Higher Risk Of Biochemical Failure Research Articles

Absolute Percentage of Pattern 4 Disease as a Prognostic Measure for Intermediate-risk Prostate Cancer Treated with Stereotactic Body Radiotherapy

AimsIntermediate-risk prostate cancer is heterogenous. The absolute percentage of biopsied tissue positive for Gleason pattern 4 disease (APP4) is a possible prognostic measure. Here we sought to determine the impact of APP4 in a prospective multi-institutional pooled analysis of men with intermediate-risk prostate cancer treated with stereotactic body radiotherapy (SBRT). Materials and methodsPatients with intermediate-risk prostate cancer treated with SBRT (40 Gy in five fractions or 26 Gy in two fractions) with or without androgen deprivation therapy treated on prospective clinical trials were included. Pathology reports were queried to obtain APP4, calculated as the percentage of Gleason pattern 4 disease within the tumour(s) multiplied by the percentage of total biopsied tissue positive for disease divided by 100. The optimal APP4 cut-off points for biochemical failure and distant metastasis were calculated and used as a stratification in the cumulative incidence of biochemical failure and distant metastasis. Multivariable competing risk models were developed. ResultsIn tota, 227 patients were included. The median follow-up was 56.5 months. The optimal APP4 cut-off points were 5% for biochemical failure and 20% for distant metastasis. At 4 years, the cumulative incidence of biochemical failure was 23.6% and 2.3% for APP4 >5% and ≤ 5%, respectively (P < 0.0001). The cumulative incidence of distant metastasis was 12.5% for APP4 >20% and 1% for APP4 ≤ 20% (P = 0.02). APP4 sub-stratified favourable intermediate-risk prostate cancer and unfavourable intermediate-risk prostate cancer into groups at similarly low and similarly high risk of biochemical failure and distant metastasis. On multivariable competing risk analysis, APP4 >5% (P = 0.0004) was significantly associated with biochemical failure, but APP4 (log) was not for distant metastasis (P = 0.08). ConclusionAPP4 may be an easily accessible promising prognostic measure for patients with intermediate-risk prostate cancer treated with SBRT. Incorporation of APP4 into prospective trials will help to determine its value.

Comparison of Clinical Outcomes of Radical Prostatectomy versus IMRT with Long-Term Hormone Therapy for Relatively Young Patients with High- to Very High-Risk Localized Prostate Cancer

Simple SummaryThat the definitive optimal treatments for relatively young men (aged ≤ 65 years) with high- or very high-risk localized prostate cancer (HR/VHR-LPC) are radical prostatectomy (RP) or radiation plus antiandrogen therapy (RT-ADT) is controversial. To the best of our knowledge, our study is the first and largest to examine biochemical failure (BF), all-cause death, locoregional recurrence, and distant metastasis in relatively young men with HR/VHR-LPC as defined by National Comprehensive Cancer Network risk strata. After head-to-head propensity score matching was used to balance the potential confounders, a multivariable Cox proportional hazards regression model was used to analyze oncologic outcomes. In relatively young men with HR/VHR-LPC, RP and RT-ADT yielded similar oncologic outcomes and RP reduced the risk of BF compared with RT-ADT.That intensity-modulated radiotherapy (IMRT) plus antiandrogen therapy (IMRT-ADT) and radical prostatectomy (RP) are the definitive optimal treatments for relatively young patients (aged ≤ 65 years) with high- or very high-risk localized prostate cancer (HR/VHR-LPC), but remains controversial. We conducted a national population-based cohort study by using propensity score matching (PSM) to evaluate the clinical outcomes of RP and IMRT-ADT in relatively young patients with HR/VHR-LPC. Methods: We used the Taiwan Cancer Registry database to evaluate clinical outcomes in relatively young (aged ≤ 65 years) patients with HR/VHR-LPC, as defined by the National Comprehensive Cancer Network risk strata. The patients had received RP or IMRT-ADT (high-dose, ≥72 Gy plus long-term, 1.5–3 years, ADT). Head-to-head PSM was used to balance potential confounders. A Cox proportional hazards regression model was used to analyze oncologic outcomes. Results: High-dose IMRT-ADT had a higher risk of biochemical failure (adjusted hazard ratio [aHR] = 2.03, 95% confidence interval [CI] 1.56–2.65, p < 0.0001) compared with RP; IMRT-ADT did not have an increased risk of all-cause death (aHR = 1.2, 95% CI 0.65–2.24, p = 0.564), locoregional recurrence (aHR = 0.88, 95% CI 0.67–1.06, p = 0.3524), or distant metastasis (aHR = 1.03, 95% CI 0.56–1.9, p = 0.9176) compared with RP. Conclusion: In relatively young patients with HR/VHR-LPC, RP and IMRT-ADT yielded similar oncologic outcomes and RP reduced the risk of biochemical failure compared with IMRT-ADT.

Impact of Target Volume and Image Guidance on Post-Prostatectomy Patients Treated With Intensity Modulated Radiation Therapy

<h3>Purpose/Objective(s)</h3> Post-operative radiotherapy (PORT) is utilized in select prostate cancer patients. IMRT has been associated with improved dosimetry and acute toxicity. Smaller treatment margins for PORT have been recommended when using image guidance (IG), which has also been associated with reduced toxicity. Compared to intact prostate IG-IMRT, however, PORT is delivered to a space at risk for recurrence with no grossly visible target, so using targeted conformal techniques with less margin for error may compromise tumor control. Our institution initiated IG-IMRT for PORT in 2005 and adopted larger planning target volumes (PTV) in 2012. We hypothesized that smaller PTV and surgical clip-based IG-IMRT associate with increased biochemical failure (BF). <h3>Materials/Methods</h3> Patients who underwent post-prostatectomy IG-IMRT without concurrent androgen deprivation therapy (ADT) from 1/2005 to 12/2016 were included, with division into pre-2012 and post-2012 cohorts. Demographics and tumor/treatment variables were recorded retrospectively. Oncologic outcomes included BF (initiation of ADT and/or PSA > 0.2 ng/ml and rising) and late toxicities (defined by RTOG criteria, occurring > 90 days after RT). <h3>Results</h3> 133 patients met criteria: 73 treated pre-2012 and 60 treated post-2012, with a median follow-up of 5 and 9 years, respectively. Compared to the pre-2012 cohort, patients in the post-2012 cohort were more often treated with salvage vs adjuvant RT (<i>P</i> = 0.007), and had higher pre-PORT PSA (0.38 vs 0.20, <i>P</i> = 0.01). 5-year BF did not differ between cohorts (36% vs 43%, <i>P</i> = 0.48). Pre-2012, a smaller percentage of patients underwent on-treatment alignment to surgical clips (40% vs 58%, <i>P</i> = 0.033), vs bony anatomy. Alignment to surgical clips was associated with increased BF in the pre-2012 cohort (HR 2.13, <i>P</i> = 0.041) but not in the post-2012 cohort. Notably, significantly more patients received IG with CBCT in the post-2012 cohort (82% vs 33%). Pre-2012, the median PTV was 198.63 cc versus 242.59 cc post-2012 (<i>P</i> = 0.002). Among the entire cohort on univariate analysis, however, clinical target volume (CTV), CTV-PTV ratio and PTV as continuous variables were not associated with increased risk of BF. Late toxicities were not different between the two cohorts. <h3>Conclusion</h3> This retrospective analysis reports on toxicity and oncologic outcomes of post-prostatectomy patients treated with IG-IMRT. Despite changes in tumor/treatment characteristics, dosimetric parameters, and image guidance techniques, toxicity and cancer-related outcomes remain similar over a 7-year period. Clip-based IG-IMRT in conjunction with small target volumes may be associated with higher risk of BF, and use of CBCT IG may offset this risk. Additional dosimetric and treatment analyses will be presented. These findings should be validated in prospective datasets.

Development and internal validation of multivariable prediction models for biochemical failure after MRI-guided focal salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer

Background and purposeMagnetic resonance-guided focal salvage high-dose-rate brachytherapy (FS-HDR-BT) for radiorecurrent prostate cancer (PCa) shows low toxicity rates. However, biochemical failure (BF) after treatment occurs frequently. We developed two prediction models for BF (Phoenix definition) with the aim of enhancing patient counselling before FS-HDR-BT and during follow-up. Materials and methodsA prospective cohort of 150 radiorecurrent PCa patients treated with FS-HDR-BT between 2013 and 2020 was used for model development and internal validation. Multivariable Cox Proportional Hazards regression was applied. For model 1, only pre-salvage variables were included as candidate predictors. For model 2, additional (post-)salvage characteristics were tested. After calibration, nomograms and webtools were constructed. Finally, three risk groups were identified. ResultsSixty-one patients (41%) experienced BF. At baseline (model 1), age, gross tumour volume, pre-salvage PSA, and pre-salvage PSA doubling time (PSADT) were predictive of BF. During follow-up (model 2), age, pre-salvage PSA and PSADT, seminal vesicle involvement, post-salvage time to PSA nadir, and percentage PSA reduction were predictive of BF. The adjusted C-statistics were 0.73 (95% CI: 0.66–0.81) and 0.84 (95% CI: 0.78–0.90), respectively, with acceptable calibration. Estimated 2-year biochemical disease-free survival for the low-, intermediate-, and high-risk groups were 84%, 70%, and 31% (model 1), and 100%, 71%, and 5% (model 2). ConclusionTwo models are provided for prediction of BF in patients with radiorecurrent PCa treated with FS-HDR-BT. Based on pre- and post-salvage characteristics, we are able to identify patients with a high risk of BF. These findings can aid patient counselling for FS-HDR-BT.

Clinical predictors for biochemical failure in patients with positive surgical margin after robotic-assisted radical prostatectomy.

Patients with positive surgical margins (PSMs) after radical prostatectomy for localized prostate cancer have a higher risk of biochemical failure (BCF). We investigated the risk factors of BCF in patients with PSMs after robotic-assisted radical prostatectomy (RARP). We evaluated 462 patients who underwent RARP in a single medical center from 2006 through 2013. Of them, 61 with PSMs did not receive any treatment before BCF. Kaplan-Meier curve and Cox regression analysis were used to compare patients with (n = 19) and without (n = 41) BCF. Overall, 13.2% of patients had PSMs, and of those, 31.7% experienced BCF during follow-up. The mean follow-up duration was 43.7 months (42.4 [non-BCF] vs 46.35 (BCF], p = 0.51). In univariant analyses, the platelet to lymphocyte ratio (6.26 [non-BCF] vs 8.02 [BCF], p = 0.04) differed statistically. When patients were grouped by pathologic grade ≦2 or ≧3 (p = 0.004), the BCF-free survival rates differed significantly. Seminal vesicle invasion also differed significantly (5 [non-BCF] vs 7 [BCF], p = 0.005). Patients with undetectable nadir prostate-specific antigen (PSA) after RARP (BCF rate 4/34) differed statistically from those with detectable PSA after RARP (BCF rate 15/26) (p < 0.001). In the multivariate analysis, the platelet/lymphocyte (P/L) ratio, pathologic grade, and undetectable nadir PSA remained statistically significant. In patients who undergo RARP and have PSMs, P/L ratio >9 preoperatively, pathologic grade ⩾3, and detectable nadir PSA after RARP should be considered adverse features. Early intervention such as salvage radiation therapy or androgen deprivation therapy should be offered to these patients.

Novel functions of the luteinizing hormone/chorionic gonadotropin receptor in prostate cancer cells and patients.

Prostate cancer (PCa) cells become castrate-resistant after initial tumor regression following castration-based lowering of testosterone (T). De-novo intra-tumoral steroid synthesis is a suggested biological mechanism of castration resistant PCa, but the regulators are unknown. Testicular T production is controlled by the luteinizing hormone/choriogonadotropin receptor (LHCGR). To elucidate the influence of LHCGR on PCa development the presence and effects of LHCGR in PCa and whether LHCGR in serum holds prognostic information in PCa patients is investigated. LHCGR expression was investigated by RT-PCR, WB, IHC, qPCR in PCa cell lines and prostatic tissue. Steroid production was measured in media from cell lines with LC-MS/MS and expression of steroidogenic enzymes with qPCR. Serum LHCGR (sLHCGR) was measured with ELISA in PCa patients (N = 157). Presence of LHCGR was established in prostatic tissue and PCa cell lines. Cell proliferation increased by 1.29-fold in LNCaP (P = 0.007) and 1.33-fold in PC-3 cells (P = 0.0007), when stimulated by luteinizing hormone. Choriogonadotropin stimulation decreased proliferation 0.93-fold in DU145 cells (P = 0.05), but none of the treatments altered steroid metabolite secretion. Low sLHCGR concentration was associated with a higher risk of biochemical failure after radical prostatectomy (HR = 3.05, P = 0.06) and castration resistance (HR = 6.92, P = 0.004) compared to high sLHCGR concentration. LHCGR is expressed in PCa and may exert a growth regulatory role in PCa derived cell lines. A potential prognostic role of sLHCGR for determining recurrence risk in PCa patients is found in this pilot study but needs verification in larger cohorts.

MRI detected extaprostatic extension (EPE) in prostate cancer: Do all T3a patients have the same outcomes?

MRI-detected T3a prostate cancer is a heterogeneous disease. This post-hoc analysis of a prospective trial found that patients with T3a disease presenting obliteration of the recto-prostatic angle, contact-asymmetry of neuro-vascular bundle and periprostatic fat invasion, may be at higher risk of biochemical failure and metastases.

Interim PSA: Predicting for Biochemical Failure during Salvage Radiotherapy Following Prostatectomy

It is challenging to identify patients at higher risk of biochemical failure following salvage radiotherapy after having a radical prostatectomy. This work aims to determine if an interim PSA during radiotherapy would predict two year biochemical failure for patients who have salvage radiotherapy for a rising PSA following a radical prostatectomy for prostate cancer. A total of 185 patients in one center having salvage radiotherapy following a radical prostatectomy to a dose of 68Gy without androgen deprivation therapy between the years of 2010 and 2016 had their PSA recorded on the first day of radiotherapy, and again after completing the 25th fraction of 34 total fractions. Biochemical failure after radiotherapy was defined as a PSA value ≥0.2ng/mL within two years following radiotherapy. Univariate and multivariate Cox regression models were used for statistical analysis using statistical software. Factors investigated in univariate analysis other than a drop in PSA during radiotherapy included age, a Gleason score above 7, surgical margins status, the presence of extracapsular extension, PSA doubling time prior to radiotherapy, PSA at the time of radiotherapy, the presence of a detectable post-operative PSA immediately after surgery, whether or not a pelvic lymph node dissection was performed and whether or not there was seminal vesicle invasion. Factors with a p value <0.2 in univariate analysis were then used in a multivariate analysis. The two year freedom from biochemical failure was 60% (95% CI: 53% to 67%). Table 1 shows that on multivariate analysis, a drop in PSA during radiotherapy (p=0.003) and a positive surgical margin (p<0.0001) were significant factors for freedom from subsequent biochemical failure, while seminal vesicle invasion was associated with biochemical failure at two years (p=0.007). A PSA rise during salvage radiotherapy is predictive of biochemical failure at two years (HR 2.05). Factors such as seminal vesicle invasion and a negative surgical margin also predict for poor responders to salvage radiotherapy. If this is confirmed in further studies, then it may allow salvage radiotherapy to be abandoned at 50Gy into the treatment course, thereby potentially averting further futile radiotherapy and the risks of higher dose salvage treatment.Abstract 2619; Table 1Prognostic factors for biochemical failure at two years on multivariate analysis. *[Reference value]PSA During RadiotherapySurgical MarginsSeminal Vesicle InvasionGleason scoreSame or riseFallNegativePositiveYesNo>7≤7HR(95% Cl)2.050 (1.273-3.299)1*2.437 (1.493-3.978)1*2.044 (1.218-3.431)1*1.247 (0.731-2.127)1*P Value0.003<0.0010.0070.418 Open table in a new tab

Prostate brachytherapy with iodine-125 seeds: analysis of a single institutional cohort.

ABSTRACTObjectives:Brachytherapy (BT) with iodine-125 seeds placement is a consolidated treatment for prostate cancer. The objective of this study was to assess the clinical outcomes in patients with prostate cancer who underwent low-dose-rate (LDR) -BT alone in a single Brazilian institution.Materials and Methods:Patients treated with iodine-125 BT were retrospectively assessed after at least 5 years of follow-up. Patients who received combination therapy (External beam radiation therapy-EBRT and BT) and salvage BT were not included.Results:406 men were included in the study (65.5% low-risk, 30% intermediate-risk, and 4.5% high-risk patients). After a median follow-up of 87.5 months, 61 (15.0%) patients developed biochemical recurrence. The actuarial biochemical failure-free survival (BFFS) at 5 and 10 years were 90.6% and 82.2%, respectively. A PSA nadir ≥ 1 ng / mL was associated with a higher risk of biochemical failure (HR = 5.81; 95% CI: 3.39 to 9.94; p ≤ 0.001). The actuarial metastasis-free survival (MFS) at 5 and 10 years were 98.3% and 94%, respectively. The actuarial overall survival (OS) at 5 and 10 years were 96.2% and 85.1%, respectively. Acute and late grade 2 and 3 gastrointestinal toxicities were observed in 5.6%, 0.5%, 4.6% and 0.5% of cases, respectively. For genitourinary the observed acute and late grade 2 and 3 toxicities rates were 57.3%, 3.6%, 28% and 3.1%, respectively. No grade 4 and 5 were observed.Conclusions:BT was effective as a definitive treatment modality for prostate cancer, and its endpoints and toxicities were comparable to those of the main series in the literature.

Combining the Prostate Cancer Risk Index (PRIX) with the Presence of Secondary Circulating Prostate Cells to Predict the Risk of Biochemical Failure after Radical Prostatectomy for Prostate Cancer

Introduction:The use of pre- and post-surgery variables has been used to create nomograms in order to identify patients at high risk of treatment failure. The PRIX nomogram is one such device; we compare the PRIX nomogram with the presence of secondary circulating prostate cells to predict those men who will undergo treatment failure.Methods and Patients:Men who underwent radical prostatectomy for prostate cancer entered the study. The PRIX score was calculated from the total serum PSA pre-surgery, the biopsy Gleason score and clinical stage. Circulating prostate cells were detected from venous blood one month after surgery, using differential gel centrifugation and standard immunocytochemistry with anti-PSA. A test was considered positive when 1 CPC/blood sample was detected. Patients were followed up for five years and biochemical failure was defined as a serum PSA >0.2ng/ml. Kaplan-Meier and Cox proportional models were used to calculate survival curves.Results:321 men participated, of whom 131 (40.8%) underwent biochemical failure within 5 years. A higher PRIX score was associated with increased failure risk, as was the presence of CPCs. The predictive power of CPCs was significantly higher than the PRIX score. Combining the two methods, for equal PRIX scores, scores but CPC positive had a worse biochemical failure free survival than men with high PRIX scores but CPC negative. For men with PRIX scores of ≥4 the use of CPC detection did not aid in the clinical decision making process. For those with PRIX scores of 0 and 1, CPC detection identified men with a high risk of treatment failure.Conclusions:The combined PRIX/CPC score improved the predictive values of men at high risk of biochemical failure. Both are simple systems that could be incorporated in a general hospital. Further multicenter studies are warranted to confirm these results.

Salvage HDR Brachytherapy: Multiple Hypothesis Testing Versus Machine Learning Analysis

Salvage high-dose-rate brachytherapy (sHDRB) is a treatment option for recurrences after prior radiation therapy. However, only approximately 50% of patients benefit, with the majority of second recurrences after salvage brachytherapy occurring distantly. Therefore, identification of characteristics that can help select patients who may benefit most from sHDRB is critical. Machine learning may be used to identify characteristics that predict outcome following sHDRB. We aimed to use machine learning to identify patient characteristics associated with biochemical failure (BF) following prostate sHDRB. We analyzed data for 52 patients treated with sHDRB for locally recurrent prostate cancer after previous definitive radiation therapy between 1998 and 2009. Following pathologic confirmation of locally recurrent disease without evidence of metastatic disease, 36Gy in 6 fractions was administered to the prostate and seminal vesicles. BF following sHDRB was defined using the Phoenix definition. Sixteen different clinical risk features were collected, and machine learning analysis was executed to identify subpopulations at higher risk of BF. Decision tree-based algorithms including classification and regression trees, MediBoost, and random forests were constructed. Patients were followed up for a minimum of 5years after sHDRB. Those with a fraction of positive cores ≥0.35 and a disease-free interval <4.12years after their initial radiation treatment experienced a higher failure rate after sHDRB of 0.75 versus 0.38 for the rest of the population. Using machine learning, we have identified that patients with a fraction of positive cores ≥0.35 and a disease-free interval <4.1years might be associated with a high risk of BF following sHDRB.

The Impact of Tobacco Use on Outcomes and Toxicity in a Predominantly Minority Population of Males with Prostate Cancer Receiving External Beam Radiation.

IntroductionTo investigate whether current or prior smoking history had any impact on prostate cancer outcomes and toxicity in our predominantly minority population of males receiving dose-escalated external beam radiation therapy (EBRT).MethodsOf the 500 patients treated with EBRT between 2003-2011, 444 had smoking histories recorded. Patients were classified as current smoker, former smoker, or never smoker. Biochemical failure-free survival (BFFS) and distant metastatic-free survival (DMFS) endpoints were analyzed. Multivariate Cox regression and multivariate logistic regression were used to assess whether smoking had an impact on outcomes and toxicity respectively.Results There were 176 males (39.6%) classified as never smokers, 169 (38.1%) as prior smokers, and 99 (22.3%) as current smokers. The median follow-up was 76 months (range nine-146) and 61.9% of patients were African American. The eight-year BFFS for never smokers, prior smokers and current smokers was 73.6%, 80.2%, and 73.4% respectively, p=0.38. Similarly, the eight-year DMFS was 92.8%, 96.8%, and 95.3% respectively, p=0.54. On multivariate analysis, prior smoking (HR 0.72, p=0.19) and current smoking (HR 1.02, p=0.93) were not associated with increased biochemical failure. Similarly, smoking use was not associated with increased distant metastatic disease (hormone receptor (HR) 0.71, p=0.51 for prior smokers, HR 1.41, p=0.52 for current smokers). The presence of intermediate-risk disease (HR 2.87, p=0.002) was associated with an increased likelihood of biochemical failure. The high-risk disease was associated with both a higher risk of biochemical failure (HR 8.02, p <0.001) as well as distant metastatic disease (HR 17.61, p=0.01). On multivariate regression, prior or current smoking use was not associated with an increased likelihood of late grade two genitourinary or gastrointestinal toxicity.ConclusionCurrent or prior smoking use was not associated with inferior outcomes or increased toxicity in this study comprising a predominantly minority population undergoing dose escalated radiation therapy for prostate cancer.

Risk of Biochemical Failure in Patients With High-Risk Prostate Cancer Treated Definitively or Postoperatively With Intensity Modulated Radiation Therapy

Current treatments for high risk prostate cancer include surgery and definitive radiation. Many patients treated with prostatectomy require adjuvant radiation for high risk pathologic features, or salvage radiation after biochemical failure. No randomized trials comparing these modalities have been completed. Here we present outcomes of patients with high risk prostate cancer treated with definitive radiation or post-operative radiation in the adjuvant or salvage setting using intensity modulated radiation therapy (IMRT). One hundred eighty-one patients with National Comprehensive Cancer Network high risk prostate cancer treated with IMRT at our institution between 2006 and 2010 were included. One hundred fifty-four patients were treated definitively (prostate doses ranging 7020-7920 cGy, 180 cGy daily fractions), and 27 were treated post-operatively; 12 adjuvantly for high-risk pathologic features, and 15 as salvage treatment following biochemical failure (prostate bed doses 6480-6660 cGy). Pelvic lymph nodes were treated in 105 patients with high risk of lymph node involvement at diagnosis as determined by the Kattan Nomogram. Rates of concurrent or adjuvant androgen deprivation therapy (ADT) were 59% (definitive cohort) and 52% (post-operative cohort). Overall survival (OS) and freedom from biochemical failure (defined by 2 consecutive PSA rises to >1.5 ng/mL) were determined using Kaplan-Meier analysis, and hazard ratios were determined by Cox Proportional hazards model. The mean age at diagnosis was 59.8 years (post-operative), and 65.6 years (definitive cohort) (range, 46-85.4 years). With a median follow-up of 43 months (5.1 months-15.4 years), 3- and 5-year OS was 96% and 88% for the post-operative cohort, and 92% and 83% for the definitive cohort, respectively. Overall survival for the two groups was not statistically different. Patients treated with post-operative as opposed to definitive IMRT were significantly more likely to experience biochemical failure with a hazard ratio of 6.4 (p = 0.006). Biochemical failure was not different with ADT (p = 0.12). Many patients with preoperative high risk prostate cancer require adjuvant or salvage RT after surgery. In our cohort, patients with high risk prostate cancer treated with postoperative IMRT following prostatectomy had a statistically higher risk of biochemical failure compared to those treated with definitive IMRT. Possible referral bias of highest risk post-operative patients was not accounted for, but we plan to expand the analysis to include all high risk patients treated with up-front prostatectomy at our institution.

Use of biopsy detail to identify subgroup risk in high-risk patients with prostate cancer.

169 Background: High Risk (HR) prostate cancer (CaP) patients (pts) are a heterogeneous group. A recursive partitioning analysis (RPA) was performed to determine if tissue involvement could identify patients at risk for biochemical failure (BF). Methods: Between 1992-2009, 608 HR CaP pts with complete prostate biopsy detail data (% overall tissue involvement (%TI), GP45 (weighted average of %TI for Gleason Pattern 4 or 5), Gleason Score (GS)) underwent RT with/out ADT. Primary endpoint was freedom from biochemical failure (FFBF). RPA based on time to BF was used to determine cutpoints for each prognostic variable. Multivariable (MVA) RPAs were used to assess interactions of significant variables (p&lt;0.05) from univariate analysis (UVA). Results: Median follow up for PSA measurement was 45 months (3-193 mo). UVA RPA revealed significant cutpoints for FFBF for Tstage (higher risk of BF(HRBF) for T2c,T3b,T3c,T4,Tx vs lower risk of BF(LRBF) for T1,T2a,T2b,T3a, (p&lt;0.001)); GS(HRBF 3+4/5, 4+5 vs LRBF 2-6, 2+3/4, 5+3/4/5 (p=0.011); iPSA (LRBF ≤37 vs HRBF &gt;37 ng/ml (p&lt;0.001)); dose (HRBF ≤74.9 vs LRBF &gt;74.9 Gy); RT type(LRBF IMRT vs HRBF 3D-CRT, p=0.032), %TI (LRBF ≤53% vs HRBF &gt;53% (p&lt;0.001)); GP45 (LRBF ≤33% vs HRBF &gt;33%(p&lt;0.001)). Overall, FFBF at 5 yr was 79.2% (95%CI 75.0-82.8). For MVA RPA, splits are same as UVA unless noted. MVA RPA excluding GP45 and %TI showed 5 groups (5 yr FFBF 45.9%, 66.8%, 74.2%, 84.2% and 89.5%; N 16, 195, 69, 20 and 308, respectively). Tstage, iPSA, GS and RT type had significant interactions, with highest risk group including PSA &gt;44ng/ml, low Tstage and 3D-CRT, and lowest risk group including PSA ≤44 ng/ml, lower risk Tstage, and lower risk GS. Including %TI in the RPA, significant interactions were between %TI (2 splits), iPSA and GS (5 yr FFBF 50.0%, 62.5%, 71.9%, 80.4% and 92.7%; N 80, 24, 65, 233, and 206, respectively). Highest risk group included pts with %TI &gt;53%; lowest risk included pts with %TI &lt;17%, iPSA &lt;40 ng/mL, and GS lower risk. Using GP45 instead of %TI, 3 groups were found: high GP45; low GP45 and iPSA ≥40; low GP45 and iPSA&lt;40 ng/ml, (5 yr FFBF 58.9%, 67.7% and 85.5%; N 103, 63 and 442, respectively). Conclusions: Pts with &gt; 53% TI, &gt; 33% GP45 and iPSA &gt; 40 ng/ml are at highest risk of failure, and should be considered for most aggressive treatment.

Influence of Race on Outcomes of Patients with Localized Prostate Cancer Considered Intermediate or High Risk of Biochemical Failure Treated with High Dose Rate Brachytherapy and External Beam Radiotherapy

Purpose: There is a growing need to identify prognostic factors in prostate cancer (pca) to avoid excessive or inappropriate treatment of patients. It may be helpful to identify patients with poor outcomes who would be candidates for more intensive treatments.   Methods: we performed a retrospective analysis of data of the charts of all unfavorable PCA treated with the combination of High-Dose-Rate Brachytherapy (HDR-BT) and External Beam Radiotherapy (EBRT) at the department of radiation oncology (ac camargo cancer center), sao paulo, brazil, between 1997 and 2010. Ethnicity definition was based on 4 categorizations: black, mulatto, white and asiatic. We included 229 patients (age range 47-83 years). The median follow-up was 70.3 months (range, 36 –155 months). There were 7.4% (17) yellow, 79.0% (181) white, 7.9% (18) black and 5.7% (13) mulatto patients.   Results: EBRT and HDR-BT doses ranged from 40 to 54 gy and 16 to 30 gy given in 4 fractions, respectively. Actuarial 5- and 10-year overall and disease free survical (DFS) rates were 87.6%, 61.3%, 90.9% and 54.2%, respectively. On univariate analysis prognostic factors related to improved DFS were white/asiatic race (p 20 gy (p<0.001) and gleason-score <7 (p<0.001). On multivariate analysis black/mulatto race (p=0.037), advanced clinical stage (p=0.038) and HDR-BT dose <20gy (p<0.001) were associated with biochemical failure.   Conclusion: The race seems to be one of the markers of prognosis for PCA. Already known predictive factors of biochemical failure were confirmed in our analysis (clinical stage, gleason score). An improved DFS was related to HDR-BT dose escalation. Further studies are still necessary to provide more information about clinical and genetic predictive factors of aggressiveness that can be used to guide a personalized dose intensification treatment.

Outcome Predictors of Radical Prostatectomy Followed by Adjuvant Androgen Deprivation in Patients with Clinical High Risk Prostate Cancer and pT3 Surgical Margin Positive Disease

Patients with high risk prostate cancer with pT3 tumor and positive surgical margins have a high risk of biochemical failure after radical prostatectomy and adjuvant androgen deprivation therapy. Predictors of cancer related death in this patient group are necessary. We performed subset analysis of a prospective trial including 550 consecutive patients with preoperative high risk prostate cancer (prostate specific antigen greater than 20 ng/ml ± cT3/4 ± biopsy Gleason 8-10). Men who underwent radical prostatectomy and received continuous adjuvant androgen deprivation therapy for pT3a/b N0-1 positive surgical margin disease were included in the analysis, and none of the patients received neoadjuvant androgen deprivation therapy or adjuvant radiation therapy. Overall 173 of 550 patients (31.5%) with a median followup of 67 months met the study inclusion criteria. For these men the estimated 8-year prostate cancer specific and overall survival rates were 86.3% and 77.0%, respectively. Tumor stage and positive surgical margin at the bladder neck were independent predictors of prostate cancer specific survival and overall survival, and were used to substratify cases. Those with pT3b disease with positive surgical margins at the bladder neck had the highest risk of death (5-year cancer specific survival 60.0% and overall survival 52.3%), while pT3a disease (regardless of positive surgical margin location and lymph node invasion) and pT3b tumors with negative bladder neck margins had 8-year prostate cancer specific survival and overall survival rates of 92.0% and 84.9%, respectively. The results of this trial demonstrated the heterogeneity of high risk prostate cancer cases with T3 tumors and positive surgical margins. The presented substratification by tumor stage and positive surgical margin location identifies men at high risk for prostate cancer related death and might help in the design of adjuvant therapy trials.

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.

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.

Defining pathological variables to predict biochemical failure in patients with positive surgical margins at radical prostatectomy: implications for adjuvant radiotherapy

To evaluate the utility of estimated tumour volume, number of positive surgical margins (PSMs), and margin location for predicting biochemical failure in patients with PSM, in an attempt to better risk-stratify the heterogeneous group of patients at high risk of biochemical failure after radical prostatectomy (RP) for prostate cancer. We reviewed our database of 2410 patients who had RP, and isolated 423 with PSMs who had a prostate-specific antigen (PSA) nadir at undetectable levels. Kaplan-Meier curves were used for univariate survival analysis, with the log-rank test used to examine differences between survival curves. Multivariate Cox regression analysis was used to assess the independent main effect of estimated tumour volume, number of PSMs and margin location on biochemical-free survival. Increasing estimated tumour volume was directly associated with increasing risk of biochemical failure in patients with PSMs (P = 0.041). Patients with more than one PSM were at greater risk of biochemical failure than those with one PSM (P = 0.001). Margin location had no effect on biochemical-free survival in patients with PSMs. When incorporated into a multivariate Cox regression model including age, preoperative PSA level and pathological Gleason score, estimated tumour volume and number of PSMs remained independent predictors of biochemical recurrence. Coupled with other variables before and after RP, both estimated tumour volume and number of PSMs might serve to further discriminate those patients most likely to benefit from immediate adjuvant radiotherapy after RP.

Clinical Results of Long-Term Follow-Up of a Large, Active Surveillance Cohort With Localized Prostate Cancer

PURPOSE We assessed the outcome of a watchful-waiting protocol with selective delayed intervention by using clinical prostate-specific antigen (PSA), or histologic progression as treatment indications for clinically localized prostate cancer. PATIENTS AND METHODS This was a prospective, single-arm, cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a PSA doubling time of less than 3 years, Gleason score progression (to 4 + 3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data. Results A total of 450 patients have been observed with active surveillance. Median follow-up was 6.8 years (range, 1 to 13 years). Overall survival was 78.6%. The 10-year prostate cancer actuarial survival was 97.2%. Overall, 30% of patients have been reclassified as higher risk and have been offered definitive therapy. Of 117 patients treated radically, the PSA failure rate was 50%, which was 13% of the total cohort. PSA doubling time of 3 years or less was associated with an 8.5-times higher risk of biochemical failure after definitive treatment compared with a doubling time of more than 3 years (P < .0001). The hazard ratio for nonprostate cancer to prostate cancer mortality was 18.6 at 10 years. CONCLUSION We observed a low rate of prostate cancer mortality. Among the patients who were reclassified as higher risk and who were treated, PSA failure was relatively common. Other-cause mortality accounted for almost all of the deaths. Additional studies are warranted to improve the identification of patients who harbor more aggressive disease despite favorable clinical parameters at diagnosis.