M. Spahn

Natural history of surgically treated high-risk prostate cancer

BACKGROUND No data exist on the patterns of biochemical recurrence (BCR) and their effect on survival in patients with high-risk prostate cancer (PCa) treated with surgery. The aim of our investigation was to evaluate the natural history of PCa in patients treated with radical prostatectomy (RP) alone. MATERIALS AND METHODS Overall, 2,065 patients with high-risk PCa treated with RP at 7 tertiary referral centers between 1991 and 2011 were identified. First, we calculated the probability of experiencing BCR after surgery. Particularly, we relied on conditional survival estimates for BCR after RP. Competing-risks regression analyses were then used to evaluate the effect of time to BCR on the risk of cancer-specific mortality (CSM). RESULTS Median follow-up was 70 months. Overall, the 5-year BCR-free survival rate was 55.2%. Given the BCR-free survivorship at 1, 2, 3, 4, and 5 years, the BCR-free survival rates improved by+7.6%,+4.1%,+4.8%,+3.2%, and+3.7%, respectively. Overall, the 10-year CSM rate was 14.8%. When patients were stratified according to time to BCR, patients experiencing BCR within 36 months from surgery had higher 10-year CSM rates compared with those experiencing late BCR (19.1% vs. 4.4%; P<0.001). At multivariate analyses, time to BCR represented an independent predictor of CSM (P<0.001). CONCLUSIONS Increasing time from surgery is associated with a reduction of the risk of subsequent BCR. Additionally, time to BCR represents a predictor of CSM in these patients. These results might help provide clinicians with better follow-up strategies and more aggressive treatments for early BCR.

Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma

BackgroundRenal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs.MethodsExpression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC).ResultsRCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease.ConclusionsA combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.

Radical prostatectomy in very high-risk localized prostate cancer: Long-term outcomes and outcome predictors

Abstract Objective. The objective of this study was to present the long-term outcomes and determine outcome predictors in very high-risk (cT3b–T4) prostate cancer (PCa) after radical prostatectomy (RP). Material and methods. Between January 1989 and December 2004, 51 patients with cT3b–T4 PCa underwent RP. Kaplan-Meier survival analysis was used to calculate the biochemical progression-free survival (BPFS), clinical progression-free survival (CPFS), cancer-specific survival (CSS) and overall survival (OS) rate. Multivariate Cox proportional hazard models were used to determine the predictive power of clinical and pathological variables in BPFS and CPFS. Results. Median follow-up was 108 months [interquartile range (IQR) 73.5–144.5]. The median serum prostate-specific antigen (PSA) was 16.9 ng/ml (IQR 7–37.2). Median biopsy and pathological Gleason (pGS) score were both scored as 7 (range 4–10 and 5–9, respectively). Overstaging was frequent (37.2%); four patients (7.8%) had organ-confined stage pT2, while 15 (29.4%) had extracapsular extension only (pT3a). Another 23 (45.1%) were confirmed with seminal vesicle invasion (pT3b) and nine (17.7%) had adjacent structure invasion (pT4). Eleven patients (21.6%) had lymph-node involvement. Thirty-two patients (62.7%) had positive surgical margins. The BPFS, CPFS, CSS and OS at 5 and 10 years were 52.7%, 45.8%;78.0%, 72.5%; 91.9%, 91.9% and 88.0%, 70.7%. In the multivariate Cox proportional hazard models, pathological stage was an independent predictor of BPFS while preoperative PSA and pGS was an independent predictor of CPFS. Conclusions. The management of cT3b–T4 PCa typically consists of a multimodality treatment in which RP is a valuable first step. Overstaging was frequent (37.2%), and almost one-quarter of the patients remained free of additional treatments. Long-term cancer-related outcomes were very satisfactory.

Results of surgery for high-risk prostate cancer

Purpose of review Surgery for high-risk prostate cancer (PCa) is applied frequently nowadays. Nevertheless, this approach is still surrounded by many controversies. The present review discusses the most recent literature regarding surgery for high-risk PCa. Recent findings As there is no standard definition of high-risk PCa, outcome comparison between series and treatment approaches is hampered. Nevertheless, recent radical prostatectomy series have shown excellent cancer-specific survival in patients with high-risk PCa. Even for very-high-risk PCa (cT3b-T4 or any cT, N1), surgery may be applied to highly selected patients as a first step of a multimodality approach. Recent experience with robot-assisted surgery opens new possibilities for a minimally invasive approach in this field. Patient selection for surgery was also addressed in recent studies. Excellent cancer-specific survival is seen when specimen-confined PCa is found at final histopathology; a recently published nomogram enables the prediction of specimen-confined disease. Another issue in high-risk PCa is the impact of age and comorbidities on cancer-specific and overall mortality. In a recent study, it was shown that patients with low comorbidity scores, even when at least 70 years old, had a significant risk of dying from their cancer and may benefit most from a surgical approach. A modified extended pelvic lymphadenectomy template was presented, providing optimal removal of positive lymph nodes. Summary Radical prostatectomy with extended pelvic lymphadenectomy delivers very good cancer-related outcomes in high-risk and very-high-risk PCa, often within a multimodal approach. Minimally invasive surgery and improved patient selection will be key to further improve oncological and functional outcomes.

Predicting prostate cancer-specific outcome after radical prostatectomy among men with very high-risk cT3b/4 PCa: a multi-institutional outcome study of 266 patients

Background:The value of radical prostatectomy (RP) as an approach for very high-risk prostate cancer (PCa) patients is controversial. To examine the risk of 10-year cancer-specific mortality (CSM) and other-cause mortality (OCM) according to clinical and pathological characteristics of very high-risk cT3b/4 PCa patients treated with RP as the primary treatment option.Methods:In a multi-institutional cohort, 266 patients with very high-risk cT3b/4 PCa treated with RP were identified. All patients underwent RP and pelvic lymph-node dissection. Competing-risk analyses assessed 10-year CSM and OCM before and after stratification for age and Charlson comorbidity index (CCI).Results:Overall, 34 (13%) patients died from PCa and 73 (28%) from OCM. Ten-year CSM and OCM rates ranged from 5.6% to 12.9% and from 10% to 38%, respectively. OCM was the leading cause of death in all subgroups. Age and comorbidities were the main determinants of OCM. In healthy men, CSM rate did not differ among age groups (10-year CSM rate for ⩽64, 65–69 and ⩾70 years: 16.2%, 11.5% and 17.1%, respectively). Men with a CCI ⩾1 showed a very low risk of CSM irrespective of age (10-year CSM: 5.6–6.1%), whereas the 10-year OCM rates increased with age up to 38% in men ⩾70 years.Conclusion:Very high-risk cT3b/4 PCa represents a heterogeneous group. We revealed overall low CSM rates despite the highly unfavorable clinical disease. For healthy men, CSM was independent of age, supporting RP even for older men. Conversely, less healthy patients had the highest risk of dying from OCM while sharing very low risk of CSM, indicating that this group might not benefit from an aggressive surgical treatment. Outcome after RP as the primary treatment option in cT3b/4 PCa patients is related to age and comorbidity status.

Pretreatment Tables Predicting Pathologic Stage of Locally Advanced Prostate Cancer

BACKGROUND Pretreatment tables for the prediction of pathologic stage have been published and validated for localized prostate cancer (PCa). No such tables are available for locally advanced (cT3a) PCa. OBJECTIVE To construct tables predicting pathologic outcome after radical prostatectomy (RP) for patients with cT3a PCa with the aim to help guide treatment decisions in clinical practice. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter retrospective cohort study including 759 consecutive patients with cT3a PCa treated with RP between 1987 and 2010. INTERVENTION Retropubic RP and pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Patients were divided into pretreatment prostate-specific antigen (PSA) and biopsy Gleason score (GS) subgroups. These parameters were used to construct tables predicting pathologic outcome and the presence of positive lymph nodes (LNs) after RP for cT3a PCa using ordinal logistic regression. RESULTS AND LIMITATIONS In the model predicting pathologic outcome, the main effects of biopsy GS and pretreatment PSA were significant. A higher GS and/or higher PSA level was associated with a more unfavorable pathologic outcome. The validation procedure, using a repeated split-sample method, showed good predictive ability. Regression analysis also showed an increasing probability of positive LNs with increasing PSA levels and/or higher GS. Limitations of the study are the retrospective design and the long study period. CONCLUSIONS These novel tables predict pathologic stage after RP for patients with cT3a PCa based on pretreatment PSA level and biopsy GS. They can be used to guide decision making in men with locally advanced PCa. PATIENT SUMMARY Our study might provide physicians with a useful tool to predict pathologic stage in locally advanced prostate cancer that might help select patients who may need multimodal treatment.

Apples and oranges: comparison of treatment methods for prostate cancer using biochemical recurrence as an endpoint.

We read with great interest the recent article by Grimm et al. [ 1 ] from the Prostate Cancer Results Study Group (PCRSG) comparing different treatment methods for prostate cancer. The authors are to be congratulated for attempting to evaluate differences in oncological outcome between surgery, radiotherapy treatments, cryotherapy and high-intensity focused ultrasonography (HIFU). Unfortunately, we believe that their choice of endpoint of biochemical recurrence (BCR) is inappropriate, and this fact alone precludes any meaningful interpretation of their fi ndings. The defi nition of BCR is different for surgery and radiotherapy, and even for radiotherapy different defi nitions were allowed – ASTRO and Phoenix. Hence, we would contend that comparing treatments using BCR is like comparing apples with oranges.

Very long-term survival patterns of young patients treated with radical prostatectomy for high-risk prostate cancer

OBJECTIVE In patients with a long life expectancy with high-risk (HR) prostate cancer (PCa), the chance to die from PCa is not negligible and may change significantly according to the time elapsed from surgery. The aim of this study was to evaluate long-term survival patterns in young patients treated with radical prostatectomy (RP) for HRPCa. MATERIALS AND METHODS Within a multiinstitutional cohort, 600 young patients (≤59 years) treated with RP between 1987 and 2012 for HRPCa (defined as at least one of the following adverse characteristics: prostate specific antigen>20, cT3 or higher, biopsy Gleason sum 8-10) were identified. Smoothed cumulative incidence plot was performed to assess cancer-specific mortality (CSM) and other cause mortality (OCM) rates at 10, 15, and 20 years after RP. The same analyses were performed to assess the 5-year probability of CSM and OCM in patients who survived 5, 10, and 15 years after RP. A multivariable competing risk regression model was fitted to identify predictors of CSM and OCM. RESULTS The 10-, 15- and 20-year CSM and OCM rates were 11.6% and 5.5% vs. 15.5% and 13.5% vs. 18.4% and 19.3%, respectively. The 5-year probability of CSM and OCM rates among patients who survived at 5, 10, and 15 years after RP, were 6.4% and 2.7% vs. 4.6% and 9.6% vs. 4.2% and 8.2%, respectively. Year of surgery, pathological stage and Gleason score, surgical margin status and lymph node invasion were the major determinants of CSM (all P≤0.03). Conversely, none of the covariates was significantly associated with OCM (all P≥ 0.09). CONCLUSIONS Very long-term cancer control in young high-risk patients after RP is highly satisfactory. The probability of dying from PCa in young patients is the leading cause of death during the first 10 years of survivorship after RP. Thereafter, mortality not related to PCa became the main cause of death. Consequently, surgery should be consider among young patients with high-risk disease and strict PCa follow-up should enforce during the first 10 years of survivorship after RP.

What is the Need for Prostatic Biomarkers in Prostate Cancer Management

Discriminating patients with a low risk of progression from those with lethal prostate cancer is one of the main challenges in prostate cancer management. Indeed, such discrimination is essential if we aim to avoid overtreatment in men with indolent disease and to improve survival in those men with lethal disease. We are reporting on the current literature on such prognostic tools that are now available, their clinical role and their limitations in individualizing care. There is an urgent need to incorporate such genomic tools into new platform-based clinical trial structures to further develop and validate prognostic and predictive biomarkers and provide prostate cancer patients with an effective and cost-efficient access to new drugs in the setting of personalized treatment.

Non-metastatic castrate-resistant prostate cancer: a call for improved guidance on clinical management

BackgroundGuidelines on the clinical management of non-metastatic castrate-resistant prostate cancer (nmCRPC) generally focus on the need to continue androgen deprivation therapy and enrol patients into clinical trials of investigational agents. This guidance reflects the lack of clinical trial data with established agents in the nmCRPC patient population and the need for trials of new agents.AimTo review the evidence base and consider ways of improving the management of nmCRPC.ConclusionUpon the development of castrate resistance, it is essential to rule out the presence of metastases or micrometastases by optimising the use of bone scans and possibly newer procedures and techniques. When nmCRPC is established, management decisions should be individualised according to risk, but risk stratification in this diverse population is poorly defined. Currently, prostate-specific antigen (PSA) levels and PSA doubling time remain the best method of assessing the risk of progression and response to treatment in nmCRPC. However, optimising imaging protocols can also help assess the changing metastatic burden in patients with CRPC. Clinical trials of novel agents in nmCRPC are limited and have problems with enrolment, and therefore, improved risk stratification and imaging may be crucial to the improved management. The statements presented in this paper, reflecting the views of the authors, provide a discussion of the most recent evidence in nmCRPC and provide some advice on how to ensure these patients receive the best management available. However, there is an urgent need for more data on the management of nmCRPC.