Equal Access Regional Cancer Hospital Research Articles

Abstract B72: Metformin use and risk of biochemical recurrence following radical prostatectomy: Results from the SEARCH database

Abstract Introduction: Metformin is currently the drug of choice for management of type II diabetes mellitus. Recent epidemiological studies have reported that metformin use among diabetics decreases the risk of developing a variety of cancer types, including prostate cancer (PCa). However, the effect of metformin use on PCa outcome has yet to be clarified. The aim of this study was to investigate the association between pre-operative metformin use and biochemical recurrence (BCR) in a cohort of diabetic men who underwent radical prostatectomy (RP). Methods: We performed a retrospective analysis of 337 men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database treated for PCa with RP and with a diagnosis of diabetes prior to surgery. Cox proportional hazard models were used to assess time to BCR for diabetic men taking metformin in the year prior to RP compared to diabetic men not taking metformin. Models were adjusted for age, race, year of surgery, surgical center, pre-operative PSA and biopsy Gleason score. Results: Of 337 diabetic men, 173 (51%) were taking metformin in the year before RP. The median follow-up among men who did not recur was 49 months, during which 112 men (33%) experienced BCR. Metformin use was associated with more recent year of surgery (median 2005 vs. 2001; p<0.001) but not with age, race, BMI or biopsy Gleason score (all p>0.1). Diabetics taking metformin had lower pre-operative PSA (p=0.12) yet higher prostate volume (p=0.17), relative to diabetics not on metformin, though these associations did not reach statistical significance. On unadjusted analyses, metformin use was not significantly associated with BCR (log-rank, p=0.29). After adjusting for multiple pre-operative features, metformin use in the year before surgery remained not related to BCR (HR 0.97, 95% CI 0.59 to 1.60, p=0.912). Conclusion: In this cohort of diabetic men treated for PCa with RP, metformin use in the year prior to surgery was not significantly associated with time to BCR. Although this is the largest study to date to test the role of metformin among diabetics undergoing RP, larger studies with longer follow-up are needed to better assess whether metformin is associated with improved PCa outcomes, though the current study suggested no role for metformin for PCa control. Citation Format: Emma H. Allott, Michael R. Abern, Leah Gerber, Christopher J. Keto, William J. Aronson, Martha K. Terris, Joseph C. Presti, Christopher J. Kane, Christopher L. Amling, Stephen J. Freedland. Metformin use and risk of biochemical recurrence following radical prostatectomy: Results from the SEARCH database. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B72.

Delayed radical prostatectomy for intermediate‐risk prostate cancer is associated with biochemical recurrence: Possible implications for active surveillance from the SEARCH database

Active surveillance (AS) is increasingly accepted as appropriate management for low-risk prostate cancer (PC) patients. It is unknown whether delaying radical prostatectomy (RP) is associated with increased risk of biochemical recurrence (BCR) for men with intermediate-risk PC. We performed a retrospective analysis of 1,561 low and intermediate-risk men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database treated with RP between 1988 and 2011. Patients were stratified by interval between diagnosis and RP (≤ 3, 3-6, 6-9, or >9 months) and by risk using the D'Amico classification. Cox proportional hazard models were used to analyze BCR. Logistic regression was used to analyze positive surgical margins (PSM), extracapsular extension (ECE), and pathologic upgrading. Overall, 813 (52%) men were low-risk, and 748 (48%) intermediate-risk. Median follow-up among men without recurrence was 52.9 months, during which 437 men (38.9%) recurred. For low-risk men, RP delays were unrelated to BCR, ECE, PSM, or upgrading (all P > 0.05). For intermediate-risk men, however, delays >9 months were significantly related to BCR (HR: 2.10, P = 0.01) and PSM (OR: 4.08, P < 0.01). Delays >9 months were associated with BCR in subsets of intermediate-risk men with biopsy Gleason score ≤ 3 + 4 (HR: 2.51, P < 0.01), PSA ≤ 6 (HR: 2.82, P = 0.06), and low tumor volume (HR: 2.59, P = 0.06). For low-risk men, delayed RP did not significantly affect outcome. For men with intermediate-risk disease, delays >9 months predicted greater BCR and PSM risk. If confirmed in future studies, this suggests delayed RP for intermediate-risk PC may compromise outcomes.

Obesity, Prostate-Specific Antigen Nadir, and Biochemical Recurrence After Radical Prostatectomy: Biology or Technique? Results from the SEARCH Database

BackgroundObesity is associated with an increased risk of biochemical recurrence (BCR) after radical prostatectomy (RP). It is unclear whether this is due to technical challenges related to operating on obese men or other biologic factors. ObjectiveTo examine whether obesity predicts higher prostate-specific antigen (PSA) nadir (as a measure of residual PSA-producing tissue) after RP and if this accounts for the greater BCR risk in obese men. Design, setting, and participantsA retrospective analysis of 1038 RP patients from 2001 to 2010 in the multicenter US Veterans Administration–based Shared Equal Access Regional Cancer Hospital database with median follow-up of 41 mo. InterventionAll patients underwent RP. Outcome measurements and statistical analysisWe evaluated the relationship between body mass index (BMI) and ultrasensitive PSA nadir within 6 mo after RP. Adjusted proportional hazards models were used to examine the association between BMI and BCR with and without PSA nadir. Results and limitationsMean BMI was 28.5kg/m2. Higher BMI was associated with higher PSA nadir on both univariable (p=0.001) and multivariable analyses (p<0.001). Increased BMI was associated with increased BCR risk (hazard ratio [HR]: 1.06; p=0.007). Adjusting for PSA nadir slightly attenuated, but did not eliminate, this association (HR: 1.04, p=0.043). When stratified by PSA nadir, obesity only significantly predicted BCR in men with an undetectable nadir (p=0.006). Unfortunately, other clinically relevant end points such as metastasis or mortality were not available. ConclusionsObese men are more likely to have a higher PSA nadir, suggesting that either more advanced disease or technical issues confound an ideal operation. However, even after adjusting for the increased PSA nadir, obesity remained predictive of BCR, suggesting that tumors in obese men are growing faster. This provides further support for the idea that obesity is biologically associated with prostate cancer progression.

Are Repeat Prostate Biopsies Safe? A Cohort Analysis From the SEARCH Database

Patients question whether multiple biopsy sessions cause worse prostate cancer outcomes. Therefore, we investigated whether there is an association between the number of prior biopsy sessions and biochemical recurrence after radical prostatectomy. Men in the SEARCH (Shared Equal Access Regional Cancer Hospital) database who underwent radical prostatectomy between 1988 and 2010 after a known number of prior biopsies were included in the analysis. Number of biopsy sessions (range 1 to 8) was examined as a continuous and categorical (1, 2 and 3 to 8) variable. Biochemical recurrence was defined as a prostate specific antigen greater than 0.2 ng/ml, 2 values at 0.2 ng/ml or secondary treatment for an increased prostate specific antigen. The association between number of prior biopsy sessions and biochemical recurrence was analyzed using the Cox proportional hazards model. Kaplan-Meier estimates of freedom from biochemical recurrence were compared among the groups. Of the 2,739 men in the SEARCH database who met the inclusion criteria 2,251 (82%) had only 1 biopsy, 365(13%) had 2 biopsies and 123 (5%) had 3 or more biopsies. More biopsy sessions were associated with higher prostate specific antigen (p<0.001), greater prostate weight (p<0.001), lower biopsy Gleason sum (p=0.01) and more organ confined (pT2) disease (p=0.017). The Cox proportional hazards model demonstrated no association between number of biopsy sessions as a continuous or categorical variable and biochemical recurrence. Kaplan-Meier estimates of freedom from biochemical recurrence were similar across biopsy groups (log rank p=0.211). Multiple biopsy sessions are not associated with an increased risk of biochemical recurrence in men undergoing radical prostatectomy. Multiple biopsy sessions appear to select for a low risk cohort.

162 MULTI-INSTITUTIONAL VALIDATION OF THE CAPRA-S SCORE TO PREDICT OUTCOMES AFTER RADICAL PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Epidemiology and Natural History I1 Apr 2012162 MULTI-INSTITUTIONAL VALIDATION OF THE CAPRA-S SCORE TO PREDICT OUTCOMES AFTER RADICAL PROSTATECTOMY Sanoj Punnen, Stephen Freedland, Joseph Presti, Christopher Kane, Christopher Amling, Martha Terris, William Aaronson, Peter Carroll, and Matthew Cooperberg Sanoj PunnenSanoj Punnen San Francisco, CA More articles by this author , Stephen FreedlandStephen Freedland Durham, NC More articles by this author , Joseph PrestiJoseph Presti Palo Alto, CA More articles by this author , Christopher KaneChristopher Kane San Diego, CA More articles by this author , Christopher AmlingChristopher Amling Portland, OR More articles by this author , Martha TerrisMartha Terris Augusta, GA More articles by this author , William AaronsonWilliam Aaronson Los Angeles, CA More articles by this author , Peter CarrollPeter Carroll San Francisco, CA More articles by this author , and Matthew CooperbergMatthew Cooperberg San Francisco, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.213AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The UCSF Cancer of the Prostate Risk Assessment - post-Surgical (CAPRA-S) score is a novel risk assessment tool that uses postoperative pathological data to predict the risk of recurrence post radical prostatectomy. The objective of this study was to validate its use in a large external database. METHODS The Shared Equal Access Regional Cancer Hospital (SEARCH) database is a registry of men who underwent radical prostatectomy at one of 4 Veterans Affairs medical centers. 2078 (94%) of the 2,211 men in SEARCH had complete data available to calculate a CAPRA-S score. The CAPRA-S is determined by adding up to 3 points each for PSA and pathological Gleason score, 2 points each for positive surgical margins and seminal vesicle invasion and 1 point each for extracapsular extension and lymph node involvement. Performance of the CAPRA-S score was assessed using proportional hazards regression, and compared to the Stephenson nomogram by the concordance (c) index, calibration plots and decision curves analysis. RESULTS Among this cohort, the mean age was 62 (SD 6.3) years and 33.3 % of men recurred. Median follow up was 60.7 months among men who did not recur. The hazard ratio (HR) for each one-point increase in the CAPRA-S score was 1.42 (95%CI 1.37-1.46). The 5-year progression free probability for those patients with a CAPRA-S score of 0-2, 3-5 and 6-10 (a priori defined as low-, intermediate-, and high-risk from the initial CAPRA-S development paper) were 72%, 41%, and 14%, respectively. The CAPRA-S c-index was 0.75 in this validation set, compared to a c-index of 0.73 for the Stephenson nomogram and 0.77 for CAPRA-S in the original development set. The CAPRA-S score performed better than the Stephenson nomogram on both calibration plots and decision curves analysis. CONCLUSIONS In this external validation study the CAPRA-S score accurately predicted recurrence after radical prostatectomy in a large cohort of men better than another published nomogram. The score is an effective prognostic tool with potential broad applicability in the clinical and research settings. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e67 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sanoj Punnen San Francisco, CA More articles by this author Stephen Freedland Durham, NC More articles by this author Joseph Presti Palo Alto, CA More articles by this author Christopher Kane San Diego, CA More articles by this author Christopher Amling Portland, OR More articles by this author Martha Terris Augusta, GA More articles by this author William Aaronson Los Angeles, CA More articles by this author Peter Carroll San Francisco, CA More articles by this author Matthew Cooperberg San Francisco, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Does salvage radiation therapy (SRT) change the biology of recurrent prostate cancer (PCa) based on PSA doubling times (PSADT)? Results from the SEARCH database.

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).

Poor Agreement of Prostate Specific Antigen Doubling Times Calculated Using Ultrasensitive Versus Standard Prostate Specific Antigen Values: Important Impact on Risk Assessment

In men with biochemical recurrence after radical prostatectomy, a rapid prostate specific antigen doubling time is associated with adverse outcomes, and is often used to guide the type and timing of salvage therapy. It is unknown whether prostate specific antigen doubling time calculated in the ultrasensitive range (prostate specific antigen less than 0.2 ng/ml) accurately reflects measures performed in the traditional range (prostate specific antigen greater than 0.2 ng/ml). We studied 394 men in a national disease registry of men with prostate cancer (CaPSURE™) who underwent radical prostatectomy, experienced biochemical failure, and had prostate specific antigen doubling time assessed using ultrasensitive and traditional prostate specific antigen values. Agreement between these measurements was assessed using Cohen's kappa score. Median ultrasensitive prostate specific antigen doubling time was 11.9 months (IQR 6-29) and median traditional prostate specific antigen doubling time was 240 months (IQR 18-240). Agreement between ultrasensitive and traditional prostate specific antigen doubling time was poor, with a weighted Cohen's kappa score of 0.04 (95% CI -0.02-0.10). Using a dichotomous prostate specific antigen doubling time cutoff of 9 months, there was a statistically significant difference between ultrasensitive and standard prostate specific antigen doubling time (exact McNemar p <0.01). Ultrasensitive prostate specific antigen doubling time was more or less rapid than traditional prostate specific antigen doubling time by more than 15 months in 244 (62%) and 35 (9%) patients, respectively. Agreement between prostate specific antigen doubling time calculated using ultrasensitive vs traditional prostate specific antigen values is poor. Ultrasensitive prostate specific antigen doubling time is often significantly more rapid than traditional prostate specific antigen doubling time, potentially overestimating the risk of clinical recurrence. Until the significance of ultrasensitive prostate specific antigen doubling time is better characterized, the decision to proceed with salvage therapy should not be based on prostate specific antigen doubling time calculated using ultrasensitive prostate specific antigen values.

Preoperative weight change and risk of adverse outcome following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital database

We examined the relationship between weight change in the year before radical prostatectomy (RP) and biochemical recurrence (BCR) and adverse pathology. We abstracted data from 359 men undergoing RP in the SEARCH (Shared Equal Access Regional Cancer Hospital) database between 2001-2007. Logistic regression and Cox proportional hazards models were used to test the association between weight change in the year before surgery and adverse pathology and BCR, respectively. In all, 152 (42%) men gained weight, 193 (54%) lost weight and 14 (4%) had the same weight. Among weight gainers, median gain was 2.4 kg and among weight losers, median loss was 2.7 kg. As a continuous variable, weight change was not associated with adverse pathology or BCR (all P>0.05). In secondary analysis, on multivariate analysis, men gaining ≥ 2.5 kg were at higher BCR risk (hazards ratio=1.65, 95% confidence interval (CI): 1.03-2.64, P=0.04) while weight loss ≥ 2.5 kg was not associated with BCR (hazards ratio=0.83, 95% CI: 0.54-1.29, P=0.41). As a continuous variable, weight change was not associated with outcome. In secondary hypothesis-generating analyses, weight gain ≥ 2.5 kg in the year before surgery, regardless of final body mass index, was associated with increased BCR following RP. If validated, these data suggest weight gain ≥ 2.5 kg may promote prostate cancer progression.

Oxidative Stress Measured by Urine F2-Isoprostane Level is Associated With Prostate Cancer

Oxidative stress is implicated in prostate cancer by several lines of evidence. We studied the relationship between the level of F2-isoprostanes, a validated biomarker of oxidative stress, and prostate cancer and high grade prostatic intraepithelial neoplasia. This case-control analysis within the Nashville Men's Health Study included men recruited at prostate biopsy. Body morphometrics, health history and urine were collected from more than 2,000 men before biopsy. F2-isoprostanes were measured by gas chromatography/mass spectrometry within an age matched sample of Nashville Men's Health Study participants that included 140 patients with high grade prostatic intraepithelial neoplasia, 160 biopsy negative controls and 200 prostate cancer cases. Multivariable linear and logistic regression was used to determine the associations between F2-isoprostane level, and high grade prostatic intraepithelial neoplasia and prostate cancer. Mean patient age was 66.9 years (SD 7.2) and 10.1% were nonwhite. Adjusted geometric mean F2-isoprostane levels were higher in patients with prostate cancer (1.82, 95% CI 1.66-2.00) or high grade prostatic intraepithelial neoplasia (1.82, 95% CI 1.68-1.96) than in controls (1.63, 95% CI 1.49-1.78, p <0.001), but were similar across Gleason scores (p = 0.511). The adjusted odds of high grade prostatic intraepithelial neoplasia and prostate cancer increased with increasing F2-isoprostane quartile (p-trend = 0.015 and 0.047, respectively) and the highest F2-isoprostane quartile was associated with significantly increased odds of prostate cancer (OR 2.44, 95% CI 1.17-5.09, p = 0.017). Pre-diagnosis urine F2-isoprostane level is increased in men with high grade prostatic intraepithelial neoplasia or prostate cancer, suggesting urinary F2-isoprostane provides a biomarker for the role for oxidative stress in prostate carcinogenesis. F2-isoprostanes may also serve to estimate the efficacy of interventions targeting oxidative stress mechanisms in prostate cancer prevention or treatment.

2292 PSA NADIR DURING ANDROGEN DEPRIVATION THERAPY PREDICTS ADVERSE PROSTATE CANCER SPECIFIC OUTCOMES: RESULTS FROM THE SEARCH DATABASE

You have accessJournal of UrologyProstate Cancer: Markers1 Apr 20112292 PSA NADIR DURING ANDROGEN DEPRIVATION THERAPY PREDICTS ADVERSE PROSTATE CANCER SPECIFIC OUTCOMES: RESULTS FROM THE SEARCH DATABASE Christopher J. Keto, William J. Aronson, Martha K. Terris, Joseph C. Presti, Christopher L. Amling, Christopher J. Kane, and Stephen J. Freedland Christopher J. KetoChristopher J. Keto Durham, NC More articles by this author , William J. AronsonWilliam J. Aronson Los Angeles, CA More articles by this author , Martha K. TerrisMartha K. Terris Augusta, GA More articles by this author , Joseph C. PrestiJoseph C. Presti Palo Alto, CA More articles by this author , Christopher L. AmlingChristopher L. Amling Portland, OR More articles by this author , Christopher J. KaneChristopher J. Kane San Diego, CA More articles by this author , and Stephen J. FreedlandStephen J. Freedland Durham, NC More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2537AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Traditionally, a PSA nadir on androgen deprivation therapy (ADT) >4 ng/ml has been correlated with poor outcome. More recently, a PSA nadir >0.2 ng/ml has been associated with prostate cancer (PC) specific mortality (PCSM). However, whether all men with nadir values <0.2 ng/ml have similar outcomes is untested. We examined the predictive value of PSA nadir including small but detectable nadir values during ADT on PC specific outcomes in men treated with early ADT for PSA-only recurrence after radical prostatectomy (RP) within the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort. METHODS We retrospectively reviewed data from 2892 men treated with RP between 1988 and 2010 within the SEARCH database to identify men treated with early ADT, defined as no evidence of metastatic disease at the start of ADT. PSA nadir on ADT was defined as the lowest PSA value during continuous ADT. PSA nadir was analyzed as a continuous variable and was also categorized to three groups: 0, 0.01–0.2, and >0.2ng/mL. Cox proportional hazards models were used to examine the link between PSA nadir and castrate resistant PC (CRPC), metastatic disease, and PCSM with the date of PSA nadir on ADT as time zero. RESULTS During a median follow-up of 73 months after RP, 405 men (14%) were treated with early ADT. Of these men, 322 had complete data for analysis with a median follow-up after ADT nadir of 51 months. When examined as a continuous variable, higher PSA nadir on ADT was associated with progression to CRPC (HR=2.5, p<0.0001), development of metastatic disease (HR=2.1, p=0.001) and PCSM (HR=1.8, p=0.020). Men with a PSA nadir between 0.01–0.2 ng/mL were more likely to progress to CRPC (HR=4.1, p=0.001), develop metastases (HR=3.3, p=0.027) and ultimately die of prostate cancer (HR=4.5, p=0.011) than men with an undetectable nadir. Finally, relative to men with an undetectable nadir, those with a nadir >0.2ng/mL were at the greatest risk of progression to CRPC (HR=29.0, p=0.001), development of metastases (HR=13.1, p<0.001) and PCSM (HR=9.3, p<0.0001). CONCLUSIONS A detectable PSA nadir on ADT of any level is associated with increased risk for CRPC, metastases, and PCSM. Men who do not achieve an undetectable PSA nadir during ADT are at a dramatically increased risk of disease progression and therefore, should be considered for clinical trials. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e919 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher J. Keto Durham, NC More articles by this author William J. Aronson Los Angeles, CA More articles by this author Martha K. Terris Augusta, GA More articles by this author Joseph C. Presti Palo Alto, CA More articles by this author Christopher L. Amling Portland, OR More articles by this author Christopher J. Kane San Diego, CA More articles by this author Stephen J. Freedland Durham, NC More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Obese men, higher PSA nadir values after radical prostatectomy (RP), and higher biochemical recurrence (BCR) rates: Results from the SEARCH database.

186 Background: Obesity is associated with risk of BCR after RP. It has been suggested this may be due to poor surgical technique and greater risk of positive margins. We examined whether obesity predicted the risk of a detectable PSA nadir after RP (as a measure of residual PSA-producing tissue left behind) and if this accounted for the greater risk of BCR in obese men in the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Methods: We identified 1,011 men treated with RP from 2001 to 2010 in SEARCH who had known data for pre-operative BMI and ultrasensitive PSA nadir within 6 months after RP. The association between BMI (&lt;25, 25-29.9, and &gt;30 kg/m2) and PSA nadir (0, 0.01-0.09, 0.10-0.19, and &gt;0.2) was tested using chi-squared and linear regression adjusting for clinical and pathological characteristics. A proportional hazards model was used to test the association between BMI and BCR adjusted for clinical and pathological characteristics and with and without PSA nadir. Results: Higher BMI was associated with higher PSA nadir (chi-squared, p=0.03). On multivariate analysis, obesity (p&lt;0.001) was associated with higher PSA nadir. Among men with a PSA nadir &lt;0.2 ng/ml (i.e. those who did not recur based upon PSA nadir alone), obesity was associated with BCR when not adjusted for PSA nadir (HR 1.85, 95% CI 1.19-2.89, p=0.007). Adjusting for PSA nadir attenuated, but did not eliminate this association (HR 1.65, 95% CI 1.05-2.59, p=0.03). Even among men with an undetectable PSA nadir, obesity remained significantly associated with BCR (HR 3.45, 95% CI 1.41-8.47, p=0.007). Interestingly, among men with a detectable PSA nadir, but &lt;0.2 ng/ml, obesity did not predict BCR with (HR 1.21, 95% CI 0.71-2.07, p=0.49) or without adjustment for PSA nadir (HR 1.41, 95% CI =0.82-2.41, p=0.22). Conclusions: Obese men are more likely to have a higher PSA nadir suggesting technical issues confound an ideal operation in obese men. However, the increased PSA nadir does not completely explain the higher PSA recurrence rates. These data further support the idea that obesity is biologically associated with prostate cancer progression. No significant financial relationships to disclose.

Editorial Comment to Postoperative prostate‐specific antigen nadir improves accuracy for predicting biochemical recurrence after radical prostatectomy: Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) and Duke Prostate Center databases

The follow up and management of patients who have undergone surgery for prostate cancer involves surveillance for recurrent disease and the functional rehabilitation of the patient. There are a number of established nomograms for predicting biochemical relapse in prostate cancer1 using available tumor and patient specific data, thus allowing the practitioner to tailor the follow up regime to the patient. This paper has introduced another commonly available variable, the PSA nadir, which involves no extra cost to the patient or the clinician.2 The authors have added this to the established nomogram variables to develop a more accurate nomogram. The paper uses some very good statistical tools to show the superiority of their nomogram, but it does not go on to show the clinical value of this improvement. They have validated their nomogram for both the traditional and the ultrasensitive prostate-specific antigen (uPSA) assays, showing the superiority of their nomogram. There is differing opinion on the merits of the use of the uPSA assay, which has advantages over standard assays in postoperative surveillance and prognostication. It allows for earlier detection of biochemical relapse by approximately 11–18 months over traditional methods.3, 4 Defining biochemical relapse in uPSA monitored patients is still debated. Some authors feel there is too much “background noise” with uPSA at the very lowest levels to make this technique specific enough.5 Others recommend that two sequential rises in uPSA is not specific enough and that one should wait to see four sequential rises before diagnosing biochemical failure.4 By identifying and characterizing relapsing patients early, they can be offered salvage therapeutic interventions. It has been suggested that early salvage treatment helps increase the chance of relapse-free survival.6 This paper provides further literature to support the use of the uPSA assay. The strengths in this paper are found in their statistical handling of the data. The principal weakness is the retrospective nature of their cohort. The clinical value of their nomogram is unclear and an evaluation of this in comparison with other nomograms in a prospective study would be valuable. I look forward to using this assay with my prostatectomy patients.

Postoperative prostate‐specific antigen nadir improves accuracy for predicting biochemical recurrence after radical prostatectomy: Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) and Duke Prostate Center databases

We previously showed that prostate-specific antigen (PSA) nadir after radical prostatectomy (RP) significantly predicts biochemical recurrence (BCR). Herein, we sought to explore the effect of including PSA nadir into commonly used models on their accuracy to predict BCR after RP. This was a retrospective analysis of 943 and 1792 subjects from the Shared Equal Access Regional Cancer Hospital (SEARCH) and Duke Prostate Cancer (DPC) databases, respectively. The discrimination accuracy for BCR of seven previously published models was assessed using concordance index and compared with and without adding PSA nadir level in SEARCH. Using data from SEARCH, we developed a new nomogram incorporating PSA nadir to other known predictors (preoperative PSA, pathological Gleason score, PSA nadir level, surgical findings, prostate weight, body mass index and race) of BCR and externally validated it in the DPC. In SEARCH, the mean concordance index across all seven nomograms was 0.687. After the inclusion of PSA nadir, the concordance index increased by nearly 7% (mean=0.753). The concordance index of the new nomogram in SEARCH was 0.779 (bias-corrected=0.767), which was 5% better than the next best model. In DPC, the new nomogram yielded a concordance index of 0.778. The addition of postoperative PSA nadir to commonly used nomograms increased their accuracies by nearly 7%. Based upon this, we developed and externally validated a new nomogram, which was well calibrated and highly accurate, and is a potentially valuable tool for patients and physicians to predict BCR after RP.

A natural history of weight change in men with prostate cancer on androgen-deprivation therapy (ADT): results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

• To better understand the natural history of weight change with androgen-deprivation therapy (ADT), we investigated the effect of ADT on body weight among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. • Men undergoing ADT lose lean muscle but gain fat mass, contributing to an overall gain in weight. • We identified 132 men in SEARCH who received ADT after radical prostatectomy. • 'Weight change' was defined as the difference in weight before starting ADT (6 months before ADT) and the on-ADT weight (between 6 and 18 months after starting ADT). • In a subanalysis, baseline characteristics of weight-gainers and -losers were analysed using univariate and multivariate analysis to test association with weight change. • In all, 92 men (70%) gained weight, and 40 (30%) either lost or maintained a stable weight. • On average, weight on ADT was 2.2 kg higher than the weight before ADT, with the mean change for weight-gainers and -losers being +4.2 kg and -2.4 kg, respectively. • This compared with no significant weight change in the year before starting ADT (paired t-test, change -0.7 kg, P= 0.19) or in the second year on ADT (paired t-test, change -0.5 kg, P= 0.46) for 84 men in whom these additional weight values were recorded. • There was no significant association between any of the features examined and weight change on univariate and multivariate analysis. • In this longitudinal study, ADT was accompanied by significant weight gain (+2.2 kg). This change occurred primarily in the first year of therapy, with men neither losing nor gaining additional weight thereafter.

External validation of the SEARCH model for predicting aggressive recurrence after radical prostatectomy: results from the Duke Prostate Center Database

To validate a model previously developed using the Shared Equal Access Regional Cancer Hospital (SEARCH) database to predict the risk of aggressive recurrence after surgery, defined as a prostate-specific antigen (PSA) doubling time (DT) of <9 months, incorporating pathological stage, preoperative PSA level and pathological Gleason sum, that had an area under the curve (AUC) of 0.79 using a cohort of men from the Duke Prostate Center (DPC). Data were included from 1989 men from the DPC database who underwent RP for node-negative prostate cancer between 1987 and 2003. Of these men, 100 had disease recurrence, with a PSADT of <9 months, while 1889 either did not have a recurrence but had > or =36 months of follow-up or had a recurrence with a PSADT of > or =9 months. We examined the ability of the SEARCH model to predict aggressive recurrence within the DPC cohort, and examined the correlation between the predicted risk of aggressive recurrence and the actual outcome within DPC. The SEARCH model predicted aggressive recurrence within DPC with an AUC of 0.82. There was a strong and significant correlation between the predicted risk of aggressive recurrence based on the SEARCH tables and the actual outcomes within DPC (r= 0.68, P < 0.001), although the model predictions tended to be slightly higher than the actual risk. The SEARCH model to predict aggressive recurrence after RP predicted aggressive recurrence in an external dataset with a high degree of accuracy. These tables, now validated, can be used to help select men for adjuvant therapy and clinical trials.

Glycemic control and prostate cancer progression: Results from the SEARCH database

Several studies have examined the association between diabetes mellitus (DM) and prostate cancer (PCa) risk and progression, however nearly all of these studies have compared diabetic versus non-diabetic men. We sought to investigate the role of glycemic control, as measured by HbA1c, on PCa aggressiveness and prognosis in men with DM and PCa from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. We identified 247 men in SEARCH with DM and a recorded HbA1c value within the 12 months prior to radical prostatectomy between 1988 and 2009. We divided these men into tertiles by HbA1c level. The associations between HbA1c tertiles and risk of adverse pathology and biochemical recurrence were tested using multivariate logistic regression and Cox proportional hazards models, respectively. Median HbA1c level was 6.9. On multivariate analysis, HbA1c tertiles were predictive of pathological Gleason score (P-trend = 0.001). Relative to the first tertile, men in the second (OR 4.68, P = 0.003) and third tertile (OR 6.60, P < 0.001) were more likely to have Gleason score > or = 4 + 3. HbA1c tertiles were not associated with margin status, node status, extracapsular extension or seminal vesicle invasion (all P-trend > 0.2). In the multivariate Cox proportional hazards model, increasing HbA1c tertiles were not significantly related to risk of biochemical recurrence (P-trend = 0.56). Men with higher HbA1c levels presented with more biologically aggressive prostate tumors at radical prostatectomy. Although risk of recurrence was unrelated to HbA1c levels, further studies are needed to better explore the importance of glycemic control on long-term outcomes in diabetic men with PCa.

Statin medication use and the risk of biochemical recurrence after radical prostatectomy

Although controversial, evidence suggests statins may reduce the risk of advanced prostate cancer (PC), and recently statin use was associated with prostate-specific antigen (PSA) reductions among men without PC. The authors sought to examine the association between statin use and PSA recurrence after radical prostatectomy (RP). The authors examined 1319 men treated with RP from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. Time to PSA recurrence was compared between users and nonusers of statin at surgery using Cox proportional hazards models adjusted for multiple clinical and pathological features. In total, 236 (18%) men were taking statins at RP. Median follow-up was 24 months for statin users and 38 for nonusers. Statin users were older (P<.001) and underwent RP more recently (P<.001). Statin users were diagnosed at lower clinical stages (P=.009) and with lower PSA levels (P=.04). However, statin users tended to have higher biopsy Gleason scores (P=.002). After adjusting for multiple clinical and pathological factors, statin use was associated with a 30% lower risk of PSA recurrence (hazard ratio "HR", 0.70; 95% confidence interval "CI", 0.50-0.97; P=.03), which was dose dependent (relative to no statin use; dose equivalent<simvastatin 20 mg: HR, 1.08; 95% CI, 0.66-1.73; P=.78; dose equivalent=simvastatin 20 mg: HR, 0.57; 95% CI, 0.32-1.00; P=.05; dose equivalent>simvastatin 20 mg: HR, 0.50; 95% CI, 0.27-0.93; P=.03). In this cohort of men undergoing RP, statin use was associated with a dose-dependent reduction in the risk of biochemical recurrence. If confirmed in other studies, these findings suggest statins may slow PC progression after RP.

Definition and preoperative predictors of persistently elevated prostate‐specific antigen after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

To define a level of persistently elevated prostate-specific antigen (PSA) after radical prostatectomy (RP) that equates with high-risk for disease progression, and to identify preoperative predictors of PSA persistence among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. A total of 901 men treated with RP between 2001 and 2008 were separated into groups based upon PSA nadir within 6 months after RP. We explored the association between nadir groups and time to biochemical recurrence (BCR) using multivariate Cox proportional hazards and determined the preoperative predictors of PSA persistence using logistic regression. Relative to men with undetectable PSA levels, those with a PSA nadir of 0.03 (hazard ratio [HR] 3.88, P < 0.001), 0.04 (HR 4.87, P < 0.001), 0.05-0.09 (HR 12.69, P < 0.001), 0.1-0.19 (HR 13.17, P < 0.001), and 0.2 ng/mL (HR 13.23, P < 0.001) were at increased risk of BCR while men with a nadir of 0.01 (HR 1.36, P = 0.400) and 0.02 (HR 1.64, P = 0.180) were not. Using the PSA persistence definition of a PSA nadir > or = 0.03 ng/mL, 230 men (26%) had persistence. The independent preoperative predictors of PSA persistence were higher body mass index (BMI, P = 0.002), pathological Gleason score (relative to 2-6: 4 + 3-10, P = 0.001) and preoperative PSA level (P < 0.001). Men with a PSA nadir > or = 0.03 ng/mL after RP were at higher risk for BCR. Using a PSA persistence definition of a PSA nadir > or = 0.03 ng/mL, persistence was predicted by known factors associated with aggressive disease (tumour grade, PSA level and BMI). Validation of the present definition in different populations using later end-points remains necessary to assess its prognostic usefulness.

Outcomes After Radical Prostatectomy Among Men Who Are Candidates for Active Surveillance: Results From the SEARCH Database

We sought to evaluate outcomes after radical prostatectomy among men with low-risk prostate cancer who would be candidates for active surveillance. Using the Shared Equal Access Regional Cancer Hospital (SEARCH) database of men treated with radical prostatectomy at multiple equal-access medical centers between 1988 and 2007, 398 of 2062 men (19%) met our criteria for potential active surveillance: clinical stage T1c or T2a, prostate-specific antigen (PSA) <10 ng/mL, Gleason sum ≤6, and no more than 1 or 2 positive cores on at least a sextant biopsy. We examined the risk of adverse pathology, biochemical progression, and PSA doubling time (PSADT) at the time of recurrence. We used a Cox proportional hazards model to determine the significant predictors of PSA progression. Of the men with low-risk prostate cancer, 85% had organ-confined disease, only 2% had seminal vesicle invasion, and no patient had lymph node metastasis. The 5- and 10 year PSA-free survival rates were 81% (95% CI: 76-86%) and 66% (95% CI: 54-76%). On multivariate analysis, older age (P = .005), Agent Orange exposure (P = .02), and obesity (P = .03) were all significantly associated with biochemical failure. Mean and median PSADT among men who experienced recurrence were 37 and 20 months. Only 3 patients experienced recurrence with PSADT < 9 months. Most men with low-risk prostate cancer treated with radical prostatectomy experience long-term PSA control. Those who did experience recurrence often did so with a long PSADT. Consistent with prior SEARCH database reports, older age, Agent Orange exposure, and obesity increased the risk of recurrence.

Association of Cigarette Smoking With Interval to Biochemical Recurrence After Radical Prostatectomy: Results from the SEARCH Database

To analyze the association between cigarette smoking and biochemical recurrence (BCR) after radical prostatectomy among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort. We performed a retrospective analysis of 1267 subjects from the SEARCH cohort treated from 1998 to 2008 with smoking status available from the preoperative notes. A comparison of the baseline patient and disease characteristics between the current smokers and nonsmokers (past and never smokers combined) was performed using the chi-square and rank sum tests. The univariate and multivariate associations between smoking status and BCR-free survival were analyzed using Kaplan-Meier plots, the log-rank test, and Cox proportional hazard models. Of the 1267 patients, 408 (32%) were active smokers and 859 (68%) were nonsmokers at surgery. The current smokers were younger (P < .001), more likely to be black (P < .001), and had a lower body mass index (P < .001), a greater percentage of positive biopsy cores (P = .039), a greater preoperative prostate-specific antigen level (P = .003), more extracapsular extension (P = .003) and seminal vesicle invasion (P = .029), and lower prostate volumes (P = .002). On univariate analysis, smokers had a risk of BCR similar to that of nonsmokers (hazard ratio 1.19, P = .129). On multivariate analysis, smoking was associated with an increased risk of BCR when adjusted for body mass index only (hazard ratio 1.37, P = .008). However, after adjustment for multiple preoperative characteristics, the association was attenuated and no longer statistically significant (hazard ratio 1.12, P = .325). After additional adjustment for postoperative features, such as tumor grade and stage, smoking was unrelated to the risk of BCR (hazard ratio 0.91, P = .502). Among patients undergoing radical prostatectomy in the SEARCH cohort, cigarette smoking was associated with slightly more advanced disease but a similar risk of BCR.