Background: In men undergoing definitive radiation for prostate cancer, it is unclear whether early biochemical response can provide additional prognostic value beyond pre-treatment risk stratification. Methods: Prostate cancer patients consecutively treated with definitive radiation at our institution by a single provider from 1993 to 2006 and who had an end-of-radiation (EOR) PSA ( n =688, median follow-up 11.2 years). We analyzed the association of an EOR PSA level, obtained during the last week of radiation, with survival outcomes. Multivariable-adjusted cox proportional hazards models were constructed to assess associations between a detectable EOR PSA (defined as ⩾0.1 ng ml −1 ) and biochemical failure-free survival (BFFS), metastasis-free survival (MFS), prostate cancer-specific survival (PCSS) and overall survival (OS). Kaplan–Meier survival curves were constructed, with stratification by EOR PSA. Results: At the end of radiation, the PSA level was undetectable in 30% of patients. Men with a detectable EOR PSA experienced inferior 10-year BFFS (49.7% versus 64.4%, P <0.001), 10-year MFS (84.8% versus 92.0%, P =0.003), 10-year PCSS (94.3% versus 98.2%, P =0.007) and 10-year OS (75.8% versus 82.5%, P =0.01), as compared to men with an undetectable EOR PSA. Among National Comprehensive Care Network (NCCN) intermediate- and high-risk men who were treated with definitive radiation and androgen deprivation therapy (ADT), a detectable EOR PSA was more strongly associated with PCSS than initial NCCN risk level (EOR PSA: HR 5.89, 95% CI 2.37–14.65, P <0.001; NCCN risk level: HR 2.01, 95% CI 0.74–5.42, P =0.168). Main study limitations are retrospective study design and associated biases. Conclusions: EOR PSA was significantly associated with survival endpoints in men who received treatment with definitive radiation and ADT. Whether the EOR PSA can be used to modulate treatment intensity merits further investigation.

BACKGROUND: To evaluate the relationship between PSA testing history and high-risk disease among older men diagnosed with prostate cancer.METHODS: Records from 1993 to 2014 were reviewed for men who underwent radiotherapy for prostate cancer at age 75 years or older. Patients were classified into one of four groups based on PSA-testing history: (1) no PSA testing; (2) incomplete/ineffective PSA testing; (3) PSA testing; or (4) cannot be determined. Outcomes of interest were National Comprehensive Cancer Network (NCCN) risk group (that is, low, intermediate or high risk) and biopsy grade at diagnosis. Multivariable logistic regression was used to determine the association between PSA testing history and high-risk cancer.RESULTS: PSA-testing history was available in 274 (94.5%) of 290 subjects meeting study criteria. In total, 148 men (54.0%) underwent PSA testing with follow-up biopsy, 72 (26.3%) underwent PSA testing without appropriate follow-up, and 54 men (19.7%) did not undergo PSA testing. Patients who underwent PSA testing were significantly less likely to be diagnosed with NCCN high-risk cancer (23.0% vs 51.6%, P < 0.001). On multivariable analysis, men with no/incomplete PSA testing had more than three-fold increased odds of high-risk disease at diagnosis (odds ratio 3.39, 95% confidence interval 1.96-5.87, P < 0.001) as compared to the tested population.CONCLUSIONS: Older men who underwent no PSA testing or incomplete testing were significantly more likely to be diagnosed with high-risk prostate cancer than those who were previously screened. It is reasonable to consider screening in healthy older men likely to benefit from early detection and treatment.

Intraoperative transrectal ultrasound (TRUS) dosimetry during LDR prostate brachytherapy is imprecise due to sonographic distortion caused by seed echoes, needle tracks, and traumatic edema, which obscure seed positions or create false signals. We have previously described a system of combined ultrasound and fluoroscopy based real-time seed localization (RUF) for intraoperative dose calculation. Here we report the final results of a prospective study of 80 patients comparing RUF to standard TRUS based dosimetry. 80 patients undergoing permanent Pd-103 seed implantation for prostate cancer were prospectively enrolled between July 2011 and Aug 2014. Seed implantation was performed using standard ultrasound-based localization (USD). Intraoperatively, 6 fluoroscopic images were acquired using a non-isocentric C-arm; offline, a 3D seed cloud configuration was reconstructed from fluoroscopies and registered to axial ultrasound images of the implanted prostate. Images were not used for implant modification. CT/MRI scans were acquired on post-op day 1 for contouring and dose calculation. Standard dosimetric parameters were calculated for RUF, USD, and day 1 CT/MRI image sets. Differences between dosimetric measures were calculated and root mean square deviations were evaluated. Correlation coefficients and paired two-tailed T-tests were used to evaluate patient specific and aggregate pairwise similarity between USD, RUF, and CT/MRI data sets. Of the 80 patients enrolled, 12 were excluded due to lack of postoperative MRIs. RUF based intraoperative dosimetry showed higher correlation with day 1 CT/MRI for all prostate dosimetric parameters (D90, V100, V150, V200; P<0.05) compared to USD with Pearson correlation for prostate D90 of 0.81 for RUF vs CT/MRI and 0.61 for USD vs CT/MRI (P<0.05). When compared to CT/MRI, RUF dosimetry showed a significant variation for 0 out of 8 dosimetric parameters analyzed, whereas US dosimetry varied significantly for 6 of 8 parameters (paired two-tailed T test, alpha < 0.01). Root mean squared differences from CT/MRI were smaller for RUF for 6 of 8 parameters examined compared with USD. USD demonstrated a tendency to over-estimate dose to the prostate when compared to RUF. RUF demonstrated better predictive characteristics for prostatic dosimetry and identified cold implants more reliably than USD (P<0.05), however with a tendency to overestimate rectal dose, possibly attributable to deformation associated with the rectal probe. Intraoperative registered ultrasound and fluoroscopy (RUF) approximated post-operative CT/MRI prostate and urethral dosimetry to a greater degree than the current ultrasound-based intraoperative method. RUF is deployable in combination with a standard non-isocentric C-arm, and demonstrates potential to minimize prostate underdosage not otherwise detected. A confirmatory phase II trial utilizing RUF for intraoperative iterative plan modification is underway.

113 Background: Conventional dosimetric standards for implant quality do not adequately predict patient reported QoL measures following prostate brachytherapy. We used a dynamic learning knowledgebase (Oncospace) to explore relationships between dose and patient-reported outcomes. Methods: Patient reported quality of life outcomes were prospectively collected for 366 patients with stage cT1-T2 PCa over a 10 year interval. Patients received Pd-103 seed implantation under real-time ultrasound guidance, and completed a QoL instrument (IIEF-5) prior to treatment and at follow-up. Multivariate risk models were used to evaluate dose/toxicity relationships and the Oncospace learning environment generated prediction models using granular dose volume relationships. Results: Median follow-up was 36 months (SD 28.5). In the cohort, 23.7% (n = 87) received combined brachytherapy and EBRT; 14.7% (n = 54) had received prior androgen suppression therapy. Sexual QoL data at minimum of 2 years was available in 141 men. Th...

The absence of a reliable biomarker for monitoring response to radiation therapy (RT) during androgen suppression is a barrier to early salvage and risk-adapted treatment modification. We are developing a platform for noninvasive detection of cell-free tumor DNA (ctDNA) in blood and urine and testing its applicability to real-time assessment of response to RT. We evaluated the analytical and clinical performance of a novel molecular assay for parallel detection of tumor-specific hypermethylation, hypomethylation, copy number, and structural alterations in ctDNA. Genetic and epigenetic biomarker credentialing in prostate cancer (PCa) specimens and normal tissues was performed previously. Our assay relies on assessment of total input and enriched methylated fragments coupled with next-generation sequencing (NGS) for detection of ctDNA in the blood and urine of men with high-risk primary PCa. We explored the ability to detect rare DNA molecules harboring methylation alterations and structural rearrangements. Combined methyl-CpG affinity purification and methylation sensitive restriction enzyme digestion (COMPARE-MS) allowed 637.7 (SEM=24.88) fold enrichment of methylated DNA over unmethylated DNA and allowed detection of rare hypermethylated target genes from as few as 20 genome equivalents. Methylated tumor suppressor DNA was quantitatively detected in a dilution series of as few as 5 LNCaP cells in 100 mL of urine (range: 5 to 5x105 cells). Five genome equivalents of M.SssI methylated WBC DNA (30 pg) were quantitatively detected in 20 ng excess unmethylated DNA by COMPARE-MS. The TMPRSS2-ERG gene rearrangement was detected from as few as 100 genome equivalents of VCaP cell line DNA spiked into 5 mL of whole blood by qPCR. Analysis of NGS libraries prepared from plasma isolates demonstrated preservation of input fragmentation patterns and >3 fold increased CpG density in enriched libraries (input=1.34% [99% CI, 0.79%-1.89%]; enriched=4.02% [99% CI, 2.79%-5.24%]; P<.01), suggesting unbiased amplification and robust methylation enrichment. NGS analysis revealed GSTP1 promoter hypermethylation only in a PCa containing enriched ctDNA library. Further analytical validation in reference samples is ongoing and an institutional review board (IRB)–approved study for prospective validation is accruing healthy volunteers and men with high-risk PCa to determine background and cancer-specific changes, respectively. We report a novel molecular assay for detecting low copy number PCa-specific epigenetic and genetic alterations in blood and urine. Preclinical validation demonstrates sensitive and specific detection of ctDNA in biospecimens, supporting further testing to establish efficacy in monitoring treatment response. An IRB-approved study for prospective clinical validation had accrued 28 of 60 subjects at the time of submission.