Benign Prostate-specific Antigen Research Articles

Abstract 4801: Clinical polygenic model to stratify risk of any, metastatic, and fatal prostate cancer in a randomized controlled trial of precision screening

Abstract Introduction: Lifetime risk of prostate cancer (PCa) is strongly associated with three factors: ancestry, family history, and genetics. We previously developed a polygenic hazard score (PHS) for PCa comprised of 290 common genetic variants (PHS290). When accounting for family history and ancestry (self-reported or genetically determined), PHS290 remained a powerful independent predictor of age at PCa diagnosis, metastatic PCa diagnosis, and PCa death. Additional variants associated with PCa susceptibility or benign elevation of prostate-specific antigen (PSA) have since been published. Here, we evaluate their impact on lifetime risk predictions for metastatic and fatal PCa and develop an updated polygenic score. This score will inform the design of the Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS, ClinicalTrials.gov ID NCT05926102), a nationwide randomized controlled trial evaluating precision PCa screening in the VA healthcare system. Methods: We utilized a machine learning approach to update the PHS. Over 450 variants associated with PCa, aggressive PCa, benign prostatic hyperplasia, or benign PSA elevation were evaluated for inclusion. First, we identified pairs of variants with highly correlated genotype (defined as R2 > 0.95) and utilized univariable Cox proportional hazards models (using age at diagnosis of PCa) to exclude one variant from each pair. We then evaluated all remaining candidate variants for inclusion in a new PHS using a LASSO-regularized Cox proportional hazards model. We combined the new PHS with clinical predictors (ancestry and family history) to create a comprehensive, quantitative polygenic score in a diverse, population-based cohort of n=590,750 (Million Veteran Program). Both self-reported and genetic ancestry (based on 2,309 ancestry informative markers) were assessed. We estimated hazard ratios (HRs) to compare men with high versus low polygenic score and evaluated absolute predictions of any, metastatic, and fatal PCa. Results: The updated polygenic score included 356 variants, as well as family history and genetic ancestry. When comparing the highest to the lowest quintile of the population for polygenic score, the HRs for any PCa, metastatic PCa, and fatal PCa were 5.6, 5.8, and 5.2 respectively. These HRs are all greater than those achieved with PHS290, which yielded 5.2, 4.9, and 4.4 respectively. Risk stratification improved within each ancestry group, including within the >100,000 participants of African ancestry—a group known to have elevated risk of fatal PCa. Absolute risk prediction was accurate for both metastatic and fatal PCa. Conclusion: The polygenic score accurately predicts risk of metastatic and fatal PCa in multiple ancestry groups. A clinical polygenic model has potential utility for precision PCa screening and will now be evaluated prospectively in the ProGRESS trial. Citation Format: Anna M. Dornisch, Roshan Karunamuni, Kara N. Maxwell, Julie Lynch, Isla P. Garraway, Adam Kibel, Charles A. Brunette, Morgan E. Danowski, Kyung M. Lee, Scott L. DuVall, J M. Gaziano, Brent S. Rose, Richard L. Hauger, Jason L. Vassy, Tyler M. Seibert. Clinical polygenic model to stratify risk of any, metastatic, and fatal prostate cancer in a randomized controlled trial of precision screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4801.

Glycoprofiling of proteins as prostate cancer biomarkers: A multinational population study.

The glycoprofiling of two proteins, the free form of the prostate-specific antigen (fPSA) and zinc-α-2-glycoprotein (ZA2G), was assessed to determine their suitability as prostate cancer (PCa) biomarkers. The glycoprofiling of proteins was performed by analysing changes in the glycan composition on fPSA and ZA2G using lectins (proteins that recognise glycans, i.e. complex carbohydrates). The specific glycoprofiling of the proteins was performed using magnetic beads (MBs) modified with horseradish peroxidase (HRP) and antibodies that selectively enriched fPSA or ZA2G from human serum samples. Subsequently, the antibody-captured glycoproteins were incubated on lectin-coated ELISA plates. In addition, a novel glycoprotein standard (GPS) was used to normalise the assay. The glycoprofiling of fPSA and ZA2G was performed in human serum samples obtained from men undergoing a prostate biopsy after an elevated serum PSA, and prostate cancer patients with or without prior therapy. The results are presented in the form of an ROC (Receiver Operating Curve). A DCA (Decision Curve Analysis) to evaluate the clinical performance and net benefit of fPSA glycan-based biomarkers was also performed. While the glycoprofiling of ZA2G showed little promise as a potential PCa biomarker, the glycoprofiling of fPSA would appear to have significant clinical potential. Hence, the GIA (Glycobiopsy ImmunoAssay) test integrates the glycoprofiling of fPSA (i.e. two glycan forms of fPSA). The GIA test could be used for early diagnoses of PCa (AUC = 0.83; n = 559 samples) with a potential for use in therapy-monitoring (AUC = 0.90; n = 176 samples). Moreover, the analysis of a subset of serum samples (n = 215) revealed that the GIA test (AUC = 0.81) outperformed the PHI (Prostate Health Index) test (AUC = 0.69) in discriminating between men with prostate cancer and those with benign serum PSA elevation.

Abstract 1441: Genetic determinants of PSA levels improve prostate cancer screening

Abstract Prostate-specific antigen (PSA) screening for prostate cancer (PCa) remains controversial due to poor sensitivity and specificity that lead to overdiagnosis and overtreatment. The aim of our study is to characterize genetic determinants of PSA levels in cancer-free men in order to personalize PCa screening. We hypothesize that test accuracy may be improved by accounting for PSA variation that is due to genetic factors and does not reflect PCa. We conducted the largest ever genome-wide association study (GWAS) of PSA in men without PCa (N=95,768; 85,924 predominantly European ancestry) using data from the UK Biobank, BioVU, PLCO, and Kaiser Permanente cohorts. Our GWAS discovered 129 PSA-associated variants (P<5×10-8), 82 of which were novel. A polygenic score (PGSPSA) comprised of these 129 variants was successfully validated in two cancer prevention trials: PCPT (n=5737) and SELECT (n=22,247). PGSPSA explained 7.3% (p=7.0×10-98) of variation in baseline PSA in PCPT and 8.7% (p=7.0×10-476) in SELECT. Importantly, PGSPSA was not associated with PCa status in PCPT (OR=0.98, p=0.71) or SELECT (OR=1.04, p=0.98), which confirms that it reflects benign PSA variation. Potential clinical utility of PSA genetic adjustment was explored by examining reclassification at thresholds used for biopsy referrals in a real-world setting at Kaiser Permanente. We estimated that correction using PGSPSA would have avoided 21.2% of negative biopsies in non-cases. Reclassification below the biopsy referral threshold was also more common in cases, particularly with low-grade disease with Gleason score <7 (7.3% below vs. 2.6% above). Overall, genetic correction of PSA appeared to improve the accuracy of referral decisions, with a Net Reclassification Index of 0.148. Next, we evaluated genetically adjusted PSA in the context of detection of aggressive PCa, defined as Gleason score ≥7, PSA ≥10 ng/mL, T3-T4 stage, and/or distant or nodal metastases. Genetically adjusted baseline PSA was more robustly associated with aggressive PCa than observed PSA and yielded a higher area under the curve (AUC) in PCPT (OR=3.03, p=3.5×10-7; AUC: 0.72 vs. 0.68) and SELECT (OR=3.37, p=3.5×10-11; AUC: 0.78 vs. 0.74) when added to a baseline model with age and trial arm. Furthermore, genetically adjusted PSA provides complementary information to PCa risk variants. In PCPT, a logistic regression model that included genetically corrected PSA and the 269-variant PGSPCa achieved a significantly higher AUC than PGSPCa-269 alone for aggressive PCa (AUC: 0.73 vs. 0.65, p=3.3×10-4) and overall PCa (AUC=0.69 vs. 0.66, p=3.3×10-6). Our work provides evidence that accounting for genetic determinants of PSA has the potential to reduce unnecessary testing and overdiagnosis of low-risk PCa, as well as increase detection of aggressive disease. Larger and more diverse study populations are required to fully characterize the genetic basis of PSA variation and optimize its clinical utility. Citation Format: Linda Kachuri, Rebecca E. Graff, Sonja I. Berndt, Mitchell Machiela, Neal D. Freedman, Stephen J. Chanock, John P. Shelley, Kerry Schaffer, Jonathan D. Mosley, Phyllis J. Goodman, Cathee Till, Ian Thompson, Robert J. Klein, Stephen K. Van Den Eeden, Thomas J. Hoffmann, John S. Witte. Genetic determinants of PSA levels improve prostate cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1441.

Multi-Institutional Analysis of Prostate-Specific Antigen Kinetics After Stereotactic Body Radiation Therapy

Understanding prostate-specific antigen (PSA) kinetics after radiation therapy plays a large role in the management of patients with prostate cancer (PCa). This is particularly true in establishing expectations regarding PSA nadir (nPSA) and PSA bounces, which can be disconcerting. As increasingly more patients are being treated with stereotactic body radiation therapy (SBRT) for low- and intermediate-risk PCa, it is imperative to understand the PSA response to SBRT. PSA data from 5 institutions were retrospectively analyzed for patients with localized PCa treated definitively with SBRT alone from 2004 to 2016. Patients received 35 to 40 Gy in 5 fractions, per institutional standards. Patients who had less than 12 months of PSA data or received androgen deprivation therapy were excluded from this study. Linear and logistic multivariable analysis were performed to identify predictors of nPSA, bounce, and biochemical recurrence, and joint latent class models were developed to identify significant predictors of time to biochemical failure. A total of 1062 patients were included in this study. Median follow-up was 66 months (interquartile range [IQR], 36.4-89.9 months). Biochemical failure per the Phoenix criteria occurred in 4% of patients. Median nPSA was 0.2 ng/mL, median time to nPSA was 40 months, 84% of patients had an nPSA ≤0.5 ng/mL, and 54% of patients had an nPSA ≤0.2 ng/mL. On multivariable analysis, nPSA was a significant predictor of biochemical failure. Benign PSA bounce was noted in 26% of patients. The median magnitude of PSA bounce was 0.52 ng/mL (IQR, 0.3-1.0 ng/mL). Median time to PSA bounce was 18.1 months (IQR, 12.0-31.1 months). On multivariable analysis, age and radiation dose were significantly associated with a lower incidence of bounce. Joint latent class models modeling found that nPSA and radiation dose were significantly associated with longer time to biochemical failure. In this multi-institutional cohort of patients with long-term follow-up, we found that SBRT led to low nPSAs. In turn, lower nPSAs are associated with reduced incidence of, and longer time to, biochemical failure. Benign PSA bounces occurred in a quarter of patients, as late as several years after treatment. Further studies are needed to directly compare the PSA response of patients who receive SBRT versus other treatment modalities.

Reduced PSA Surveillance Following SBRT for Favorable Prostate Cancer Decreases the Incidence of Anxiety-Promoting Benign PSA Bounces without Limiting the Early Detection of Biochemical Failures

Reduced PSA Surveillance Following SBRT for Favorable Prostate Cancer Decreases the Incidence of Anxiety-Promoting Benign PSA Bounces without Limiting the Early Detection of Biochemical Failures

(P20) Decreased PSA Nadir as a Result of Dose-Escalated Stereotactic Body Radiation for Patients With Low- and Intermediate-Risk Prostate Cancer

Prostate cancer (CaP) is characterized by a low a/b ratio relative to surrounding normal tissue, and consequently a therapeutic gain could be achieved with dose escalation. While potentially ablative PSA nadirs have been demonstrated following LDR brachytherapy, the ability to achieve ablation following stereotactic body radiation therapy (SBRT) remains unclear. The purpose of this study was to report the clinical outcomes, PSA kinetics, and toxicities in patients with low and intermediate-risk CaP treated on a prospective, Phase I/II, IRB approved dose-escalated SBRT trial. From 2011 to 2016, 26 patients with low and intermediate-risk CaP received 40, 45, and 50 Gy in five fractions to the prostate and seminal vesicles in cohorts of 9, 10, and 7 patients (pts). Self-reported QOL was prospectively measured from the Expanded Prostate Cancer Index Composite (EPIC) and International Prostate Symptom Score (IPSS) at baseline and intervals of every 3 months for the first two years followed by every 6 months thereafter. Common Toxicity Criteria for Adverse Events v. 4.03, data was collected to observe acute and late toxicities. No pts received androgen deprivation therapy. Median follow-up was 4.8 years. A PSA nadir <0.5 ng/ml was seen in 22%, 80%, and 71% of patients receiving 40, 45, and 50 Gy, and <0.2 ng/ml in 11%, 50%, and 71% of patients after 3 years. After 5 years, a PSA nadir <0.5 ng/ml was achieved in 100% of patients receiving 45 Gy compared to 33% receiving 40 Gy. PSA nadir was significantly reduced when comparing cohorts receiving 45 or 50 Gy to 40 Gy one to five years following treatment (p<0.02). PSA velocity was not significantly different among treatment groups, demonstrating a sharp initial decline followed by gradual reduction at -1.394, -0.706, -0.330, -0.160, -0.104, -0.070, and -0.050 ng/mL/month, after 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, and 5 years. A benign PSA bounce was observed in 8 patients (32%) at a median bounce height of 0.72 ng/ml after 18 months, demonstrating a trend towards an increased bounce height with increasing fractional dose. There was an acute increase in EPIC and IPSS scores followed by a return to baseline over two years. Acute Grade 2 urinary toxicity occurred in 10 pts with no significant difference among treatment arms. The three patients experiencing late Grade 2 toxicity were in the 45 or 50 Gy cohort. There were no Grade 3 or higher toxicities. Univariate analysis revealed that Grade 2 toxicity was associated with prostate size >60 cc (p<.01). One biochemical failure was observed in the 40 Gy arm after 3.6 years resulting in a freedom from biochemical failure rate of 96% at 5 years. Prostate cancer specific survival was 100% and actuarial overall survival was 96%. This small prospective dose-escalation study identified that higher doses of 45 and 50 Gy, respectively are associated with improved PSA nadir without increased risk of GU or GI toxicity. Further follow-up is needed to assess PSA freedom from recurrence and late toxicity.

Long-term prognostic significance of rising PSA levels following radiotherapy for localized prostate cancer \u2013 focus on overall survival

BackgroundThe aim of this study was to evaluate the long-term prognostic significance of rising PSA levels, particularly focussing on overall survival.MethodsTwo hundred ninety-five patients with localized prostate cancer were either treated with low-dose-rate (LDR) brachytherapy with I-125 seeds as monotherapy (n = 94; 145Gy), high-dose-rate (HDR) brachytherapy with Ir-192 as a boost to external beam RT (n = 66; 50.4Gy in 1.8Gy fractions EBRT + 18Gy in 9Gy fractions HDR) or EBRT alone (70.2Gy in 1.8Gy fractions; n = 135). “PSA bounce” was defined as an increase of at least 0.2 ng/ml followed by spontaneous return to pre-bounce level or lower, biochemical failure was defined according to the Phoenix definition.ResultsMedian follow-up after the end of radiotherapy was 108 months. A PSA bounce showed to be a significant factor for biochemical control (BC) and overall survival (OS) after ten years (BC10 of 83% with bounce vs. 34% without, p < 0.01; OS10 of 82% with bounce vs. 59% without bounce, p < 0.01). The occurrence of a bounce, a high nadir and the therapy modality (LDR-BT vs. EBRT and HDR-BT + EBRT vs. EBRT) proved to be independent factors for PSA recurrence in multivariate Cox regression analysis. A bounce was detected significantly earlier than a PSA recurrence (median 20 months vs. 32 months after RT; p < 0.01; median PSA doubling time 5.5 vs. 5.0 months, not significant). PSA doubling time was prognostically significant in case of PSA recurrence (OS10 of 72% vs. 36% with PSA doubling time ˃ 5 months vs. ≤ 5 months; p < 0.01).ConclusionsRising PSA levels within the first two years can usually be classified as a benign PSA bounce, with favourable recurrence-free and overall survival rates. PSA doubling time is an important predictor for overall survival following the diagnosis of a recurrence.

Increasing Fractional Doses Increases the Probability of Benign PSA Bounce in Patients Undergoing Definitive HDR Brachytherapy for Prostate Cancer

Prostate-specific antigen (PSA) bounce is a temporary elevation of the PSA level above a prior nadir. The purpose of this study was to determine whether the frequency of a PSA bounce following high-dose-rate (HDR) interstitial brachytherapy for the treatment of prostate cancer is associated with individual treatment fraction size. Between 1999 and 2014, 554 patients underwent treatment of low- or intermediate-risk prostate cancer with definitive HDR brachytherapy as monotherapy and had ≥3 subsequent PSA measurements. Four different fraction sizes were used: 950cGy × 4 fractions, 1200cGy × 2 fractions, 1350cGy × 2 fractions, 1900cGy × 1 fraction. Four definitions of PSA bounce were applied: ≥0.2, ≥0.5, ≥1.0, and ≥2.0ng/mL above the prior nadir with a subsequent return to the nadir. The median follow-up period was 3.7years. The actuarial 3-year rate of PSA bounce for the entire cohort was 41.3%, 28.4%, 17.4%, and 6.8% for nadir +0.2, +0.5, +1.0, and +2.0ng/mL, respectively. The 3-year rate of PSA bounce >0.2ng/mL was 42.2%, 32.1%, 41.0%, and 59.1% for the 950-, 1200-, 1350-, and 1900-cGy/fraction levels, respectively (P=.002). The hazard ratio for bounce >0.2ng/mL for patients receiving a single fraction of 1900cGy compared with those receiving treatment in multiple fractions was 1.786 (P=.024). For patients treated with a single 1900-cGy fraction, the 1-, 2-, and 3-year rates of PSA bounce exceeding the Phoenix biochemical failure definition (nadir +2ng/mL) were 4.5%, 18.7%, and 18.7%, respectively, higher than the rates for all other administered dose levels (P=.025). The incidence of PSA bounce increases with single-fraction HDR treatment. Knowledge of posttreatment PSA kinetics may aid in decision making regarding management of potential biochemical failures.

Outcomes of hypofractionated stereotactic body radiotherapy boost for intermediate and high-risk prostate cancer.

Background and purposeTreatment of intermediate and high-risk prostate cancer with a high BED has been shown to increase recurrence free survival (RFS). While high dose rate (HDR) brachytherapy, given as a boost is effective in delivering a high BED, many patients are not candidates for the procedure or wish to avoid an invasive procedure. We evaluated the use of stereotactic body radiotherapy (SBRT) as a boost, with dosimetry modeled after HDR-boost.Material and methodsFifty patients were treated with two fractions of SBRT (9.5-10.5 Gy/fraction) after 45 Gy external-beam radiotherapy, with 48 eligible for analysis at a median follow-up of 42.7 months.ResultsThe Kaplan-Meier estimates of biochemical control post-radiation therapy (95 % Confidence Interval) at 3, 4 and 5 years were 95 % (81–99 %), 90 % (72–97 %) and 90 % (72–97 %), respectively (not counting 2 patients with a PSA bounce as failures). RFS (defined as disease recurrence or death) estimates at 3, 4 and 5 years were 92 % (77–97 %), 88 % (69–95 %) and 83 % (62–93 %) if patients with PSA bounces are not counted as failures, and were 90 % (75–96 %), 85 % (67–94 %) and 75 % (53–88 %) if they were. The median time to PSA nadir was 26.2 months (range 5.8–82.9 months), with a median PSA nadir of 0.05 ng/mL (range <0.01–1.99 ng/mL). 2 patients had a “benign PSA bounce”, and 4 patients recurred with radiographic evidence of recurrence beyond the RT fields. Treatment was well tolerated with no acute G3 or higher GI or GU toxicity and only a single G3 late GU toxicity of urinary obstruction.ConclusionsSBRT boost is well-tolerated for intermediate and high-risk prostate cancer patients with good biochemical outcomes and low toxicity.

Biomarkers in localized prostate cancer.

Biomarkers can improve prostate cancer diagnosis and treatment. Accuracy of prostate-specific antigen (PSA) for early diagnosis of prostate cancer is not satisfactory, as it is an organ- but not cancer-specific biomarker, and it can be improved by using models that incorporate PSA along with other test results, such as prostate cancer antigen 3, the molecular forms of PSA (proPSA, benign PSA and intact PSA), as well as kallikreins. Recent reports suggest that new tools may be provided by metabolomic studies as shown by preliminary data on sarcosine. Additional molecular biomarkers have been identified by the use of genomics, proteomics and metabolomics. We review the most relevant biomarkers for early diagnosis and management of localized prostate cancer.

Prostate-specific antigen kinetics after stereotactic body radiotherapy as monotherapy or boost after whole pelvic radiotherapy for localized prostate cancer.

PurposeStereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate-specific antigen (PSA) kinetics after SBRT has not been well characterized. The purpose of the current study is to assess the kinetics of PSA for low- and intermediate-risk prostate cancer patients treated with SBRT using Cyberknife as both monotherapy and boost after whole pelvic radiotherapy (WPRT) in the absence of androgen deprivation therapy.MethodsA total of 61 patients with low- and intermediated-risk prostate cancer treated with SBRT as monotherapy (36.25 Gy in 5 fractions in 32 patients) and SBRT (21 Gy in 3 fractions in 29 patients) boost combined with WPRT (45 Gy in 25 fractions). Patients were excluded if they failed therapy by the Phoenix definition or had androgen deprivation therapy. PSA nadir and rate of change in PSA over time (slope) were calculated and compared.ResultsWith a median follow-up of 52.4 months (range, 14–74 months), for SBRT monotherapy, the median PSA nadir was 0.31 ng/mL (range, 0.04–1.15 ng/mL) and slopes were –0.41 ng/mL/mo, –0.17 ng/mL/mo, –0.12 ng/mL/mo, and –0.09 ng/mL/mo, respectively, for durations of 1 year, 2 years, 3 years, and 4 years postradiotherapy. Similarly, for SBRT boost after WPRT, the median PSA nadir was 0.34 ng/mL (range, 0.04–1.44 ng/mL) and slopes were –0.53 ng/mL/mo, –0.25 ng/mL/mo, –0.14 ng/mL/mo, and –0.09 ng/mL/mo, respectively. The median nadir and slopes of SBRT monotherapy did not differ significantly from those of SBRT boost after WPRT. Benign PSA bounces were common in 30.4% of all cohorts, and the median time to PSA bounce was 12 months (range, 6–25 months).ConclusionsIn this report of low- and intermediate-risk prostate cancer patients, an initial period of rapid PSA decline was followed by a slow decline, which resulted in a lower PSA nadir. The PSA kinetics of SBRT monotherapy appears to be comparable to those achieved with SBRT boost with WPRT.

Increasing Fractional Doses Increases the Probability of Benign Prostate-Specific Antigen Bounce in Patients Undergoing Definitive High-Dose-Rate Brachytherapy for Prostate Cancer

Increasing Fractional Doses Increases the Probability of Benign Prostate-Specific Antigen Bounce in Patients Undergoing Definitive High-Dose-Rate Brachytherapy for Prostate Cancer

Dose escalation of five-fraction SABR for prostate cancer: Biochemical outcome and toxicity comparison of two prospective trials.

224 Background: To compare the biochemical outcomes and toxicities of two different 5 fraction stereotactic ablative body radiotherapy (SABR) schedules for the treatment of localized prostate cancer. Methods: Two sequential phase I/II studies of 5-fraction SABR for the treatment of low and intermediate risk (LR and IR) prostate cancer have been conducted. In the first trial, 84 LR patients(pts) received 35 Gy in 5 fractions, once per week over 29 days (Group 1). In the second trial, 30 pts (18 LR, 11 IR) received 40 Gy in 5 fractions, once per week over 29 days (Group 2). Treatment was delivered to the prostate with intensity modulated radiotherapy using daily image guidance and a 4mm (Group 1) or 5 mm (Group 2) CTV-PTV margin. PSA nadir and bRFS(nadir+2 definition) were compared between the two groups. Acute (CTCv3.0), late (RTOG) and cumulative toxicity for late grade ≥ 2 GU/GI toxicities were also compared. Results: Median follow up was 74 (IQR 67-81) and 36 (IQR 32-39) months. Median PSA nadir was 0.4 ng/ml and 0.3 ng/ml. Time to PSA nadir was 54 and 32.5 months. 44.0% in group 1 and 30% in Group 2 experienced benign PSA bounce. There were 3 and 0 PSA failures in Groups 1 and 2. 2-, 4- and 6-year bRFS was 100%, 98.7% and 95.9% and 100%, 100% and not reached in groups 1 and 2, respectively (p=0.91). The only acute grade 3 toxicity was noticed in Group 1 (1 pt, GU). Late grade 4 GI toxicity was noted in Group 1 (1 pt, GI, fistula). Up to 4 years of follow-up, Group 2 pts have had a greater percentage of grade 2+ cumulative GU (5.0% vs 24.2%) and GI (7.6% vs 26.2%) toxicities. Conclusions: Pts receiving a dose escalated SABR had slightly lower PSA nadir and similar bRFS - longer follow up is needed to better estimate biochemical outcomes in Group 2. There seemed to be a greater risk of grade 2 toxicities in the higher dose cohort but grade 3+ toxicities were not increased. Quality of life analyses will be presented separately. Clinical trial information: NCT01578902 , NCT01146340 .[Table: see text]

Prostate specific antigen kinetics following robotic stereotactic body radiotherapy for localized prostate cancer

Background. Stereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate specific antigen (PSA) kinetics after prostate SBRT have not been well characterized. The purpose of this study was to analyze the trend in PSA decline following robotic SBRT from a prospective cohort of patients.Material and methods. In total 175 patients were treated definitively for localized prostate cancer to a dose of 35–36.25 Gy in 5 fractions using robotic SBRT in the absence of androgen deprivation therapy (ADT). PSA and testosterone were collected at regular intervals following treatment and patients were assessed for biochemical failure and benign PSA bounce. A PSA nadir threshold of 0.5 ng/ml was used as a predictor of long-term disease-free survival. Multivariate logistic regression was used to assess the effect of disease specific covariates on the likelihood of achieving a PSA nadir less than threshold. PSA kinetics were analyzed a multi-component exponential model accounting for benign and malignant sources of PSA.Results and conclusion. At a median follow-up of 3 years, 70% of patients achieved a PSA nadir below 0.5 ng/ml with a median PSA nadir of 0.3 ng/ml at a median time to nadir of 30 months. In our cohort, 36.2% experienced a benign PSA bounce. Absence of PSA bounce, initial PSA, and testosterone at the time of nadir proved to be significant predictors of achieving a PSA nadir below threshold. PSA kinetics after prostate SBRT were well described with a functional volume model with fitted half-lives of 4.4 and 14.8 months for malignant and benign sources of PSA, respectively. Patients treated with prostate SBRT experience an initial period of rapid PSA decline followed by a slow decline which will likely result in lower PSA nadirs after longer follow-up. The long-term disease specific impacts of these results remain to be determined.

Clinical implications of a prostate-specific antigen bounce after radiation therapy for prostate cancer.

The objectives are to determine predictors of a prostate-specific antigen (PSA) bounce, whether a PSA bounce after radiotherapy for prostate cancer is associated with biochemical disease-free survival (bDFS), and the time course to a PSA bounce versus a biochemical failure post-irradiation. Between July 2000 and December 2012, 691 prostate cancer patients without regional or distant metastases were treated with external beam radiation therapy and/or brachytherapy, and had at least 12 months of follow-up. A PSA bounce was defined as a temporary PSA increase of ≥ 0.4 ng/mL. bDFS was defined according to the nadir + 2 definition. The median follow-up was 42 months. The median time to first PSA bounce was 17 months (95% confidence interval 15-18 months). In contrast, the median time to biochemical failure was 41 months (95% confidence interval 28-53 months). Two hundred and twenty-six of 691 (33%) patients had at least one PSA bounce with a median magnitude of 1.0 ng/mL (range 0.4-17.0). A Gleason score of 6 (p < 0.0001) predicted a PSA bounce on multivariate analysis. Patients with a PSA bounce experienced improved bDFS on multivariate analysis (p = 0.002). Patients with a Gleason score of 6 were more likely to experience a PSA bounce which was associated with improved bDFS. A PSA bounce occurred sooner after radiotherapy than a biochemical failure. The authors recommend against performing prostate biopsies within 24-30 months of radiotherapy since an elevated PSA may simply represent a benign PSA bounce.

The role of transperineal template prostate biopsies in prostate cancer diagnosis in biopsy naïve men with PSA less than 20 ng ml−1

To compare prostate cancer detection rates between transrectal ultrasound (TRUS) prostate biopsy and transperineal template prostate biopsy (TPTPB) in biopsy naïve men. TRUS biopsy is still regarded as gold standard for prostate cancer diagnosis. TPTPB has been shown to improve prostate cancer detection in men with rising PSA and previous negative TRUS biopsies. We carried out a prospective study performing both biopsies in the same group of men with a benign feeling digital rectal examination (DRE), PSA <20 ng ml(-1) and no previous prostate biopsies. A total of 50 patients with mean age of 67 years (range: 54-84), mean prostate volume 58 cc (range: 19-165) and mean PSA 8 ng l(-1) (range: 4-18) underwent standard 12-core TRUS biopsy followed immediately by 36-core TPTPB under general anaesthetic. We determined the prostate cancer detection rate between the two diagnostic modalities. In total, 20/50 (40%) had benign pathology. Of 30/50 (60%) diagnosed with prostate cancer, 16 (32%) had positive results in both TRUS and TPTPB, whereas 14 (28%) had negative TRUS but positive TPTPB. No cancers were detected solely by TRUS biopsy. TRUS biopsy detected cancer in 32% versus 60% with TPTPB. In total, 19/30(63%) cancers detected by TPTPB had Gleason score > or =7.2 (4%) experienced urosepsis, 7 (14%) temporary urinary retention, 16 (32%) mild haematuria and 19 (38%) haematospermia. TPTPB is associated with significantly higher prostate cancer detection rate than TRUS biopsies in biopsy naïve men with a benign feeling DRE and PSA <20 ng ml(-1). PSA appears to be better biomarker than previously thought.

Distinguishing Prostate-Specific Antigen Bounce from Biochemical Failure after Low-Dose-Rate Prostate Brachytherapy

Low-dose-rate (LDR) brachytherapy is a popular treatment option for men with localized prostate cancer. Patient outcomes are excellent, with minimal toxicity and excellent disease-free survival. However, temporary increases in prostate-specific antigen (PSA) levels are common after brachytherapy, a phenomenon known as a benign PSA bounce. The purpose of this study was to characterize PSA rises of at least 2.0 ng/mL as benign bounces or biochemical failures after LDR prostate brachytherapy at our institution, and to investigate distinguishing features between them.

Distinguishing prostate-specific antigen bounces from biochemical failure after low-dose-rate prostate brachytherapy.

PurposeThe purpose of this study was to characterize benign prostate-specific antigen (PSA) bounces of at least 2.0 ng/mL and biochemical failure as defined by the Phoenix definition after prostate brachytherapy at our institution, and to investigate distinguishing features between three outcome groups: patients experiencing a benign PSA bounce, biochemical failure, or neither.Material and methodsFive hundred and thirty consecutive men treated with low-dose-rate brachytherapy with follow-up of at least 3 years were divided into outcome groups experiencing bounce, failure, or neither. A benign bounce was defined as a rise of at least 2.0 ng/mL over the pre-rise nadir followed by a decline to 0.5 ng/mL or below, without intervention. Patient and tumor characteristics, treatment variables, and PSA kinetics were analyzed between groups.ResultsThirty-two (6.0%) men experienced benign bounces and 47 (8.9%) men experienced failure. Men experiencing a bounce were younger (p = 0.01), had a higher 6-month PSA level (p = 0.03), and took longer to reach a final nadir (p < 0.01). Compared to the failure group, men with bounce had a lower pre-treatment PSA level (p = 0.01) and experienced a rise of at least 2.0 ng/mL that occurred sooner after the implant (p < 0.01) with a faster PSA doubling time (p = 0.01). Only time to PSA rise independently differentiated between bounce and failure (p < 0.01), with a benign bounce not being seen after 36 months post-treatment. Prostate-specific antigen levels during a bounce reached levels as high as 12.6 ng/mL in this cohort, and in some cases took over 5 years to decline to below 0.5 ng/mL.ConclusionsAlthough there is substantial overlap between the features of benign PSA bounces and failure, physicians may find it useful to evaluate the timing, absolute PSA level, initial response to treatment, and rate of rise when contemplating management for a PSA rise after low-dose-rate brachytherapy.

A single-center study of 100 consecutive patients with localized prostate cancer treated with stereotactic body radiotherapy

BackgroundRadiotherapy is an increasingly preferred treatment option for localized prostate cancer, and stereotactic body radiation therapy (SBRT) a relatively established modality of therapeutic irradiation. The present study analyzes the toxicity and biochemical efficacy of SBRT in 100 consecutive prostate cancer patients treated with CyberKnife Robotic Radiosurgery System.MethodsOne hundred patients were treated with SBRT at the Radiation Oncology department of San Bortolo Hospital, Vicenza, Italy. All patients included in this IRB-approved protocol-driven prospective study had biopsy-proven prostate cancer. Risk category was low in 41, intermediate in 42, and high in 17 patients. The patients were treated with CyberKnife-SBRT (CK-SBRT), the prescription dose was 35 Gy in five fractions, corresponding to 92 Gy in 2-Gy fractions (α/β =1.5 Gy); 29 patients also received androgen deprivation therapy (ADT).ResultsMedian follow-up was 36 months (range, 6–76 months). Acute Grade 2 genitourinary and gastrointestinal toxicity occurred in respectively 12% and 18% of the patients; there were no Grade 3 or higher acute toxicities. Late Grade 1, 2, and 3 genitourinary toxicities occurred in 4%, 3%, and 1% of the patients, respectively; late Grade 1 gastrointestinal toxicity occurred in two patients and Grade 2 toxicity in one patient; no late gastrointestinal toxicities of grade 3 or 4 were observed. Median PSA nadir was 0.45 ng/ml at 36 months for all patients. In the SBRT-monotherapy group, the median PSA nadir at 36 months was 0.62 ng/ml; in the ADT-SBRT group, it was 0.18 ng/ml. Four patients had clinical recurrence: one local, two lymph nodes, and one to the bone. Ninety-six patients had no evidence of biochemical or clinical recurrence. A benign PSA bounce of median 1.08 ng/ml occurred in 12% of the 71 SBRT monotherapy patients at a mean 23 months (range, 18–30 months).ConclusionsIn this study CK-SBRT has provided promising outcomes in localized prostate cancer with good PSA response, minimal toxicity and patient inconvenience.

Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials

PurposeThe effectiveness of stereotactic body radiotherapy (SBRT) for localized prostate cancer is tested. Methods and materialsA total of 1100 patients with clinically localized prostate cancer were enrolled in separate prospective phase 2 clinical trials of SBRT from 8 institutions during 2003–11 and pooled for analysis. SBRT using the CyberKnife delivered a median dose of 36.25Gy in 4–5 fractions. Patients were low-risk (58%), intermediate-risk (30%) and high-risk (11%). A short-course of androgen deprivation therapy (ADT) was given to 14%. PSA relapse defined as a rise >2ng/ml above nadir was analyzed with the Kaplan Meier method. ResultsWith a median follow-up of 36months there were 49 patients with PSA failure (4.5%), 9 of whom were subsequently determined to be benign PSA bounces. The 5-year biochemical relapse free survival (bRFS) rate was 93% for all patients; 95%, 83% and 78% for GS ⩽6, 7 and ⩾8, respectively (p=0.001), and 95%, 84% and 81% for low-, intermediate- and high-risk patients, respectively (p<0.001). No differences were observed with ADT (p=0.71) or as a function of total dose (p=0.17). A PSA bounce of >0.2ng/ml was noted among 16% of patients. For 135 patients possessing a minimum of 5years follow-up, the 5-year bRFS rate for low- and intermediate-risk patients was 99% and 93%, respectively. ConclusionPSA relapse-free survival rates after SBRT compare favorably with other definitive treatments for low and intermediate risk patients. The current evidence supports consideration of SBRT among the therapeutic options for these patients.