Independent Predictor Of Biochemical Failure Research Articles

The significance of metabolic response to neoadjuvant androgen deprivation therapy detected with [68Ga]Ga-PSMA-11-PET/CT in high-risk prostate cancer patients treated with definitive radiotherapy.

We examined the prognostic significance of early changes in primary tumor SUV measured with Gallium-68-labeled prostate-specific membrane antigen positron emission tomography ([68Ga]Ga-PSMA-11-PET/CT) and serum PSA values after neoadjuvant androgen deprivation treatment (nADT) in high-risk prostate cancer (PCa) patients treated with definitive radiotherapy (RT). The clinical data and SUV parameters of 71 PCa patients were reviewed retrospectively. The serum PSA and primary tumor SUV values were calculated before and after the start of ADT. Using univariable and multivariable analyses, the prognostic factors predicting biochemical disease free survival (bDFS) and prostate cancer specific survival (PCSS) were investigated. In addition, logistic regression analysis was used to identify predictors of biochemical failure (BF). All but one patient responded with a 98.8% reduction in serum PSA (21.8ng/mL vs. 0.3ng/mL; p < 0.001), and 64 patients (91.1%) had a median 66.6% decrease in primary tumor SUV after ADT (13.2 vs. 4.8, p < 0.001). The primary tumor SUV response rate was significantly higher in patients with Gleason score (GS) of 7 than in patients with GS > 7 (59.5% vs. 40.5%; p = 0.04), and it was significantly lower in patients with inadequate treatment response than in those with complete (CR) or partial response (PR) (1.1% vs. 66.1%; p < 0.001). There was a strong and significant correlation (Spearman = 0.41, p < 0.001) and a high concordance (91.5%) between PSA response and SUV response after ADT. With a median follow-up time of 76.1months, the 5-year bDFS and PCSS rates were 77.2% and 92.2%, respectively. Nineteen patients (26.7%) patients had recurrence at a median of 44.6months after the completion of RT. In multivariate analysis, lymph node metastasis, GS greater than 7, and SD/PD after nADT were independent predictors of worse bDFS. However, no significant factor for PCSS was identified. In the multivariable logistic regression analysis, advanced age, GS of > 7 disease, lymph node metastasis, and SD or PD after nADT were independent predictors of BF. These results imply that the metabolic response measured with [68Ga]Ga-PSMA-11-PET/CT after nADT could be used to predict progression in high-risk PCa patients treated with definitive RT.

Pretreatment Multiparametric Magnetic Resonance Imaging Findings Are More Accurate Independent Predictors of Outcome Than Clinical Variables in Localized Prostate Cancer

To prospectively determine whether multiparametric magnetic resonance imaging (mpMRI)-based staging is a more accurate independent predictor of outcome than traditional clinical variables for patients undergoing brachytherapy and external beam radiation therapy. The primary endpoints were biochemical (nadir plus 2ng/mL) and metastatic failure. Descriptive, univariate, and multivariate competing risks analyses were performed. The cumulative incidence rates were estimated to describe the cumulative risk of the events of interest. The magnitude of the increased risk was estimated using univariate and multivariate subdistribution hazard ratios. A total of 185 patients had undergone prospective treatment (123 with high risk and 62 with intermediate risk). The median age was 71years (range 56-82). Of the patients, 20.5% had mpMRI-determined (mrT) stage mrT1-mrT2b, 37.3% had mrT2c, 31% had mrT3a, and 11.2% had mrT3b. The Gleason score was 6 in 22.2%, 7 in 49.5%, and 8 to 10 in 28.2%. The median baseline prostate-specific antigen was 11.7ng/mL (range 2.9-153). After a median follow-up period of 46months (range 16-70), 15 patients (8.1%) had developed biochemical failure and 9 (4.9%) had developed distant metastases. None of the traditional clinical variables (prostate-specific antigen, Gleason score, clinical stage) predicted for biochemical or metastatic failure. The multivariate competing risk analysis demonstrated that the 2 independent predictors of biochemical failure were the presence of extraprostatic extension (EPE; mrT3a; hazard ratio [HR] 4.80; P=.035) and presence of seminal vesicle invasion (SVI; mrT3b; HR 10.17; P=.003) on mpMRI. The only independent predictor of metastatic failure was the percentage of positive cores on prostate biopsy (HR 13.95; P=.014). After excluding patients with SVI, the only independent predictor of biochemical failure and metastatic failure was the presence of EPE (stage mrT3a) on mpMRI (HR 4.36; P=.042; and HR 5.76; P=.010, respectively). The pretreatment mpMRI findings might be more accurate independent predictors of the outcome than traditional clinical variables. In particular, the presence of EPE, SVI and a greater percentage of positive cores on biopsy predicted for a worse prognosis.

Prostate-specific antigen nadir within 12 months as an early surrogate marker of biochemical failure and distant metastasis after low-dose-rate brachytherapy or external beam radiotherapy for localized prostate cancer.

Prostate‐specific antigen nadir (nPSA) after radiotherapy for localized prostate cancer has been investigated as a predictor. However, nPSA usually requires several years, limiting its clinical utility. We investigated the significance of nPSA within 12 months (nPSA12) after low‐dose‐rate prostate brachytherapy (LDR‐PB) or external beam radiotherapy (EBRT) on treatment outcomes. Between 2006 and 2014, 663 patients with prostate cancer were treated with LDR‐PB or EBRT at two institutions. Four hundred and seventy‐four men received LDR‐PB and 189 men received EBRT, without androgen deprivation therapy. The Kaplan–Meier method was used for biochemical failure (BF)‐free survival (BFFS) and distant metastasis (DM)‐free survival (DMFS) analyses, and multivariable Cox regression analysis was performed. The median follow‐up was 61.3 months. The median nPSA12 in the LDR‐PB and EBRT cohorts was 0.7 and 1.0 ng/mL, respectively. The 7‐year BFFS and DMFS rates in LDR‐PB patients with nPSA12 ≤ 0.7 ng/mL were 99.1% and 99.5%, respectively; when nPSA12 was >0.7 ng/mL, they were 90.2% and 94.8%, respectively. In EBRT patients with nPSA12 ≤ 1.0 ng/mL, BFFS and DMFS rates were 85.4% and 98.5%, respectively; when nPSA12 was >1.0 ng/mL, they were 67.1% and 87.2%, respectively. nPSA12 was an independent predictor of BF and DM in both cohorts (LDR‐PB, P = 0.004 and 0.020, respectively; EBRT, P = 0.005 and 0.041, respectively). The nPSA12 after LDR‐PB or EBRT is significantly associated with treatment outcomes of prostate cancer. Higher nPSA12 may identify patients at high risk of relapse who might benefit from salvage treatment.

Pretreatment Multiparametric Magnetic Resonance Imaging Findings Are More Accurate Independent Predictors of Outcome Than Clinical Variables in Localized Prostate Cancer

The objective of this study is to prospectively determine whether multiparametric MRI (mpMRI) based staging is more accurate independent predictor of outcome than traditional clinical variables in patients treated with brachytherapy (BT) and external beam radiotherapy (EBRT). In September 2010 we launched a prospective study of mpMRI guided High-Dose-Rate (HDR) BT (15 Gy) and supplemental EBRT (37.5 Gy). Inclusion criteria included localized intermediate or high-risk prostate cancer, patients with seminal vesicle invasion (SVI) extension >1cm or positive pelvic nodes were excluded. The primary endpoints were biochemical (nadir +2 ng/mL) and metastatic failure. Clinical variables included baseline PSA value, clinical T-stage, Gleason score, percentage of positive cores on prostate biopsy, use of hormonal therapy, MRI T-stage, risk-group based on clinical T-stage and risk-group based on MRI T-stage. Descriptive, univariate and multivariate Cox analyses were performed. Cumulative hazard rate function was estimated through the Nelson-Aalen method in order to describe the cumulative risk of the events of interest. Univariate and multivariate hazard ratios were obtained from proportional hazards Cox regression models. Log-rank tests were used to compare hazards across categories of MRI-based T stages. One hundred eighty-five patients had been prospectively treated (123 high-risk and 62 intermediate-risk). Median age was 71 years (range 56-82); 20.5% had MR T-stage T1-T2b, 37.3% T2c, 31% T3a and 11.2% T3b; 22.2% Gleason 6, 49.5% Gleason 7 and 28.2% Gleason 8-10; and median baseline PSA was 11.7 ng/mL (2.9–153). Median follow-up was 46 months (range 16-70). At the time of the current analysis, 15 (8.1%) patients had a biochemical failure and 9 (4.9%) had developed distant metastases. None of the traditional clinical variables (PSA, Gleason, and clinical stage) predicted for biochemical or metastatic failure. The 5-year cumulative risk of biochemical failure for patients with MRI-T1/T2 stage and MRI-T3 stage were 5% (95% CI 1.5-16) and 30.2% (95% CI 15.9-57.4) respectively. The 5-year cumulative risk of metastatic failure was 2% (95% CI 0.2-14) and 18.4% (95% CI 8.3-40.6) respectively. Multivariate Cox analysis demonstrated that the only independent predictor of biochemical failure was SVI on mpMRI (HR 12.7, 95% CI 2.9–55.7; P = 0.001). The two independent predictors of metastatic failure were SVI (HR 19.3, 95% CI 1.9-193.9; P = 0.012) and the percentage of positive cores on prostate biopsy (HR 10.4, 95% CI 1.2-88.6; P = 0.032). Pretreatment mpMRI findings are more accurate independent predictors of outcome than clinical variables, and in particular, the presence of extracapsular extension (T3a), SVI (T3b) and higher percentage of positive cores on biopsy predict a worse prognosis.

Prostate brachytherapy as salvage for local failure after external beam radiation.

125 Background: Local failure (LF) after external beam radiation (EBRT) for prostate cancer is a serious problem. Most patients receive non-curative androgen deprivation therapy (ADT), but there is a subset with LF who are still potentially curable. There is limited evidence to suggest that prostate brachytherapy (BT) is an effective, potentially curative salvage therapy with acceptable toxicity. We hypothesize that salvage BT following EBRT can achieve high rates of biochemical control with acceptable toxicity. Methods: We analyzed 39 consecutive patients treated from 1998-2013 with salvage BT at 2 centers. All patients had pathologically confirmed LF following previous EBRT without distant mets &amp; a disease-free interval of ≥ 18-24 mo. Salvage BT to the whole prostate was delivered to 29 patients using low-dose rate I-125 or Pd-103 seed implants (median dose 100 Gy with Pd-103) while 10 received HDR BT (median 30 Gy in 6 fractions). Cases were planned as if de novo but to a lower dose. 33 (85%) received neoadjuvant and/or adjuvant ADT as part of their salvage therapy. Biochemical failure (BF) was defined using the Phoenix criteria. Risk factor analysis was conducted to identify characteristics that predict BF after salvage BT. Results: For the 39 patients, median PSA at diagnosis was 8.4, and 21 (54%) had high-risk disease. Median EBRT dose was 70 Gy with 11 patients (28%) receiving ADT. Median PSA nadir following EBRT was 0.8 (range 0 – 2.6). Median time to recurrence was 53 mo (range 18 – 150), and median pre-salvage PSA was 4.8. Median follow-up after salvage BT was 60.1 mo (range 7 – 150). Biochemical failure-free survival, DMFS and OS at 5 &amp; 7 yrs were 76% &amp; 67%; 91% &amp; 85% and 92% &amp; 84%, respectively. On univariate analysis, PSA nadir after EBRT &amp; pre-salvage PSA were significant predictors of BF (p&lt; 0.01 for both). On multivariate analysis, only pre-salvage PSA was a significant independent predictor of BF (p&lt; 0.01). Freedom from late grade 3 GU toxicity at 3 yrs was 83%. There were no late Grade 3 GI toxicities. Conclusions: This is the largest series reporting on salvage prostate brachytherapy plus ADT for local-only failures after EBRT &amp; suggests that salvage BT with ADT offers selected patients prolonged disease-free survival with acceptable toxicity.

Prostate-specific antigen nadir after high-dose-rate brachytherapy predicts long-term survival outcomes in high-risk prostate cancer.

PurposeTo evaluate the prognostic value of prostate-specific antigen nadir (nPSA) after high-dose-rate (HDR) brachytherapy in clinically non-metastatic high-risk prostate cancer patients.Material and methodsData from 216 patients with high-risk or locally advanced prostate cancer who underwent HDR brachytherapy and external beam radiation therapy with long-term androgen deprivation therapy (ADT) between 2003 and 2008 were analyzed. The median prostate-specific antigen (PSA) level at diagnosis was 24 ng/ml (range: 3-338 ng/ml). The clinical stage was T1c-2a in 55 cases (26%), T2b-2c in 48 (22%), T3a in 75 (35%), and T3b-4 in 38 (17%). The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After 5 fractions, external beam radiation therapy with 10 fractions of 3 Gy was administered. All patients initially underwent neoadjuvant ADT for at least 6 months, and adjuvant ADT was continued for 36 months. The median follow-up was 7 years from the start of radiotherapy.ResultsThe 7-year PSA relapse-free rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 94%, compared with 23% for patients with higher nPSA values (HR = 28.57; 95% CI: 12.04-66.66; p < 0.001). Multivariate analysis revealed that the nPSA value after radiotherapy was a significant independent predictor of biochemical failure, whereas pretreatment predictive values for worse biochemical control including higher level of initial PSA, Gleason score ≥ 8, positive biopsy core rate ≥ 67%, and T3b-T4, failed to reach independent predictor status. The 7-year cancer-specific survival rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 99%, compared with 82% for patients with higher nPSA values (HR = 32.25; 95% CI: 3.401-333.3; p = 0.002).ConclusionsA post-radiotherapy nPSA value of ≤ 0.02 ng/ml was associated with better long-term biochemical tumor control even if patients had pretreatment predictive values for worse control.

Ten-year outcomes of I¹²⁵ low-dose-rate brachytherapy for clinically localized prostate cancer: a single-institution experience in Japan.

To report 10-year outcomes of patients treated with I(125) low-dose-rate brachytherapy (BT) for clinically localized prostate cancer. A group of 1,060 patients with clinically localized prostate cancer treated with I(125) BT between March 2004 and December 2013 at the Yokohama City University Hospital were identified. The records of 743 patients with a minimum of 2 years of follow-up were reviewed. Cohorts were categorized according to National Comprehensive Cancer Network risk classification, and biochemical outcomes plus overall survival were examined. Biochemical failure was defined as nadir prostate-specific antigen (PSA) level + 2 ng/mL. Univariate and multivariate Cox proportional hazards were used to determine predictors of biochemical failure. A total of 743 patients met the criteria with a median follow-up of 54.6 months (range 24-114 months). The median age was 70 years (range 48-83). The 5- and 7-year overall survival rates were 98.8 and 97.6 %, and the 5- and 7-year biochemical failure-free survival rates were 92.6 and 91.0 %, respectively. With regard to distant metastases and survival, the 5- and 7-year metastatic-free survival rates were 98.2 and 95.9 %, respectively. A multivariate analysis revealed that initial PSA (p = 0.005; HR 1.097, 95 % CI 1.028-1.170), age (p = 0.001; HR 0.931, 95 % CI 0.893-0.971), and T stage (T1c vs. T2a) (p = 0.002; HR2.417, 95 % CI 1.319-4.267) were independent predictors of biochemical failure. I(125) low-dose-rate BT resulted in excellent survival and morbidity outcomes for localized prostate cancer at a single institution. Further studies are needed to obtain long-term outcomes.

Positive margin length and Gleason grade of tumor focus at the margin predict for biochemical failure after radical prostatectomy in patients with pT2 prostate cancer.

103 Background: While three prospective trials have demonstrated benefit from adjuvant radiation (XRT) after radical prostatectomy (RP) in patients with positive surgical margins (PSM), its use varies amongst physicians. Many rely on clinical acumen to determine the optimal strategy for application of XRT post RP. We aim to determine if the length of PSM and highest Gleason grade (GG) of tumor at the PSM (hGGPSM) can be used to identify patients at greatest risk of biochemical failure (BCF) post RP. Methods: A retrospective review of all RP patients at The University of Texas MD Anderson Cancer Center from 2002 to 2010 was performed. After a single pathologist review, patients with organ confined disease (pT2), pathologic N0/Nx and a PSM were included. BCF was defined as 2 sequential PSA values of ≥0.2 or any detectable PSA prompting XRT. Patients receiving adjuvant XRT or with &lt;12 months follow-up were excluded. Results: 205 patients met the inclusion criteria. Median PSA was 5.3 ng/mL (0.5-33) and median follow-up was 64 months (13-130). The majority were low clinical stage (cT1c: 65%), low (11%)/intermediate (82%) grade and had a single site of a PSM (90%). BCF occurred in 47 patients for a 5 yr BCF free survival (BCFFS) of 69%. PSM length was significantly associated with BCFFS (≤1mm vs &gt;1, p=0.02). When accounting for hGGPSM, Gl 3 tumors were less likely to experience BF (5 yr BCFFS-96%) regardless of PSM length, while BCFFS for Gl &gt;3 tumors were significantly lower dependent upon length of PSM ( ≤1mm vs &gt;1mm, p=0.03). On multivariable analysis length of PSM (p=0.05) and hGGPSM (p=0.007) remained independent predictors of BCF (Table). Conclusions: Length of PSM and hGGPSM are independent predictors of BCF. These should be considered when evaluating patients for adjuvant XRT and in risk stratifying patients in prospective clinical trials. [Table: see text]

Does family history of prostate cancer affect outcomes following radiotherapy?

ObjectiveTo examine family history (FH) as a prognostic factor following radiotherapy (RT). Materials and methodsBetween 1989 and 2007, 1711 men with clinically localized prostate cancer and complete family history who had received RT (median RT dose=74Gy) without androgen deprivation therapy were analyzed. FH was defined as any prostate cancer in a first degree relative. For the biochemical failure (BF) outcome, this sample size has 85% power to detect a hazard ratio of 1.56 for positive versus negative FH. ResultsWith a median follow-up of 71months, there was no significant difference in the distribution of Gleason score (GS) or prostate specific antigen (PSA) based on FH. A positive FH was not an independent predictor of BF, distant metastasis (DM), prostate cancer specific mortality (PCSM), or overall mortality (OM) in Cox proportional multivariable analysis. On further analysis in a Cox proportional multivariable analysis, men with two or more first degree relatives with prostate cancer had a significantly higher likelihood of BF and DM than those with no FH, although there was no difference in PCSM or OM. Men with a positive FH (23%) were more likely to be younger, have a lower PSA, and non-palpable disease. There was no interaction between a positive FH and neither race nor treatment era (pre-PSA vs. PSA era). ConclusionsA positive FH is not a prognostic factor following RT and should not alter standard treatment recommendations. Patients with two or more first degree relatives with prostate cancer had a higher likelihood of BF and DM, but there was no effect on survival. There was no interaction between a positive FH and African American race or treatment era. A positive FH was however, associated with more favorable PSA values and T-stage that may be the result of earlier screening.

Serum testosterone level as a predictor of biochemical failure after radical prostatectomy for localized prostate cancer

• To investigate serum testosterone levels as a predictor for biochemical failure (BF) after radical retropubic prostatectomy (RRP). • Prospective cohort study with 227 patients and a median follow-up of 7.7 years. • Total serum testosterone was measured at diagnosis. • Primary endpoint: 5-year BF-free survival defined as first PSA > 0.2 ng/mL. • Testosterone was tested as a predictor of BF as a dichotomized and continuous variable. • Median (range) age was 62 years (45-74), median PSA 9.9 ng/mL (0.4-96), and median testosterone was 14 nmol/L (2.2-40). • BF occurred for 57 patients (26%) within 5 years. • In multivariate analysis with age, PSA, and biopsy Gleason score, testosterone levels >11 nmol/L were an independent predictor for reduced risk of BF (hazard ratio, 0.53; 95% confidence interval, 0.31-0.90; P= 0.02). • When analyzed as a continuous variable, testosterone was not a statistically significant predictor of BF. • Low pretreatment serum testosterone levels correlate with a higher risk of BF, and testosterone may possess biological information about prostate cancer progression potential, which makes it an independent predictor of biochemical failure after RRP.

Biochemical and clinical experience with real-time intraoperatively planned permanent prostate brachytherapy

PurposeTo evaluate patient characteristics and dosimetric parameters that predict biochemical failure (BCF) after real-time planned low-dose-rate prostate brachytherapy. MethodsFrom 1998 to 2008, a low-risk cohort by National Comprehensive Cancer Network criteria of 341 men with a median followup of 41.6 months was analyzed. This cohort had a median age of 65.1 years, prostate volume of 35.8cc, and pretreatment prostate-specific antigen of 5.6ng/mL. Patients had predominately Gleason 6 (95.9%) and T1c (81.3%) disease. About 3.6% of the patients received androgen deprivation therapy. Kaplan–Meier and Cox proportional hazards survival analysis methods were used to analyze predictors of BCF (Phoenix definition). ResultsAt 72 months, freedom from BCF was 91.1% (95% confidence interval=85.0–94.8). The median D90 was 145.9Gy, and the median V100 was 90.3%. Because of infrequent BCF, the following prostate volume groups were examined: 15–<25, 25–<35, 35–<45, and 45+cc. Of all possible predictors, only small prostate volume (15–<25cc group) was significantly associated with BCF (hazard ratio=8.44, 95% confidence interval=1.82–39.14, p=0.007). Using Kaplan–Meier analysis, time to BCF was also significantly increased in the lowest prostate volume 15–<25cc group with 24.1% failing at 48 months compared with 1.6–5.1% among the other groups. ConclusionsReal-time planned low-dose-rate prostate brachytherapy provides excellent biochemical control as a single-agent treatment for low-risk prostate cancer with 91.1% freedom from BCF at 72 months. Only prostate volume less than 25cc was an independent predictor of BCF.

The clinical significance of in-depth pathological assessment of extraprostatic extension and margin status in radical prostatectomies for prostate cancer

Despite recent Level 1 evidence on the benefits of adjuvant radiotherapy for locally advanced prostate cancer (PCa), the timing and decision to administer adjuvant radiotherapy post-radical prostatectomy (post-RP) remains debatable, particularly for patients with focal extraprostatic extension (EPE) and/or focal positive surgical margins (PSMs). In this study, we assess the utility of detailed pathological assessment of EPE and PSM, as this may influence the criteria for instituting adjuvant radiotherapy. A total of 148 RP cases (1993-2001) were identified retrospectively as having EPE and/or PSM. All slides were re-reviewed, incorporating recent proposals by the Collage of American Pathologists (CAP) for the reporting of EPE and PSM, and correlated with clinical data. Both EPE and PSM were found to be independent predictors of biochemical failure (BCF); however, only EPE was associated with metastasis and death. BCF was also more likely to be associated with cases that had non-focal EPE than focal EPE. Similarly, non-focal PSM cases had a significantly higher risk of BCF than focal cases. Our study confirms the value of detailed pathological assessment of EPE and PSM post-RP. The results support the concept of selective adjuvant radiotherapy in patients with EPE and PSM, based on focality and extent.

1099 ANALYSIS OF RISK FACTORS FOR BIOCHEMICAL RECURRENCE FOLLOWING RADICAL PERINEAL PROSTATECTOMY IN A LARGE CONTEMPORARY SERIES: A DETAILED ASSESSMENT OF MARGIN STATUS AND LOCATION

on biochemical failure (BCF), metastasis and survival were correlated, with a median follow-up of 99 months, Positive EPE and positive surgical margin ( EPE Margin), 2. Positive EPE and negative surgical margin ( EPE-Margin), 3. Negative EPE and positive surgical margin (-EPE Margin), and 4. Negative EPE and negative surgical margin (-EPE-Margin). RESULTS: Although both EPE (H.R.2.68, C.I. 1.23 & 5.82)and PSM (H.R.2.53, C.I. 1.25 & 5.13) were independent predictors of biochemical failure (BCF), only EPE was associated with metastasis and death from prostate cancer In addition, patients with EPE Margin or EPE-Margin had higher risks of BCF, metastasis and death from prostate cancer than patients with -EPE Margin or -EPE-Margin. Patients with a non-focal PSM 0.1 mm had a significantly higher risk of BCF compared with those with a focal PSM 0.1 mm (P value 0.028). CONCLUSIONS: Our study confirms the value of in depth pathologic analysis and reporting on radical prostatectomy specimens. The results support the concept of selective adjuvant radiotherapy in patients with EPE, based on focality and extent of EPE as well as extent of PSM, to minimize the likelihood of BCF.

Clinical Significance of Polymorphism and Expression of Chromogranin A and Endothelin-1 in Prostate Cancer

We investigated the clinical significance of chromogranin A and endothelin-1 polymorphism and expression in prostate cancer. We analyzed 2 CHGA polymorphisms by polymerase chain reaction-restriction fragment length polymorphism in DNA samples of 435 patients with prostate cancer and 316 age matched male controls. Chromogranin A and endothelin-1 expression was evaluated by immunohistochemistry in prostate specimens of 114 men with prostate cancer who underwent radical retropubic prostatectomy and in 27 with bladder cancer who underwent radical cystectomy and served as controls. For the CHGA Glu264Asp polymorphism men with the GG genotype were at 2.05 times higher risk for prostate cancer than men with the CC genotype (p = 0.014). In men with prostate cancer higher chromogranin A immunohistochemistry grade was associated with higher stage and higher Gleason score (p = 0.011 and 0.044, respectively). Multivariate analysis showed that chromogranin A immunohistochemistry grade was an independent variable for predicting biochemical failure after radical prostatectomy (p = 0.023). Higher endothelin-1 expression was observed in prostate cancers (p = 0.011), especially those with a higher Gleason score (p = 0.042). There was no significant relationship between chromogranin A polymorphisms, and chromogranin A and endothelin-1 expression. Polymorphism and expression of chromogranin A and endothelin-1 have clinical significance in prostate cancer. Chromogranin A expression was an independent predictor of biochemical failure after prostatectomy in patients with localized prostate cancer.

Does a tertiary Gleason pattern 4 or 5 influence the risk of biochemical relapse after radical prostatectomy for clinically localized prostate cancer?

The presence of a tertiary Gleason grade (TGG) pattern 4 or 5 in radical prostatectomy (RP) specimens has been reported with adverse pathology and a higher biochemical relapse rate after RP. This study investigated the impact of a TGG pattern 4 or 5 on biochemical and pathological outcome in men operated with RP. The study reviewed 151 consecutive cases treated at the hospital between 1985 and 2006; 148 were included in the study. All prostatectomy specimens were re-examined by a genitourinary pathologist and among others parameters the presence of TGG pattern 4 or 5 was recorded. The hospital files were examined retrospectively for clinical follow-up data. Prostate-specific antigen (PSA) relapse was defined as two subsequent rising measurements above 0.20 ng/ml. The influence of a TGG pattern 4 or 5 on prognosis was assessed in a Cox proportional hazards regression model controlling for pathological stage, surgical margin (SM) status, seminal vesicle invasion (SVI) and extraprostatic extension (EPE). Fifty-six patients (38%) experienced PSA relapse during follow-up. Twenty-one patients (58%) with a TGG pattern 4 or 5 had a biochemical relapse compared with 35 patients (31%) without TGG pattern 4 or 5. In the Cox regression model, TGG pattern 4 or 5 was an independent predictor of biochemical failure (p = 0.020). In patients undergoing RP the presence of a TGG pattern 4 or 5 is an independent predictor for biochemical relapse. Consequently, the RP specimens should routinely be investigated for TGG pattern 4 or 5.

Proliferation of Immature Tumor Vessels Is a Novel Marker of Clinical Progression in Prostate Cancer

Nestin (neuroepithelial stem cell protein) is expressed in immature endothelial cells, and we here introduce coexpression of Nestin and Ki-67 as a novel angiogenesis marker on tissue sections. Including vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1alpha (HIF-1alpha) expression, we studied relation to disease progression in prostate cancer. Different patient series were included. Sections from 104 radical prostatectomies with long follow-up, 33 castration-resistant prostate cancers, 28 nonskeletal metastases, 13 skeletal metastases, and 41 benign prostatic hyperplasias were immunostained for Nestin/Ki-67, VEGF-A, and HIF-1alpha. Vascular proliferation by Nestin/Ki-67-positive vessels was counted within "hotspot" areas. Median vascular proliferation counts were 4- to 5-fold higher in castration-resistant prostate cancers and metastases versus localized cancers and prostatic hyperplasias (P < 0.0005). Among localized cancers, high vascular proliferation was significantly related to adverse clinicopathologic features and was a strong and independent predictor of biochemical failure (P < 0.005), clinical recurrence (P = 0.005), and skeletal metastasis (P = 0.025) in multivariate analysis. Castration-resistant cancers were characterized by reduced VEGF-A and increased HIF-1alpha expression, and vascular proliferation was associated with reduced patient survival in this group. Thus, vascular proliferation was of independent prognostic importance among prostate cancers. When compared with localized cancers, vascular proliferation was significantly increased in castration-resistant cases and metastatic lesions. The castration-resistant tumors exhibited weak VEGF-A but strong HIF-1alpha expression. These novel data might have an effect on clinical evaluation and treatment of prostate cancer patients.

Interaction of obesity and race in predicting recurrence rates after radical prostatectomy

5070 Background: Black men are twice as likely to die from prostate cancer compared to white men. Obese men are known to have higher mortality rates and recurrence rates, and blacks are 1.4 times as likely to be obese than white Americans. However, the relative contribution of BMI and race to biochemical failure (BCF) after radical prostatectomy (RP) has not been well-characterized. We examined the interaction of BMI and race in predicting BCF after RP. Methods: A retrospective analysis of the Columbia Urologic Oncology Database found that 3,736 consecutive men underwent RP between 1988 and 2008. 1,461 men had BMI and race data available. 213 (14.6%) were black men, 1,004 (68.7%) were white, 162 (11.1%) were Hispanic, and 82 (5.6%) were Asian. Overweight and obese men were defined as having a BMI &gt; 25 kg/m2 and a BMI &gt; 30 kg/m2, respectively. BCF was defined as a post-surgery PSA level &gt;0.2 ng/mL on &gt; 2 measurements. Cox regression methods were used to model the relationship between race, BMI and BCF. Results: The 1,461 men had a median age of 60 years, and median pre-operative PSA of 5.5. There was no significant difference in BMI among the four races (p = 0.58). The 5 year disease-free survival for black obese men was the lowest at 69%, compared to non-obese black (71%), obese white (80%), and non-obese white men (80%, p &lt; 0.001). BMI did not have a significant impact on BCF. After adjusting for preoperative PSA level, tumor stage, and Gleason sum, race remained an independent predictor of BCF (HR = 1.65, p = 0.04). An analysis assessing the effect of an interaction between race and BMI demonstrated that hazard ratios for increased BMI did not differ significantly by race. Black men who were normal, overweight and obese were 2.0, 3.0 and 2.5 times more likely than white men to have BCF in the respective weight categories, but the differences were not significant. Conclusions: Black race is an independent predictor of biochemical failure after adjusting for pathologic factors. The impact of BMI on BCF did not vary among different races. However, BMI does contribute to the accurate estimation of the risk of BCF. These findings suggest that elevated BMI does not affect the BCF rates of black men more than in other races, and that other factors may influence the racial variability in disease-free survival and BCF risk. No significant financial relationships to disclose.

CAN WE USE PREOPERATIVE PSA KINETICS TO PREDICT PATHOLOGIC UPGRADING IN CONTEMPORARY PATIENTS DIAGNOSED WITH GLEASON 6 PROSTATE CANCER?

INTRODUCTION AND OBJECTIVE: Patients with positive margins at radical prostatectomy represent a heterogeneous group with a wide range of post-prostatectomy outcomes. In attempt to better stratify those at high risk for biochemical failure, we evaluated the power of estimated tumor volume, margin amplitude, and margin location in the prediction of biochemical failure. METHODS: We reviewed our database of 2410 patients who underwent radical prostatectomy and isolated 453 total patients (18.8%) with positive surgical margins, with an overall pT2 positive margin rate of 3.9% and a pT3 margin rate of 15.2%. Kaplan-Meier, log-rank, and multivariate logistic regression analyses were undertaken to assess the relationship between estimated tumor volume, margin amplitude, and margin location and biochemical-free survival. RESULTS: Increasing estimated tumor volume, when stratified by quartile (<2%, 2-10%, 10-25%, and 26%) or categorized (<25% vs. 26%) was directly associated with increasing risk of biochemical failure (p=0.006, p=0.002, respectively). Patients with multiple positive margins were at increased risk of biochemical failure when compared to those with one positive margin (p<0.001). Margin location did not impact biochemical-free survival in patients with positive margins. When incorporated into a multivariable model including age, preoperative PSA, pathologic Gleason score, and pathologic stage, both estimated tumor volume and margin amplitude remained independent predictors of biochemical failure. CONCLUSIONS: Increasing estimated tumor volume and the presence of multiple positive margins at radical prostatectomy are independent predictors of biochemical failure in patients with positive surgical margins. Coupled with other preand postoperative parameters, these pathologic parameters may serve to further discriminate those who serve to benefit from immediate adjuvant radiation therapy.

Pretreatment Endorectal Magnetic Resonance Imaging and Magnetic Resonance Spectroscopic Imaging Features of Prostate Cancer as Predictors of Response to External Beam Radiotherapy

To evaluate whether pretreatment combined endorectal magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) findings are predictive of outcome in patients who undergo external beam radiotherapy for prostate cancer. We retrospectively identified 67 men with biopsy-proven prostate cancer who underwent combined endorectal MRI and MRSI at our institution between January 1998 and October 2003 before whole-pelvis external beam radiotherapy. A single reader recorded tumor presence, stage, and metabolic abnormality at combined MRI and MRSI. Kaplan-Meier survival and Cox univariate and multivariate analyses explored the relationship between clinical and imaging variables and outcome, using biochemical or metastatic failure as endpoints. After a mean follow-up of 44 months (range, 3-96), 6 patients developed both metastatic and biochemical failure, with an additional 13 patients developing biochemical failure alone. Multivariate Cox analysis demonstrated that the only independent predictor of biochemical failure was the volume of malignant metabolism on MRSI (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.29-2.06; p < 0.0001). The two independent predictors of metastatic failure were MRI tumor size (HR 1.34, 95% CI 1.03-1.73; p = 0.028) and the finding of seminal vesicle invasion on MRI (HR 28.05, 95% CI 3.96-198.67; p = 0.0008). In multivariate analysis, MRI and MRSI findings before EBRT in patients with prostate cancer are more accurate independent predictors of outcome than clinical variables, and in particular, the findings of seminal vesicle invasion and extensive tumor predict a worse prognosis.

Utility of Bcl-2, P53, Ki-67, and Caveolin-1 Immunostaining in the Prediction of Biochemical Failure After Radical Prostatectomy in a Japanese Population

To identify predictive markers for biochemical failure after radical prostatectomy in patients with clinically confined prostate cancer. Immunohistochemistry of bcl-2, p53, Ki-67, and caveolin-1 was performed in samples of paraffin-embedded prostate cancer from 119 Japanese patients. The clinicopathologic significance of staining with these markers was analyzed in relation to biochemical failure (prostate-specific antigen [PSA] >0.2 ng/mL). Univariate analysis showed the pretreatment PSA level (P = 0.03), postoperative Gleason score (P = 0.04), pathologic stage (P <0.001), seminal vesicle invasion (P <0.001), p53 staining (P <0.001), Ki-67 staining (P = 0.04), and caveolin-1 staining (P <0.0001) to be associated with biochemical failure. Multivariate Cox proportional hazards modeling showed that pretreatment PSA in group A (clinicopathologic parameters), caveolin-1 staining in group B, biomarkers, and the combination (group C) were independently associated with prediction of biochemical failure. The accuracy rate of each group was 76.2% (group A), 75.1% (group B), and 83.1% (group C), respectively. The combination of clinicopathologic parameters and biomarkers (group C) showed the highest accuracy rate. Caveolin-1 staining is an independent predictor of biochemical failure after radical prostatectomy.