Biopsy features associated with prostate cancer progression in active surveillance patients: comparison of three statistical models.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Active surveillance is an established management option for patients with favourable-risk prostate cancer. However, about 25-30% of active surveillance patients demonstrate biopsy progression within the first 3-5 years of follow-up. Although several factors, such as the results of the diagnostic and surveillance biopsies, are known to be associated with the risk of progression, our ability to accurately predict this risk remains limited. Our analysis demonstrated that the overall number of positive cores in the diagnostic and first surveillance biopsies is strongly associated with the risk of progression in active surveillance patients. Furthermore, combined results of diagnostic and first surveillance biopsies provide more information about the probability of progression than they do separately. The most important variable affecting the progression-free survival was the overall number of cores positive for cancer. By 3 years of active surveillance, most of the patients who had four positive cores in the diagnostic and surveillance biopsies progressed, while those who had only one positive core had an excellent prognosis. These findings could be used to improve the accuracy of assessments of the prognosis of patients with low-risk prostate cancer and to help them make informed decisions about their treatment. OBJECTIVE: To analyse the prognostic importance of information provided by the diagnostic biopsy, the first surveillance biopsy and a combination thereof to identify active surveillance patients with a particularly high risk of progression. MATERIALS AND METHODS: The present study included 161 active surveillance patients who had at least two surveillance biopsies. The first surveillance biopsy was performed within 1 year of the diagnosis. Further surveillance biopsies usually took place every 1-2 years. Progression on the surveillance biopsy was defined as the presence of Gleason 4/5 cancer, > two positive cores or >20% involvement of any core. Cox proportional hazards regression analysis was used to examine the relationship between biopsy characteristics and progression. Three distinct statistical models were built using characteristics of diagnostic biopsies, surveillance biopsies, and a combination thereof. Harrell's c-index was used to quantify the predictive accuracy of each multivariate Cox model. RESULTS: The median follow-up was 3.6 years; 46 (28.6%) patients progressed. In multivariate analysis the major factor associated with progression was the number of positive cores. The model based on the combined results of diagnostic and first surveillance biopsies was significantly more predictive than the models based on the individual results of each biopsy. Patients with four positive cores in the diagnostic and first surveillance biopsies had estimated 5-year progression rate of 100%. CONCLUSION: The total number of positive cores in the diagnostic and first surveillance biopsies provides important information about the risk of prostate cancer progression in active surveillance patients.

Comprehensive analysis of post-diagnostic prostate-specific antigen kinetics as predictor of a prostate cancer progression in active surveillance patients.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: A significant proportion of patients diagnosed with prostate cancer do not require immediate treatment and could be managed by active surveillance, which usually includes serial measurements of prostate-specific antigen (PSA) levels and regular biopsies. The rate of rise in PSA levels, which could be calculated as PSA velocity or PSA doubling time, was previously suggested to be associated with the biological aggressiveness of prostate cancer. Although these parameters are obvious candidates for predicting tumour progression in active surveillance patients, earlier studies that examined this topic provided conflicting results. Our analysis showed that PSA velocity and PSA doubling time calculated at different time-points, by different methods, over different intervals, and in different sub-groups of active surveillance patients provide little if any prognostic information. Although we found some significant associations between PSA velocity and the risk of progression as determined by biopsy, the actual clinical significance of this association was small. Furthermore, PSA velocity did not add to the predictive accuracy of total PSA. OBJECTIVE: To study whether prostate-specific antigen (PSA) velocity (PSAV) and PSA doubling time (PSADT) are associated with biopsy progression in patients managed by active surveillance. PATIENTS AND METHODS: Our inclusion criteria for active surveillance are biopsy Gleason sum <7, two or fewer positive biopsy cores, ≤20% tumour present in any core, and clinical stage T1-T2a. Changes in any of these parameters during the follow-up that went beyond these limits are considered to be progression. This study included 250 patients who had at least one surveillance biopsy, an available PSA measured no earlier than 3 months before diagnosis, and at least one PSA measurement before each surveillance biopsy. We evaluated the association between PSA kinetics and progression at successive surveillance biopsies in different sub-groups of patients by calculating the area under the curve (AUC) as well as sensitivity and specificity of different thresholds. RESULTS: Over a median follow-up of 3.0 years, the disease of 64 (26%) patients progressed. PSADT was not associated with biopsy progression, whereas PSAV was only weakly associated with progression in certain sub-groups. However, incorporation of PSAV in models including total PSA resulted in a moderate increase in AUC only when the entire cohort was analysed. In other sub-groups the predictive accuracy of total PSA was not significantly improved by adding PSAV. CONCLUSIONS: Our findings confirm that PSA kinetics should not be used in decision-making in patients with low-risk prostate cancer managed by active surveillance. Regular surveillance biopsies should remain as the principal method of monitoring cancer progression in these men.

Pathological findings at radical prostatectomy in patients initially managed by active surveillance: a comparative analysis.

BACKGROUND: The purpose of our analysis was to determine if delays in treatment caused by active surveillance result in significant pathological changes when patients no longer meet the criteria on repeat biopsy and to study whether or not these changes may affect treatment outcomes. METHODS: Out of 207 men who were on active surveillance, 47 (23%) no longer met the criteria after one of the repeat biopsies. Twenty-two underwent radical prostatectomy at our institution and formed the main group (Group 1) of this study. One hundred sixty-four patients met the criteria for active surveillance but underwent immediate surgery. Of these patients, we selected 38 (23%) with the lowest predicted biochemical recurrence-free survival. These patients formed the comparison group (Group 2). Pathological features as well as postoperative biochemical outcomes were compared between the groups. RESULTS: Seven patients (32%) in Group 1 and four (11%) in Group 2 have predominantly high-grade cancer (i.e., ≥4/5 + 3) at pathology. The visually estimated percent of carcinoma was also higher in patients initially managed by active surveillance (median 12.5 vs. 5.0 in Groups 1 and 2, respectively, P = 0.009). Other pathological characteristics were similar in both groups. With limited duration of follow-up, postoperative biochemical recurrence-free survival did not differ significantly between the groups. CONCLUSIONS: Our study has demonstrated that both tumor grade and volume may increase during active surveillance. However, the clinical significance of these changes with respect to the outcomes of delayed treatment remains to be established.

Tumor focality is not associated with biochemical outcome after radical prostatectomy.

BACKGROUND: The clinical and prognostic significance of unifocal prostatic carcinoma is not clearly understood. In the current study, we sought to characterize the clinical and pathologic characteristics of unifocal and multifocal prostate cancers and to investigate the effects of tumor focality on biochemical outcome after radical prostatectomy. METHODS: Our analysis included 1,444 radical prostatectomy patients with available information concerning the number and location of tumor foci in the specimen. Each patient was assigned to one of three groups depending on whether they had unifocal, multifocal, or extensive cancer. Clinical and pathological features as well as biochemical outcomes were compared between the groups. RESULTS: Two hundred and seventy-two mens in the study cohort (18.8%) had unifocal cancer. The rates of unifocal cancer did not differ significantly between the three studied time intervals (17.3% in 1992-1998, 20.5% in 1999-2004, and 17.8% in 2005-2011). The number of positive biopsy cores was slightly lower in the unifocal group, while the overall amount of biopsy tissue containing cancer was similar in both groups. The patients in the multifocal group had higher pathologic Gleason scores, increased incidence of positive surgical margin, and larger tumors. The rate of clinically significant Gleason score upgrade was significantly higher in the multifocal group compared to the unifocal group (35.7% vs. 21.7%, respectively, P < 0.001). The biochemical outcome after radical prostatectomy did not differ between patients with unifocal and multifocal cancers both on univariate and multivariate analyses. CONCLUSIONS: Tumor focality is not an independent prognostic factor of biochemical outcome in radical prostatectomy patients.

Clinically significant Gleason sum upgrade: external validation and head-to-head comparison of the existing nomograms.

BACKGROUND: Several nomograms have been developed for the purpose of predicting the likelihood of an increase in Gleason sum (GS) from biopsy information compared with the GS determined after examination of the "entire prostate" in patients with prostate cancer. In this study, the authors evaluated and compared the ability of 4 nomograms (published by Capitanio et al, Chun et al, Kulkarni et al, and Moussa et al) to predict GS upgrades for patients with biopsy GS ≤6 prostate cancer who underwent radical prostatectomy (RP) at their center. METHODS: The entire study cohort included 942 patients with a biopsy GS ≤6. Predictive performances of the nomograms were compared using area under the receiver operating characteristic curve (AUC-ROC) analysis, calibration plots, and decision curve analysis (DCA) in the entire cohort, in patients with low-risk prostate cancer (LRPC), and a subgroup of those patients who underwent extended biopsy with ≥10 cores. RESULTS: Patients with a GS ≥7 at prostatectomy included 319 of 942 patients (33.9%) in the entire study cohort, 263 of 814 patients (32.2%) with LRPC, and 84 of 301 patients (27.9%) with LRPC who underwent extended biopsy. With an AUC-ROC of 0.637 to 0.647 in the different subgroups of patients with low-risk cancer, the Kulkarni et al nomogram demonstrated significantly higher discriminative ability compared with the other nomograms. The same nomogram provided a small clinical benefit at DCA. All nomograms were poorly calibrated. CONCLUSIONS: The available prognostic tools had limited ability to predict clinically significant upgrading in patients with biopsy GS ≤6 and, thus, the authors concluded that these tools are not ready for clinical application.

Clinical and demographic characteristics associated with prostate cancer progression in patients on active surveillance.

PURPOSE: Active surveillance is an established management option for patients with low risk prostate cancer. However, little is known about the characteristics associated with the increased probability of progression in patients on active surveillance. We analyzed our active surveillance cohort in search of such features. MATERIALS AND METHODS: A total of 272 men with prostate cancer have enrolled in our active surveillance program since 1994, of whom 249 underwent at least 1 surveillance biopsy and were included in analysis. Our active surveillance inclusion criteria are biopsy Gleason grade less than 7, 2 or fewer positive biopsy cores, 20% or less tumor in any core and clinical stage T1-T2a. Changes in any of these parameters during followup that went beyond these limits were considered progression. Univariate and multivariate Cox regression analysis was done to determine patient characteristics associated with an increased risk of progression. RESULTS: A total of 64 patients (26%) showed progression at a median 2.9-year followup on a mean of 2.3 surveillance biopsies. The progression risk was significantly increased in black patients (adjusted HR 3.87-4.12), and in men with a smaller prostate and higher prostate specific antigen density. The latter 2 variables had no specific cutoff for an association with progression. CONCLUSIONS: Black men with low risk prostate cancer should be advised that the risk of progression on active surveillance may be higher than that in the available literature. Integral prognostic tools incorporating race and prostate specific antigen density may be useful to accurately assess the individual risk of progression in patients on active surveillance.

Comparative validation of nomograms predicting clinically insignificant prostate cancer.

OBJECTIVE: To validate and compare the accuracy and performance of nomograms predicting insignificant prostate cancer and to analyze their performance in patients with different cancer locations. METHODS: Our cohort consisted of 370 radical prostatectomy patients with Gleason ≤6 prostate cancer diagnosed on transrectal biopsy with at least 10 cores. We quantified the performance of each nomogram with respect to discrimination, calibration, predictive accuracy at different cut points, and the clinical net benefit. We also evaluated these parameters in subgroups of patients with predominantly anterior-apical (AA) and posterior-basal (PB) tumor location. RESULTS: Insignificant prostate cancer was present in 141 patients (38%). The Kattan and Steyerberg nomograms outperformed other studied models and demonstrated fair discrimination (areas under the receiver operating characteristics curve 0.768 and 0.770, respectively), good calibration, balanced predictive accuracy, and the highest net benefit. All nomograms were less accurate at higher levels of predicted probability. The performance of the nomograms was better in patients with PB tumors than in those with AA tumors. The loss of correlation with the actual prevalence of insignificant prostate cancer at higher levels of predicted probability was not seen in the PB subgroup but was particularly noticeable in the AA subgroup. CONCLUSION: The Kattan and Steyerberg nomograms demonstrated the best performance in predicting the probability of insignificant prostate cancer in a contemporary cohort of patients with Gleason ≤6 cancer diagnosed on specimens from an extended transrectal biopsy. However, all studied nomograms were more accurate in identifying significant rather than insignificant disease, particularly for tumors located in the apical and anterior prostate.

Prostate cancers of different zonal origin: clinicopathological characteristics and biochemical outcome after radical prostatectomy.

OBJECTIVE: To evaluate the effect of prostate cancer zonal origin on the biochemical outcome after radical prostatectomy, to analyze clinicopathological features of tumors arising in different zones and to test the ability of the nomogram to predict the probability of transition zone cancer at radical prostatectomy. METHODS: Our cohort consisted of 1441 patients who underwent radical prostatectomy who did not receive neoadjuvant treatment. Clinicopathological characteristics and biochemical outcomes were compared between the groups of men with different zonal location of prostate cancer. Performance of the nomogram in predicting cancer location was evaluated with respect to discrimination and calibration. RESULTS: The rates of positive margin were similar in men with transition zone and mixed tumors and were significantly higher than those with peripheral zone tumors. Most of the positive margins in patients with transition zone and mixed cancers were located at the apico-anterior part of the gland. On multivariate analysis, transition zone cancer location was associated with better biochemical recurrence-free survival (P = .043). The Harrel c-index of the models that did and did not include zonal origin of cancer was 0.810 and 0.807, respectively. Performance of the nomogram was poor. CONCLUSION: The association between transition zone tumor origin and the risk of biochemical recurrence does not add important predictive value to the standard prognostic factors. Although information about the risk of prostate cancer involvement of the transition zone may be important for surgical planning, our ability to predict this risk preoperatively is limited.

Pathologic prostate cancer characteristics in patients eligible for active surveillance: a head-to-head comparison of contemporary protocols.

BACKGROUND: Although the rationale for active surveillance (AS) in patients with low-risk prostate cancer is well established, eligibility criteria vary significantly across different programs. OBJECTIVE: To compare the ability of contemporary AS criteria to identify patients with certain pathologic tumor features based on the results of an extended transrectal prostate biopsy. DESIGN, SETTINGS, AND PARTICIPANTS: The study cohort included 391 radical prostatectomy patients who had prostate cancer with Gleason scores ≤ 6 on transrectal biopsy with ≥ 10 cores. INTERVENTION: Radical prostatectomy without neoadjuvant treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We identified patients who fulfilled the inclusion criteria of five AS protocols including those of Epstein, Memorial Sloan-Kettering Cancer Center, Prostate Cancer Research International: Active Surveillance (PRIAS), University of California, San Francisco, and University of Miami (UM). We evaluated the ability of these criteria to predict three pathologic end points: insignificant disease defined using a classical and updated formulation, and organ-confined Gleason ≤ 6 prostate cancer. Measures of diagnostic accuracy and areas under the receiver operating curve were calculated for each protocol and compared. RESULTS AND LIMITATIONS: A total of 75% of the patients met the inclusion criteria of at least one protocol; 23% were eligible for AS by all studied criteria. The PRIAS and UM criteria had the best balance between sensitivity and specificity for both definitions of insignificant prostate cancer and a higher discriminative ability for the end points than any criteria including patients with two or more positive cores. The Epstein criteria demonstrated high specificity but low sensitivity for all pathologic end points, and therefore the discriminative ability was not superior to those of other protocols. CONCLUSIONS: Significant variations exist in the ability of contemporary AS criteria to predict pathologically insignificant prostate cancer at radical prostatectomy. These differences should be taken into account when making treatment choices in patients with low-risk prostate cancer.

Prostate sampling by 12-core biopsy: comparison of the biopsy results with tumor location in prostatectomy specimens.

OBJECTIVE: To analyze the diagnostic performance of individual prostate biopsy cores. The 12-core transrectal prostate biopsy scheme has emerged as a standard of care. However, quality of sampling may vary in different areas of the prostate included in this procedure. MATERIAL AND METHODS: Two-hundred fifty men underwent radical prostatectomy at our institution. All participants had a systematic 12-core transrectal prostate biopsy containing lateral and medial cores from each side of the apical, medial and basal thirds of the prostate. Biopsy results were matched with histologic maps of the prostatectomy specimens. Sensitivity, negative predictive value (NPV), and overall accuracy were calculated for each biopsy core location and compared between different groups of cores. In addition, patients in the upper quartile of prostate weight were compared with the rest of the cohort. RESULTS: Sensitivity, NPV, and overall accuracy were significantly lower for apical cores. Average NPV and overall accuracy of basal and mid-lateral biopsies were inferior to those of medial biopsies on the same levels. However, sensitivity of these lateral cores was similar to that of the medial cores. Sensitivities of apical and mid cores were significantly lower in patients with larger prostates. CONCLUSION: Decreased accuracy in lateral mid- and basal cores results from higher frequencies of cancer in corresponding prostate areas, and therefore additional samples should be taken at these locations. In addition, diagnostic accuracy of apical cores may be improved through better targeting of the prostatic apex. This may be particularly important in patients with larger prostates.