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Journal of Robotic Surgery Feb 2023To assess the cost-effectiveness of the robotic-assisted laparoscopic radical prostatectomy (RALRP) compared to open radical prostatectomy (ORP) for localized prostate...
To assess the cost-effectiveness of the robotic-assisted laparoscopic radical prostatectomy (RALRP) compared to open radical prostatectomy (ORP) for localized prostate cancer from a healthcare perspective in Colombia. A systematic review was conducted in Embase, Scopus, Web of Science, PubMed, and Cochrane CENTRAL databases, to identify relevant publications up to January 2020 to summarize clinical outcomes related to effectiveness of robot-assisted and open radical prostatectomy. A tree decision model was designed given the clinical outcomes and possibilities of complication and success. Outcomes were defined as complications according to Clavien - Dindo classification and success measured as urethral stricture rate. Cost was divided into two categories: surgical procedure and complications. Incremental cost-effectiveness ratio (ICER) was calculated and a deterministic sensitivity analysis was performed to evaluate the impact of the uncertainty on the conclusions of the model. A 90-day horizon was defined. Direct medical costs associated with RALRP were $6.511 ($ 5.127- $8.138), and for ORP were $4.476 ($2.170-$ 6.511). The average cost for complication management was rated at $ 327 for RALRP and $ 382 for ORP, based on an augmented risk of post-operative urethral stricture in the ORP group (2.4% vs 10.8%). ICER was calculated in USD $18.987. The cost of RALRP has to be reduced to around USD 5.345 to achieve an ICER under 1 GDP making the intervention feasible. Using a 3 GDP per capita threshold, the implementation of RALRP could be cost-effective for the treatment of localized prostate cancer in emerging economies. Bolder measures including the use of one needle carrier, three robotic arms, and a shorten hospitalization program of 24 h, can save around $1000 for each patient, achieving the goal cost of $5345 needed for a favorable ICER.
Topics: Male; Humans; Robotic Surgical Procedures; Cost-Effectiveness Analysis; Urethral Stricture; Prostatectomy; Prostatic Neoplasms; Laparoscopy; Treatment Outcome
PubMed: 35668314
DOI: 10.1007/s11701-022-01431-8 -
Journal of Robotic Surgery Feb 2023To establish the feasibility of robotic surgical procedures in urology in terms of the applications, merits, and demerits as well as the postoperative and oncological... (Review)
Review
To establish the feasibility of robotic surgical procedures in urology in terms of the applications, merits, and demerits as well as the postoperative and oncological outcomes while comparing it with the conventional approaches. A systematic search of electronic databases was performed to identify Randomized Controlled Trials and Cohort studies on Robot-Assisted urological surgical procedures in comparison with the conventional methods. The quality assessment of included studies was performed using the Newcastle-Ottawa Scale and the revised Cochrane "Risk of Bias" tool. A qualitative narrative synthesis of the data extracted from the studies was performed and presented in tabulated form. After screening, 39 studies were included in our review (7 Randomized Controlled Trials and 32 Cohort studies). Robot-Assisted Prostatectomy appears to be associated with lower estimated blood loss and shorter length of hospital stay. For Robot-Assisted Cystectomy, the results suggest longer operative time and fewer complications. Robot-Assisted Radical Nephrectomy was found to be associated with fewer perioperative complications and longer mean operative time while Robot-Assisted Partial Nephrectomy was associated with less positive surgical margins and reduced need for postoperative analgesia. The mean operative time was longer while the length of stay was shorter for the robotic approach in inguinal lymphadenectomy and ureteral reimplantation. The feasibility of Robot-Assisted surgery varied for different outcome measures as well as for different procedures. Some common advantages were a shorter length of stay, lesser blood loss, and fewer complications while the drawbacks included longer operative time.Study protocol PROSPERO database (Registration Number: CRD42021256623).
Topics: Male; Humans; Robotic Surgical Procedures; Urology; Postoperative Complications; Treatment Outcome; Laparoscopy
PubMed: 35526260
DOI: 10.1007/s11701-022-01416-7 -
International Braz J Urol : Official... 2022This study aimed to explore the prevalence and clinical risk factors in patients diagnosed with incidental prostate cancer (IPC) during certain surgeries (transurethral... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This study aimed to explore the prevalence and clinical risk factors in patients diagnosed with incidental prostate cancer (IPC) during certain surgeries (transurethral resection of the prostate [TURP], open prostatectomy [OP], and holmium laser enucleation of the prostate [HoLEP]) after clinically suspected benign prostatic hyperplasia (BPH).
MATERIALS AND METHODS
Literature search of the MEDILINE, Web of Science, Embase, and Cochrane Library databases was performed to identify eligible studies published before June 2021. Multivariate adjusted odds ratios (ORs) and associated 95% confidence intervals (CIs) of the prevalence and clinical risk factors of IPC were calculated using random or fixed-effect models.
RESULTS
Twenty-three studies were included in the meta-analysis. Amongst the 94.783 patients, IPC was detected in 24.715 (26.1%). Results showed that the chance of IPC detection (10%, 95% CI: 0.07-4.00; P<0.001; I2=97%) in patients treated with TURP is similar to that of patients treated with HoLEP (9%, 95% CI: 0.07-0.11; P<0.001; I2=81.4%). However, the pooled prevalence estimate of patients treated with OP was 11% (95% CI: -0.03-0.25; P=0.113; I2=99.1%) with no statistical significance. We observed increased incidence of IPC diagnosis after BPH surgery amongst patients with higher prostate-specific antigen (PSA) level (OR: 1.13, 95% CI: 1.04-1.23; P=0.004; I2=89%), whereas no effect of age (OR: 1.02, 95% CI: 0.97-1.06; P=0.48; I2=78.8%) and prostate volume (OR: 0.99, 95% CI: 0.96-1.03; P=0.686; I2=80.5%) were observed.
CONCLUSIONS
The prevalence of IPC was similar amongst patients undergoing TURP, HoLEP, and OP for presumed BPH. Interestingly, increased PSA level was the only independent predictor of increasing risk of IPC after BPH surgery rather than age and prostate volume. Hence, future research should focus on predictors which accurately foretell the progression of prostate cancer to determine the optimal treatment for managing patients with IPC after BPH surgery.
Topics: Humans; Laser Therapy; Lasers, Solid-State; Male; Prevalence; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms; Risk Factors; Transurethral Resection of Prostate; Treatment Outcome
PubMed: 35195386
DOI: 10.1590/S1677-5538.IBJU.2021.0653 -
American Journal of Men's Health 2021The objective of this study was to compare the efficacy and safety of 10 different surgical treatments for benign prostatic hyperplasia (BPH) with volume >60 mL. A... (Meta-Analysis)
Meta-Analysis
Comparison on the Efficacy and Safety of Different Surgical Treatments for Benign Prostatic Hyperplasia With Volume >60 mL: A Systematic Review and Bayesian Network Meta-Analysis of Randomized Controlled Trials.
The objective of this study was to compare the efficacy and safety of 10 different surgical treatments for benign prostatic hyperplasia (BPH) with volume >60 mL. A systematic literature review and network meta-analysis of randomized controlled trials (RCTs) within a Bayesian framework was performed. A total of 52 parallel-group RCTs included, reporting on 6,947 participants, comparing open prostatectomy (OP), monopolar/bipolar transurethral resection of prostate (monopolar/ bipolar TURP), thulium, holmium and diode laser enucleation of prostate (LEP), bipolar enucleation of prostate, potassium titanyl phosphate laser vaporization of prostate (KTP LVP), bipolar vaporization of prostate (bipolar VP), and laparoscopic simple prostatectomy (laparoscope SP). Compared with OP, laparoscope SP identified better maximal flow rate (Qmax; mean differences [MDs] = 2.89 mL/s) at the 24th month, but bipolar VP demonstrated worse Qmax (MD = -3.20 mL/s) and International Prostate Symptom Score (IPSS; MD = 2.60) at the 12th month. Holmium LEP (MD = 1.37) demonstrated better International Index of Erectile Function-5 at the 12th month compared with OP. However, compared with OP, KTP LVP demonstrated worse postvoid residual volume (PVR) at the sixth (MD = 10.42 mL) and 12th month (MD = 5.89 mL) and monopolar TURP (MD = 6.9 mL) demonstrated worse PVR at the 12th month. Eight new surgical methods for BPH with volume >60 mL appeared to be superior in safety compared with OP and monopolar TURP due to fewer complications. Bipolar VP and KTP LVP maybe not suitable for prostates more than 60 mL due to short- and middle-term worse Qmax, IPSS, and PVR than OP.
Topics: Humans; Male; Network Meta-Analysis; Prostatic Hyperplasia; Quality of Life; Randomized Controlled Trials as Topic; Transurethral Resection of Prostate; Treatment Outcome
PubMed: 34939514
DOI: 10.1177/15579883211067086 -
Investigative and Clinical Urology Nov 2021To review safety and efficacy of robotic-assisted simple prostatectomy (RASP) compared to open simple prostatectomy (OP). (Meta-Analysis)
Meta-Analysis
PURPOSE
To review safety and efficacy of robotic-assisted simple prostatectomy (RASP) compared to open simple prostatectomy (OP).
MATERIALS AND METHODS
A comprehensive literature search was performed to assess the differences in perioperative course and functional outcomes in patients with benign prostatic hyperplasia and surgical indication. The incidences of complications were pooled using the Cochran-Mantel-Haenszel Method and expressed as odds ratio (OR), 95% confidence interval (CI), and p-values. Perioperative course and functional outcomes were pooled using the inverse variance of the mean difference (MD), 95% CI, and p-values. Analyses were two-tailed and the significance was set at p<0.05.
RESULTS
Eight studies were accepted. Meta-analysis showed significantly longer surgical time (MD, 43.72; 95% CI, 30.57-56.88; p<0.00001) with a significantly lower estimated blood loss (MD, -563.20; 95% CI, -739.95 to -386.46; p<0.00001) and shorter postoperative stay (MD, -2.85; 95% CI, -3.72 to -1.99; p<0.00001) in RASP. Catheterization time did not differ (MD, 0.65; 95% CI, -2.17 to 3.48; p=0.65). The risk of blood transfusion was significantly higher in OP (OR, 0.23; 95% CI, 0.17-0.33; p<0.00001). The risk of recatheterization (OR, 1.96; 95% CI, 0.32-11.93; p=0.47), postoperative urinary infections (OR, 0.89; 95% CI, 0.23-3.51; p=0.87) and 30-day readmission rate (OR, 0.96; 95% CI, 0.61-1.51; p=0.86) did not differ. At 3-month follow-up, functional outcomes were similar.
CONCLUSIONS
RASP demonstrated a better perioperative outcome and equal early functional outcomes as compared to OP. These findings should be balanced against the longer operative time and higher cost of robotic surgery.
Topics: Comparative Effectiveness Research; Cost-Benefit Analysis; Humans; Male; Operative Time; Postoperative Complications; Prostatectomy; Prostatic Hyperplasia; Recovery of Function; Robotic Surgical Procedures
PubMed: 34729963
DOI: 10.4111/icu.20210297 -
Frontiers in Surgery 2021To compare the efficacy and safety of robotic-assisted simple prostatectomy and open simple prostatectomy for large benign prostatic hyperplasia. We systematically...
To compare the efficacy and safety of robotic-assisted simple prostatectomy and open simple prostatectomy for large benign prostatic hyperplasia. We systematically searched the Cochrane Library, PubMed, Embase, and Science databases for studies published through December 2020. Controlled trials on RASP and OSP for large prostates were included. The meta-analysis was conducted with the Review Manager 5.4 software. A total of seven studies with 3,777 patients were included in the analysis. There were no significant differences in IPSS (WMD, 0.72; 95%CI: -0.31, 1.76; = 0.17), QoL (WMD, 0.00; 95%CI: -0.39, 0.39; > 0.99), Qmax (WMD, 1.88; 95% CI: -1.15, 4.91; = 0.22), or PVR (WMD, -10.48; 95%CI: -25.13, 4.17; = 0.16) among patients undergoing RASP and OSP. However, compared with patients who underwent OSP, patients who underwent RASP had a shorter LOS (WMD, -2.83; 95%CI: -3.68, -1.98; < 0.001), less EBL (WMD, -304.68; 95% CI: -432.91, -176.44; < 0.001), a shorter CT (WMD, -2.61; 95%CI: -3.94, -1.29; < 0.001), and fewer overall complications (OR, 0.30; 95% CI: 0.16, 0.57; < 0.001). Nevertheless, RASP was associated with a longer OT (WMD, 59.69, 95% CI: 49.40, 69.98; < 0.001). The results of the current study demonstrated that RASP provided similar efficacy to those of OSP in the treatment of large prostate, while maintaining better security. Our findings indicate that RASP is a feasible and effective alternative to OSP.
PubMed: 34355017
DOI: 10.3389/fsurg.2021.695318 -
Minerva Urology and Nephrology Dec 2021Robotic technologies are being increasingly implemented in healthcare, including urology, and holding promises for improving medicine worldwide. However, these new...
INTRODUCTION
Robotic technologies are being increasingly implemented in healthcare, including urology, and holding promises for improving medicine worldwide. However, these new approaches raise ethical concerns for professionals, patients, researchers and institutions that need to be addressed. The aim of this review was to investigate the existing literature related to bioethical issues associated with robotic surgery in urology, in order to identify current challenges and make preliminary suggestions to ensure an ethical implementation of these technologies.
EVIDENCE ACQUISITION
We performed a review of the pertaining literature through a systematic search of two databases (PubMed and Web of Science) in August 2020.
EVIDENCE SYNTHESIS
Our search yielded 76 articles for full-text evaluation and 48 articles were included in the narrative review. Several bioethical issues were identified and can be categorized into five main subjects: 1) robotic surgery accessibility (robotic surgery is expensive, and in some health systems may lead to inequality in healthcare access. In more affluent countries the national distribution of several robotic platforms may influence the centralization of robotic surgery, therefore potentially affecting oncological and functional outcomes in low-volume centers); 2) safety (there is a considerable gap between surgical skills and patients' perception of competence, leading to ethical consequences on modern healthcare. Published incidence of adverse events during robotic surgery in large series is between 2% and 15%, which does not significantly differ amongst open or laparoscopic approaches); 3) gender gap (no data about gap differences in accessibility to robotic platforms were retrieved from our search); 4) costs (robotic platforms are expensive but a key reason why hospitals are willing to absorb the high upfront costs is patient demand. It is possible to achieve cost-equivalence between open and robotic prostatectomy if the volume of centers is higher than 10 cases per week); and 5) learning curve (a validated, structured curriculum and accreditation has been created for robotic surgery. This allows acquisition and development of basic and complex robotic skills focusing on patient safety and short learning curve).
CONCLUSIONS
Tech-medicine is rapidly moving forward. Robotic approach to urology seems to be accessible in more affluent countries, safe, economically sustainable, and easy to learn with an appropriate learning curve for both sexes. It is mandatory to keep maintaining a critical rational approach with constant control of the available evidence regarding efficacy, efficiency and safety.
Topics: Female; Humans; Learning Curve; Male; Prostatectomy; Robotic Surgical Procedures; Robotics; Urology
PubMed: 34308607
DOI: 10.23736/S2724-6051.21.04240-3 -
Anaesthesia, Critical Care & Pain... Aug 2021The aim of this review was to update the recommendations for optimal pain management after open and laparoscopic or robotic prostatectomy. Optimal pain management is... (Review)
Review
The aim of this review was to update the recommendations for optimal pain management after open and laparoscopic or robotic prostatectomy. Optimal pain management is known to influence postoperative recovery, but patients undergoing open radical prostatectomy typically experience moderate dynamic pain in the immediate postoperative day. Robot-assisted and laparoscopic surgery may be associated with decreased pain levels as opposed to open surgery. We performed a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) with PROcedure SPECific Postoperative Pain ManagemenT (PROSPECT) methodology. Randomised controlled trials (RCTs) published in English language, from January 2015 until March 2020, assessing postoperative pain, using analgesic, anaesthetic and surgical interventions, were identified from MEDLINE, EMBASE and Cochrane Databases. Of the 1797 studies identified, 35 RCTs and 3 meta-analyses met our inclusion criteria. NSAIDs and COX-2 selective inhibitors proved to lower postoperative pain scores. Continuous intravenous lidocaine reduced postoperative pain scores during open surgery. Local wound infiltration showed positive results in open surgery. Bilateral transversus abdominis plane (TAP) block was performed at the end of surgery and lowered pain scores in robot-assisted procedures, but results were conflicting for open procedures. Basic analgesia for prostatic surgery should include paracetamol and NSAIDs or COX-2 selective inhibitors. TAP block should be recommended as the first-choice regional analgesic technique for laparoscopic/robotic radical prostatectomy. Intravenous lidocaine should be considered for open surgeries.
Topics: Abdominal Muscles; Humans; Male; Neoplasms; Nerve Block; Pain Management; Pain, Postoperative; Practice Guidelines as Topic; Prostatectomy
PubMed: 34197976
DOI: 10.1016/j.accpm.2021.100922 -
Ontario Health Technology Assessment... 2021Benign prostatic hyperplasia (BPH) is a noncancerous enlargement of the prostate that commonly affects older people with prostates and may lead to obstructive urinary...
BACKGROUND
Benign prostatic hyperplasia (BPH) is a noncancerous enlargement of the prostate that commonly affects older people with prostates and may lead to obstructive urinary symptoms. Symptoms may initially be mild but tend to worsen over time. Prostatic artery embolization (PAE) is an endovascular procedure to treat BPH, wherein an interventional radiologist inserts a catheter into the patient to inject tiny particles intended to reduce blood flow to the enlarged prostate, causing it to shrink in size. We conducted a health technology assessment on PAE for people with BPH, which included an evaluation of effectiveness, safety, cost-effectiveness, the budget impact of publicly funding PAE, and patient preferences and values.
METHODS
We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Risk of Bias in Nonrandomized Studies-of Interventions (ROBINS-I) tool for observational studies. We assessed the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic review of the economic literature. We then assessed the cost-effectiveness of PAE compared with alternative treatments (i.e., transurethral resection of the prostate [TURP] or open simple prostatectomy [OSP]) using a Markov microsimulation model. The analysis was conducted from the Ontario Ministry of Health perspective over a time horizon of 6.5 years. We also analyzed the budget impact of publicly funding PAE in people with moderate to severe BPH in Ontario.
RESULTS
We included six studies in our systematic review. Four RCTs and one observational study compared PAE with TURP, and one observational study compared PAE with OSP. All studies had considerable risk-of-bias concerns. PAE may improve BPH symptoms and urodynamic measures, but we are uncertain whether PAE achieves better results than TURP (GRADE: Very low to Low). Compared with TURP, PAE may result in higher patient satisfaction and fewer adverse events (GRADE: Not assessed). Compared with OSP, PAE may result in smaller improvements in BPH symptoms and urodynamic measures and may lead to fewer adverse events, but the evidence is very uncertain (GRADE: Very low).We did not find any published cost-effectiveness studies in the economic literature review. Our primary economic evaluation showed that, compared with TURP, PAE has an incremental cost of $328 (95% CrI: -$686 to $1,423) and a very small incremental quality-adjusted life-year (QALY) of 0.007 (95% CrI: -0.004 to 0.018). The resulting incremental cost-effectiveness ratio (ICER) of PAE versus TURP is $44,930 per QALY gained. At the commonly used willingness-to-pay values of $50,000 and $100,000 per QALY, the cost-effectiveness of PAE is uncertain (52% and 68% probability, respectively, of being cost-effective compared with TURP). In a scenario analysis, we compared PAE with OSP for individuals with large prostates (who may be ineligible for TURP). We found that PAE is less costly (-$1,231; 95% CrI: -$2,457 to $69) and less effective (-0.12 QALYs; 95% CrI: -0.18 to -0.04). The resulting ICER of PAE versus OSP is $10,241 saved per QALY lost. At the commonly used willingness-to-pay value of $50,000 per QALY, PAE is unlikely to be cost-effective (2% probability of being cost-effective compared with OSP). Assuming a low uptake (i.e., an additional 10 to 50 procedures per year in years 1 to 5), we estimated that publicly funding PAE in Ontario would lead to an additional cost of about $11,400 over the next 5 years.People we spoke with who have lived experience with BPH reported on the negative impact it can have on their quality of life. Those who had received PAE reported a positive experience with the procedure and meaningful improvement in their symptoms.
CONCLUSIONS
Prostatic artery embolization may improve BPH symptoms and urodynamic measures, but we are uncertain if the procedure results in similar outcomes to those of TURP. Based on one observational study, PAE may result in smaller improvements compared with OSP, but we are very uncertain of the evidence. Compared with TURP and OSP, PAE may result in fewer adverse events. Longer-term comparative studies are needed to assess the durability and long-term adverse events of PAE, the potential need for reintervention after PAE, and how PAE compares with other available BPH treatment options.We found the cost-effectiveness of PAE compared with TURP to be uncertain. Also, PAE is unlikely to be cost-effective compared with OSP. If PAE is publicly funded in Ontario, the budget impact is estimated to be small over the next 5 years.People who have lived experience with BPH reported that PAE improves quality of life and reduces negative symptoms of BPH.
Topics: Aged; Humans; Male; Arteries; Cost-Benefit Analysis; Observational Studies as Topic; Prostatic Hyperplasia; Quality-Adjusted Life Years; Technology Assessment, Biomedical; Embolization, Therapeutic
PubMed: 34188733
DOI: No ID Found -
European Urology Nov 2021The impact of surgeon and hospital volume on outcomes after radical prostatectomy (RP) for localised prostate cancer (PCa) remains unknown. (Review)
Review
A Systematic Review of the Impact of Surgeon and Hospital Caseload Volume on Oncological and Nononcological Outcomes After Radical Prostatectomy for Nonmetastatic Prostate Cancer.
CONTEXT
The impact of surgeon and hospital volume on outcomes after radical prostatectomy (RP) for localised prostate cancer (PCa) remains unknown.
OBJECTIVE
To perform a systematic review on the association between surgeon or hospital volume and oncological and nononcological outcomes following RP for PCa.
EVIDENCE ACQUISITION
Medline, Medline In-Process, Embase, and the Cochrane Central Register of Controlled Trials were searched. All comparative studies for nonmetastatic PCa patients treated with RP published between January 1990 and May 2020 were included. For inclusion, studies had to compare hospital or surgeon volume, defined as caseload per unit time. Main outcomes included oncological (including prostate-specific antigen persistence, positive surgical margin [PSM], biochemical recurrence, local and distant recurrence, and cancer-specific and overall survival) and nononcological (perioperative complications including need for blood transfusion, conversion to open procedure and within 90-d death, and continence and erectile function) outcomes. Risk of bias (RoB) and confounding assessments were undertaken. Both a narrative and a quantitative synthesis were planned if the data allowed.
EVIDENCE SYNTHESIS
Sixty retrospective comparative studies were included. Generally, increasing surgeon and hospital volumes were associated with lower rates of mortality, PSM, adjuvant or salvage therapies, and perioperative complications. Combining group size cut-offs as used in the included studies, the median threshold for hospital volume at which outcomes start to diverge is 86 (interquartile range [IQR] 35-100) cases per year. In addition, above this threshold, the higher the caseload, the better the outcomes, especially for PSM. RoB and confounding were high for most domains.
CONCLUSIONS
Higher surgeon and hospital volumes for RP are associated with lower rates of PSMs, adjuvant or salvage therapies, and perioperative complications. This association becomes apparent from a caseload of >86 (IQR 35-100) per year and may further improve hereafter. Both high- and low-volume centres should measure their outcomes, make them publicly available, and improve their quality of care if needed.
PATIENT SUMMARY
We reviewed the literature to determine whether the number of prostate cancer operations (radical prostatectomy) performed in a hospital affects the outcomes of surgery. We found that, overall, hospitals with a higher number of operations per year have better outcomes in terms of cancer recurrence and complications during or after hospitalisation. However, it must be noted that surgeons working in hospitals with lower annual operations can still achieve similar or even better outcomes. Therefore, making hospital's outcome data publicly available should be promoted internationally, so that patients can make an informed decision where they want to be treated.
Topics: Delivery of Health Care; Hospitals; Hospitals, High-Volume; Humans; Male; Neoplasm Recurrence, Local; Outcome Assessment, Health Care; Prostate; Prostatectomy; Prostatic Neoplasms; Surgeons; Treatment Outcome; Workload
PubMed: 33962808
DOI: 10.1016/j.eururo.2021.04.028