Development and External Validation of a Novel Nomogram to Predict the Probability of Pelvic Lymph-node Metastases in Prostate Cancer Patients Using Magnetic Resonance Imaging and Molecular Imaging with Prostate-specific Membrane Antigen Positron Emission Tomography.

BACKGROUND: Preoperative assessment of the probability of pelvic lymph-node metastatic disease (pN1) is required to identify patients with prostate cancer (PCa) who are candidates for extended pelvic lymph-node dissection (ePLND). OBJECTIVE: To develop a novel intuitive prognostic nomogram for predicting pathological lymph-node (pN) status in contemporary patients with primary diagnosed localized PCa, using preoperative clinical and histopathological parameters, magnetic resonance imaging (MRI), and prostate-specific membrane antigen (PSMA) positron emission tomography (PET). DESIGN, SETTING, AND PARTICIPANTS: In total, 700 eligible patients who underwent robot-assisted radical prostatectomy and ePLND were included in the model-building cohort. The external validation cohort consisted of 305 surgically treated patients. Logistic regression with backward elimination was used to select variables for the Amsterdam-Brisbane-Sydney nomogram. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Performance of the final model was evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision-curve analyses. Models were subsequently validated in an external population. RESULTS AND LIMITATIONS: The Amsterdam-Brisbane-Sydney nomogram included initial prostate-specific antigen value, MRI T stage, highest biopsy grade group (GG), biopsy technique, percentage of systematic cores with clinically significant PCa (GG ≥2), and lymph-node status on PSMA-PET. The AUC for predicting pN status was 0.81 (95% confidence interval [CI] 0.78-0.85) for the final model. On external validation, the Amsterdam-Brisbane-Sydney nomogram showed superior discriminative ability to the Briganti-2017 and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms (AUC 0.75 [95% CI 0.69-0.81] vs 0.67 [95% CI 0.61-0.74] and 0.65 [95% CI 0.58-0.72], respectively; p < 0.05), and similar discriminative ability to the Briganti-2019 nomogram (AUC 0.78 [95% CI 0.71-0.86] vs 0.80 [95% CI 0.73-0.86]; p = 0.76). The Amsterdam-Brisbane-Sydney nomogram showed excellent calibration on external validation, with an increased net benefit at a threshold probability of ≥4%. CONCLUSIONS: The validated Amsterdam-Brisbane-Sydney nomogram performs superior to the Briganti-2017 and MSKCC nomograms, and similar to the Briganti-2019 nomogram. Furthermore, it is applicable in all patients with newly diagnosed unfavorable intermediate- and high-risk PCa. PATIENT SUMMARY: We developed and validated the Amsterdam-Brisbane-Sydney nomogram for the prediction of prostate cancer spread to lymph nodes before surgery. This nomogram performs similar or superior to all presently available nomograms.

External Validation and Addition of Prostate-specific Membrane Antigen Positron Emission Tomography to the Most Frequently Used Nomograms for the Prediction of Pelvic Lymph-node Metastases: an International Multicenter Study.

BACKGROUND: Different nomograms exist for the preoperative prediction of pelvic lymph-node metastatic disease in individual patients with prostate cancer (PCa). These nomograms do not incorporate modern imaging techniques such as prostate-specific membrane antigen (PSMA) positron emission tomography (PET). OBJECTIVE: To determine the predictive performance of the Briganti 2017, Memorial Sloan Kettering Cancer Center (MSKCC), and Briganti 2019 nomograms with the addition of PSMA-PET in an international, multicenter, present-day cohort of patients undergoing robot-assisted radical prostatectomy (RARP) and extended pelvic lymph-node dissection (ePLND) for localized PCa. DESIGN, SETTING, AND PARTICIPANTS: All 757 eligible patients who underwent a PSMA-PET prior to RARP and ePLND in three reference centers for PCa surgery between January 2016 and November 2020 were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Performance of the three nomograms was assessed using the receiver operating characteristic curve-derived area under the curve (AUC), calibration plots, and decision curve analyses. Subsequently, recalibration and addition of PSMA-PET to the nomograms were performed. RESULTS AND LIMITATIONS: Overall, 186/757 patients (25%) had pelvic lymph-node metastatic (pN1) disease on histopathological examination. AUCs of the Briganti 2017, MSKCC, and Briganti 2019 nomograms were 0.70 (95% confidence interval [95% CI]: 0.64-0.77), 0.71 (95% CI: 0.65-0.77), and 0.76 (95% CI: 0.71-0.82), respectively. PSMA-PET findings showed a significant association with pN1 disease when added to the nomograms (p < 0.001). Addition of PSMA-PET substantially improved the discriminative ability of the models yielding cross-validated AUCs of 0.76 (95% CI: 0.70-0.82), 0.77 (95% CI: 0.72-0.83), and 0.82 (95% CI: 0.76-0.87), respectively. In decision curve analyses, the addition of PSMA-PET to the three nomograms resulted in increased net benefits. CONCLUSIONS: The addition of PSMA-PET to the previously developed nomograms showed substantially improved predictive performance, which suggests that PSMA-PET is a likely future candidate for a modern predictive nomogram. PATIENT SUMMARY: Different tools have been developed to individualize the prediction of prostate cancer spread to lymph nodes before surgery. We found that the inclusion of modern imaging (prostate-specific membrane antigen positron emission tomography) improved substantially the overall performance of these prediction tools.

A prospective study of psychological distress after prostate cancer surgery.

BACKGROUND: Men treated for prostate cancer experience heightened psychological distress and have an increased risk of suicide. Management of this distress and risk is crucial for quality urological care. OBJECTIVE: To identify risk indicators for poorer trajectories of psychological adjustment and health-related quality of life (QoL) after surgery for localised prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Patients were newly diagnosed with localised prostate cancer scheduled for surgical treatment. Patients were assessed at baseline (pre-surgery) and 6 weeks, 3 months, 6 months, 12 months, and 24 months post-surgery. MEASUREMENTS: Assessment measures included sociodemographics, domain-specific and health-related QoL, and psychological distress. Mixed effects regression models were used to analyse the data. RESULTS AND LIMITATIONS: A total of 233 patients provided data for this analysis (Mage = 60 years, standard deviation [SD] = 4.02; MPSA = 7.37 ng/mL). At baseline, the prevalence of high psychological distress was 28% reducing to 21% at 24 months. Before treatment, younger age, more comorbidities, and worse bowel function were related to greater psychological distress; and younger age and better urinary, sexual, and bowel function were related to better health-related QoL. By contrast, for changes over time, only bowel function was important with better bowel function predicting decreasing psychological distress for men. CONCLUSIONS: Regular distress screening is indicated over the 24 months after surgery for localised prostate cancer. Care pathways for men with prostate cancer need also to respond to age-specific concerns and health problems associated with comorbidities in aging men. Focussed symptom control for bowel bother should be a priority.

Outcomes and learning curve for robotic-assisted radical cystectomy: an Australian experience.

BACKGROUND: This study aimed to describe perioperative, oncological and learning curve outcomes for robotic-assisted radical cystectomy (RARC) across the first 100 cases performed by an Australian high-volume, fellowship-trained robotic surgeon. METHODS: A retrospective cohort study was performed on a consecutive group of 100 patients who underwent RARC between 2010 and 2016 in Brisbane, Australia. Perioperative, oncological and survival data were collected. Demographic, survival and learning curve analyses were performed in MedCalc. RESULTS: A total of 100 patients underwent RARC over the study period. Median operative time was 389 min, with a reduction in median times from 420 to 330 min when comparing the first 50 versus the second 50 patients (P < 0.001). Median estimated blood loss was 500 mL, while urinary diversion was performed extracorporeally in 20 patients, intracorporeally in 69 patients and using a hybrid technique in 11 patients. Median length of hospital stay was 11 days. Post-operative complications occurred in 56% of patients (Clavien-Dindo classification I-II 32%, III-V 24%). Positive operative margins were 2% and median lymph node yield was 21 nodes. Overall recurrence-free survival was 50.3 months. CONCLUSION: Initial short-term experience with RARC shows favourable outcomes with regard to operative, perioperative and pathological indicators compared to open radical cystectomy and other RARC series.

Outcomes following radical cystectomy: a population-based study from Queensland, Australia.

BACKGROUND: Radical cystectomy (RC) is a complex uro-oncology surgical procedure with high surgical morbidity. We report on outcomes following RC for bladder cancer using a population-based cohort of patients. METHODS: Patients receiving an RC from 2002 to 2016 were included and linked to their cancer-related surgical procedures. Hospitals were categorized as high (>7 RCs/year) and low (≤7 RCs/year). Outcomes included 30- and 90-day mortalities and 2-year overall survival (OS). Multivariable logistic regression models were used to examine factors associated with the outcomes of interest. OS was estimated using the Kaplan-Meier survival function. RESULTS: During the 15-year study period, 1230 patients underwent an RC for invasive bladder cancer. In-hospital mortality was 1.1%, and 30- and 90-day mortality was 1.4% and 2.9%, respectively. Both 30- and 90-day mortalities were significantly higher for older versus younger patients (P = 0.01 and P < 0.001, respectively), and lymph node involvement was significantly associated with 90-day mortality (P = 0.002). Patients treated more recently were about 80% less likely to die within 90 days. The 2-year OS was 71.5%, with significant improvements observed over time (P < 0.001). While we found no evidence of a hospital-volume relationship for post-operative mortality or survival, patients treated in low-volume compared to high-volume hospitals were more likely to have surgical margin involvement (10.9% versus 7.1%, respectively, P = 0.03). CONCLUSION: We observed low post-operative mortality rates overall, with rates decreasing significantly over time. Some subgroups of patients experience poorer post-operative outcomes. Reporting on post-operative outcomes, and survival over time helps monitor clinical progress and identify areas for improvement.

Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: 24-month outcomes from a randomised controlled study.

BACKGROUND: Previous trials have found similar early outcomes after robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy. We report functional and oncological postoperative outcomes up to 24 months after surgery for these two surgical techniques. METHODS: In this randomised controlled phase 3 study, men who had newly diagnosed clinically localised prostate cancer and who had chosen surgery as their treatment approach, and were aged between 35 years and 70 years were eligible and recruited from the Royal Brisbane and Women's Hospital (Brisbane, QLD, Australia). Participants were randomly assigned (1:1) to have either robot-assisted laparoscopic prostatectomy or open radical retropubic prostatectomy. Randomisation was computer generated and occurred in blocks of ten. This was an open trial; however, study investigators involved in data analysis were masked to each patient's surgical treatment. Primary outcomes were urinary function (urinary domain of Expanded Prostate Cancer Index Composite [EPIC]) and sexual function (sexual domain of EPIC and International Index of Erectile Function Questionnaire [IIEF]) at 6 months, 12 months, and 24 months and oncological outcome (biochemical recurrence and imaging evidence of progression). The trial was powered to assess health-related and domain-specific quality-of-life outcomes over 24 months. All analyses were done on a per-protocol basis. The trial was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000661976. FINDINGS: Between Aug 23, 2010, and Nov 25, 2014, 326 men were enrolled, of whom 163 were randomly assigned to robot-assisted laparoscopic prostatectomy and 163 to open radical retropubic prostatectomy. 18 withdrew (12 assigned to radical retropubic prostatectomy and six assigned to robot-assisted laparoscopic prostatectomy); thus, 151 in the radical retropubic prostatectomy group and 157 in the robot-assisted laparoscopic prostatectomy group proceeded to surgery. At the 24-month follow-up time point, 150 men remained in the robot-assisted laparoscopic prostatectomy group and 146 remained in the open radical retropubic prostatectomy group. Urinary function scores did not differ significantly between robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy at 6 months post-surgery (88·68 [95% CI 86·79-90·58] vs 88·45 [86·54-90·36]; p1<0·0001, p2<0·0001), 12 months post-surgery (90·76 [88·89-92·62] vs 91·53 [90·07-92·98]; p1<0·0001, p2<0·0001), or 24 months post-surgery (91·33 [89·64-93·03] vs 90·86 [89·01-92·70]; p1<0·0001, p2<0·0001). Sexual function scores were not significantly different between robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy at 6 months post-surgery (EPIC: 37·40 [33·60-41·19] vs 38·63 [34·76-42·49], p1=0·0001, p2<0·0001; IIEF: 29·75 [26·66-32·84] vs 29·78 [26·41-33·16], p1<0·0001, p2<0·0001), 12 months post-surgery (EPIC: 42·28 [38·05-46·51] vs 42·51 [38·29-46·72], p1<0·0001, p2<0·0001; IIEF: 33·10 [29·59-36·61] vs 33·50 [29·87-37·13], p1=0·0002, p2<0·0001), or 24 months post-surgery (EPIC: 45·70 [41·17-50·23] vs 46·90 [42·20-51·60], p1=0·0003, p2<0·0001; IIEF: 33·95 [30·11-37·78] vs 33·89 [29·82-37·96], p1=0·0003, p2=0·0004). Equivalence testing on the difference between the proportion of biochemical recurrences between the two groups (13 [9%] in the open radical retropubic prostatectomy group vs four [3%] in the robot-assisted laparoscopic prostatectomy group) showed that equality between the two techniques could not be established based on a 90% CI with a prespecified margin of 10%. However, a superiority test showed that the two proportions were significantly different (p=0·0199). Equivalence testing on the proportion of patients who had imaging evidence of progression revealed that the two groups were not significantly different (p=0·2956). INTERPRETATION: Robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy yielded similar functional outcomes at 24 months. We advise caution in interpreting the oncological outcomes of our study because of the absence of standardisation in postoperative management between the two trial groups and the use of additional cancer treatments. Clinicians and patients should view the benefits of a robotic approach as being largely related to its minimally invasive nature. FUNDING: Cancer Council Queensland.

Design and Clinical Verification of Surface-Enhanced Raman Spectroscopy Diagnostic Technology for Individual Cancer Risk Prediction.

The use of emerging nanotechnologies, such as plasmonic nanoparticles in diagnostic applications, potentially offers opportunities to revolutionize disease management and patient healthcare. Despite worldwide research efforts in this area, there is still a dearth of nanodiagnostics which have been successfully translated for real-world patient usage due to the predominant sole focus on assay analytical performance and lack of detailed investigations into clinical performance in human samples. In a bid to address this pressing need, we herein describe a comprehensive clinical verification of a prospective label-free surface-enhanced Raman scattering (SERS) nanodiagnostic assay for prostate cancer (PCa) risk stratification. This contribution depicts a roadmap of (1) designing a SERS assay for robust and accurate detection of clinically validated PCa RNA targets; (2) employing a relevant and proven PCa clinical biomarker model to test our nanodiagnostic assay; and (3) investigating the clinical performance on independent training ( n = 80) and validation ( n = 40) cohorts of PCa human patient samples. By relating the detection outcomes to gold-standard patient biopsy findings, we established a PCa risk scoring system which exhibited a clinical sensitivity and specificity of 0.87 and 0.90, respectively [area-under-curve of 0.84 (95% confidence interval: 0.81-0.87) for differentiating high- and low-risk PCa] in the validation cohort. We envision that our SERS nanodiagnostic design and clinical verification approach may aid in the individualized prediction of PCa presence and risk stratification and may overall serve as an archetypical strategy to encourage comprehensive clinical evaluation of nanodiagnostic innovations.

Can atorvastatin with metformin change the natural history of prostate cancer as characterized by molecular, metabolomic, imaging and pathological variables? A randomized controlled trial protocol.

BACKGROUND: Atorvastatin and metformin are known energy restricting mimetic agents that act synergistically to produce molecular and metabolic changes in advanced prostate cancer (PCa). This trial seeks to determine whether these drugs favourably alter selected parameters in men with clinically-localized, aggressive PCa. METHODS/DESIGN: This prospective phase II randomized, controlled window trial is recruiting men with clinically significant PCa, confirmed by biopsy following multiparametric MRI and intending to undergo radical prostatectomy. Ethical approval was granted by the Royal Brisbane and Women's Hospital Human and The University of Queensland Medical Research Ethics Committees. Participants are being randomized into four groups: metformin with placebo; atorvastatin with placebo; metformin with atorvastatin; or placebo alone. Capsules are consumed for 8weeks, a duration selected as the most appropriate period in which histological and biochemical changes may be observed while allowing prompt treatment with curative intent of clinically significant PCa. At recruitment and prior to RP, participants provide blood, urine and seminal fluid. A subset of participants will undergo 7Tesla magnetic resonance spectroscopy to compare metabolites in-vivo with those in seminal fluid and biopsied tissue. The primary end point is biochemical evolution, defined using biomarkers (serum prostate specific antigen; PCA3 and citrate in seminal fluid and prostatic tissue). Standard pathological assessment will be undertaken. DISCUSSION: This study is designed to assess the potential synergistic action of metformin and atorvastatin on PCa tumour biology. The results may determine simple methods of tumour modulation to reduce disease progression.

Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study.

BACKGROUND: The absence of trial data comparing robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy is a crucial knowledge gap in uro-oncology. We aimed to compare these two approaches in terms of functional and oncological outcomes and report the early postoperative outcomes at 12 weeks. METHOD: In this randomised controlled phase 3 study, men who had newly diagnosed clinically localised prostate cancer and who had chosen surgery as their treatment approach, were able to read and speak English, had no previous history of head injury, dementia, or psychiatric illness or no other concurrent cancer, had an estimated life expectancy of 10 years or more, and were aged between 35 years and 70 years were eligible and recruited from the Royal Brisbane and Women's Hospital (Brisbane, QLD). Participants were randomly assigned (1:1) to receive either robot-assisted laparoscopic prostatectomy or radical retropubic prostatectomy. Randomisation was computer generated and occurred in blocks of ten. This was an open trial; however, study investigators involved in data analysis were masked to each patient's condition. Further, a masked central pathologist reviewed the biopsy and radical prostatectomy specimens. Primary outcomes were urinary function (urinary domain of EPIC) and sexual function (sexual domain of EPIC and IIEF) at 6 weeks, 12 weeks, and 24 months and oncological outcome (positive surgical margin status and biochemical and imaging evidence of progression at 24 months). The trial was powered to assess health-related and domain-specific quality of life outcomes over 24 months. We report here the early outcomes at 6 weeks and 12 weeks. The per-protocol populations were included in the primary and safety analyses. This trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12611000661976. FINDINGS: Between Aug 23, 2010, and Nov 25, 2014, 326 men were enrolled, of whom 163 were randomly assigned to radical retropubic prostatectomy and 163 to robot-assisted laparoscopic prostatectomy. 18 withdrew (12 assigned to radical retropubic prostatectomy and six assigned to robot-assisted laparoscopic prostatectomy); thus, 151 in the radical retropubic prostatectomy group proceeded to surgery and 157 in the robot-assisted laparoscopic prostatectomy group. 121 assigned to radical retropubic prostatectomy completed the 12 week questionnaire versus 131 assigned to robot-assisted laparoscopic prostatectomy. Urinary function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (74·50 vs 71·10; p=0·09) or 12 weeks post-surgery (83·80 vs 82·50; p=0·48). Sexual function scores did not differ significantly between the radical retropubic prostatectomy group and robot-assisted laparoscopic prostatectomy group at 6 weeks post-surgery (30·70 vs 32·70; p=0·45) or 12 weeks post-surgery (35·00 vs 38·90; p=0·18). Equivalence testing on the difference between the proportion of positive surgical margins between the two groups (15 [10%] in the radical retropubic prostatectomy group vs 23 [15%] in the robot-assisted laparoscopic prostatectomy group) showed that equality between the two techniques could not be established based on a 90% CI with a Δ of 10%. However, a superiority test showed that the two proportions were not significantly different (p=0·21). 14 patients (9%) in the radical retropubic prostatectomy group versus six (4%) in the robot-assisted laparoscopic prostatectomy group had postoperative complications (p=0·052). 12 (8%) men receiving radical retropubic prostatectomy and three (2%) men receiving robot-assisted laparoscopic prostatectomy experienced intraoperative adverse events. INTERPRETATION: These two techniques yield similar functional outcomes at 12 weeks. Longer term follow-up is needed. In the interim, we encourage patients to choose an experienced surgeon they trust and with whom they have rapport, rather than a specific surgical approach. FUNDING: Cancer Council Queensland.

A progress report on a prospective randomised trial of open and robotic prostatectomy.

A randomised trial of robotic and open prostatectomy commenced in October 2010 and is progressing well. Clinical and quality of life outcomes together with economic costs to individuals and the health service are being examined critically to compare outcomes.

Preliminary analysis of the feasibility and safety of salvage robot-assisted radical prostatectomy after radiation failure: multi-institutional perioperative and short-term functional outcomes.

BACKGROUND AND PURPOSE: Open radical prostatectomy after radiation treatment failure for prostate cancer is associated with significant morbidity. The purpose of the study is to report multi-institutional experiences while performing salvage robot-assisted radical prostatectomy (sRARP). PATIENTS AND METHODS: We retrospectively identified 15 patients with biopsy-proven prostate cancer after definitive radiotherapy who underwent sRARP in three academic institutions over a 20-month period. Continence was defined as the use of 0 pads after surgery. Potency was defined as the ability to achieve erections adequate enough for penetration with or without the use of phosphodiesterase-5 inhibitors. Biochemical recurrence after sRARP was defined as a prostate-specific antigen value of >0.2 ng/mL. RESULTS: Radiation treatment consisted of external-beam radiation therapy (XRT) in five cases, interstitial radioactive 125-iodine brachytherapy (BT) in five cases, proton beam therapy in two cases, and XRT followed by interstitial radioactive 125-iodine BT in three cases. The median operative time, the median estimated blood loss, and the median length of hospital stay were 140.5 min (interquartile range [IQR] 97.5-157 min), 75 mL (IQR 50-100 mL), and 1 day (IQR 1-2 d), respectively. There were no rectal injuries. Two (13.3%) patients had a positive surgical margin. A total of three (20%) patients had postoperative complications. One patient had a deep vein thrombosis (Clavien grade II), one had wound infection (Clavien grade II), and one patient had an anastomotic leak (Clavien gradeId). An anastomotic stricture (Clavien grade IIIa) later developed in this same patient, which was managed by direct visual internal urethrotomy. Of the patients, 71.4% were continent. At a median follow-up of 4.6 months (IQR 3-9.75 mos), four (28.6%) patients presented with biochemical recurrence after sRARP. CONCLUSIONS: The challenge during sRALP is the presence of extensive fibrosis and loss of dissection planes secondary to radiation therapy. It is a technically challenging but feasible procedure. The early complication rates were low, and early continence rates are encouraging.

Launching a successful robotic surgery program.

Robotic-assisted laparoscopic prostatectomy is rapidly becoming the most commonly performed surgical approach to treat clinically localized prostate cancer. The establishment of a robotic surgery program at any institution requires a structured plan and certain key elements to be in place to allow successful development. At least five essential phases are necessary for successful implementation of a robotics program. A thorough initial design and implementation lead to the execution of clinical services that meet previously established goals. Once the execution phase is established, the next step is to focus on maintenance and growth to maximize the benefits of the program. In this paper, we discuss the necessary phases for creating a successful robotic program, paying special attention to the aspects that allowed our facility to create a profitable robotic-assisted laparoscopic prostatectomy program in year 1.