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Objectives: To determine whether 6 months of preoperative apalutamide for intermediate‐risk prostate cancer (IRPCa) reduces the aggregate postoperative radiotherapy risk and to evaluate associations of molecular perturbations with clinical outcomes in this study cohort. Patients and Methods: Between May 2018 and February 2020, eligible patients with IRPCa (Gleason 3 + 4 or 4 + 3 and clinical T2b‐c or prostate‐specific antigen level of 10–20 ng/mL) were treated with apalutamide 240 mg/day for 6 months followed by radical prostatectomy (RP) in this single‐arm, phase II trial. The primary endpoint was presence of any adverse pathological feature at risk of pelvic radiation (pathological T stage after neoadjuvant therapy [yp]T3 or ypN1 or positive surgical margins). Translational studies, including germline and somatic DNA alterations and RNA and protein expression, were performed on post‐apalutamide RP specimens, and assessed for associations with clinical outcomes. Results: A total of 40 patients underwent a RP, and only one patient discontinued apalutamide prior to 6 months. In all, 40% had adverse pathological features at time of RP, and the 3‐year biochemical recurrence (BCR) rate was 15%, with 27.5% being not evaluable. Genomic alterations frequently seen in metastatic PCas, such as androgen receptor (AR), tumour protein p53 (TP53), phosphatase and tensin homologue (PTEN), or BReast CAncer associated gene (BRCA1/2) were underrepresented in this localised cohort. Adverse pathological features and BCR at 3‐years were associated with increased expression of select cell cycle (e.g., E2F targets: adjusted P value [Padj] < 0.001, normalised enrichment score [NES] 2.47) and oxidative phosphorylation (Padj < 0.001, NES 1.62) pathways. Conclusions: Preoperative apalutamide did not reduce the aggregate postoperative radiation risk to the pre‐specified threshold in unselected men with IRPCa. However, transcriptomic analysis identified key dysregulated pathways in tumours associated with adverse pathological outcomes and BCR, which warrant future study. Further investigation of preoperative therapy is underway for men with high‐risk PCa. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to report the treatment outcomes of radiation therapy for early‐stage endometrial cancer patients. In addition, this study intended to identify high‐risk factors that require pelvic radiotherapy (PRT) in addition to vaginal brachytherapy (VBT) for intermediate‐risk endometrial cancer patients. Methods: Patients with early‐stage endometrial cancer receiving postoperative VBT alone or with PRT were included. Propensity score matching was used to balance the two study groups. The primary endpoint was locoregional recurrence (LRR). Age‐adjusted Charlson comorbidity index and substantial lymphovascular space invasion were selected for subgroup analyses to identify the benefits of PRT over VBT alone. Results: From 2005 to 2017, a total of 288 patients underwent analysis following propensity score matching. Of these, 144 received VBT and 144 received PRT. There was no significant difference in 5‐year LRR between VBT and PRT for both intermediate (0% vs. 0%) and high‐intermediate risk patients (3.5% VBT vs. 5.4% PRT; HR 0.54: 0.05–6.00; p = 0.616). The subgroup analyses revealed no significant factors favoring PRT over VBT. Patients with high comorbidities may have higher risks of non‐cancer death after receiving PRT. Conclusions: Postoperative VBT alone is sufficient for early‐stage intermediate‐risk endometrial cancer patients. [ABSTRACT FROM AUTHOR]

Objectives: To validate the risk stratification newly defined in the Japanese Urological Association guidelines 2019 for non‐muscle invasive bladder cancer and provide a more accurate stratification model for a heterogeneous intermediate‐risk group. Methods: A total of 1610 patients, who underwent transurethral resection, diagnosed with non‐muscle invasive bladder cancer in nine collaborating hospitals were retrospectively reviewed. They were classified into low‐risk, intermediate‐risk, high‐risk, and highest‐risk groups, and recurrence‐free survival, progression‐free survival, cancer‐specific survival, and overall survival were compared among the groups. The intermediate‐risk group was subdivided into two groups based on the multivariable Cox regression model of recurrence and progression risk factors, and a revised risk model was created. Results: The progression‐free survival, cancer‐specific survival, and overall survival were well stratified, while the recurrence‐free survival of the intermediate‐risk group was the shortest among the four groups (p < 0.001). The independent risk factors for recurrence and progression‐free survival in the intermediate‐risk group were as follows: age ≥ 70 years, sex, multiple tumors, tumor size ≥3 cm, and recurrent cases. The intermediate‐risk group was subdivided into two groups: favorable intermediate‐risk group and unfavorable intermediate‐risk group. The revised risk model showed significant differences. Conclusion: We validated the Japanese Urological Association guidelines 2019 stratification model. The revised risk model provided a more accurate treatment selection for this disease subset. [ABSTRACT FROM AUTHOR]

Objectives: Active surveillance (AS), now the standard of care for most men with favourable‐risk prostate cancer, is appealing for selected men with 'favourable' intermediate‐risk prostate cancer. Methods: This is a review of the indications for conservative management in this population, the outcomes reported in prospective series, and the use of molecular biomarkers and imaging to identify optimal candidates. Results: Candidates are those patients who are categorized as having intermediate‐risk disease either because of a prostate‐specific antigen level between 10 and 20 ng/mL, or by virtue of having Grade Group 2 disease, with a small percentage of Gleason 4 pattern, and a negative magnetic resonance imaging result or negative targeted biopsy of a region of interest. Confirmation with a favourable score on a tissue‐based genetic assay can provide further reassurance. A subset of patients with intermediate‐risk disease has indolent disease that may benefit from AS; at the same time, some patients with intermediate‐risk disease have an aggressive clinical course that requires early definitive therapy. This heterogeneity is not adequately captured with traditional histopathological staging. Clinical, genomic and radiological biomarkers are the key to appropriate risk stratification and patient selection. Conclusions: The benefits of AS make it an appealing option for selected patients with intermediate‐risk disease. [ABSTRACT FROM AUTHOR]

Background: Partial prostate treatment has emerged as a potential method for treating patients with favorable-risk prostate cancer while minimizing toxicity. The authors previously demonstrated poor rates of biochemical disease control for patients with National Comprehensive Cancer Network (NCCN) intermediate-risk disease using partial gland treatment with brachytherapy. The objective of the current study was to estimate the rates of distant metastasis and prostate cancer-specific mortality (PCSM) for this cohort.Methods: Between 1997 and 2007, a total of 354 men with clinical T1c disease, a prostate-specific antigen (PSA) level < 15 ng/mL, and Gleason grade ≤3 + 4 prostate cancer underwent partial prostate treatment with brachytherapy to the peripheral zone under 0.5-Tesla magnetic resonance guidance. The cumulative incidences of metastasis and PCSM for the NCCN very low-risk, low-risk, and intermediate-risk groups were estimated. Fine and Gray competing risk regression was used to evaluate clinical factors associated with time to metastasis.Results: A total of 22 patients developed metastases at a median of 11.0 years (interquartile range, 6.9-13.9 years). The 12-year metastasis rates for patients with very low-risk, low-risk, and intermediate-risk disease were 0.8% (95% confidence interval [95% CI], 0.1%-4.4%), 8.7% (95% CI, 3.4%-17.2%), and 15.7% (95% CI, 5.7%-30.2%), respectively, and the 12-year PCSM estimates were 1.6% (95% CI, 0.1%-7.6%), 1.4% (95% CI, 0.1%-6.8%), and 8.2% (95% CI, 1.9%-20.7%), respectively. On multivariate analysis, NCCN risk category (low risk: hazard ratio, 6.34 [95% CI, 1.18-34.06; P = .03] and intermediate risk: hazard ratio, 6.98 [95% CI, 1.23-39.73; P = .03]) was found to be significantly associated with the time to metastasis.Conclusions: Partial prostate treatment with brachytherapy may be associated with higher rates of distant metastasis and PCSM for patients with intermediate-risk disease after long-term follow-up. Treatment of less than the full gland may not be appropriate for this cohort. [ABSTRACT FROM AUTHOR]

Objective To evaluate the cancer control outcomes and long-term treatment-related morbidity of brachytherapy as well as combination brachytherapy and external beam radiation therapy (EBRT) in patients with intermediate-risk prostate cancer. Materials and Methods A retrospective review was conducted in a prospectively collected database of patients with intermediate-risk prostate cancer who were treated either with brachytherapy or brachytherapy and EBRT, with or without androgen deprivation therapy (ADT), in the period 1990--2014. Urinary and erectile dysfunction symptoms were measured using the International Prostate Symptom Score (IPSS), the Mount Sinai erectile function scale and the Sexual Health Inventory for Men (SHIM). Cancer control endpoints included biochemical failure and development of distant metastases. All statistical analyses were carried out using the Statistical Package for Social Science (SPSS). Survival curves were calculated using Kaplan--Meier actuarial methods and compared using log-rank tests. Cox regression multivariate analyses were used to test the effect of multiple variables on treatment outcomes. Results A total of 902 patients were identified, with a median follow- up of 91 months. Of these, 390 received brachytherapy and 512 received combination therapy with EBRT. In patients with one intermediate-risk factor, the addition of EBRT did not significantly affect freedom from biochemical failure or distant metastases. Among patients with two or three intermediate-risk factors, added EBRT did not improve freedom from biochemical failure. Significant differences in late toxicity between patients treated with brachytherapy vs combination brachytherapy and EBRT were identified including urge incontinence (P < 0.001), haematuria (P < 0.001), dysuria (P < 0.001), and change in quality-of-life IPSS (P = 0.002). These symptoms were reported by patients at any point during treatment follow-up. Analysis of patients who were potent before treatment using actuarial methods showed that patients receiving combination therapy more frequently experienced loss of potency, as measured by the Mount Sinai erectile function scale (P = 0.040). Conclusion Brachytherapy monotherapy results in equal biochemical and distant control in both patients with one and more than one intermediate-risk features. While no significant benefit was shown, we believe that the addition of EBRT may prevent recurrence in patients with multiple intermediate-risk features and should be considered. [ABSTRACT FROM AUTHOR]

Objective To improve on the existing risk-stratification systems for prostate cancer. Patients and Methods This was a retrospective investigation including 2 248 patients undergoing dose-escalated external beam radiotherapy ( EBRT) at a single institution. We separated National Comprehensive Cancer Network ( NCCN) intermediate-risk prostate cancer into 'favourable' and 'unfavourable' groups based on primary Gleason pattern, percentage of positive biopsy cores ( PPBC), and number of NCCN intermediate-risk factors. Similarly, NCCN high-risk prostate cancer was stratified into 'standard' and 'very high-risk' groups based on primary Gleason pattern, PPBC, number of NCCN high-risk factors, and stage T3b-T4 disease. Patients with unfavourable-intermediate-risk ( UIR) prostate cancer had significantly inferior prostate-specific antigen relapse-free survival ( PSA- RFS, P < 0.001), distant metastasis-free survival ( DMFS, P < 0.001), prostate cancer-specific mortality ( PCSM, P < 0.001), and overall survival ( OS, P < 0.001) compared with patients with favourable-intermediate-risk ( FIR) prostate cancer. Similarly, patients with very high-risk ( VHR) prostate cancer had significantly worse PSA- RFS ( P < 0.001), DMFS ( P < 0.001), and PCSM ( P = 0.001) compared with patients with standard high-risk ( SHR) prostate cancer. Moreover, patients with FIR and low-risk prostate cancer had similar outcomes, as did patients with UIR and SHR prostate cancer. Results Consequently, we propose the following risk-stratification system: Group 1, low risk and FIR; Group 2, UIR and SHR; and Group 3, VHR. These groups have markedly different outcomes, with 8-year distant metastasis rates of 3%, 9%, and 29% ( P < 0.001) for Groups 1, 2, and 3, respectively, and 8-year PCSM of 1%, 4%, and 13% ( P < 0.001) after EBRT. This modified stratification system was significantly more accurate than the three-tiered NCCN system currently in clinical use for all outcomes. Conclusion Modifying the NCCN risk-stratification system to group FIR with low-risk patients and UIR with SHR patients, results in modestly improved prediction of outcomes, potentially allowing better personalisation of therapeutic recommendations. [ABSTRACT FROM AUTHOR]

Aim Benefit of adjuvant imatinib therapy following curative resection in patients with intermediate-risk gastrointestinal stromal tumor (GIST) is unclear. GIST-specific exon mutations, in particular exon 11 deletions, have been shown to be prognostic. We hypothesize that specific KIT mutations may improve risk stratification in patients with intermediate-risk GIST, identifying a subgroup of patients who may benefit from adjuvant therapy. Methods In total, 142 GIST patients with complete clinicopathologic and mutational data from two sites were included. Risk classification was based on the modified National Institute of Health (NIH) criteria. Results In this cohort, 74% ( n = 105) of patients harbored a KIT mutation; 61% ( n = 86) were found in exon 11 of which nearly 70% were KIT exon 11 deletions ( n = 60). A total of 18% ( n = 25) of cases were classified as having intermediate-risk disease. Univariate analysis confirmed tumor size, mitotic index, nongastric origin, presence of tumor rupture and modified NIH criteria were adversely prognostic for relapse-free survival (RFS). Among KIT/PDGFRA mutants, KIT exon 11 deletions had a significantly worse prognosis (hazard ratio 2.31; 95% confidence interval, 1.30-4.10; P = 0.003). Multivariate analysis confirmed KIT exon 11 deletion ( P = 0.003) and clinical risk classification ( P < 0.001) as independent adverse prognostic factors for RFS. Intermediate-risk patients harboring KIT exon 11 deletions had RFS outcomes similar to high-risk patients. Conclusion The presence of KIT exon 11 deletion mutation in patients with intermediate-risk GIST is associated with an inferior clinical outcome with RFS similar to high-risk patients. [ABSTRACT FROM AUTHOR]

Background: The role of hormone therapy (HT) with dose-escalated external-beam radiotherapy (DE-EBRT) in the treatment of intermediate-risk prostate cancer (IRPC) remains controversial. The authors report the long-term outcome of a phase 3 study of DE-EBRT with or without HT for patients with localized prostate cancer (LPC).Methods: From 1999 to 2006, 252 of an intended 338 patients with LPC were randomized to receive DE-EBRT with or without 5 months of neoadjuvant and concurrent bicalutamide 150 mg once daily. The study was closed early because of contemporary concerns surrounding bicalutamide. The primary outcome was biochemical failure (BF) incidence, and the secondary endpoints were overall survival (OS), local control (LC), and quality of life. The BF and OS rates were estimated using the cumulative incidence function and Kaplan-Meier methods and were compared using the Gray test and the log-rank test.Results: Eleven patients were excluded from analysis. Characteristics were well balanced in each treatment arm. Ninety-five percent of patients had IRPC. The prescribed dose increased from 75.6 grays (Gy) in 42 fractions to 78 Gy in 39 fractions over the period. At a median follow-up of 9.1 years, 98 BFs occurred, with no significant effect of HT versus no HT on the BF rate (40% vs 47%; P = .32), the OS rate (82% vs 86%; P = .37), the LC rate (52% vs 48 %; P = .32) or quality of life, in the patients who completed the questionnaires. Dose escalation to 75.6 Gy versus >75.6 Gy reduced the BF rate by 26% (P = .004).Conclusions: For patients who predominantly have IRPC, the addition of HT to DE-EBRT did not significantly affect BF, OS, or LC. Bicalutamide appeared to be well tolerated. The conclusions from the study are limited by incomplete recruitment. Cancer 2016;122:2595-603. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Current guidelines on the treatment of acute pulmonary embolism (PE) recommend stratification of hemodynamically stable patients in 'low risk' and 'intermediate risk'. Validated risk scores, cardiac biomarkers, and imaging of the right ventricle all help in distinguishing both patient categories. The relevance of this risk stratification lies in the determination of the most optimal treatment for the individual patient. In this clinical review, we will discuss how patients with 'intermediate-risk' PE can be identified as well as recent advances in their therapeutic management. Based on a clinical case, we will highlight the indications for reperfusion therapy and the current experience with non-vitamin K-dependent oral anticoagulant (NOACs) in this specific patient's category. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the outcome of low-dose-rate permanent brachytherapy combined with anti-androgen deprivation therapy for intermediate-risk prostate cancer excluding biopsy Gleason score 4 + 3. Methods Patients included in the intermediate-risk group were those presenting clinical stage T1c to T2c (by magnetic resonance imaging staging), Gleason score 3 + 4 or lower and/or prostate-specific antigen less than 20 ng/mL, whereas those with clinical stage T1c to T2a, Gleason score 3 + 3 and prostate-specific antigen less than 10 ng/mL represented the low-risk group, and were used as controls. In the intermediate-risk group, therapy with a luteinizing hormone-releasing hormone analog was continued for at least 6 months before and after permanent brachytherapy. Results A total of 147 low-risk group patients and 139 intermediate-risk group patients were included in the study. The median follow up was 51 and 52 months for the intermediate-risk group and low-risk group, respectively. The 5-year overall, cause-specific and distant-metastasis-free survival rates in the low-risk group and intermediate-risk group were 97.6/99.2, 100/100 and 100/100%, respectively. The 5-year biochemical disease-free survival in these groups were 95.9 and 92.5%, respectively ( P = 0.18). There was no sexual activity and desire for erection before treatment in 50%, and in 46% of the patients in the low-risk group and intermediate-risk group, respectively. Overall satisfaction score at 2 years after permanent brachytherapy significantly improved, compared with pretreatment ( P = 0.0399). Conclusions In intermediate-risk prostate cancer, excluding biopsy Gleason score 4 + 3, permanent brachytherapy combined with androgen deprivation therapy for 6 months or more represents an effective treatment option in Japanese patients, based on a favorable prognosis, adverse event profile and quality of life analysis. [ABSTRACT FROM AUTHOR]

Study Type – Prognosis (cohort) Level of Evidence 2a OBJECTIVES To validate the Shared Equal Access Regional Cancer Hospital (SEARCH) nomogram to better risk stratify men with intermediate-risk pathology after prostatectomy (positive surgical margins, PSM, and/or extracapsular disease, ECE, without seminal vesicle or lymph node involvement) in a tertiary referral centre (the Duke Prostate Center, DPC). PATIENTS AND METHODS We retrospectively analysed 485 men in the DPC cohort with PSM and/or ECE but without seminal vesicle or lymph node involvement. The predicted risk of biochemical progression-free probability at 1, 3 and 5 years was estimated by the SEARCH and updated Kattan postoperative nomograms. Calibration plots were generated and accuracy assessed with the concordance index. RESULTS The SEARCH nomogram appeared to be well calibrated, with the highest-risk quartile having a predicted <60% progression-free probability at 5 years, vs >80% for the lowest risk. In comparison, overall external calibration appeared to be similar for the updated Kattan nomogram, although there was less separation between the highest- and lowest-risk quartiles. The SEARCH model had an overall predictive accuracy of 0.65, which compared favourably with the updated Kattan nomogram (0.57). CONCLUSION In an external dataset, the SEARCH nomogram to predict progression-free probability for men at intermediate risk after prostatectomy was well calibrated and performed better than the updated postoperative Kattan nomogram. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate the metastatic risk of pT1 G2 squamous cell carcinoma (SCC) of the penis. PATIENTS AND METHODS We retrospectively reviewed 20 patients with pT1 G2 penile SCC and determined their groin status at first presentation, their nodal status after inguinal lymph node dissection and their follow-up for at least 18 months. RESULTS Four of the 20 patients had a clinically positive groin; three of these were found to have lymph node metastases. Among the 16 patients with a clinically negative groin, one of five who had surgical lymph node staging had lymph node metastases. During surveillance six of 11 patients developed lymph node metastases. There was lymphovascular invasion in three of 10 patients with lymph node metastases. CONCLUSIONS As the metastatic risk of pT1 G2 penile SCC was 50% in this series of patients, and 44% in those with an initially negative groin, surgical staging of inguinal lymph nodes is recommended in patients with pT1 G2 penile SCC. [ABSTRACT FROM AUTHOR]