Node-negative Prostate Cancer Research Articles

Patterns of Failure After Prostate-Only Radiotherapy in High-Risk Prostate Cancer: Implications for Refining Pelvic Nodal Contouring Guidelines

PurposeTo study prostate specific membrane antigen – positron emission tomography (Ga68PSMA-PETCT) based patterns of relapse at biochemical failure (BCF) after prostate-only radiotherapy (PORT) in high-risk (HR) prostate cancer and its implications on pelvic contouring recommendations. Methods and materialsPatients with clinico-radiological high-risk node-negative prostate cancer treated with curative PORT and androgen deprivation therapy (ADT), either within the POP-RT randomised trial or off trial, who underwent a Ga68PSMA-PETCT upon BCF were included. Patterns of regional and distant recurrence on Ga68PSMA-PETCT were studied. Pelvic nodal recurrences were mapped with reference to the superior border of pubic symphysis. Pelvic lymph nodal caudal border (PLNcb) recommendations in the published contouring guidelines (RTOGcb, GETUGcb, PIVOTALcb, NRGcb, GFRUcb) were evaluated. ResultsOf the total 262 patients screened, 68 eligible patients were included (POP-RT trial 35 patients; off-trial 33 patients). Median follow-up was 91 months (IQR, 72–117) and median time to BCF was 65 months (IQR, 49–83). Regional and distant recurrence was seen in 31 (46%) and 31 (46%) patients, respectively. Of the nodal recurrences, nearly half (46%, 14/31) had no distant metastases and 64% (20/31) had a failure in the common iliac nodal region. The lower-most nodal recurrence was 20 mm cranial to the top of pubic symphysis (RTOGcb, GETUGcb, GFRUcb) and 10 mm cranial to the PIVOTALcb. The PLNcb recommended by NRG guideline (NRGcb) had an inter-patient variability of 32 mm, ranging from 16 mm above to 16 mm below the top of pubic symphysis, and the lower most nodal recurrence ranged from 4 mm to 36 mm cranial to NRGcb. ConclusionPelvic failures accounted for a major proportion of recurrences after prostate-only radiotherapy, with the caudal most nodal recurrence being 20 mm cranial to the top of pubic symphysis. This could have implications in defining the caudal border of contouring recommendations.

High-risk prostate cancer treated with a stereotactic body radiation therapy boost following pelvic nodal irradiation.

Modern literature has demonstrated improvements in long-term biochemical outcomes with the use of prophylactic pelvic nodal irradiation followed by a brachytherapy boost in the management of high-risk prostate cancer. However, this comes at the cost of increased treatment-related toxicity. In this study, we explore the outcomes of the largest cohort to date, which uses a stereotactic body radiation therapy (SBRT) boost following pelvic nodal radiation for exclusively high-risk prostate cancer. A large institutional database was interrogated to identify all patients with high-risk clinical node-negative prostate cancer treated with conventionally fractionated radiotherapy to the pelvis followed by a robotic SBRT boost to the prostate and seminal vesicles. The boost was uniformly delivered over three fractions. Toxicity was measured using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Oncologic outcomes were assessed using the Kaplan-Meier method. Cox proportional hazard models were created to evaluate associations between pretreatment characteristics and clinical outcomes. A total of 440 patients with a median age of 71 years were treated, the majority of whom were diagnosed with a grade group 4 or 5 disease. Pelvic nodal irradiation was delivered at a total dose of 4,500 cGy in 25 fractions, followed by a three-fraction SBRT boost. With an early median follow-up of 2.5 years, the crude incidence of grade 2+ genitourinary (GU) and gastrointestinal (GI) toxicity was 13% and 11%, respectively. Multivariate analysis revealed grade 2+ GU toxicity was associated with older age and a higher American Joint Committee on Cancer (AJCC) stage. Multivariate analysis revealed overall survival was associated with patient age and posttreatment prostate-specific antigen (PSA) nadir. Utilization of an SBRT boost following pelvic nodal irradiation in the treatment of high-risk prostate cancer is oncologically effective with early follow-up and yields minimal high-grade toxicity. We demonstrate a 5-year freedom from biochemical recurrence (FFBCR) of over 83% with correspondingly limited grade 3+ GU and GI toxicity measured at 3.6% and 1.6%, respectively. Long-term follow-up is required to evaluate oncologic outcomes and late toxicity.

Consensus Delineation Guidelines for Pelvic Lymph Node Radiation Therapy of Prostate Cancer: On Behalf of the Francophone Group of Urological Radiation Therapy (GFRU)

Clinical target volume (CTV) delineation for pelvic lymph nodes in prostate cancer is currently based on 3 consensus guidelines with some inherent discrepancies. To improve the reproducibility in nodal delineation, the Francophone Group of Urological Radiotherapy (Groupe Francophone de Radiothérapie Urologique [GFRU]) worked toward proposing an easily applicable, reproducible, and practice-validated contouring guideline for pelvic nodal CTV. The nodal CTV data sets of a high-risk node-negative prostate cancer clinical case contoured by 86 radiation oncologists participating in a GFRU contouring workshop were analyzed. CTV volumes were defined before and after a structured presentation of literature data on lymphatic drainage pathways and patterns of nodal involvement and relapse, illustrated using a reference contour (CRef) defined by 3 GFRU experts. The consistency between the participants' contours and CRef was assessed quantitively by means of the Simultaneous Truth and Performance Level Estimation (STAPLE) method, the Dice coefficient, and the Hausdorff distance and qualitatively using a count map. These results combined with the literature review were thoroughly discussed among GFRU experts to reach a consensus. From the 86 workshop participants, the volume of the STAPLE CTV was 591 cc compared with 502 cc for CRef. The Dice coefficient of the STAPLE CTV compared with the experts' CRef was 0.736 (±0.084) before and 0.823 (±0.070) after the workshop; the standard deviation decreased from 11.5% to 8.5% over the workshop. The Hausdorff distance of the STAPLE CTV compared with the CRef was 34.5 mm (±12.4) before the workshop and 21.8 mm (±9.3) after the workshop. Four areas of significant interobserver variability were identified, and a consensus was reached. Using a robust methodology, our cooperative group proposed an easily applicable, reproducible, and practice-validated guideline for the delineation of the pelvic CTV in prostate cancer, useful for implementation in daily practice and clinical trials.

The Diagnostic Value of the Sentinel Node Procedure to Detect Occult Lymph Node Metastases in PSMA PET/CT Node-Negative Prostate Cancer Patients.

Our objective was to assess the diagnostic value of the sentinel node (SN) procedure for lymph node staging in primary intermediate- and high-risk prostate cancer patients with node-negative results on prostate-specific membrane antigen PET/CT (miN0). Methods: From 2016 to 2022, 154 patients with primary, miN0 PCa were retrospectively included. All patients had a Briganti nomogram-assessed nodal risk of more than 5% and underwent a robot-assisted SN procedure for nodal staging. The prevalence of nodal metastases at histopathology and the occurrence of surgical complications according to the Clavien-Dindo classification were evaluated. Results: The SN procedure yielded 84 (14%) tumor-positive lymph nodes with a median metastasis size of 3 mm (interquartile range, 1-4 mm). In total, 55 patients (36%) were reclassified as pN1. A complication of Clavien-Dindo grade 3 or higher occured in 1 patient (0.6%). Conclusion: The SN procedure classified 36% of patients with miN0 prostate cancer with an elevated risk of nodal metastases as pN1.

Second malignancy probabilities in patients with prostate cancer treated with whole pelvis radiation therapy versus prostate only radiation therapy.

Whole pelvic radiation therapy (WPRT) may improve outcomes compared with prostate only radiation therapy (PORT) in some subsets of men with prostate cancer, as in the POP-RT trial. However, there is concern about increased risk of adverse effects with WPRT, including the development of radiation-induced second malignancies (SM). Given the rarity of SM, little is known about relative rates of SM between WPRT and PORT. A retrospective cohort analysis was performed of men with nonmetastatic, node-negative prostate cancer with at least 60 months of follow-up using a national database. SM probabilities were compared in men receiving either WPRT or PORT using multivariable logistic models adjusting for clinical and sociodemographic factors. Temporal sensitivity analyses stratified by year of diagnosis and length of follow-up were also conducted. Of 50,237 patients in the study, 39,338 (78.4%) received PORT, and 10,899 (21.7%) received WPRT. Median follow-up was 106.2 months (interquartile range 82.32-132.25). Crude probabilities of SM were 9.16% for WPRT and 8.88% for PORT. The adjusted odds ratio (AOR) for development of SM with PORT versus WPRT was 1.046 (95% confidence interval 0.968-1.130). Temporal sensitivity analyses by stratifying by year of diagnosis and follow-up length also did not demonstrate any significant difference in rates of SM between WPRT and PORT using AORs with WPRT as the referent. Retrospective analysis of over 50,000 patients did not demonstrate an association between WPRT and an increased probability of SM compared to PORT. Given the findings of POP-RT, the use of WPRT may become widespread for certain subsets of men. Thus, our findings could help guide how we counsel patients deciding between WPRT and PORT and suggest the need for prospective assessment of SM risk with WPRT and PORT.

A nodal risk cutoff for whole pelvic radiotherapy for prostate cancer?

In their recent Review paper in The Lancet Oncology, Gert De Meerleer and colleagues take a comprehensive look at evidence for pelvic irradiation in patients with prostate cancer.1 Specifically, for clinically node-negative prostate cancer, the value of elective whole pelvic radiotherapy (WPRT) has been discussed at length. For patients with Roach nodal risk of at least 20%, the POP-RT trial showed significant improvement in biochemical control, disease-free survival, and metastasis-free survival with WPRT.

On the probability of lymph node negativity in pN0-staged prostate cancer—a theoretically derived rule of thumb for adjuvant needs

PurposeThe extent of lymphadenectomy and clinical features influence the risk of occult nodes in node-negative prostate cancer. We derived a simple estimation model for the negative predictive value (npv) of histopathologically node-negative prostate cancer patients (pN0) to guide adjuvant treatment.MethodsApproximations of sensitivities in detecting lymph node metastasis from current publications depending on the number of removed lymph nodes were used for a theoretical deduction of a simplified formulation of npv assuming a false node positivity of 0.ResultsA theoretical formula of npv = p(N0IpN0) = (100 − prevalence) / (100 − sensitivity × prevalence) was calculated (sensitivity and preoperative prevalence in %). Depending on the number of removed lymph nodes (nLN), the sensitivity of pN0-staged prostate cancer was derived for three sensitivity levels accordingly: sensitivity = f(nLN) = 9 × nLN /100 for 0 ≤ nLN ≤ 8 and f(nLN) = (nLN + 70) /100 for 9 ≤ nLN ≤ 29 and f(nLN) = 1 for nLN ≥ 30.ConclusionWe developed a theoretical formula for estimation of the npv in pN0-staged prostate cancer patients. It is a sine qua non to use the formula in a clinically experienced context before deciding to electively irradiate pelvic lymph nodes or to intensify adjuvant systemic treatment.

Elective nodal radiotherapy in prostate cancer.

In patients with prostate cancer who have a high risk of pelvic nodal disease, the use of elective whole pelvis radiotherapy is still controversial. Two large, randomised, controlled trials (RTOG 9413 and GETUG-01) did not show a benefit of elective whole pelvis radiotherapy over prostate-only radiotherapy. In 2020, the POP-RT trial established the role of elective whole pelvis radiotherapy in patients who have more than a 35% risk of lymph node invasion (known as the Roach formula). POP-RT stressed the importance of patient selection. In patients with cN1 (clinically node positive) disease or pN1 (pathologically node positive) disease, the addition of whole pelvis radiotherapy to androgen deprivation therapy significantly improved survival compared with androgen deprivation therapy alone, as shown in large, retrospective studies. This patient population might increase in the future because use of the more sensitive prostate-specific membrane antigen PET-CT will become the standard staging procedure. Additionally, the SPORTT trial suggested a benefit of whole pelvis radiotherapy in biochemical recurrence-free survival in the salvage setting. A correct definition of the upper field border, which should include the bifurcation of the abdominal aorta, is key in the use of pelvic radiotherapy. As a result of using modern radiotherapy technology, severe late urinary and intestinal toxic effects are rare and do not seem to increase compared with prostate-only radiotherapy.

Association of lymph node yield with overall survival in patients with pathologically node negative prostate cancer

We investigated the association between lymph node yield (LNY) with overall survival (OS) and post-radical prostatectomy (RP) secondary treatments among men with pathologically node negative (pN0) prostate cancer. We reviewed the National Cancer Database for men with Gleason Grade Group 2 or higher prostate cancer treated with RP and had pathologically node-negative disease. LNY was modeled as a continuous and categorical variable grouped by quartiles of LNY. Secondary treatment was defined as the use of radiation or systemic therapy post-RP. Multivariable Cox proportional hazards and logistic regression models were used to test for an association of LNY with OS and secondary treatments, respectively. We identified 89,416 men with pN0 prostate cancer treated with RP from 2010-2015. LNY was associated with improved OS when modeled as a categorical and continuous variable. The third (6-9 nodes) and fourth (≥10 nodes) quartiles of LNY were associated with improved OS (HR 0.87, 95% CI 0.79-0.96, P = 0.006 and HR 0.88, 95% CI 0.79-0.98, P= 0.017, respectively) when compared with the lowest quartile of LNY (≤3 nodes) and the hazard of death decreased by 1% for each benign lymph node removed (HR 0.99, 95% CI 0.98-0.99, P= 0.022). Additionally, categorical and continuous LNY was associated with significantly less use of post-RP secondary treatments. Removal of additional negative lymph nodes was associated with improved OS and less secondary treatments in patients with pN0 prostate cancer. These data suggest that removing a higher quantity of lymph nodes provides more accurate staging and prognosis.

Machine Learning-Based Interpretation and Visualization of Nonlinear Interactions in Prostate Cancer Survival.

Shapley additive explanation (SHAP) values represent a unified approach to interpreting predictions made by complex machine learning (ML) models, with superior consistency and accuracy compared with prior methods. We describe a novel application of SHAP values to the prediction of mortality risk in prostate cancer. Patients with nonmetastatic, node-negative prostate cancer, diagnosed between 2004 and 2015, were identified using the National Cancer Database. Model features were specified a priori: age, prostate-specific antigen (PSA), Gleason score, percent positive cores (PPC), comorbidity score, and clinical T stage. We trained a gradient-boosted tree model and applied SHAP values to model predictions. Open-source libraries in Python 3.7 were used for all analyses. We identified 372,808 patients meeting the inclusion criteria. When analyzing the interaction between PSA and Gleason score, we demonstrated consistency with the literature using the example of low-PSA, high-Gleason prostate cancer, recently identified as a unique entity with a poor prognosis. When analyzing the PPC-Gleason score interaction, we identified a novel finding of stronger interaction effects in patients with Gleason ≥ 8 disease compared with Gleason 6-7 disease, particularly with PPC ≥ 50%. Subsequent confirmatory linear analyses supported this finding: 5-year overall survival in Gleason ≥ 8 patients was 87.7% with PPC < 50% versus 77.2% with PPC ≥ 50% (P < .001), compared with 89.1% versus 86.0% in Gleason 7 patients (P < .001), with a significant interaction term between PPC ≥ 50% and Gleason ≥ 8 (P < .001). We describe a novel application of SHAP values for modeling and visualizing nonlinear interaction effects in prostate cancer. This ML-based approach is a promising technique with the potential to meaningfully improve risk stratification and staging systems.

Comparison by Race of Conservative Management for Low-Risk and Intermediate-Risk Prostate Cancers in Veterans From 2004 to 2018

Conservative management (ie, active surveillance or watchful waiting) is a guideline-based strategy for men with low-risk and intermediate-risk prostate cancer. However, use of conservative management is controversial for African American patients, who have worse prostate cancer outcomes compared with White patients. To examine the association of African American race with the receipt and duration of conservative management in the Veterans Health Administration (VA), a large equal-access health system. This cohort study used data from the VA Corporate Data Warehouse for 51 543 African American and non-Hispanic White veterans diagnosed with low-risk and intermediate-risk localized node-negative prostate cancer between January 1, 2004, and December 31, 2013. Men who did not receive continuous VA care were excluded. Data were analyzed from February 1 to June 30, 2020. All patients received either definitive therapy (ie, prostatectomy, radiation, androgen deprivation therapy) or conservative management (ie, active surveillance or watchful waiting). Receipt of conservative management and (for patients receiving conservative management) time from diagnosis to definitive therapy. The median (interquartile range) age of the 51 543 veterans in our cohort was 65 (61-70) years, and 14 830 veterans (28.8%) were African American individuals. Compared with White veterans, African American veterans were more likely to have intermediate-risk disease (18 988 [51.7%] vs 8526 [57.5%]), 3 or more comorbidities (15 438 [42.1%] vs 7614 [51.3%]), and high disability-related or income-related needs (9078 [24.7%] vs 4614 [31.1%]). Overall, 20 606 veterans (40.0%) received conservative management. African American veterans with low-risk disease (adjusted relative risk, 0.95; 95% CI, 0.92-0.98; P < .001) and intermediate-risk disease (adjusted relative risk, 0.92; 95% CI, 0.87-0.97; P = .002) were less likely to receive conservative management than White veterans. Compared with White veterans, African American veterans with low-risk disease (adjusted hazard ratio, 1.71; 95% CI, 1.50-1.95; P < .001) and intermediate-risk disease (adjusted hazard ratio, 1.46; 95% CI, 1.27-1.69; P < .001) who received conservative management were more likely to receive definitive therapy within 5 years of diagnosis (restricted mean survival time [SE] at 5 years, 1679 [5.3] days vs 1740 [2.4] days; P < .001). In this study, conservative management was less commonly used and less durable for African American veterans than for White veterans. Prospective trials should assess the comparative effectiveness of conservative management in African American men with prostate cancer.

National trends in the management of patients with positive surgical margins at radical prostatectomy.

To evaluate practice patterns of planned post-operative radiation therapy (RT) among men with positive surgical margins (PSM) at radical prostatectomy. We identified 43,806 men within the National Cancer Database with pathologic node-negative prostate cancer diagnosed in 2010 through 2014 with PSM. The primary endpoint was receipt of planned (RT) within a patient's initial course of treatment. We examined post-RP androgen deprivation therapy (ADT) with RT as a secondary endpoint. We evaluated patterns of post-operative management and characteristics associated with planned post-prostatectomy RT. Within 12months of RP, 87.0% received no planned RT, 8.5% RT alone, 1.3% ADT alone, and 3.1% RT with ADT. In a multivariable logistic regression model, planned RT use was associated with clinical and pathologic characteristics as estimated by surgical Cancer of the Prostate Risk Assessment (CAPRA-S) category (intermediate versus low, OR = 2.87, 95% CI 2.19-3.75, P < 0.001; high versus low, OR = 10.23, 95% CI 7.79-13.43, P < 0.001), treatment at community versus academic centers (OR = 1.24, 95% CI 1.15-1.34, P < 0.001), shorter distance to a treatment facility (OR = 0.97 for each 10-mile, 95% CI 0.96-0.98, P < 0.001), and uninsured status (OR = 1.39, 95% CI 1.10-1.77, P = 0.005). The odds of receiving planned RT were lower in 2014 versus 2010 (OR = 0.76, 95% CI 0.68-0.85, P < 0.001). There was no significant change in the use of ADT with RT. High versus low CAPRA-S category was associated with the use of ADT in addition to RT (OR = 5.13, 95% CI 1.57-16.80, P = 0.007). The use of planned post-prostatectomy RT remained stable among patients with PSM and appears driven primarily by the presence of other adverse pathologic features.

Ten-year disease progression and mortality rates in men who experience biochemical recurrence versus persistence after radical prostatectomy and undergo salvage radiation therapy: A post-hoc analysis of RTOG 9601 trial data

PurposeTo compare local/metastatic disease progression and overall mortality rates in men with node-negative prostate cancer at radical prostatectomy (RP) that experience biochemical recurrence vs. persistence postoperatively and undergo salvage radiation therapy (sRT). Materials and methodsData on 760 men who participated in the RTOG 9601 trial were extracted using the NCTN data archive platform. Patients were stratified into biochemical recurrence (nadir-PSA ≤0.4 ng/ml) or persistence (nadir-PSA >0.4 ng/ml) groups, based on the cut-off reported in the original trial. Inverse probability of treatment weighting (IPTW) methodology was utilized to minimize the baseline differences among groups. Competing-risk and Kaplan-Meier analyses estimated the impact of prostate-specific antigen (PSA) persistence vs. recurrence on local and metastatic disease progression and overall-mortality in the IPTW-adjusted model; a 2-sided P < 0.05 was considered significant. ResultsAll patients received sRT, and about 50% of the patients in either group received concomitant antiandrogen therapy (P = 0.951). The median follow-up was 12 years. After IPTW, the 2 groups were well-matched with standardized mean differences ∼10%. In the IPTW-adjusted cohort, the 10-year local and metastatic disease occurrence rates were 3.2% vs. 1.4% (Gray's P = 0.0001) and 28.6% vs. 10.1% (Gray's P < 0.0001) in patients with persistent vs. recurrent PSA, respectively. Similarly, the 10-year overall-mortality rates were 24.9% vs. 11.9% (Log-rank P = 0.029), respectively. ConclusionsPatients with biochemical persistence after RP are approximately 2.5 times more likely to experience local/metastatic failure and death, compared to patients with biochemical recurrence after RP, despite equivalent sRT with/without antiandrogen therapy use. These data may facilitate patient counseling and shared treatment selection.

Late toxicity and quality of life with prostate only or whole pelvic radiation therapy in high risk prostate cancer (POP-RT): A randomised trial

AimTo report toxicity and quality of life (QOL) outcomes from a randomised trial of prostate only versus whole pelvic radiotherapy in high risk, node negative prostate cancer. Materials/methodsPatients with localised prostate adenocarcinoma and nodal involvement risk > 20%, were randomised to prostate only (PORT, 68 Gy/25# to prostate) and whole pelvis (WPRT, 68 Gy/25# to prostate and 50 Gy/25# to pelvis) arms with stratification for TURP, Gleason score, baseline PSA, and type of androgen deprivation therapy (ADT). Image guided intensity modulated radiotherapy (IG-IMRT) and two years of ADT were mandatory. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were graded using RTOG grading. QOL was assessed using EORTC QLQ-C30 and PR-25 questionnaire pre-treatment and every 3–6 months post RT. ResultsTotal 224 patients were randomised (PORT 114, WPRT 110) from November 2011 to August 2017. Median follow up was 44.5 months. No RTOG grade IV toxicity was observed. Acute GI and GU toxicities were similar between both the arms. Cumulative ≥ grade II late GI toxicity was similar for WPRT and PORT (6.5% vs. 3.8%, p = 0.39) but GU toxicity was higher (17.7% vs. 7.5%, p = 0.03). Dosimetric analysis showed higher bladder volume receiving 30–40 Gy in the WPRT arm (V30, 60% vs. 36%, p < 0.001; V40, 41% vs. 25%, p < 0.001). There was no difference in QOL scores of any domain between both arms. ConclusionPelvic irradiation using hypofractionated IG-IMRT resulted in increased grade II or higher late genitourinary toxicity as compared to prostate only RT, but the difference was not reflected in patient reported QOL. Clinicaltrials.gov NCT02302105Prostate Only or Whole Pelvic Radiation Therapy in High Risk Prostate Cancer (POP-RT).

Stereotactic Body Radiation Therapy to the Prostate Bed: Results of a Phase 1 Dose-Escalation Trial

The primary objectives of this study were to evaluate toxicity of escalating doses of prostate bed stereotactic body radiation therapy and to provide dose recommendations for a phase 2 study. Patients with organ-confined, node-negative prostate cancer who had biochemical failure (prostate-specific antigen [PSA] less than 2.0) after prostatectomy were eligible for this phase 1 dose-escalation trial. Doses delivered were 35 Gy, 40 Gy, and 45 Gy in 5 fractions, given every other day. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events (version 4.0) grade 3 or higher gastrointestinal or genitourinary (GU) toxicity within 90 days of treatment. Maximum tolerated dose was the highest dose to be tested where fewer than 2 of the patients experienced DLT. Patients completed quality-of-life questionnaires at regular time intervals. Twenty-six patients completed treatment between October 2013 and December 2017. Three patients received 35 Gy, 8 patients received 40 Gy, and 15 patients received 45 Gy. The median follow-up was 60 months for 35 Gy, 48 months for 40 Gy, and 33 months for 45 Gy. No acute DLT events were observed. Late grade ≥2 and ≥3 gastrointestinal toxicity occurred in 11% and 0%, respectively, and late grade ≥2 and ≥3 GU toxicity occurred in 38% and 15%, respectively. No difference was observed in late GU toxicity between 40 Gy and 45 Gy. Sexual function scores were significantly lower in the patients receiving androgen deprivation therapy (P < .01). In all patients, the crude rate of PSA control (<0.2 ng/mL) was 11 out of 26 (42%). Dose escalation to 45 Gy did not result in acute DLT events, had similar rates of late grade 3 toxicity, and did not demonstrate higher rates of PSA control, compared with 40 Gy. While allowing for higher plan heterogeneity, the recommended dose for phase 2 study will be 40 Gy in 5 fractions.

Differentially Expressed Genes Associated With Prognosis in Locally Advanced Lymph Node-Negative Prostate Cancer.

Older age is one of the main risk factors for cancer development. The incidence of prostate cancer, as a multifactorial disease, also depends upon demographic factors, race, and genetic predisposition. Prostate cancer most frequently occurs in men over 60 years of age, indicating a clear association between older age and disease onset. Carcinogenesis is followed by the deregulation of many genes, and some of these changes could serve as biomarkers for diagnosis, prognosis, prediction of drug therapy efficacy, as well as possible therapeutic targets. We have performed a bioinformatic analysis of a The Cancer Genome Atlas (TCGA) data and RNA-Seq profiling of a Russian patient cohort to reveal prognostic markers of locally advanced lymph node-negative prostate cancer (lymph node-negative LAPC). We also aimed to identify markers of the most common molecular subtype of prostate cancer carrying a fusion transcript TMPRSS2-ERG. We have found several genes that were differently expressed between the favorable and unfavorable prognosis groups and involved in the enriched KEGG pathways based on the TCGA (B4GALNT4, PTK6, and CHAT) and Russian patient cohort data (AKR1C1 and AKR1C3). Additionally, we revealed such genes for the TMPRSS2-ERG prostate cancer molecular subtype (B4GALNT4, ASRGL1, MYBPC1, RGS11, SLC6A14, GALNT13, and ST6GALNAC1). Obtained results contribute to a better understanding of the molecular mechanisms behind prostate cancer progression and could be used for further development of the LAPC prognosis marker panel.

Baseline genomic and circulating tumor cell (CTC) correlative data from very high-risk (VHR), localized, node-negative prostate cancer patients.

e16563 Background: Few data exist on CTC frequency and number, genetic landscape, and tumor mutational burden (TMB) in VHR, node negative, localized prostate cancer (PCa). Methods: We are conducting a single-arm phase 2 trial of ultra-hypofractionated radiation (RT) with 6 months of abiraterone, apalutamide and leuprolide in VHR PCa, defined as: Gleason (Gl) 9-10 or 2 high risk features (including radiographic (r) T3/T4 disease) or &gt; 4 cores of Gl8. We report baseline correlatives in the first 38 screened patients (pts). CTCs were isolated using a non-selection based platform (EPIC Sciences). Additional analyses were conducted using MSK IMPACT, a next generation sequencing assay. Results: Median PSA was 14.8 ng/mL (IQR, 7.7-28.1); Gl7 was present in 5% (n = 2), Gl8 in 32% (n = 12), Gl9 in 61% (n = 23) and Gl10 in 2% (n = 1) of pts; on MR, 42% of pts were rT2 (n = 16), 39% had rT3a disease (n = 15) and 18% had rT3b disease (n = 7). CTC data were available on 31 pts; 74% (n = 23) had ≥1 detectable CTC (range, 0.8-14.6 cells per mL); 29% (n = 9) had CK+ clusters (range, 0.8-7.1 clusters per mL). IMPACT was available for 20 pts: KMT2D/C mutations were present in 25% (n = 4), TP53 missense mutations in 20% (n = 4), FOXA1 mutations in 20% (n = 4), PTEN truncating or missense mutations in 15% (n = 3), SPOP missense mutations in 15% (n = 3), PIK3CA activating mutations in 15% (n = 3), APC deletions in 15% (n = 3); 85% (17/20) had alterations in one of these genes. No clinically significant germline mutations were present. Median TMB was 2.63 mutations/mB (range, 0.87-60.56); the TMB-highest pt had an in-frame deletion in MSH2. Among IMPACTed pts with normalized testosterone post-protocol treatment (n = 16), there was a trend towards an association with SPOP/FOXA1 mutations and undetectable ( &lt; 0.05 ng/mL) PSA; 5/6 pts with mutations had undetectable PSA (83.3%) vs 3/10 without (30%) (p = 0.12). The trial is managed by the PCCTC and funded by Janssen. Conclusions: The genetic profile and TMB of VHR, localized PCa resembles non-castrate, metastatic disease. The frequency of detectable CTCs is high with implications for post-treatment surveillance. SPOP/FOXA1 mutations may predict initial response to RT with total androgen blockade. Clinical trial information: NCT02772588.

Added value of diffusion-weighted MRI for nodal radiotherapy planning in pelvic malignancies.

To evaluate the added value of diffusion-weighted imaging (DWI) to T2-weighted imaging (T2WI) for improved identification of pelvic lymph nodes (LN) by radiation oncologists. This retrospective study included 20 patients with histopathologically proven node-negative prostate cancer. All patients underwent 3T-MRI of the prostate; matched axial T2WI and DWI sequences were assessed by an experienced uro-radiologist as the reference standard. Consultant and specialist registrar radiation oncologists were asked to identify all LN first on T2WI alone (read 1) and then on T2WI and DWI combined (read 2); LN were measured in size and divided into true positives (TP), false positives (FP) and false negatives (FN). Sensitivity, positive predictive value (PPV) and false negative rate (FNR) were then calculated and compared using Pearson's Chi square test. A total of 177 LN comprised the reference standard. 16 TP, 16 FP and 161 FN LN (sensitivity 9.0%, PPV 50.0%, FNR 91.0%) and 124, 15 and 53 LN (70.1%, 89.2%, 30%) were identified by reader 1 on reads 1 and 2, respectively; χ2 (2, N = 385) = 137.8, p < 0.0001. 27, 21 and 150 LN (15.3%, 56.3%, 84.8%) and 120, 13 and 57 LN (67.8%, 90.2%, 32.2%) were identified by reader 2 on the two reads; χ2 (2, N = 388) = 102.4, p < 0.0001. Adding DWI to T2WI significantly improved identification of pelvic LN by radiation oncologists and can therefore be regarded as a useful LN contouring technique for RT planning in pelvic malignancies.

650 - Rates and patterns of metastases in patients with node-negative prostate cancer at radical prostatectomy that experience PSA failure: Post-hoc analysis of RTOG 9601 trial data

650 - Rates and patterns of metastases in patients with node-negative prostate cancer at radical prostatectomy that experience PSA failure: Post-hoc analysis of RTOG 9601 trial data

Impact of testosterone replacement therapy after radical prostatectomy on prostate cancer outcomes.

100 Background: Currently there is little data to guide the use of post-radical prostatectomy (RP) testosterone replacement therapy in prostate cancer. We sought to evaluate the impact of post-RP testosterone replacement on prostate cancer outcomes in a large national cohort. Methods: We conducted a population-based cohort study using the Veterans Affairs Informatics and Computing Infrastructure. We identified node-negative and non-metastatic prostate cancer patients diagnosed between 2001-2015 treated with RP. We excluded patients for missing covariate and follow-up data. We then coded receipt of testosterone replacement after RP as a time-dependent covariate. Other covariates included: age, Charlson Comorbidity index, diagnosis year, body mass index, race, PSA, clinical T/N/M stage, Gleason score, and receipt of hormone therapy. Biochemical recurrence was defined as a post-RP PSA≥0.2. We evaluated prostate cancer-specific survival, overall survival, and biochemical recurrence free survival using multivariable Cox regression. Results: Our cohort included 28,651 patients, of whom 469 (1.6%) received testosterone replacement after RP. Median follow up was 7.4 years. There were no differences in clinical T stage, median post-RP PSA (testosterone: 0 non-testosterone: 0; p = 0.18), or hormone therapy use between treatment groups. Testosterone patients were more likely to be of younger age, have higher comorbidity, non-black, have a lower median pre-treatment PSA (5.0 vs 5.8; p &lt; 0.001), and have higher BMI. The median time from RP to TRT was 3.0 years. After controlling for potential confounders, we found no difference in prostate cancer specific mortality (HR 0.73; 95% CI 0.32-1.62; p = 0.43), overall survival (HR 1.11; 95% CI 0.86-1.44; p = 0.43), non-cancer mortality (HR 1.17; 95% CI 0.89-1.55; p = 0.26) biochemical recurrence free survival (HR 1.07; 95% CI 0.84-1.36; p = 0.59) between testosterone users and non-users. Conclusions: Our results suggest that testosterone replacement is safe in prostate cancer patients who have undergone RP, though prospective data is necessary to confirm this finding.