Multicentric experience in Retzius-sparing robot-assisted radical prostatectomy performed by expert surgeons for high-risk prostate cancer.

BACKGROUND: The study aim was to report the results of Retzius-Sparing robot-assisted radical Prostatectomy (RSP) in high-risk prostate cancer (HR-PCa) patients in a multicentric setting of expert surgeons and to analyze predictors of positive surgical margins (PSMs) and urinary continence recovery. METHODS: We retrospectively evaluated all consecutive HR-PCa patients who underwent RSP by expert surgeons in 7 centers. Pre-, peri- and postoperative features were collected. Minimum surgical experience required was 100 RSP cases. The oncological outcomes evaluated were PSMs and biochemical relapse (BCR). Urinary continence was defined as no pad or safety pad. Erectile function was defined as erections sufficient for intercourse. RESULTS: We collected 579 patients operated by 9 surgeons. Median age was 66, median PSA was 9,6 ng/mL. ISUP biopsy was 1 in 3.8%, 2 in 23%, 3 in 32,6%, 4 in 19,9%, 5 in 20,7; median surgical time was 195 minutes. Pathological stage was pT2 in 40,1%, pT3a in 35,9%, pT3b in 23,1%, and pT4 in 0,9% of cases. PSMs were present in 31,3% of cases. Urinary continence was achieved in 66,8% of cases one week after catheter removal. At 22 months (median follow-up), 89,1% patients were continent, BCR occurred in 27,5% patients. In multivariate analysis, PSA, prostate volume, surgical time were independent predictors of PSMs; ASA score and PSMs predicted urinary continence. CONCLUSIONS: We report the first multicentric experience of RSP for HR-PCa. Considering HR cases as those with the worst functional results, 89% of continent patients confirms that RSP helps achieve good functional results.

Survival Outcomes and Pattern of Relapse After SABR for Oligometastatic Prostate Cancer.

Introduction: The addition of stereotactic ablative radiotherapy (SABR) to standard of care for patients with oligometastatic prostate cancer has the potential of improving survival and delaying further metastases. The primary aim of this analysis is to report survival outcomes and pattern of recurrence of patients with hormone-sensitive (HSPC) and castrate-resistant (CRPC) oligometastatic prostate cancer treated with SABR. Methods: This is a single-center retrospective study of patients with oligometastatic prostate cancer treated in Iridium Network between 2014 and 2018. All patients with oligometastatic (≤3 active lesions) HSPC and CRPC treated with SABR were included. Data were collected using electronic records. Patterns of first progression following SABR were reported. Kaplan-Meier methods were used to determine survival outcomes. Results: Eighty-seven men received SABR to 115 metastases. Nineteen patients were castrate-resistant and 68 hormone-sensitive at the time of SABR. Median follow-up was 41.6 months. In 25% of patients, no decline from baseline PSA was recorded. Median bPFS was 11.7 months (95% CI 7.6 - 18.3) for HSPC as well as CRPC (95% CI 6.4 - 24.0) (p=0.27). Median DMFS was 21.8 (95% CI 16.9 - 43.2) versus 17.6 months (95% CI 6.7 - 26.2) for HSPC versus CRPC, respectively (p=0.018). Median OS was 72.6 months (95% CI 72.6 - not reached) for HSPC and not reached for CRPC (95% CI 35.4 months - not reached) (p=0.026). For the subgroup of oligorecurrent HSPC, short-term androgen-deprivation therapy was associated with improved bPFS (median 6.0 vs. 18.3 months, HR 0.31, p<0.001) and DMFS (median 15.8 vs 29.6 months, HR 0.5, p=0.06). Information on pattern of relapse was retrieved for 79 patients: 45% (36/79) of these patients were long-term disease-free (>18 months), 28% (22/79) of patients wmere oligoprogressive (≤3 new lesions) and 27% (21/79) developed a polymetastatic relapse. Conclusion: In this cohort, oligometastatic HSPC showed potential benefit from SABR with a median DMFS of 21.8 months. Well-selected patients with oligometastatic CRPC may also benefit from SABR. For patients with metachronous and repeat oligorecurrent HSPC, combining SABR with short-term androgen-deprivation therapy was associated with improved bPFS and DMFS. Overall, 36/87 (41%) of patients were still free from clinical relapse at 18 months.

Multicentre, prospective study on local treatment of metastatic prostate cancer (LoMP study).

OBJECTIVES: To investigate the role of cytoreductive radical prostatectomy in addition to standard of care for patients with newly diagnosed metastatic prostate cancer. MATERIALS AND METHODS: This multicentre, prospective study included asymptomatic patients from 2014 to 2018 (NCT02138721). Cytoreductive radical prostatectomy was offered to all fit patients with resectable tumours, resulting in 40 patients. Standard of care was administered to 40 patients who were ineligible or unwilling to undergo surgery. The primary endpoint was castration resistant cancer-free survival at the time point of ≥50% events. The secondary endpoint was local event-free survival. Kaplan-Meier and Cox regression analyses with propensity-score analysis were applied. RESULTS: After a median (quartiles) follow-up of 35 (24-47) months, 42 patients became castration-resistant or died. The median castration resistant cancer-free survival was 53 (95% confidence interval [CI] 14-92) vs 21 (95% CI 15-27) months for cytoreductive radical prostatectomy compared to standard of care (P = 0.017). The 3-year estimates for local event-free survival were 83% (95% CI 71-95) vs 59% (95% CI 51-67) for cytoreductive radical prostatectomy compared to standard of care (P = 0.012). However, treatment group showed no significance in the multivariable models for castration resistant cancer-free survival (P = 0.5) or local event-free survival (P = 0.3), adjusted for propensity-score analysis. Complications were similar to the non-metastatic setting. Patients undergoing surgery were younger, with lower baseline prostate-specific antigen levels, alkaline phosphatase levels and metastatic burden. CONCLUSION: The present LoMP study was unable to show a difference between the two inclusion groups regarding castration resistant cancer-free survival for asymptomatic patients with newly diagnosed metastatic prostate cancer. These results validate previous evidence that, in well-selected and informed patients, cytoreductive radical prostatectomy is feasible and safe, with corresponding continence rates compared to the non-metastatic, high-risk setting. Whether cytoreductive radical prostatectomy could be a valuable option to achieve good local palliation needs to be further researched. Overall, the role of cytoreductive radical prostatectomy needs to be further explored in randomized studies to correct for potential bias.

Comparative Outcomes of Salvage Retzius-Sparing versus Standard Robotic Prostatectomy: An International, Multi-Surgeon Series.

PURPOSE: Salvage radical prostatectomy is rare due to the risk of postoperative complications. We compare salvage Retzius-sparing robotic assisted radical prostatectomy (SRS-RARP) with salvage standard robotic assisted radical prostatectomy (SS-RARP). MATERIALS AND METHODS: A total of 72 patients across 9 centers were identified (40 SRS-RARP vs 32 SS-RARP). Demographics, perioperative data, and pathological and functional outcomes were compared using Student's t-test and ANOVA. Cox proportional hazard models and Kaplan-Meier curves were constructed to assess risk of incontinence and time to continence. Linear regression models were constructed to investigate postoperative pad use and console time. RESULTS: Median followup was 23 vs 36 months for SRS-RARP vs SS-RARP. Console time and estimated blood loss favored SRS-RARP. There were no differences in complication rates or oncologic outcomes. SRS-RARP had improved continence (78.4% vs 43.8%, p <0.001 for 0-1 pad, 54.1% vs 6.3%, p <0.001 for 0 pad), lower pads per day (0.57 vs 2.03, p <0.001), and earlier return to continence (median 47 vs 180 days, p=0.008). SRS-RARP was associated with decreased incontinence defined as >0-1 pad (HR 0.28, 95% CI 0.10-0.79, p=0.016), although not when defined as >0 pad (HR 0.56, 95% CI 0.31-1.01, p=0.053). On adjusted analysis SRS-RARP was associated with decreased pads per day. Lymph node dissection and primary treatment with stereotactic body radiation therapy were associated with longer console time. CONCLUSIONS: SRS-RARP is a feasible salvage option with significantly improved urinary function outcomes. This may warrant increased utilization of SRS-RARP to manage men who fail nonsurgical primary treatment for prostate cancer.

Retzius-sparing robot-assisted radical prostatectomy: early learning curve experience in three continents.

OBJECTIVE: To assess the effect of surgical experience on peri-operative, functional and oncological outcomes during the first 50 Retzius-sparing robot-assisted radical prostatectomy (RsRARP) cases performed by surgeons naïve to this novel approach. MATERIALS AND METHODS: We retrospectively evaluated the initial cases operated by 14 surgeons in 12 different international centres. Pre-, peri- and postoperative features of the first 50 patients operated by each surgeon in all the participating centres were collected. The effect of surgical experience on peri-operative, functional and oncological outcomes was firstly evaluated after stratification by level of surgical experience (initial [≤25 cases] and expert [>25 cases]) and after using locally weighted scatterplot smoothing to graphically explore the relationship between surgical experience and the outcomes of interest. RESULTS: We evaluated 626 patients. The median follow-up was 13 months in the initial group and 9 months in the expert group (P = 0.002). Preoperative features overlapped between the two groups. Shorter console time (140 vs 120 min; P = 0.001) and a trend towards lower complications rates (13 vs 5.5%; P = 0.038) were observed in the expert group. The relationship between surgical experience and console time, immediate urinary continence recovery and Clavien-Dindo grade ≥2 complications was linear, without reaching a plateau, after 50 cases. Conversely, a non-linear relationship was observed between surgical experience and positive surgical margins (PSMs). CONCLUSIONS: In this first report of a multicentre experience of RsRARP during the learning curve, we found that console time, immediate urinary continence recovery and postoperative complications are optimal from the beginning and further quickly improve during the learning process, while PSM rates did not clearly improve over the first 50 cases.

Simultaneous laparoscopic proctocolectomy (TaTME) and robot-assisted radical prostatectomy for synchronous rectal and prostate cancer.

OBJECTIVE: We would like to present a patient with a history of ulcerative colitis suffering from a synchronous rectal and prostate cancer treated with a laparoscopic total proctocolectomy (with TaTME) and Retzius sparing RARP simultaneously. METHODS: Retzius sparing RARP with bilateral lymph node harvesting was performed first. Afterwards, TaTME was commenced with the placement of a Lonestar® retractor and GelPort®. Anterior dissection was troubled unexpectedly by outspoken fibrosis. For that reason, it was completed laparoscopically. We then continued with the laparoscopic total proctocolectomy. Last, a transanal circular stapled ileoanal anastomosis was created and a derivating ileostomy was installed. RESULTS: Postoperative proctoscopy showed a patent ileoanal anastomosis. After removal of the Foley catheter on day 21, the patient was immediately continent. Prostate specimen revealed a pT2cN1M0 transmural invasive adenocarcinoma with a Gleason score of 7 (3 + 4). Pathology analysis of the rectum revealed a stage IIIc transmural invasive moderately differentiated rectal adenocarcinoma (pT3N2bM0) with free margins. He was referred for adjuvant chemotherapy. CONCLUSIONS: In this case, the combination of TaTME and Retzius sparing RARP for synchronous rectal and prostate cancer was feasible and safe. We suggest performing the anterior TaTME dissection last, due to disturbing blood flow into the operating field after prostatectomy.

TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi).Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. RESULTS: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). CONCLUSIONS: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

Circulating tumor cells and survival in abiraterone- and enzalutamide-treated patients with castration-resistant prostate cancer.

BACKGROUND: The outcome to treatment administered to patients with metastatic castration-resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers guiding treatment decision making. OBJECTIVE: To investigate the prognostic value of circulating tumor cell (CTC) enumeration and dynamics, in the context of second-line endocrine therapies (ie, abiraterone acetate or enzalutamide), irrespective of prior systemic therapies. DESIGN, SETTINGS, AND PARTICIPANTS: In a prospective, multicentre study blood samples for CTC enumeration were collected from patients with mCRPC at baseline (n = 174). In patients who responded for minimally 10-12 weeks a follow-up sample was collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For baseline analysis, patients were stratified in <5 or ≥5 CTCs/7.5 mL, whereas for the analysis of CTC dynamics at 10-12 weeks, in patients with stable, increasing or decreasing CTC counts. Progression-free survival (PFS), overall survival (OS), and PSA changes at 10-12 weeks were compared between groups. RESULTS: Patients demonstrating increasing CTCs on therapy had a shorter median PFS (4.03 vs 12.98 vs 13.67 months, HR 3.6, 95%CI 1.9-6.8; P < 0.0001) and OS (11.2 months vs not reached, HR 9.5, 95%CI 3.7-24; P < 0.0001), compared to patients with decreasing or stable CTCs. Multivariable Cox regression showed that prior chemotherapy (HR 4.1, 95%CI 1.9-8.9; P = 0.0003), a high baseline CTC count (HR 1.5, 95%CI 1.2-1.9; P = 0.002) and increasing CTCs at follow-up (HR 3.3, 95%CI 1.4-7.6; P = 0.005) were independent predictors of worse PFS. Previous chemotherapy (HR 7, 95%CI 1.9-25; P = 0.003), high baseline CTC counts (HR 2.2, 95%CI 1.4-3.7; P = 0.002) and increasing CTCs during therapy (HR 4.6, 95%CI 1.4-15; P = 0.01) were independently associated with shorter OS. ≥30% and ≥50% PSA responses less frequently occurred in patients with CTC inclines at 10-12 weeks on therapy (χ2 test: P < 0.01). CONCLUSIONS: CTC dynamics during therapy are associated with PSA response and provide independent clinical prognostication over PSA declines. Hence the study demonstrates the pharmacodynamic properties of CTCs.

Results of buccal mucosa grafts for repairing long bulbar urethral strictures.

OBJECTIVES: To report the medium-term results at our institution of repairing long bulbar urethral strictures with buccal mucosal grafts. PATIENTS AND METHODS: Between January 2003 and June 2007, a buccal mucosa graft repair was used in 34 patients with recurrent bulbar strictures >2 cm. The follow-up included uroflowmetry with an ultrasonographic estimate of residual volume at 3 months, 1 year and yearly thereafter, or at the onset of obstructive voiding symptoms. A retrograde urethrogram with a voiding cysto-urethrogram was taken at 6 months. Flexible urethroscopy was used whenever a recurrent stricture was suspected. A successful outcome was defined as normal voiding with no stricture on the voiding cysto-urethrogram and no need for subsequent instrumentation. RESULTS: The median (range) age of the patients was 55.5 (23-74) years. The mean (sd) preoperative maximum flow rate was 6.6 (2.5) mL/s with a mean (sd) residual volume of 51.7 (89.7) mL. Seven patients (21%) had had one or more previous urethral dilatations, 15 (44%) had undergone one or more internal urethrotomies and 10 (30%) received both treatments. Eight patients (24%) had previous open urethral surgery; two had no previous treatment. A dorsal onlay technique was used in 30 patients, a ventral onlay in one, a combined technique (dorsal onlay and ventral fasciocutaneous flap) in two and a two-stage buccal mucosa urethroplasty in one. The mean (sd) operative duration was 147 (36) min, and the stricture length and buccal mucosa graft length were, respectively, 3.2 (1.2) cm and 4.4 (0.6) cm. Follow-up was available in 33 patients (97%) with a mean of 23 (15.4) months. The success rate was then 94%. Both failures occurred within the first year and were managed successfully by internal urethrotomy. The mean (sd) postoperative maximum flow rate was 20 (11) mL/s with a mean (sd) residual volume of 46 (68) mL. There were no medium-term donor-site complications. Postmicturition dribbling was noted in eight patients (24%). None of the patients had de novo impotence or urinary incontinence, and to date no patient has needed a repeat open reconstruction. CONCLUSION: Our results show that in patients with bulbar urethral strictures of >2 cm, urethroplasty using buccal mucosa is feasible, with very encouraging medium-term results. We confirm that this type of reconstruction could be considered the standard of care for bulbar strictures of >2 cm.

Comparison between open partial and radical nephrectomy for renal tumours: perioperative outcome and health-related quality of life.

OBJECTIVE: To compare perioperative outcome and health-related quality of life (HRQOL) after open partial and radical nephrectomy for renal tumours. METHODS: Literature search of Medline and additional references from non-Medline-indexed journals for documents concerning treatment of renal tumours, perioperative outcome, and HRQOL after radical and partial nephrectomy. RESULTS: A total of 39 references were used of which 7 discussed complications, 3 included hospital costs and length of stay, and 7 each discussed renal function and QOL. No statistical difference was found concerning perioperative complications although there seems to be a trend towards a slightly higher complication rate after partial nephrectomy. No statistical difference was reported between the two procedures concerning hospital costs and length of stay. For postoperative renal function, a higher incidence of chronic renal failure was noted after radical nephrectomy. When considering the HRQOL a benefit was found after elective partial nephrectomy. In case of mandatory partial nephrectomy the fear of recurrence and the worry about having fewer than two normal kidneys were significantly higher. CONCLUSIONS: Partial nephrectomy achieves a better HRQOL due to better preservation of renal function and overall quality of life. Considering perioperative outcome no statistical difference was found for hospital costs and length of stay. A trend towards a higher perioperative complication rate was found after partial nephrectomy.