers et al, BMC Med Inform Decis Mak, 2008).

Methods: A total of 232 consecutive patients with locally advanced or metastatic urothelial carcinoma (UC) were treated at our institute. Among them, 9 patients with missing data were excluded. The current study cohort was comprised of the remaining 223 patients. A nomogram predicting 6- and 12-month survival probability was developed based on the results of the final multivariate analytic model. To evaluate the efficacy of this nomogram, a quantified concordance-index (c-index) was computed and a decision curve analysis was performed.

Results: Overall, 184 patients died of the primary disease and the remaining 39 were censored. The median follow-up period and length of overall survival were 5 and 6 months, respectively. The 6- and 12-month survival rates were 48% and 30% respectively. A nomogram was developed which included the parameters of age, PS, visceral metastasis, hemoglobin and CRP. The c-index of this prediction model was 0.79 compared with 0.75 for that of a model without CRP. The decision curve analysis revealed that a novel nomogram which incorporated CRP had a superior net benefit to that without CRP for most of the examined threshold probabilities.

Conclusions: Incorporation of CRP increased the predictive accuracy of a prognostic nomogram for advanced UC. In clinical practice, this nomogram would contribute to the decision making process in the treatment of patients suffering from this form of carcinoma.
Frequency of cisplatin administration in patients presenting with advanced urothelial carcinoma in the community.
Authors: Sonpavde Guru , Watson Deidre , Tourtellott Marcia , Higgins Erica , Cowey Charles Lance , Hellerstedt Beth A. , Hutson Thomas E. , Zhan Feng , Vogelzang Nicholas J.
Published: February 2017

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Background: Renal dysfunction, poor performance status, advanced age, and comorbidities may preclude standard frontline cisplatin-based chemotherapy in patients with advanced urothelial carcinoma (UC). We hypothesized that cisplatin-based regimens are not administered to the majority of patients in the community. A study was conducted to identify chemotherapy regimens administered by medical oncologists in community-based cancer centers.

Methods: A retrospective study was conducted on patients with AJCC stage 4 UC presenting from 2001 to 2010 to Texas Oncology Cancer Centers. The frontline chemotherapy regimen was classified as cisplatin-based, carboplatin-based, non-platinum based and no chemotherapy administered. The association of age with administration of cisplatin was studied.

Results: A total of 298 patients with stage 4 disease were eligible for this analysis out of 3574 patients with UC in this database. Of the 298 patients, 197 (66.1%) were male, the median age was 70 years (range 28-97), and the primary sites of disease were bladder (243, 81.5%), renal pelvis (41, 13.8%) and ureter (14, 4.7%). The regimens administered were cisplatin-based in 107 patients (35.9%), carboplatin-based in 81 (27.2%), non-platinum in 25 (8.4%), no chemotherapy was administered in 71 (23.8%) and data were not available in 14 patients (4.7%). Cisplatin administration appeared more common in patients aged ≤70 years (62 of 150, 41.3%) as opposed to >70 years (45 of 148, 30.4%), p=0.05. Non-cisplatin regimens or no chemotherapy were trending to be more commonly administered to patients >70 years (64.2 vs. 54.7%, p=0.10). Limitations of a retrospective database study apply and the reasons for not administering cisplatin are unclear.

Conclusions: Cisplatin-based chemotherapy was administered to 35.9% of patients presenting with AJCC stage 4 UC to community cancer centers. Given that the majority of patients may not be cisplatin-eligible or candidates for chemotherapy, this population has a significant unmet need. Drug development focused on single agent therapy with tolerable, convenient and efficacious agents or combination regimens without a cisplatin backbone should be a priority.