Prognostic Significance of Gleason Score Discrepancies between Needle Biopsy and Radical Prostatectomy

Objectives

Discordance between the Gleason score (GS) on needle biopsy (NB) and the GS of the radical prostatectomy (RP) specimen is a common finding. The objective of this study was to evaluate the prognostic significance of these discrepancies with respect to outcomes following RP.

Methods

In the study, 6625 men treated by RP were categorized as having NB=RP (68.8%), NB<RP (25.0%) or NB>RP (6.2%) GS, and stratified for analyses into RP GS groups. The Kaplan-Meier method was used to analyze differences in biochemical recurrence–free survival (BRFS), and multivariate Cox analyses were performed to estimate the independent relative risk of progression associated with GS discrepancies.

Results

Across multiple RP GS strata (3+4, 7, 8, 8–10), patients with a lower NB GS experienced significantly better BRFS than patients with equal NB and RP GS (all p < 0.05). NB<RP GS was independently associated with better (pooled HR, 0.76, p = 0.001) BRFS, within and across RP GS strata. Similarly, patients with NB>RP GS had poorer BRFS than patients with NB=RP GS across multiple RP GS strata (≤3+3, 3+4, 7; all p < 0.05). NB>RP GS was independently associated with worse (pooled HR, 1.91, p < 0.001) BRFS probabilities, within and across RP GS strata.

Conclusions

Our data suggest that the GS of the NB adds additional prognostic value to the RP GS in a consistent manner that may be applicable to strategies of risk stratification and patient counseling after surgery.     

Simplifying Patient Positioning and Port Placement During Robotic-Assisted Laparoscopic Prostatectomy

Proper patient positioning and port placement is of critical importance in robotic-assisted laparoscopic radical prostatectomy (RALP). Not having the patient in the correct Trendelenburg position or not being able to move the surgical instruments freely in the abdominal cavity can be frustrating, especially for naïve robotic surgeons (ie, those at the beginning of the learning curve for this procedure), and can lead to further difficulties in performing the intervention. We describe the use of a nautical inclinometer and a plastic, double-equilateral triangle with an 8-cm-long border to reach the correct Trendelenburg position easily and to place trocars correctly during RALP.     

Prospective Evaluation With Standardised Criteria for Postoperative Complications After Robotic-Assisted Laparoscopic Radical Prostatectomy

Background

Very few studies have evaluated the risk of complications following robotic-assisted laparoscopic radical prostatectomy (RARP), and all were flawed by several methodological biases.

Objective

To evaluate the prevalence of early complications and risk factors following RARP, reporting complications in agreement with the standardised Martin criteria.

Design, setting, and participants

All 415 patients who underwent surgery for clinically localised prostate cancer from April 2005 to April 2009 at a single tertiary academic centre were prospectively studied.

Intervention

RARP was performed by two surgeons with the same technique.

Measurements

Complications were collected and reported according to the standardised Martin criteria.

Results and limitations

One hundred and two complications were observed in 90 patients (21.6%), with bleeding (5.3%), lymphorrhoea (4.3%), and pelvic haematoma (2.4%) the most common ones. According to the modified Clavien system, 41 patients (10%) had grade 1, 37 (9%) had grade 2, 11 (3%) had grade 3, and 1 (0.2%) had grade 4 complications.On multivariable analysis, prostate volume (odds ratio: 0.985; p < 0.001) and the number of cases performed (p < 0.001) were independent predictors of the occurrence of any grade complications. Considering grade 3 to 4 complications, only the number of cases performed by the surgeons was significantly associated with major complications in a univariable analysis (p < 0.001). The major limitation of the study is represented by the relatively small number of patients and events included in the analysis, resulting in the study being underpowered to identify some factors predicting any or high-grade complications.

Conclusions

Applying standardised criteria to collect and report complications, we identified early complications in about 22% of our patients undergoing RARP. Although most of the patients experienced minor complications, 3% of them did experience grade 3 or 4 complications. Prostate volume and number of RARP performed by the surgeons were independent predictors of the occurrence of complications.     

Predictive and Prognostic Models in Radical Prostatectomy Candidates: A Critical Analysis of the Literature

Context

Numerous predictive and prognostic tools have recently been developed for risk stratification of prostate cancer (PCa) patients who are candidates for or have been treated with radical prostatectomy (RP).

Objective

To critically review the currently available predictive and prognostic tools for RP patients and to describe the criteria that should be applied in selecting the most accurate and appropriate tool for a given clinical scenario.

Evidence acquisition

A review of the literature was performed using the Medline, Scopus, and Web of Science databases. Relevant reports published between 1996 and January 2010 identified using the keywords prostate cancer, radical prostatectomy, predictive tools, predictive models, and nomograms were critically reviewed and summarised.

Evidence synthesis

We identified 16 predictive and 22 prognostic validated tools that address a variety of end points related to RP. The majority of tools are prediction models, while a few consist of risk-stratification schemes. Regardless of their format, the tools can be distinguished as preoperative or postoperative. Preoperative tools focus on either predicting pathologic tumour characteristics or assessing the probability of biochemical recurrence (BCR) after RP. Postoperative tools focus on cancer control outcomes (BCR, metastatic progression, PCa-specific mortality [PCSM], overall mortality). Finally, a novel category of tools focuses on functional outcomes. Prediction tools have shown better performance in outcome prediction than the opinions of expert clinicians. The use of these tools in clinical decision-making provides more accurate and highly reproducible estimates of the outcome of interest. Efforts are still needed to improve the available tools’ accuracy and to provide more evidence to further justify their routine use in clinical practice. In addition, prediction tools should be externally validated in independent cohorts before they are applied to different patient populations.

Conclusions

Predictive and prognostic tools represent valuable aids that are meant to consistently and accurately provide most evidence-based estimates of the end points of interest. More accurate, flexible, and easily accessible tools are needed to simplify the practical task of prediction.     

Pelvic Lymph Node Dissection in Prostate Cancer

Context

Pelvic lymph node dissection (PLND) is considered the most reliable procedure for the detection of lymph node metastases in prostate cancer (PCa); however, the therapeutic benefit of PLND in PCa management is currently under debate.

Objective

To systematically review the available literature concerning the role of PLND and its extent in PCa staging and outcome. All of the existing recommendations and staging tools determining the need for PLND were also assessed. Moreover, a systematic review was performed of the long-term outcome of node-positive patients stratified according to the extent of nodal invasion.

Evidence acquisition

A Medline search was conducted to identify original and review articles as well as editorials addressing the significance of PLND in PCa. Keywords included prostate cancer, pelvic lymph node dissection, radical prostatectomy, imaging, and complications. Data from the selected studies focussing on the role of PLND in PCa staging and outcome were reviewed and discussed by all of the contributing authors.

Evidence synthesis

Despite recent advances in imaging techniques, PLND remains the most accurate staging procedure for the detection of lymph node invasion (LNI) in PCa. The rate of LNI increases with the extent of PLND. Extended PLND (ePLND; ie, removal of obturator, external iliac, hypogastric with or without presacral and common iliac nodes) significantly improves the detection of lymph node metastases compared with limited PLND (lPLND; ie, removal of obturator with or without external iliac nodes), which is associated with poor staging accuracy. Because not all patients with PCa are at the same risk of harbouring nodal metastases, several nomograms and tables have been developed and validated to identify candidates for PLND. These tools, however, are based mostly on findings derived from lPLND dissections performed in older patient series. According to these prediction models, a staging PLND might be omitted in low-risk PCa patients because of the low rate of lymph node metastases found, even after extended dissections (<8%). The outcome for patients with positive nodes is not necessarily poor. Indeed, patients with low-volume nodal metastases experience excellent survival rates, regardless of adjuvant treatment. But despite few retrospective studies reporting an association between PLND and PCa progression and survival, the exact impact of PLND on patient outcomes has not yet been clearly proven because of the lack of prospective randomised trials.

Conclusions

On the basis of current data, we suggest that if a PLND is indicated, then it should be extended. Conversely, in view of the low rate of LNI among patients with low-risk PCa, a staging ePLND might be spared in this patient category. Whether this approach is also safe from oncologic perspectives is still unknown. Patients with low-volume nodal metastases have a good long-term prognosis; to what extent this prognosis is the result of a positive impact of PLND on PCa outcomes is still to be determined.     

Timing of Curative Treatment for Prostate Cancer: A Systematic Review

Context

Delaying definitive therapy unfavourably affects outcomes in many malignancies. Diagnostic, psychological, and logistical reasons but also active surveillance (AS) strategies can lead to treatment delay, an increase in the interval between the diagnosis and treatment of prostate cancer (PCa).

Objective

To review and summarise the current literature on the impact of treatment delay on PCa oncologic outcomes.

Evidence acquisition

A comprehensive search of PubMed and Embase databases until 30 September 2012 was performed. Studies comparing pathologic, biochemical recurrence (BCR), and mortality outcomes between patients receiving direct and delayed curative treatment were included. Studies presenting single-arm results following AS were excluded.

Evidence synthesis

Seventeen studies were included: 13 on radical prostatectomy, 3 on radiation therapy, and 1 combined both. A total of 34 517 PCa patients receiving radical local therapy between 1981 and 2009 were described. Some studies included low-risk PCa only; others included a wider spectrum of disease. Four studies found a significant effect of treatment delay on outcomes in multivariate analysis. Two included low-risk patients only, but it was unknown whether AS was applied or repeat biopsy triggered active therapy during AS. The two other studies found a negative effect on BCR rates of 2.5–9 mo delay in higher risk patients (respectively defined as any with T ≥2b, prostate-specific antigen >10, Gleason score >6, >34–50% positive cores; or D’Amico intermediate risk-group). All studies were retrospective and nonrandomised. Reasons for delay were not always clear, and time-to-event analyses may be subject to bias.

Conclusions

Treatment delay of several months or even years does not appear to affect outcomes of men with low-risk PCa. Limited data suggest treatment delay may have an impact on men with non–low-risk PCa. Most AS protocols suggest a confirmatory biopsy to avoid delaying treatment in those who harbour higher risk disease that was initially misclassified.     

The Role of Biopsy Core Number in Selecting Prostate Cancer Patients for Active Surveillance

Background

Studies offer wide variations in inclusion criteria for active surveillance (AS) in prostate cancer (PCa), but the role of the biopsy core number has not been thoroughly assessed.

Objective

To evaluate the impact of the biopsy core number on the risk of misclassification for AS eligibility.

Design, setting, and participants

: This prospective study included 411 men eligible for AS who fulfilled at least one of four of the criteria reported in the literature groupings among a screening cohort of 2917 patients.

Intervention

All patients underwent a 21-core biopsy with cores mapped by location and acted as controls of themselves for the analysis of biopsy core number (6-, 12- and 21-core schemes). Radical prostatectomy (RP) was performed in 297 men (72%).

Measurements

The number of included patients, PCa extent on biopsy, rate of unfavorable disease in RP specimens, and biochemical recurrence-free survival were compared as a function of (1) the different criteria groupings for AS and (2) the biopsy core number (6, 12, or 21).

Results and limitations

Of the 1104 patients with PCa, the proportion eligible for AS ranged from 22.5% to 35.4% based on AS criteria. In men who fulfilled AS criteria only in a 12-core strategy, tumor length and percentage of cancer involvement on biopsy were significantly greater than in those who fulfilled AS criteria in a 21-core scheme. The rate of unfavorable disease on RP specimens was also higher in the former group, from 28.6% to 35.9% relative to AS criteria (p = 0.014, 0.044, and 0.113 in groups 2, 3, and 4, respectively).

Conclusions

Men eligible for AS based on a 21-core strategy have cancers with a lower extent of disease on biopsies and a lower risk of unfavorable disease on RP specimens regardless of how AS criteria are defined, compared with men eligible in a 12-core scheme.     

Current Applications for Prostate-Specific Antigen Doubling Time

OBJECTIVE: To review the current status of prostate-specific antigen doubling time (PSADT) as it pertains to the evolution of prostate cancer (PCa), specifically assessing its role in the following four stages: before diagnosis, prior to definitive treatment, following treatment including salvage therapy after recurrence, and lastly, after onset of androgen-insensitive PCa. METHODS: We searched PubMed literature for current articles on PSADT using the key words listed for this review and, where possible, selected those with significant levels of evidence that were deemed relevant, seminal, or controversial. We summarized the data regarding PSADT as a marker for diagnosis and disease characterization, as well as a predictor of progression, response to treatment, and mortality. RESULTS: PSADT may offer an advantage in providing a more dynamic picture of tumor behavior, providing clues regarding the relative aggressiveness of the underlying pathology. Evidence points toward a role for PSADT in the management of PCa, specifically in active surveillance, disease recurrence after treatment, and in androgen-independent PCa. PSADT is an important prognostic factor that may serve as an auxiliary end point for cancer-specific survival; however, optimal cut-off points denoting risk remain debatable. CONCLUSIONS: PCa management requires risk stratification with a combination of variables, PSADT being one of the most reliable predictors. It is now a parameter included in many predictive nomograms and in treatment guidelines for expectant management and salvage therapy.     

Prediction of Outcome Following Early Salvage Radiotherapy Among Patients with Biochemical Recurrence After Radical Prostatectomy

Background

Early salvage radiotherapy (eSRT) represents the only curative option for prostate cancer patients experiencing biochemical recurrence (BCR) for local recurrence after radical prostatectomy (RP).

Objective

To develop and internally validate a novel nomogram predicting BCR after eSRT in patients treated with RP.

Design, setting, and participants

Using a multi-institutional cohort, 472 node-negative patients who experienced BCR after RP were identified. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at prostate-specific antigen (PSA) ≤0.5 ng/ml.

Outcome measurement and statistical analysis

BCR after eSRT was defined as two consecutive PSA values ≥0.2 ng/ml. Uni- and multivariable Cox regression models predicting BCR after eSRT were fitted. Regression-based coefficients were used to develop a nomogram predicting the risk of 5-yr BCR after eSRT. The discrimination of the nomogram was quantified with the Harrell concordance index and the calibration plot method. Two hundred bootstrap resamples were used for internal validation.

Results and limitations

Mean follow-up was 58 mo (median: 48 mo). Overall, 5-yr BCR-free survival rate after eSRT was 73.4%. In univariable analyses, pathologic stage, Gleason score, and positive surgical margins were associated with the risk of BCR after eSRT (all p ≤ 0.04). These results were confirmed in multivariable analysis, where all the previously mentioned covariates as well as pre-RT PSA were significantly associated with BCR after eSRT (all p ≤ 0.04). A coefficient-based nomogram demonstrated a bootstrap-corrected discrimination of 0.74. Our study is limited by its retrospective nature and use of BCR as an end point.

Conclusions

eSRT leads to excellent cancer control in patients with BCR for presumed local failure after RP. We developed the first nomogram to predict outcome after eSRT. Our model facilitates risk stratification and patient counselling regarding the use of secondary therapy for individuals experiencing BCR after RP.

Patient summary

Salvage radiotherapy leads to optimal cancer control in patients who experience recurrence after radical prostatectomy. We developed a novel tool to identify the best candidates for salvage treatment and to allow selection of patients to be considered for additional forms of therapy.     

Comprehensive Standardized Report of Complications of Retropubic and Laparoscopic Radical Prostatectomy

Background

The lack of standardized reporting of the complications of radical prostatectomy in the literature has made it difficult to compare incidences across institutions and across different surgical approaches.

Objective

To define comprehensively the incidence, severity, and timing of onset of medical and surgical complications of open retropubic prostatectomy (RP) and laparoscopic radical prostatectomy (LP) using a standardized reporting methodology to facilitate comparison.

Design, setting, and participants

Between January 1999 and June 2007, 4592 consecutive patients underwent RP or LP without prior radiation or hormonal therapy. Median follow-up was 36.9 mo (interquartile range: 20.3–60.6).

Intervention

Open or laparoscopic radical prostatectomy.

Measurements

All medical and surgical complications of radical prostatectomy were captured and graded according to the modified Clavien classification and classified by timing of onset.

Results and limitations

There were 612 medical complications in 467 patients (10.2%) and 1426 surgical complications in 925 patients (20.1%). The overall incidences of early minor and major medical and surgical complications for RP were 8.5% and 1.5% for medical and 11.4% and 4.9% for surgical complications, respectively. The overall incidences of early minor and major medical and surgical complications for LP were 14.2% and 2.3% for medical and 23.1% and 6.6% for surgical complications, respectively. On multivariate analysis, LP approach was associated with a higher incidence of any grade medical and surgical complications but a lower incidence of major surgical complications than RP. Six hundred fifty-two men (14.2%) visited the emergency department, and 240 men (5.2%) required readmission. The main limitation is the retrospective nature.

Conclusions

With standardized reporting, the incidence of some complications is higher than recognized in the literature. Although most complications are minor in severity, medical and surgical complications are observed in approximately 10% and 20% of patients, respectively. Accurate reporting of complications through a standardized methodology is essential for counseling patients regarding risk of complications, for identifying modifiable risk factors, and for facilitating comparison across institutions and approaches.     

A New Anatomic Approach for Robot-Assisted Laparoscopic Prostatectomy: A Feasibility Study for Completely Intrafascial Surgery

Robot-assisted laparoscopic prostatectomy (RALP) has been disseminated widely, changing the knowledge of surgical anatomy of the prostate. The aim of our study is to demonstrate the feasibility of a new, purely intrafascial approach.     

Initial Series of Robotic Radical Nephrectomy with Vena Caval Tumor Thrombectomy

Laparoscopy has become a standard modality for most renal tumors but not as yet for renal cell carcinoma (RCC) involving the inferior vena cava (IVC). Robotic technology may facilitate such complex procedures. We report the first series of robotic nephrectomy with IVC tumor thrombectomy including the first cases requiring cross-clamping of the IVC in a minimally invasive fashion. Five patients underwent robotic nephrectomy with IVC tumor thrombectomy including one patient having two renal veins, each with an IVC thrombus, for a total of six IVC thrombi. The IVC was opened in all patients, and tumor thrombi were delivered intact, followed by sutured closure. The mean patient age was 64 yr (53–70 yr) with a mean body mass index of 36.6 kg/m² (22–43 kg/m²). Thrombi protruded 1 cm, 2 cm, 4 cm, and 5 cm into the IVC in five patients and 3 cm and 2 cm in the patient with two thrombi. The mean estimated blood loss was 170 ml (50–400 ml). Mean operative time was 327 min (240–411 min). Mean length of stay was 1.2 d. There were no complications, transfusions, or readmissions. This early series represents a limited experience by a single surgeon with a new procedure and may not be reproducible in larger numbers or by all surgeons. Further experience is necessary to validate this application.     

Testosterone and Prostate Cancer: Revisiting Old Paradigms

Context

Androgens are vital for growth and maintenance of the prostate; however, the notion that pathologic prostate growth, benign or malignant, can be stimulated by androgens is a commonly held belief without scientific basis. Therefore, the current prostatic guidelines for testosterone therapy (TT) appear to be overly restrictive and should be reexamined.

Objective

To review the literature addressing the possible relationship between testosterone and prostate cancer (PCa) and to summarize the main aspects of this issue.

Evidence acquisition

A Medline search was conducted to identify original articles, review articles, and editorials addressing the relationship between testosterone and the risk of PCa development, as well as the impact of TT on PCa development and its natural history in men believed to be cured by surgery or radiation.

Evidence synthesis

Serum androgen levels, within a broad range, are not associated with PCa risk. Conversely, at time of PCa diagnosis, low rather than high serum testosterone levels have been found to be associated with advanced or high-grade disease. The available evidence indicates that TT neither increases the risk of PCa diagnosis nor affects the natural history of PCa in men who have undergone definitive treatment without residual disease. These findings can be explained with the saturation model (which states that prostatic homeostasis is maintained by a relatively low level of androgenic stimulation) and with the observation that exogenous testosterone administration does not significantly increase intraprostatic androgen levels in hypogonadal men. It must, however, be recognized that the literature remains limited regarding the effect of TT on PCa risk. Nonetheless, the current European Association of Urology guidelines state that in hypogonadal men who were successfully treated for PCa, TT can be considered after a prudent interval.

Conclusions

Although no controlled studies have yet been performed and there is a paucity of long-term data, the available literature strongly suggests that TT neither increases the risk of PCa diagnosis in normal men nor causes cancer recurrence in men who were successfully treated for PCa. Large prospective studies addressing the long-term effect of TT are needed to either refute or corroborate these hypotheses.     

Photodynamic Diagnosis in Urology: State-of-the-Art

Objectives

To provide an overview on the methodology and clinical relevance of fluorescence diagnosis with exogenous fluorochromes or fluorochrome prodrugs in urology.

Methods

The methodology is summarised on the basis of our experience and the relevant literature. Clinical results and perspectives are reported and concluded after we scanned and evaluated sources from PubMed. Search items were “aminolev*” or “hypericin” or “photodyn*” or “porphyrin” or “fluorescence” or “autofluorescence” and “bladder” or “prostate” or “kidney” or “peni*” or “condylo*”. Some literature was also obtained from journals not indexed.

Results

A large number of clinical trials have shown that photodynamic diagnosis (PDD) improves the ability to detect inconspicuous urothelial carcinoma of the bladder. Fluorescence diagnosis has recently been approved in Europe for the detection of bladder cancer after instillation of a hexaminolevulinate (Hexvix^®) solution. PDD is recommended by the European Association of Urology for the diagnosis of carcinoma in situ of the bladder. To date, the major weakness of PDD for the detection of bladder cancer is its relatively low specificity. Initial results with PDD for the detection of penile carcinoma, prostate cancer, kidney tumours, and urethral condylomata are promising.

Conclusions

To determine the actual impact of PDD on recurrence and progression rates of bladder cancer, further long-term observational studies are necessary. These studies also will clarify whether PDD is cost efficient.     

Optimal Definition of Biochemical Recurrence After Radical Prostatectomy Depends on Pathologic Risk Factors: Identifying Candidates for Early Salvage Therapy

Background

The use of prostate-specific antigen (PSA) thresholds (<0.2 ng/ml) below currently accepted biochemical recurrence (BCR) definitions for patients treated with radical prostatectomy may be useful in the identification of candidates for early salvage therapy with improved outcome; however, the practice risks overtreatment, as the risk of subsequent PSA progression may be low.

Objective

To analyze 14 BCR definitions for their association with subsequent PSA and treatment progression among subgroups of patients at varying risk of prostate cancer–specific mortality.

Design, setting, and participants

The subsequent risk of PSA and treatment progression after BCR based on 14 BCR definitions (six standard definitions and eight definitions requiring one or more successive PSA rises ≤0.1 ng/ml) was analyzed according to various clinicopathologic risk criteria among 2348 patients with a detectable PSA ≥0.03 ng/ml at least 6 wk after radical prostatectomy.

Intervention

Radical prostatectomy.

Outcome measurements and statistical analysis

Probability of subsequent PSA progression after BCR, defined as a PSA rise >0.1 ng/ml above BCR PSA, initiation of secondary treatment, or clinical progression.

Results and limitations

Using standard BCR definitions, the risk of PSA progression was >70%, regardless of clinicopathologic features. A single PSA ≤0.1 ng/ml was associated with PSA progression in only 30–55% of patients but ranged from 18–25% to 73–88% for patients without and with adverse pathologic features, respectively. Based on discrimination and calibration analysis, the optimal BCR definition for patients with 5-yr progression-free probability of <50%, 50–75%, 76–90%, and >90% was a single PSA ≥0.05 ng/ml, two or more rising PSAs ≥0.05 ng/ml, PSA ≥0.2 ng/ml and rising, and PSA ≥0.4 ng/ml and rising.

Conclusions

BCR definitions below currently accepted PSA thresholds appear to be valid for selecting patients with adverse clinicopathologic risk factors for secondary therapy. This information may be useful in selecting for early salvage radiotherapy to improve clinical outcome.     

Effects of Tadalafil Treatment on Erectile Function Recovery Following Bilateral Nerve-sparing Radical Prostatectomy: A Randomised Placebo-controlled Study (REACTT)

Background

The potential rehabilitative and protective effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on penile function after nerve-sparing radical prostatectomy (NSRP) remains unclear.

Objective

The primary objective was to compare the efficacy of tadalafil 5 mg once daily and tadalafil 20 mg on demand versus placebo taken over 9 mo in improving unassisted erectile function (EF) following NSRP, as measured by the proportion of patients achieving an International Index of Erectile Function-Erectile Function domain (IIEF-EF) score ≥22 after 6-wk drug-free washout (DFW). Secondary measures included IIEF-EF, Sexual Encounter Profile question 3 (SEP-3), and penile length.

Design, setting, and participants

Randomised, double-blind, double-dummy, placebo-controlled trial in men ≤68 yr of age with adenocarcinoma of the prostate (Gleason ≤7) and normal preoperative EF who underwent NSRP at 50 centres from nine European countries and Canada.

Interventions

1:1:1 randomisation to 9 mo of treatment with tadalafil 5 mg once daily, tadalafil 20 mg on demand, or placebo followed by a 6-wk DFW and 3-mo open-label tadalafil once daily (all patients).

Outcome measurements and statistical analysis

Logistic regression, mixed-effects model for repeated measures, and analysis of covariance, adjusting for treatment, age, and country, were applied to IIEF-EF scores ≥22, SEP-3, and penile length.

Results and limitations

Four hundred twenty-three patients were randomised to tadalafil once daily (n = 139), on demand (n = 143), and placebo (n = 141). The mean age was 57.9 yr of age (standard deviation: 5.58 yr); 20.9%, 16.9%, and 19.1% of patients in the tadalafil once daily, on demand, and placebo groups, respectively, achieved IIEF EF scores ≥22 after DFW; odds ratios for tadalafil once daily and on demand versus placebo were 1.1 (95% confidence interval [CI], 0.6–2.1; p = 0.675) and 0.9 (95% CI, 0.5–1.7; p = 0.704). At the end of double-blind treatment (EDT), least squares (LS) mean IIEF-EF score improvement significantly exceeded the minimally clinically important difference (MCID: ΔIIEF-EF ≥4) in both tadalafil groups; for SEP-3 (MCID ≥ 23%), this was the case for tadalafil once daily only. Treatment effects versus placebo were significant for tadalafil once daily only (IIEF-EF: p = 0.016; SEP-3: p = 0.019). In all groups, IIEF-EF and SEP-3 decreased during DFW but continued to improve during open-label treatment. At month 9 (EDT), penile length loss was significantly reduced versus placebo in the tadalafil once daily group only (LS mean difference 4.1 mm; 95% CI, 0.4–7.8; p = 0.032).

Conclusions

Tadalafil once daily was most effective on drug-assisted EF in men with erectile dysfunction following NSRP, and data suggest a potential role for tadalafil once daily provided early after surgery in contributing to the recovery of EF after prostatectomy and possibly protecting from penile structural changes. Unassisted EF was not improved after cessation of active therapy for 9 mo.

Trial registration

ClinicalTrials.gov identifier NCT01026818.     

Obesity and Prostate Cancer: Weighing the Evidence

Context

Obesity and prostate cancer (PCa) affect substantial proportions of Western society. Mounting evidence, both epidemiologic and mechanistic, for an association between the two is of public health interest. An improved understanding of the role of this modifiable risk factor in PCa etiology is imperative to optimize screening, treatment, and prevention.

Objective

To consolidate and evaluate the evidence for an epidemiologic link between obesity and PCa, in addition to examining the proposed underlying molecular mechanisms.

Evidence acquisition

A PubMed search for relevant articles published between 1991 and July 2012 was performed by combining the following terms: obesity, BMI, body mass index and prostate cancer risk, prostate cancer incidence, prostate cancer mortality, radical prostatectomy, androgen-deprivation therapy, external-beam radiation, brachytherapy, prostate cancer and quality of life, prostate cancer and active surveillance, in addition to obesity, BMI, body mass index and prostate cancer and insulin, insulin-like growth factor, androgen, estradiol, leptin, adiponectin, and IL-6. Articles were selected based on content, date of publication, and relevancy, and their references were also searched for relevant articles.

Evidence synthesis

Increasing evidence suggests obesity is associated with elevated incidence of aggressive PCa, increased risk of biochemical failure following radical prostatectomy and external-beam radiotherapy, higher frequency of complications following androgen-deprivation therapy, and increased PCa-specific mortality, although perhaps a lower overall PCa incidence. These results may in part relate to difficulties in detecting and treating obese men. However, multiple molecular mechanisms could explain these associations as well. Weight loss slows PCa in animal models but has yet to be fully tested in human trials.

Conclusions

Obesity appears to be linked with aggressive PCa. We suggest clinical tips to better diagnose and treat obese men with PCa. Whether reversing obesity slows PCa growth is currently unknown, although it is an active area of research.     

Prostate-Specific Antigen (PSA) Isoform p2PSA in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection

Background

Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA = tPSA/fPSA) lack diagnostic specificity.

Objective

To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia–associated PSA (BPHA).

Design, setting, and participants

Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University.

Measurements

BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi = (p2PSA/fPSA) × √(tPSA).

Results and limitations

The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity.

Conclusions

This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7).     

Salvage Cryosurgery of the Prostate for Failure After Primary Radiotherapy or Cryosurgery: Long-term Clinical,Functional, and Oncologic Outcomes in a Large Cohort at a Tertiary Referral Centre

Background

Salvage cryosurgery (SC) is a recognised option for patients who fail either primary radiation or cryosurgery.

Objective

To report outcomes of patients undergoing SC.

Design, setting, and participants

A consecutive series of 396 patients who had failed either primary radiotherapy or cryosurgery underwent SC between October 1994 and August 2011.

Outcome measurements and statistical analysis

Demographic and clinical parameters before primary and salvage treatment were evaluated; disease-free-survival (DFS), overall-survival (OS), disease-specific-survival (DSS), and complications were assessed.

Results and limitations

Sufficient follow-up data were available for 328 patients. Median age was 65.8 yr (range: 45–81 yr), median serum prostate-specific antigen (PSA) level was 8.0 ng/ml (range: 0.6–290.0 ng/ml). After primary treatment, median time to recurrence was 55 mo (range: 0.0–183.6 mo). SC was performed at a median of 67.5 mo (range: 7.0–212.7 mo) later; median pre-SC PSA level was 4.0 ng/ml (range: 0.1–112.4 ng/ml). Median PSA nadir was 0.2 ng/ml (range: 0.01–70.70 ng/ml), reached after a median of 2.6 mo (range: 2.0–67.3 mo) after SC. Median follow-up was 47.8 mo (range: 1.6–203.5 mo). Respective 5- and 10-yr DFS was 63% and 35%; OS: 74% and 45%; and DSS: 91% and 79%. In univariate analyses, time from primary treatment to SC or recurrence, PSA level before SC, and PSA nadir after SC were all significant predictors of recurrence (p ≤ 0.01). PSA before SC and time to recurrence were also predictive of DSS (p = 0.003 and p = 0.01, respectively). In multivariate analyses, only PSA nadir after SC was predictive of recurrence and DSS (p < 0.001 and p = 0.012, respectively). Complications were rare (range: 0.6–4.6%). Fifty-five patients (16.7%) underwent focal SC. Median PSA nadir after focal SC was 0.44 ng/ml (range: 0.04–20.1 ng/ml). Twenty-seven patients (49%) experienced recurrence. Respective 5- and 10-yr DFS was 47% and 42%; OS: 87% and 81%; and DSS: 100% and 83%.

Conclusions

Our analysis confirms SC as an effective treatment option for patients failing primary therapy. Patients experienced excellent survival outcome and minimal associated morbidity after SC. Focal SC is an efficacious treatment for properly selected patients.