Active Surveillance for Prostate Cancer:Past, Current, and Future Trends

In response to the rising incidence of indolent, low-risk prostate cancer (PCa) due to increased prostate-specific antigen (PSA) screening in the 1990s, active surveillance (AS) emerged as a treatment modality to combat overtreatment by delaying or avoiding unnecessary definitive treatment and its associated morbidity. AS consists of regular monitoring of PSA levels, digital rectal exams, medical imaging, and prostate biopsies, so that definitive treatment is only offered when deemed necessary. This paper provides a narrative review of the evolution of AS since its inception and an overview of its current landscape and challenges. Although AS was initially only performed in a study setting, numerous studies have provided evidence for the safety and efficacy of AS which has led guidelines to recommend it as a treatment option for patients with low-risk PCa. For intermediate-risk disease, AS appears to be a viable option for those with favourable clinical characteristics. Over the years, the inclusion criteria, follow-up schedule and triggers for definitive treatment have evolved based on the results of various large AS cohorts. Given the burdensome nature of repeat biopsies, risk-based dynamic monitoring may further reduce overtreatment by avoiding repeat biopsies in selected patients.</p

The measurement of membranous urethral length using transperineal ultrasound prior to radical prostatectomy

Objective: To compare preoperative membranous urethral length (MUL) measurements using magnetic resonance imaging (MRI) with two-dimensional transperineal ultrasound imaging (TPUS) in two supine positions on two separate days in men prior to radical prostatectomy. Materials and methods: MUL was prospectively measured in 18 male volunteers using MRI and on two separate occasions in two different patient positions using TPUS; the patient supine with the knees extended (Supine) and supine with the knees flexed to 70 degrees (Supine KF). Agreement between TPUS and MRI measurements of MUL was assessed using Bland-Altman method comparison techniques and a two-way mixed-effects single measures intraclass correlation (ICC). Test-retest reliability was assessed using a two-way random effects single measures ICC. Results: The mean difference in MUL measurements between MRI and i) TPUS Supine was -0.8 mm (95% limits of agreement (LOA): -3.2, 1.7) and ii) TPUS Supine KF was -0.8mm (95% LOA: -3.5, 1.9). ICC indicated a point estimate of excellent agreement between MRI and TPUS Supine ICC 0.93 (95% CI: 0.76, 0.98) and TPUS Supine KF ICC 0.91 (95 0 /0CI 0.79, 0.97). There was excellent agreement between TPUS Supine and TPUS Supine KF (ICC 0.98, 95% CI: 0.96, 0.99) with a mean difference of 0.3mm (95% LOA: -1.2 to 1.3mm). Conclusions: Preoperative MUL can be reliably measured using TPUS and demonstrates excellent agreement with MRI measurements of MUL. TPUS provides clinicians with an accessible non-invasive alternative to MRI for the measurement of MUL that can be used in outpatient urological settings and for patients where MRI is contraindicated

False positives in PIRADS (V2) 3, 4, and 5 lesions:relationship with reader experience and zonal location

PURPOSE: To investigate the effect of reader experience and zonal location on the occurrence of false positives (FPs) in PIRADS (V2) 3, 4, and 5 lesions on multiparametric (MP)-MRI of the prostate. MATERIALS AND METHODS: This retrospective study included 139 patients who had consecutively undergone an MP-MRI of the prostate in combination with a transrectal ultrasound MRI fusion-guided biopsy between 2014 and 2017. MRI exams were prospectively read by a group of inexperienced radiologists (cohort 1; 54 patients) and an experienced radiologist (cohort 2; 85 patients). Multivariable logistic regression analysis was performed to determine the association of experience of the radiologist and zonal location with a FP reading. FP rates were compared between readings by inexperienced and experienced radiologists according to zonal location, using Chi-square (χ2) tests. RESULTS: A total of 168 lesions in 139 patients were detected. Median patient age was 68 years (Interquartile range (IQR) 62.5-73), and median PSA was 10.9 ng/mL (IQR 7.6-15.9) for the entire patient cohort. According to multivariable logistic regression, inexperience of the radiologist was significantly (P = 0.044, odds ratio 1.927, 95% confidence interval [CI] 1.017-3.651) and independently associated with a FP reading, while zonal location was not (P = 0.202, odds ratio 1.444, 95% CI 0.820-2.539). In the transition zone (TZ), the FP rate of the inexperienced radiologists 59% (17/29) was significantly higher (χ2P = 0.033) than that of the experienced radiologist 33% (13/40). CONCLUSION: Inexperience of the radiologist is significantly and independently associated with a FP reading, while zonal location is not. Inexperienced radiologists have a significantly higher FP rate in the TZ

Prostate cancer upgrading with serial prostate magnetic resonance imaging and repeat biopsy in men on active surveillance: are confirmatory biopsies still necessary?

Objectives: To investigate whether serial prostate magnetic resonance imaging (MRI) may guide the utility of repeat targeted (TBx) and systematic biopsy (SBx) when monitoring men with low-risk prostate cancer (PCa) at 1-year of active surveillance (AS). Patients and Methods: We retrospectively included 111 consecutive men with low-risk (International Society of Urological Pathology [ISUP] Grade 1) PCa, who received protocolled repeat MRI with or without TBx and repeat SBx at 1-year of AS. TBx was performed in Prostate Imaging-Reporting and Data System (PI-RADS) score ≥3 lesions (MRI-positive men). Upgrading defined as ISUP Grade ≥2 PCa (I), Grade ≥2 with cribriform growth/intraductal carcinoma PCa (II), and Grade ≥3 PCa (III) was investigated. Upgrading detected by TBx only (not by SBx) and SBx only (not by TBx) was investigated in MRI-positive and -negative men, and related to radiological progression on MRI (Prostate Cancer Radiological Estimation of Change in Sequential Evaluation [PRECISE] score). Results: Overall upgrading (I) was 32% (35/111). Upgrading in MRI-positive and -negative men was 48% (30/63) and 10% (5/48) (P < 0.001), respectively. In MRI-positive men, there was upgrading in 23% (seven of 30) by TBx only and in 33% (10/30) by SBx only. Radiological progression (PRECISE score 4–5) in MRI-positive men was seen in 27% (17/63). Upgrading (I) occurred in 41% (seven of 17) of these MRI-positive men, while this was 50% (23/46) in MRI-positive men without radiological progression (PRECISE score 1–3) (P = 0.534). Overall upgrading (II) was 15% (17/111). Upgrading in MRI-positive and -negative men was 22% (14/63) and 6% (three of 48) (P = 0.021), respectively. In MRI-positive men, there was upgrading in three of 14 by TBx only and in seven of 14 by SBx only. Overall upgrading (III) occurred in 5% (five of 111). Upgrading in MRI-positive and -negative men was 6% (four of 63) and 2% (one of 48) (P = 0.283), respectively. In MRI-positive men, there was upgrading in one of four by TBx only and in two of four by SBx only. Conclusion: Upgrading is significantly lower in MRI-negative compared to MRI-positive men with low-risk PCa at 1-year of AS. In serial MRI-negative men, the added value of repeat SBx at 1-year surveillance is limited and should be balanced individually against the harms. In serial MRI-positive men, the added value of repeat SBx is substantial. Based on this cohort, SBx is recommended to be performed in combination with TBx in all MRI-positive men at 1-year of AS, also when there is no radiological progression

Use of gallium-68 prostate-specific membrane antigen positron-emission tomography for detecting lymph node metastases in primary and recurrent prostate cancer and location of recurrence after radical prostatectomy: an overview of the current literature

Objectives: To review the literature to determine the sensitivity and specificity of gallium-68 prostate-specific membrane antigen (68Ga-PSMA) positron-emission tomography (PET) for detecting pelvic lymph node metastases in patients with primary prostate cancer (PCa), and the positive predictive value in patients with biochemical recurrence (BCR) after initial curative treatment, and, in addition, to determine the detection rate and management impact of 68Ga-PSMA PET in patients with BCR after radical prostatectomy (RP). Materials and Methods: We performed a comprehensive literature search. Search terms used in MEDLINE, EMBASE and Science Direct were ‘(PSMA, 68Ga-PSMA, 68Gallium-PSMA, Ga-68-PSMA or prostate-specific membrane antigen)’ and ‘(histology, lymph node, staging, sensitivity, specificity, positive predictive value, recurrence, recurrent or detection)’. Relevant abstracts were reviewed and full-text articles obtained where possible. References to and from obtained articles were searched to identify further relevant articles. Results: Nine retrospective and two prospective studies described the sensitivity and specificity of 68Ga-PSMA PET for detecting pelvic lymph node metastases before initial treatment, which ranged from 33.3% to 100% and 80% to 100%, respectively. In eight retrospective studies, the positive predictive value of 68Ga-P

Improving the prediction of biochemical recurrence after radical prostatectomy with the addition of detailed pathology of the positive surgical margin and cribriform growth

The risk on biochemical recurrence (BCR) after radical prostatectomy (RP) is usually estimated using PSA and pathological stage and grading including the presence of positive surgical margins (PSM). Objective was to investigate whether the presence of cribriform growth in the primary tumor, Grade Group (GG) at the PSM, and length of the PSM have added value in the prognostication. We analyzed data of 835 patients initially treated with RP between 2000 and 2017. Cox regression models were developed to compare the baseline model (PSA, pT-stage, pN-stage, GG at RP, and presence of PSM) with an extended model (adding the presence of cribriform growth, length and GG at the PSM) using the likelihood ratio test. Discrimination was assessed at internal validation by the time-dependent area under the receiver operating characteristic curve (AUC) at 3- and 5-year. A total of 224 men experienced BCR. Median follow-up for men without BCR was 50.4 months (interquartile range, IQR 11.9–95.5). The extended model had a significant better fit, χ2(4) = 31.0, p < 0.001 than the baseline model. The AUC of the 3- and 5-year extended model was 0.85 (95% CI 0.81–0.88) compared to 0.83 (95% CI 0.79–0.87) for the baseline model. Importantly, the presence of cribriform growth in the primary tumor, and GG ≥ 2 at PSM were associated with a higher risk on BCR. In conclusion, the addition of pathological variables improved the prediction of the risk on BCR after RP slightly. However, the clinical implications of this model are important

Use of gallium-68 prostate-specific membrane antigen positron-emission tomography for detecting lymph node metastases in primary and recurrent prostate cancer and location of recurrence after radical prostatectomy: an overview of the current literature

Objectives: To review the literature to determine the sensitivity and specificity of gallium-68 prostate-specific membrane antigen (68Ga-PSMA) positron-emission tomography (PET) for detecting pelvic lymph node metastases in patients with primary prostate cancer (PCa), and the positive predictive value in patients with biochemical recurrence (BCR) after initial curative treatment, and, in addition, to determine the detection rate and management impact of 68Ga-PSMA PET in patients with BCR after radical prostatectomy (RP). Materials and Methods: We performed a comprehensive literature search. Search terms used in MEDLINE, EMBASE and Science Direct were ‘(PSMA, 68Ga-PSMA, 68Gallium-PSMA, Ga-68-PSMA or prostate-specific membrane antigen)’ and ‘(histology, lymph node, staging, sensitivity, specificity, positive predictive value, recurrence, recurrent or detection)’. Relevant abstracts were reviewed and full-text articles obtained where possible. References to and from obtained articles were searched to identify further relevant articles. Results: Nine retrospective and two prospective studies described the sensitivity and specificity of 68Ga-PSMA PET for detecting pelvic lymph node metastases before initial treatment, which ranged from 33.3% to 100% and 80% to 100%, respectively. In eight retrospective studies, the positive predictive value of 68Ga-PSMA PET in patients with BCR before salvage lymph node dissection ranged from 70% to 100%. The detection rate of 68Ga-PSMA PET in patients with BCR after RP in the PSA subgroups <0.2 ng/mL, 0.2–0.49 ng/mL and 0.5 to <1.0 ng/mL ranged from 11.3% to 50.0%, 20.0% to 72.7% and 25.0% to 87.5%, respectively. Conclusion: The review results showed that 68Ga-PSMA PET had a high specificity for the detection of pelvic lymph node metastases in primary PCa. Furthermore, 68Ga-PSMA PET had a very high positive predictive value in detecting lymph node metastases in patients with BCR. By contrast, sensitivity was only moderate; therefore, based on the currently available literature, 68Ga-PSMA PET cannot yet replace pelvic lymph node dissection to exclude lymph node metastases. In the salvage phase, 68Ga-PSMA PET had both a high detection rate and impact on radiotherapy planning in early BCR after RP

External Validation of Two Nomograms Developed for 68Ga-PSMA-11 Applied to the Prostate-specific Membrane Antigen Tracer 18F-DCFPyl: Is Prediction of the Optimal Timing of Salvage Therapy Feasible?

Two nomograms have been developed to predict the outcome of positron emission tomography (PET)/computed tomography (CT) imaging with68Ga-labeled ligands for prostate-specific membrane antigen (68Ga-PSMA) for patients with rising prostate-specific antigen after radical prostatectomy (RP). These nomograms quantify the ability of PSMA PET/CT to detect prostate cancer recurrences, and therefore provide critical information in determining the optimal timing for PSMA PET/CT in guiding salvage therapies. We validated the ability of these nomograms to accurately predict PET/CT outcome using another ligand tracer, 18F-DCFPyL. The external validation cohort consisted of 157 men from the Prostate Cancer Network Netherlands who underwent 18F-DCFPyL PET/CT to guide salvage therapies after RP. The nomogram of Rauscher et al (predicting a positive scan) showed accurate prediction of 50–80% (discrimination 0.68, 95% confidence interval [CI] 0.59–0.76). The nomogram of Luiting et al (predicting recurrence outside the prostatic fossa) showed accurate prediction for predicted probability values between 15% and 65%, with a small degree of overestimation for predicted probability values between 30% and 50% (discrimination 0.74, 95% CI 0.28–1.24). According to calibration curves, discrimination results, and decision curve analysis, we conclude that clinicians can use these 68Ga-PSMA–based nomograms to predict 18F-DCFPyL PET/CT outcome. These nomograms improve shared decision-making in determining the optimal time to initiate PSMA PET/CT–guided salvage therapies. Patient summary: Prediction tools developed for prostate scans (positron emission tomography, PET) using one type of radioactive tracer (chemicals labeled with gallium-68) are also accurate in predicting scan findings with another tracer (a chemical labeled with fluorine-18). Our study confirms that these tools can be used to guide decisions on the timing of treatments for prostate cancer recurrence

False positives in PIRADS (V2) 3, 4, and 5 lesions : relationship with reader experience and zonal location

PURPOSE: To investigate the effect of reader experience and zonal location on the occurrence of false positives (FPs) in PIRADS (V2) 3, 4, and 5 lesions on multiparametric (MP)-MRI of the prostate. MATERIALS AND METHODS: This retrospective study included 139 patients who had consecutively undergone an MP-MRI of the prostate in combination with a transrectal ultrasound MRI fusion-guided biopsy between 2014 and 2017. MRI exams were prospectively read by a group of inexperienced radiologists (cohort 1; 54 patients) and an experienced radiologist (cohort 2; 85 patients). Multivariable logistic regression analysis was performed to determine the association of experience of the radiologist and zonal location with a FP reading. FP rates were compared between readings by inexperienced and experienced radiologists according to zonal location, using Chi-square (χ2) tests. RESULTS: A total of 168 lesions in 139 patients were detected. Median patient age was 68 years (Interquartile range (IQR) 62.5-73), and median PSA was 10.9 ng/mL (IQR 7.6-15.9) for the entire patient cohort. According to multivariable logistic regression, inexperience of the radiologist was significantly (P = 0.044, odds ratio 1.927, 95% confidence interval [CI] 1.017-3.651) and independently associated with a FP reading, while zonal location was not (P = 0.202, odds ratio 1.444, 95% CI 0.820-2.539). In the transition zone (TZ), the FP rate of the inexperienced radiologists 59% (17/29) was significantly higher (χ2P = 0.033) than that of the experienced radiologist 33% (13/40). CONCLUSION: Inexperience of the radiologist is significantly and independently associated with a FP reading, while zonal location is not. Inexperienced radiologists have a significantly higher FP rate in the TZ

Prostate cancer upgrading with serial prostate magnetic resonance imaging and repeat biopsy in men on active surveillance: are confirmatory biopsies still necessary?

Objectives: To investigate whether serial prostate magnetic resonance imaging (MRI) may guide the utility of repeat targeted (TBx) and systematic biopsy (SBx) when monitoring men with low-risk prostate cancer (PCa) at 1-year of active surveillance (AS). Patients and Methods: We retrospectively included 111 consecutive men with low-risk (International Society of Urological Pathology [ISUP] Grade 1) PCa, who received protocolled repeat MRI with or without TBx and repeat SBx at 1-year of AS. TBx was performed in Prostate Imaging-Reporting and Data System (PI-RADS) score ≥3 lesions (MRI-positive men). Upgrading defined as ISUP Grade ≥2 PCa (I), Grade ≥2 with cribriform growth/intraductal carcinoma PCa (II), and Grade ≥3 PCa (III) was investigated. Upgrading detected by TBx only (not by SBx) and SBx only (not by TBx) was investigated in MRI-positive and -negative men, and related to radiological progression on MRI (Prostate Cancer Radiological Estimation of Change in Sequential Evaluation [PRECISE] score). Results: Overall upgrading (I) was 32% (35/111). Upgrading in MRI-positive and -negative men was 48% (30/63) and 10% (5/48) (P < 0.001), respectively. In MRI-positive men, there was upgrading in 23% (seven of 30) by TBx only and in 33% (10/30) by SBx only. Radiological progression (PRECISE score 4–5) in MRI-positive men was seen in 27% (17/63). Upgrading (I) occurred in 41% (seven of 17) of these MRI-positive men, while this was 50% (23/46) in MRI-positive men without radiological progression (PRECISE score 1–3) (P = 0.534). Overall upgrading (II) was 15% (17/111). Upgrading in MRI-positive and -negative men was 22% (14/63) and 6% (three of 48) (P = 0.021), respectively. In MRI-positive men, there was upgrading in three of 14 by TBx only and in seven of 14 by SBx only. Overall upgrading (III) occurred in 5% (five of 111). Upgrading in MRI-positive and -negative men was 6% (four of 63) and 2% (one of 48) (P = 0.283), respectively. In MRI-positive men, there was upgrading in one of four by TBx only and in two of four by SBx only. Conclusion: Upgrading is significantly lower in MRI-negative compared to MRI-positive men with low-risk PCa at 1-year of AS. In serial MRI-negative men, the added value of repeat SBx at 1-year surveillance is limited and should be balanced individually against the harms. In serial MRI-positive men, the added value of repeat SBx is substantial. Based on this cohort, SBx is recommended to be performed in combination with TBx in all MRI-positive men at 1-year of AS, also when there is no radiological progression