Pretreatment PSA Research Articles

909P - Predictive and Prognostic Roles of Body Mass Index (BMI) in Docetaxel(D)-Treated Castrate-Resistant Prostate Cancer (CRPC)

ABSTRACT Introduction Studies have suggested that overweight and obese patients with early stage prostate cancer present with lower PSA, higher grade disease and have poorer outcomes. Data remains limited on the influence of BMI on CRPC receiving D. We previously reported lower pretreatment PSA and rate of PSA response in obese pts (Teo et al, ASCO GU 2011). With an expanded cohort, we sought to examine the influence of BMI on PSA kinetics and CRPC survival. Methods Two institutional databases were analysed to identify pts who received D for CRPC. Demographics and serial PSA levels were extracted. Pts were divided into Group A, B and C, based on BMI range of ≤25.0, 25.1-29.9 and ≥30 kg/m respectively. PSA responses and half life were calculated using PCWG2 guidelines. Results were compared with Mann-Whitney and Fisher's exact tests. Time to PSA progression (TPP) and overall survival (OS) were estimated with Kaplan Meier and logrank methods. Results 78 pts were identified, with median age of 66 yrs (44-80), median cycles of D of 7 (1-26), and median BMI of 28.5. Gleason score was evaluable in 75%, with a median score of 8. The number of pts in each BMI group was 21, 24 and 33, respectively. Pts in Gp C had significantly lower baseline PSA (table). More pts in Gp C were PSA non-responders compared to Gp A and B (p = .004). PSA nadir and rates of PSA reduction >30%, >50% and >90% at 3months were comparable in all groups. MMMMMedian TPP was 4.2 months in Gp A, 5.2 months in Gp B, and 4.4 months in Gp C (logrank p = .49). The longest median OS was observed in Gp A at 20 months, followed by Gp B at 19 months and Gp C at 15 months; these differences were not statistically significant (p = 0.38). Of 45 pts with treatment details, 24% had dose reduction and 44% had ≥1 infusion delays. Rates were similar across Gps A to C. Conclusions Obese CRPC pts have lower pre-D PSA levels and higher rate of non-responsive disease. However, BMI does not appear to influence PSA kinetics, tolerability of D and survival. BMI (kg/m2) p ≤25 25.1 - 29.9 ≥30 n 21 24 33 NS Baseline PSA, median ng/mL 131.0 236.6 81.6 0.007 PSA Reduction at 12wks, median % 34.4 47.2 41.4 NS PSA Nadir as % of Baseline, median 51.1 41.6 39.6 NS PSA Flare, % 9.5 25.0 14.8 NS PSA Non-Responders, % 0.0 4.2 25.9 0.004 >30% PSA Reduction at 12wks, % 66.7 79.2 70.4 NS >50% PSA Reduction at 12wks, % 47.6 62.5 59.3 NS >90% PSA Reduction at 12wks, % 9.5 29.2 14.8 NS PSA Half-life, days, median 51.1 41.6 39.6 NS Disclosure All authors have declared no conflicts of interest.

Expression of Pituitary Tumor Transforming Gene 1 is an Independent Factor of Poor Prognosis in Localized or Locally Advanced Prostate Cancer Cases Receiving Hormone Therapy

We investigated the prognostic value of pituitary tumor transforming gene 1 (PTTG1) expression according to clinicopathological features among localized or locally advanced prostate cancer cases receiving hormone therapy. A retrospective study involved 64 patients receiving combined androgen blockade treatment was performed. PTTG1 expression was determined by immunohistochemical staining using initial needle biopsy specimens for diagnosis. Associations of PTTG1 with various clinicopathological features and disease-free survival were examined via uni- and multivariate analyses. No association between PTTG1 expression and clinical T stage, Gleason score, pretreatment PSA levels, risk groups was found (p=0.682, 0.184, 0.487, 0.571, respectively). Univariate analysis revealed that increased PTTG1 expression, T3 stage and high risk group were associated with increased risk of disease progression (p=0.000, 0.042, and 0.001), and high PSA level had a tendency to predict disease progression (p=0.056). Cox hazard ratio analysis showed that PTTG1 low expression (p=0.002), PTTG1 high expression (p=0.000) and high risk group (p=0.0147) were significantly related to decreased disease-free survival. In conclusion, PTTG1 expression determined by immunohistochemical staining in needle biopsy specimens for diagnosis is a negative prognostic factor for progression in localized or locally advanced prostate cancer receiving hormone therapy.

Is Androgen Deprivation Therapy Necessary in All Intermediate-Risk Prostate Cancer Patients Treated in the Dose Escalation Era?

The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease. In patients with GS 4+3 or T2c disease, the addition of ADT to dose-escalated RT did improve FFF.

Impact of Percentage of Positive Biopsy Cores on Biochemical Outcome in Patients Treated With Low-Dose Rate (Iodine-125) Brachytherapy for Prostate Cancer

To investigate the significance of the percentage of positive biopsy cores (PPBCs) in predicting the biochem- ical outcome in patients with clinically localised prostate cancer undergoing low-dose rate brachytherapy (LDRB).  A total of 326 consecutive patients underwent LDRB between February 1997 and January 2007. The cohort consisted of 68.7%, 30.4% and 0.9% of low-, intermediate- and high-risk groups respectively as defined by the D'Amico classifica- tion. Patients were stratified according to PPBCs ( 50%).  Of the 326 men, 316 (97%) met the study criteria and were included in the analysis. The median follow-up was 66.3 (12.9-147.5) months. Thirty-eight men (12%) developed evidence of biochemical relapse as defined by the Phoenix defi- nition at a median of 44.5 (4-133) months. The overall 5-year and 10-year biochemical relapse-free rate (BRFR) was 91.9% (95% CI 87.9% to 94.6%) and 76.9% (95% CI 66% to 84%) respectively.  On univariate analysis, Gleason score (p=0.03), D'Amico risk groups (p=0.004) and PPBCs (p=0.001) were significant predictors of biochemical failure. In the multivariate model, the PPBCs (p=0.0006) and pretreatment PSA (p=0.004) were the only variables that predicted for biochemical failure. The 5-year biochemical relapse-free rate was 93.5%, 93.0% and 76.5% for the PPBCs 50% respectively (p=0.001). Conclusions:  The PPBC is an important independent predictor of the 5-year biochemical relapse-free survival after LDRB. This finding suggests that patients with high volume tumour are at increased risk of biochemical failure with LDRB.

OC-24 TEN-YEAR OUTCOMES FOR PATIENTS WITH GLEASON 8-10 TREATED WITH HIGH DOSE RATE BRACHYTHERAPY BOOST

Purpose/Objective: To report long term multi-institutional outcomes for Gleason 8–10 prostate cancer patients treated with external beam radiotherapy (EBRT) and high dose rate (HDR) brachytherapy boost. Materials and Methods: Between 1987 and 2002, 483 patients with Gleason 8-10 disease were treated for localized prostate cancer at William Beaumont Hospital (WBH), the California Endocurietherapy Center (CET), Kiel University, and the Universidad de Navarra on four prospective HDR boost trials. Conformal EBRT was delivered to the pelvis (dose range 36 Gy–50.4 Gy) along with HDR boost for a combined biologic equivalent dose (BED) of 215–366 Gy (α/β=1.2). Conformal intensity modulated HDR-BT was planned and treatment was delivered using on-line trans-rectal ultrasound (TRUS) images at WBH. At CET, Kiel University, and Navarra University, HDR-BT treatment planning was CT based. Biochemical control (BC) was defined according to the Phoenix criteria (freedom from PSA rise of 2ng/ml above nadir). Results: Mean patient age was 68.4 years with mean initial PSA (iPSA) of 18.8 ng/ml. Mean follow-up was 6.1 years. 10-year outcomes were: biochemical control (BC) 53.5%, distant metastases (DM) 22.1%, clinical failure (CF) 25.6%, cause specific survival (CSS) 82.6% and overall survival (OS) 62.7%. Hormones were given in 69.9% of patients but did not significantly improve BC, DM, CSS, or OS. 10-year outcomes stratified by iPSA ( 40 ng/ml) were improved for all outcomes with lower iPSA including BC (57.4% v. 10.3%, p<0.001), freedom from distant metastases (81.5% v. 43.4% (p<0.001), CSS (85.0% v. 59.1% (p<0.001), and OS (63.8% vs. 47.9%, p=0.02). Univariate analysis of biochemical control found tumor stage (OR 1.35, p<0.001), pre-treatment PSA (OR 1.03, p<0.001), and Gleason score (OR 1.69, p=0.05) to be associated with no association noted with hormonal therapy (p=0.94) and BED (0.34). Multivariate analysis confirmed tumor stage (p=0.03), pre-treatment PSA (p=0.02), and Gleason score (p=0.03) but not hormonal therapy (p=0.57) or BED (p=0.42).

PO-213 POST-IMPLANT DOSIMETRIC COMPARISON OF LOW, HIGH, AND VARIABLE STRENGTH IMPLANTS

Results: The mean age was 63.93 years (44-88); means pretreatment PSA was 6.34 ng/mL (0,6733.09); 88.20% of patients ha initial PSA less 10 ng/mL; 83.28 had Gleason score = 0,285 significantly discriminated between patients with and without biochemical recurrence. Conclusions: Prostate low-dose-rate Iodine-125 seeds brachytherapy is an excellent choice for conservative treatment of localized prostate cancer in selected patients presenting small prostate, Gleason score less than 7 and PSA less than 10. PSA nadir <1,0 ng/mL is a good prognostic factor in these patients.

Abstract 4443: Body weight status predicts pre-treatment risk of PSA failure in men with clinically localized prostate cancer

Abstract Introduction and Objective: Obesity/excessive adiposity in men with clinically organ-confined prostate cancer is of growing concern, because it associates with an increased risk of cancer recurrence after definitive therapy based on post-treatment prognostic parameters. The objective of this study was to evaluate whether body weight status associates with pre-treatment predictors of cancer recurrence in this patient population. Methods: We performed a cross-sectional study of body weight status and pre-treatment risk of PSA failure in 119 men awaiting radical prostatectomy for clinically localized prostate cancer in four urologic clinics in the Chicago area. Body weight status was assessed using the body mass index (BMI) and dual-energy x-ray absorptiometry (DXA). D'Amico risk scores, which are based on clinical tumor stage, biopsy Gleason sum, and pre-treatment PSA, were used to rank each patient's 5-year risk of PSA failure as low, intermediate, or high. Ordinal logistical regression analyzed the association between BMI quartile and D'Amico risk scores after accounting for age, race, total grams of body fat, and study site. Results: The risk of PSA failure increased with increasing quartile of BMI. Relative to the lowest BMI quartile, the cumulative odds of an intermediate or higher D'Amico risk score vs. a low risk score (the “cumulative odds ratio”) for patients in the second BMI quartile (mean BMI = 27.8 kg/m2) was 3.51 (95% CI = 1.07 to 11.5, p = .038). For patients in the third quartile (mean BMI = 32.0 kg/m2) and forth quartile (mean BMI = 37.0 kg/m2), the cumulative OR was 6.52 (95% CI = 1.72 to 24.6, p = .0057) and 7.74 (95% CI = 1.18 to 50.9, p = .033), respectively (OR trend = 1.98, 95% CI = 1.09 to 3.59, p = .0254). Conclusions: Body weight status predicts pre-treatment risk of PSA failure in men with clinically localized prostate cancer. This provides further support for a mechanistic link between body weight status, which reflects energy balance, and prostate cancer prognosis. The results also highlight the potential for using body weight status and other lifestyle-related factors pertinent to prostate cancer to identify men who are at high risk for unfavorable treatment outcomes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4443. doi:1538-7445.AM2012-4443

Twelve-Month Prostate-Specific Antigen Values and Perineural Invasion as Strong Independent Prognostic Variables of Long-Term Biochemical Outcome After Prostate Seed Brachytherapy

To determine whether post-treatment prostate-specific antigen (ptPSA) values at 12 months and other clinical parameters predict long-term PSA relapse-free survival (PRFS) following prostate seed brachytherapy. Records of 204 hormone-naïve patients with localized adenocarcinoma of the prostate treated at St. Mary's Regional Medical Center in Reno, NV, and at Carson Tahoe Regional Medical Center in Carson City, NV, between 1998 and 2003, using I-125 or Pd-103 seed brachytherapy, were retrospectively analyzed. Treatment planning was done using a preplanned, modified peripheral loading technique. A total of 185 of 204 patients had PSA records at 12 months after implant. Variables included were age, initial pretreatment PSA, Gleason score, T stage, National Comprehensive Cancer Network (NCCN) risk group (RG), perineural invasion (PNI), external beam boost, dose, and ptPSA levels at 12 months with cutpoints at ≤1, 1.01 to 2.00, 2.01 to 3.00, and >3.00 ng/ml. Median follow-up was 80 months, and median age was 69 years. The numbers of patients stratified by NCCN low, intermediate, and high RG were 110:65:10, respectively. Monotherapy and boost prescription doses were 145 Gy and 110 Gy for I-125, and 125 Gy and 100 Gy for Pd-103 seeds, respectively. The median dose (D90) was 95.4% of the prescribed dose. The 5-year PRFS at the 12-months ptPSA levels of ≤1, 1.01 to 2.00, 2.01 to 3.00, and >3.00 ng/ml were 98.5%, 85.7%, 61.5%, and 22.2%, respectively. The 10-year PRFS at the 12-months ptPSA levels of ≤1 and 1.01 to 2.00 ng/ml were 90.5% and 85.7%, respectively. In multivariate analysis, both ptPSA and PNI were significant independent predictors of PRFS. Hazard ratios (HR) for ptPSA levels at ≤1, 1.01 to 2.00, 2.01 to 3.00, and >3.00 ng/ml at 12 months were 1, 4.96, 27.57, and 65.10, respectively. PNI had an HR of 6.1 (p=0.009). Presence of PNI and ptPSA values at 12 months are strong prognostic variables for long-term PRFS after definitive prostate brachytherapy seed implantation.

1475 FACTORS PREDICTIVE OF DEVELOPING COMPLICATIONS FOLLOWING PRIMARY AND SALVAGE CRYOABLATION OF THE PROSTATE

You have accessJournal of UrologyProstate Cancer: Localized VII1 Apr 20121475 FACTORS PREDICTIVE OF DEVELOPING COMPLICATIONS FOLLOWING PRIMARY AND SALVAGE CRYOABLATION OF THE PROSTATE Edward N. Rampersaud, Frederic D. Birkhauser, Yvonne Chan, Joshua E. Logan, Alex Wonnaparhown, Geoffrey Sonn, and Arie S. Belldegrun Edward N. RampersaudEdward N. Rampersaud Los Angeles, CA More articles by this author , Frederic D. BirkhauserFrederic D. Birkhauser Los Angeles, CA More articles by this author , Yvonne ChanYvonne Chan Los Angeles, CA More articles by this author , Joshua E. LoganJoshua E. Logan Los Angeles, CA More articles by this author , Alex WonnaparhownAlex Wonnaparhown Los Angeles, CA More articles by this author , Geoffrey SonnGeoffrey Sonn Los Angeles, CA More articles by this author , and Arie S. BelldegrunArie S. Belldegrun Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1996AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cryoablation of the prostate is a treatment option for selected patients with prostate cancer in both primary and salvage settings. We sought to assess factors predictive of developing various treatment-related complications in a single-surgeon practice at a quaternary-care institution. METHODS The UCLA Prostate Cancer Program cryotherapy database contains records of 144 consecutive patients treated with identical cryotherapy equipment in an outpatient setting since 2005. Of these patients, 68 were treated with primary cryotherapy (Primary) and 76 with salvage cryotherapy (Salvage) after primary radiotherapy. A verbal questionnaire regarding possible complications was administered to all patients contacted by an independent research monitor. Clinicopathologic factors were compared and binary logistic regression models were employed to assess the factors predictive of individual complications. RESULTS Average age for patients in Primary and Salvage groups were 70.8 and 72.4 years (p=0.748). The two groups were also balanced for other baseline demographic variables, including race, body mass index (BMI), and pretreatment PSA. Prostate volume was significantly greater in Primary group than Salvage group (41.4cc and 26.1cc, p<0.001). Low-risk Gleason was more commonly treated in the Primary group (p=0.011). Incontinence (more than one pad per day), urethral strictures, and post-treatment erectile dysfunction (ED) were more common in the Salvage group (34.7% vs 16.7%, p=0.013), (16.0% vs 2.82%, p=0.007), and (81.6% vs 59.7%, p=0.003). Urinary retention, bladder overactivity, fistulae, and hematuria were similar among the groups. In total, 85% Primary patients and 75% Salvage patients were free from major complication (stricture, fistula, new-onset ED) at a median follow-up of 56 months. Number of needles used was independently associated with the development of incontinence (HR=1.22, 95% CI 1.02-1.47, p=0.034). Prostate volume (HR=1.14, 95% CI 1.01-1.3, p=0.05) and number of probes used (HR=1.62, 95% CI 1.03-2.58, p=0.044) were independently associated with development of urethral strictures. Salvage cryotherapy was significantly more likely to predict development of post-treatment erectile dysfunction (HR=4.33, 95% CI 1.08-17.46, p=0.039). CONCLUSIONS Major complications after cryotherapy of the prostate are relatively uncommon, though they are more likely to occur in the salvage setting. Cryotherapy for prostate cancer can be safely performed in appropriately selected patients. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e598 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Edward N. Rampersaud Los Angeles, CA More articles by this author Frederic D. Birkhauser Los Angeles, CA More articles by this author Yvonne Chan Los Angeles, CA More articles by this author Joshua E. Logan Los Angeles, CA More articles by this author Alex Wonnaparhown Los Angeles, CA More articles by this author Geoffrey Sonn Los Angeles, CA More articles by this author Arie S. Belldegrun Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

2037 INITIAL STAGING FOR HIGH RISK PROSTATE CANCER: IS THERE A ROLE FOR 11C-CHOLINE PET/CT SCAN?

INTRODUCTION AND OBJECTIVES: Initial staging of high risk prostate cancer has traditionally included a pretreatment CT and bone scan to assess for metastatic disease. We investigate the performance of C-choline PET/CT scan for staging of prostate cancer prior to definitive treatment. METHODS: Retrospective review was performed of all prostate cancer patients who underwent evaluation using C-choline PET/CT scan from 9/2007 to 11/2010 at Mayo Clinic. Test results for Ccholine PET/CT scan were compared to results from conventional imaging, targeted biopsy, or surgical resection. Statistical analysis was performed to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: 45 patients with high risk prostate cancer underwent C-choline PET/CT scan for initial staging prior to treatment. The mean and median pretreatment PSA were 29.2 and 8.4 ng/ml. The mean and median Gleason score were 8. Of these men 19 (35.5%), 13 (28.9%), and 10 (22.2%) ultimately underwent radical prostatectomy, radiotherapy, and primary androgen deprivation therapy, respectively as treatment for prostate cancer. In the setting of initial staging, the sensitivity, specificity, PPV, and NPV were 100%, 100%, 100%, and 93% respectively. C-choline PET/CT scan correctly predicted metastatic disease in 16/18 patients (89%) with confirmed metastasis. The only 2 false negative scans occurred in patients on androgen deprivation therapy at the time of PET scan who were found to have lymph node metastasis at radical prostatectomy. Additionally C-choline PET/CT scan improved detection of metastasis over conventional imaging in 5/45 patients (11%). CONCLUSIONS: C-choline PET/CT scan is an accurate diagnostic tool when used as the initial staging modality prior to definitive treatment and could potentially eliminate the need for conventional imaging modalities in this setting. C-choline PET/CT scan should be used with caution in hormone naive men on androgen deprivation therapy as false negative results are more likely.

The impact of neoadjuvant hormone therapy on the permanent 125I-seed brachytherapy for low- or intermediate-risk prostate cancer.

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 (&lt;= 5 vs &gt;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]

Tolerability of and biochemical control of permanent Pd-103 brachytherapy followed by external beam radiotherapy for localized prostate adenocarcinoma.

245 Background: The optimal sequencing of brachytherapy and external radiotherapy (EBRT) for patients receiving combined therapy for localized prostate cancer has not been established, and in this series we report our experience of patients treated with brachytherapy followed by EBRT. Methods: Retrospective review of patients treated with combined Pd-103 brachytherapy and EBRT with minimum of 2 years of follow-up. Variables assessed included T stage, Gleason score, pre-treatment PSA, use of androgen suppression (ADT), EBRT dose and brachytherapy dose. Biochemical failure was defined as a PSA rise of ≥ 2 ng/mL above nadir. Results: 87 patients received Pd-103 brachytherapy (median 80 Gy) followed by EBRT (median 45 Gy). Median age was 65 years (49–80). By risk groupings (Zelefsky) 26.4% of patients were low risk, 47.1% were intermediate risk, and 26.4% were high risk. Most low risk patients had either perineural invasion or ≥ 50% involved biopsy cores. Neoadjuvant and concurrent ADT was given in 21% of patients. With a median follow-up of 56 months (range 24 to 113), there were 4 failures (all in the intermediate or high risk group), with an overall 5-year biochemical failure free survival (BFFS) of 91.8%. 2 patients had documented distant failures, while none of the presumed local failures had a positive biopsy. There was no statistical difference in BFFS based on risk group, T stage, Gleason score, initial PSA, or ADT use. The median PSA nadir was 0.1 and occurred at a median of 30 months from brachytherapy. A nadir of ≤ 0.5 was seen in 87% of patients and was associated with improved 5-year BFFS (100% vs 22%, p&lt;.0001). The median time to PSA nadir for patients &lt; 60 years was 34.5 months compared to 26.5 months in patients ≥ 60 (p=.036). Overall, treatment was well-tolerated with no cases of late Grade ≥ 2 rectal or urinary toxicity reported. Conclusions: Excellent long-term disease control and low morbidity was observed for patients with localized prostate adenocarcinoma treated with interstitial brachytherapy followed by EBRT. Future prospective research assessing the relative therapeutic ratio of alternate sequencing approaches would appear warranted.

Positive surgical margins and biochemical recurrence in obese patients with intermediate- and high-grade prostate cancer with radical prostatectomy.

50 Background: The relationship between obesity and prostate cancer outcomes is unclear. We performed a retrospective cohort study to determine the effect of body mass index (BMI) on a cohort of patients with intermediate to high grade prostate cancer treated with radical prostatectomy (RP). Methods: Our retrospective study cohort included 582 men diagnosed with Gleason 7-10 prostate cancer between 1998 and 2008 and treated with RP at a single institution. Patients were stratified into four groups on the basis of their BMI at the time of prostate cancer diagnosis (&lt;25, 25-30, 30-35 or &gt;35). The primary endpoints for comparison were biochemical failure free survival (BFFS) and the incidence of positive margins. PSA &gt;0.2 ng/dl was used to define biochemical failure. Results: After adjusting for age, Gleason score, pre-treatment PSA and the presence of diabetes, we found patients with increasing BMI had an increased frequency of biochemical failure after RP. Compared to patients with a normal BMI (&lt;25), patients with BMI 25-30, 30-35, and &gt;35 had 1.82 (1.12, 2.97; p = 0.02), 2.14 (1.33, 3.45; p = 0.002) and 2.29 (1.1, 4.78; p = 0.03) times higher rates of biochemical failure, respectively. We additionally found increased positive margins after RP in patients with a BMI 30-35 and &gt;35 (41.4% and 45.5%, respectively) when compared to patients with a BMI of &lt;25 and 25-30 (33.3% and 28.9%, respectively); p = 0.02. Conclusions: Patients with increasing BMI seem to be at significantly increased risk for biochemical failure following RP potentially due to the increased technical difficulty of the surgery and increased incidence of positive margins. [Table: see text]

TMPRSS2-ERG status and biochemical recurrence following radiotherapy for intermediate-risk prostate cancer.

11 Background: Approximately 50% of prostate cancers (PC) contain TMPRSS2-ERG gene fusions leading to ERG overexpression. Pre-clinical data suggest that these fusions are due to altered DNA double-strand break repair status which could have therapeutic ramification for the use of radiotherapy (RT) and PARP inhibitors. The aim of this study was to correlate TMPRSS2-ERG status to biochemical failure following clinical induction of DNA breaks in the form of image-guided radiotherapy (IGRT) in intermediate-risk PC. Methods: Pre-treatment biopsies from two separate cohorts of intermediate-risk PC patients (T1/T2, GS &lt; 8, PSA &lt; 20ng/ml) were analyzed: 1) 126 patients assessed by array Comparative Genomic Hybridization (aCGH) for TMPRSS2:ERG fusion; and 2) 121 patients assessed by tissue microarray (TMA) for ERG expression by immunohistochemistry (IHC). All patients received IGRT with a median dose of 79.8 Gy (60-79.8 Gy). TMPRSS2:ERG status was correlated to Gleason score, T stage, initial PSA and biochemical-free relapse rate (bFRR; Phoenix definition: nadir + 2ng/ml). Results: At a median follow-up time of 6.36 years, the biochemical relapse event rate was 37% and 18% in the aCGH and IHC cohorts, respectively. ERG expression by IHC was found in 49.6% of the 121 PC. TMPRSS2-ERG status was not correlated to increased Gleason score, pre-treatment PSA or T stage. On multivariate analyses in models containing clinical factors, TMPRSS2:ERG status (either using aCGH or IHC) was not prognostic for biochemical outcome (ERG expression: HR=0.78, 95% CI: 0.33-1.85; p= 0.568; TMPRSS2-ERG fusion: HR=0.71, 95% CI: 0.35-1.41; p=0.326). Conclusions: In two separate cohorts, TMPRSS2-ERG status was not prognostic for bRFR after IGRT. Although a trend was observed, these clinical data do not support the hypothesis that these cancers have DNA repair defects that render them significantly more radiosensitive when compared to other PC. Further clinical trials are required to understand the utility of TMPRSS2:ERG status and response to DNA damaging agents, including that of PARP inhibitors. The trans-Canadian PROFIT trial is completing accrual of close to 1200 patients allowing for TMPRSS2:ERG studies in a larger RT cohort.

The effects of body mass index on pretreatment characteristics, treatment choice, and response to treatment of intermediate- and high-grade prostate cancer.

142 Background: The relationship between obesity and prostate cancer outcomes remains unclear. A retrospective cohort study was performed to determine the effect of body mass index (BMI) on patients with intermediate to high-grade prostate cancer. Methods: Our retrospective study cohort included 1077 men from the South Texas Veteran’s Healthcare System Tumor Registry diagnosed with Gleason 7-10 prostate cancer in 1998-2008 and treated with either radical prostatectomy (RP), radiation therapy (RT) or hormone therapy (HT). Mean follow up was 4.6 ± 2.7 years. Patients were stratified into four groups on the basis of their BMI at the time of prostate cancer diagnosis (&lt;25, 25-30, 30-35 or &gt;35). Statistical analysis included Kruskal-wallis test and Pearson’s Chi-square test. Results: There was an inverse relationship between PSA and BMI at diagnosis; however, we found no difference in Gleason score at diagnosis. There was a difference in the primary treatment modality chosen between the BMI groups. Primary treatment modality decision was likely influenced by PSA at diagnosis, among other pre-treatment characteristics. Patients with a BMI &gt;35 were significantly less likely to undergo RP. However, after controlling for age, primary treatment modality, Gleason score, pre-treatment PSA and diabetes diagnosis, there was no difference in overall mortality. Conclusions: Patients with an increasing BMI have a lower PSA at diagnosis, are less likely to receive RP but do not have significantly worse overall survival.

A randomized phase II study of bicalutamide (BIC) followed by placebo or gamma secretase inhibitor RO4929097 (RO492) in men with rising PSA.

219 Background: Notch signaling is a key determinant of cell fate. RO492 is a selective γ-secretase inhibitor blocking cleavage of Notch. We hypothesize that anti-androgen therapy will lead to an enriched population of basal prostate cancer stem cells. Targeting Notch following anti-androgen treatment will lead to delay in re-growth of mature luminal PC cells. We are using a novel double blind, placebo controlled randomized discontinuation design to treat men with rising PSA. A non-castrating anti-androgen (BIC) was used to induce initial tumor regression Methods: Pts with rising PSA after primary therapy for PC, and no radiographic evidence of disease were enrolled in this ongoing study. All pts received BIC 50mg/day for 16 weeks (induction phase). Pts achieving a &gt;50% (modified from 80% decrease after the first 8 pts) decrease in PSA were randomized to placebo or RO492 20mg orally 3 days on/ 4 days off per week (randomization phase). Primary endpoint is PSA progression (increase in PSA by 50% over nadir with minimum PSA rise of 2ng/mL) during randomization phase. Pts meeting primary endpoint could receive 12 months of RO492 and BIC (combination phase). Serum is collected for evaluation of soluble markers of gamma secretase inhibition. 29 pts/arm in randomization phase gives 90% power to detect a decrease in1 yr PFS from 80% to 45% with 5% alpha. Results: We report on the first 16 patients that have enrolled. Median pretreatment PSA was 6.3ng/ml (0.35 to 34). 9 of 16 pts on the induction phase came off study due to PSA progression, although 5 of 9 pts would have been randomized using the 50% PSA response criteria. 6 pts have been randomized to RO492 or placebo (1 pt not yet randomized) and 2 pts have proceeded to combination phase. Median PSA decrease during induction phase in 6 pts who went on to randomization was 86% (69–97). Overall decline in PSA in induction phase was 67% (7.3-99%). Placebo/RO492 has been well tolerated with 1 pt experiencing g1 fatigue, and 1 pt experiencing g1 nausea in the combination phase. 8/16 pts had g1 breast tenderness with BIC. Conclusions: In this ongoing randomized phase II trial, BIC decreased PSA by &gt;50% in 12/16 pts. Placebo/RO492 is well tolerated. Enrollment continues with analysis of plasma correlates to be compared to clinical results.

A phase II study of atorvastatin and celecoxib in patients with rising PSA following local therapy for prostate cancer (PC).

89 Background: Single agent atorvastatin and celecoxib have been associated with reductions in the risk of PC. Our laboratories have demonstrated that low doses of the drug combination have synergistic effects inhibiting the progression of LNCaP tumors to androgen independence. We therefore sought to determine the effects of the combination in androgen-dependent PC on PSA kinetics and the plasma correlates of IL-6, C-reactive protein (CRP), PGE-2, and the pharmacokinetics of the drug combination to validate preclinical biomarker findings. Methods: Patients with rising PSA after primary therapy for PC were enrolled. Patient must have three rising PSA values, each obtained at least 1 month apart. No prior hormone-ablative therapy was allowed, except in the neoadjuvant setting or in the setting of salvage XRT completed 3 months prior to enrollment. Patients with any history of coronary artery disease or a previous myocardial infarction in the past 6 months were excluded. All patients were treated with atorvastatin 20 mg daily and celecoxib 200 mg twice a day for 6 months. Paired pre-treatment and on treatment PSA kinetics were compared using the Wilcoxon Signed Rank test. Results: We report on 14 patients that have completed therapy. Median pretreatment PSA slope was 0.14 log PSA/mo (median PSADT 4.98 mos), in contrast to the median on treatment slope of 0.09 log PSA/mo (median PSADT 7.37 mos); p=0.11. Eleven of the fourteen patients completed the 6 months of therapy, 1 patient withdrew and 2 patients therapy was stopped early due to lack of response. A declining PSA was observed in one patient. The combination was well tolerated, with no clinically significant therapy related toxicities ( &gt; grade 1) reported in 76 months of therapy. Conclusions: In this ongoing phase II trial, the combination of low dose atorvastatin and celecoxib has been well tolerated and demonstrates a tendency of increasing PSA doubling time. Enrollment continues with analysis of IL-6, CRP, and PGE-2 to be correlated to individual clinical results.

The Effect of Obesity and Diabetes on Intermediate to High Grade Prostate Cancer Patients Treated with Radical Prostatectomy

Aims: The relationships between obesity, diabetes and prostate cancer are unclear. A retrospective study was performed to determine the effects of body mass index (BMI) and diabetes on patients with intermediate to high grade prostate cancer treated with radical prostatectomy. Methods: We reviewed 582 patients with Gleason score ≥ 7 non-metastatic prostate cancer treated with radical prostatectomy. Patients were stratified by BMI. End points were biochemical failure free survival (BFFS), overall survival (OS), and cancer specific survival (CSS). Results: Mean pre-treatment PSA decreased with increasing BMI (12.5, 7.6, 7.8 and 5.3 ng/mL with BMI 35, respectively; p 35, respectively. However, for overall mortality the adjusted hazard ratio was 0.39 (0.18, 0.82; p = 0.01) for overweight patients (BMI 25 - 30) compared to patients with a BMI in the normal range. Patients with a BMI of 30 - 35 and > 35 had increased rates of positive margins than those with a BMI of 25 - 30 or 35 2.04) on multivariate analysis, margin positivity alone was not a significant factor. Conclusions: Patients with increasing BMI tend to have a lower PSA at diagnosis but are more likely to have biochemical failure after radical prostatectomy. In our cohort, this was not due to the increased incidence of positive margins. Having diabetes had no effect.

Prediction of Response to Androgen Deprivation Therapy and Castration Resistance in Primary Metastatic Prostate Cancer

Purpose: We tried to establish the predictive factors influencing the initial response, as well as its duration, and time to castration resistance (CR) for primary advanced prostate cancer (PC) with bone metastasis. Methods: We evaluated all patients initially receiving androgen deprivation therapy (ADT) for primary advanced PC with bone metastasis. A total of 982 patients with complete medical records available for analysis from 18 centers were included in this study. Age, initial PSA, Gleason score (GS) and extent of bone involvement (EBI) were recorded in a database. Results: Among all the patients, 896 (91.2%) responded to ADT initially. Pretreatment PSA and EBI were significant predictors in the multivariate model. Among the 659 patients who progressed into a CR state, the mean duration of response was 22.4 months. There was a significant correlation between the CR state and nadir PSA (nPSA) level and time to nPSA. Pretreatment PSA, EBI, GS, highest tumor volume in biopsy cores (%), number of positive biopsy cores, percent positive biopsy cores and time to nPSA were proven to be significant to predict a nPSA. Pretreatment PSA, GS and EBI were statistically significant predictors of PSA normalization in multivariate analysis. The limitation of the study depends on the retrospective design and a model was developed for low standardization as a result of using multicenter data. The patients enrolled in this study were from a relatively long period of time (1989–2008). Conclusions: The results of this study indicate that it is possible to predict the initial response to ADT by pretreatment PSA levels and EBI, while the duration of response can be reflected by a multitude of clinical factors including nPSA, TTnPSA, percent positive cores, biopsy GS and EBI.

The additional value of TGFβ1 and IL-7 to predict the course of prostate cancer progression

BackgroundGiven the fact that prostate cancer incidence will increase in the coming years, new prognostic biomarkers are needed with regard to the biological aggressiveness of the prostate cancer diagnosed. Since cytokines have been associated with the biology of cancer and its prognosis, we determined whether transforming growth factor beta 1 (TGFβ1), interleukin-7 (IL-7) receptor and IL-7 levels add additional prognostic information with regard to prostate cancer-specific survival.Materials and methodsRetrospective survival analysis of forty-four prostate cancer patients, that underwent radical prostatectomy, was performed (1989–2001). Age, Gleason score and pre-treatment PSA levels were collected. IL-7, IL-7 receptor and TGFβ1 levels in prostate cancer tissue were determined by quantitative real-time RT-PCR and their additional prognostic value analyzed with regard to prostate cancer survival. Hazard ratios and their confidence intervals were estimated, and Akaike’s information criterion was calculated for model comparison.ResultsThe predictive ability of a model for prostate cancer survival more than doubled when TGFβ1 and IL-7 were added to a model containing only the Gleason score and pre-treatment PSA (AIC: 18.1 and AIC: 6.5, respectively).ConclusionIL-7 and TGFβ1 are promising markers to indicate those at risk for poor prostate cancer survival. This additional information may be of interest with regard to the biological aggressiveness of the diagnosed prostate cancer, especially for those patients screened for prostate cancer and their considered therapy.