Unfavorable Intermediate-risk Patients Research Articles

Risk Factors Predicting Relapse 10 Years Following Extreme Dose-Escalated SBRT for Intermediate-Risk Prostate Cancer: Is De-Intensification Feasible in Unfavorable Subgroups?

Adding short-term androgen-deprivation therapy (ADT) to radiotherapy is recommended in unfavorable intermediate-risk (UIR) prostate cancer (PCa). Data supporting the addition of ADT to stereotactic body radiotherapy (SBRT) in intermediate-risk (IR) patients are limited. Given ADT has well-documented toxicities, we sought to identify the UIR prognostic factors that predict for relapse following SBRT without ADT. We combined results from two mature multicenter trials to determine if extreme dose-escalated SBRT yielded UIR subgroups in which the omission of ADT may be considered. Between 2008 and 2011, two prospective national trials enlisted 39 centers to enroll 285 patients with IR PCa: 182 had Memorial Sloan Kettering (MSK) favorable intermediate-risk (FIR) and 103 had MSK UIF PCa. All were treated with a non-coplanar robotic SBRT platform using real-time tracking of implanted fiducials. Two dose regimens were used: 40Gy in 5 fractions of 8Gy, and 38Gy in 4 fractions of 9.5Gy. ADT was not allowed. Univariate and multivariate analyses using a Cox proportional hazards model was performed for relapse free survival (RFS): relapse included pathologic or radiographic failure, initiation of salvage or systemic therapy, or biochemical relapse by the nadir + 2 definition. Insufficient events prevented similar analyses for local control, metastasis-free and PCa-specific survival. Examined risk factors included dose regimen, clinical T-stage, Gleason score, pre-treatment PSA, % positive biopsy cores, and number of unfavorable risk factors (URFs). All reported rates are actuarial, using Kaplan-Meier method. Median follow-up was 8.1 years. 71 patients were followed 10 years. There were no statistically significant differences in rates of toxicity, local failure, RFS, overall nor metastasis-free survival between the two dose regimens. For the entire group, 10-year overall survival was 82.9%, RFS was 83.2%, and the local failure rate was 3.6%. On univariate analysis, primary Gleason pattern 4 (PGP4) and >2 URFs predicted for RFS. On multivariate analysis, only PGP4 (hazard ratio: 3.71, p = 0.0053) was statistically significant. Examining the UIR subgroup, the only predictor for RFS was PGP4 (HR: 3.64, p = 0.0253). 10-year RFS was 88.4% for FIR and 89.1% for UIR without PGP4; this fell to 58.5% in patients with a PGP4. Following dose-escalated SBRT monotherapy, 10-year RFS rates were favorable in UIR patients without PGP4. Extreme dose escalation appeared to effectively address UIR factors correlating with tumor bulk (i.e., CS T2b, >50% cores+, PSA 10-20), but was less effective with biologically aggressive pathology (PGP4). A randomized trial, ideally including genomic classification, would be necessary to determine if dose-escalated SBRT allows de-intensification (omission of ADT) in such biologically less aggressive UIR subgroups. The high relapse rate observed in UIR patients with PGP4 affirms the need for adjuvant ADT in this subgroup.

LDR-Brachytherapy monotherapy appears unsuited for NCCN unfavorable intermediate-risk prostate cancer patients

BackgroundTo validate the subdivision of intermediate-risk (IR) prostate cancer (PCa) into favorable intermediate-risk (FIR) and unfavorable intermediate-risk (UIR) PCa in a historical patient cohort and to compare 2 different radiotherapy regimens. MethodsPatients with intermediate-risk (IR) PCa, treated either by 125J-LDR-brachytherapy monotherapy (BT) or by combined-modality radiation therapy (CRT), were retrospectively subclassified into FIR and UIR and reanalyzed with regard to biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS), and prostate cancer-specific survival (CSS). Kaplan-Meier product-limit method and log-rank tests were applied to estimate survival probabilities and compare survival, respectively. Uni- and multivariable analyses were performed using Cox proportional hazard regression. ResultsOf 490 IR patients, 252 had received BT (86.5% FIR, 13.5% UIR), and 238 had received CRT (30% FIR, 70% UIR). Retrospective analysis revealed that BRFS at 10 years was 81% for BT, and 94% for CRT in FIR patients. For UIR patients, BRFS at 10 years was 37% for BT, and 89% for CRT. MFS at 10 years for FIR patients was 87% for BT, and 94% for CRT. For UIR patients MFS at 10 years was 78% for BT, and 95% for CRT. In multivariable analysis treatment (BT vs. CRT) was the single associated factor for biochemical recurrence, and for metastases in the UIR group (BFRS, P < 0.001, HR 16.07 (CI 4.23–61.10); MFS, P = 0.011, HR 8.43 (CI 1.62–43.9). ConclusionsSubclassification of IR prostate cancer into FIR and UIR subcategories appears mandatory. For FIR patients, outcomes after BT monotherapy were acceptable. However, clinical failure after 125J-LDR-BT in UIR patients was notably increased, suggesting that BT monotherapy was less successful in this risk group. In contrast, the outcome in UIR patients after CRT was excellent.

Experience from a hypofractionation curriculum pilot: Overcoming education as a barrier to implement hypofractionation

<h3>Background</h3> Hypofractionation has equivalent oncologic outcomes to conventional fractionation, with the advantage of shortening treatment time. This is beneficial for health systems in low-to-middle income countries (LMICs); however, little is known about how to promote its adoption globally. <h3>Methods</h3> The non-profit Rayos Contra Cancer developed a hypofractionation e-learning program to pilot in Colombia, free of charge, and shared through the Colombian Association of Radiation Oncology. Two electronic surveys were distributed, one before and one after the completion of the course. Physicians were asked questions regarding their attitudes to hypofractionation. Different sections focused on clinical scenarios related to breast, prostate, rectal, and CNS gliomas, asking current practices regarding conventional fractionation, hypofractionation (15-20 fractions), and ultra-hypofractionation (5 fractions). To measure the impact of the curriculum, we categorized physicians' use of hypofractionation with a numerical score from 0 to 12 (12 = More conventional, 0=more hypofractionation). <h3>Results</h3> Across 19 cities in Colombia, 149 participants enrolled: 61 radiation oncologists, 59 medical physicists, 7 radiation oncology residents, 18 physics residents, 1 technologist, and 1 dosimetrist. 33 physicians responded both surveys. More respondents chose hypofractionation after the curriculum for all scenarios (mean "pre-curriculum" score=5.9, vs. "post-curriculum" score = 4.15, p=0.03). For breast cancer, hypofractionation use after N0 lumpectomy increased by 24.2% for older patients (51% to 75%, p=0.766) and 18.2% for younger patients (42% to 60%, p=0.00), and for locally advanced postmastectomy increased by 12.1% (76% to 85%, p=0.435). For prostate cancer, use for unfavorable intermediate-risk patients increased by 15% (67% to 82%, p=0.176), for favorable intermediate-risk by 12.1% (76% to 85%, p=0.00), and for high-risk by 12.1% (42% to 54%, p=0.52). For rectal cancer, the increase in hypofractionation for T3N1 and T4N1 mid-rectal patients was 24.2% and 21.2%, respectively. In CNS high-grade gliomas respondents increased the use of hypofractionation in older patients with poor performance status (18.2%). At baseline, education was perceived as a barrier for the use of breast (ultra-hypo/hypo), prostate (ultra-hypo/hypo), rectal, and CNS hypofractionation in 69.7%, 45.5%, 78.8%, 63.6%, respectively. These percentages decreased by 24.2%, 9.1%, 18.2% and 12.1%. When asked if the course had increased their confidence and knowledge towards hypofractionation 100% of respondents said yes. <h3>Discussion</h3> Education is a perceived barrier for the use of ultra-hypofractionation schedules in a LMIC with a bundled payment system. An E-learning approach appears to be feasible and effective at reducing the educational barrier and increasing the use of hypofractionation.

High Dose "HDR-Like" Prostate SBRT: PSA 10-Year Results From a Mature, Multi-Institutional Clinical Trial.

Purpose/Objective(s)Although ample intermediate-term prostate stereotactic body radiotherapy (SBRT) outcomes have been reported, 10-year results remain relatively sparse.Materials/MethodsEighteen institutions enrolled 259 low- and intermediate-risk patients. Median follow-up is 5.5 years, with 66 patients followed ≥ 10 years. This SBRT regimen specifically emulated an existing HDR brachytherapy dose schedule and isodose morphology, prescribed to 38 Gy/4 fractions, delivered daily by robotic SBRT, mandating > 150% dose escalation in the peripheral zone. Androgen deprivation therapy was not allowed, and a hydrogel spacer was not available at that time.ResultsMedian pre-SBRT PSA 5.12 ng/mL decreased to 0.1 ng/mL by 3.5 years, with further decrease to a nadir of < 0.1 ng/mL by 7 years, maintained through 10 years. Ten-year freedom from biochemical recurrence measured 100% for low-risk, 84.3% for favorable intermediate risk (FIR), and 68.4% for unfavorable intermediate (UIR) cases. Multivariable analysis revealed that the UIR group bifurcated into two distinct prognostic subgroups. Those so classified by having Gleason score 4 + 3 and/or clinical stage T2 (versus T1b/T1c) had a significantly poorer 10 year freedom from biochemical recurrence rate, 54.8% if either or both factors were present, while UIR patients without these specific factors had a 94.4% 10-year freedom from biochemical recurrence rate. The cumulative incidence of grade 2 GU toxicity modestly increased over time – 16.3% at 5 years increased to 19.2% at 10 years-- while the incidence of grade 3+ GU and GI toxicity remained low and stable to 10 years - 2.6% and 0%, respectively. The grade 2 GI toxicity incidence also remained low and stable to 10 years – 4.1% with no further events after year 5.ConclusionThis HDR-like SBRT regimen prescribing 38 Gy/4 fractions but delivering much higher intraprostatic doses on a daily basis is safe and effective. This treatment achieves a median PSA nadir of <0.1 ng/mL and provides high long-term disease control rates without ADT except for a subgroup of unfavorable intermediate-risk patients.

Metastasis and Mortality in Men With Low- and Intermediate-Risk Prostate Cancer on Active Surveillance.

Active surveillance (AS) is a safe treatment option for men with low-risk, localized prostate cancer. However, the safety of AS for patients with intermediate-risk prostate cancer remains unclear. We identified men with NCCN-classified low-risk and favorable and unfavorable intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration. We analyzed progression to definitive treatment, metastasis, prostate cancer-specific mortality (PCSM), and all-cause mortality using cumulative incidences and multivariable competing-risks regression. The cohort included 9,733 men, of whom 1,007 (10.3%) had intermediate-risk disease (773 [76.8%] favorable, 234 [23.2%] unfavorable), followed for a median of 7.6 years. The 10-year cumulative incidence of metastasis was significantly higher for patients with favorable (9.6%; 95% CI, 7.1%-12.5%; P<.001) and unfavorable intermediate-risk disease (19.2%; 95% CI, 13.4%-25.9%; P<.001) than for those with low-risk disease (1.5%; 95% CI, 1.2%-1.9%). The 10-year cumulative incidence of PCSM was also significantly higher for patients with favorable (3.7%; 95% CI, 2.3%-5.7%; P<.001) and unfavorable intermediate-risk disease (11.8%; 95% CI, 6.8%-18.4%; P<.001) than for those with low-risk disease (1.1%; 95% CI, 0.8%-1.4%). In multivariable competing-risks regression, favorable and unfavorable intermediate-risk patients had significantly increased risks of metastasis and PCSM compared with low-risk patients (all P<.001). Compared with low-risk patients, those with favorable and unfavorable intermediate-risk prostate cancer managed with AS are at increased risk of metastasis and PCSM. AS may be an appropriate option for carefully selected patients with favorable intermediate-risk prostate cancer, though identification of appropriate candidates and AS protocols should be tested in future prospective studies.

Assessing the Risk of Pathologic Lymph Node Involvement in Intermediate Risk Prostate Cancer

Most intermediate risk (IR) prostate cancer (PCa) patients are predicted to have low rates of pelvic lymph node (PLN) involvement. The standard of care for radiation therapy in IR disease includes radiation to the prostate only, with PLN irradiation typically reserved for high-risk disease. This treatment strategy represents a divergence from the surgical approach, wherein PLN dissections (PLND) are recommended by NCCN guidelines for men with 2% or higher risk of nodal metastasis-a threshold typically met by men with IR disease. We conducted an analysis of radical prostatectomy (RP) patients to assess the rates of pathologic nodal involvement in IR disease. We aimed to evaluate the correlation of the NCCN risk strata of favorable and unfavorable disease on nodal outcomes among IR men treated by radical prostatectomy (RP).This is a National Cancer Database (NCDB) analysis from 2004-2015 of IR PCa patients treated by RP. Baseline clinical and demographic data were collected, and men were stratified into favorable and unfavorable risk groups. Treatment information assessed included performance of PLND at the time of surgery, number of nodes dissected, and pathologic outcomes at RP. The primary outcome of interest was the rate of pathologic nodal involvement.A total of 295,819 patients were identified in NCDB with IR PCa who underwent RP. Using NCCN risk stratification criteria, 147,193 (49.8%) men were identified with favorable intermediate risk (FIR) disease and 148,626 (50.2%) with unfavorable intermediate risk (UIR) disease. 90,410 (61.4%) FIR patients underwent pelvic node dissection compared to 107,135 (72.1%) UIR patients. Of the 189,304 (64.0%) total men who underwent PLND, 1.9% had pathologically involved nodes, with a rate of 0.7% for FIR disease and 2.8% for UIR (P < 0.001). The median [IQR] number of nodes resected on pelvic node dissection was 3[2-4] and 5[3-7] for FIR and UIR, respectively (P < 0.0001). Initial PSA > 5, Gleason pattern 4 on biopsy, and UIR disease were associated with pathologic nodal involvement (P < 0.0001).NCCN-defined FIR and UIR strata are associated with risk of PLN disease. The low number of nodes assessed on PLND may have contributed to the low rates of pathologic nodal involvement in IR PCa patients seen in this large database analysis. Even so, the low rates of pathologic nodal disease in this IR cohort, especially in FIR patients, should be considered in conjunction with upcoming clinical trial data to inform the therapeutic approach to PLN management for all intermediate risk patients undergoing surgery or radiation.

Long-term and pathological outcomes of low- and intermediate-risk prostate cancer after radical prostatectomy: implications for active surveillance

PurposeThe safety of active surveillance (AS) in favorable intermediate-risk (FIR) prostate cancer (PCa) remains uncertain. To provide guidance on clinical decision-making, we examined long-term and pathological outcomes of low-risk and intermediate-risk PCa patients after radical prostatectomy (RP).MethodsThe study involved 5693 patients diagnosed between 1994 and 2019 with low-risk, FIR, and unfavorable intermediate-risk (UIR) PCa (stratification according to the AUA guidelines) who underwent RP. Pathological outcomes were compared, and Kaplan–Meier analysis determined biochemical recurrence-free survival (BRFS) and cancer-specific survival (CSS) at 5, 10, 15, and 20 years. Multiple Cox regression was used to simultaneously control for relevant confounders.ResultsThose at FIR had higher rates of upgrading and upstaging (12.8% vs. 7.2%, p < 0.001; 19.8% vs. 12.0%, p < 0.001) as well as pathological tumor and node stage (≥ pT3a: 18.8% vs. 11.6%, p < 0.001; pN1: 2.7% vs. 0.8%, p > 0.001) compared to patients at low risk. The 20-year BRFS was 69%, 65%, and 44% and the 20-year CSS was 98%, 95%, and 89% in low-risk, FIR, and UIR patients. On multiple Cox regression, FIR was not associated with a worse BRFS (HR 1.07, CI 0.87–1.32), UIR was associated with a worse BRFS (HR 1.49, CI 1.20–1.85).ConclusionPatients at FIR had only slightly worse pathological and long-term outcomes compared to patients at low risk, whereas the difference compared to patients at UIR was large. This emphasizes AS in these patients as a possible treatment strategy in well-counseled patients.

Optimizing Treatment in Intermediate-Risk Prostate Cancer: Secondary Analysis of a Randomized Phase 3 Trial

To identify patients with intermediate-risk prostate cancer (IRPC) benefiting from de-escalation of androgen deprivation therapy (ADT) and/or dose escalated radiation therapy (DERT), we performed a secondary analysis of a phase 3 trial by measuring biochemical failure (BF), distant metastases, prostate cancer-specific mortality, overall survival (OS), and distant metastases-free survival (DMFS) rates according to prognostic intermediate risk factors (IRF). The initial trial randomized 600 patients with IRPC to a 3-arm trial with 200 patients per arm, consisting of 6 months of ADT plus 70 Gy radiation therapy (ADT+RT70) versus ADT plus a DERT of 76 Gy (ADT+DERT76) versus DERT of 76 Gy alone (DERT76). We performed an analysis based on IRF: clinical stage, prostate-specific antigen level, Gleason score, percentage of positive biopsy cores (PBC) ≥50%, and Gleason pattern. Patients were allocated to 2 groups: favorable intermediate risk (FIR), defined as patients with only 1 IRF without Gleason pattern 4+3 or PBC ≥50%; and unfavorable intermediate risk (UIR), defined as all other patients. BF, distant metastases, prostate cancer-specific mortality, OS, and DMFS were compared between FIR and UIR. The median follow-up was 11.3 years (interquartile range, 10.9-11.7). In the FIR cohort, BF and OS were not significantly different between arms. UIR patients had significantly worse DMFS (hazard ratio [95% confidence interval], 1.61 [1.20-2.15]; P=.026) and OS (1.51 [1.12-2.04]; P=.0495) and a nonsignificant higher cumulative incidence of BF rate (1.55 [0.98-2.47]; P=.08). In UIR patients, a significant improvement in BF was seen in the arms receiving ADT compared to DERT76 alone. On multivariable analysis, Gleason pattern 4+3 and prostate-specific antigen >10 ng/mL independently affected BF and OS, regardless of the treatment arm. In IRPC, therapeutic optimization appears possible. To avoid ADT side effects, DERT76 alone appears sufficient in patients harboring only 1 risk factor without Gleason pattern 4+3 and PBC ≥50% (FIR). All other UIR patients seem to benefit from ADT+DERT76.

The Effect of Positive Biopsy Cores on the Prognosis of Patients with Intermediate Risk Prostate Cancer Treated with Cs-131 Prostate Brachytherapy

Patients diagnosed with intermediate risk (IR) prostate cancer (PC) have a widely variable prognosis and treatment options. Favorable intermediate risk (FIR) is defined as having only 1 IR factor (Gleason Grade (GG) 2-3, PSA>10 but <20, T2b-c) and no GG3. Unfavorable intermediate risk (UIR) patients have either GG3 disease or >1 IR factors. The amount of disease, as defined by % of positive biopsy cores, has also been proposed as a risk factor, but this to be better defined. In addition, it is unknown whether only the highest GG should be considered or if any core with PC should be counted in the total number of positive cores. We report on our cohort of 299 IR PC patients who were treated with Cs-131 prostate brachytherapy (PB), all of whom have at least 24 mo of follow up and median follow up of 70.6 mo. In general, FIR patients were treated with PB alone (115 Gy) and UIR patients were treated with EBRT (45 Gy) + PB (85 Gy). We stratified patients based on their % of positive cores to determine the effect of this on outcome. The Kaplan-Meier method was used to estimate actuarial event-time probabilities for biochemical progression free survival (bPFS), which was defined as the absence of a serum PSA that rose at least 2 ng/mL greater than post-treatment nadir PSA. 164 patients were FIR and 135 were UIR. 203 had GG2 histology and 96 had GG3. Patients with GG2 trended toward a higher 5-year bPFS of 95.9% (SE 0.015) when compared to GG3 patients who had a 5-year bPFS of 87.3% (SE 0.041) (p = 0.065). Looking at the cohort of patients with GG2 disease, patients with <50% cores positive for GG2 disease (n = 178) had a 5-year bPFS of 95.3%, with 81.9% of those patients receiving PB alone. Patients with > 50% cores positive for GG2 disease (n = 25), had a 5-year bPFS of 100% with 80% of those patients receiving EBRT + PB. In the group with GG3, patients with > 50% cores positive for GG3 trended toward a worse outcome (5-year bPFS of 82.1%) compared to those with <50% positive (5-year bPFS = 89.4%) (p = 0.095). In patients treated with Cs-131 PB, those with GG2 disease have an excellent prognosis, regardless of % of biopsy cores positive for PC. Patients with GG3 and < 50% of cores positive also have an excellent prognosis, while patients with GG3 and >50% of cores positive seem to have a worse prognosis and likely would benefit from more aggressive treatment, such as trimodality therapy.

Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Twelve-Year Study

This is the first study using Stereotactic Body Radiotherapy (SBRT) for organ confined prostate cancer to have patients with twelve-year follow-up. In this study, we report outcomes for prostate robotic SBRT in 560 patients, with NCCN low-, intermediate- and high- risk disease. We report on biochemical disease-free survival (bDFS), toxicity and Quality of Life (QOL). We studied 560 patients with organ-confined prostate cancer, treated with SBRT to a dose covering the PTV (prostate +3-5 mm) of 35-36.25 Gy. The prostate was covered by a dose of 38.4-40 Gy. Treatment was delivered in 5 daily fractions between 2006-2009. We included 45 high risk patients who received a 18-21 Gy SBRT boost after 45 Gy to the pelvis with EBRT. Median follow up is 132 months. The median age was 69 years, and median PSA was 6.58. 324 patients were low-risk, 153 were intermediate-risk and 83 were high-risk. ADT up to 9 months was administered to 102 patients. Patients were further stratified into low-intermediate risk versus high-intermediate risk, with high-intermediate risk criteria of Gleason 4+3 = 7 or >1 intermediate risk factors (cT2b-c, PSA 10-20, Gleason 7). Biochemical failure was assessed using the Phoenix criterion. Cox regression analysis was used to determine which risk factors were significantly associated with increased risk of biochemical failure. Twelve-year bDFS was 92.0, 79.1 and 64.0% for low, intermediate and high-risk group patients, respectively. Local control was 97.0, 91.7 and 88.0% respectively. Favorable intermediate-risk patients had excellent outcomes, with no significant difference compared to low-risk patients with 12-year bDFS 89.8 vs 92.0%, respectively (p = 0.35). Unfavorable intermediate-risk patients had outcomes similar to high risk patients, with 12-year bDFS of 67.5 and 64.0% respectively (p = .24). Median PSA declined to 0.1. For low and intermediate risk patients, Gleason score was the only significant factor predicting for biochemical failure on multivariate analysis (p = 0.0003), with ADT, dose and PSA not significant. For high risk patients, PSA was the only significant predictor of bDFS (p = .01), with Gleason score, ADT or EBRT not significant. Toxicity was mild. 36.25 Gy was associated with more Grade 2-3 late urinary toxicity than 35 Gy. (13.8% vs 6%) p = .01 Patients receiving EBRT had a higher rate of late Grade 2 late rectal toxicity. Mean EPIC QOL urinary and bowel domains for all patients declined during the first 3 months and then returned to baseline, where they remain. Mean sexual QOL scores have slowly declined by 47% This study suggests that early excellent control rates for SBRT for prostate cancer remain durable over 12 years. Similarly, toxicity rates remain low and QOL scores remain high over that period. For patients receiving SBRT alone, 35 Gy is as effective as 36.25 Gy with less urinary toxicity, suggesting 35 Gy may be the optimal dose. For high risk patients, use of EBRT and ADT do not appear to increase long term control rates.

Impact of Health-related Quality of Life and Prediagnosis Risk of Major Depressive Disorder on Treatment Choice in Low- and Intermediate-Risk Prostate Cancer

BackgroundTreatment for low-risk (LR), favorable intermediate-risk (FIR), and unfavorable intermediate-risk (UIR) prostate cancer (PC) is complicated by clinical equipoise between multiple options. It is unknown how prediagnosis health-related quality of life (HRQoL) and major depressive disorder (MDD) risk impact treatment decisions. ObjectiveTo analyze associations of patient-reported HRQoL and MDD risk with treatment for LR, FIR, and UIR PC patients. Design, setting, and participantsUsing the Surveillance, Epidemiology and End Results and Medicare Health Outcomes Survey–linked database, we identified 1678 PC patients (498 with LR, 685 with FIR, and 495 with UIR) aged ≥65 yr and diagnosed between 2004 and 2015, who completed the health outcomes survey ≤24 mo before diagnosis. Outcome measurements and statistical analysisHRQoL was measured by physical (PCS) and mental (MCS) component summaries of the Medical Outcomes Study Short Form 36 (SF-36) and Veterans RAND 12-item (VR-12) health survey instruments. MDD risk was derived from survey items screening for depressive symptoms. Associations with treatment choice were assessed by multivariable multinomial logistic regression. Results and limitationsLR patients with higher PCS scores were more likely to receive radiation than surgery (adjusted odds ratio [AOR] 1.5 [95% confidence interval {CI}: 1.1–2.1; p = 0.02]). FIR patients with MDD risk were more likely to receive neither treatment than surgery or radiation (surgery: AOR 2.6 [95% CI: 1.1–6.2; p = 0.03]; radiation: AOR 2.2 [95% CI: 1.2–4.2; p = 0.01]). UIR patients with MDD risk were more likely to undergo radiation than surgery (AOR 2.3 [95% CI: 1.0–4.9; p =0.04]). Additionally, higher PCS scores were associated with receipt of surgery compared with neither treatment (AOR 1.5 [95% CI: 1.1–2.0; p =0.01]). This study is limited by its retrospective design. ConclusionsOlder PC patients with MDD risk received less invasive treatments in the FIR and UIR groups. Higher PCS scores were associated with treatment modality in LR and UIR patients. HRQoL and MDD risk impact treatment choice, warranting additional study. Patient summaryTreatment of prostate cancer requires thoughtful decision-making processes. This study shows that both pretreatment mental status and pretreatment physical status affect treatment decisions, and should be considered during counseling.

Role of combined radiation and androgen deprivation therapy in intermediate-risk prostate cancer : Statement from the DEGRO working group on prostate cancer.

This article aims to provide an overview of the role of combined radiation and androgen deprivation (ADT) therapy in patients with intermediate-risk prostate cancer. The current German, European, and NCCN (National Comprehensive Cancer Network) guidelines as well as relevant literature in the PubMed database which provide information on sub-classification within the intermediate-risk group and the use of ADT in terms of oncological outcome were reviewed. Different recommendations for risk-group assessment of patients with localized prostate cancer are available. Subdivision of intermediate risk into afavorable and an unfavorable group seems to be justified to allow for amore individualized therapy in aquite heterogenous group of patients. So far, multiple randomized trials have shown abenefit when radiation therapy (RT) is combined with ADT. The use of dose-escalated RT without ADT also appears to be an adequate therapy associated with avery low rate of cancer-specific deaths. Therefore, taking into account the increased rate of toxicity associated with ADT, dose-escalated RT alone might be justified, especially in favorable intermediate-risk patients. Dose-escalated RT alone appears to be an appropriate treatment in favorable intermediate-risk patients. Addition of short course ADT (4-6months) might improve outcomes in unfavorable intermediate-risk patients.

The Impact of Clinical Pathways on Adoption of Hypofractionated External Beam Radiation in Patients with Low- or Intermediate-Risk Prostate Cancer

Hypofractionated external beam radiation (HF-EBRT) in low- and intermediate-risk prostate cancer provides non-inferior disease control with a more convenient regimen compared to conventionally fractionated external beam radiation (CF-EBRT). Two phase III trials, RTOG 0415 and CHHiP, were published in 2016 confirming the non-inferiority of HF-EBRT to CF-EBRT. However, HF-EBRT remains underutilized nationally. Clinical pathways (CP) are a method for standardizing care in alignment with evidence to avoid unnecessary variations in practice. We evaluated whether a change in our CP would increase utilization of HF-EBRT in patients with low- or intermediate-risk prostate cancer. We implemented a CP for management of patients with low- and intermediate-risk prostate cancer, which was modified in January 2018 to reflect HF-EBRT as the first-choice modality for patients planned for definitive EBRT without brachytherapy. We performed a retrospective analysis on 946 patients seen in consultation at one of 16 network radiation oncology sites between 2015 and 2018. All patients had low-risk (LR), favorable intermediate-risk (FIR), or unfavorable intermediate-risk (UIR) prostate cancer. Patterns of practice in patients with LR, FIR, and UIR prostate cancer were analyzed on a year-by-year basis. In patients treated with EBRT alone, the Chi-square test was used to determine whether utilization of HF-EBRT increased after CP modification. Based on treating physicians’ pathway selection at the time of consultation, from 2015 to 2018, utilization of HF-EBRT increased on a year-by-year basis in LR, FIR, and UIR subgroups (Table 1). Use of CF-EBRT decreased over time in all subgroups from 2015 to 2018 (LR, from 41.1% to 20.0%; FIR, from 55.6% to 35.7%; UIR, from 52.3% to 35.5%). Utilization of brachytherapy alone decreased during the same time period in LR patients (58.9% to 40.0%) but remained relatively stable in FIR (34.3% to 35.7%) and UIR patients (5.3% to 3.2%). Utilization of EBRT with brachytherapy boost remained stable among UIR patients (42.4% to 41.9%). Among patients treated with definitive EBRT alone, utilization of HF-EBRT increased after CP modification from 4.4% to 92.8% (p<0.001). Modification of our CP to reflect HF-EBRT as the first-choice modality for low- or intermediate-risk patients treated with EBRT alone increased the utilization of HF-EBRT from <10% to >90% over a short period of time. Despite the publication of phase III data indicating the non-inferiority of HF-EBRT in 2016, this change in practice pattern was not observed until we modified the CP in January 2018. Clinical pathways are an effective way to standardize practice patterns in alignment with the newest evidence.Abstract 2688; Table 1Risk Category2015201620172018Low Risk0%1.4%5.2%40.0%Favorable-Intermediate Risk0%0%3.7%28.6%Unfavorable-Intermediate Risk0%0%4.7%19.4% Open table in a new tab

Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Ten-Year Study

Stereotactic body radiation therapy (SBRT) is a newer treatment option for localized prostate cancer (PCa), with recent studies demonstrating excellent control rates and low toxicity with short to intermediate follow-up. Longer term patient outcomes demonstrating efficacy and safety, however, have not yet been previously reported. In this present study, we report 10-year outcomes for prostate SBRT in 515 patients. Consecutively treated patients (n=515) between 2006-2009 were evaluated (median FU = 108 mos). There were 324, 153 and 38 low-, intermediate- and high-risk patients by NCCN criteria. Patients received Robotic SBRT (35-36.25 Gy in 5 fractions on consecutive days). The dose was defined to cover 95% of the Planning Treatment Volume, which was a 5 mm expansion (3mm posteriorly) of the prostate and proximal seminal vesicles. 95% of the prostate was covered by 38.5-40 Gy. Real time tracking of fiducial seeds was employed. 102 patients received ADT for up to 6 months. For the entire patient cohort, 10-year biochemical recurrence free survival (bRFS) was 93, 81 and 66% for low-risk, intermediate-risk, and high-risk patients. Biopsy proven local failure was found in 2, 6 and 10%, respectively. Favorable intermediate-risk patients (Gleason 3+4=7 with no other intermediate-risk factors, or Gleason 3+3 = 6 with only one intermediate-risk factor) had excellent outcomes, with no significant difference compared to low-risk patients (10y DFS 89 vs 93%, P=0.3). Unfavorable intermediate-risk patients had outcomes similar to high-risk patients (10y bDFS of 63 vs 66%, P=0.8). PSA and Gleason score were the only significant factors predicting for bRFS on multivariate analysis (P<0.002) with dose, ADT not significant. Toxicity was overall mild. There was significantly higher late G2-3 GU toxicity with 36.25 Gy compared to 35 Gy (14.6 vs 8.2%, P=0.04), but no difference in G2 GI toxicity. Mean EPIC QOL urinary and bowel domains for all patients declined during the first 3 months and then returned to baseline. Mean sexual QOL scores declined by 40% at 10 years In conclusion, prostate SBRT continues to demonstrate excellent biochemical and local control rates with low toxicity and excellent QOL with now 10 years of follow up. Our results are at least as favorable as other forms of radiation therapy. We continue to find 35 Gy to be as effective as 36.25 Gy, with significantly lower GU toxicity, suggesting 35 Gy may be a preferable dose for patients with low- and favorable intermediate-risk disease. Long-term results of prospective studies are needed to validate our findings. For higher risk patients, the use of ADT failed to demonstrate improvement in long-term disease control. Given that most SBRT failures were not local, we hypothesize that dose escalation will not translate to improved bFRS, and strategies to reduce systemic failures should be explored.

Whole-Pelvic Versus Prostate-Only Radiation Therapy in Unfavorable Intermediate-Risk and High-Risk Prostate Cancer Treated with Androgen Deprivation Therapy and Brachytherapy Boost

The ASCENDE-RT randomized controlled trial showed that brachytherapy boost significantly reduces biochemical recurrence in unfavorable intermediate-risk and high-risk prostate cancer treated with whole-pelvic radiation therapy (WPRT) and androgen deprivation therapy (ADT). However, previous level 1 data have not shown an oncologic benefit for WPRT compared to prostate-only radiation therapy (PORT) in patients who did not receive brachytherapy boost. Therefore, we examined the association between WPRT, compared to PORT, and overall survival in patients with unfavorable intermediate-risk or high-risk prostate cancer treated with brachytherapy boost and ADT. Using the National Cancer Database, we identified 7,292 men diagnosed with unfavorable intermediate-risk disease (Gleason 4+3 or ≥2 intermediate-risk factors [Gleason 3+4, prostate-specific antigen (PSA) 10-20 ng/mL, or cT2b-T2c stage]) or high-risk disease (Gleason 8-10, PSA >20 ng/mL, or cT3-T4 stage) from 2004 through 2014 who were treated with brachytherapy boost, ADT, and either WPRT or PORT to 39.6-50.4 Gy. Patients with nodal or metastatic disease were excluded. Risk of lymph node metastases was estimated using the Roach formula ([2/3] × PSA + 10 × [Gleason score - 6]). Cox proportional hazards regression was used to examine the association between WPRT, versus PORT, and overall survival. Median follow-up was 6.3 years. The study cohort consisted of 35.1% unfavorable intermediate-risk patients and 64.9% high-risk patients. Overall, 52.5% of patients received WPRT. On multivariable analysis, WPRT, compared to PORT, was not associated with a significant improvement in overall survival for the entire cohort (adjusted hazard ratio [AHR] 1.02, 95% confidence interval [CI] 0.91-1.14, P =0.702). This lack of overall survival benefit was observed for subgroups of unfavorable intermediate-risk patients (AHR 1.12, 95% CI 0.93-1.35, P =0.246), high-risk patients (AHR 0.98, 95% CI 0.85-1.12, P =0.726), and patients with >15% risk of lymph node metastases (AHR 1.00, 95% CI 0.89-1.13, P =0.985). These results suggest that patients with unfavorable intermediate-risk or high-risk prostate cancer treated with brachytherapy boost and ADT may not benefit from receiving WPRT. Providers should thoughtfully weigh the risks and benefits of WPRT compared to PORT when planning to treat unfavorable-risk patients with brachytherapy boost and ADT.

Detectable end of radiation prostate specific antigen assists in identifying men with unfavorable intermediate-risk prostate cancer at high risk of distant recurrence and cancer-specific mortality.

Undetectable End of Radiation PSA (EOR-PSA) has been shown to predict improved survival in prostate cancer (PCa). While validating the unfavorable intermediate-risk (UIR) and favorable intermediate-risk (FIR) stratifications among Johns Hopkins PCa patients treated with radiotherapy, we examined whether EOR-PSA could further risk stratify UIR men for survival. A total of 302 IR patients were identified in the Johns Hopkins PCa database (178 UIR, 124 FIR). Kaplan-Meier curves and multivariable analysis was performed via Cox regression for biochemical recurrence free survival (bRFS), distant metastasis free survival (DMFS), and overall survival (OS), while a competing risks model was used for PCa specific survival (PCSS). Among the 235 patients with known EOR-PSA values, we then stratified by EOR-PSA and performed the aforementioned analysis. The median follow-up time was 11.5 years (138 months). UIR was predictive of worse DMFS and PCSS (P = 0.008 and P = 0.023) on multivariable analysis (MVA). Increased radiation dose was significant for improved DMFS (P = 0.016) on MVA. EOR-PSA was excluded from the models because it did not trend towards significance as a continuous or binary variable due to interaction with UIR, and we were unable to converge a multivariable model with a variable to control for this interaction. However, when stratifying by detectable versus undetectable EOR-PSA, UIR had worse DMFS and PCSS among detectable EOR-PSA patients, but not undetectable patients. UIR was significant on MVA among detectable EOR-PSA patients for DMFS (P = 0.021) and PCSS (P = 0.033), while RT dose also predicted PCSS (P = 0.013). EOR-PSA can assist in predicting DMFS and PCSS among UIR patients, suggesting a clinically meaningful time point for considering intensification of treatment in clinical trials of intermediate-risk men.

Prospective analysis of 4,474 prostate biopsies to evaluate potential treatment management impact of combined clinical-genomic risk classification.

39 Background: Prior studies suggested integrated clinical-genomic risk grouping can more accurately prognosticate prostate cancer (PCa) outcome than NCCN clinical risk. We evaluated the potential for genomic testing to reclassify patients in a manner that could change management compared to NCCN risk groups. Methods: We evaluated 4,474 consecutive patients with PCa who received the Decipher Biopsy test between 01/2016-08/2017 and had information to determine NCCN risk. Genomic categorizations with the potential to change management were defined as NCCN very low/low to genomic intermediate or high (active surveillance to active treatment), NCCN favorable intermediate to genomic high (radiation therapy [RT] alone to RT plus androgen deprivation therapy [ADT]), NCCN unfavorable intermediate to genomic low (RT + ADT to RT alone), NCCN high risk to genomic low (RT + long term ADT to RT + short term ADT). Results: There were 927 NCCN low-risk, 2,427 intermediate, and 1,120 high-risk patients. Among NCCN low-risk, the incidence of genomic low, intermediate, and high risk was 58.7%, 25.0%, and 16.3% respectively, for NCCN intermediate it was 36.5%, 27.6%, and 35.8%, and for NCCN high risk it was 15.9%, 17.1%, and 67.1%. Management could have been changed in the 41.3% of NCCN low risk patients with intermediate or high genomic risk, 26.7% of favorable intermediate risk patients who had high genomic risk, 32.4% of unfavorable intermediate risk patients with low genomic risk, and 15.9% of high risk patients with low genomic risk. Conclusions: A slight majority (54%) of Decipher Biopsy users have NCCN intermediate-risk disease, likely reflecting a need for further prognostic information to refine recommendations in intermediate risk. Reclassification of NCCN groups by genomic risk was common and an integrated clinical-genomic risk system could have altered treatment recommendations in 41.3% of NCCN low, 26.7% of favorable intermediate, 32.4% of unfavorable intermediate risk, and 15.9% of high risk patients.

External beam radiation therapy with or without low-dose-rate brachytherapy: Analysis of favorable and unfavorable intermediate-risk prostate cancer patients

PurposeTo compare the tumor control and toxicity in men with intermediate-risk prostate cancer treated with either external beam radiation therapy (EBRT) or EBRT plus low-dose-rate brachytherapy (combo-RT). Methods and MaterialsBetween 1995 and 2012, 579 men with intermediate-risk prostate cancer were treated with either EBRT (n = 388) or combo-RT (n = 191). Outcomes assessed included biochemical recurrence–free survival (bRFS), distant metastasis–free survival (DMFS), and cumulative incidence of genitourinary (GU) and gastrointestinal toxicity. Favorable and unfavorable intermediate-risk subgroups were analyzed. ResultsMedian followup was 7.5 years. Combo-RT group had improved 10-year bRFS compared with EBRT (91.7% vs. 75.4%, p = 0.014). On multivariable analysis, combo-RT (hazard ratio, 0.48; 95% confidence interval: 0.25, 0.92; p = 0.03) was associated with improved bRFS. Combo-RT had significantly improved bRFS compared with EBRT in the unfavorable subgroup (p = 0.02) but not in the favorable subgroup (p = 0.37). DMFS was similar within the entire cohort and by risk group. Combo-RT was associated with an increased rate in the 6-year cumulative incidence of Grade 3 GU toxicity (hazard ratio, 3.48; 95% confidence interval: 1.1, 11.1; p = 0.026); however, 57% of Grade 3 GU toxicity was resolved, 29% had partial improvement, and only 1 patient had persistent Grade 3 GU toxicity. ConclusionsIn intermediate-risk prostate cancer, combo-RT improved bRFS but not DMFS and increased Grade 3 GU toxicity. The bRFS benefit was limited to unfavorable intermediate-risk patients.

MP20-02 NOVEL RISK STRATIFICATION GROUPING USING STANDARD CLINICAL AND BIOPSY INFORMATION FOR PATIENTS UNDERGOING RADICAL PROSTATECTOMY: RESULTS FROM SEARCH

You have accessJournal of UrologyProstate Cancer: Staging I1 Apr 2017MP20-02 NOVEL RISK STRATIFICATION GROUPING USING STANDARD CLINICAL AND BIOPSY INFORMATION FOR PATIENTS UNDERGOING RADICAL PROSTATECTOMY: RESULTS FROM SEARCH Zachary Zumsteg, Zinan Chen, Lauren Howard, Christopher Amling, William Aronson, Matthew Cooperberg, Christopher Kane, Martha Terris, Daniel Spratt, Howard Sandler, and Stephen Freedland Zachary ZumstegZachary Zumsteg More articles by this author , Zinan ChenZinan Chen More articles by this author , Lauren HowardLauren Howard More articles by this author , Christopher AmlingChristopher Amling More articles by this author , William AronsonWilliam Aronson More articles by this author , Matthew CooperbergMatthew Cooperberg More articles by this author , Christopher KaneChristopher Kane More articles by this author , Martha TerrisMartha Terris More articles by this author , Daniel SprattDaniel Spratt More articles by this author , Howard SandlerHoward Sandler More articles by this author , and Stephen FreedlandStephen Freedland More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.634AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer is a heterogeneous disease, and risk stratification systems have been proposed to guide treatment decisions and inform patient prognosis. However, significant heterogeneity remains, especially among those with high risk disease, and thus improved stratification is needed. METHODS Data on 3335 men, including 605 high risk, undergoing radical prostatectomy without adjuvant treatment were collected in the SEARCH database. Patients were grouped into five categories: low risk (biopsy Gleason 2-6, T1a-T2a, and PSA <10ng/ml), favorable intermediate risk (FIR), unfavorable intermediate risk (UIR), standard high risk (SHR), very high risk (VHR). Intermediate risk patients by NCCN guidelines (T2b or T2c, biopsy Gleason 7, or PSA 10-20ng/ml) were UIR if they had biopsy Gleason 4+3, ≥50% positive biopsy cores, or multiple intermediate-risk factors (T2b or T2c, biopsy Gleason 7, or PSA 10-20ng/ml), and FIR otherwise. High risk patients by NCCN guidelines (biopsy Gleason score 8-10, T3-T4, or PSA ≥20ng/ml) were VHR if they had primary Gleason 5, >50% positive biopsy cores, T3b-T4 or multiple high-risk factors (biopsy Gleason score 8-10, T3-T4, or PSA ≥20ng/ml), and SHR otherwise. Cox models were used to test the association between risk group and time to biochemical recurrence (BCR) and distant metastases (DM). Competing risks was used to test the association between risk group and prostate cancer-specific mortality (PCSM). Models were adjusted for age, race, year, and surgical center. RESULTS Median follow-up was 78 mo. Men with VHR disease had increased risk of BCR (p<0.001), DM (P=0.004), and PCSM (P=0.011) in comparison to SHR, but there were no differences in BCR, DM, or PCSM between SHR and UIR patients (p>0.4). FIR men had increased risk of BCR (HR 1.34, p=0.006) and DM (HR 2.42, p=0.035) compared to low risk men, but there was no difference in PCSM (p=0.17). Therefore, we propose a novel risk grouping: Group 1 (low risk), Group 2 (FIR), Group 3 (UIR and SHR), and Group 4 (VHR). These groups have markedly different outcomes, with 10 year DM rates of 0.7%, 2.8%, 6.9%, and 16.3% (p<0.001) for Groups 1-4 respectively, and 10 year PCSM of 0.3%, 1.9%, 3.3%, and 10.9% (P<0.001). The c-index of this grouping was 0.80 for DM vs. 0.76 for D'Amico risk groups. CONCLUSIONS Patients classified as VHR have increased rates of PSA relapse, DM, and PCSM in comparison to SHR patients, whereas UIR and SHR patients have similar prognosis. Novel therapeutic strategies are needed for patients with VHR, likely involving multimodality therapy. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e239 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Zachary Zumsteg More articles by this author Zinan Chen More articles by this author Lauren Howard More articles by this author Christopher Amling More articles by this author William Aronson More articles by this author Matthew Cooperberg More articles by this author Christopher Kane More articles by this author Martha Terris More articles by this author Daniel Spratt More articles by this author Howard Sandler More articles by this author Stephen Freedland More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Improved decision making in intermediate-risk prostate cancer: a multicenter study on pathologic and oncologic outcomes after radical prostatectomy.

Prognoses for intermediate-risk prostate cancer (PCa) remain heterogeneous. Improved substratification could optimize treatment and monitoring strategies. The objective was to validate this subclassification in a radical prostatectomy (RP) series. Between 2000 and 2011, 4038 patients who underwent RP for intermediate-risk PCa in seven French academic centers were included. Unfavorable intermediate-risk (UIR) PCa was defined as having a primary Gleason score of 4, ≥50% positive biopsy cores (PPBC), or more than one D'Amico intermediate-risk factor (i.e., cT2b, PSA 10-20, or Gleason score 7). Remaining PCa cases were classified as favorable. Main endpoints were pathologic results (pT stage, final Gleason score, surgical margin status), and oncologic outcomes were assessed according to PSA recurrence-free survival (PSA-RFS). Univariate and multivariate analyses were performed using the log-rank test and the Cox proportional hazards model. Median follow-up was 48months (95% CI=[45-49]). Patients with UIR had worse PSA-RFS (68.17 vs. 81.98% at 4years, HR=1.97, 95% CI=[1.71; 2.27], p<0.0001) compared to those with a favorable disease. The need for adjuvant therapy was significantly greater for UIR patients (43.5 vs. 29.2%, p<0.0001). In multivariate analysis, primary Gleason score of 4 (HR=1.81, 95% CI=[1.55; 2.12], p<0.0001) and PPBC≥50% (HR=1.26, 95% CI=[1.02; 1.56], p=0.0286) were significant preoperative predictors for worse PSA-RFS. This study highlights the heterogeneity of NCCN intermediate-risk patients and validates (in a large RP cohort) the previously proposed subclassification for this group. This classification can significantly predict both pathologic and oncologic outcomes. This easy-to-use stratification could help physicians' decision making. Prospective study and new tools as genomic tests and novel molecular-based approaches can improve this stratification in the future for patient counseling.