Comparison of models to predict clinical failure after radical prostatectomy.

BACKGROUND: Models are available to accurately predict biochemical disease recurrence (BCR) after radical prostatectomy (RP). Because not all patients experiencing BCR will progress to metastatic disease, it is appealing to determine postoperatively which patients are likely to manifest systemic disease. METHODS: The study cohort consisted of 881 patients undergoing RP between 1985 and 2003. Clinical failure (CF) was defined as metastases, a rising prostate-specific antigen (PSA) in a castrate state, or death from prostate cancer. The cohort was randomized into training and validation sets. The accuracy of 4 models to predict clinical outcome within 5 years of RP were compared: 'postoperative BCR nomogram' and 'Cox regression CF model' based on standard clinical and pathologic parameters, and 2 CF 'systems pathology' models that integrate clinical and pathologic parameters with quantitative histomorphometric and immunofluorescent biomarker features ('systems pathology Models 1 and 2'). RESULTS: When applied to the validation set, the concordance index for the postoperative BCR nomogram was 0.85, for the Cox regression CF model 0.84, for systems pathology Model 1 0.81, and for systems pathology Model 2 0.85. CONCLUSIONS: Models predicting either BCR or CF after RP exhibit similarly high levels of accuracy because standard clinical and pathologic variables appear to be the primary determinants of both outcomes. It is possible that introducing current or novel biomarkers found to be uniquely associated with disease progression may further enhance the accuracy of the systems pathology-based platform.

Recovery of urinary continence after radical prostatectomy: association with urethral length and urethral fibrosis measured by preoperative and postoperative endorectal magnetic resonance imaging.

BACKGROUND: Limited data on endorectal magnetic resonance imaging (MRI) features and urinary continence after radical prostatectomy (RP) are available. OBJECTIVE: To assess whether recovery of urinary continence after RP is associated with endorectal MRI findings regarding preoperative and postoperative membranous urethral length (MUL), percent change in MUL, and postoperative urethral and periurethral fibrosis. DESIGN, SETTING, AND PARTICIPANTS: Sixty-four patients who received an MRI scan before and after RP for localized prostate cancer were evaluated in a retrospective study at a single institution. INTERVENTION: All patients underwent RP. MEASUREMENTS: The postoperative scan was performed to detect local recurrence in patients with rising levels of prostate-specific antigen. Urinary continence was graded on a five-point scale. MUL was measured on T2-weighted images. Urethral and periurethral fibrosis was graded from 0 to III based on axial T2-weighted images. Univariate Cox proportional hazards regression was performed to assess variables associated with continence. RESULTS AND LIMITATIONS: Forty-eight patients regained continence following surgery. The median follow-up for patient who were incontinent at their last assessment was 7 mo. The median interval from RP to postoperative endorectal MRI was 10 mo. A longer preoperative or postoperative MUL was associated with superior continence (both p<0.01). The MUL loss ratio was significantly associated with postoperative continence (p=0.02). Patients with a high grade of postoperative periurethral fibrosis tended to have worse postoperative continence; nevertheless a statistical correlation was not reached (hazard ratio: 0.64, p=0.16). This is a retrospective study. CONCLUSIONS: Preoperative and postoperative MUL and the MUL loss ratio are related to the recovery time and level of urinary continence after RP. Therefore, preservation of urethral length during surgery is recommended. Periurethral fibrosis might impede the recovery of continence after RP by altering the elasticity of the external sphincter.

Activator protein-1 transcription factors are associated with progression and recurrence of prostate cancer.

To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors--the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer.

Age-adjusted Charlson comorbidity score is associated with treatment decisions and clinical outcomes for patients undergoing radical cystectomy for bladder cancer.

BACKGROUND: By using the age-adjusted Charlson comorbidity index (ACCI), the authors characterized the impact of age and comorbidity on disease progression and overall survival after radical cystectomy (RC) for transitional cell carcinoma of the bladder. Also evaluated was whether ACCI was associated with clinicopathologic and treatment characteristics. METHODS: The authors evaluated 1121 patients treated by RC for transitional cell carcinoma of the bladder at a single institution (1990-2004). Logistic regression was used to determine the relation between ACCI and clinical features. They evaluated the association between ACCI and overall and progression-free survival by using multivariate survival-time models with pathologic stage and nodal status as covariates. RESULTS: ACCI scores increased during the study period (P = .009). Extravesical disease was present in 43% of patients with ACCI 5 (P = .051). Despite their higher prevalence of extravesical disease, patients with higher ACCI were less likely to have lymph-node dissection (odds ratio, 0.55 and 0.35, respectively, for ACCI 3-5 and >5 vs 5 vs

Surgeon experience is strongly associated with biochemical recurrence after radical prostatectomy for all preoperative risk categories.

PURPOSE: We have previously reported that there is a learning curve for open radical prostatectomy. In the current study we determined whether the effects of the learning curve are modified by patient risk, as defined by preoperative tumor characteristics. MATERIALS AND METHODS: The study included 7,683 eligible patients with prostate cancer treated with open radical prostatectomy by 1 of 72 surgeons. Surgeon experience was coded as the total prior number of radical prostatectomies done by the surgeon before a patient surgery. Multivariate survival time regression models were used to evaluate the association between surgeon experience and biochemical recurrence separately in each preoperative risk group. RESULTS: We saw no evidence that patient risk affected the learning curve. There was a statistically significant association between biochemical recurrence and surgeon experience on all analyses. The absolute risk difference in a patient receiving treatment from a surgeon with 10 vs 250 prior radical prostatectomies was 6.6% (95% CI 3.4-10.3), 12.0% (95% CI 6.9-18.2) and 9.7% (95% CI 1.2-18.2) in patients at low, medium and high preoperative risk. Recurrence-free probability in patients with low risk disease approached 100% for the most experienced surgeons. CONCLUSIONS: Cancer control after radical prostatectomy improves with increasing surgeon experience irrespective of patient risk. Excellent rates of cancer control in patients with low risk disease treated by the most experienced surgeons suggest that the primary reason that recurrence develops in such patients is inadequate surgical technique. The results have significant implications for clinical care.

Comprehensive prospective comparative analysis of outcomes between open and laparoscopic radical prostatectomy conducted in 2003 to 2005.

PURPOSE: In a nonrandomized prospective fashion we compared the oncological, functional and morbidity outcomes after laparoscopic and retropubic radical prostatectomy. MATERIALS AND METHODS: Between January 2003 and December 2005 a total of 1,430 consecutive men with clinically localized prostate cancer underwent radical prostatectomy, laparoscopic in 612 and retropubic in 818. The surgical approach was selected by the patient. Preoperative staging, respective surgical techniques, pathological examination and followup were uniform. Functional outcome was measured by patient completed health related quality of life questionnaire. RESULTS: Positive surgical margin rates (11%) and freedom from progression (median followup 18 months) were comparable between laparoscopic and retropubic radical prostatectomy (HR 0.99 for laparoscopic vs retropubic radical prostatectomy, p = 0.9). We found no significant association between operation type and time to postoperative potency (HR 1.04 for laparoscopic vs retropubic radical prostatectomy; 95% CI 0.74, 1.46; p = 0.8). Patients who underwent laparoscopic radical prostatectomy were less likely to become continent than those treated with retropubic radical prostatectomy (HR 0.56 for laparoscopic vs retropubic radical prostatectomy; 95% CI 0.44, 0.70; p <0.0005). Laparoscopic radical prostatectomy was associated with less blood loss (mean ml +/- SD 315 +/- 186 vs 1,267 +/- 660) and lower overall transfusion rate (3% vs 49%). No significant difference was noted in cardiovascular, thromboembolic and urinary complications. Emergency room visits and readmissions were higher after laparoscopic radical prostatectomy (15% vs 11% and 4.6% vs 1.2%, respectively). CONCLUSIONS: At our institution and during the study period laparoscopic radical prostatectomy and retropubic radical prostatectomy provided comparable oncological efficacy. Laparoscopic radical prostatectomy was associated with less blood loss and a lower transfusion rate, and higher postoperative hospital visits and readmission rate. While the recovery of potency was equivalent, that of continence was superior after retropubic radical prostatectomy.

Modified technique for neurovascular bundle preservation during radical prostatectomy: association between technique and recovery of erectile function.

OBJECTIVES: To prospectively evaluate whether a modified surgical technique for neurovascular bundle (NVB) preservation during radical prostatectomy (RP) is associated with an improvement in erectile function (EF) recovery after RP. PATIENTS AND METHODS: Data from patients treated before technique modification was used to create a predictive model for EF at 6 months after RP using age, date of surgery, and nerve sparing (none vs unilateral vs bilateral) as predictors for patients who received the modified technique (MT) to estimate the expected outcomes had they received the standard technique (ST), and compared these with actual outcomes. In the MT, the neurovascular bundle (NVB) is completely mobilized off the prostate from the apex to above the seminal vesicles including incision of Denonvilliers' fascia before urethral division and mobilization of the prostate off the rectum. RESULTS: Of 372 patients with evaluable data, 275 (74%) underwent the ST from 1 January 2001 to 31 December 2004 and 97 (26%) underwent the MT from 1 January 2005 to 30 May 2006. Sixty-five of 97 patients (67%) receiving the MT had EF recovery at 6 months, whereas the expected probability of 6-month recovery of EF, had they received the ST, was 45%. The absolute improvement in EF recovery attributable to the MT was 22% (95% confidence interval 5-40%; P = 0.013). CONCLUSIONS: Technical modifications to NVB preservation during RP were associated with improved rates of EF recovery.

Long-term prediction of prostate cancer: prostate-specific antigen (PSA) velocity is predictive but does not improve the predictive accuracy of a single PSA measurement 15 years or more before cancer diagnosis in a large, representative, unscreened population.

PURPOSE: We tested whether total prostate-specific antigen velocity (tPSAv) improves accuracy of a model using PSA level to predict long-term risk of prostate cancer diagnosis. METHODS: During 1974 to 1986 in a preventive medicine study in Sweden, 5,722 men aged

Longitudinal risk of upper tract recurrence following radical cystectomy for urothelial cancer and the potential implications for long-term surveillance.

PURPOSE: The defined risk of upper tract recurrence in published series ranges from 2% to 6%, with most recurrence reported within 2 to 3 years of surgery. However, these recurrence rates are based on statistical methodology that does not take censoring into account. We used landmark time analysis to determine whether the risk of upper tract recurrence changes over time. MATERIALS AND METHODS: We present a retrospective institutional review board approved review of 1,329 patients who underwent radical cystectomy from 1990 to 2004. Upper tract recurrence was defined as any radiographic, endoscopic or pathologically proven recurrence in the kidney or ureter. Cumulative incidence of upper tract recurrence was estimated by accounting for death without recurrence as a competing risk. Landmark analyses were used to estimate the probability of upper tract recurrence within the next 3 years if recurrence-free at various times after surgery. RESULTS: A total of 80 patients experienced upper tract recurrence. Median followup for patients alive and recurrence-free was 38 months. The 3 and 5-year cumulative incidence of upper tract recurrence was 4% (95% CI 3, 6) and 7% (95% CI 5, 8), respectively. Landmark time analysis showed the 3-year cumulative incidence of upper tract recurrence remained 4% to 6% even at 4 years after radical cystectomy. Any ureteral involvement at radical cystectomy (including carcinoma in situ) portends a significantly higher risk of upper tract recurrence. CONCLUSIONS: The incidence for upper tract recurrence was 4% at 3 years and 7% at 5 years. However, the 3-year risk of upper tract recurrence remained around 4% to 6% at any point measured up to 4 years after radical cystectomy and, therefore, did not change over time. This indicates the critical importance of long-term vigilance for upper tract recurrence following radical cystectomy.

Secondary therapy, metastatic progression, and cancer-specific mortality in men with clinically high-risk prostate cancer treated with radical prostatectomy.

OBJECTIVES: Commonly used definitions for high-risk prostate cancer identify men at increased risk of PSA relapse after radical prostatectomy (RP). We assessed how accurately these definitions identify patients likely to receive secondary cancer therapy, experience metastatic progression, or die of prostate cancer. MATERIALS AND METHODS: Among 5960 men with clinically localized or locally advanced prostate cancer who underwent RP, we identified eight different high-risk subsets, each comprising 4-40% of the study population. Estimates of freedom from radiation therapy, hormonal therapy, and metastatic progression after surgery were generated for each high-risk cohort with the Kaplan-Meier method, and hazard ratios (HR) were calculated with a Cox proportional hazards regression. The cumulative incidence and HR for prostate cancer-specific mortality (PCSM) were estimated with competing risk analysis. RESULTS: Each of the studied high-risk criteria was associated with increased hazard of secondary cancer therapy (HR=1.3-5.2, p<0.05) and metastatic progression (HR=2.1-6.9, p<0.05). However, depending on the definition, the probability of freedom from additional therapy 10 yr after surgery ranged from 35% to 76%. The 10-yr cumulative incidence of PCSM in high-risk patients ranged from 3% to 11% (HR=3.2-10.4, p<0.0005). CONCLUSIONS: Commonly used definitions for high-risk prostate cancer identify men at increased risk of secondary cancer therapy, metastatic progression, and PCSM following RP. However, a substantial proportion of high-risk patients remain free from additional therapy or metastatic disease many years after surgery. The risk of PCSM within 10 yr of treatment is remarkably low, even for patients at the highest risk of recurrent disease.

Multi-institutional study of symptomatic deep venous thrombosis and pulmonary embolism in prostate cancer patients undergoing laparoscopic or robot-assisted laparoscopic radical prostatectomy.

OBJECTIVES: The true incidence of symptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing laparoscopic radical prostatectomy is unknown. Our aim was to determine the incidence of symptomatic DVT and PE and the risk factors for these complications. METHODS: Fourteen surgeons from 13 referral institutions from both Europe and the United States provided retrospective data for all 5951 patients treated with laparoscopic radical prostatectomy (LRP), with or without robotic assistance, since the start of their institution's experience. Symptomatic DVT and PE within 90 d of surgery were regarded as venous thromboembolism (VTE). DVT was diagnosed mostly by Doppler ultrasound or contrast venography and PE by lung ventilation/perfusion scan or chest computed tomography or both. Statistical analysis included evaluation of incidence of symptomatic DVT and PE and risk factors as determined by exact methods and logistic regression. RESULTS: Of 5951 patients in the study, 31 developed symptomatic VTE (0.5%; 95% confidence interval [CI], 0.4%, 0.7%). Among patients with an event, 22 (71%) had DVT only, 4 had PE without identified DVT, and 5 had both. Two patients died of PE. Prior DVT (odds ratio [OR]=13.5; 95%CI, 1.4, 61.3), current tobacco smoking (OR=2.8; 95%CI, 1.0, 7.3), larger prostate volume (OR=1.18; 95%CI, 1.09, 1.28), patient re-exploration (OR=20.6; 95%CI, 6.6, 54.0), longer operative time (OR=1.05; 95%CI, 1.02, 1.09), and longer hospital stay (OR=1.05; 95%CI, 1.01, 1.09) were associated with VTE in univariate analysis. Neoadjuvant therapy, body mass index, surgical experience, surgical approach, pathologic stage, perioperative transfusion, and heparin administration were not significant predictors. CONCLUSIONS: The incidence of symptomatic VTE after LRP is low. These data do not support the administration of prophylactic heparin to all patients undergoing LRP, especially those without risk factors for VTE.

Prognostic significance of location of positive margins in radical prostatectomy specimens.

OBJECTIVES: Cancer at the resection margin is associated with an increased risk of biochemical recurrence after radical prostatectomy (RP) even after adjusting for other known clinical and pathologic risk factors. In this study, we assessed the prognostic significance of sites of positive surgical margins (+SMs) in RP specimens. METHODS: We reviewed the data from 2442 patients with clinical Stage T1-T3 prostate cancer treated with RP from 1983 to 2004 who had had tumor maps generated from whole mount sections. The site of +SMs was assigned to six different areas (apex, bladder neck, seminal vesicle, anterior, posterolateral, and posterior). RESULTS: Of the 2442 patients, 201 (8.2%) had a +SM at a single site and 74 (3.0%) had a +SM at multiple sites in the RP specimen. The posterolateral and apex sections were the most commonly involved sites for a +SM. Those with a +SM had a greater risk of biochemical recurrence than those with negative surgical margins (hazard ratio 1.39, 95% confidence interval 1.004 to 1.92; P = 0.047). We found that a +SM at the posterolateral site was significantly associated with an increased risk of biochemical recurrence (hazard ratio 2.80 for +SMs versus negative SMs at the posterolateral region; 95% confidence interval 1.76 to 4.44). CONCLUSIONS: The effect on biochemical recurrence was influenced by the site of the +SM, with a posterolateral location having the most significant effect on prognosis. This heterogeneity of margin status has implications for predictive modeling, as well as the recommendation for adjuvant radiotherapy.

B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome.

B7-H3 and B7x are recently discovered members of the B7-CD28 family thought to dampen peripheral immune responses via negative costimulation. We evaluated their potential expression in human prostate cancer using a large cohort of patients with 7 years of follow-up. We identified 823 patients with tissue available treated with radical prostatectomy between 1985 and 2003. Immunohistochemistry was performed on tissue microarray sections using anti-B7-H3 and -B7x. The percentage and intensity of immunoreactivity by tumor cells were blindly evaluated by two urological pathologists, and outcome analyses were conducted. Both B7-H3 and B7x were highly expressed; 93% and 99% of tumors had aberrant expression, respectively. The median percentage of tumor cells staining positive was 80% for each molecule. Strong intensity for B7-H3 and B7x was noted in 212 (26%) and 120 (15%) patients, respectively. Patients with strong intensity for B7-H3 and B7x were significantly more likely to have disease spread at time of surgery (P < 0.001 and P = 0.005, respectively). Additionally, patients with strong intensity for B7-H3 and B7x were at significantly increased risk of clinical cancer recurrence (P < 0.001 and P = 0.005) and cancer-specific death (P = 0.004 and P = 0.04, respectively). To our knowledge, we present the largest investigation of B7 family molecules in a human malignancy and a previously undescribed evaluation of B7x in prostate cancer. B7-H3 and B7x are abundantly expressed in prostate cancer and associated with disease spread and poor outcome. Given the proposed immune-inhibitory mechanisms of B7-H3 and B7x, these molecules represent attractive targets for therapeutic manipulation in prostate cancer.

Improved clinical outcome in recent years for men with metastatic nonseminomatous germ cell tumors.

PURPOSE: The integration of chemotherapy and surgery for metastatic nonseminomatous germ cell tumors (NSGCT) results in survival rates of greater than 80% overall. We evaluated men undergoing postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for NSGCT to determine associations between year of treatment and clinical outcome. PATIENTS AND METHODS: We evaluated 504 men who underwent PC-RPLND from 1989 to 2002 for NSGCT at our center. Data were obtained from our prospective surgical database and a multivariable logistic regression model was constructed to evaluate variables associated with 15-month relapse in 392 patients with complete data. RESULTS: From 1989 to 1997, clinical stage IIa, IIb, IIc, and III NSGCT was seen in 4%, 20%, 23%, and 47% of patients, respectively, compared with 18%, 26%, 11%, and 38%, respectively, from 1998 to 2002 (P < .001). The median prechemotherapy nodal size for 1989 to 1997 and 1998 to 2002 was 5.0 and 3.5 cm, respectively (P < .001). On multivariable analysis, prechemotherapy retroperitoneal nodal size (odds ratio [OR], 1.12; 95% CI, 1.03 to 1.21; P = .005) and presence of visceral metastasis (OR, 2.10; 95% CI, 1.02 to 4.33; P = .04) were significantly associated with 15-month relapse. Men who received a complete RPLND were significantly less likely to experience relapse (OR, 0.22; 95% CI, 0.09 to 0.50; P < .0005). CONCLUSION: In more recent years, men are presenting with less advanced metastatic NSGCT. This stage migration together with effective therapy has resulted in an improved relapse-free survival.

Needle biopsies on autopsy prostates: sensitivity of cancer detection based on true prevalence.

BACKGROUND: It is difficult to estimate the diagnostic accuracy of biopsy for prostate cancer because men with negative biopsy do not undergo radical prostatectomy and thus have no confirmation of biopsy findings. METHODS: We performed 18-core needle biopsies on autopsy prostates from 164 men who had no history of prostate cancer. Six-core biopsies were taken from each of the mid peripheral zone (MPZ), the lateral peripheral zone (LPZ), and the central zone (CZ). We tested associations between age and tumor characteristics and analyzed the sensitivity of biopsies at each site. All statistical tests were two-sided. RESULTS: Prostate cancer was present in 47 (29%) prostates. Of the 47 cancers detected, 20 were clinically significant according to histologic criteria. Tumor volume was associated with tumor grade (P = .012) and with age (P<.001). The biopsies from the CZ did not detect any cancer that was not present in biopsies of either the MPZ or LPZ. The sensitivity of the biopsies taken from the MPZ and LPZ together (53%, 95% confidence interval [CI] = 38% to 68%) was therefore the same as that of 18-core biopsies and was superior to that of biopsies of the MPZ alone (30%, 95% CI = 17% to 45%) (P = .003). The sensitivities of biopsies from the MPZ for clinically significant and insignificant cancer were 55% (95% CI = 32% to 77%) and 11% (95% CI = 2% to 29%), respectively, compared with 80% (95% CI = 56% to 94%) and 33% (95% CI = 17% to 54%) for those from the MPZ and LPZ combined. CONCLUSIONS: The ability to detect prostate cancer was more related to the biopsy site than to the number of biopsy cores taken. The 12-core biopsies, six cores each from the MPZ and LPZ, were most likely to detect the majority of clinically significant cancers but also detected many insignificant cancers. When the six-core biopsies from the CZ were added, no increase in sensitivity was observed.

Association of cysteine-rich secretory protein 3 and beta-microseminoprotein with outcome after radical prostatectomy.

PURPOSE: It has been suggested that cysteine-rich secretory protein 3 (CRISP-3) and beta-microseminoprotein (MSP) are associated with outcome in prostate cancer. We investigated whether these markers are related to biochemical recurrence and whether addition of the markers improves prediction of recurring disease. EXPERIMENTAL DESIGN: Tissue microarrays of radical prostatectomy specimens were analyzed for CRISP-3 and MSP by immunohistochemistry. Associations between marker positivity and postprostatectomy biochemical recurrence [prostate-specific antigen (PSA) >0.2 ng/mL with a confirmatory level] were evaluated by univariate and multivariable Cox proportional hazards regression. Multivariable analyses controlled for preoperative PSA and pathologic stage and grade. RESULTS: Among 945 patients, 224 had recurrence. Median follow-up for survivors was 6.0 years. Patients positive for CRISP-3 had smaller recurrence-free probabilities, whereas MSP-positive patients had larger recurrence-free probabilities. On univariate analysis, the hazard ratio for patients positive versus negative for CRISP-3 was 1.53 (P=0.010) and for MSP was 0.63 (P=0.004). On multivariable analysis, both CRISP-3 (P=0.007) and MSP (P=0.002) were associated with recurrence. The hazard ratio among CRISP-3-positive/MSP-negative patients compared with CRISP-3-negative/MSP-positive patients was 2.38. Adding CRISP-3 to a base model that included PSA and pathologic stage and grade did not enhance the prediction of recurrence, but adding MSP increased the concordance index minimally from 0.778 to 0.781. CONCLUSION: We report evidence that CRISP-3 and MSP are independent predictors of recurrence after radical prostatectomy for localized prostate cancer. However, addition of the markers does not importantly improve the performance of existing predictive models. Further research should aim to elucidate the functions of CRISP-3 and MSP in prostate cancer cells.

The surgical learning curve for prostate cancer control after radical prostatectomy.

BACKGROUND: The learning curve for surgery--i.e., improvement in surgical outcomes with increasing surgeon experience--remains primarily a theoretical concept; actual curves based on surgical outcome data are rarely presented. We analyzed the surgical learning curve for prostate cancer recurrence after radical prostatectomy. METHODS: The study cohort included 7765 prostate cancer patients who were treated with radical prostatectomy by one of 72 surgeons at four major US academic medical centers between 1987 and 2003. For each patient, surgeon experience was coded as the total number of radical prostatectomies performed by the surgeon before the patient's operation. Multivariable survival-time regression models were used to evaluate the association between surgeon experience and prostate cancer recurrence, defined as a serum prostate-specific antigen (PSA) of more than 0.4 ng/mL followed by a subsequent higher PSA level (i.e., biochemical recurrence), with adjustment for established clinical and tumor characteristics. All P values are two-sided. RESULTS: The learning curve for prostate cancer recurrence after radical prostatectomy was steep and did not start to plateau until a surgeon had completed approximately 250 prior operations. The predicted probabilities of recurrence at 5 years were 17.9% (95% confidence interval [CI] = 12.1% to 25.6%) for patients treated by surgeons with 10 prior operations and 10.7% (95% CI = 7.1% to 15.9%) for patients treated by surgeons with 250 prior operations (difference = 7.2%, 95% CI = 4.6% to 10.1%; P<.001). This finding was robust to sensitivity analysis; in particular, the results were unaffected if we restricted the sample to patients treated after 1995, when stage migration related to the advent of PSA screening appeared largely complete. CONCLUSIONS: As a surgeon's experience increases, cancer control after radical prostatectomy improves, presumably because of improved surgical technique. Further research is needed to examine the specific techniques used by experienced surgeons that are associated with improved outcomes.

The predictive value of prostate cancer biomarkers depends on age and time to diagnosis: towards a biologically-based screening strategy.

Both benign and malignant prostate diseases elevate total prostate-specific antigen (tPSA), and the incidence of benign disease increases markedly with age. There is evidence, however, that free-to-total PSA ratio (%fPSA) and human kallikrein 2 (hK2) more closely reflect the malignant process. We tested the hypothesis that tPSA levels are more strongly predictive of cancer in younger when compared to older men, whereas %fPSA and hK2 are more strongly predictive in men tested closer to diagnosis. The study included 13,676 men age >/= 44 in Sweden, where PSA screening was uncommon during the study period. fPSA, tPSA and hK2 were measured in archived plasma collected during 1974-1986 in 501 men subsequently diagnosed with prostate cancer up to 1999 and in 1,292 matched controls. The predictive value of tPSA was lower in older men (p = 0.003) but was not strongly affected by time to diagnosis (p = 0.3); the predictive value of hK2 was higher closer to diagnosis (p < 0.0005) but was not modified by age (p = 0.7). A model including tPSA, fPSA and hK2 was superior (p = 0.02) to tPSA alone in older (AUC 0.819 vs. 0.794), but not in younger men (0.758 vs. 0.759). Total PSA can be used as a single marker at early middle age to predict long-term risk of prostate cancer and thus to determine intensity of subsequent screening. In contrast, %fPSA and hK2 add important predictive value in older men and much closer to diagnosis. Strategies for prostate cancer screening should be based on thorough understanding of the interaction of kallikrein-related biomarkers with prostate pathobiology.

Radical prostatectomy shortly after prostate biopsy does not affect operative difficulty or efficacy.

OBJECTIVES: To examine whether radical prostatectomy (RP) conducted before 4 or 6 weeks after prostate biopsy is associated with surgical difficulty or efficacy. Many urologists recommend an interval of at least 4 to 6 weeks between prostate biopsy and RP. METHODS: Using our surgical database, we identified 2996 men undergoing open RP and compared the outcomes after surgery stratified by the interval from biopsy, analyzed as a dichotomous variable with cutpoints of either 4 or 6 weeks. The estimated blood loss and operating room time were considered surrogates for surgical difficulty, and surgical margin status and postoperative urinary and erectile function surrogates for surgical efficacy. We used regression models to assess whether the time to RP affected these surgical outcomes after controlling for the surgeon, surgeon experience, and various clinical and pathologic disease features. RESULTS: The interval between biopsy and RP was 4 weeks or less for 168 men (6%) and 6 weeks or less for 416 men (14%). Using an interval of 4 weeks or less or 6 weeks or less, multivariate mixed effects regression analyses did not show a significant association between early surgery and operating room time, estimated blood loss, surgical margin status, urinary continence, or erectile function (all P > or = 0.18). Our results were sufficiently precise to exclude an important effect of early surgery. CONCLUSIONS: The results of our study have shown that performing radical prostatectomy shortly after prostate biopsy, within 4 to 6 weeks, does not adversely influence surgical difficulty or efficacy.