Feasibility study of a clinically-integrated randomized trial of modifications to radical prostatectomy

<p>Abstract</p> <p>Background</p> <p>Numerous technical modifications to radical prostatectomy have been proposed. Such modifications are likely to lead to only slight improvements in outcomes. Although small differences would be worthwhile, an appropriately powered randomized trial would need to be very large, and thus of doubtful feasibility given the expense, complexity and regulatory burden of contemporary clinical trials. We have proposed a novel methodology, the clinically-integrated randomized trial, which dramatically streamlines trial procedures in order to reduce the marginal cost of an additional patient towards zero. We aimed to determine the feasibility of implementing such a trial for radical prostatectomy.</p> <p>Methods</p> <p>Patients undergoing radical prostatectomy as initial treatment for prostate cancer were randomized in a factorial design to involvement of the fascia during placement of the anastomotic sutures, urethral irrigation, both or neither. Endpoint data were obtained from routine clinical documentation. Accrual and compliance rates were monitored to determine the feasibility of the trial.</p> <p>Results</p> <p>From a total of 260 eligible patients, 154 (59%) consented; 56 patients declined to participate, 20 were not approached on recommendation of the treating surgeon, and 30 were not approached for logistical reasons. Although recording by surgeons of the procedure used was incomplete (~80%), compliance with randomization was excellent when it was recorded, with only 6% of procedures inconsistent with allocation. Outcomes data was received from 71% of patients at one year. This improved to 83% as the trial progressed.</p> <p>Conclusions</p> <p>A clinically-integrated randomized trial was conducted at low cost, with excellent accrual, and acceptable compliance with treatment allocation and outcomes reporting. This demonstrates the feasibility of the methodology. Improved methods to ensure documentation of surgical procedures would be required before wider implementation.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00928850">NCT00928850</a></p

Editorial comment

The authors present a robust single-surgeon series of RARP performed using an EP approach. The study focuses on complications, and the authors are to be applauded for using the rigorous Martin-Donat criteria to collect, analyze, and present their data.1,2 In highly experienced hands, it appears that this technique results in morbidity that compares favorably with the much more common TP approach. Specifically, the overall rate of any complication was 8.45%, with lymphoceles, bladder neck contracture, anastomotic leaks, and transfusions all well under 2%..

Can pelvic node dissection at radical prostatectomy influence the nodal recurrence at salvage lymphadenectomy for prostate cancer?

Purpose: To verify the quality of pelvic lymph node dissection (PLND) performed at radical prostatectomy (RP) and its impact on nodal recurrence in patients undergoing salvage lymph node dissection (sLND). Materials and Methods: Retrospective review of 48 patients who underwent sLND for presumed nodal recurrence, to describe the PLND characteristics at RP and correlate the anatomical sites and number of suspicious nodes reported in radiological imaging and final pathology of sLND. Results: Overall, at RP, 8 (16.7%) did not undergo PLND, 32 (66.7%) and 8 (16.7%) received a “limited” (between external iliac vein and obturator nerve) and an “extended” (external iliac, hypogastric, and obturator) dissection, respectively. Median nodes removed during limited and extended dissection were 2 and 24, respectively. At sLND, the mean age was 61.3 years and median prostate specific antigen (PSA) was 1.07 ng/mL. Median nodes removed at sLND were 17 with a median of 2 positive nodes. Recurrent nodes were identified within the template of an extended PLND in 62.5%, 50.0% and 12.5% patients, respectively, following prior no, limited and extended dissection at RP. Recurrence outside the expected lymphatic drainage pathway was noted in 37.5% patients with prior extended dissection at RP. There was a correlation between imaging and pathology specimen in 83% for node location and 58.3% for number of anatomical sites involved. Conclusions: In prostate cancer patients undergoing sLND, most had inadequate PLND at the original RP. Pattern of nodal recurrence may be influenced by the prior dissection and pre sLND imaging appears to underestimate the nodal recurrence

Independent validation of a pre-specified four-kallikrein marker model for prediction of adverse pathology and biochemical recurrence

Background: Accurate markers for prostate cancer (PC) risk stratification could aid decision-making for initial management strategies. The 4Kscore has an undefined role in predicting outcomes after radical prostatectomy (RP). Methods: We included 1476 patients with 4Kscore measured prior to RP at two institutions. The 4Kscore was assessed for prediction of adverse pathology at RP and biochemical recurrence (BCR) relative to a clinical model. We pre-specified that all analyses would be assessed in biopsy Grade Group 1 (GG1) or 2 (GG2) PC patients, separately. Results: The 4Kscore increased discrimination for adverse pathology in all patients (delta area under the receiver operative curve (AUC) 0.009, 95% confidence interval (CI) 0.002, 0.016; clinical model AUC 0.767), driven by GG1 (delta AUC 0.040, 95% CI 0.006, 0.073) rather than GG2 patients (delta AUC 0.005, 95% CI −0.012, 0.021). Adding 4Kscore improved prediction of BCR in all patients (delta C-index 0.014, 95% CI 0.007, 0.021; preop-BCR nomogram C-index 0.738), again with larger changes in GG1 than in GG2. Conclusions: This study validates prior investigations on the use of 4Kscore in men with biopsy-confirmed PC. Men with GG1 PC and a high 4Kscore may benefit from additional testing to guide treatment selection. Further research is warranted regarding the value of the 4Kscore in men with biopsy GG2 PC

Predictive value of kallikrein forms and β-microseminoprotein in blood from patients with evidence of detectable levels of PSA after radical prostatectomy

PURPOSE: To determine whether β-microseminoprotein or any of the kallikrein forms in blood-free, total or intact PSA or total hK2-predict metastasis in patients with evidence of detectable levels of PSA in blood after radical prostatectomy.METHOD: We determined marker concentrations in blood from 173 men treated with radical prostatectomy and evidence of detectable levels of PSA in the blood (PSA ≥ 0.05) after surgery between 2014 and 2015 and at least 1 year after any adjuvant therapy. We used Cox regression to determine whether any marker was associated with metastasis using both univariate and multivariable models that included standard clinical predictors.RESULTS: Overall, 42 patients had metastasis, with a median follow-up of 67 months among patients without an event. The levels of intact and free PSA and free-to-total PSA ratio were significantly associated with metastasis. Discrimination was highest for free PSA (c-index: 0.645) and free-to-total PSA ratio (0.625). Only free-to-total PSA ratio remained associated with overall metastasis (either regional or distant) after including standard clinical predictors (p = 0.025) and increased discrimination from 0.686 to 0.697. Similar results were found using distant metastasis as an outcome (p = 0.011; c-index increased from 0.658 to 0.723).CONCLUSION: Our results provide evidence that free-to-total PSA ratio can risk stratifying patients with evidence of detectable levels of PSA in blood after RP. Further research is warranted on the biology of prostate cancer markers in patients with evidence of detectable levels of PSA in blood after radical prostatectomy. Our findings on the free-to-total ratio for predicting adverse oncologic outcomes need to be validated in other cohorts