Unfavorable Intermediate-risk Disease Research Articles

Early surrogate measures for ablative therapies for intermediate-risk prostate cancer patients.

241 Background: Stereotactic body radiotherapy (SBRT) is increasingly used to treat patients with intermediate-risk prostate cancer (IR-PCa), but there is a lack of early surrogate measures in this patient population treated with SBRT to guide clinicians and patients. We aim to explore the outcomes of IR-PCa patients treated with SBRT and to assess the role of PSA response at 4 years (4yPSARR) as an early surrogate measure given its encouraging results in patients treated with brachytherapy. Methods: Individual patient data from 6 institutions for 820 patients with IR-PCa treated with SBRT between 2006 and 2014 were analyzed. Cumulative incidence of biochemical recurrence (defined by Phoenix criteria) was calculated using Nelson-Aalen estimates, and metastases-free survival and overall survival were calculated using the Kaplan-Meier method. Biochemical recurrence-free survival was analyzed according to 4yPSARR with groups dichotomized based on PSA < 0.4 ng/mL or >0.4 ng/mL and compared using Log-rank test. Results: 820 patients were included, including 549 (67%) with favorable intermediate and 271 (33%) with unfavorable intermediate risk disease defined by NCCN risk group classification. Median age at time of treatment was 70 years. The most common dose, fractionation and treatment schedule was 36.25 Gy in 5 fractions prescribed to the planning target volume delivered every other day. Androgen deprivation therapy was used in combination with SBRT in 9.2% of patients for a median duration of 3 months. Median follow-up was 5.9 years. The cumulative incidence of biochemical recurrence was 7.9% at 5 years. Metastases-free survival and overall survival rates at 5 years were 99.4% and 94.6%, respectively. Median 4yPSARR (n = 504) was 0.2 ng/mL. Biochemical recurrence-free survival in patients with 4yPSARR < 0.4 ng/mL (n = 387) was 99.2%, and in patients with 4yPSARR >0.4 ng/mL (n = 117) was 81.5% at 5 years (p < 0.0001). Conclusions: Prostate SBRT is an effective treatment modality in men with IR-PCa with at least comparable rates of biochemical failure and metastases compared to other standard treatment modalities in patients with IR-PCa. 4yPSARR may represent an early surrogate measure for use in this patient population treated with SBRT and should be included for further study in prospective SBRT trials.

Personalizing Localized Prostate Cancer: Validation of a Combined Clinical Cell-cycle Risk (CCR) Score Threshold for Prognosticating Benefit From Multimodality Therapy.

The combined clinical cell-cycle risk (CCR) score is a validated model that combines the cell-cycle progression (CCP) score with the University of California San Francisco Cancer of the Prostate Risk Assessment (CAPRA) score. This score determines the risk of progressive disease for men with prostate cancer. Here, we further validate the prognostic ability of the CCR score and evaluate its ability to help determine which patients may safely forgo multimodality therapy. We evaluated the CCR and a CCR-based multimodality threshold (2.112) in a retrospective, multi-institutional cohort of men with National Comprehensive Cancer Network intermediate- or high-risk localized disease (N= 718). These men received single or multimodality therapy (androgen deprivation with radiation [RT], or surgery with adjuvant RT or hormones). CCR score prognosticated metastasis for single-modality therapy, as a continuous variable (hazard ratio, 3.97; 95% confidence interval [CI], 2.61-6.06) and when dichotomized at the threshold (hazard ratio, 15.90; 95% CI, 5.43-46.52). The 10-year Kaplan-Meier risk for those receiving single-modality (RT or surgical) therapy with CCR scores below and above the threshold for single-modality treatment was 4.3% (95% CI, 1.0%-17.1%) and 20.4% (95% CI, 13.2%-30.7%), respectively. Using the threshold, 27% of men with newly diagnosed high-risk and 73% with unfavorable intermediate-risk disease could avoid multimodality therapy. Patients with CCR scores below the multimodality threshold (2.112) may safely forgo multimodality therapy. The CCR score can be used as a decision aid to counsel men whether or not single-modality therapy would be sufficient for their intermediate- or high-risk prostate cancer.

Decision support for men with prostate cancer: Concordance between treatment choice and tumor risk.

Decision support tools improve decisional conflict and elicit patient preferences related to prostate cancer treatment. It was hypothesized that men using the Personal Patient Profile-Prostate (P3P) would be more likely to pursue guideline-concordant treatment. Men from a trial assessing the P3P decision support intervention were identified. The primary exposure was allocation to P3P (vs usual care), and the outcome was appropriate treatment per guidelines (eg, low risk = active surveillance). It was assessed whether providers recommended against any treatment options (ie, restricted). A multivariable model was fit for men with low-risk cancer that estimated the odds of the outcome of interest. This study identified 295 men in the cohort: 113 (38%) had low-risk disease, 119 (40%) had favorable intermediate-risk disease, and 63 (21%) had unfavorable intermediate-risk disease. Among low-risk patients, more men pursued active surveillance after using P3P whether they were given unrestricted (62% vs 54% with usual care; P = .54) or restricted options (71% vs 59% with usual care; P = .34). After adjustments, only Black race (odds ratio [OR], 0.31; 95% CI, 0.11-0.89) and restricted options (OR, 0.23; 95% CI, 0.08-0.65) had an inverse association with the receipt of surveillance for patients with low-risk prostate cancer. An impact associated with P3P versus usual care (OR, 0.89; 95% CI, 0.36-2.20) was not observed. Among men in a trial assessing a decision support tool, Black race and restricted treatment options were associated with less use of active surveillance for low-risk prostate cancer. Although the P3P instrument ameliorates decisional conflict, its use was not associated with more appropriate alignment of treatment with disease risk.

Prostate Cancer Radiation Therapy Recommendations in Response to COVID-19

PurposeDuring a global pandemic, the benefit of routine visits and treatment of patients with cancer must be weighed against the risks to patients, staff, and society. Prostate cancer is one of the most common cancers radiation oncology departments treat, and efficient resource utilization is essential in the setting of a pandemic. Herein, we aim to establish recommendations and a framework by which to evaluate prostate radiation therapy management decisions. Methods and MaterialsRadiation oncologists from the United States and the United Kingdom rapidly conducted a systematic review and agreed upon recommendations to safely manage patients with prostate cancer during the COVID-19 pandemic. A RADS framework was created: remote visits, and avoidance, deferment, and shortening of radiation therapy was applied to determine appropriate approaches. ResultsRecommendations were provided by the National Comprehensive Cancer Network risk group regarding clinical node-positive, postprostatectomy, oligometastatic, and low-volume M1 disease. Across all prostate cancer stages, telemedicine consultations and return visits were recommended when resources/staff available. Delays in consultations and return visits of between 1 and 6 months were deemed safe based on stage of disease. Treatment can be avoided or delayed until safe for very low, low, and favorable intermediate-risk disease. Unfavorable intermediate-risk, high-risk, clinical node-positive, recurrence postsurgery, oligometastatic, and low-volume M1 disease can receive neoadjuvant hormone therapy for 4 to 6 months as necessary. Ultrahypofractionation is preferred for localized, oligometastatic, and low-volume M1, and moderate hypofractionation is preferred for postprostatectomy and clinical node positive disease. Salvage is preferred to adjuvant radiation. ConclusionsResources can be reduced for all identified stages of prostate cancer. The RADS (remote visits, and avoidance, deferment, and shortening of radiation therapy) framework can be applied to other disease sites to help with decision making in a global pandemic.

Three-tiered Subclassification System of High-risk Prostate Cancer in Men Managed With Radical Prostatectomy: Implications for Treatment Decision-making

To inform treatment decisions for patients with high-risk prostate cancer (PCa), we determined rates of adverse pathologic factors and overall survival (OS) among subgroups of high-risk men. Using the National Cancer Database, 89,450 patients with clinical N0M0 unfavorable intermediate-risk, favorable high-risk (cT1c, Gleason 6, prostate-specific antigen [PSA] > 20 ng/mL or cT1c, biopsy Gleason 8, PSA < 10 ng/mL), standard high-risk (all other cT3a, biopsy Gleason ≥ 8, or PSA > 20 ng/mL), or very high-risk (cT3b-T4 or biopsy primary Gleason pattern 5) PCa treated with radical prostatectomy were identified. Rates of adverse pathologic factors (positive surgical margins, T4 disease, or pathologic lymph node involvement) were compared across subgroups. Patients with unfavorable intermediate-risk (n=31,381) and favorable high-risk (n=10,296) disease had similar rates of adverse features (7.6% vs 8.2%, adjusted odds ratio 1.00, 95% confidence interval 0.92-1.08, P= .974). Patients with standard high-risk (n=30,260) or very high-risk (n=7513) disease were significantly more likely to have adverse pathologic factors (15.9% and 26.5%, P < .001 for both). Patients with unfavorable intermediate-risk and favorable high-risk disease had similar 5-year OS (95.7% vs 95.1%, adjusted hazard ratio 1.06, 95% confidence interval 0.92-1.21, P = .411) but better OS compared to standard and very high-risk patients (93.4% and 88.1%, respectively; P < .001). Unfavorable intermediate-risk or favorable high-risk PCa patients had low rates of adverse pathologic factors and similar OS. In contrast, standard and very high-risk PCa patients had significantly higher rates of adverse pathologic factors and worse OS. This 3-tiered subclassification of high-risk disease may allow for improved treatment selection among patients considering surgery.

The 17-Gene Genomic Prostate Score Test as a Predictor of Outcomes in Men with Unfavorable Intermediate Risk Prostate Cancer

To evaluate the association of the Genomic Prostate Score (GPS) assay result with biochemical recurrence (BCR), distant metastases (DM), and prostate-specific death (PCD) in unfavorable intermediate (UFI) risk prostate cancer patients. The GPS assay is used to help guide management decisions for newly diagnosed low and favorable intermediate (FI) risk disease. GPS results from 2 studies (Center for Prostate Disease Research [CPDR]; Kaiser Permanente Northern California [KPNC]) in men treated with radical prostatectomy were analyzed to determine associations of the GPS result with BCR, DM, and PCD in UFI risk disease. Analyses included 299 intermediate risk prostate patients, 175 of whom had UFI risk disease (KPNC=103; CPDR=72). The GPS result as a dichotomous value (≤40 vs >40) was a significant predictor of BCR in UFI patients in multivariate analyses (hazard ratio [HR] 6.0; 95% confidence interval [CI] 2.0-22.4; P=.0035; CPDR). The GPS result was a strong predictor of all 3 endpoints in multivariate analyses (BCR HR 7.1; 95% CI 5.7-8.8; P < .0001; DM HR 5.4; 95% CI 3.8-7.8; P < .0001; PCD HR 3.4; 95% CI 1.5-8.9; P=.006; KPNC). UFI patients with GPS >40 had outcomes consistent with high-risk disease, whereas UFI patients with GPS ≤40 had outcomes similar to FI risk patients (CPDR/KPNC). The GPS result was a strong independent predictor of BCR, DM, and PCD in intermediate risk prostate cancer. UFI patients with GPS >40 have a poor prognosis and may benefit from additional therapeutic options.

Prostate Cancer Radiation Therapy Recommendations in Response to COVID-19

PurposeDuring a global pandemic, the benefit of routine visits and treatment of patients with cancer must be weighed against the risks to patients, staff, and society. Prostate cancer is one of the most common cancers radiation oncology departments treat, and efficient resource utilization is essential in the setting of a pandemic. Herein, we aim to establish recommendations and a framework by which to evaluate prostate radiation therapy management decisions. Methods and MaterialsRadiation oncologists from the United States and the United Kingdom rapidly conducted a systematic review and agreed upon recommendations to safely manage patients with prostate cancer during the COVID-19 pandemic. A RADS framework was created: remote visits, and avoidance, deferment, and shortening of radiation therapy was applied to determine appropriate approaches. ResultsRecommendations were provided by the National Comprehensive Cancer Network risk group regarding clinical node-positive, postprostatectomy, oligometastatic, and low-volume M1 disease. Across all prostate cancer stages, telemedicine consultations and return visits were recommended when resources/staff available. Delays in consultations and return visits of between 1 and 6 months were deemed safe based on stage of disease. Treatment can be avoided or delayed until safe for very low, low, and favorable intermediate-risk disease. Unfavorable intermediate-risk, high-risk, clinical node-positive, recurrence postsurgery, oligometastatic, and low-volume M1 disease can receive neoadjuvant hormone therapy for 4 to 6 months as necessary. Ultrahypofractionation is preferred for localized, oligometastatic, and low-volume M1, and moderate hypofractionation is preferred for postprostatectomy and clinical node positive disease. Salvage is preferred to adjuvant radiation. ConclusionsResources can be reduced for all identified stages of prostate cancer. The RADS (remote visits, and avoidance, deferment, and shortening of radiation therapy) framework can be applied to other disease sites to help with decision making in a global pandemic.

Trends in the Use of Stereotactic Body Radiotherapy for Treatment of Prostate Cancer in the United States

Stereotactic body radiotherapy is a hypofractionated, cost-effective treatment option for localized prostate cancer. To characterize US national trends and the clinical and socioeconomic factors associated with the use of stereotactic body radiotherapy in prostate cancer. This retrospective cohort study used data collected by the National Cancer Database to assess the clinical and socioeconomic factors among 106 926 men diagnosed as having prostate cancer from 2010 to 2015 who underwent definitive radiotherapy and the trends in the use of this therapy. The initial analysis was performed between January and February 2018, with final updates performed August 2019. Stereotactic body radiotherapy, defined as 5 fractions of radiotherapy. Temporal trends and clinical and sociodemographic factors associated with stereotactic body radiotherapy use. In total, 106 926 patients diagnosed as having localized prostate cancer between 2010 and 2015 and receiving definitive radiotherapy were identified. White patients composed 77.3% of this cohort, whereas black patients composed 18.7%. Government-issued insurance was used by 61.2% of patients. More than 80% of patients had a Charlson-Deyo Comorbidity Index score of 0 (range, 0 to ≥3, with lower numbers indicating fewer comorbidities). In the study population, 25.7% had low-risk disease; 26.3%, favorable intermediate-risk disease; 23.3%, unfavorable intermediate-risk disease; and 24.7%, high-risk disease. The proportion of patients who underwent radiotherapy and received stereotactic body radiotherapy (a total of 5395 patients) increased from 3.1% in 2010 to 7.2% in 2015 (odds ratio, 0.36; 95% CI, 0.33-0.40; P < .001). Among the entire cohort, patients received a median dose of 36.25 Gy (range, 30.00-50.00 Gy). Androgen deprivation therapy use increased significantly as disease risk level increased among all patients receiving radiotherapy (9.5% with low risk to 76.6% with high risk; P = .02) and among those receiving stereotactic body radiotherapy (4.1% with low risk to 33.2% with high risk; P = .04) or not receiving stereotactic body radiotherapy (9.9% with low risk to 77.6% with high risk; P = .04). Patients treated at an academic center, living in an urban area, or possessing higher incomes and those who were healthier, white individuals, or were diagnosed as having lower-risk prostate cancer had higher odds of receiving stereotactic body radiotherapy. This study found that stereotactic body radiotherapy use in prostate cancer more than doubled from 2010 to 2015 but accounted for less than 10% of all patients undergoing radiotherapy. Androgen deprivation therapy use increased with disease risk among patients overall, regardless of receiving stereotactic body radiotherapy. Socioeconomic and clinical determinants of stereotactic body radiotherapy included risk category, Charlson-Deyo Comorbidity Index score, facility type and location, income, race/ethnicity, and year of diagnosis. These results are hypothesis generating; further studies evaluating potential disparities in stereotactic body radiotherapy use in localized prostate cancer are warranted.

Age dependence of modern clinical risk groups for localized prostate cancer-A population-based study.

Optimal prostate cancer (PCa) screening strategies will focus on men likely to have potentially lethal disease. Age-specific incidence rates (ASIRs) by modern clinical risk groups could inform risk stratification efforts for screening. This cross-sectional population study identified all men diagnosed with PCa in Norway from 2014 to 2017 (n=20,356). Age, Gleason score (primary plus secondary), and clinical stage were extracted. Patients were assigned to clinical risk groups: low, favorable intermediate, unfavorable intermediate, high, regional, and metastatic. Chi-square tests analyzed the independence of Gleason scores and modern PCa risk groups with age. ASIRs for each risk group were calculated as the product of Norwegian ASIRs for all PCa and the proportions observed for each risk category. Older age was significantly associated with a higher Gleason score and more advanced disease. The percentages of men with Gleason 8 to 10 disease among men aged 55 to 59, 65 to 69, 75 to 79, and 85 to 89years were 16.5%, 23.4%, 37.2%, and 59.9%, respectively (P<.001); the percentages of men in the same age groups with at least high-risk disease were 29.3%, 39.1%, 60.4%, and 90.6%, respectively (P<.001). The maximum ASIRs (per 100,000 men) for low-risk, favorable intermediate-risk, unfavorable intermediate-risk, high-risk, regional, and metastatic disease were 157.1 for those aged 65 to 69years, 183.8 for those aged 65 to 69years, 194.8 for those aged 70 to 74years, 408.3 for those aged 75 to 79years, 159.7 for those aged ≥85years, and 314.0 for those aged ≥85years, respectively. At the ages of 75 to 79years, the ASIR of high-risk disease was approximately 6 times greater than the ASIR at 55 to 59years. The risk of clinically significant localized PCa increases with age. Healthy older men may benefit from screening.

Gantry-Mounted Linear Accelerator–Based Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer

PurposeTo establish the safety and efficacy of gantry-mounted linear accelerator-based stereotactic body radiation therapy (SBRT) for low- and intermediate-risk prostate cancer. MethodsWe pooled 921 patients enrolled on 7 single-institution prospective phase II trials of gantry-based SBRT from 2006 to 2017. The cumulative incidences of biochemical recurrence (defined by the Phoenix definition) and physician-scored genitourinary (GU) and gastrointestinal (GI) toxicities (defined per the original trials using Common Terminology Criteria for Adverse Events) were estimated using a competing risk framework. Multivariable logistic regression was used to evaluate the relationship between late toxicity and prespecified covariates: biologically effective dose, every other day versus weekly fractionation, intrafractional motion monitoring, and acute toxicity. ResultsMedian follow-up was 3.1 years (range, 0.5-10.8 years). In addition, 505 (54.8%) patients had low-risk disease, 236 (25.6%) had favorable intermediate-risk disease, and 180 (19.5%) had unfavorable intermediate-risk disease. Intrafractional motion monitoring was performed in 78.0% of patients. The 3-year cumulative incidence of biochemical recurrence was 0.8% (95% confidence interval [CI], 0-1.7%), 2.2% (95% CI, 0-4.3%), and 5.1% (95% CI, 1.0-9.2%) for low-, favorable intermediate-, and unfavorable intermediate-risk disease. Acute grade ≥2 GU and GI toxicity occurred in 14.5% and 4.6% of patients, respectively. Three-year cumulative incidence estimates of late grade 2 GU and GI toxicity were 4.1% (95% CI, 2.6-5.5%) and 1.3% (95% CI, 0.5-2.1%), respectively, with late grade ≥3 GU and GI toxicity estimates of 0.7% (95% CI, 0.1-1.3%) and 0.4% (95% CI, 0-0.8%), respectively. The only identified significant predictors of late grade ≥2 toxicity were acute grade ≥2 toxicity (P < .001) and weekly fractionation (P < .01), although only 12.4% of patients were treated weekly. ConclusionsGantry-based SBRT for prostate cancer is associated with a favorable safety and efficacy profile, despite variable intrafractional motion management techniques. These findings suggest that multiple treatment platforms can be used to safely deliver prostate SBRT.

MRI assisted focal boost integrated with HDR monotherapy study in low and intermediate risk prostate cancer (MARS): Results from a phase II clinical trial

PurposeThere is growing concern that single-fraction HDR monotherapy to a dose of 19 Gy is suboptimal for the treatment of localized prostate cancer. We report the results of a phase II prospective trial of single-fraction 19 Gy HDR monotherapy with MRI-guided simultaneous focal boost. MethodsEligible patients had low or intermediate risk prostate cancer and an identified lesion on MRI. TRUS based single-fraction HDR monotherapy with MRI fusion was delivered. The dose prescribed was 19 Gy to the prostate and ≥23 Gy to the dominant intraprostatic lesion (DIL). ADT was not used. The purpose is to report early efficacy results. Results60 patients were enrolled, with a median follow-up of 39 months. With MRI T-stage incorporated into the risk-group criteria, 8% had low-risk, 35% had favorable intermediate-risk and 57% had unfavorable intermediate-risk disease. The median dose to 90% of the DIL (D90) was 27.2 Gy, and the median prostate V100% was 96.9%. No acute or late grade ≥3 bowel or urinary toxicity was observed. The cumulative BF probability was 15.2% at 36 months and 31.6% at 48 months. All patients that were fully investigated had local failure only, and 88% of the local failures were at the site of original DIL. The median PSA nadir was 0.79 ng/ml, with a median time to nadir of 32 months. ConclusionsFocal boost to the MRI-specified gross tumor was well tolerated, but did not adequately improve local control. Single-fraction HDR monotherapy to 19 Gy for prostate cancer provides suboptimal local control, and should not be offered outside of clinical trials.

Results of 15 Gy HDR-BT boost plus EBRT in intermediate-risk prostate cancer: Analysis of over 500 patients

Purpose/objectiveTo report biochemical control associated with single fraction 15 Gy high-dose-rate brachytherapy (HDR-BT) boost followed by external beam radiation (EBRT) in patients with intermediate-risk prostate cancer. Materials and methodsA retrospective chart review of all patients with intermediate-risk disease treated with a real-time ultrasound-based 15 Gy HDR-BT boost followed by EBRT between 2009 and 2016 at a single quaternary cancer center was performed. Freedom from biochemical failure (FFBF), cumulative incidence of androgen deprivation therapy use for biochemical or clinical failure post-treatment (CI of ADT) and metastasis-free survival (MFS) outcomes were measured. Results518 patients met the inclusion criteria for this study. Median age at HDR-BT was 67 years (IQR 61–72). 506 (98%) had complete pathologic information available. Of these, 146 (28%) had favorable (FIR) and 360 (69%) had unfavorable (UIR) intermediate-risk disease. 83 (16%) received short course hormones with EBRT + HDR.Median overall follow-up was 5.2 years. FFBF was 91 (88–94)% at 5 years. Five-year FFBF was 94 (89–99)% and 89 (85–94)% in FIR and UIR patients, respectively (p = 0.045). CI of ADT was 4 (2–6)% at 5 years. Five-year CI of ADT was 1 (0–3)% and 5 (2–8)% in FIR and UIR patients, respectively (p = 0.085). MFS was 97 (95–98)% at 5 years. Five-year MFS was 100 (N/A-100)% and 95 (92–98)% in FIR and UIR patients, respectively (p = 0.020). ConclusionIn this large cohort of intermediate-risk prostate cancer patients, 15 Gy HDR-BT boost plus EBRT results in durable biochemical control and low rates of ADT use for biochemical failure.

Evidence of Stage Migration to Higher Risk Prostate Cancer and its Financial Implications in a Single Institution

The association between the United States Preventive Services Task Force (USPSTF) recommendations limiting PSA screening in 2012 and the subsequent increased detection of higher risk prostate cancer has been characterized in cancer registries. We investigated whether this phenomenon of stage migration could be measured in a high volume department and examine its impact on the cost of treatment. We analyzed an IRB approved database of patients with newly diagnosed prostate cancer treated at our institution from 2006-2018. Patients were stratified according to NCCN Risk groups (Low, Intermediate, and High), as well as by the modified Zumsteg/Zelefsky classification including Favorable and Unfavorable Intermediate risk disease. The frequency of risk group change across time was investigated. Differences in proportions were tested using the Pearson chi-square test. Treatment costs of radiation and androgen deprivation therapy were also obtained at our institution for risk groups. Between 2006 and 2018, 3447 consecutive patients with clinically localized prostate cancer were treated in our practice. The overall risk distribution of treated patients was 31% Low risk, 51% Intermediate risk, and 18% High risk. Further characterization of the Intermediate grouping revealed 25% for Favorable Intermediate risk and 25% for Unfavorable Intermediate risk by Zumsteg/Zelefsky criteria. The distribution of Low risk patients decreased from 48% to 23% in years 2006-2011 compared with 2012-2018; there was a corresponding increase in the High risk cohort from 14% to 19% (p<.0001). Further stratification demonstrated a decrease in patients treated with Low or Favorable Intermediate risk disease (69% vs. 47%) in years 2006-2011 compared with 2012-2018 with a significant increase in those treated with Unfavorable Intermediate or High risk disease (31% vs. 53%, p<.0001). The added cost to our institution due to stage migration was $5,593,500 in 2017. Despite a decreasing incidence of newly diagnosed prostate cancer cases occurring nationally, we have seen an increased percentage of aggressive prostate cancer at our practice over time. Stratified before and after the 2012 release of the USPSTF recommendation to cease PSA screening, this data validates registry series showing an associated stage migration towards more aggressive variants. Over 50% of patients treated in our department now have Unfavorable Intermediate or High risk disease, with only 23% harboring Low risk prostate cancer adding significant cost to treatment. As higher risk subtypes have poorer disease free outcomes compared to lower risk disease, the long-term effects on biochemical control, metastatic-free disease states, and prostate cancer specific survival will need to be assessed over time. While a strong correlation with the 2012 USPSTF recommendation is statistically compelling, competing factors which could also explain these findings should continue to be explored.

Stereotactic body radiotherapy with periprostatic hydrogel spacer for localized prostate cancer: toxicity profile and early oncologic outcomes

BackgroundMultiple phase I-II clinical trials have reported on the efficacy and safety of prostate stereotactic body radiotherapy (SBRT) for the treatment of prostate cancer. However, few have reported outcomes for prostate SBRT using periprostatic hydrogel spacer (SpaceOAR; Augmenix). Herein, we report safety and efficacy outcomes from our institutional prostate SBRT experience with SpaceOAR placement.MethodsFifty men with low- or intermediate-risk prostate cancer treated at a single institution with linear accelerator-based SBRT to 3625 cGy in 5 fractions, with or without androgen deprivation therapy (ADT) were included. All patients underwent SpaceOAR and fiducial marker placement followed by pre-treatment MRI. Toxicity assessments were conducted at least weekly while on treatment, 1 month after treatment, and every follow-up visit thereafter. Post-treatment PSA measurements were obtained 4 months after SBRT, followed by every 3–6 months thereafter. Acute toxicity was documented per RTOG criteria.ResultsMedian follow up time was 20 (range 4–44) months. Median PSA at time of diagnosis was 7.4 (2.7–19.5) ng/ml. Eighteen men received 6 months of ADT for unfavorable intermediate risk disease. No PSA failures were recorded. Median PSA was 0.9 ng/mL at 20 months; 0.08 and 1.32 ng/mL in men who did and did not receive ADT, respectively. Mean prostate-rectum separation achieved with SpaceOAR was 9.6 ± 4 mm at the prostate midgland.No grade ≥ 3 GU or GI toxicity was recorded. During treatment, 30% of men developed new grade 2 GU toxicity (urgency or dysuria). These symptoms were present in 30% of men at 1 month and in 12% of men at 1 year post-treatment. During treatment, GI toxicity was limited to grade 1 symptoms (16%), although 4% of men developed grade 2 symptoms during the first 4 weeks after SBRT. All GI symptoms were resolving by the 1 month post-treatment assessment and no acute or late rectal toxicity was reported > 1 month after treatment.ConclusionsPeriprostatic hydrogel placement followed by prostate SBRT resulted in minimal GI toxicity, and favorable early oncologic outcomes. These results indicate that SBRT with periprostatic spacer is a well-tolerated, safe, and convenient treatment option for localized prostate cancer.

Use and early mortality outcomes of active surveillance in patients with intermediate-risk prostate cancer.

Certain patients with intermediate-risk prostate cancer (PCa) may be appropriate candidates for active surveillance (AS). In the current study, the authors sought to characterize AS use and early mortality outcomes for patients with intermediate-risk PCa in the United States. The novel Surveillance, Epidemiology, and End Results Active Surveillance/Watchful Waiting database identified 52,940 men diagnosed with National Comprehensive Cancer Network intermediate-risk PCa (cT2b-c, Gleason score of 7, or a prostate-specific antigen level of 10-20ng/mL) and actively managed (AS, radiotherapy, or radical prostatectomy) from 2010 through 2015. The Cuzick test assessed AS time trends, and logistic multivariable regression characterized features associated with AS. Fine-Gray and Cox modeling determined PCa-specific mortality (PCSM) and overall survival, respectively. The rate of AS increased from 3.7% in 2010 to 7.3% in 2015, and from 7.2% to 11.7% among men aged ≥70years. Among men with favorable and unfavorable intermediate-risk disease, the use of AS increased from 7.2% to 14.9% and from 2.2% to 3.8%, respectively (all P value for trend, <.001). The mean age of those patients managed with AS decreased from 69.9years to 67.9years (P=.0004). Factors found to be associated with AS included favorable risk disease; black race; higher socioeconomic status; older age; and diagnosis in the West, Northwest, or Midwest regions of the United States. The 5-year PCSM rate was comparable to AS versus treatment among patients with low-risk and favorable intermediate-risk disease, but was worse with AS among those with unfavorable intermediate-risk disease (PCSM, 1.3% vs 0.5%; adjusted hazard ratio, 2.48 [95% CI, 1.11-5.50; P=.026]) and intermediate-risk disease overall (PCSM, 1.1% vs 0.4%; adjusted hazard ratio, 2.34 [95% CI, 1.25-4.37; P=.008]). The use of AS for patients with intermediate-risk PCa is increasing across the United States, particularly for older men and those with favorable intermediate-risk disease. Early estimates of cancer-specific and overall mortality rates are low with AS, although significantly higher compared with treatment.

Single-fraction brachytherapy as monotherapy for early-stage prostate cancer: The UCSF experience

PurposeHigh-dose-rate (HDR) brachytherapy as monotherapy is an effective treatment option for localized prostate cancer, but experience with single-fraction brachytherapy is limited by studies with small sample size. We report a large single-institution experience with single-fraction HDR brachytherapy as monotherapy for early-stage prostate cancer. Methods and MaterialsRetrospective chart review was performed for men treated with HDR brachytherapy as monotherapy for low- to intermediate-risk prostate cancer. Competing risk analyses were performed to estimate subdistribution hazard ratio and cumulative incidence of biochemical recurrence (BCR) and prostate cancer–specific mortality. ResultsWe identified 124 men with a median followup of 2.2 years (interquartile range 25th to 75th percentile: 1.8–3). Overall, 21.0% of patients (n = 26) were low risk, 44.4% (n = 55) were favorable intermediate risk, and 34.7% (n = 43) were unfavorable intermediate risk. At 2 years, the cumulative incidence of BCR was 3.5%: 0% for low risk, 4.0% for favorable intermediate risk patients, and 4.5% for unfavorable intermediate risk patients. In total, 12 BCRs were observed (9.7%) and approximately half occurred after median followup of 2.2 years. Compared with low-risk and favorable intermediate-risk disease, unfavorable intermediate-risk disease was significantly associated with BCR (subdistribution hazard ratio: 3.6, 95% CI: 1.1 to 11.1, p = 0.03). Prostate cancer–specific mortality was 0%. No patient experienced Grade 3 or higher acute or late genitourinary toxicity. ConclusionsSingle-fraction brachytherapy for early-stage prostate cancer was safe with promising short-term disease control rates, especially for low-risk patients. Longer term followup is needed as we observed an overall BCR rate of 9.7%.

Variations in patterns of concurrent androgen deprivation therapy use based on dose escalation with external beam radiotherapy vs. brachytherapy boost for prostate cancer

PurposeRetrospective data suggest less benefit from androgen deprivation therapy (ADT) in the setting of dose-escalated definitive radiation for prostate cancer, especially when a combination of external beam radiotherapy (EBRT) and brachytherapy approaches are used. This study aimed to test the hypothesis that patients with prostate cancer with intermediate- or high-risk disease undergoing extreme dose escalation with a brachytherapy boost are less likely to receive ADT. Methods and MaterialsData from the National Cancer Database were extracted for men aged 40–90 years diagnosed with node-negative, non-metastatic prostate cancer from 2004 to 2015. Only patients with intermediate- or high-risk disease who were treated with definitive radiotherapy were included. The association and patterns of care between dose escalated radiotherapy and ADT receipt were assessed using multivariable logistic regression. ResultsPatients with unfavorable intermediate- and high-risk prostate cancer were significantly less likely to receive ADT if they underwent dose escalation with a combination of EBRT and brachytherapy (odds ratio 0.67, p < 0.0001). Over time, this decrease in ADT utilization has widened for patients with unfavorable intermediate-risk disease. There was no difference in ADT utilization when comparing patients treated with non–dose-escalated EBRT to those treated with dose-escalated EBRT (without brachytherapy). ConclusionIn this large national database, patients with unfavorable intermediate- and high-risk prostate cancer were significantly less likely to receive guideline-indicated ADT if they underwent extreme dose escalation with combined radiation modalities. As we await prospective data guiding the utility of ADT with dose escalated radiation, these findings suggest potential underutilization of ADT in patients at higher risk of advanced disease.

Long-term Outcomes of Stereotactic Body Radiotherapy for Low-Risk and Intermediate-Risk Prostate Cancer

ImportanceStereotactic body radiotherapy harnesses improvements in technology to allow the completion of a course of external beam radiotherapy treatment for prostate cancer in the span of 4 to 5 treatment sessions. Although mounting short-term data support this approach, long-term outcomes have been sparsely reported.ObjectiveTo assess long-term outcomes after stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer.Design, Setting, and ParticipantsThis cohort study analyzed individual patient data from 2142 men enrolled in 10 single-institution phase 2 trials and 2 multi-institutional phase 2 trials of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer between January 1, 2000, and December 31, 2012. Statistical analysis was performed based on follow-up from January 1, 2013, to May 1, 2018.Main Outcomes and MeasuresThe cumulative incidence of biochemical recurrence was estimated using a competing risk framework. Physician-scored genitourinary and gastrointestinal toxic event outcomes were defined per each individual study, generally by Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events scoring systems. After central review, cumulative incidences of late grade 3 or higher toxic events were estimated using a Kaplan-Meier method.ResultsA total of 2142 men (mean [SD] age, 67.9 [9.5] years) were eligible for analysis, of whom 1185 (55.3%) had low-risk disease, 692 (32.3%) had favorable intermediate-risk disease, and 265 (12.4%) had unfavorable intermediate-risk disease. The median follow-up period was 6.9 years (interquartile range, 4.9-8.1 years). Seven-year cumulative rates of biochemical recurrence were 4.5% (95% CI, 3.2%-5.8%) for low-risk disease, 8.6% (95% CI, 6.2%-11.0%) for favorable intermediate-risk disease, 14.9% (95% CI, 9.5%-20.2%) for unfavorable intermediate-risk disease, and 10.2% (95% CI, 8.0%-12.5%) for all intermediate-risk disease. The crude incidence of acute grade 3 or higher genitourinary toxic events was 0.60% (n = 13) and of gastrointestinal toxic events was 0.09% (n = 2), and the 7-year cumulative incidence of late grade 3 or higher genitourinary toxic events was 2.4% (95% CI, 1.8%-3.2%) and of late grade 3 or higher gastrointestinal toxic events was 0.4% (95% CI, 0.2%-0.8%).Conclusions and RelevanceIn this study, stereotactic body radiotherapy for low-risk and intermediate-risk disease was associated with low rates of severe toxic events and high rates of biochemical control. These data suggest that stereotactic body radiotherapy is an appropriate definitive treatment modality for low-risk and intermediate-risk prostate cancer.

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.

Management of Unfavorable Intermediate and High Risk Prostate Cancer with Stereotactic Body Radiation Therapy as Monotherapy Versus Boost: A Ten Year Study

The use of stereotactic body radiotherapy (SBRT) in prostate cancer has been increasing in recent years. However, management of high-risk prostate cancer with SBRT remains controversial, in part due to the limited number of reports published and lack of long-term data. In this present study, we add to the existing body of literature by reporting 10-year outcomes for high-risk patients treated with SBRT alone or as a boost to external beam radiotherapy(EBRT). We studied 130 patients with organ-confined prostate cancer, treated between 2006-2009, with robotic arm SBRT (35-36.25 Gy in 5 fx, n=85) or EBRT followed by SBRT boost (45 Gy plus 18-21 Gy boost, n=45). EBRT was delivered as a four field box with 3D planning. SBRT dose was defined to cover a PTV created by a 5mm expansion of the prostate (3mm posteriorly). All patients had NCCN high- (n=73) or unfavorable intermediate-risk disease (n=57; defined as Gleason 4+3=7, or more than 1 intermediate risk factor). Median PSA was 12; median Grade Group of 4; 61 patients received ADT up to 6 months. Biochemical failure was defined using Phoenix criterion. Survival estimates were determined using Kaplan-Meier methods. The 10y biochemical recurrence free survival (bRFS) was 63.0% for both unfavorable intermediate and high-risk patients, with no significant difference between the two groups. Overall local control was 91% and median PSA nadir was 0.12 ng/ml. There was no significant difference in 10y bRFS amongst patients treated with SBRT monotherapy versus SBRT boost (65.0 versus 60.4%), or ADT versus no ADT (62.8 vs 63.3%). On multivariate analysis, PSA was significant for bRFS (P=0.006), whereas ADT, EBRT and Gleason score were not. Toxicity was overall mild. There was no significant difference in G2-3 GU toxicity between patients treated with SBRT boost vs SBRT alone (5.4 vs 9.4%, P=0.29), but a higher (P=0.042) incidence of G2 GI toxicity was noted after EBRT + SBRT boost compared to SBRT alone (13.3% vs 3.5%). There was no G3 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 appears to be a safe and effective approach for high risk prostate cancer, with biochemical outcomes comparable to HDR brachytherapy and IMRT. The addition of pelvic EBRT or ADT fails to demonstrate clinical benefit with now up to 10 years of follow up. Mature results of prospective studies are awaited to validate these findings.